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Factores de tratamiento Estos ensayos se describen aqu y en la Tabla 62.4. 41,71-78 Las referencias originales
se deben consultar para ms detalles de la elegibilidad del paciente, los regmenes
La respuesta temprana, y el grado de respuesta, a la quimiorradioterapia se correlacionaron
de tratamiento, los resultados y anlisis estadsticos. Tambin se han producido ms
con la supervivencia en varios anlisis multivariantes. 54,69,70 Una asociacin con la dosis total
de 100 estudios no aleatorios, muchas de las cuales proporcionados posteriormente
de radiacin o con la duracin del tratamiento, mientras que se esperaba, no se ha
hiptesis ensayada en los estudios aleatorios, o la informacin que ha guiado el
demostrado de forma consistente, ya sea para control locorregional o la supervivencia. Un
desarrollo de los aspectos tcnicos del tratamiento de radiacin. 79
tamao de la fraccin diaria de 2,5 Gy parece estar asociado con aumento de la toxicidad
aguda y tarda, en comparacin con 2-Gy fracciones. 39
Ensayo (Referencia) norte Tratamiento fallo (%) (CSA) (%) de enfermedad (%) Sobrevivencia promedio (%)
UKCCCR (ACT I) (41) 292 RT, 5-FU, MMC 39 24 notario pblico sesenta y cinco
52 RT 48 un 40 un notario pblico 53 un
RTOG 8704 / ECOG 1289 (73) 146 RT, 5-FU, MMC diecisis 9 73 76
145 RT, 5-FU 34 22 51 67
PAG . 0008 . 002 . 0003 . 31
UKCR (ACT II) (76) 471 RT, 5-FU, MMC notario pblico 14 notario pblico notario pblico
469 RT, 5-FU, CDDP notario pblico 11 notario pblico notario pblico
ACCORD-03 (77,78) 307 totales Std RT, 5-FU, CDDP 10 86 67 notario pblico
UKCCCR, Reino Unido Comit de Coordinacin para la Investigacin del Cncer; EORTC, Organizacin Europea para la Investigacin sobre el Tratamiento del Cncer; RTOG, Radiation Therapy Oncology Group; ECOG,
Eastern Cooperative Oncology Group; np, no publicado; sig, significativa; No sig, no significativo; RT, la terapia de radiacin; 5-FU, 5-fluorouracilo; MMC, mitomicina C; CDDP, cisplatino; Std, estndar; HD RT, radiacin de alta
dosis; Ind CT, la quimioterapia de induccin; RTQT, quimiorradioterapia.
un Nmeros derivados de curvas. segundo En los pacientes que recibieron quimioterapia de mantenimiento.
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captulo 62 El cncer anal 1237
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1238 seccin III Oncologa de Radiacin clnica parte G Gastrointestinal
toxicidad fue similar en cada grupo (11% vs. 10% MMC CDDP). El primer informe de este ensayo En Suecia, la bleomicina se le dio forma concurrente con RT en estudios no
(despus de la mediana seguimiento de los pacientes de aleatorios, pero no beneficio era evidente. 97-98, 99 Un estudio piloto en el Reino Unido en
2.5 aos) describieron una significativamente mayor tasa de colostoma a los 3 aos el que los tres de los principales frmacos investigados, 5FU, MMC, y CDDP, se
en los que recibieron CDDP en lugar de MMC plus 5-FU y TA. No hubo diferencias combinaron con RT que no se prosigui debido a la toxicidad excesiva. 100
significativas en libre de enfermedad o tasas de supervivencia global.
Despus de seguimiento ms largo, las tasas de colostoma de 5 aos y las tasas de Conclusin
fracaso locorregional mostraron tendencias a favor de 5-FU, MMC-y RT, pero no fueron Queda mucho por aprender acerca de los mecanismos de interaccin entre la radiacin y
significativos. Sin embargo, la libre de enfermedad (68% vs. 58% a los 5 aos; P = . 004) y en la quimioterapia en el tratamiento del cncer. Las interacciones sinrgicas de varias
general las tasas de supervivencia (78% frente a 71%; P = . 021) de manera significativa a favor combinaciones de RT, 5-FU, MMC-y CDDP observado en algunos estudios de laboratorio
de RT, 5-FU, y son difciles de evaluar clnicamente, y no se han realizado ensayos diseados para
MMC. 75 Los investigadores concluyeron que la RT, 5-FU, y MMC deben seguir siendo estudiar dichas interacciones. Adems, no ha habido comparaciones formales de ms
el enfoque estndar. prolongada, pero intensa de dosis menos diarias, infusiones de 5-FU con las de 96 horas
El segundo UK cncer anal de prueba (ACT II) tambin tiene no identi fi c un papel a 120 horas infusiones generalmente favorecidas, ni de inyecciones en bolo con
para CDDP, adems de o en lugar de MMC. Este ensayo ha sido descrito hasta ahora infusiones continuas de 5-FU o CDDP . En la mayora de serie, el momento de
slo en abstracto. 76 El ensayo incorpora un doble asignacin al azar, ya sea para 5-FU y administracin de quimioterapia cada da con respecto a la irradiacin no estaba
MMC o para 5-FU y CDDP simultneamente con RT; y a 2 ciclos de adyuvante (o estrechamente controlada, y la importancia de la programacin no se conoce.
mantenimiento) 5-FU y CDDP o a ninguna quimioterapia adicional despus de
quimiorradiacin concurrente. Los puntos finales primarios fueron mejoras en las tasas
de respuesta completa del tumor y las tasas de supervivencia libre de enfermedad. las La combinacin quimiorradiacin estndar actual es RT con dos 96 horas o 120
tasas de respuesta completa del tumor a los 6 meses fueron similares: 94% (brazo MMC) horas infusiones intravenosas continuas concurrentes de 5-FU y una o dos
y 95% (brazo CDDP). las tasas de supervivencia de tres aos libre de enfermedad y no inyecciones de bolo MMC. No se han establecido las dosis ms eficaces. Cuando los
se mejoraron en aquellos que recibieron adyuvante con 5-FU y CDDP. pacientes MMC pacientes deben ser manejados fuera de un ensayo clnico, se sugiere que un horario
tratados tuvieron toxicidad hematolgica ms grave, pero las tasas de sepsis utilizado en uno de los ensayos aleatorios, para los que existen datos sobre la e fi
neutropnica fueron similares (aproximadamente 3%). cacia y la toxicidad, se adoptar.
Salvage para metstasis en los ganglios inguinales es por lo general por linfadenectoma
Los estudios iniciales de laboratorio sugieren que el EGFR y K-RAS anlisis de la mutacin no es inguinofemoral radical o selectiva. Plvicos metstasis en los ganglios de la pared lateral pueden
probable que sea til como una prueba de deteccin para la sensibilidad a la terapia anti-EGFR no ser resecable debido a la invasin de msculo o hueso o estructuras neurovasculares.
en cncer del canal anal. 96
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captulo 62 El cncer anal 1239
Seria
Control de Tumor primario T1 complicaciones-
Autor (Referencia) Radiacin T2 T3T4 colostoma Supervivencia a 5 aos
Newman et al. (101) 50 Gy / 20/4 sem 8/9 42/52 (81%) 13/20 (65%) 2 66%
( 2 cm) ( 5 cm) (> 5 cm o T4)
Cummings et al. (102) 50 Gy / 20/4 sem 6/6 19/29 (66%) 13/28 (46%) 6 61%
(Algunos EB-I / I) ( 2 cm) ( 5 cm) (> 5 cm o T4)
Martenson y 45-50 Gy / 25-28 / 5-6 sem Plus 9/9 ( 2 17/17 (100%) ( 5 - 2 temp 94%, actuarial
Gunderson (103) impulso a 55-67 Gy cm) cm)
Otim-Oyet et al. (104) 60-65 Gy / 30-33 / 6-7 sem 2/2 16/22 (73%) 8/17 (47%) 1 56%
(Algunos con impulso) ( 2 cm) ( 4 cm) (> 4 cm) causas especficas
Papillon y 42 Gy / 10 / 2,5 sem Plus NS 29/39 (74%) ( 4 27/64 (42%) (> 6 60%
Montbarbon (80) I 20 Gy en 8 sem cm) 4 cm)
de clulas escamosas bien diferenciadas <2 cm de tamao. 31 , 34 La escisin local de relativamente resistente hasta el momento para todos quimioterapia, RT, o protocolos
pequeos cnceres del canal o perianal piel distal es generalmente ms conveniente y de modalidad combinada. 117 La combinacin ms activo es 5-FU y CDDP, aunque las
asociado con una menor morbilidad que los tratamientos basados en la radiacin. Sin respuestas completas duraderas o son poco comunes. Muchos frmacos recientemente
embargo, si los mrgenes de reseccin son positivos escisin local o se considera desarrollados y agentes moleculares dirigidas an no han sido evaluadas, pero la
inadecuada y, adems, no es posible, el paciente debe recibir quimiorradioterapia o RT posibilidad de nuevos enfoques se ilustra con los informes preliminares de las
sola. No hay evidencia de que la administracin electiva por escisin del tumor limitado y respuestas a cetuximab e irinotecn. 118 La radioterapia sola puede proporcionar
protocolos basados en radiacin postoperatoria mejora el control local. 116 paliacin til, especialmente para las metstasis dolorosas. radioterapia corporal
estereotctica o metastasectoma se pueden ofrecer a los pacientes seleccionados,
pero las metstasis son comnmente mltiple.
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1240 seccin III Oncologa de Radiacin clnica parte G Gastrointestinal
su juicio posterior. 76 En serie a base de institucin, las tasas de control locorregionales Cualquier ventaja de la radiacin y la quimioterapia adyuvante es desconocida, aunque, por
vari de 60% a 90%, las tasas de preservacin del esfnter de 65% a 85%, y la analoga, los protocolos utilizados para los cnceres rectales primarios se aplican a veces.
supervivencia global a los 5 aos del 55% al 80%. 40, 69119 , 120-121, 122-123 La necrosis local fue Unos pocos centros han tratado algunos adenocarcinomas anales por protocolos de
visto como una complicacin ms frecuentemente cuando se utiliza la braquiterapia, quimiorradiacin desarrollados para los cnceres de clulas escamosas o
aunque en general las tasas de complicaciones graves fueron <5%. adenocarcinomas rectales y han diferido ciruga. La experiencia es limitada, pero la funcin
anorrectal se ha mantenido, y se ha informado de curaciones aparentes, particularmente en
Los nodos regionales para la piel perianal son los ganglios inguinales ipsilaterales. pacientes con cnceres de menor tamao, despus del tratamiento con RT solo o con RT y
metstasis en los ganglios perirrectal y plvicos son comunes a menos que el cncer la quimioterapia. 131, 132 , 133, 134-135 , 136-137
implica el canal anal ampliamente. El riesgo de metstasis en los ganglios inguinales es
aproximadamente 10%, principalmente, a la categora T3 o T4 tumores o cnceres
pobremente diferenciados. irradiacin nodal inguinal bilateral electiva puede ser
considerada cuando estos tumores ms grandes son tratados, aunque algunos defensor Carcinomas de clulas SMALL
inguinal electiva RT para todos los cnceres perianales. 123
Los carcinomas de clulas pequeas son cnceres poco frecuentes que se caracterizan por
metstasis temprana y tienen un mal pronstico. 31 El tumor primario puede ser administrado por
Los ganglios plvicos inferiores deben ser incluidos si es invadido el canal anal. La ciruga o radiacin. La quimioterapia sistmica similar a la utilizada para los pequeos cnceres de
gestin de los ganglios inguinales anormales es similar a la de cncer del canal anal. clulas que surgen en otros lugares puede ser combinado con la radiacin para el tumor primario y
usarse para tratar las metstasis, pero las respuestas son generalmente limitados.
Los principios de gestin de la clula basal poco comn y adenocarcinomas de la
piel perianal son similares a los de estos tipos histolgicos en otras partes de la piel.
106). En el grupo de no-ENI, las tasas de recidiva fueron del 12% de T1 a T2 y 30% a
< 200 / L al inicio del tratamiento, o la presencia de SIDA. 63130 partir de T3 a los tumores T4. 38 En un estudio prospectivo en Australasia en la que los
Sin embargo, estos hallazgos no estn asociados inevitablemente con escasa tolerancia. pacientes con T1 o T2 tumores de hasta 4 cm de dimetro no recibi inguinal ENI,
terapia antirretroviral concomitante no reduce de forma fiable la gravedad o la incidencia de la fallo de nodo inguinal ocurri en 9 de 40 (23%), en 5 como primer sitio de fallo. 141
toxicidad de la RT y la quimioterapia. 30
las tasas de control locorregional de alrededor de 65% o mejor se describieron en El tratamiento de los cnceres ms grandes por braquiterapia intersticial solo result en
algunas series, similares a los de los pacientes VIH negativos. Sin embargo, algunos fracaso en linfticos plvicos por encima del volumen tratado en el 16% (14 de 88). 142 El
investigadores informaron menores tasas de control local y la preservacin del control de la mayora de las metstasis en los ganglios plvicos subclnicas por plvica ENI y
esfnter en pacientes VIH positivos, a pesar de la enfermedad anterior etapa y buena la quimioterapia se puede inferir de las tasas de fracaso bajos reportados en sitios de
respuesta inicial tumor. 64.128 En un estudio de 40 pacientes VIH-positivos, la tasa de ganglios plvicos. 138-140 La dosis mnima eficaz para ENI no se conoce. Dosis tan bajas como
supervivencia global a los 5 aos fue similar a la de 81 pacientes VIH-negativos, pero 24 Gy en 12 fracciones en 2,5 semanas apareci eficaz en una serie, 39
la principal causa de muerte en los pacientes VIH-positivos fue del cncer anal, a
diferencia del VIH-negativas pacientes en los que causas distintas al cncer
pero la mayora de los centros de dan de 30,6 Gy en 17 fracciones en 3,5 semanas a 50 Gy en 25
predominaba. 64 fracciones en 5 semanas. 38,73,74
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captulo 62 El cncer anal 1241
impulsa a las reas inguinal y reduce algunos de los inhomogeneidades producidos La ubicacin y la profundidad de los ganglios inguinales deben obtenerse mediante
por las curvaturas naturales de los tejidos blandos de la pelvis. En esa posicin, es formacin de imgenes axial. 144 Otra alternativa popular, si
difcil de asegurar que bolo se coloca sobre la zona anal permanece en su lugar. 30,6 a 36 Gy en 3,5 a 4 semanas se percibe como bastar dosis fi ciente para ENI
para los nodos normales radiolgicamente, es tratar a los nodos primario y plvicos e
En la discusin que sigue, las dosis de radiacin descritas son tpicas de las inguinales con la AP: campos PA, y luego utilizar una disposicin de campo de tres fi
prescritas cuando RT se combina con 5-FU y MMC. Cuando se utiliza un par opuesto (posterior y dos campos laterales) para abarcar el tumor primario a 45 a 59.4 dosis
anterior-posterior de campos, el borde superior de los campos se coloca en la unin total Gy, de acuerdo con el tamao del cncer primario y la prctica local. Otros
lumbosacra si la intencin es incluir la ilaca comn, presacro superior, e inferior nodos arreglos de campo, tales como campos oblicua fi 145 y una fi perineal directo ELD
rectosigmoides, adems de los nodos regionales. Esta frontera se mueve comnmente acopla con un haz de arco parcial posterior 142 se han descrito. Cuando se utilizan
abajo durante el tratamiento para el extremo inferior de las articulaciones sacroilacas campos asimtricos o coincidentes, hay potencial para tanto sobre y infradosificacin. 146
(tpicamente despus de 30,6 Gy en 17 fracciones a 36 Gy en 20 fracciones),
abarcando as en la reduccin del volumen slo el perirrectal, inferior presacro, y los
nodos ilacas internas ( y, si los campos estn su fi cientemente amplia, los ganglios La fase final del tratamiento, ms all de que incluye tanto los ganglios linfticos
iliacos externos ms bajos), con el fin de reducir el riesgo de enteritis por radiacin y cncer primario, tpicamente entrega del 9 al 20 Gy a un volumen reducido que
(Fig. 62.3). Una reduccin adicional de campo se realiza en 45 Gy, despus de lo cual abarca slo el tumor primario. Esta fase puede ser entregado por braquiterapia. La
una fase final de tratamiento de 9 Gy en 5 fracciones o 14,4 Gy en 8 fracciones se braquiterapia se utiliza ms comnmente en Europa que en Amrica del Norte, donde
entrega al tumor primario. Es aconsejable aadir un margen de CTV de 2 a 3 cm se favorece el tratamiento de haz externo. Hay una serie de informes de braquiterapia
alrededor del tumor primario para esta fase de impulso. Si el tumor primario no puede eficaz, incluyendo tasa de dosis baja (LDR), 69147 , 161 Tasa de dosis pulsadas (PDR), 148 ,
ser identificado fi en la CT de planificacin, el complejo del esfnter anal se utiliza a 149-150 y la alta tasa de dosis (HDR) tcnicas. 151152 La braquiterapia generalmente se ha
posterior restringido al tumor primario y linfticos de la pelvis. En esta ltima particular los de las regiones nodales a ser irradiada de forma electiva. 158
disposicin,
El RTOG public posteriormente un atlas de plantillas CTV electivos desarrollados por un
panel de consenso para su uso en la planificacin de IMRT para los cnceres anales y
rectales. 160 Cuando las tcnicas de IMRT
Estudio (Referencia) RTOG 9811 brazo MMC (74) Boston (159) RTOG 0529 (158) Toronto (139)
N de pacientes 324 43 51 58
tcnica de radiacin conformacional 3D IMRT IMRT IMRT
aguda grado 3 o 4 toxicidad
Hematolgicas (%) 61 49 notario pblico 38
Piel (%) 48 7 20 46
GI (%) 36 7 22 (GI / GU) 9
GU (%) 4 5 22 (GI / GU) 0
interrupciones en el tratamiento 61 40 49 55
resultados de 2 aos
RTOG, Radiation Therapy Oncology Group; MMC, mitomicina-C; 3D, tridimensional; IMRT, la radioterapia de intensidad modulada; NP, no publicado; GI,
gastrointestinal; GU, genitourinario.
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1242 seccin III Oncologa de Radiacin clnica parte G Gastrointestinal
se van a utilizar, una atencin particular a la posicin del paciente y la inmovilizacin es tiempo ment (OTT), incluyendo el tiempo para la quimioterapia de induccin si se les da y
necesario. Si es posible, la exactitud de la configuracin debe ser verificable ed con para intervalos prolongados antes de aumentar la temperatura ambiente, puede tener
frecuencia, por ejemplo, por tratamiento de radiacin guiado por imgenes. ms influencia sobre el resultado de la duracin de la radiacin (RTT). Revisin del
proceso UKCCCR ACT I no identific una asociacin entre OTT y el fracaso
A pesar de que los resultados observados en la IMRT parecen similares a los locorregional. 166 El anlisis de dos ensayos RTOG 73,74 mostr una tendencia hacia una
conseguidos con conformacional 3D RT, este ltimo todava se considera el estndar, hasta asociacin entre ya fracaso OTT y colostoma y una asociacin estadsticamente
ahora no se ha informado de los resultados clnicos a largo plazo con la IMRT. significativa con el fracaso local. RTT y OTT no se correlacionaron con los ndices
generales o libre de colostoma de supervivencia. 170
El aumento de la dosis de radiacin total se han defendido. Cuando se combina con La radioterapia sola
5-FU y MMC, dosis de radiacin de tan poco como 30 Gy en 15 fracciones se han mostrado Si se da la irradiacin de haz externo sin quimioterapia concurrente, es usual, como en
ms de 3 semanas para erradicar hasta aproximadamente 90% de los cnceres 3 cm de otros tipos de cncer, para prescribir dosis cercanas a la tolerancia de los tejidos
tamao. Las dosis ms altas, a partir de 45 Gy en 25 fracciones en 5 semanas a 54 Gy en normales. No se han realizado estudios para establecer los factores ptimos en tiempo de
30 fracciones en 6 semanas, a veces complementados con radiacin adicional despus de la dosis. Una dosis al tumor primario de 60 a 65 Gy durante 6 a 7 semanas, en 1.8to
un intervalo de 6 a 8 semanas para un total de 60 a 65 Gy durante un tiempo total de fracciones 2-Gy, se prescribe comnmente, con dosis a los ganglios linfticos a ser
aproximadamente 12 semanas, han controlado de 65% a 75% de primario tumores> 4 cm. 39
tratados de forma electiva en el intervalo de 36 Gy en 4 semanas a 50,4 Gy en 5,5
, 57,106,162,163-165 Los ensayos recientes en Amrica del Norte utilizados hasta 59 Gy en 32
semanas. La braquiterapia puede ser usada para parte del tratamiento. Al igual que con
fracciones durante 6,5 semanas para los cnceres grande o ganglios positivos 74 , 83,91,92; la
quimiorradioterapia, interrupciones en el tratamiento deben ser minimizados.
eficacia y la tolerabilidad a largo plazo de estas dosis ms elevadas todava no ha sido
reportado en detalle. Un anlisis reciente del ensayo UKCCCR ACT I sugiri que la entrega
de radiacin impulso de 15 a 25 Gy 6 semanas despus de la inicial de 45 Gy en 4 a 5
semanas no mejor el control local pero se asoci con un mayor riesgo de necrosis (8% vs
. 0% si no se le dio impulso). 166 Muchos centros estn desarrollando programas de dosis
cncer perianal
Si pequeos (<4 cm) cnceres perianales con bajo riesgo de metstasis en los ganglios
graduadas de acuerdo con el tamao de las metstasis tumorales y de ganglios linfticos
regionales son tratados por radiacin, una dosis de 60 a 66 Gy en fracciones de 2-Gy de
primarios. 74138 , 155, 159
ms de 6 semanas puede ser utilizado. Se prefiere un campo perineal directo ya que
esto reduce al mnimo el rea de la piel irradiada. equipo ortovoltaje puede bastar,
aunque electrones o fotones de baja energa megavoltage (con bolo) son ms
comnmente utilizados. Se debe tener cuidado para aplanar el perineo tanto como sea
Una ventaja potencial propuesto con frecuencia para IMRT es la capacidad de
posible para evitar zonas de sobre o infradosificacin. cnceres perianales ms grandes,
aumentar selectivamente la dosis de radiacin al cncer. No se sabe si esto ser
o los cnceres que invaden el canal anal, generalmente se tratan por las tcnicas y los
posible como estrategia para aumentar las tasas de control para los tumores anales
horarios de la radiacin y la quimioterapia se usa para cnceres del canal anal, en base
ms grandes debido a las tolerancias limitadas del recto distal, canal anal y la piel
a los resultados del ensayo UKCCCR ACT I. 41 irradiacin ganglionar electiva se da a los
perianal. 167168 La introduccin de planes de IMRT monofsicos ha llevado al uso de
ganglios iliacos inguinales e inferior externos y a los nodos ilacas perirrectales e internos
fraccionamiento de la dosis no estndar, en particular para regiones de ganglios
inferiores si el tumor se extiende en el canal anal. El borde superior de los campos se
linfticos tratados de forma electiva. Por ejemplo, si todos los volmenes de destino
coloca generalmente en el extremo inferior de las articulaciones sacroilacas. La fase
deben ser tratados a 30 fracciones y el tumor primario es recibir 54 Gy a 1,8 Gy por
final de la radiacin puede ser dada por fotn perineal directa o terapia de electrones.
fraccin, tratamiento electivo de nodos no involucrados a 36 Gy sera entregado a 1,2
Aunque la braquiterapia se puede utilizar para la fase final, el tratamiento completo de
Gy por fraccin y a 45 Gy en 1,5 Gy por fraccin. Algunos autores tambin han
los cnceres perianales por braquiterapia se asoci con altas tasas de necrosis en
introducido correcciones dosis biolgicamente eficaces para permitir diferentes dosis
algunas series.
fraccionadas o alteraciones en tiempo sobre el cual se entregan las dosis ms bajas. 155,
159 La eficacia a largo plazo de estas dosis no estndar no se ha determinado.
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captulo 62 El cncer anal 1243
CDDP sustituido por MMC, toxicidad sea fue menor, pero a dosis de radiacin de 59,4 Gy 3. Sobin L, Gospodarowicz M, Wittekind C, eds. Unin Internacional Contra el Cncer (UICC). TNM
clasificacin de los tumores malignos. 7 ed. Nueva York: WileyBlackwell de 2009.
en 6,5 semanas, las tasas de toxicidad de los tejidos blandos agudos fueron similares. 74 , 83 La
mayora de los estudios grandes de RT, 5-FU, y MMC o CDDP informado de algunos 6. Fenger C, Frisch M, Mart MC, et al. Los tumores del canal anal. En: Hamilton SR, Aaltonen LA, eds. Patologa
y gentica de los tumores del sistema digestivo.
mortalidad (<2% en total) asociado con toxicidad aguda, por lo general como resultado de
Lyon: IARC Press, 2000: 145-155.
la neutropenia con sepsis. Este riesgo puede reducirse con antibiticos profilcticos 41 y la 7. Pastor NA. neoplasia intraepitelial anal y otras lesiones precursoras neoplsicas del canal anal y la regin
perianal. Gastoenterol Clin North Am
atencin de apoyo agresivo.
2007; 36: 969-987.
8. Cocine MB, Dawsey SM, Freedman ND, et al. disparidades entre sexos en la incidencia de cncer de perodo y la
Serious toxicidad tarda no se ha informado despus de dosis de 30 Gy en 3 edad. Cancer Epidemiol Biomarkers Prev 2009; 18: 1174-82.
10. Grupo de Trabajo Monogrfico del Cncer IARC. Una revisin de humano carcingenos-Parte B: agentes biolgicos. The
semanas con 5-FU y MMC, pero las complicaciones significativas, requiriendo a menudo Lancet Oncol 2009; 10: 321-322.
la ciruga, se registraron en aproximadamente 5% a 10% de los que recibieron las dosis 11. Hoots BE, Palefsky JM, Pimenta JM, et al. distribucin de tipo virus del papiloma humano en el cncer anal
y lesiones intraepiteliales anales. Int J Cancer 2009; 124: 2375-
ms altas de radiacin. Una revisin de la gestin del cncer anal en Dinamarca
2383.
1995-2003 encontr 5 aos incidencias acumuladas de y colostoma de 26% (IC del 12. De Vuyst H, Clifford GM, Nascimento MC, et al. Prevalencia y distribucin tipo de virus del papiloma humano
en el carcinoma y neoplasia intraepitelial de la vulva, la vagina y el ano: un meta-anlisis. Int J Cancer 2009;
95%, 21% a 32%) y 8% treatmentrelated relacionada con el tumor (95%
124: 1626-1636.
15. Frisch M. En la etiologa de carcinoma escamoso anal. Dan Med Bull 2002;
CI, 5% a 12%), respectivamente. 172 En el ensayo aleatorizado RTOG-9811, en los que 49: 194-209.
18. Frisch M, Biggar RJ, Engels EA, et al. Asociacin de cncer con inmunosupresin relacionada con el SIDA
recibieron RT, 5-FU, y MMC, slo 10 de los 30 procedimientos de colostoma realizadas por en adultos. JAMA 2001; 285: 1736-1745.
cerca de 3 aos fueron por problemas relacionados con el tratamiento, la tasa bruta de 19. Adami J, Gabel H, Lindelof B, et al. El riesgo de cncer despus de un trasplante de rganos: un estudio de
cohorte a nivel nacional en Suecia. Br J Cancer 2003; 89: 1221-27.
aproximadamente 3%. 59 Es probable que algunos informes, muchos de los cuales eran
23. Simard EP, Pfeiffer RM, Engels EA. Espectro de riesgo de cncer tarde despus de la aparicin del SIDA en los
retrospectivos, tambin daba cierta toxicidad relacionada con el tratamiento. Por ejemplo, Estados Unidos. Arch Intern Med 2010; 170: 1337-1345.
recibieron radiacin (n = 399) en comparacin con los no irradiados (n = 157). La tasa de 28. Frisch M, Olsen JH, Bautz A, et al. lesiones benignas y anales el riesgo de cncer anal. N Engl J Med 1994; 331:
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fractura acumulativa 5 aos fue del 14% frente a 7,5% ( P <. 01). 173 Uno de los objetivos de 29. Frisch M, carcinoma Johansen C. Anal en la enfermedad intestinal inflamatoria. Br J
las tcnicas de conformacin en 3D y de IMRT actuales es para reducir la dosis RT a los Cncer 2000; 83: 89-90.
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32. Myerson RJ, Karnell LH, Menck HR. En el informe del National Cancer Data Base sobre el carcinoma del
ano. Cncer 1997; 80: 805-815.
33. Bilimoria KY, Bentrem DJ, Roca CE, et al. Los resultados y los factores de pronstico para el carcinoma de
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36. Gerard JP, Chapet O, Samiei F, et al. Tratamiento de las metstasis de los ganglios linfticos inguinales en
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estos riesgos no han sido ed fi cuanti en detalle para los pacientes tratados de cncer revisin de la literatura. Cncer 2001; 92: 77-84.
38. Ortholan C, Resbeut M, Hannoun-Levi JM, et al. cncer del canal anal: gestin de los ganglios inguinales y
anal. En segundo lugar, en el nico informe en lo que va de largo plazo de seguimiento
beneficio de la irradiacin inguinal profilctica (estudio CORS-03). Int J Radiat Oncol Biol Phys 2012; 82 (5):
de los pacientes en un ensayo aleatorio, se encontr que haba ms muertes debido a 1988-1995.
39. Cummings BJ, Keane TJ, O'Sullivan B, et al. Epidermoide anal cncer: tratamiento por radiacin y
causas distintas al cncer, especialmente cardiovascular relacionada, en la primera 10
5-fluorouracilo con y sin mitomicina C. Int J Radiat Oncol Biol Phys 1991; 21: 1115-1125.
aos despus del tratamiento con RT , 5-FU, y MMC. 71 Esta diferencia alcanz + 9% a
los 5 aos, pero el efecto desapareci casi por 10 aos. La magnitud de esta diferencia 41. Partido UKCCCR canal anal cncer prueba de trabajo. cncer anal epidermoide: resultados del ensayo
aleatorizado UKCCCR de la radioterapia sola versus uorouracilo radioterapia, 5-fl y mitomicina C. Lanceta 1996;
fue menor que la reduccin de las muertes por cncer del ano. Se necesita informacin 348: 1049-1054.
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del ganglio centinela en la deteccin de metstasis en los ganglios inguinales en pacientes con cncer anal. Int
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53. de Jong JS, Beukema JC, Van Dam GM, et al. limitado valor de puesta en escena carcinoma de clulas escamosas del
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plazo de seguimiento. Ann Surg Oncol 2010; 17: 2656-
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A pesar de que la preservacin de la anatoma anorrectal es una ventaja del 54. Cummings BJ. El cncer anal. En: Gospodarowicz MK, O'Sullivan B, Sobin LH, eds.
Los factores de pronstico en el cncer, 3 ed. Hoboken, NJ: Wiley, 2006: 139-142.
tratamiento con quimiorradioterapia, a finales de la funcin anorrectal es a menudo 55. Greenall MJ, Quan SHQ, DeCosse JJ. cncer epidermoide del ano. Br J Surg
anormal. Los efectos secundarios del tratamiento son muy comunes y pueden causar a 1985; 72 (Suppl): S97.
59. Ajani JA, Winter KA, Gunderson LL, et al. US Intergroup anal Carcinoma de prueba: el dimetro del tumor
los pacientes una considerable malestar y discapacidad social, aunque a menudo se
predice para colostoma. J Clin Oncol 2009; 27: 1116-21.
clasifican como nico nivel 1 o 2 toxicidad. 175-176, 177-178 Estos efectos incluyen cambios en 60. Ajani JA, Winter KA, Gunderson LL, et al. Los factores de pronstico derivadas de una base de datos
prospectiva dictan biologa clnica de cncer anal. La prueba entre grupos (RTOG 98-11). Cncer 2010; 116:
la funcin anorrectal tales como urgencia y frecuencia de la defecacin, sangrado de
4007 hasta 4013.
telangiectasia anorrectal, dermatitis perineal, fibrosis plvica, dispareunia, y la 64. Oehler-Janne C, Huguet F, Provender S, et al. diferencias fi c VIH-especfica en el resultado del carcinoma de
impotencia. Por lo general son tratados mdicamente con xito variable. Las clulas escamosas del conducto anal: un estudio de cohorte multicntrico de pacientes con VIH que reciben
terapia antirretroviral de gran actividad. J Clin Oncol
evaluaciones sistemticas y potenciales de la funcin de la regin anorrectal y de otros 2008; 26: 2550-2557.
rganos que puedan verse afectados por el tratamiento ahora se estn reportando, al 65. factores Fenger C. de pronstico en carcinoma anal. Patologa 2002; 34: 573-578.
67. Ajani JA, Wang X, Izzo JG, et al. Biomarcadores moleculares se correlacionan con libre de enfermedad supervivencia en
igual que los estudios formales de calidad de vida. 139 , 179 A menudo hay disociacin entre
pacientes con carcinoma del canal anal tratados con quimiorradiacin.
un paciente y su o de la evaluacin de su mdico de la funcin y la continencia anal y Dig Dis Sci 2010; 55: 1198-05.
68. Bruland O, Fluge O, Immervoll H, et al. La expresin de genes revela 2 grupos distintos de carcinomas
rectal y mediciones fisiolgicas de la funcin anorrectal. Los pocos estudios en esta
anales con implicaciones clnicas. Br J Cancer 2008; 98: 1264-73.
rea han sido concluyentes. 177 , 180 se puede esperar que los estudios prospectivos de la 69. Peiffert D, Bey P, Pernot M, et al. El tratamiento conservador por irradiacin de los cnceres epidermoides
funcin del rgano plvico para ayudar al desarrollo de protocolos de tratamiento de de canal anal: factores pronsticos de control de tumoral y las complicaciones. Int J Radiat Oncol Biol Phys 1997;
37: 313-324.
radiacin, facilitando la correlacin de la funcin con las interacciones radiacin de 70. Chapet O, Gerard JP, Riche B, et al. Valor pronstico de la regresin del tumor evala despus de la primera
quimioterapia, tcnicas de radiacin y distribuciones de dosis, y los factores de dosis curso de la radioterapia para el cncer del canal anal. Int J Radiat Oncol Biol Phys 2005; 63: 1316-24.
tiempo.
71. Northover J, Glynne-Jones R, Sebag-Monte mineral fi D, et al. Quimio-radioterapia para el tratamiento del cncer
anal epidermoide: 13-aos de seguimiento de la primera aleatorizado UKCCCR anal cncer de prueba (ACT
I). Br J Cancer 2010; 102: 1123-1128.
72. Bartelink H, Roelofsen F, Eschwege F, et al. la radioterapia y la quimioterapia concomitante es superior a la
radioterapia sola en el tratamiento de cncer anal localmente avanzado: resultados de un ensayo
aleatorizado de fase III de la Organizacin Europea para la Investigacin y Tratamiento del Cncer de
Radioterapia y grupos cooperativos gastrointestinales. J Clin Oncol 1997; 15: 2040-2049.
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del ano (ACT II). J Clin Oncol 2009; 27 (Suppl): LBA4009. Radiat Oncol Biol Phys 1999; 45: 1199-1205.
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77. Conroy T, Ducreux M, Lemanski C, et al. Tratamiento intensi fi cacin por la quimioterapia de induccin (TIC) y predictores de fallo y las implicaciones para el tratamiento de radiacin de intensidad modulada y la
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30: 324-333. 147. Papillon J, Montbarbon JF, Gerard JP, et al. curieterapia intersticial en el tratamiento conservador de los
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oral de 5 das por semana de capecitabina e intravenosa mitomicina C en el cncer anal. Int J Radiat Oncol 1989; 17: 1161-1169.
Biol Phys 2008; 72: 119-126. 148. Gerard JP, Mauro F, Thomas L, et al. El tratamiento de clulas de carcinoma del canal anal escamosas con
96. Van Damme N, Deron P, Van Roy N, et al. Epidrmico receptor del factor de crecimiento y el estado de K-RAS en dos braquiterapia de tasa de dosis de pulso. Estudio de viabilidad de un Grupo de Cooperacin Francs. radioter
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poblacin de 308 pacientes consecutivos tratados de acuerdo con protocolos posibles. Int J Radiat Oncol combinacin con uorouracilo 5-fl y mitomicina-C para reduccin de la morbilidad aguda en el carcinoma
Biol Phys 2005; 61: 92-102. del canal anal. Int J Radiat Oncol Biol Phys
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1993; 71: 1736-1740. 159. Kachnic LA, Tsai HK, Coen JJ, et al. Dosis-pintado radioterapia de intensidad modulada para el cncer anal;
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109. Renehan AG, Sanders MP, Scho campo PF, et al. Los modelos de fracaso local de la enfermedad y el resultado el cncer anorrectal: un panel de consenso Terapia de Radiacin Oncology Group contorneado atlas. Int J
despus de la ciruga de rescate en pacientes con cncer anal. Br J Surg Radiat Oncol Biol Phys 2009; 74: 824-830.
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escamosas del conducto anal. Ann Surg Oncol 2007; 14: 2780-2789. I). Int J Radiat Oncol Biol Phys 2011; 81: 1488-
116. Ortholan C, Ramaioli A, Peiffert D, et al. El carcinoma del canal anal: tumores en estadios tempranos 10 mm 1494.
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Oncol Biol Phys 2005; 62: 479-485. 2007; 19: 730-737.
117. Eng C, opciones Pathak P. tratamiento en carcinoma de clulas escamosas metastsico del canal anal. Curr 168. Heemsbergen WD, Hoogeman MS, Hart GA, et al. La toxicidad gastrointestinal y su relacin con la dosis
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119. Bieri S, Allal AS, Kurtz JM. tratamiento de carcinomas del margen anal esfnter de conservacin. Acta Oncol 2001; Radiat Oncol Biol Phys 2005; 61: 1001-18.
40: 29-33. 169. Wong CS, Tsang RW, Cummings BJ, et al. parmetros de la proliferacin en carcinomas epidermoides de
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del margen anal. Ann Surg Oncol 2008; 15: 1092-98. 2010; 28: 5061 a 5.066.
125. Edelman S, Johnstone PA. La terapia de modalidad combinada para los pacientes infectados por VIH con 172. Sunesen KG, Norgaard M, Lundby L, et al. las tasas por causas espec fi cas de colostoma despus de la radioterapia para
carcinoma de clulas escamosas del ano: resultados y efectos txicos. Int J Radiat Oncol Biol Phys 2006; 66: 206-211. el cncer anal: un estudio de cohortes multicntrico dans. J Clin Oncol
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infectados por VIH que reciben terapia antirretroviral altamente activa. Am J Clin Oncol 2011; 34: 135-139. la irradiacin plvica. JAMA 2005; 294: 2587-2593.
174. Wright JD, St Clair CM, Deutsch I, et al. radioterapia plvica y el riesgo de leucemia secundaria y mieloma
128. Chiao EY, Giordano TP, Richardson P, et al. inmunodeficiencia humana deficiencia virusassociated el cncer de mltiple. Cncer 2010; 116: 2486-2492.
clulas escamosas del ano: epidemiologa y los resultados en la era de la terapia antirretroviral de gran 177. Vordermark D, Sailer M, Flentje M, et al. La terapia de radiacin intencin curativa en el carcinoma anal:
actividad. J Clin Oncol 2008; 299: 1914-1921. calidad de vida y la funcin del esfnter. radioter Oncol 1999; 52: 239-
129. Formenti SC, Chak L, Gill P, et al. Aumento de la radiosensibilidad de fibroblastos de tejido normal en 243.
pacientes con inmunodeficiencia adquirida sndrome de deficiencia (SIDA) y con el sarcoma de Kaposi. Int J 178. Das P, Cantor SB, Parker CL, et al. calidad a largo plazo de la vida despus de la radioterapia para el tratamiento del
Radiat Biol 1995; 68: 411-412. cncer de ano. Cncer 2010; 116: 822-829.
booksmedicos.org
Parte H Tracto urinario
captulo 63
El cncer de rin, pelvis renal, urter y
1245
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1246 seccin III Oncologa de Radiacin clnica Parte H Tracto urinario
PRESENTACIN CLNICA
Carcinoma de clulas renales
Los pacientes con RCC pueden presentar con un tumor primario oculto, o con signos
Cigarette smoking is the most important factor contributing to the overall y sntomas atribuibles a una masa local o sndromes paraneoplsicos sistmicos.
incidence of urothelial cancer in Western countries. Patients with Lynch syndrome, an hematuria, masa palpable flanco y dolor describen una trada clsica que se produce
autosomal dominant genetic condition attributable to inherited mutations that impair slo en un 5% a un 10% de los pacientes. 36 , 37 De hecho, un hallazgo de la triada
DNA mismatch repair, have an increased risk of developing urinary tract cancer. 24 clsica sugiere a menudo la enfermedad avanzada con un mal pronstico. El sntoma
ms frecuente asociado con RCC es la hematuria, ya sea macroscpica o
microscpica, cuando hay invasin del sistema colector. 38 varicoceles escrotales,
Exposure to aristolochic acid has been associated with acute, near end-stage sobre todo del lado izquierdo, se observan hasta en el 11% de los hombres con CCR. 39
renal disease. Aristolochic acid is commonly found in the Aristolochiaceae family of Otros sntomas incluyen anemia, disfuncin heptica en ausencia de metstasis
plants commonly used in Chinese herbal medicine. A high incidence of cellular atypia hepticas (llamada sndrome de Stauffer y atribuible a una elevacin paraneoplsico
and urothelial carcinoma of the renal pelvis, ureter, and bladder has been associated de la fosfatasa alcalina), la amiloidosis AA secundaria, fiebre, hipercalcemia,
with aristolochic acid nephropathy. 25 Arsenic-contaminated water has been associated caquexia, eritrocitosis, trombocitosis, y un sndrome que se asemeja rhumatica
with a high incidence of upper urinary tract urothelial carcinoma in Taiwan. 26 Prolonged polimialgia. 39, 40 , 41-44, 45 RCC se presenta como una masa incidental en un estudio de
heavy phenacetin-containing analgesic use can lead to urothelial carcinomas of the diagnstico por imagen ordenada para otros fines representa el 61% de todos los
renal pelvis, ureter, and bladder (which may be multiple and bilateral). 27 diagnsticos. 46
Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease of Una amplia gama de sndromes paraneoplsicos se ha asociado con RCC.
unknown etiology most commonly reported in southeastern Europe. A high frequency Parathyroidlike hormonas, eritropoyetina, la renina, gonadotropinas, lactgeno de la
of urothelial atypia, occasionally progressing to tumors of the renal pelvis and urethra, placenta, prolactina, enteroglucagn, hormonas a la insulina, la hormona
but also involving the bladder, is associated with BEN. 27 adrenocorticotrpica, y prostaglandinas han sido identificados en pacientes con CCR. 47,48
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captulo 63 El cncer de rin, pelvis renal, urter y 1247
Pelvis renal y el urter Carcinoma TABLA 63.2 Estudio diagnstico PARA pelvis renal y el urter
hematuria macroscpica o microscpica se produce en 70% a 95% de los pacientes CARCINOMA
con tumores de la pelvis renal o del urter. 20 Los otros sntomas menos comunes General
incluyen dolor (8% a 40%), irritacin de la vejiga (5% a 10%), u otros sntomas Historia y examen fsico
constitucionales (5%). Alrededor del 10% al 20% de los pacientes puede presentar con
Los estudios radiogrficos
un flanco masa secundaria a tumor o hidronefrosis.
TC del abdomen y la pelvis o urografa RM
urografa TC multidetector
TC de trax o radiografa de trax
La gammagrafa sea, si el paciente tiene dolor de huesos o tiene una fosfatasa alcalina elevada
estudio diagnstico RM cerebral, si sospecha de metstasis cerebrales
Las masas renales no son poco comunes, y la mayora de ellos son benignos. Una masa La cistoscopia-todo el tracto urinario tiene que ser evaluada debido a la alta incidencia de tumores
renal central puede sugerir carcinoma urotelial; si es as, la citologa de orina o ureteroscopia mltiples
visualizacin Uteroscopic del tumor es deseable, y biopsia de tejido a travs de un uteroscopio
deben ser considerados. masas renales son frecuentemente diagnosticados como un
puede llevarse a cabo si es factible
hallazgo incidental durante la exploracin abdominal para la evaluacin metastsico de un
citologa de orina puede ayudar a determinar el grado del tumor si el tejido no est disponible. tasa de
tumor maligno no relacionado o otra enfermedad.
falsos negativos puede ser alta en la parte alta del tracto y tumores de bajo grado
63.1. The diagnosis of RCC is established clinically and radiographically in most pruebas de la funcin renal. Uro-TAC ahora se utiliza para evaluar a los pacientes con
cases. Pathologic conrmation often is made at the time of nephrectomy. carcinoma de pelvis renal. CT o MRI del abdomen y la pelvis antes y despus de la
administracin de contraste proporciona informacin til con respecto a la posible
Once a radiographic diagnosis is made, a staging evaluation should be extensin del tumor fuera del sistema colector. visualizacin Uteroscopic del tumor es
undertaken, which should include: a complete history and physical examination, deseable, y biopsia de tejido a travs de un uteroscopio debe realizarse si es factible.
complete blood count, and liver and kidney function tests. A metastatic workup should La cistoscopia es muy importante debido a la alta incidencia de tumores mltiples.
include a chest CT and an abdominal/pelvic CT (preferred) or abdominal MRI scan. citologa de orina puede ayudar a determinar el grado del tumor si el tejido no est
Patients with symptoms suggestive of bone metastases and those with an elevated disponible; sin embargo, las tasas de falsos negativos pueden ser altos para los
alkaline phosphatase level should undergo a bone scan. If metastatic lesions are tumores del tracto superior y de bajo grado.
detected, histologic conrmation should be made by biopsy of either the metastatic
focus or the primary tumor. MRI can be valuable when evaluating the extent of
involvement of the collecting system or inferior vena cava, or radiographic contrast
cannot be administered. Renal arteriography is sometimes helpful in planning surgery.
PUESTA EN ESCENA
General Cancer Staging Manual: lesiones T2 se dividieron en T2a (> 7 cm pero 10 cm) and
History and physical examination T2b (>10 cm); ipsilateral adrenal involvement was reclassied as T4 if contiguous
invasion and M1 if not contiguous; renal vein involvement was reclassied as T3a;
Los estudios radiogrficos
and nodal involvement was simplied to N0 versus N1.
CT MRI plvico / abdominal (preferido) o abdominal con o sin contraste dependiendo de la funcin renal.
La RM es superior a la TC en la evaluacin de la vena cava inferior y la aurcula derecha de la
afectacin tumoral
Considere urografa CT, lo que permite obtener imgenes de ambos el parnquima renal y el sistema Renal Pelvis and Ureter Carcinoma
colector Tumors of the renal pelvis and ureter have a natural history that is not too dissimilar
TC de trax o radiografa de trax from that of other urothelial malignancies originating in the bladder. Their prognoses
La gammagrafa sea, si el paciente tiene dolor de huesos o tiene una fosfatasa alcalina elevada depend on tumor invasiveness and pathologic grade. The 2010 AJCC 7th edition
RM cerebral, si sospecha de metstasis cerebrales
staging classication for renal pelvis and ureter carcinoma is shown in Table 63.4. 51
Evitar la biopsia si se est considerando la reseccin. Considere la biopsia con aguja, si est indicado
clnicamente, para lesiones pequeas para confirmar el diagnstico o gua de vigilancia, criociruga, o
estrategias de ablacin por radiofrecuencia
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1248 seccin III Oncologa de Radiacin clnica Parte H Tracto urinario
TABLA 63.3 AMERICAN COMIT MIXTO DE CNCER 2010 ESTADIFICACIN TABLA 63.4 AMERICAN COMIT MIXTO DE CNCER 2010 ESTADIFICACIN
CLASIFICACIN PARA tumores renales CLASIFICACIN PARA pelvis renal y tumores del urter
T2b Tumor> 10 cm, limitado al rin en grasa periplvica o la T3 parnquima renal (Slo para urter) El tumor
T3 El tumor se extiende a las venas principales o tejidos perirrenales pero no en la glndula invade ms all de la capa muscular en la grasa periureteral
segmental ramas, o tumor invade la grasa del seno perirrenal y / o renal, pero no la grasa perirrenal
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The
rin. 18 The World Health Organization (WHO) classies renal cell tumors as clear cell
original source for this material is the AJCC Cancer Staging Manual, 7th ed. (2010) published by
RCC, multilocular clear cell RCC, papillary RCC, chromophobe RCC, carcinoma of
Springer Science and Business Media LLC, www.springer.com.
the collecting ducts of Bellini, renal medullary carcinoma, Xp11 translocation
carcinomas, carcinoma associated with neuroblastoma, mucinous tubular and spindle
cell carcinoma, papillary adenoma, oncocytoma, and RCC unclassied. 18
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Chapter 63 Cancer of the Kidney, Renal Pelvis, and Ureter 1249
Several molecular markers are being explored for their prognostic signicance,
including lack of B7H1 expression, 73
< 1 year from original diagnosis to start of systemic therapy. Laboratory prognostic immunohistochemical detection of carbonic anhydrase IX (CAIX), 74 the proliferative
factors include thrombocytosis as well as elevated erythrocyte sedimentation rate marker Ki67, 74 immunohistochemical expression of IMP3, 75 and others.
For patients with metastatic RCC, the following factors were predictive of survival
in a retrospective study of 670 patients: low Karnofsky performance status (KPS; Renal Pelvis and Ureter Carcinoma
<80), high lactate dehydrogenase (LDH; >1.5 times upper limit of normal), low The major prognostic factors in patients with renal pelvis or ureter carcinoma are initial
hemoglobin (less than the lower limit of normal), high corrected serum calcium (>10 stage and grade of the tumor. There is no signicant difference in prognosis between
mg/dL or 2.5 mmol/L), and absence of prior nephrectomy. 57 urothelial carcinomas originating in the ureter compared to those arising in the renal
pelvis. 76 Using the current 7th edition AJCC staging, the 5-year renal pelvis and ureter
cancer survival is as follows: stage 0a, 72.3%; stage 0is, 70.0%; stage I, 63.9%; stage
Lymph node metastases are associated with increased rates of local recurrence
and distant metastasis. 36 ,5859, 60 Nuclear grade, sarcomatoid component, tumor size,
stage, and the presence of tumor necrosis increase the likelihood of lymph node II, 56.7%; stage III, 36.5%; and stage IV, 10.2%. High-grade tumors are associated
involvement. 61 The overall risk of lymph node metastases is 20%. 62 , 63 Patients with with a higher incidence of metastases and worse survival. Corrado et al. 77 reported
lymph node metastases in radical nephrectomy specimens have a local failure rate of 5-year survival rates of 83%, 75%, 52%, and 0% for grades 1 through
21%, compared with only 4% in patients without lymph node metastases ( p = . 0002). 60 A
select group of patients with solitary metastases may have a 5-year survival rate of 4, respectively. These results are comparable to those described by Heney et al., 78 who
25% to 35%. 64, 65 reported 100% survival for grade 1, 81% for grade 2, and 0% for grade 3. Local
recurrence was identied in 3 of 24 patients with grade 3 tumors. No survival
differences were seen for patients with papillary versus solid tumors. In the series of
Nuclear grade, after stage, is the most important prognostic feature of clear cell Charbit et al., 23 lymph node metastases were seen exclusively in patients with
carcinoma. Fuhrman et al. 66 developed a four-tier grading system that is based on high-grade tumors. Of tumor-related deaths, 90% were in patients with high-grade
nuclear and nucleolar size, shape, and content. Fuhrmans grade is the most widely tumors. Hall et al. 79 reported a retrospective series of 252 patients treated surgically for
used grading system. Grade is also an independent prognostic factor for papillary upper urinary tract urothelial cancers. Signicant factors for recurrence included high
RCC and chromophobe RCC especially when using standardized criteria. 67 Worsening tumor grade and advanced clinical stage. Older patients and patients treated with
pathologic grade is associated with a poor 5-year disease-free survival. 31, 36 parenchymal-sparing surgical procedures had higher rates of recurrence. In their
series of 77 patients, Akdogan et al. 80
Papillary RCC has a 5-year survival rate that approaches 90% and metastasizes
less frequently than clear cell RCC. The spindle cell or sarcomatoid variants of RCC
are associated with statistically signicant inferior 5-year survival rates, compared with reported from a multivariate analysis that higher recurrence rates were associated
pure clear, or clear and granular, histologic variants. 31, 36 with tumor location, higher grade, and advanced T-stage. Tumors in the ureters were
more likely to recur than tumors involving the renal pelvis. In a series of 86 patients,
Nuclear morphology is a strong predictor of tumor stage and prognosis. 66 High Park et al. 81 also reported a higher rate of recurrence in ureteral tumors, compared to
nuclear grade is associated with an increased incidence of advanced tumor stage, those arising in the renal pelvis.
lymph node involvement, distant metastases, renal vein involvement, tumor size, and
perirenal fat involvement. In a series of 190 patients reported by Bretheau et al., 68 the
5-year actuarial survival rates of patients with grade I, II, III, and IV tumors were 76%, A prior history of bladder cancer has been reported to worsen the prognosis of
72%, 51%, and 35%, respectively. Sarcomatoid differentiation carries a signicantly patients with second urothelial cancers involving the upper tracts. 80,82 From the
poorer prognosis than the clear cell or granular cell subtypes. Almost half of patients Memorial SloanKettering Cancer Center series of 129 patients, a multivariate analysis
with sarcomatoid RCC have bone metastases at presentation. The median survival demonstrated that patients with advanced primary tumors and a prior history of
time of patients with sarcomatoid renal cell cancer is only 6.6 months, compared with bladder cancer were associated with worse disease-free survival. 82
19 months for other histologic types. 69
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1250 Section III Clinical Radiation Oncology Part H Urinary Tract
hypermethylation of the promoter region of patients with urothelial cancers is favorably to 77% in patients undergoing radical nephrectomy. 93
associated with a worse prognosis. Tumors of the renal pelvis and ureters In 117 patients with renal tumors 4 cm undergoing partial nephrectomy at the
demonstrate hypermethylation in 94% of cases compared to 76% of similar-appearing Memorial Sloan-Kettering Cancer Center, the 5-year freedom from recurrence was
tumors in the bladder ( p < 0.0001). Hypermethylation was also associated with higher 98.6% compared to
tumor stage, tumor progression, and mortality. 83 96.4% in a similar group of 173 patients undergoing radical nephrectomy. Compared
to patients undergoing partial nephrectomy, those undergoing radical nephrectomy
were at a higher risk of chronic renal insufciency. 94 There is some risk that sparing of
the renal parenchyma may leave microscopic residual tumor or inadequately treat
multifocal cancers. 9596, 97 Bilateral RCC occurs in 2% to 3% of patients. In these
GENERAL MANAGEMENT patients, nephronsparing surgery is an attractive option because bilateral radical
nephrectomy sentences the patient to a lifetime of renal dialysis or the need for a
Renal Cell Carcinoma renal transplant.
Surgery is the therapeutic foundation for the management of kidney cancer.
Radiotherapy has an important and growing role in the palliative management of
RCC. Although RCC is traditionally considered to be radioresistant, it has a clear dose
Following surgery, 20% to 30% of patients with localized tumors relapse, with a
response to radiation. 84,85 As long as sufcient radiation dose is delivered to the tumor
median time to relapse of 1 to 2 years, and most occurring within 3 years. 86 Although
while respecting normal tissue dose constraints, RCC radioresistance can be
at present there is no role for adjuvant therapy after surgery, several recent trials are
overcome with modern techniques. At present, no effective, clinically proven, adjuvant
exploring the role of targeted therapy.
therapy exists for RCC. The kidney cancer National Comprehensive Cancer Network
(NCCN) guidelines (version 1.2013) offers the following surgical options depending on
Patients who have local symptoms, such as hematuria, pain, hypertension, or
the stage 86 :
other paraneoplastic syndromes, may benet from palliative nephrectomy.
Spontaneous regression of metastatic renal cell cancer after nephrectomy has been
reported. In an extensive literature review, the incidence of regression of metastatic
Stage IA: Partial (preferred) or radical nephrectomy, active surveillance in foci induced by nephrectomy was
selected patients, or ablative techniques for nonsurgical candidates
0.8% (4 of 474 patients). 33 Cytoreductive surgery performed to prolong or increase the
Stage IB: Partial or radical nephrectomy response of metastatic disease in response to systemic therapy may be benecial. 98 ,99100,
101
Stage II and III: Radical nephrectomy
Stage IV: Nephrectomy and surgical metastasectomy for a solitary metastasis if
feasible, followed by systemic rst-line therapy; cytoreductive nephrectomy if Thermal Ablation
feasible when multiple metastatic sites, followed by systemic rst-line therapy; or Recently, the minimally invasive ablative technologies of cryoablation and
systemic rst-line therapy if surgery is not feasible. radiofrequency ablation (RFA) have emerged as potential treatment options for
clinically localized RCC, especially in the elderly or in patients with a solitary kidney or
comorbidities impeding surgery. Long-term oncologic efcacy for these modalities
Active surveillance should be considered for patients with localized disease and remains to be established. The most favorable lesions for this approach are <4 cm
short life expectancy, or signicant comorbidities placing them at a surgical risk. and in the periphery of the kidney. Relative contraindications for RFA and cryoablation
include distant metastases, tumors >5 cm, tumors in the hilum or central collecting
system, and life expectancy <1 year. A meta-analysis comparing cryoablation and
Surgery RFA suggested that cryoablation results in fewer re-treatments and improved local
A radical nephrectomy includes a perifascial resection of the kidney, perirenal fat, tumor control, and that cryoablation may be associated with a lower risk of metastatic
regional lymph nodes, and ipsilateral adrenal gland. It is the preferred treatment if the progression compared with RFA. 101
tumor extends into the inferior vena cava and usually requires the assistance of a
cardiovascular surgeon if there is a caval or atrial thrombus. An experienced team
should be involved in the context of a thrombus, as treatment-related mortality can
reach 10%. 86 This operation is undertaken by a thoracoabdominal or transabdominal
approach. Improved preoperative assessment with CT can identify patients who have Renal Stereotactic Body Radiotherapy
no signicant risk of adrenal gland involvement. 87 In 76% of cases, the adrenal gland Renal stereotactic body radiotherapy (SBRT) as an alternative to thermal ablation is in
can be spared at the time of surgery. The European Organisation for Research and its infancy. Beitler et al. 102 identied nine RCC patients with primary kidney tumors who
Treatment of Cancer 88 ( EORTC) conducted a randomized trial of radical nephrectomy received SBRT to 8 Gy ve fractions. The tumors ranged from 1.5 to 10 cm in
with or without an elective lymph node dissection, and there was no survival diameter. With a median follow up of 26.7 months, four of the nine patients were alive.
advantage between the two study groups. The incidence of unsuspected lymph node One of the nine patients failed in the ipsilateral kidney, away from the initial radiation
metastases was low (4%). 88 treatment volume, while the other eight patients had durable local control. One patient
had a radiation injury to the stomach resulting in a 30 lb weight loss in 1 month. 102 Wersall
et al. 103 reported eight patients treated with stereotactic radiotherapy to medically
inoperable primary tumors using a radiation treatment schedule of 8 Gy ve
fractions. Seven of the eight patients were locally controlled, and the median survival
Nevertheless, lymph node dissection does provide valuable prognostic information. exceeded 58 months. 103 Ponsky et al. 104 also reported their initial experience on three
patients treated with 4 Gy four fractions. Two of three patients had evidence of
Radical nephrectomies should be avoided if nephron-sparing surgery is feasible residual disease at these low doses at the time of partial nephrectomy 8 weeks later. 104
for T1a and T1b renal tumors. In this setting, nephron-sparing surgery has shown
equivalent outcomes to radical nephrectomy. 89,90 Radical nephrectomyinduced
chronic renal insufciency is associated with an increased risk of cardiovascular death
and death from any cause. 91 For this reason, nephron-sparing surgery is preferred in
T1a and T1b tumors. Nephron-sparing surgery is also preferred in patients with
hereditary RCC to preserve renal function and decrease the risk of cardiovascular Svedman et al. 105 reported their SBRT experience with seven patients who were
events. 92 In a matched pair analysis of 164 patients undergoing nephron-sparing treated for metastases from a malignant kidney to its contralateral counterpart.
surgery at the Mayo Clinic, the disease-free survival was 79%, which compared Dose/fractionation schedules varied between 10 Gy three fractions and 10 Gy
four fractions depending on target location and size. Local control was obtained in six
of seven patients and regained after
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Chapter 63 Cancer of the Kidney, Renal Pelvis, and Ureter 1251
TABLE 63.5 SURVIVAL AFTER NEPHRECTOMY OR NEOADJUVANT RADIOTHERAPY AND NEPHRECTOMY FOR RENAL
retreatment in the one patient whose lesion progressed. Side effects were generally after radiotherapy to a right-sided nephrectomy bed. Patients in this study received 55
mild, and in ve of the seven patients kidney function remained unaffected after Gy in 2.04 Gy daily fractions. 7 A second randomized study conducted by the
treatment. In two patients, the creatinine levels remained moderately elevated but Copenhagen Renal Cancer Study Group compared patients with stage II or III renal
dialysis was not required. 105 cell cancer treated with nephrectomy alone with patients who received nephrectomy
and adjuvant 50 Gy in 20 fractions to the kidney bed and regional ipsilateral and
TABLE 63.6 SURVIVAL AFTER NEPHRECTOMY OR NEPHRECTOMY AND ADJUVANT RADIOTHERAPY FOR RENAL CELL CARCINOMA, PROSPECTIVE RANDOMIZED TRIALS
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1252 Section III Clinical Radiation Oncology Part H Urinary Tract
immunotherapy based on results from phase III trials from the Southwest Oncology twice daily) or placebo. The median progression-free survival was signicantly longer
Group (SWOG) and the EORTC. A combined analysis of these trials showed that in those receiving sorafenib compared with placebo (5.5 months vs. 2.8 months, HR
median survival favored the surgery plus interferon (IFN)- group (13.6 vs. 0.44, 95% CI 0.35 to 0.55). Overall survival with sorafenib was not signicantly
prolonged compared to placebo. 119,120
7.8 months for IFN- alone). 99,100, 114,115 Treatment with IL-2 is associated with
considerable toxicity and is limited to patients with excellent performance status and Everolimus, an orally administered mTOR inhibitor, was studied in 410 patients
normal organ function. Currently, newer targeted agents are often favored over with metastatic clear cell RCC whose disease had progressed on VEGF
cytokine therapy as rst-line therapy owing to their efcacy and more favorable toxicity receptortyrosine kinase inhibitors (sunitinib, sorafenib). The median progression-free
prole. survival with everolimus was signicantly prolonged compared to placebo (4.9 months
vs. 1.9 months, HR 0.30, 95% CI 0.22 to
At present, seven targeted agents are U.S. Food and Drug Administration (FDA)
approved in the treatment for advanced RCC: sunitinib, sorafenib, pazopanib, 0.40). There was no statistically signicant difference in overall survival. 121 Other
temsirolimus, everolimus, axitinib, and bevacizumab in combination with IFN. As targeted agents in development are cediranib, tivozanib, and regorafenib.
rst-line therapy for relapsed or medically unresectable predominantly clear cell
carcinoma, the options are sunitinib (category 1), bevacizumab with IFN (category 1), Chemotherapy has limited use in RCC because it is one of the most
pazopanib (category 1), temsirolimus (category 1 for poor-prognosis patients), chemotherapy-resistant solid tumors. For patients with relapsed or medically
sorafenib and high dose IL-2 for selected patients. Subsequent category 1 therapy unresectable stage IV disease with nonclear cell histology, gemcitabine in
following a tyrosine kinase inhibitor for predominant clear cell carcinoma includes combination with doxorubicin or capecitabine has shown moderate activity in patients
everolimus or axitinib. Subsequent category 1 therapy following cytokine therapy for with sarcomatoid tumors and may be considered as rst-line therapy. 86
predominant clear cell carcinoma includes sorafenib, sunitinib, pazopanib, and
axitinib. For nonclear cell RCC, temsirolimus is a category 1 agent. 86
Metastasectomy
Patients with a solitary metastatic lesion have a 5-year survival rate of 24%
Sunitinib, an oral small-molecule multityrosine kinase inhibitor, was studied in a (compared with 4% for those with more than one metastatic focus), and they may
large multinational phase III trial of 750 patients with largely good- or benet from aggressive therapy. 122 The resection of one or a limited number of
intermediate-prognosis metastatic clear cell RCC who had not received prior systemic metastases in combination with nephrectomy or at relapse has been associated with a
therapy. Patients were randomly assigned to 6-week cycles of sunitinib (50 mg daily 13% to 50% 5-year survival in small series of selected patients. 123, 124125 Selected lung,
for 4 weeks, followed by 1 week off ) or IFN- bone, brain, liver, and even pancreatic metastases, among other sites, have been
treated using this approach.
(9 million units three times per week). The objective response rate was signicantly
increased with sunitinib (47% vs. 12% with IFN- ). Median progression-free survival
was signicantly prolonged with sunitinib (11 months vs. 5 months, hazard ratio [HR]
0.54). As well, overall survival was prolonged with sunitinib (median 26.4 months vs. Whole-Brain Radiotherapy for Brain Metastases
21.8 months, HR 0.82, 95% condence interval [CI] 0.673 to 1.001, p = . 051). 116 A retrospective study of 60 patients receiving whole-brain radiotherapy (WBRT) for
RCC brain metastases showed that local control at 6 months was 21% after 3 Gy 10
fractions and 57% after higher doses of 2 Gy 20 fractions or 3 Gy 15 fractions ( p = . 013).
Pazopanib, a multitargeted receptor tyrosine kinase inhibitor, was evaluated in a The local control at 12 months was 7% and 35%, respectively. The overall survival at
phase III trial of 435 patients who were previously untreated or had received only 6 months was 29% after 3 Gy 10 fractions and 52% after higher doses ( p = . 003).
cytokine therapy and were randomly assigned to pazopanib or placebo. There was a The overall survival at 12 months was 13% and 47%, respectively. The authors 126 concluded
signicant increase in progression-free survival with pazopanib compared with that escalating the WBRT dose beyond 3 Gy 10 fractions could improve the
placebo (median 9.2 months vs. 4.2 months, HR 0.46, 95% CI 0.34 to 0.62). 117 outcomes in RCC patients with brain metastases and proposed a randomized trial.
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Chapter 63 Cancer of the Kidney, Renal Pelvis, and Ureter 1253
FIGURE 63.1. Patient with renal cell carcinoma (RCC) who received 375 cGy 13 fractions over 5 weeks to a painful, fixed, and pulsatile cutaneous RCC metastasis. Appearance
after 3 fractions ( A) and complete response 6 months after the completion of treatment ( B). The patient had durable pain palliation without local recurrence until death. (From Gay HA,
et al. Complete response in a cutaneous facial metastatic nodule from renal cell carcinoma after hypofractionated radiotherapy. Dermatol Online J 2007;13:6; 2007 Dermatology
Online Journal.)
Conventional Radiotherapy for Extracranial Metastases fractions, or 6 Gy ve fractions. The actuarial 1-year spine tumor progression-free
Palliative radiotherapy is effective in relieving symptoms from metastatic RCC. 130131, 132, survival was 82.1%. At pretreatment baseline, 23% of patients were pain free; at 1
month and 12 months post-SBRT, 44% and 52% of patients were pain free,
133 A patient with a solitary bone metastasis may have a long survival time, and a
respectively. No grade 3 or 4 neurologic toxicity was observed. 137
sufcient radiation dose should be administered to allow durable pain relief. If surgery
is used to remove a metastatic lesion, postoperative radiotherapy is indicated to
prevent its recurrence. In a prospective phase II study using validated quality-of-life A unique case report showed how a large 7-cm RCC metastasis in the
questionnaires, Lee et al. 132 from the Princess Margaret Hospital demonstrated that parieto-occipital vertex of the skull was treated with SBRT to 7 Gy ve fractions. No
83% of patients treated for pain had experienced signicant pain relief with 30-Gy signicant bleeding was observed 5 weeks later at the time of tumor resection.
delivered in 10 fractions. DiBiase et al. 84 Histologically, the tumor was largely avascular and necrotic, and the authors 138 proposed
SBRT as a potential alternative to preoperative embolization.
observed a dose response in the palliative treatment of 107 patients with RCC. A
A potential added benet of extracranial stereotactic radiotherapy is what is called
biologically effective dose (BED) >50 Gy 10
( / ratio of 10) was associated with a statistically signicant increased rate of the abscopal effect, in which there is tumor response at a distance from the irradiated
response: 59% versus 39% ( p = 0.001). Figure 63.1 illustrates a painful RCC volume. Wersall et al. 139 observed an abscopal effect in 4 out of 28 RCC patients with
cutaneous metastasis that had a complete response after 375 cGy 13 fractions treated and untreated metastatic lesions. In these 4 patients, nonirradiated
(BED = 67 Gy 10) over 5 weeks. The lesion was treated with electrons, a custom bolus, metastases regressed either temporarily or seemingly permanently after treatment
and a 2-cm peripheral margin. 134 with SBRT of either the primary tumor or other metastatic lesions. The authors 139 ndings
argued for a more active and liberal use of SBRT in metastatic RCC. They suggested
that further studies were necessary to dene the underlying mechanisms behind such
Stereotactic Body Radiation Therapy for responses or to combine SBRT with immunomodulating agents.
Extracranial Metastases
In a series of 50 patients with metastatic RCC, Wersall et al. 103
reported that stereotactically delivered radiation to sites including the lung, liver, and
adrenal resulted in complete regression in 30% of cases and either partial regression
or stabilization of the lesions in 60%. Of 162 treated tumors, only 3 tumors recurred. Ongoing Phase III Clinical Trials
Dose and fractionation ranged from 8 Gy four fractions, 10 Gy There are numerous clinical trials taking place in advanced RCC. Many of these trials
are employing antiangiogenesis agents, thymidine kinase inhibitors, mTOR inhibitors,
four fractions, and 15 Gy three fractions all delivered in 1 week. and immunological therapies, alone or in combination.
A retrospective study of 17 patients with metastatic melanoma (28 lesions) and 13
patients with RCC (25 lesions) to the lung, liver, and bone concluded that to achieve
high rates of durable control, SBRT of at least 16 Gy three fractions were necessary. 135 Renal Pelvis and Ureter Carcinoma
Another retrospective study of 126 extracranial metastases in 103 patients treated Surgery is the therapeutic foundation for the management of renal pelvis and ureter
with single fractions observed that RCC displayed a profound dose-response effect, carcinoma. The bladder cancer NCCN guidelines (version 1.2013) recommend the
with an 80% local relapse-free survival at the high-dose level (23 to 24 Gy) versus following treatment options for renal pelvis low-grade tumors: nephroureterectomy
37% at low doses ( 22 Gy) ( p = . 04). 136 with a cuff of bladder, a nephron-sparing procedure, or endoscopic resection with or
without postsurgical intrapelvic chemotherapy or bacille Calmette-Guerin (BCG). 140 High-grade
renal pelvis tumors or large tumors that invade the renal parenchyma have the
Further analysis of RCC patients revealed that a single 24-Gy dose had a 3-year local following management options: nephroureterectomy with a cuff of bladder and
progression-free survival of 88%. 85
regional lymphadenectomy,
In study of 48 patients (55 lesions) with metastatic RCC to the spine, patients
received 24 Gy one fraction, 9 Gy three
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1254 Section III Clinical Radiation Oncology Part H Urinary Tract
with neoadjuvant chemotherapy in selected patients, extrapolating from bladder the course of the ureter to the entire bladder, and the paracaval and para-aortic lymph
cancer series. nodes (Fig. 63.2). The tumor bed or residual tumor was targeted in 14 patients. The
The management of ureter tumors depends on the location of the tumorupper, median radiation dose administered was 50 Gy. There was a signicant difference
mid, or distaland on disease extent. Neoadjuvant chemotherapy may be considered between the survival rates for these groups based on patients with stage T3 and T4
in selected patients. 141 Tumors in the upper ureter are more commonly treated with cancer. A signicant difference was observed in the bladder tumor relapse rate
nephroureterectomy with a cuff of bladder and regional lymphadenectomy for between the irradiated and nonirradiated bladder groups ( p = . 004). The authors 144 concluded
high-grade tumors. Low-grade tumors may be managed endoscopically. that radiotherapy may improve the overall survival for patients with T3 and T4 cancer
of the renal pelvis or ureter and may delay bladder tumor recurrences.
Tumors in the mid portion of the ureter can be managed according to grade and
size. Small, low-grade tumors can be treated with ureteroureterostomy, endoscopic
resection, or nephroureterectomy with a cuff of bladder with or without regional The patterns of failure were described in 252 patients undergoing surgery at the
lymphadenectomy. High-grade lesions are managed with nephroureterectomy with a University of Texas Southwest Medical Center for urothelial carcinoma of the upper
urinary tract. 79
cuff of bladder and regional lymphadenectomy with consideration of neoadjuvant
chemotherapy in selected patients. Local recurrence occurred only 9% of the time, whereas new invasive urothelial
tumors or distant metastases occurred in 69% and 22% of cases, respectively.
Isolated local recurrences were rare. Another series from the Princess Margaret
Finally, distal ureteral tumors may be managed with a distal ureterectomy and Hospital conrms the high rate of distant metastases. Although local failure occurred
reimplantation of the ureter (ideal if feasible), endoscopic resection, or in 35% of patients with locally advanced disease, most patients also experienced
nephroureterectomy with a cuff of bladder and regional lymphadenectomy for distant metastases as well. 145
high-grade tumors. Neoadjuvant chemotherapy may be considered in select patients.
For both renal pelvis and ureter tumors, once the pathologic staging is obtained, Systemic Chemotherapy
patients with pathologic stage pT2, pT3, pT4, or N+ should be considered for adjuvant The pathologic similarity of urothelial carcinoma of the renal pelvis and ureter to
chemotherapy with or without radiotherapy. bladder cancer has encouraged medical oncologists to use similar chemotherapeutic
regimens in the management of upper-tract urothelial carcinomas. The MVAC
regimen (methotrexate, vinblastine, doxorubicin, and cisplatin) has objective response
Surgery rates of almost 70% in patients with metastatic urothelial carcinoma of the bladder,
Radical nephroureterectomy is the only potentially curative treatment for most patients ureter, and kidney. 146,147 Gemcitabine plus cisplatin is also effective in urothelial
with urothelial carcinoma of the renal pelvis or ureter. This operation includes removal carcinoma. Palliative chemotherapy may be considered in patients with metastatic
of the contents of Gerotas fascia, including the ipsilateral ureter with a cuff of bladder disease.
at its distal extent. Less radical surgeries have been plagued by high local or regional
recurrence rates, sometimes approaching 30%. 142 Hall et al. 79 reported an increase rate
of recurrence when parenchymal-sparing procedures were performed. Conservative A series of 31 patients treated with adjuvant radiotherapy for nonmetastatic
surgical excision should be considered only in patients with low-grade, low-stage, urothelial cancer of the upper urinary tract was reported by Czito et al. 148 Nine patients
solitary tumors in whom radical nephrectomy is not indicated because of poor kidney also received chemotherapy consisting of methotrexate, cisplatin, and vinblastine
function or an absent contralateral kidney. prior to receiving radiation concurrent with cisplatin. The 5-year locoregional control
rate was 67%. The 5-year overall and diseasespecic survival appeared to be
improved with the administration of concurrent chemotherapy. The overall survival for
patients receiving concurrent chemotherapy and radiotherapy was 67% compared to
27% receiving postoperative radiation alone ( p = . 01). The disease-free survival for
Adjuvant Radiotherapy patients receiving concurrent chemotherapy and radiotherapy was 76% compared to
There are no randomized trials on the role of postoperative radiotherapy in patients 41% receiving postoperative radiation alone ( p = . 06). In circumstances in which
who have had a complete resection of an upper urinary tract cancer. Tumors of the conservative resection is performed, postoperative radiotherapy should be
renal pelvis and ureter have a signicantly high local recurrence rate after considered. Conservative surgical options in selected cases include laparoscopic
nephroureterectomy, particularly in patients with high-grade tumors or deep invasion. 53 nephroureterectomy, nephrectomy and partial ureterectomy, endoscopic resection,
Retrospective studies suggest that adjuvant radiotherapy may diminish the likelihood and fulguration. The role of lymph node dissection in this disease is unclear. Patients
of local recurrence, although it does not appear to have an impact on overall survival who have the highest risk of lymph node metastases also have a high risk of systemic
or reduction of future distant metastases. 34,143 disease.
RADIOTHERAPY TECHNIQUES
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Chapter 63 Cancer of the Kidney, Renal Pelvis, and Ureter 1255
A B
E F
FIGURE 63.2. Dose distribution of a patient with renal pelvis cancer and beam arrangements of 0-degree, 129-degree, and 229-degree gantry.
A: Renal fossa. B,C: Course of ureter. D: Bladder. Digitally reconstructed radiograph for views of 0-degree gantry ( E) and 90-degree gantry ( F).
Internal pink and yellow lines represent the clinical tumor volume (CTV) 50 and CTV 40, respectively. (From Chen B, et al. Radiotherapy may improve overall survival of patients with T3
and T4 transitional cell carcinoma of the renal pelvis or ureter and delay bladder tumour relapse. BMC Cancer
2011;11:297; 2011 Chen et al; licensee BioMed Central Ltd.)
There are no established dose constraints for sparing the remaining kidney after mean bilateral kidney dose <15 to 18 Gy and a bilateral kidney dose-volume
nephrectomy or in the palliative setting when both kidneys are present. In the context histogram (DVH) with a V 12 < 55%, V 20 < 32%, V 23
of two normal kidneys, the Qualitative Analyses of Normal Tissue Effects in the Clinic < 30%, and V 28 < 20%. 149 The dose to the stomach should be kept at <45 Gy, and the
(QUANTEC) Kidney Cancer Panel recommended a small bowel V 45 < 195 cc when it is contoured as a bowel bag 150 ( Fig. 63.3). The male
and female
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1256 Section III Clinical Radiation Oncology Part H Urinary Tract
0.9
0.8
0.7
0.6
Norm. 0.5
volume
0.4
0.3
0.2
0.1
Spleen
Cord
0.0 0
1,000 2,000 3,000 4,000 5,000 6,000
A B Dose (cGy)
FIGURE 63.3. Patient with metastatic clear cell renal cell carcinoma (RCC) who developed a painful, destructive, 55-cc metastasis in the left 12th rib. Treatment plan ( A) and
dose-volume histogram ( B) showing the normalized volume versus dose (cGy). The metastasis was treated with 10 Gy five fractions using a six-field step and shoot, 6-MV IMRT
technique. The isodose-based methodology was used to evaluate the plan. 158 The skin was limited to the 40% isodose (400 cGy five fractions), the spinal cord to the 30% isodose
(300 cGy five fractions), and the spleen to the 10% isodose (100 cGy five fractions) or less as feasible. The cyan-filled contour is the gross tumor volume (GTV). Doses to the
bowel, liver, remaining kidney, and duodenum were well below tolerance. Patient was pain free one month later.
Radiation Therapy Oncology Group (RTOG) normal pelvis atlases illustrate how to regional lymphatics may improve resectability. 107 Multiple-eld techniques, similar to
contour the bowel bag (accessible at those described for adjuvant radiotherapy, should be considered in patients receiving
http://www.rtog.org/CoreLab/ContouringAtlases.aspx). The mean liver dose should be preoperative treatment.
kept at <30 to 32 Gy, excluding patients with pre-existing liver disease or
hepatocellular carcinoma who have a lower tolerance. Sparing at least 700 cc of liver CT-based treatment planning contributes to good local control with minimal
from radiation is another potential strategy to avoid complications. 151 There are no morbidity. Careful denition of the target volume to encompass the nephrectomy bed,
recognized splenic or adrenal dose constraints. Nevertheless, based on the spleens lymph node drainage sites, and surgical clips on the planning CT scan is important.
exquisite radiosensitivity and experience with palliative radiotherapy for Exclusive use of anterior- and posterior-eld arrangements, particularly on the right
myeloproliferative disorders, 152 it seems prudent to limit the spleen to a total of 5 to 10 side, is likely to result in irradiation of large volumes of bowel and liver beyond
Gy. The spinal dose should be limited to an absolute maximum of 45 Gy. tolerance. The use of multiple beams is paramount for protecting the surrounding
normal structures. Total radiation doses of 45 to 50 Gy (1.8 to 2 Gy per fraction) to the
nephrectomy bed and regional lymph nodes with a boost to small volumes of
microscopic or gross residual disease of 10 to 15 Gy (total dose 50 to 60 Gy) are
appropriate. Stein et al. 157 reported two scar recurrences and recommended that the
Renal Cell Carcinoma incision site be included in the target volume. If the scar cannot be covered without
Neoadjuvant or adjuvant radiotherapy is not routinely recommended for patients with increasing the amount of normal tissue irradiated, an additional electronbeam eld to
RCC. However, there may be special cases where the clinician may consider treat the scar may be considered.
neoadjuvant radiotherapy to improve respectability or adjuvant radiotherapy if there
are clinical tumor features suggestive of a high risk of local recurrence. Careful
planning is paramount because ignoring any of the critical structures surrounding the
kidney or nephrectomy bed could result in serious, even fatal, patient toxicity.
Figure 63.3 illustrates a patient with metastatic clear cell RCC, with sarcomatoid
and rhabdoid differentiation, status post left radical nephrectomy, pT3aN1M1. The
Patients receiving radiotherapy to the kidney may be simulated supine, arms up, kidney tumor was Fuhrman nuclear grade IV and 15.5 cm in diameter. The patient
using a wing board or alpha cradle, a wire on the surgical scar, and a planning CT was treated with temsirolimus, pazopanib, bevacizumab, and nally Adriamycin plus
scan. The kidneys are mobile organs and move vertically within the retroperitoneum gemcitabine with some objective response. The patient developed a painful,
an average of 0.9 to 1.3 cm, and as much as 4 cm during normal respiration. 153154, 155 In destructive, 55-cc metastasis in the left 12th rib. The metastasis was treated with 10
going from the supine to upright position, the kidneys can shift inferiorly between 0.5 Gy ve fractions using a six-eld (RPO 210, LAO 60, LT LAT 90, LPO 120, LPO 150,
cm and PA) step and shoot, 6-MV IMRT technique. The isodose-based methodology was
used to evaluate the plan and is explained in detail in Gay et al. 158 The skin was limited
7.5 cm with an average of 3.6 cm. 156 This nding, although critical for total body to the 40% isodose (400 cGy ve fractions), the spinal cord to the 30% isodose (300
irradiation treatments, further highlights the mobility of the kidneys. cGy ve fractions), and the spleen to the 10% isodose (100 cGy ve fractions) or
less as feasible. Doses to the bowel, liver, remaining kidney, and duodenum were well
The high complication rates reported in the prospective trials of postoperative below tolerance (Fig.
radiotherapy have taught radiation oncologists an important lesson regarding radiation
therapy planning, patient selection, and the tolerance of the upper abdominal viscera.
Intensity-modulated radiotherapy (IMRT) may be a reasonable consideration owing to
the sensitivity of adjacent surrounding structures. If IMRT is considered, a plan to
manage the uncertainties in target localization such as fourdimensional (4D) CT 63.3A). Daily imaging with two-dimensional (2D):2D match and cone-beam CT was
treatment planning, image-guided radiotherapy (IGRT), abdominal immobilization used prior to the delivery of the ve fractions over 3 weeks.
devices, gating, or breathing control needs to be considered. Renal function scans
may assist in the treatment planning or patient selection process, although this has Because of the possibility of long survival even in the presence of distant
not been formally studied. metastases, aggressive treatment for palliation should be considered in patients who
have limited metastatic disease with good performance status. Treatment elds
should encompass metastatic foci with adequate (2- to 3-cm) margins. (See the
following previous sections: Conventional Radiotherapy for Extracranial Metastases,
In unresectable lesions, 40 to 50 Gy neoadjuvant radiotherapy (1.8 to 2 Gy per Whole-Brain Radiotherapy for
fraction) directed to the kidney tumor and
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Chapter 63 Cancer of the Kidney, Renal Pelvis, and Ureter 1257
Brain Metastases, and Stereotactic Radiosurgery for Brain Metastases.) expected from irradiation of the upper abdomen and pelvis. These side effects include
nausea, vomiting, diarrhea, and abdominal cramping. Patients with right-sided tumors
may have signicant portions of the liver irradiated, and radiation-induced liver
Renal Pelvis and Ureter Carcinoma damage is possible. The Copenhagen Renal Cancer Study Group reported that 12
Adjuvant radiotherapy has been used in the management of renal pelvis and ureter (44%) of 27 patients developed signicant complications: 3 patients had biochemical
cancers. For elective radiotherapy, the clinical target volume should include the renal changes indicating radiation hepatitis, 3 patients had duodenum and small bowel
fossa, the course of the ureter to the bladder, the entire bladder, and the paracaval stenosis, and 6 patients had duodenum and small bowel bleeding. 110 Surgery was
and para-aortic lymph nodes 144 ( Fig. 63.2). As in RCC, CT-based planning may performed on 4 of 9 patients with bowel-related radiotherapy complications, and 5
facilitate dosimetric coverage of the regions at risk while minimizing dose to normal patients died of treatment-related complications. The total radiation dose in this study
tissues. Radiation doses of 45 to 50 Gy at 1.8 to 2 Gy per day are appropriate to treat was 50 Gy given in 2.5-Gy fractions per daya fractionation schedule that may
subclinical and microscopic disease. For more extensive disease (e.g., multiple account for the high rate of complications. Fugitt et al. 109 also reported four cases of
positive nodes), R1 (microscopic positive margins) or R2 (macroscopic residual liver failure among 52 patients who received postoperative radiotherapy.
margins) resections, a boost of 5 to 10 Gy should be considered. For unresectable or
gross residual disease, higher doses may be necessary. In this case, multiple-eld
arrangements including oblique and lateral elds with eld reductions are important to
minimize toxicity to surrounding normal structures (Fig. 63.2). CT-based simulation,
three-dimensional (3D) treatment planning, and contrast-enhanced radiographs are
helpful in dening the radiotherapy target volume. IMRT can be considered if organ The complication rate after radiotherapy for tumors of the kidney and upper
motion is managed to avoid underdosing the planning target volume. Chemotherapy urinary tract is related to the total dose, fraction size, and technique of irradiation.
ACKNOWLEDGMENTS
Thanks to Michael Watts, MS, CMD, for masterfully planning the case in Figure 63.3
FOLLOW-UP and obtaining screen captures of the plan.
36. Skinner DG, et al. Diagnosis and management of renal cell carcinoma. A clinical and pathologic study of 309
cases. Cancer 1971;28(5):11651177.
40. Gold PJ, Fefer A, Thompson JA. Paraneoplastic manifestations of renal cell carcinoma. Semin Urol Oncol 1996;14(4):216222.
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Renal Pelvis and Ureter Carcinoma after nephrectomy. Arch Intern Med 1993; 153(17):20432045.
Patients with urothelial carcinoma of the upper urinary tract are at a high risk of 46. Jayson M, Sanders H. Increased incidence of serendipitously discovered renal cell carcinoma. Urology 1998;51(2):203205.
urothelial tumors of the bladder, thus monitoring with cystoscopy at periodic intervals
49. McClennan BL. Oncologic imaging. Staging and follow-up of renal and adrenal carcinoma. Cancer 1991;67(4
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with CT or MRI and/or ureteroscopy may be necessary. The NCCN Bladder Cancer 50. Kidney. In: Edge SB, et al. AJCC cancer staging manual, 7th ed. New York:
Springer, 2010:479490.
Panel recommends a cystoscopy every 3 months for 1 year, then at increasing
51. Renal pelvis and ureter. In: Edge SB, et al. AJCC cancer staging manual, 7th ed.
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urography, retrograde pyelogram, ureteroscopy, or MRI urogram) of the upper tract 52. Bruno D, et al. Genitourinary complications of sickle cell disease. J Urol 2001;
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collecting system at 3- to 12-month intervals is recommended. Imaging to exclude 54. National Cancer Institute. SEER cancer statistics review, 19752008, based on November 2010 SEER data
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considered. 55. Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. J Urol 2001;166(5):16111623.
56. Hudes G, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356(22):22712281.
57. Motzer RJ, et al. Survival and prognostic stratication of 670 patients with advanced renal cell carcinoma. J
Clin Oncol 1999;17(8):25302540.
60. Rabinovitch RA, et al. Patterns of failure following surgical resection of renal cell carcinoma: implications for
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62. Pantuck AJ, et al. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benets of 110. Kjaer M, Frederiksen PL, Engelholm SA. Postoperative radiotherapy in stage II and III renal adenocarcinoma.
immunotherapy. Cancer 2003;97(12):29953002. A randomized trial by the Copenhagen Renal Cancer Study Group. Int J Radiat Oncol Biol Phys 1987;13(5):665672.
63. Vasselli JR, et al. Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal
cell carcinoma. J Urol 2001;166(1):6872. 111. Aref I, Bociek RG, Salhani D. Is post-operative radiation for renal cell carcinoma justied? Radiother Oncol 1997;43(2):155157.
64. Kjaer M. The treatment and prognosis of patients with renal adenocarcinoma with solitary metastasis. 10
year survival results. Int J Radiat Oncol Biol Phys 112. Yossepowitch O, et al. Positive surgical margins at partial nephrectomy: predictors and oncological
1987;13(4):619621. outcomes. J Urol 2008;179(6):21582163.
66. Fuhrman SA, Lasky LC, Limas C. Prognostic signicance of morphologic parameters in renal cell 113. Tunio MA, Hashmi A, Ra M. Need for a new trial to evaluate postoperative radiotherapy in renal cell
carcinoma. Am J Surg Pathol 1982;6(7):655663. carcinoma: a meta-analysis of randomized controlled trials. Ann Oncol 2010;21(9):18391845.
67. Lohse CM, et al. Comparison of standardized and nonstandardized nuclear grade of renal cell carcinoma to
predict outcome among 2,042 patients. Am J Clin Pathol 2002;118(6):877886. 114. Flanigan RC, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J
Urol 2004;171(3):10711076.
68. Bretheau D, et al. Prognostic value of nuclear grade of renal cell carcinoma. 115. Polcari AJ, et al. The role of cytoreductive nephrectomy in the era of molecular targeted therapy. Int J Urol 2009;16(3):227233.
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70. Kattan MW, et al. A postoperative prognostic nomogram for renal cell carcinoma. 116. Motzer RJ, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients
J Urol 2001;166(1):6367. with metastatic renal cell carcinoma. J Clin Oncol 2009; 27(22):35843590.
71. Frank I, et al. An outcome prediction model for patients with clear cell renal cell carcinoma treated with
radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol 2002;168(6):23952400.117. Sternberg CN, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a
randomized phase III trial. J Clin Oncol 2010;28(6):10611068.
72. Zisman A, et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin 118. Escudier B, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a
Oncol 2001;19(6):16491657. randomised, double-blind phase III trial. Lancet
73. Thompson RH, Kwon ED. Signicance of B7-H1 overexpression in kidney cancer. 2007;370(9605):21032111.
Clin Genitourin Cancer 2006;5(3):206211. 119. Escudier B, et al. Sorafenib for treatment of renal cell carcinoma: nal efcacy and safety results of the phase
74. Bui MH, et al. Prognostic value of carbonic anhydrase IX and KI67 as predictors of survival for renal clear III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009;27(20):33123318.
cell carcinoma. J Urol 2004;171(6 Pt 1):24612466.
75. Jiang Z, et al. Analysis of RNA-binding protein IMP3 to predict metastasis and prognosis of renal-cell 120. Escudier B, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J
carcinoma: a retrospective study. Lancet Oncol 2006; 7(7):556564. Med 2007;356(2):125134.
121. Motzer RJ, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: nal results and analysis of
76. Raman JD, et al. Impact of tumor location on prognosis for patients with upper tract urothelial carcinoma prognostic factors. Cancer 2010;116(18):42564265.
managed by radical nephroureterectomy. Eur Urol 124. Piltz S, et al. Long-term results after pulmonary resection of renal cell carcinoma metastases. Ann Thorac Surg 2002;73(4):10821087.
2010;57(6):10721079.
77. Corrado F, et al. Transitional cell carcinoma of the upper urinary tract: evaluation of prognostic factors by 125. Zerbi A, et al. Pancreatic metastasis from renal cell carcinoma: which patients benet from surgical
histopathology and ow cytometric analysis. J Urol resection? Ann Surg Oncol 2008;15(4):11611168.
1991;145(6):11591163. 126. Rades D, Heisterkamp C, Schild SE. Do patients receiving whole-brain radiotherapy for brain metastases
79. Hall MC, et al. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary from renal cell carcinoma benet from escalation of the radiation dose? Int J Radiat Oncol Biol Phys 2010;78(2):398403.
tract: a 30-year experience in 252 patients.
Urology 1998;52(4):594601. 127. Shuto T, et al. Treatment strategy for metastatic brain tumors from renal cell carcinoma: selection of gamma
80. Akdogan B, et al. Prognostic signicance of bladder tumor history and tumor location in upper tract knife surgery or craniotomy for control of growth and peritumoral edema. J Neurooncol 2010;98(2):169175.
transitional cell carcinoma. J Urol 2006;176(1):4852.
81. Park S, et al. The impact of tumor location on prognosis of transitional cell carcinoma of the upper urinary 128. Kim WH, et al. Early signicant tumor volume reduction after radiosurgery in brain metastases from renal cell
tract. J Urol 2004;171(2 Pt 1):621625. carcinoma results in long-term survival. Int J Radiat Oncol Biol Phys 2012;82(5):17491755.
82. Mullerad M, et al. Bladder cancer as a prognostic factor for upper tract transitional cell carcinoma. J Urol 2004;172(6
Pt 1):21772181. 129. Kano H, et al. Outcome predictors of gamma knife radiosurgery for renal cell carcinoma metastases. Neurosurgery
83. Catto JW, et al. Promoter hypermethylation is associated with tumor location, stage, and subsequent 2011;69(6):12321239.
progression in transitional cell carcinoma. J Clin Oncol 2005; 23(13):29032910. Epub 2005 Mar 7. 132. Lee J, et al. A phase II trial of palliative radiotherapy for metastatic renal cell carcinoma. Cancer 2005;104(9):18941900.
84. DiBiase SJ, et al. Palliative irradiation for focally symptomatic metastatic renal cell carcinoma: support for 134. Gay HA, et al. Complete response in a cutaneous facial metastatic nodule from renal cell carcinoma after
dose escalation based on a biological model. J Urol hypofractionated radiotherapy. Dermatol Online J 2007;13(4):6.
1997;158(3 Pt 1):746749.
85. Zelefsky MJ, et al. Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided 135. Stinauer MA, et al. Stereotactic body radiation therapy for melanoma and renal cell carcinoma: impact of
intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma. Int J Radiat Oncol single fraction equivalent dose on local control. Radiat Oncol 2011;6(1):34.
Biol Phys 2012;82(5):17441748.
86. National Comprehensive Cancer Network. Kidney cancer. In: NCCN clinical prac- 136. Greco C, et al. Predictors of local control after single-dose stereotactic imageguided intensity-modulated
tice guidelines in oncology 2012, Version 1.2013. Available at: http://www.nccn. radiotherapy for extracranial metastases. Int J Radiat Oncol Biol Phys 2011;79(4):11511157.
org/professionals/physician_gls/pdf/kidney.pdf.
87. Gill IS, et al. Adrenal involvement from renal cell carcinoma: predictive value of computerized tomography. J 137. Nguyen Q-N, et al. Management of spinal metastases from renal cell carcinoma using stereotactic body
Urol 1994;152(4):10821085. radiotherapy. Int J Radiat Oncol Biol Phys 2010; 76(4):11851192.
88. Blom JH, et al. Radical nephrectomy with and without lymph-node dissection: nal results of European
Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol 2009;55(1):2834. 138. Mitera G, et al. Preoperative stereotactic body radiotherapy to a skull renal cell metastasis: an alternative to
preoperative embolization? J Palliat Med 2011;14(2): 157160.
89. Hollingsworth JM, et al. Surgical management of low-stage renal cell carcinoma: technology does not
supersede biology. Urology 2006;67(6):11751180. 139. Wersall PJ, et al. Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in
90. Leibovich BC, et al. Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and metastatic renal cell carcinoma. Acta Oncol 2006; 45(4):493497.
7 cm results in outcome similar to radical nephrectomy. J Urol 2004;171(3):10661070.
140. National Comprehensive Cancer Network. Bladder cancer. In: NCCN clinical
91. Weight CJ, et al. Nephrectomy induced chronic renal insufciency is associated with increased risk of practice guidelines in oncology 2012, Version 1.2013 Available at: http://www.
cardiovascular death and death from any cause in patients with localized cT1b renal masses. J Urol 2010;183(4):13171323. nccn.org/professionals/physician_gls/pdf/bladder.pdf.
141. Audenet F, et al. The role of chemotherapy in the treatment of urothelial cell carcinoma of the upper urinary
92. Weight CJ, et al. Partial nephrectomy is associated with improved overall survival compared to radical tract (UUT-UCC). Urol Oncol 2010 Sep 28. [Epub ahead of print].
nephrectomy in patients with unanticipated benign renal tumours. Eur Urol 2010;58(2):293298.
143. Cozad SC, et al. Adjuvant radiotherapy in high stage transitional cell carcinoma of the renal pelvis and ureter.
93. Lau WK, et al. Matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with Int J Radiat Oncol Biol Phys 1992;24(4):743
unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc 2000;75(12):12361242. 745.
144. Chen B, et al. Radiotherapy may improve overall survival of patients with T3/T4 transitional cell carcinoma of
94. McKiernan J, et al. Natural history of chronic renal insufciency after partial and radical nephrectomy. Urology 2002;59(6):816820.
the renal pelvis or ureter and delay bladder tumour relapse. BMC Cancer 2011;11(1):297.
97. Whang M, et al. The incidence of multifocal renal cell carcinoma in patients who are candidates for partial 145. Catton CN, et al. Transitional cell carcinoma of the renal pelvis and ureter; outcome and patterns of relapse in
nephrectomy. J Urol 1995;154(3):968970; discussion 970971. patients treated with postoperative radiation.
Urol Oncol 1996;2:171176.
98. Bennett RT, et al. Cytoreductive surgery for stage IV renal cell carcinoma. J Urol 148. Czito B, et al. Adjuvant radiotherapy with and without concurrent chemotherapy for locally advanced
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101. Kunkle DA, Uzzo RG. Cryoablation or radiofrequency ablation of the small renal mass: a meta-analysis. Cancer J Urol 2004;172(4 Pt 1):12711275.
2008;113(10):26712680. 149. Dawson LA, et al. Radiation-associated kidney injury. Int J Radiat Oncol Biol
102. Beitler JJ, et al. Denitive, high-dose-per-fraction, conformal, stereotactic external radiation for renal cell Phys 2010;76(3 Suppl):S108S115.
carcinoma. Am J Clin Oncol 2004;27(6):646648. 150. Kavanagh BD, et al. Radiation dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol
103. Wersall PJ, et al. Extracranial stereotactic radiotherapy for primary and metastatic renal cell carcinoma. Radiother Phys 2010;76(3 Suppl):S101S107.
Oncol 2005;77(1):8895. Epub 2005 Jun 20. 151. Pan CC, et al. Radiation-associated liver injury. Int J Radiat Oncol Biol Phys
104. Ponsky LE, et al. Renal radiosurgery: initial clinical experience with histological evaluation. Surg Innov 2007;14(4):265269. 2010;76(3 Suppl):S94S100.
155. Van Sornsen de Koste JR, et al. Renal mobility during uncoached quiet respiration: an analysis of 4DCT
105. Svedman C, et al. Stereotactic body radiotherapy of primary and metastatic renal lesions for patients with scans. Int J Radiat Oncol Biol Phys 2006;64(3):799803.
only one functioning kidney. Acta Oncol 2008;47(8):15781583. 157. Stein M, et al. The value of postoperative irradiation in renal cell cancer.
106. Van der Werf-Messing B. Proceedings: carcinoma of the kidney. Cancer 1973;32(5): Radiother Oncol 1992;24(1):4144.
10561061. 158. Gay HA, et al. Isodose-based methodology for minimizing the morbidity and mortality of thoracic
107. Van der Werf-Messing B, van der Heul RO, Ledeboer RC. Renal cell carcinoma trial. Strahlentherapie hypofractionated radiotherapy. Radiother Oncol 2009; 91(3):369378.
[Sonderb] 1981;76:169715.
108. Juusela H, et al. Preoperative irradiation in the treatment of renal adenocarcinoma. Scand J Urol Nephrol 1977;11(3):277281.
159. Lam JS, et al. Postoperative surveillance protocol for patients with localized and locally advanced renal cell
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109. Fugitt RB, Wu GS, Martinelli LC. An evaluation of postoperative radiotherapy in hypernephroma discussion 472; quiz 801.
treatment-a clinical trial. Cancer 1973;32(6):13321340.
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Chapter 64 Bladder Cancer 1259
Chapter 64
Bladder Cancer
Nicholas James, Richard T. Bryan, Richard Viney, Prashant Patel, and Syed A. Hussain
The basic management of bladder tumors has remained essentially unchanged for superiorly to the bladder, which is potentially a critical site to consider when planning
over 50 years, and in spite of its importance in terms of incidence, prognosis, and radiotherapy, particularly in men. In women it is associated with the uterus and ileum.
cost, bladder cancer research remains signicantly underfunded. 1 The base of the bladder is posterior and is separated from the rectum by the vas
deferens, seminal vesicles, and ureters in the male, and by the uterus and vagina in
Every aspect of the perceptions and management of this disease requires change; the female. The seminal vesicles form a V-shaped structure at the base of the
bladder, with the vas deferens entering the middle of the V. The ureters enter into
departing from the use of the term supercial bladder cancer is just the rst step, 2 because
the term is both inaccurate and implies an inappropriate lack of importance. In the bladder slightly superior and lateral to the seminal vesicles, with the vas deferens
particular, given the very high costs to health care systems from long-term coursing above and in a caudal direction to the ureters. Again these relations are
surveillance and treatment of the disease, 3 it is particularly surprising that there has not critical as enlarging tumors either at the base or in the prostate can involve the ureters
The bladder is described as having an apex, a superior surface, two inferolateral WORLDWIDE
surfaces, a base or posterior surface, a trigone, and a neck. The apex reaches a short Cancer Site Cases All Cases (%) Deaths All Deaths (%)
distance cephalad above the pubic bone and ends as a brous cord, the remnant of
Prostate 899,102 7.1 258,133 3.4
the fetal urachus, which connects the bladder to the allantois. The urachus lies
Bladder 382,660 3.0 150,282 2.0
anterior to the peritoneal cavity and is important as tumors can arise in the urachal
Kidney 273,518 2.2 116,368 1.5
remnant. The superior surface is covered by the peritoneum, again an important
Testis 52,323 0.4 9,874 0.1
anatomical feature as it means that there is bowel lying
All cancers 12,662,554 7,564,802
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1260 Section III Clinical Radiation Oncology Part H Urinary Tract
specic challenges, mainly due to the aging population and increased life-expectancy. are remarkably similar at around 45% to 50%, 4,5 despite a higher rate of pelvic
Within two large cohorts separated by 15 years (1991 to 1992 and 2005 to 2010), recurrence after radiotherapy versus surgery, suggesting that prognosis is driven by
researchers have recently demonstrated an increase in the median age at the presence or otherwise of metastases at the time of diagnosis, driven by
presentation of 4 years, with an increase from 13% to 24% in the proportion of tumor-related factors such as stage and grade. 6
patients over 80 years old. 16 Overall around 75% to 80% of patients with bladder
cancer are male, mostly reecting historic trends in cigarette smoking.
Metastatic Disease
A minority of patients (probably <10%) present with metastatic disease; most patients
There are well-known associations of squamous cell bladder carcinomas with
with metastatic disease have had prior treatment for apparently localized disease.
bilharzia caused by Schistosoma haematobium infection in Africa, particularly in Egypt. 17
Metastatic disease carries a poor prognosis. Overall survival from diagnosis of
Aromatic amines, polycyclic aromatic and chlorinated hydrocarbons, arsenic-laced
metastasis is difcult to ascertain as many patients receive only palliative treatment. A
drinking water, aristolochic acid, cyclophosphamide exposure, and a range of
minority of patients are t for systemic chemotherapy, and there are good data on
industrial chemicals have been implicated in urothelial carcinogenesis. Importantly, as
with most carcinogens, there are variations in individual susceptibility, and the basis of outcomes with chemotherapy. In essence, extensive randomized studies, mostly
some of these polymorphisms regulating varied detoxication mechanisms has been carried out in the 1980s and 1990s, have demonstrated the superiority of
identied. 18 With increasing awareness of these industrial associations, regulation of cisplatinum-based combinations over those containing other drugs or cisplatinum
these processes means that these cases are becoming increasingly rare in the alone. 31 Of the platinumbased combinations, methotrexate/vinblastine/doxorubicin
developed world. Their principal importance now is that those with industrially linked (Adriamycin)/cisplatinum (MVAC) 32 and gemcitabine/cisplatinum (GC) 33 have proven to
tumors may be entitled to compensation payments. In Egypt there have been be superior to other combinations and broadly similar in efcacy to each other 34 ,35 ( as
successful public health approaches to the control of S. haematobium infections, reviewed by Hussain and James 36). Median survival is 12 to 18 months, depending on
leading to a substantial decline in incidence and mortality from squamous carcinomas the extent of disease and tness of the patient. Intriguingly, however, a small minority
of the bladder. 19 of patients do appear to survive long term after chemotherapy for metastatic disease,
but this percentage has sadly proved very hard to increase from that originally
observed in the MVAC trials.
Within the developed world, the overwhelming majority of bladder tumors are now
TCCs, and the main known causative factor is tobacco (particularly cigarette)
smoking, 20, 2122 ,2325
explaining approximately half of the cases in men and onethird of the cases in women
in Europe (discussed in detail below). The relation between smoking and other
ETIOLOGY
prognostic factors is interesting, as it could give insight into biological mechanisms of
disease and, perhaps more importantly, have clinical implications by increasing our The link between occupational exposure and an increased risk of urothelial cancer of
ability to identify patients at risk of more malignant disease. the bladder was established more than a century ago when Rehn 37 reported on three
cases of bladder cancer in a German chemical dye works in 1895. 38 During the
following 40 years, similar reports appeared from around the world. 39 In 1938, Hueper
et al. 39 demonstrated that when naphthylamine, an industrial arylamine used in the
synthetic dye industry, was fed to dogs, it caused bladder carcinomas identical to the
NATURAL HISTORY human disease. The link between industrial arylamines and bladder cancer was thus
established and later conrmed by Case et al. 40 in 1954. These authors also identied
Non-muscle-Invasive Bladder Cancer an excess of bladder cancer in the tire industry, attributable to the use of
Most cases (70% to 80%) present with non-muscle-invasive bladder cancer (NMIBC, 2-naphthylamine in the manufacture of rubber. 38,40
stage Ta, T1, and carcinoma in situ
[Tis]), which is rarely lethal, but shows a high recurrence rate of 50% to 70% after
treatment by transurethral resection of the bladder tumor (TURBT). 26 In about 10% to
20% of patients with NMIBC, the disease progresses to muscle invasion ( T2
Around this time the o-aminophenol hypothesis of arylamineinduced human bladder
lesions), which can lead to metastasis and death. 26 However, the majority of patients
cancer was proposed, suggesting that conjugation of aromatic amines by the liver and
with NMIBC will die of other causes, given the typically advanced age at presentation
excretion in the urine with subsequent urinary reactions would liberate the carcinogen
and the strong association with cigarette smoking, 20, 2122 ,2325 although it is worth noting
o-aminophenol. 41 Other workers later added to this hypothesis: arylamines are
that up to 21% of patients with Ta tumors and 49% of patients with T1 tumors will die
hydroxylated in the liver and conjugated with glucuronic acid, followed by excretion
from bladder cancer. 27 For patients with NMIBC, it has been observed that tumor grade
into urine and reliberalization of the active carcinogenic metabolite into the bladder
and stage, and also tumor number, size, presence of carcinoma in situ ( CIS),
lumen by urinary glucuronidases. 38,42 ,43 Slow acetylation by N- acetyltransferase, an
recurrence rate, and age at diagnosis are risk factors of progression. 2829, 30 The risk of
enzyme involved in the metabolism of arylamines, has been shown to be a
both recurrence and progression necessitates lifelong follow-up for patients with
contributory risk factor for bladder carcinogenesis. 20, 44 ,45
bladder tumors. However, there are factors that predict a higher risk of progression (to
invasion) as opposed to recurrence in lower risk tumors, and the European
Organisation for Research and Treatment of Cancer (EORTC) bladder cancer
calculator quanties the risk depending on the tumor characteristics imputed. 30
Due to the widespread use of arylamines in textile dyes, hair dyes, and paint
pigments, a number of high-risk occupations have been identied, including chemical,
dye, textile, and rubber workers and painters and hairstylists. 21 ,4648 In addition, the
presence of various arylamines in tobacco smoke means that a signicant proportion
of bladder cancer cases can be attributed to cigarette smoking. 20, 2122 ,2325 In fact,
abandonment of the manufacture of many of these arylamines in the latter half of the
20th century means that smoking is currently the single most important cause of
Invasive Disease urothelial cancer. 24,25,4951
Muscle-invasive bladder cancer has a poor prognosis due to a very high rate of occult
metastatic disease at the time of diagnosis. Evidence for this comes from the high rate
of death from metastasis after apparently successful surgery. Furthermore, reported Tobacco (particularly cigarette) smoking now explains approximately half of bladder
5-year survival rates with radiotherapy or surgery cancer cases in men and one-third of cases in women in Europe. It has been
demonstrated that an
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Chapter 64 Bladder Cancer 1261
increased smoking frequency and duration and a lower age at initiation are associated calculi, or long-term indwelling catheters. 7073 A number of metaplastic conditions
with an increased risk of bladder cancer, while cessation seems to reduce the risk. 49 The (squamous metaplasia, von Brunns nests, cystitis cystica, and cystitis glandularis)
relation between smoking and other prognostic factors is interesting, as it could give may occur prior to frank malignant change, although the premalignant nature of some
insight into biological mechanisms of disease and, perhaps more importantly, have of these lesions is still unclear. 7079
clinical implications by increasing the ability to identify patients at risk of more
malignant disease. Cigarette smoking also appears to be a risk factor for disease
recurrence following a diagnosis of bladder UC, 49,52 although due to a lack of
conclusive evidence, there is currently a low rate of physicians providing smoking Field Cancerization and Clonality
cessation assistance. 49 A fundamental characteristic of neoplasia is monoclonality, in which one transformed
cell gives rise to daughter cells that all exhibit the same genetic changes that provided
the initial growth advantages to the originally transformed parent cell. 80 Further genetic
changes accumulate in subsequent daughter cells and provide additional growth
Studies also demonstrate a relation between N- acetyltransferase-2 slow advantages. 80 However, TCC behaves as a multifocal disease, often with multiple
acetylators and cigarette smoking, resulting in a further increase in the risk of bladder primary tumors and frequent recurrences that can occur anywhere in the urinary tract
cancer, especially in those individuals with a high smoking intensity. 5355 A similar from the renal pelvis to the urethra. These observations gave rise to the idea of a
relation has also been demonstrated with arylamine exposure. 56,57 A number of other eld defect or eld cancerization, suggesting that the whole urothelium is exposed
susceptibility loci have also been identied, although such markers do not yet have to the same urinary carcinogens, leading to the transformation of many independent
sufcient discriminatory ability to be utilized for risk prediction in the general separate urothelial cells and resulting in multiple tumors developing independently in
population or for prediction or prognostication in patients diagnosed with bladder multiple sites. Such tumors are thus genetically unrelated. An alternative explanation
BLADDER CANCER
Squamous metaplasia is considered a precursor of squamous cell carcinoma of the
bladder and is a relatively common occurrence, especially on the trigone of the female
bladder where a prevalence of up to 50% is reported. 60, 61 Experimental evidence
suggests that this does not occur by direct transformation of the supercial apical Utilizing the relatively rudimentary technique of
umbrella cells of the urothelium or by their dedifferentiation and redifferentiation; it is X-inactivation, 80 ,8182 the early studies in this eld appeared to show that the urothelium
postulated that basal cells (probable stem cells) are selectively activated. 60 is derived from a small number of cells (200 to 300), which subsequently develop into
larger patches; each patch is clonally related and possesses different predispositions
to tumorigenesis. 83 Such stem cellderived clonal units actively replenish the
The normal urothelium is slowly proliferating, but urothelium undergoing squamous urothelium during aging. 84
metaplasia becomes hyperplastic, and it may be that the hyperplasia component of
urothelial squamous metaplasia is a major contributor to an enhanced risk of cancer Multiple synchronous and metachronous TCCs in the same patient appear to be
formation. 60, 61 clonally related when studied by X-inactivation. 80 ,82,8588 However, these studies only
provide a 50% probability that one particular TCC is related to the primary TCC,
Squamous cell carcinoma and adenocarcinoma of the bladder often occur in the although that probability improves when multiple TCCs are analyzed. Clonal patch
presence of chronic inammation. In Africa and the Middle East, where these tumors size also needs to be taken into consideration, and because of the large patch size of
are much more prevalent, the chronic inammation occurs as a result of infestation the urothelium (120 mm 2), X-inactivation studies are heavily biased toward
with the parasite S. haematobium ( bilharziasis), with a bladder carcinoma incidence of demonstrating monoclonality. 81 Ideally, these studies should have taken into account
2 to 4 per 100,000 in S. haematobium endemic areas. 62 ,6367 This infestation can lead to the relation of the tumors to patch boundaries. 81 In addition, DNA methylation patterns
malignancy through local tissue damage, mechanical irritation, bilharzial toxins, change as a natural consequence of aging. 89 Therefore, although X-inactivation
secondary bacterial infection, and the production of nitrosamines. 62 ,68,69 With liver studies provided an early insight into the relative importance of the processes of
involvement and subsequent liver dysfunction, tryptophan metabolism may be clonality and eld cancerization, they cannot be considered as entirely accurate and
disturbed, resulting in excretion of carcinogenic metabolites. 62 In reliable. Similarly, using immunohistochemistry to study specic p53
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1262 Section III Clinical Radiation Oncology Part H Urinary Tract
populations containing losses of forerunner genes may represent the earliest Normal urothelium
molecular change in bladder carcinogenesis. A further wave of genetic hits within
subregions of these clonally expanded cells leads to the rst microscopically
recognizable features of dysplasia, and a third and nal wave is associated with the Chromosome 9 LOH
fully transformed phenotype of severe dysplasia or CIS. 91,93 The genetic changes map
to six chromosomal regions that are suggested to represent the critical hits driving the
development of bladder cancer. 91,93 In addition, Knowles et al. 94 have demonstrated
FGFR3 or hRAS P53 mutation or RB1
that deletions of chromosome 9 occur in over half of bladder tumors of all grades and
activating mutation loss
stages (9p, 51%; 9q, 57%). Loss of heterozygosity also occurs on 17p (32%), 11p
(32%), 8p (23%), 4p (22%), and 13q (15%), and loss of heterozygosity of 5p, 8p, and
21q are signicantly associated with worse grade and stage. 94 Genomic copy number Low-grade, non-muscle- Carcinoma in situ
alterations are also frequent in bladder TCC, with the most frequent changes involving invasive tumor
complete or partial loss of 4q (83%) and gain of 20q (78%). 95 Other frequent losses are
of 18q (65%), 8p (65%), 2q (61%), 6q (61%), 3p (56%), 13q (56%), 4p (52%), 6p
(52%), 10p (52%), 10q (52%), and 5p (43%). 94 High-grade, non-muscle- RB1 mutation
invasive tumor
Taken together, the studies described above show that multifocal TCCs are FIGURE 64.1. Pathways to development of bladder cancer. (Data from Pollard C, Smith SC, Theodorescu D.
Molecular genesis of non-muscle-invasive urothelial carcinoma (NMIUC).
frequently monoclonal, whereas others show oligoclonality. The evidence for both
Expert Rev Mol Med 2010;12:e10.)
theories is compelling (as reviewed by Duggan et al. 96), with evidence supporting both
the clonality and eld cancerization theories. In reality, these theories are equally
to work in this eld have been made by Knowles et al. 110 ,113119
valid, with both processes seemingly often occurring simultaneously in the same
(Leeds, UK); in their 2010 review, Goebell and Knowles 113 propose a third
patient. 86,87 In addition, many of these studies have demonstrated that deletions on
hypothetical pathway for the development of highgrade papillary tumors.
chromosome 9p occur most frequently and early in transitional cell carcinogenesis
with 17p13 losses ( p53 gene mutations) occurring in more advanced TCCs, shedding
A detailed examination of these pathways and related biomarkers is beyond the
some light on the molecular pathology of bladder TCC.
scope of this chapter. In addition, this is a rapidly changing eld and new
developments appear frequently with the advent of high-throughput experimental
platforms, including deep sequencing, 120 proteomics, 121,122
and metabolomics, 123 so readers are directed to the reviews cited above or to the
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Chapter 64 Bladder Cancer 1263
identied as having a bladder tumor on exible cystoscopy will then require further TABLE 64.2 TNM CLASSIFICATION OF TUMORS (2009)
investigations to stage the disease.
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
Staging Bladder Cancer Ta No invasive papillary carcinoma
The next stage for most patients will be an examination under anesthetic coupled with Tis Carcinoma in situ: Flat tumor
TURBT. The presence or absence of a mass after TURBT is also an important T1 Tumor invades subepithelial connective tissue
prognostic factor as it potentially indicates either unsuccessful clearance of tumor, T2 Tumor invades muscle T2a Superficial
extravesical extension, or both. This serves as both denitive staging of the bladder muscle (inner half) T2b Deep muscle (outer
lesion as well as a substantial proportion of the initial treatment. Pathological review of half)
T3 Tumor invades perivesical tissue: T3a
the resected specimen will ascertain whether muscle invasion is present or not and
microscopically T3b macroscopically (extravesical
whether there is CIS; these are the key determinants of further investigation and
mass)
treatment. Patients with NMIBC, including CIS, do not usually require detailed further
T4 Tumor invades any of the following: prostate stroma, seminal vesicles, uterus,
imaging, and treatment and surveillance are primarily by intravesical means. The main vagina, pelvic wall, abdominal wall T4a Tumor invades prostate, stroma,
exception to this is patients with either extensive CIS or grade 3 lesions for whom seminal vesicles, uterus, or
additional cross- sectional imaging may be warranted. Patients with muscle-invasive vagina T4b Tumor invades pelvis or abdominal wall
bladder cancer (MIBC) will require detailed cross- sectional staging with CT or
magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis. If there are any N0 Regional Defined as nodes of the true pelvis below the bifurcation of the common
features suggestive of bone metastasis (e.g., raised alkaline phosphatase, bone pain), lymph nodes iliac arteries. Laterality does not affect the N classification.
effects. On the other hand, changes such as inltration of adjacent organs or M1 Distant metastasis present
hydronephrosis are likely to be reliable indicators of tumor stage and poor prognosis. Stage Grouping
Stage 0a Ta N0 M0
Stage 0is Tis N0 M0
Stage I T1 N0 M0
Stage II T2a,b N0 M0
Stage III T3a,b N0 M0
STAGING SYSTEM T4a N0 M0
Stage IV T4b N0 M0
The 2010 version of the UICC International Union Against Cancers TNM system is
Any T N1, 2, 3 M0
the current, internationally used staging system, 126 and it is based on the size and Any T Any N M1
extent of the primary tumor (T stage), presence or absence of nodal (N), and
From UICC International Union Against Cancer. TNM classication of malignant tumours, 7th ed.
metastatic (M) spread (Table 64.2). The TNM stage must be used in conjunction with
Hoboken, NJ: Wiley-Blackwell, 2009, with permission.
the pathological assessment of tumor removed at TURBT to decide on optimal
therapy. Disappointingly, despite a substantial volume of research, no biomarkers
have yet established themselves in clinical practice as either prognostic or predictive
markers as has happened, for example, with estrogen-receptor or HER2 status in TREATMENT OF BLADDER CANCER
breast cancer. It is hoped that the wider availability of high throughput systems such
as proteomics, in-depth sequencing, and others to be developed will allow the Non-muscle-Invasive Bladder Cancer
development of such markers in the future. Around 80% of patients with bladder cancer present with nonmuscle-invasive disease.
These are classied as Tis, Ta, and T1 by the TMN classication system. The gold
standard for diagnosis is the resection of the lesion with adequate sampling of the
detrusor muscle deep to the lesion (TURBT). This will give tissue for accurate staging
of the bladder lesion as well as denitive treatment for the lesion. Recurrences after
TURBT are found in up to 70% of patients undergoing surveillance, and, more
PATHOLOGY importantly, up to 15% of patients on surveillance will progress to muscle-invasive
In excess of 90% of bladder cancers are transitional cell carcinomas. Of the bladder cancer. At the time of diagnosis, the upper urinary tract also needs
remainder, around 5% are squamous, although it should be noted that squamous assessment. This can be done with intravenous urography, CT urography or
differentiation is often present in poorly differentiated TCCs, so the extent to which ultrasound. The incidence of upper tract tumors at the time of presentation with
these are genuinely distinct is open to question. As already noted, infestation with S. hematuria is only 1.8%, calling into question the use of contrast imaging for the group
haematobium can lead to squamous cell carcinoma, but this is rapidly decreasing due as a whole. 128
to eradication programs. Small cell carcinoma is rare but important as it is generally
very chemosensitive and treatment tends to follow schedules adapted from treating
small cell lung cancer. Other tumor types include melanoma, carcinosarcoma, and
adenocarcinoma (particularly in the urachal remnant). Typically bladder TCCs will be Ultrasound is now being used more frequently, with contrast imaging modalities being
graded using the standard TNM system of Gx (cannot be assessed) then G1 through used for the higher risk disease.
to G3 (well through to poorly differentiated). 127 CIS will frequently be found in addition Prognostication and management strategy are based on accurate initial staging
to a tumor mass and critically affects treatment choices. and grading of the disease. There can be variation in the interpretation of pathological
specimens, so review of pathology is recommended (European Association of Urology
[EAU] guidelines 129). If there is uncertainty over the pathology, a further early
re-resection is indicated. The risk of
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1264 Section III Clinical Radiation Oncology Part H Urinary Tract
residual tumor can be as high as 53% in T1 tumors. 130 If the disease is dened as nance. 137 BCG is a very effective treatment, but not all patients with NMIBC should be
NMIBC, it can be characterized as low, intermediate, or high risk, and this will dictate treated with BCG due to the risk of toxicity. In a phase III study for NMIBC tumors
how the disease is managed (see below). The EORTC bladder cancer calculator using maintenance BCG therapy, 20.3% patients stopped BCG due to side effects,
provides a valuable online tool for doing this and determining follow-up frequency. 131 mostly local side effects; 68% who stopped due to side effects did so during the rst 6
months. 138 The choice of treatment depends on the patients risk of recurrence and
progression based on EORTC subgroups. The use of BCG does not alter the natural
Following resection of the tumor, there is good evidence that a single dose of course of tumors in the low risk of recurrence subgroup and is therefore considered to
mitomycin-C administrated into the bladder for 1 hour within 24 hours of surgery will be overtreatment. In patients with tumors at high risk of progression, for whom
reduce the relative risk of recurrence by 24.2% but will not impact disease progression cystectomy is not carried out, BCG including at least 1-year maintenance, is indicated.
and disease survival. 132 Recurrences after TURBT are found in up to 70% of patients In patients at intermediate or high risk of recurrence and intermediate risk of
undergoing surveillance, and up to 15% of patients on surveillance will progress to progression, BCG with 1-year maintenance is more effective than chemotherapy for
muscle-invasive bladder cancer. Emerging endoscopic techniques employing prevention of recurrence; however, it has more side effects than chemotherapy. For
photodynamic therapy aimed at improving diagnostic yield and thereby ultimately this reason both BCG with maintenance and intravesical chemotherapy remain
reducing the rates of recurrence and progression have demonstrated promising options. The nal choice should reect the individual patients risk of recurrence and
results. 133 progression and the efcacy and side effects of each treatment modality (EAU
guidelines). In treatment refractory disease, the patient should be offered radical
treatment for the bladder.
Low-risk tumors are single tumors that are <3 cm in diameter are graded as G1
disease and staged as Ta with no evidence of CIS. These tumors have a 15%
probability of recurrence and a 0.2% risk of progression at 1 year. 30 These patients
should undergo a exible cystoscopy 3 months after the initial resection, and if this is
negative, a exible cystoscopy should be undertaken 9 months later and then
annually thereafter.
The use of exible cystoscopy with urine cytology is the standard of bladder
surveillance. There is ongoing research into improving the sensitivity and specicity of This phase II and III trial attempted to investigate the potential of using the response
exible cystoscopy using variations in the wavelength of the light source used (e.g., to neoadjuvant chemotherapy as a predictive tool for selecting patients for
narrow band imaging). There are a wide number of urinary biomarkers available such radiotherapy compared with the surgical standard. In the authors experience, one of
as NMP22, UroVysion (Abbott Laboratories, Abbott Park, Illinois), and ImmunoCyt the problems with the trial was that the study used response to neoadjuvant
(Scimedx, Denville, New Jersey). These agents suffer from high falsepositive rates chemotherapy to decide on suitability for bladder preservation. However, once this
and variable sensitivity and are costly (as reviewed by Vrooman and Witjes 134). was explained to the patients in the information sheet, there were patients who had a
good response but were reluctant to undergo surgery, particularly if the bladder was
free of tumor at the interim cystoscopy.
The presence of CIS in the bladder carries a 54% risk of disease progression
without treatment. 135 Patients with high-risk tumors or CIS should be offered Large population-based studies suggest that the main determinants of survival
intravesical immunotherapy using bacille Calmette-Gurin (BCG) (EAU and American after diagnosis of bladder cancer are stage, grade, age, and to some extent social
Urology Association guidelines). 129,136 There are a variety of treatment schedules in the class. For example, Hayter et al. 6 studied patterns of care and outcomes in over
literature, but the authors recommend an intravesical treatment once a week for 6 20,000 patients with bladder cancer in Ontario. They found signicant variations in the
weeks followed by a subsequent 3 weeks as an induction treatment. If there is no use of cystectomy and radiotherapy between different districts but no evidence that
cystoscopic evidence of recurrence, the patient should then be offered ongoing these variations led to any differences in long-term outcomes. They concluded that
maintenance BCG with 6-week courses of BCG every 3 to 6 months with regular bladder-sparing approaches were equivalent to surgery for invasive bladder cancer.
cystoscopic surveillance. In a recent meta-analysis of trials with BCG maintenance, a
32% reduction in the risk of recurrence was seen for BCG compared with mitomycin-C
( P <. 0001), whereas there was a 28% increase in the risk of recurrence ( P = . 006) for
patients treated with BCG in the trials without BCG mainte- Another way to compare outcomes between surgery and radiotherapy is to look at
large published series. In the United Kingdom, where both of these approaches are
routinely employed, it is possible to compare the outcomes in Cancer Registry data. A
recent paper from Munro et al. 10 examined
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Chapter 64 Bladder Cancer 1265
outcomes in 458 patients with invasive bladder cancer treated in Yorkshire between radiation failure. The median age was 62.5 years (range, 32.2 to 87.2) for the primary
1993 and 1996. The ratio of cystectomy to radiotherapy was 1 to 3, reecting UK surgical group compared with 65.5 years for the salvage group. Overall 5-year
practice at the time. Overall 10-year survival was similar between those who survivals reported were 45.5% for the primary group and 42% for the salvage group,
underwent radiotherapy (22%) versus radical cystectomy (24%). Prognostic factors for with cause-specic survivals of 51% and 50%, respectively. These differences
inferior outcome at 10 years were: female versus male, poor performance status, persisted after stratication for stage, and the authors concluded that a policy of
hydronephrosis and increasing T stage; treatment modality was not a factor in the primary radiotherapy with surgical salvage did not compromise the long-term survival
prognosis. chances of patients. 143
One of the most widely quoted surgical series comes from the University of Clearly there are surgical series with much higher survival rates than this in the
Southern California and reports the results of literature. However, there are two factors accounting for this. One is case selection,
1,054 patients undergoing cystectomy with overall 5- and 10 year survival rates of the other is that these series are, to a degree, personal, so to publish results that
60% and 43%, respectively. This series is discussed in detail below. However, this appear inferior to other major centers is potentially a threat to a centers (or surgeons)
series included patients undergoing surgery for noninvasive tumors and excluded reputation and will tend to have a ratchet effect on published results. These data
from the denominator 112 patients referred but deemed incurable at operation. If we also suggest that the predominant prognosis driver in bladder cancer is the presence
look at the 5-year survival of those with invasive tumors, the rate drops to around 47% or absence of distant micrometastasis at diagnosis of invasive disease. The (relatively
modest) effect of neoadjuvant chemotherapy tends to bear this out, particularly as the
from the quoted 60%. A contemporary series of radiotherapy cases from Rdel et al. 5 reports
5- and 10-year survivals of 51% and 31% but included patients deemed inoperable. biggest effect in the Medical Research Council (MRC)/EORTC trial was on
metastasis-free survival rather than pelvic control rates. 145
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1266 Section III Clinical Radiation Oncology Part H Urinary Tract
cystectomy when survival outcomes are optimal. 149 In these groups of patients, the mize local recurrence and positive surgical margins and to maximize cancer-specic
5-year survival rates after cystectomy exceed 80%. 150,151 survival. 162 Attention to surgical detail is important in optimizing the successful
functional outcomes of orthotopic diversion by preserving the urinary sphincter
The rationale for an aggressive treatment approach employing radical cystectomy mechanism and therefore continence. Finally, the observed associations between
for high-grade, invasive bladder cancer is based on several important observations. hospital volume and operative mortality are largely mediated by surgeon volume.
First, the good long-term survival rates, coupled with the lowest local recurrences, are Patients can often improve their chances of survival substantially, even at
seen following a denitive surgical approach removing the primary bladder tumor and high-volume hospitals, by selecting surgeons who perform the operations frequently,
regional lymph nodes. 4,152,153 as those centers that have adopted this strategy have demonstrated declining
mortality in the past decade. 163, 164
Although there are no randomized trials comparing radical cystectomy with bladder
preserving approaches, surgery remains the preferred treatment option for many
clinicians for advanced, localized invasive bladder cancer. 154 Second, the morbidity Radical cystectomy by denition implies the en bloc removal of the pelviciliac
and mortality of radical cystectomy has substantially improved over the past several lymph nodes along with the pelvic organs anterior to the rectum: the bladder, urachus,
decades. 152,155 Third, advocates say that radical cystectomy provides accurate prostate, seminal vesicles, and visceral peritoneum in men; the bladder, urachus,
pathologic staging of the primary bladder tumor (p stage) and regional lymph nodes, ovaries, fallopian tubes, uterus, cervix, vaginal cuff, and the anterior pelvic peritoneum
thus, selectively determining the need for adjuvant therapy based on precise in women. An appropriate lymphadenectomy is an important component of radical
pathologic evaluation. However, it should be noted that the evidence base for cystectomy and is related to the clinical outcomes of patients with highgrade, invasive
adjuvant (as opposed to neoadjuvant) therapy is rather weak (see on the Role of bladder cancer. Evidence suggests that a more extended lymphadenectomy is
Systemic Therapy section). For the above-mentioned reasons, radical cystectomy has benecial in both lymph node positive and lymph nodenegative patients with
become a standard form of therapy for high-grade, invasive bladder cancer. bladder cancer, 165, 166 ,167 although this could be a surrogate for either case selection or
Nonetheless, many articles on cystectomy emphasize the need for careful patient surgical skill. Although the exact limits of the lymphadenectomy for patients with
selection to achieve optimal results. Although this is undoubtedly true, it begs the bladder cancer undergoing cystectomy are currently debated, the boundaries include
question of what should be done with patients who do not meet these stringent initiation at the level of the inferior mesenteric artery (superior limits of dissection),
selection standards but still need to be treated. This issue is rarely, if ever, addressed extending laterally over the inferior vena cava or aorta to the genitofemoral nerve
in cystectomy series publications. (lateral limits of dissection), and distally to the lymph node of Cloquet medially (on
Coopers ligament) and the circumex iliac vein laterally. This dissection includes
bilaterally all obturator, hypogastric, presciatic, and presacral lymph nodes. 168170 Removal
of more than 15 lymph nodes has been postulated to be both sufcient for the
evaluation of the lymph node status as well as benecial for overall survival in
The evolution and improvements in lower urinary tract reconstruction, particularly retrospective studies. 166,171174 However, potential interindividual differences in the
orthotopic diversion, have been major components in enhancing the quality of life of number of pelvic and retroperitoneal lymph nodes and difculties in processing of the
patients requiring cystectomy. Currently, most men and women can safely undergo removed tissue by pathologists are issues. Furthermore, the reality is that even in
orthotopic lower urinary tract reconstruction to the native, intact urethra following todays practice the number of lymph nodes retrieved are low (<10) in a majority of
cystectomy, 156 although availability varies worldwide. Orthotopic reconstruction aims to patients (75%) and the chance are even lower if the patients are older, Hispanic (in
mimic the native bladder in location and function, provides a continent means to store the United States), and managed at low-volume, nonurban centers. 170 The true
urine, and allows volitional voiding per urethra, although patients need to do this by curative value of lymph node dissection and the optimal extent of dissection are both
coordinating opening the sphincter with a Valsalva maneuver, which does require still unknown.
training. The orthotopic neobladder eliminates the need for a cutaneous stoma,
urostomy appliance, and the need for intermittent catheterization in most cases.
These efforts have improved the quality of life of patients who require removal of their
bladders and have also stimulated patients and physicians to consider radical
cystectomy at an earlier more curable stage for high-grade, invasive bladder cancer. 157,158
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Chapter 64 Bladder Cancer 1267
provide a benchmark for outcomes to which other therapies can be compared. included all events related to the cystectomy, perioperative care, and urinary
diversion. The administration of preoperative therapy (radiation or chemotherapy) and
Both laparoscopic and robot-assisted cystectomy have been shown to be feasible the form of urinary diversion did not signicantly increase the early complication rate
and safe, but with a relatively shorter follow-up. 177 ,178179 Despite an increased in these cystectomy patients. Most early complications following radical cystectomy
materials cost for a robotic-assisted cystectomy, it has been demonstrated to be are unrelated to the urinary diversion (85% diversion unrelated) and can be managed
cost-effective in a subgroup of patients undergoing ileal conduit when the impact of conservatively without the need for reoperation in approximately 90% of cases. 181 The
complications are considered in a single institution series. 179,180 most common early diversion-unrelated complication is dehydration, while the most
common early diversionrelated complication following radical cystectomy is prolonged
urinary leakage. Overall, the most surgical complications after cystectomy are
associated with urinary diversion in relation to the intestinal segments. 152 ,182
Morbidity and Mortality of Radical Cystectomy and
Lymphadenectomy
The early clinical results and outcomes with regard to the morbidity and mortality of
radical cystectomy were disappointing. Lack of universal acceptance of this procedure
was attributed to the considerable complication rate and the need for improvements in Neoadjuvant chemotherapy is discussed in a later section, but it does not seem to
urinary diversion. Prior to 1970, perioperative complication rates of radical cystectomy increase the perioperative morbidity or mortality. 7, 183 Preoperative radiation therapy is
were approximately 35%, with a mortality rate of nearly 20%. However, with discussed below.
contemporary medical, surgical, and anaesthetic techniques, along with better patient Radical cystectomy may appropriately be performed in carefully selected elderly
selection, the mortality and morbidity from radical cystectomy have dramatically patients, 184 however, this emphasis in the surgical literature on careful selection
Optimising preoperative
Planned mobilisation
Referral from haemoglobin levels Admission on day
Rapid hydration &
Managing preexisting Optimised fluid nourishment
primary care hydration
comorbidities e.g. diabetes
Appropriate IV therapy
CHO loading
No wound drains
Reduced starvation
No NG (bowel surgery)
No/reduced oral bowel
Preoperative preparation (bowel Catheters removed early
surgery)
FIGURE 64.2. Schematic representation of the enhanced recovery program in patients undergoing a radical cystectomy.
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1268 Section III Clinical Radiation Oncology Part H Urinary Tract
T2a N0 94 77 57
Extravesical, Lymph NodeNegative Tumors
T2b N0 98 64 44
Nonorgan conned (extravesical), lymph nodenegative tumors were found in 20% of
T3 N0 135 49 29 University of Southern California series patients undergoing cystectomy (Table 64.4).
T4a N0 79 44 23 No obvious survival differences between extravesical P3 and P4 (node-negative)
Extravesical N0 214 47 27 tumors were observed. The 5- and 10-year recurrence-free survival for this pathologic
All node negative pooled 808 69 49 subgroup was 58% and 55%, respectively. Similar outcomes were reported by
All node positive pooled 246 31 23 Madersbacher et al. 153 and Dhar et al., 171 who demonstrated a 56% 5-year
a From ref. 192. recurrence-free survival for the same pathologic subgroup. Patients with locally
advanced tumors have higher recurrence rates and decreased survival compared with
those with organ-conned, lymph node negative tumors. 191 The 1997 AJCC TNM
bladder cancer. 4,153,155 These pathologic determinants may also be categorized into staging system 192 used for these studies straties extravesical tumor involvement
pathologic subgroups that provide risk stratication and direct the need for adjuvant (previously dened as pT3b) into microscopic (pT3a) and gross (pT3b) extravesical
therapy in the appropriately selected individual. Pathologic subgroups are dened as tumor extension. No signicant difference was observed in the recurrence-free and
organ-conned, lymph nodenegative tumors (P0, Pa, Pis, P1, P2a, P2b), nonorgan overall survival in patients when evaluating for pT3a and pT3b extravesical extension. 191
conned (extravesical) lymph node negative tumors (P3, P4), and lymph node
positive disease (N+); representing 56%, 20%, and 24% of patients, respectively. 155 The
5- and 10-year recurrence-free survival for the entire group of
The incidence of lymph node involvement was similar (approximately 45%); however,
1,054 patients in the University of Southern California series was 68% and 66%, the presence of lymph node involvement was associated with a higher risk of
respectively (Table 64.3). Most deaths occurred within the rst 3 years following recurrence and worse survival compared with node-negative patients.
radical cystectomy and were attributed to cancer recurrence. However, with longer
follow-up (>3 years), most deaths in this elderly group of patients were primarily
related to comorbid diseases unrelated to bladder cancer. This underscores the Lymph NodePositive Disease
effective and durable outcomes of radical cystectomy. Perhaps one-fourth of patients in large cystectomy series will have positive lymph
nodes (Tables 64.3 and 64.5). Although patients with lymph node tumor involvement
are a high-risk group of patients, nearly one-third of these patients were alive at 5
years in the series by Stein et al. 4 It is possible that the surgical approach employing
Organ-Confined, Lymph NodeNegative Tumors an extended lymph node dissection provides some survival advantage in selected
In the University of Southern California series, 56% of patients demonstrated individuals with node-positive disease. 171 The role of adjuvant therapy in these patients
pathologically organ-conned, lymph node negative tumor. 4 The outcomes in this is difcult to assess due to the absence of adequately powered trial data (see on the
pathologic subgroup were excellent (Table 64.4), with a 5- and 10-year recurrencefree Role of Systemic Therapy section). In an analysis of lymph nodepositive patients
survival of 85% and 82%, respectively. No signicant survival differences were carried out by the University of Southern California group, the administration of
observed when comparing supercially noninvasive (Pis, Pa), lamina propria invasive adjuvant chemotherapy was a signicant and independent predictor for recurrence
(P1), and muscle-invasive (P2a, P2b) tumors as long as the tumor was conned to the and overall survival in this group, 193 however, case-mix effects will be prominent in this
bladder without evidence of lymph node involvement. Similar outcomes for patients type of retrospective analysis as patients need to survive long enough and be t
with pathologic nonmuscle- invasive bladder tumors following cystectomy have been enough to even start chemotherapy to gure in the analysis. Inevitably this will bias
previously reported. 4,155 ,189, 190 Collectively, these data support the treatment of patients results in favor of adjuvant chemotherapy by excluding those who died early or who
with surgery when a tumor is conned to the bladder, without evidence of extravesical never became t enough postoperatively to receive chemotherapy. The authors own
extension or lymph node metastasis. Treatment delays in patients with invasive experience with attempting to recruit to adjuvant chemotherapy trials suggests that
bladder cancer should be avoided. Evidence suggests that prolonged delays may lead only the most t patients are able to recover quickly enough postoperatively to
to more advanced pathologic stage and decreased survival in patients with undergo systemic chemotherapy, so these data are highly likely
muscle-invasive bladder cancer. 160 Furthermore, caution should be
TABLE 64.5 INCIDENCE OF LYMPH NODE METASTASIS FOLLOWING RADICAL CYSTECTOMY, CORRELATION TO PRIMARY TUMOR
Poulsen et al. (292) 19901997 191 50 (26) 2 (4) 4 (18) 7 (25) 33 (51) 4 (43)
Vieweg et al. (195) 19801990 686 193 (28) 10 (10) 12 (9) 22 (23) 97 (42) 52 (41)
Leissner et al. (166) 19992002 290 81 (28) 1 (3) 5 (13) 12 (22) 53 (43) 10 (50)
Stein et al. (4) 19711997 1,054 246 (24) 19 (5) 21 (18) 35 (27) 113 (44) 58 (42)
Vazina et al. (293) 19922002 176 43 (24) 1 (215) 10 (16) 20 (236) 12 (50)
Abdel-Latif et al. (294) 19971999 418 110 (26) 3 (215) 4 (7) 29 (25) 59 (48) 15 (65)
Madersbacher et al. (153) 19852000 507 124 (24) 2 (3) 26 (17) 64 (34) 32 (41)
Hautmann et al. (155) 19862003 788 142 (18) 2 (2) 31 (10) 73 (41) 36 (43)
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Chapter 64 Bladder Cancer 1269
to be biased by underlying patient tness. A further interesting feature of the BC2001 ets observed in the neoadjuvant chemotherapy trials, where the maximum effect
trial, 194 discussed in detail below, was that although no attempt was made to include would be expected on low-volume, occult metastases rather than large-volume
pelvic nodes in the treatment eld, the rate of nodal relapse was low at around 6% primary disease (discussed below). Distant recurrence rates of 20% to 35% are
with radiotherapy alone, falling to 4% with chemoradiation. One possible interpretation reported in large series (Table 64.6). However, overall death rates from bladder
of these data is that successful treatment of the primary, with either surgery or cancer are higher than this, so there would appear to be either underreporting of
radiotherapy, may affect the subsequent behavior of low-volume nodal disease. deaths in these series or the cases selected were not representative of wider
experience.
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1270 Section III Clinical Radiation Oncology Part H Urinary Tract
invasion of the prostatic stroma), and the form of urinary diversion (orthotopic or those who are borderline t for major surgery. Radical cystectomy probably provides
cutaneous) performed. 198,200,202204
the best local pelvic control of the disease and provides accurate evaluation of the
Stein et al. 205 have evaluated urethral recurrence in a large group of male patients primary bladder tumor along with the regional lymph nodes yielding important
undergoing radical cystectomy and urinary diversion for TCC of the bladder. In this prognostic information. This, coupled with the evolution and successful application of
study, the clinical and pathological results of 768 consecutive male patients orthotopic lower urinary tract reconstruction in both men and women, has provided
undergoing radical cystectomy with a median follow-up of 13 years were analyzed. Of patients a more physiological and acceptable means to store and eliminate urine.
these 768 patients, 397 men (51%) underwent an orthotopic diversion (median However, most deaths from bladder cancer still occur due to distant metastases,
follow-up 10 years) and 371 men (49%) underwent a cutaneous diversion (median presumably present at the time of original surgery, so further improvements in
follow-up 19 years). Overall, 45 patients (7%) developed a urethral recurrence. The outcome will depend on the development of both better systemic therapies and also
median time to a urethral recurrence was 2 years (range, 0.2 to 13.6 years). Of these predictive (as opposed to prognostic) markers that will allow better selection of
45 patients, 16 men (5%) had an orthotopic and 29 (9%) had a cutaneous form of therapies.
urinary diversion. In this cohort of male patients, multiple risk factors were analyzed
with regard to urethral recurrence. In a multivariate analysis, two important variables
were identied that signicantly increased the risk of a urethral tumor recurrence
following cystectomy,
Radiotherapy
External-Beam Radiotherapy
including any prostate Whatever the merits or otherwise of radiotherapy as a treatment for bladder cancer,
its use in the United States has declined markedly since the 1980s, and the treatment
involvement and the form of urinary diversion. The estimated 5-year probability of a
is now used mainly in certain centers such as Boston in carefully selected patients
urethral recurrence was 5% without prostate involvement, which increased to 12%
rather than as a mainstream alternative to surgery. As discussed above, patterns vary
and 18% with supercial (prostatic urethra and ducts) and invasive (stroma) prostate
worldwide with the U.S. pattern of care predominating. Potential indications for
involvement, respectively. Patients undergoing an orthotopic diversion demonstrated
radiotherapy are summarized in Table 64.7. Patients with radiological node-positive or
a statistically signicantly lower risk of urethral recurrence compared with those
metastatic disease should be managed predominantly with either chemotherapy or
undergoing a cutaneous form of urinary diversion.
palliative approaches such as local radiotherapy to bulk disease (see below). Patients
with radiological node-negative, muscle-invasive disease may be considered for
radical radiotherapy. In North America, radiotherapy is administered as part of a
The follow-up and management of the urethra in male patients treated for
package of care comprising maximal TURBT, chemotherapy, and radiotherapy, the
high-grade invasive bladder cancer is of importance. The indications and timing of a
so-called trimodality therapy (Fig. 64.3). 207,208
prophylactic urethrectomy in those undergoing cystectomy and a cutaneous diversion
is debatable. It may include urethrectomy at the time of cystectomy based on
preoperative clinical parameters, based on the intraoperative frozen-section analysis
of the urethral margin, or a delayed urethrectomy based on nal pathologic evaluation
of the cystectomy specimen. These issues are best detailed with the patient
preoperatively ensuring proper informed consent. The schedules used are complex but can be summarized as initial maximal
TURBT followed by initial radiotherapy combined with synchronous chemotherapy,
usually with cisplatinum followed by interim check cystoscopy. Patients experiencing a
good response to treatment continue to consolidation chemoradiotherapy and then
adjuvant polychemotherapy, usually with a cisplatinum base. Patients remain on
Management of the Retained Urethra Following long-term cystoscopic surveillance. Noninvasive recurrence can be managed by
Cystectomy further TURBT and intravesical therapy. Those with isolated muscle-invasive
Intraoperative frozen-section analysis of the proximal urethra by an experienced recurrence or failure to respond (but with no systemic relapse) can undergo salvage
pathologist is a reliable and accurate means to determine indications for orthotopic cystectomy with or without further chemotherapy.
necessarily be excluded from an orthotopic substitute if the intraoperative biopsy is split schedules often used are 39 or 40 Gy in
normal. Similarly, female patients with bladder neck involvement should not 1.8- or 2-Gy fractions with an interval cystoscopy; patients with responding disease
proceed to a total dose of 64 to 66 Gy. Generally, these schedules achieve long-term
necessarily be excluded from an orthotopic neobladder if the intraoperative biopsy is
survival comparable to surgical series. 209,210 A signicant risk of cystectomy remains,
also normal. All patients should be carefully counseled regarding the need for
however, with 22% undergoing immediate cystectomy, 13% delayed cystectomy for
follow-up, the long-term risks of a urethral recurrence, and the possible need for
local recurrence, and 65% retaining a functioning bladder. 211
urethrectomy following cystectomy.
Salvage Cystectomy
Salvage cystectomy after prior radiotherapy was discussed above in the section
TABLE 64.7 INDICATIONS FOR RADIOTHERAPY IN BLADDER CANCER
comparing surgical with bladder-sparing approaches.
Stage Recommendation
chemotherapy and radiotherapy is essential if the best results are to be achieved in concert with systemic chemotherapy. No randomized data on the use of
the entire patient population, especially radiotherapy in this setting beyond studies of fractionation.
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Chapter 64 Bladder Cancer 1271
Adjuvant
chemotherapy in
Surveillance Intravesical therapy Salvage cystectomy selected cases
FIGURE 64.3. Trimodality therapy.
trimodality approach, patients will undergo maximal TURBT for diagnostic and staging are more likely to get surgery and older or less t patients radiotherapy. 10,12,142 ,143,194 Interestingly,
purposes. They can then be treated either with primary surgery (as elsewhere) or the long-term bladder preservation rates in older series seem similar to the rates for
alternatively with either neoadjuvant chemotherapy or primary radiotherapy. The role salvage cystectomy postradiotherapy occurring in approximately one-fourth of patients
of cystectomy was discussed above, and the evidence and use of neoadjuvant managed with radiotherapy alone at 10 years median follow-up, 213 with around
therapy is discussed in the section Role of Systemic Therapy. In the United Kingdom, two-thirds of surviving patients retaining their bladders. The authors own more recent
the radiotherapy itself is given as a single radical course, usually to the whole bladder, chemoradiotherapy series suggests a higher rate of bladder preservation with the use
only with no attempt to treat the nodes (as discussed below). Typical dose schedules of synchronous chemotherapy combined with full-dose radical radiotherapy. 11
would be 64 Gy in 32 fractions or hypofractionated schedules such as 55 Gy in 20
fractions. Following radiotherapy, patients undergo cystoscopic surveillance as in the
U.S. model, with salvage cystectomy for isolated local failure.
Treatment Results
It is difcult to compare results of older series to more contemporary ones for a
number of reasons. First, staging systems have changed over the years, as have
There are key differences between these two approaches. The rst and most imaging techniques. Patients who may have been staged as organ conned in the
obvious is that in most disease sites radical radiotherapy is not given as a split course early or pre-CT era may now be more accurately staged as more advanced with
but as a single treatment as in the United Kingdom. To understand how this approach contemporary imaging. In contrast, surgical series will report accurate pathological
has arisen, it has to be understood that trimodality therapy is offered as an alternative stage. It is well documented that more accurate staging will bring about a paradoxical
to cystectomy in countries where the prevailing opinion is that surgery is the treatment improvement in reported results by stage due to upstaging of apparently early disease
of choice. Patients undergoing this treatment are offered what is termed selective cases, the so-called Will Rogers phenomenon. 214 Treatment techniques in the past
bladder preservation, with the multiple checkpoints allowing early exit to surgery were obviously less rened, with little or no ability for conformal beam shaping and
aimed at providing reassurance to surgeons in particular that the opportunity for cure hence toxicity would have been higher. Nonetheless, it is clear from large series that
is not being lost. The median ages (mid-60s) reported in studies using this approach tumor control could be attained in signicant numbers of patients. For example, a
reect this patient selection 147,208,212 study from Western General Hospital, Edinburgh, conducted between 1971 and 1982,
reported treatment results from 963 patients. The reported stage mix was: T1, 20%,
T2, 32%, T3, 40%, and T4, 8%, with the administered dose of 55 Gy in 20
fractionsa widely used UK schedule. The overall
and are similar to large surgical series. 4,141 The UK approach is completely different in
this respect as there is a long tradition of using radical radiotherapy after TURBT, and
the much older patient groups compared with surgical series reect a different
decision-making process in which younger, more t patients
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1272 Section III Clinical Radiation Oncology Part H Urinary Tract
55 Gy / week 20 64 Gy / week 32
100% 100%
90%
80% 80%
70%
% of non-missing
60% 60%
50%
40% 40%
30%
20% 20%
10%
0% 1 2 3 4 0%
1234 1234567 1234567
Week Week Week Week
CT No CT CT No CT
FIGURE 64.5. Acute toxicity of radiotherapy with and without synchronous chemotherapy. Graphs show worst grade of on-treatment toxicity by radiotherapy dose and week.
Darkest bars indicate National Cancer Institute common terminology class grade 4; white indicates grade 0. Proportions with a grade 3 or 4 at any time on treatment: 64/178
(36.0%) chemotherapy (CT) versus 50/182 (27.5%). No CT-stratified chi-square test ( P = . 07).
5- and 10-year survival rates were 30% and 18%, respectively. 215 This study reports an optional second randomization comparing whole-bladder radiotherapy with a
tumor control at cystoscopy in 46% of patients, and this seems to be a pretty typical reduced dose to uninvolved bladder of 80% of the isocenter dose. The BC2001
response rate with radiotherapy alone. permitted neoadjuvant chemotherapy, which was a stratication factor. Around
one-third of the chemoradiotherapy patients also received neoadjuvant chemotherapy.
Similar control rates were reported in the radiotherapy alone arm of the National
Cancer Institute of Canada (NCIC) trial comparing radiotherapy with
chemoradiotherapy with cisplatinum 212 and also in the radiotherapy only arms at 2 The trials give a comprehensive insight into UK radiotherapy practice and great
years of the UK trials BCON 12 and BC2001 194 at 2 years. The latter two trials give an detail on outcomes. Median age in both trials was 73 to 74 years, with age range up to
accurate reection of the results of modern radiotherapy. They ran 90 years. Overall, around 40% of patients received 55 Gy in 20 fractions and 60% 64
contemporaneously between 2000 and 2009 and between them recruited more than Gy in 32 fractions. In both trials, over 95% of patients received at least 90% of the
800 patients from around 70 UK sites, including all major UK radiotherapy centers. target dose in both arms, with no reduction associated with the two radio-sensitizing
Both trials had similar designs, including near identical entry criteria (essentially treatments. Although the protocol recommended complete debulking at TURBT, this
T24aN0M0, with a small number of T1G3 patients entered the BCON trial), the same was only achieved in one-third to one-half of the cases, probably reecting technical
control arms (radical radiotherapy to bladder only to either 55 Gy in 20 fractions or 64 factors at surgery rather than deliberate intent.
Gy in 32 fractions), and the same outcome measures (locoregional disease-free and
overall survival). Both trials assessed both acute and late toxicity (Figs. 64.5 and
64.6). In addition, the BC2001 trial included
The overall 5-year survival rate was 50% for radiotherapy plus carbogen and
nicotinamide compared with 39% for radiotherapy alone (48% and 35%, respectively,
if T1 tumors are excluded), with the greatest effect seen in T2 tumors. For
50% 50%
45% 45%
Standard Reduced high
CT No CT
40% RT dose volume RT 40%
35% 35%
30% 30%
25% 25%
20% 20%
15% 15%
10% 10%
5% 5%
0% 0%
6 9 12 24 36 48 60 6 9 12 24 36 48 60 6 9 12 24 36 48 60 6 9 12 24 36 48 60
Month
FIGURE 64.6. Late toxicity in the BC2001 trial. Darkest bars indicate Radiation Therapy Oncology Group (RTOG) grade 4; white indicates grade
0. Proportion of patients with grade 3 or 4 RTOG toxicity at any month during follow-up (6 months onward), up to 3 months before a recurrence: RT: 12.9% sRT vs. 17.9% RHDV; odds
ratio (95% confidence interval) 1.34 (0.55, 3.24); P = . 52; CT: 8.3% CT vs. 15.7% no CT; odds ratio 0.48 (0.21,
1.10); P = . 07. Patients with no available assessment were excluded from analysis. RT, radiotherapy; sRT, standard volume radiotherapy; RHDV, reduced high dose volume
radiotherapy; CT, chemotherapy with radiotherapy.
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Chapter 64 Bladder Cancer 1273
BC2001, the estimated 5-year survival with radiotherapy alone was very similar at results. The good toxicity and functional results associated with radiotherapy are
34% (95% CI, 25% to 43%). borne out by surveys of quality of life and symptoms in cystectomy and radiotherapy
patients carried out by Henningsohn et al. 13 ,217220 Furthermore, radiotherapy and
Toxicity cystectomy patients report different patterns of symptoms, with sexual dysfunction
The toxicity of radical radiotherapy varies with the dose and schedule used. Within being more prominent in surgical patients and bowel symptoms more prominent in
BC2001 and BCON, there were two schedules: 55 Gy in 20 fractions and 64 Gy in 32 radiotherapy patients. The preservation of sexual function by radiotherapy is
fractions. Acute toxicity is shown in Figure 64.5 for both schedules, with and without particularly striking given that the patients were an average of around 10 years older.
chemotherapy with 5-uorouacil/mitomycin-C.
As can be seen, the majority of patients experience only grade 1 or 2 toxicity with
very low rates of grade 4 events. Synchronous chemotherapy increased toxicity but
was predominantly grade 1 or 2, with a nonstatistically signicant effect on grade 3 or Effect of Synchronous Chemotherapy
4 events (27.5 vs. 36%; P = . 07; boundary for signicance set at 0.01 to reect There are a large number of phase I or II trials from North America, 208 ,216,221222, 223 ,224230,
231 ,232237 mainland Europe, 5 ,238240
multiplicity of testing). The reduced volume randomization failed to demonstrate a
reduction in overall toxicity. However, when the volume of bowel irradiated was and the United Kingdom 241, 242 that have examined various chemotherapy agents in
calculated, this did show a signicant reduction; in an exploratory analysis, volume of combination with radiotherapy. There are, however, only a few trials reported in which
bowel irradiated did correlate with the risk of grade 3 or 4 toxicity. There was no radiotherapy alone is compared with radiotherapy with synchronous chemotherapy.
increase in acute toxicity observed in BC2001 if patients had received prior The only randomized study using the trimodality therapy approach was carried out by
neoadjuvant chemotherapy. the NCIC and reported in 1996. 212 This study compared radiotherapy to 40 Gy in 20
There are a number of points of note here. First, late toxicity was the same with
both randomizations in BC2001 (i.e., reduced-volume radiotherapy did not impact late
toxicity). More signicantly, the addition of synchronous chemotherapy also had no
effect on reported late side effects. In addition, at any given point, 75% to 80% of
patients report no late toxicity at all. This is supported by bladder capacity There are two randomized trials of radio sensitization using UK schedules: the
measurements in BC2001, which show a mean change in bladder volume at 1 and 2 BC2001 and BCON studies, as already discussed. These two large phase III
years of <5 mL. Of those reported side effects, fewer than 5% report grade 4 events randomized control trials reported results in 2009 to 2010. These trials used
and fewer than 10% overall grade 3. Very similar ndings pertain to the BCON trial. 12 In radiosensitization with either concurrent chemotherapy (BC2001) or carbogen and
2009, Efstathiou et al. 216 reported late toxicity results in 285 patients who had nicotinamide (BCON). BC2001 has shown a signicant improvement in locoregional
participated in four Radiation Therapy Oncology Group trimodality therapy trials. disease-free survival with concurrent 5-uorouracil and mitomycin-C of 34% (HR 0.66;
Overall 5.7% reported persistent late genitourinary and 1.9% gastrointestinal toxicity 95% CI, 0.46 to 0.95) driven by a reduction of 47% in invasive locoregional
of grade 3 or above, consistent with the BCON and BC2001 recurrences (HR 0.53; P = . 007), which is very similar to that observed in the NCIC trial
with cisplatinum using the trimodality approach. 212 Figure 64.7 shows the Kaplan-Meier
ILRDFS
CT = 28/182
82% (95% CI: 75%, 88%)
Proportion invasive locoregional disease-free
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1274 Section III Clinical Radiation Oncology Part H Urinary Tract
Any recurrence
93/182 pts
curves for invasive locoregional disease-free survival. Survival data show a trend given as a split course. The data suggest an improvement with the hyperfractionated
toward an improvement in overall survival (HR 0.81; P = . 16), although the data are regimen; however, given the suboptimal nature of the control arm, it is hard to draw
immature. 194 The BCON trial 12 with synchronous carbogen and nicotinamide narrowly rm conclusions from this. 245,246 A study from the Royal Marsden Hospital compared 64
failed to meet its primary end point of an improvement in local relapse-free survival Gy in 32 fractions to 60.8 Gy in 32 fractions over 26 days in 228 patients. 247 Hypofractionated
(HR 0.87; 63% vs. 74%; P = . 1) but did report an improvement in overall survival at 3 schedules are widely used in the United Kingdom and elsewhere for radical treatment
years (46% vs. 59%; HR 0.86; 95% CI, 0.745 to 0.996; P = . 04). Taken together the and for palliation (as discussed below). There are no modern trials comparing these
trial data with chemoradiotherapy suggests good tolerability even in relatively elderly schedules to 64 Gy in 32 fractions.
patients with excellent late toxicity proles in the majority of patients whether treated
with the North American trimodality approach 216 or the UK single treatment block. 194 The
similar hazard ratios observed with cisplatinum and 5-uorouacil/mitomycin-C
suggests that a range of chemotherapy approaches can probably be used with the Palliative Radiotherapy
selection based on toxicity. It is noteworthy that comparisons of platinum and A prospective randomized trial was conducted in 500 patients to compare the
5-uorouacil-based chemoradiotherapy combinations have been carried out in anal outcome in two treatment groups. Group 1 received 35 Gy in 10 fractions and group 2
cancer, with the two approaches being similarly effective. 244 The high rates of received 21 Gy in 3 fractions. Five hundred patients were recruited, but data on
locoregional control seen make radical chemoradiotherapy a viable treatment option symptomatic improvement at 3 months were only available on 272 patients. Of these,
for many patients presenting with muscle-invasive bladder cancer. 68% achieved symptomatic improvement (71% for 35 Gy, 64% for 21 Gy), with no
evidence of a difference in efcacy or toxicity between the two arms. On the basis of
these results, 21 Gy in 3 fractions is widely used in the United Kingdom as a palliative
schedule. 248 The data are congruent with other data on hypofractionation for palliation 249,250
as well as the growing trend for hypofractionation in other pelvic sites, in particular
Pattern of Failure the prostate.
As already discussed above, a signicant proportion of patients will experience local
failure and undergo salvage surgery. The BC2001 study gives a good indication of Preoperative Irradiation
patterns of failure using the single block approach to radical radiotherapy. A summary Preoperative radiotherapy has been investigated in the past, but interest in the
of relapse patterns in the chemoradiotherapy arm of the trial is shown in Figure 64.8. technique has waned, largely because none of the trials carried out showed any
evidence of worthwhile benet. In addition, the observed chemosensitivity of bladder
cancer lead to a wave of neoadjuvant chemotherapy trials carried out in the 1980s
There are a number of features of note here. First, the majority of locoregional and 1990s, effectively ending interest in the technique. Given the subsequent
failures are in the bladder, and there are more noninvasive than invasive recurrences. improvements in both radiotherapy and surgical technique, it may be appropriate to
This underlines the need for regular surveillance postradiotherapy and the revisit the possibility of combining surgery with radiotherapy, particularly given the
requirement for good integration of radiotherapy and surgical services if patients are apparent plateau in progress with systemic therapy since the licensing of gemcitabine
to be managed by bladder conservation. In the authors experience, the majority of more than 10 years ago. Most of the studies in the literature are old, retrospective,
noninvasive recurrences can be successfully managed conservatively without the nonrandomized comparisons and little can be concluded from them. 251
need for cystectomy. For those with invasive recurrence, cystectomy remains an
option if the patients are sufciently t. The low rate of nodal relapse in BC2001 is
also of interest, as no attempt was made to include pelvic nodes in the eld, although
lower pelvic nodes would have been included in the treated volume. For improvement
in the metastatic relapse rate, better systemic therapies must be found. However, the There are few randomized trials in the literature, and those that are available are
rate of second cancer is also notable and probably relates to the age of the patients also old, for the reasons outlined above. A study from the Royal Marsden Hospital
and the historic high rate of tobacco consumption in the bladder cancer population. randomized patients to preoperative radiotherapy to 40 Gy in 4 weeks followed by
cystectomy, against denitive radiotherapy to 60 Gy in 6 weeks. The 5-year survival in
patients receiving the combined therapy was 38% versus 29% for those treated with
radiotherapy alone, the difference not reaching statistical signicance. 252 This trial of
course did not compare radiotherapy plus surgery versus surgery alone and thus does
not address the primary question in this section. However, it is noteworthy that no
tumor was found in 31% of the cystectomy specimens, a similar complete
Altered Fractionation Schedules
There are old data examining hyperfractionation in comparison to conventional
treatment to 64 Gy in 32 fractions, both
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Chapter 64 Bladder Cancer 1275
response rate to that observed in the intergroup neoadjuvant MVAC study. 7 Similar The rectum should be empty of atus and feces. The use of daily microenemas
response rates have been reported in other series. 253 may be considered.
Patients should be asked to empty the bladder 15 minutes prior to scan.
A second randomized study was carried out by the Memorial Sloan-Kettering
Cancer Center in New York comparing radiotherapy to 40 Gy in 4 weeks followed by While breathing normally, the patient should have a CT scan performed with 3 to
cystectomy 4 weeks later with a shorter 20 Gy in a 5-day course with immediate 5-mm slice spacing. Patients are scanned from bottom of ischial tuberosities to 3
cystectomy modeled on the Swedish preoperative rectal cancer trials. Again this study cm above the dome of the bladder or bottom of L5 (whichever is higher). A at top
is not informative on the primary issue of the utility of adding radiotherapy to surgery CT scanner should be used.
but does demonstrate the feasibility and safety of such an approach. 254 A retrospective
review from the MD Anderson Cancer Center assessed the use of preoperative Neither intravenous nor oral contrast is thought to be of benet in this instance.
irradiation (50 Gy in 5 weeks) in patients with T3b bladder tumors. 255 The 5-year local
control rate was 91% in the preoperative group (n = 92) compared with 72% for those Reference tattoos should be made at the base of the abdomen and over each hip.
treated with radical cystectomy alone (n = 43; P = . 003). Parsons and Million 256 reviewed The location of the tattoos should be marked on the planning scan by the use of
the results of retrospective studies and six prospective randomized trials on the use of radio-opaque markers to allow cross-referencing of planning scan and setup
preoperative irradiation. They concluded that the use of the technique may improve instructions.
outcomes by up to 15% to 20% at 5 years. In particular, they noted that many
preoperative radiotherapy series report pathological complete response rates of
around one-third, similar to that seen with neoadjuvant chemotherapy. There are no
Volume or Field Localization
modern trials of preoperative radiotherapy, and the topic seems to be ripe for
The use of ducial markers or contrast medium such as lipiodol at the time of
TURBT has been explored and may help identify tumor for image-guided adaptive
radiotherapy.
There are few data on the optimal radiotherapy volume. A standard approach is to
dene the planning target volume as the whole bladder, identied by its
noninvolved outer bladder wall with a 1.5-cm margin plus extravesical extent of
tumor with a 2-cm margin.
Postoperative Radiotherapy
As with many areas of bladder cancer practice, there are little in the way of
All planning and treatment should be carried out with the bladder empty to
randomized data on the use of adjuvant radiotherapy following surgery. When used, it
minimize the risk of geographic miss and to keep the treated volumes as small as
is mostly based on the grounds of positive surgical margins or tumor spillage at
possible. Patients with signicant residual volumes post voiding should be
surgery, where a high local recurrence rate can be anticipated. With the use of
considered for planning and treatment with a catheter
neoadjuvant chemotherapy worldwide being at low levels, chemo-naive patients at
high risk of recurrence can be offered adjuvant chemotherapy, although the evidence
in situ, although this is likely to increase urinary toxicity.
base for this approach is also somewhat thin. What few data there are on
There are no data to support the routine irradiation of radiologically negative
radiotherapy suggests that limited doses are well tolerated. 257 Given the more solid
lymph nodes. The nodal relapse rate in the BC2001 trial, with planning target
evidence base for neoadjuvant chemotherapy and the failure of adjuvant
volume and clinical target volume dened as above, was only 3% in the
chemotherapy trials to accrue, the use of postoperative radiotherapy would also seem
chemoradiotherapy arm and 6% with radiotherapy only.
to be a topic well-worth revisiting with modern treatment techniques. An approach
combining neoadjuvant chemotherapy, surgery, and adjuvant radiotherapy for patients
at high risk of local recurrence would combine all three of the major bladder cancer
treatment modalities in a novel fashion. Brachytherapy
There is considerable historic literature on the use of brachytherapy, particularly from
the Netherlands. Reported results seem to be very good, for example, van der
Werf-Messing et al. 260 report the outcomes in 328 patients treated with 3
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1276 Section III Clinical Radiation Oncology Part H Urinary Tract
squamous elements within a transitional cell carcinoma. As these tumors are often In total, 976 patients with high-grade T2 to T4a urothelial bladder cancer accrued over
excluded from systemic therapy trials, there are few data on outcomes with treatment 5.5 years from 106 institutions were randomly assigned to 3 cycles of neoadjuvant
as most papers are retrospective collections of unconnected observations. 264265 ,266 It CMV chemotherapy (n = 491) or no chemotherapy (n = 485), followed by the
appears that local failure may be more prevalent than distant relapse, but even that institutions choice of denitive therapy with either radical cystectomy or radiation
observation is based on very few cases. Urachal adenocarcinomas are extremely therapy. Of patients in the chemotherapy and no chemotherapy groups, 42% and
rare. Surgical resection with a partial cystectomy and en bloc resection of the urachal 43%, respectively, received radiation therapy alone as denitive therapy. Pathologic
ligament with umbilicus is the treatment of choice in the setting of localized disease. complete response with neoadjuvant chemotherapy was 33%. Overall survival at 3
There is currently no denitive role for neoadjuvant or adjuvant chemotherapy in this years in the two groups was 55.5% versus 50%, respectively. The recent update, after
tumor. Unfortunately, there are many patients who present with metastatic disease, 8 years of follow-up, showed an increase in 3-year survival from 50% to 56%, an
which currently is not likely to be curable. There is no standard chemotherapy regimen increase in 10-year survival from 30% to 36%, and an increase in median survival
for these patients. Carcinosarcoma is even more rare and appears to have a poor time of 7 months (from 37 to 44 months) in CMV-treated patients compared with those
prognosis. 267269 Similar considerations apply to small cell carcinoma, although the treated with local therapy only. The SWOG study showed that of the 82% patients
consensus seems to be that metastasis is more likely and initial response to who underwent cystectomy, 38% had no evidence of disease pathologically. Patients
chemotherapy is usually good. These patients generally get treated along the same who achieved pT0 status had a better prognosis than those who did not, although this
lines as small cell lung carcinoma, but the benet of prophylactic cranial irradiation is difference may be accounted for by better disease biology rather than treatment
unclear. 270275 effect. By denition, the SWOG study did not address organ preservation, because
the mandated treatment plan was for surgery following neoadjuvant chemotherapy.
There are two particularly key studies in the area of neoadjuvant chemotherapy.
The South Western Oncology Group (SWOG) neoadjuvant study comparing surgery
alone with 3 cycles of MVAC followed by surgery reported an estimated median
survival of 6.2 years versus 3.8 years in favor of patients having neoadjuvant
chemotherapy ( P = . 027). 7 Updated results from the UK MRC/EORTC neoadjuvant
chemotherapy trial, which used 3 cycles of cisplatinum, methotrexate, and vinblastine Adjuvant Chemotherapy
(CMV) prior to surgery or radiotherapy, show a statistically signicant 16% reduction Adjuvant chemotherapy has the potential advantage of enabling better patient
in the risk of death (HR 0.84; 95% CI, selection based on the ndings at surgical and pathological staging. The major
disadvantages, although, are the delay in systemic therapy and the inability to assess
the response to chemotherapy in the absence of measurable disease. Randomized
0.72 to 0.99; P = . 037), corresponding to an increase in 10-year survival from 30% to adjuvant chemotherapy studies
36% after neoadjuvant chemotherapy. 279
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Chapter 64 Bladder Cancer 1277
Skinner et al. (295) 91 Cystectomy Cystectomy + CAP Benefit, but few patients received planned therapy.
Stockle et al. (296) 49 Cystectomy Cystectomy + MVAC Benefit, but limited trial size, premature closure, and no therapy
upon relapse.
Studer et al. (297) 77 Cystectomy Cystectomy + cisplatinum No benefit.
Freiha et al. (298) 55 Cystectomy Cystectomy + CMV Benefit limited to relapse-free survival.
Bono et al. (284) 83 Cystectomy Cystectomy + CM No benefit.
(Table 64.8) have been conducted with the methodological aws of inadequate Choice of Chemotherapy Regimen in
sample size, early closure, and suboptimal choice of chemotherapy, preventing a
Metastatic Disease
clear interpretation of the results. A systematic review and meta-analysis of updated
individual patient data from all available randomized controlled trials in the adjuvant Currently, systemic combination chemotherapy is the only treatment that may prolong
setting has been performed. Updated data were collected, validated, and reanalyzed survival in patients with metastatic disease. The chemosensitivity of bladder cancer is
for 491 patients from 6 randomized controlled trials, representing 90% of all patients demonstrated by objective response rates of 12% to 73% and complete response
An Italian multicenter randomized phase III trial enrolled 194 patients (one-third of its The triplet combination CMV is also widely used but has not been compared with
target) with muscle-invasive TCC and assigned them to 4 cycles of GC or observation MVAC directly. Experimental data suggested that a combination of gemcitabine and
after cystectomy. The trial was stopped early due to poor accrual. After a median cisplatin given using an appropriate schedule (simultaneous or close proximity
follow-up of 32.5 months, relapses were similar in both groups (43% vs. 45%) with no exposure) can act synergistically. Synergy may be mediated either by inhibition of
difference in disease-free survival. The 3-year overall survival was 67% for the ribonucleotide reductase by gemcitabine, depleting the deoxynucleotide pool required
chemotherapy arm and 48% for the observation arm and the 3-year disease-free for DNA replication and thereby inhibiting excision repair of cisplatin-induced DNA
survival was 47% and 35%, respectively, suggesting no statistically signicant crosslinks, or by gemcitabine incorporation into DNA, facilitating cisplatin crosslink
improvement in either survival rate with adjuvant GC in these patients. 284 A large formation. 287,288 The combination of the two drugs proved active and tolerable 33 and
phase III trial by EORTC (protocol 30994) evaluating observation versus adjuvant was subsequently compared with MVAC in a phase III trial. Patients were randomized
chemotherapy with one of the three chemotherapy regimens (GC, MVAC, or to GC (gemcitabine 1,000 mg/m 2 days 1, 8, and 15; cisplatin 70 mg/m 2 day 2) or
high-dose MVAC) in high-risk bladder cancer (pT34 and/or node-positive disease) standard MVAC every 28 days for a maximum of 6 cycles. Four hundred ve patients
was also prematurely closed due to poor accrual after enrollment of 278 of a planned were randomized (GC, n = 203; MVAC, n = 202). The groups were well balanced with
1,344 patients. This appropriately designed and sized study thus failed to conclusively respect to prognostic factors. Overall survival was similar on both arms (HR 1.04; 95%
address the issue of adjuvant chemotherapy following cystectomy. A possible reason CI, 0.82 to 1.32;
for the failure of this trial was the tight window postsurgery for commencing
chemotherapy. In the authors experience, relatively few patients were able to enter
the trial sufciently soon due to slow postoperative recovery. This suggests that
adjuvant chemotherapy may be less suitable than neoadjuvant chemotherapy in this
patient population. The adjuvant chemotherapy question still requires international P = . 75), as were time to progressive disease (HR 1.05; 95% CI,
collaboration with an appropriately sized pragmatic study for a conclusive answer. In 0.85 to 1.30), time to treatment failure (HR 0.89; 95% CI, 0.72 to 1.10), and response
various disease sites neoadjuvant chemotherapy followed by adjuvant chemotherapy rate (GC, 49%; MVAC, 46%). More GC patients completed 6 cycles of therapy, with
is an acceptable norm with level I evidence. With an anticipated rise in uptake of fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the
neoadjuvant chemotherapy, patients with bladder cancer should not be precluded MVAC arm. More GC than MVAC patients had grade 3 or 4 anaemia (27% vs. 18%,
from this strategy where neoadjuvant chemotherapy is followed by radical treatment respectively) and thrombocytopenia (57% vs. 21%, respectively). More MVAC
followed by a trial of adjuvant chemotherapy versus no chemotherapy in an patients, had grade 3 or 4 neutropenia (82% vs. 71%), neutropenic fever (14% vs.
appropriately sized phase III trial that meets its recruitment target, thus providing a 2%), neutropenic sepsis (12% vs. 1%), grade 3 or 4 mucositis (22% vs. 1%), and
denite answer for or against this strategy. Previous failures in meeting recruitment alopecia (55% vs. 11%). Because of the higher incidence of neutropenic fever and
targets can be overcome by using better-tolerated regimens in common use now and mucositis, more hospital admissions were required for the MVAC arm (49 admissions
by extending the recruitment window from 12 to 16 weeks to allow full recovery for a total of 272 days) than for the GC group (9 admissions for a total of 33 days),
postsurgery and to allow more dose-intense adjuvant chemotherapy treatment. resulting in considerably greater hospital resource utilization. The quality of life was
maintained during treatment on both arms; however, patients on GC fared better
regarding weight, performance status, and fatigue. This study thus demonstrated that
GC provides a similar survival to MVAC with a better safety prole and tolerability. 34 ,35 Therefore,
although this trial was not designed to show equivalence of the two regimens, many
interpret the results as showing therapeutic noninferiority and have adopted GC as the
new standard in
booksmedicos.org
1278 Section III Clinical Radiation Oncology Part H Urinary Tract
view of the better tolerability. With the upper boundary of the condence interval of the 10. Munro NP, Sundaram SK, Weston PM, et al. A 10-year retrospective review of a nonrandomized cohort of
458 patients undergoing radical radiotherapy or cystectomy in Yorkshire, UK. Int J Radiat Oncol Biol Phys 2010;77(1):119124.
adjusted hazard ratio for survival close to 1.2, noninferiority can reasonably be
assumed. Therefore, GC is a valuable alternative for the growing elderly patient 11. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder
cancer. N Engl J Med 2012;366(16):14771488.
population with metastatic bladder cancer who may derive equal benet from this
12. Hoskin PJ, Rojas AM, Bentzen SM, et al. Radiotherapy with concurrent carbogen and nicotinamide in
regimen as compared with MVAC but with fewer side effects. bladder carcinoma. J Clin Oncol 2010;28(33):49124918.
13. Henningsohn L, Wijkstrom H, Dickman PW, et al. Distressful symptoms after radical radiotherapy for urinary
bladder cancer. Radiother Oncol 2002;62(2): 215225.
The addition of paclitaxel to GC was evaluated in a phase III clinical trial by 21. Miller AB. The etiology of bladder cancer from the epidemiological viewpoint.
Cancer Res 1977;37(8 Pt 2):29392942.
EORTC (protocol 30987), which enrolled 627 patients with advanced urothelial 22. Hoffman D, Masuda Y, Wynder EL. Alpha-naphthylamine and beta-naphthylamine in cigarette smoke. Nature 1969;221(5177):255256.
carcinoma. The regimens were well tolerated. Results showed that the GCP arm
resulted in a higher rate of overall response rate (57% vs. 46%) CR (15% vs. 10%) 30. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual
patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients
and survival (15.7 vs. 12.8 months) compared with GC arm, but these differences from seven EORTC trials. Eur Urol 2006;49(3):466465.
were not statistically signicant. 289
31. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of
individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005;48(2):202205.
Combination of docetaxel and cisplatin (DC) has been compared with MVAC in a
32. Sternberg CN, Yagoda A, Scher HI, et al. Preliminary results of M-VAC (methotrexate, vinblastine,
multicenter phase III clinical trial by the Hellenic Co-operative Oncology Group. 290 Patients doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 1985;133(3):403407.
(n = 220) were randomly assigned to MVAC every 4 weeks versus docetaxel plus
33. Moore MJ, Winquist EW, Murray N, et al. Gemcitabine plus cisplatin, an active regimen in advanced
cisplatin every 3 weeks. Treatment with MVAC resulted in signicantly superior
urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin
response rate (54.2% vs. Oncol 1999;17(9):28762881.
34. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate,
vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large,
37.4%), median time to progression (9.4 vs. 6.1 months), and median survival (14.2 randomized, multinational, multicenter, phase III study. J Clin Oncol 2000;18(17):30683077.
vs. 9.3 months), suggesting that MVAC was superior to DC. Toxicity of MVAC was
37. Rehn L. Blasengeschwultse bei Fuchsein-arbeitern. Arch Clin Chir 1895;50:
considerably lower than that previously reported for MVAC administered without 588600.
granulocyte colony-stimulating factor. Currently GC, MVAC, and high-dose MVAC 38. Lower GMJ. Concepts in causality: chemically-induced human urinary bladder cancer. Cancer 1982;49:10561066.
with granulocyte colony-stimulating factor support are the acceptable standard of care
40. Case RAM, Hosker ME, McDonald DB, et al. Tumors of the urinary bladder in workmen engaged in the
as rst-line chemotherapy in advanced or metastatic bladder cancer setting. manufacture and use of certain dyestuff intermediates in the British chemical industry. Role of aniline,
benzidine, alpha-naphthylamine, and beta-naphthylamine. Br J Indust Med 1954;11:75104.
42. King CM, Phillips B. Enzyme-catalyzed reactions of the carcinogen H-hydroxy-2uorenylacetamide with
nucleic acid. Science 1968;159:13511353.
44. Risch A, Wallace DM, Bathers S, et al. Slow N-acetylation genotype is a susceptibility factor in occupational
Second-Line Chemotherapy Treatment and smoking related bladder cancer. Hum Mol Genet
1995;4(2):231236.
The role of salvage chemotherapy after relapse following rstline chemotherapy
61. Hodder SL, Mahmoud AA, Sorenson K, et al. Predisposition to urinary tract epithelial metaplasia in Schistosoma
remains an important subject of recent clinical trials. The enrollment in such trials is haematobium infection. Am J Trop Med Hyg
challenging in view of patients poor performance status and deranged renal functions. 2000;63(34):133138.
62. Tawk HN. Carcinoma of the urinary bladder associated with schistosomiasis in Egypt: the possible causal
Although various phase I or II studies have been reported, to date there is only one relationship. Princess Takamatsu Symp 1987;18: 197209.
completed phase III trial comparing vinunine with best supportive care (BSC) alone.
80. Sidransky D, Frost P, Von Eschenbach A, et al. Clonal origin bladder cancer. N
Patients (n = 370) were randomly assigned in a 2 to 1 ratio to receive vinunine plus
Engl J Med 1992;326(11):737740.
BSC (n = 253) or BSC alone (n = 117). Both arms were well balanced. Grade 3 89. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat
toxicities for the vinunine arm were neutropenia (50%), febrile neutropenia (6%), Rev Genet 2002;3(6):415428.
92. Bryan RT, Zeegers MP, James ND, et al. Biomarkers in bladder cancer. BJU Int
anemia (19%), fatigue (19%), and constipation (16%). A median survival advantage of 2009;105(5):608613.
2.3 months (6.9 months for vinunine plus BSC vs. 4.6 months for BSC) was achieved 94. Knowles MA, Elder PA, Williamson M, et al. Allelotype of human bladder cancer.
Cancer Res 1994;54(2):531538.
but was not statistically signicant ( P = . 287). Cox multivariate analysis adjusting for
97. Bryan RT, Hussain SA, James ND, et al. Molecular pathways in bladder cancer: part 1. BJU Int 2005;95(4):485490.
prognostic factors showed a statistically signicant effect of vinunine on overall
survival ( P = . 036), reducing the death risk by 23%. Objective response rate (8.6% vs. 98. Bryan RT, Hussain SA, James ND, et al. Molecular pathways in bladder cancer: part 2. BJU Int 2005;95(4):491496.
0%), disease control (41.4% vs. 24.8%), and progression-free survival (3.0 vs. 1.5 99. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100(1):5770.
months) were all statistically signicant, favoring vinunine. Because vinunine was 100. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;
144(5):646674.
well tolerated, it is a reasonable second-line therapy option for patients with bladder
101. Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells.
cancer who have relapsed following cisplatin-based therapy. 291 Nature 2001;414(6859):105111.
110. Knowles MA. Molecular pathogenesis of bladder cancer. Int J Clin Oncol 2008;
13(4):287297.
123. Hawkins RD, Hon GC, Ren B. Next-generation genomics: an integrative approach.
Nat Rev Genet 2010;11(7):476486.
132. Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of
chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a
meta-analysis of published results of randomized clinical trials. J Urol 2004;171(6 Pt 1):21862190.
141. Dalbagni G, Genega E, Hashibe M, et al. Cystectomy for bladder cancer: a contemporary series. J Urol 2001;165(4):11111116.
Future second-line chemotherapy studies should incorporate vinunine as the
142. Kotwal S, Choudhury A, Johnston C, et al. Similar treatment outcomes for radical cystectomy and radical
standard of care arm when testing any experimental treatment in a randomized trial. radiotherapy in invasive bladder cancer treated at a United Kingdom specialist treatment center. Int J
Radiat Oncol Biol Phys 2008; 70(2):456463.
145. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscleinvasive bladder cancer: a
randomised controlled trial. International Collaboration of Trialists. Lancet 1999;354:533540.
SELECTED REFERENCES
146. Harland SJ, Kynaston H, Grigor K, et al. A randomized trial of radical radiotherapy for the management of
A full list of references for this chapter is available online. pT1G3 NXM0 transitional cell carcinoma of the bladder. J Urol 2007;178(3 Pt 1):807813.
3. Riley GF, Potosky AL, Lubitz JD, et al. Medicare payments from diagnosis to death for elderly cancer 147. Michaelson MD, Shipley WU, Heney NM, et al. Selective bladder preservation for muscle-invasive transitional
patients by stage at diagnosis. Med Care 1995;33(8):828841. cell carcinoma of the urinary bladder. Br J Cancer
4. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: 2004;90(3):578581.
long-term results in 1,054 patients. J Clin Oncol 2001;19(3): 666675. 148. Prout GR, Marshall VF. The prognosis with untreated bladder tumors. Cancer
1956;9(3):551558.
5. Rdel C, Grabenbauer GG, Kuhn R, et al. Combined-modality treatment and selective organ preservation in 150. Shariat SF, Karakiewicz PI, Palapattu GS, et al. Outcomes of radical cystectomy for transitional cell
invasive bladder cancer: long-term results [see comment]. J Clin Oncol 2002;20(14):30613071. carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. J Urol 2006;176(6
Pt 1):24142422.
6. Hayter CR, Paszat LF, Groome PA, et al. The management and outcome of bladder carcinoma in Ontario, 151. Shariat SF, Palapattu GS, Amiel GE, et al. Characteristics and outcomes of patients with carcinoma in situ
19821994. Cancer 2000;89(1):142151. only at radical cystectomy. Urology 2006;68(3):538542.
8. Konety BR, Joslyn SA. Factors inuencing aggressive therapy for bladder cancer: an analysis of data from 152. Hautmann RE, Volkmer BG, Schumacher MC, et al. Long-term results of standard procedures in urology: the
the SEER program. J Urol 2003;170(5):17651771. ileal neobladder. World J Urol 2006;24(3):305314.
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153. Madersbacher S, Hochreiter W, Burkhard F, et al. Radical cystectomy for bladder cancer todaya 212. Coppin CM, Gospodarowicz MK, James K, et al. Improved local control of invasive bladder cancer by
homogeneous series without neoadjuvant therapy. J Clin Oncol concurrent cisplatin and preoperative or denitive radiation. The National Cancer Institute of Canada
2003;21(4):690696. Clinical Trials group. J Clin Oncol
155. Hautmann RE, Gschwend JE, de Petriconi RC, et al. Cystectomy for transitional cell carcinoma of the 1996;14(11):29012907.
bladder: results of a surgery only series in the neobladder era. J Urol 2006;176(2):486492. 215. Duncan W, Quilty PM. The results of a series of 963 patients with transitional cell carcinoma of the urinary
bladder primarily treated by radical megavoltage X-ray therapy. Radiother Oncol 1986;7(4):299310.
159. Herr H, Lee C, Chang S, et al. Standardization of radical cystectomy and pelvic lymph node dissection for
bladder cancer: a collaborative group report. J Urol 223. Marks LB, Kaufman SD, Prout GR Jr, et al. Invasive bladder carcinoma: preliminary report of selective
2004;171(5):18231828. bladder conservation by transurethral surgery, upfront MCV (methotrexate, cisplatin, and vinblastine)
160. Sanchez-Ortiz RF, Huang WC, Mick R, et al. An interval longer than 12 weeks between the diagnosis of chemotherapy and pelvic irradiation plus cisplatin. Int J Radiat Oncol Biol Phys 1988;15(4):877883.
muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. J Urol 2003;169(1):110115.
231. Zietman AL, Shipley WU, Kaufman DS. The combination of cis-platin based chemotherapy and radiation in
161. Lee CT, Madii R, Daignault S, et al. Cystectomy delay more than 3 months from initial bladder cancer the treatment of muscle-invading transitional cell cancer of the bladder. Int J Radiat Oncol Biol Phys 1993;27(1):161170.
diagnosis results in decreased disease specic and overall survival. J Urol 2006;175(4):12621267.
242. Choudhury A, Swindell R, Logue JP, et al. Phase II study of conformal hypofractionated radiotherapy with
164. Finks JF, Osborne NH, Birkmeyer JD. Trends in hospital volume and operative mortality for high-risk surgery. concurrent gemcitabine in muscle-invasive bladder cancer. J Clin Oncol 2011;29(6):733738.
N Engl J Med 2011;364(22):21282137.
166. Leissner J, Ghoneim MA, bol-Enein H, et al. Extended radical lymphadenectomy in patients with urothelial 243. Wallace DM, Raghavan D, Kelly KA, et al. Neo-adjuvant (pre-emptive) cisplatin therapy in invasive
bladder cancer: results of a prospective multicenter study. J Urol 2004;171(1):139144. transitional cell carcinoma of the bladder. Br J Urol 1991; 67(6):608615.
171. Dhar NB, Klein EA, Reuther AM, et al. Outcome after radical cystectomy with limited or extended pelvic 247. Horwich A, Dearnaley D, Huddart R, et al. A randomised trial of accelerated radiotherapy for localised
lymph node dissection. J Urol 2008;179(3):873878. invasive bladder cancer. Radiother Oncol 2005;75(1): 3443.
172. Herr HW, Faulkner JR, Grossman HB, et al. Surgical factors inuence bladder cancer outcomes: a
cooperative group report. J Clin Oncol 2004;22(14):2781 248. Duchesne GM, Bolger JJ, Grifths GO, et al. A randomized trial of hypofractionated schedules of palliative
2789. radiotherapy in the management of bladder carcinoma: results of medical research council trial BA09. Int J
173. Fleischmann A, Thalmann GN, Markwalder R, et al. Extracapsular extension of pelvic lymph node Radiat Oncol Biol Phys 2000;47(2):379388.
metastases from urothelial carcinoma of the bladder is an independent prognostic factor. J Clin Oncol 2005;23(10):23582365.
210. Mak RH, Zietman AL, Heney NM, et al. Bladder preservation: optimizing radiotherapy and integrated 283. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Adjuvant chemotherapy in invasive bladder
treatment strategies. BJU Int 2008;102(9 Pt B): 13451353. cancer: a systematic review and meta-analysis of individual patient data Advanced Bladder Cancer (ABC)
Meta-analysis Collaboration. Eur Urol 2005;48(2):189199.
211. Kaufman DS, Winter KA, Shipley WU, et al. The initial results in muscle-invading bladder cancer of RTOG
9506: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 291. Bellmunt J, Theodore C, Demkov T, et al. Phase III trial of vinunine plus best supportive care compared with
5-uorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist best supportive care alone after a platinumcontaining regimen in patients with advanced transitional cell
carcinoma of the urothelial tract. J Clin Oncol 2009;27(27):44544461.
2000;5(6):471476.
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Part I Male Genitourinary
Chapter 65
Low-Risk Prostate Cancer
Seminal
SV vesicle
Central zone
Pre-prostatic
(CZ)
sphincter Median lobe
CZ Periurethral
stroma
TZ
FIGURE 65.1. Zonal anatomy of the prostate. On the left, a young man with zone (PZ) AFS
minimal transition zone (TZ) hypertrophy. Note that the preprostatic sphincter and
periejaculatory duct zone (central zone of McLean) are clearly defined. On the Peripheral Transition
right, an older man with TZ hypertrophy, which effaces the preprostatic sphincter
PZ zone (TZ)
and compresses the periejaculatory duct zone. AFS, anterior fibromuscular stroma;
CZ, central zone; PZ, peripheral zone; SV, seminal vesicle. (From McLaughlin PW,
Troyer S, Berri S, et al. Functional anatomy of the prostate: implications for Verumontanum
Anterior
treatment planning. Int J Radiat Oncol Biol Phys 2005;63:479491; with permission External
fibromuscular
from Elsevier.) sphincter
stroma (AFS)
1280
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Chapter 65 Low-Risk Prostate Cancer 1281
Obturator internus m.
Urethra
Pelvic diaphragm
Sphincter urethrae m.
Perineal memb.
Corpus cavernosum
wb penis Inf. pubic
Fascia lata Deep fascia
Bulbospongiosus m. Ischiocavernosus m.
FIGURE 65.2. Frontal section of male pelvis at right angles to perineal membrane. (From Oelrich TM. The urethral sphincter muscle in the male.
Am J Anat 1980;158:229246;reproduced with permission of John Wiley & Sons, Inc.)
and parasympathetic bers, and are distributed to the prostate, seminal vesicles, and in connective tissue comprising collagen and abundant smooth muscle that
the corpora cavernosa of the penis and urethra. constitutes the prostatic stroma. This bromuscular stroma functions both to control
micturition by acting as a sphincter of the urethra and to express acidic prostatic
The prostatic apex is denable on diagnostic imaging and is important secretions into the urethra by contracting during ejaculation.
anatomically for radiation therapy treatment planning. Although the apex and the
GUD, which surrounds the membranous sphincter, are easily visualized on coronal The major function of the prostate is the production of seminal uid that protects
magnetic resonance imaging (MRI), it is important to recognize that the level of the and nourishes the sperm after ejaculation. The prostate contributes approximately
GUD from the apex to the penile bulb may vary because the absence of an apical 30% to the seminal uid, and the seminal vesicles, testicles, and bulbourethral glands
capsule contributes to the difculty in discrimination of the gland from the GUD during provide the remaining 70%. Enzymes, including acid phosphatase and
computed tomography (CT)-based treatment planning. Delineation of the prostate-specic antigen (PSA), are secreted into the seminal uid. PSA is a serine
neurovascular bundle is also limited on CT imaging. protease that is involved in the liquefaction of the seminal coagulum. Because PSA is
produced primarily by benign and malignant prostatic epithelial cells and normally
found at low concentrations in the serum, it is useful for prostate cancer screening and
posttreatment monitoring of disease status.
Prostatic Zonal Anatomy
Zonal anatomy has essentially replaced lobar anatomy of the prostate. There are four
zones of the prostate (Fig. 65.1): the peripheral zone (PZ), transition zone (TZ),
central zone, and anterior bromuscular stroma zone. The central zone that surrounds The synthetic activity and growth of the prostate gland is regulated by androgens.
the ejaculatory ducts has marked histologic differences from the PZ. It is the PZ, The primary circulating androgen is testosterone. In the prostatic stroma, testosterone
extending across the entire posterior surface of the gland that is palpated on rectal is converted to its active and more potent form, - dihydrotestosterone, by 5- - reductase.
examination and is the location of most prostate cancers. The TZ is the location of Secretory epithelial cells and stromal cells have intracellular androgen receptors.
benign prostatic hypertrophy. The anterior bromuscular zone consists of an anterior Dihydrotestosterone forms a complex with the dihydrotestosterone-binding domain of
band of bromuscular tissue contiguous with bladder muscle and external sphincter. the androgen receptor, altering the structure of the DNA-binding domain such that it
In young men, the PZ is the prominent zone, whereas the TZ becomes the dominant can reversibly bind DNA sequences known as androgen response elements in
zone with age. It is important to note that there is no median lobe zone in this promoter or enhancer regions of androgen-regulated genes. The response includes
nomenclature, although such a lobe may be present in some prostate cancer stimulation of cell division, inhibition of apoptosis (programmed cell death), or cellular
patients and may have important implications for treatment planning and treatment differentiation. In secretory epithelial cells, testosterone stimulation may result in the
selection. Histologically, the median lobe arises from the TZ or periurethral stroma, production and secretion of prostatic uid. These mechanisms are tightly regulated at
with varying proportions of brous, glandular, and muscle tissue. many levels, from the hypothalamus secreting luteinizing hormone releasing
hormone to maintain testosterone levels in the blood, to the local regulation of 5- - reductase
in the prostate stroma. All of these factors acting at the same time determine the
balance between cellular proliferation, cell death, and differentiation of a prostatic
epithelial cell.
Prostate Physiology
Histologically, the prostate consists of compound tubuloalveolar glands lined by two
layers of cells. The glands are embedded
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1282 Section III Clinical Radiation Oncology Part I Male Genitourinary
EPIDEMIOLOGY AND RISK FACTORS TABLE 65.1 KNOWN OR SUSPECTED RISK FACTORS FOR PROSTATE CANCER
men in the United States, accounting for 33% of non-skin cancers. The lifetime risk for African American race Increase
Geography Scandinavia, high; Asia, low
American White and African American men is 18% and 21%, respectively. This
Family history Increase
corresponds to a respective lifetime risk of prostate-specic mortality of 3% and 5%. 1,2 After
Dietary fat Increase
large annual increases from 1988 to 1992, coinciding with the introduction of the PSA
Agent Orange May increase
screening test, prostate cancer incidence in the United States leveled off, then
Vasectomy No effect
showed modest decreases of approximately 1.9% per year between 2000 and 2008
Benign prostatic conditions No effect
(Fig. 65.3). Incidence rates between 2004 and 2008 were approximately 153 per Sexually transmitted diseases No effect
100,000 men. 2 Tobacco Inconclusive data
Androgens Inconclusive data
FIGURE 65.3. Surveillance, Epidemiology, and End Results (SEER) prostate cancer incidence and mortality rates by race, United States, 19752008. (SEER Cancer Statistics
Review, 19752008. Available at: http://seer.cancer.gov.)
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Chapter 65 Low-Risk Prostate Cancer 1283
prostate cancer, and it has been noted that men decient in not linoleic acid (omega-6 fatty acid found in sh oil), was implicated, with an increase
2,5 reductase are rarely diagnosed with benign prostatic hypertrophy or prostate in risk for prostate cancer of more than threefold. Conversely, a subsequent Canadian
cancer. In a study of 1,008 men, there was a positive correlation with plasma casecontrolled study suggested that saturated fat consumption, not
androstenedione levels and the development of prostate cancer. 9 However, Gann et
al. 10 found no clear association between individual hormone levels, including - linolenic acid consumption, may play a role in prostate cancer progression. 24 Finally,
dihydrotestosterone, and the incidence of prostatic cancer. Yet, these investigators a Swedish study of 406 men with prostate cancer and 1,208 without it (control
noted that high levels of testosterone in combination with low levels of the serum subjects) demonstrated that body mass index and total amount of food consumed
protein that binds testosterone, sex hormonebinding globulin, correlated with a were independent risk factors. 25
higher risk of prostate cancer. Meikle et al. 11
Plant-based foods and their products, such as soy, tomatoes, cruciferous
vegetables, and certain nutrients, are favorably associated with prostate cancer. It is
observed a higher sex hormonebinding globulin level and a higher rate of believed that these dietary factors contribute to antioxidant effects against DNA and
testosterone synthesis in men with prostate cancer compared with control subjects. cell damage.
The most conclusive evidence supporting the hormonal inuence in the Several vitamins and trace nutrients, including selenium, vitamin E, and vitamin
development of prostate cancer comes from two large, randomized trials evaluating C, have garnered attention as potential protective agents. Selenium is an essential
the use of 5 - reductase inhibitors in chemoprevention. The Prostate Cancer trace nutrient that humans obtain through their diet of plants (related to soil
Prevention Trial was the rst large-scale, population-based trial testing the hypothesis composition; highest in Brazil nuts) and animal products (highest in seafood) and is
that treatment with nasteride, which lowers intraprostatic dihydrotestosterone levels, present in nutritional supplements. Early experimental and epidemiologic data
Dietary Influences
The development of prostate cancer may be attributed to both familial and
environmental factors. Epidemiologic studies strongly suggest that a diet decient in
certain micronutrients is an important environmental risk factor. This has been
supported through migration studies that indicate higher rates of prostate cancer in The benecial effects of soy are attributed to isoavones, one of several plant
Asian men living in the United States compared with their counterparts in Japan or pigments found in soybeans. Isoavones are a type of phytoestrogencompounds
China. 15,16 It has been postulated that nutritional factors play a role in stimulating the that have weak estrogenic, antiestrogenic, and antioxidant effects that may all be
progression of microscopic disease. Salient features of the Western diet that differ protective against progression of prostate cancer in humans. These isoavones, most
from the traditional Asian diet are high fat intake and low soy consumption. A Western signicantly genistein and daidzein, have been shown to inhibit the growth of prostate
diet has been associated with increased production of both androgens and estrogens cancer cell lines in nude mice. 18 In particular, genistein has been shown to be a potent
and a vegetarian diet with lower levels. 17 inhibitor of several steroid-metabolizing enzymes, such as aromatase, 5 - reductase,
and 17 - hydroxysteroid dehydrogenase, as well as enzymes that are crucial to
cellular proliferation, such as tyrosine kinase and topoisomerases I and II. Genistein is
also an inhibitor of angiogenesis. It is estimated that Japanese men consume
Numerous casecontrol and cohort studies demonstrated an association between approximately 20 mg of isoavones per day, whereas for Western men the daily
increased dietary fat intake and a higher risk of prostate cancer. 18 Diets high in fat consumption is <1 mg/day. This is reected in a mean plasma concentration of
content may increase the relative risk of prostate cancer by a factor of 1.6 to 1.9. 19,20 genistein of 180 ng/mL in Japanese men, compared with a level of <10 ng/mL for
Western men. 31
In addition, several studies showed that men with diets high in ber and presumably
lower in fat have a decreased risk of prostate cancer. 21,22
One prospective study found that the type of fat intake was directly related to risk
of prostate cancer. 23 Red meat represented the food group with the strongest positive Another protective nutrient is lycopene, prevalent in the Western diet, a
association with advanced cancer, with a relative risk of 2.64. Fat from dairy products carotenoid that is present in tomatoes, processed tomato products, and other fruits. It
(with the exception of butter) or sh was unrelated to risk. When analyzed by fatty acid is one of the most potent antioxidants among dietary carotenoids. Although the
type, only - linolenic acid (an omega-3 fatty acid found in red meats and butter), and antioxidant properties of lycopene are believed to be primarily responsible for its
benecial effects, other mechanisms may
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1284 Section III Clinical Radiation Oncology Part I Male Genitourinary
Modied from Chan JM, Gann PH, Giovannucci, EL. Role of diet in prostate cancer development and
progression. J Clin Oncol 2005;23:81528160.
Familial Associations
A large cohort study of the Utah Mormon population demonstrated a positive family
history of prostate cancer in 6.6% of families of probands with prostate cancer and
only 2.2% of families of probands without prostate cancer. 37 A subsequent study using
data from the Utah State Cancer Registry reported a familial relative risk of prostate
cancer of 2.2. 38 Multiple studies have conrmed these ndings, including a large
casecontrol study from Johns Hopkins. 39 Extensive cancer pedigrees were obtained Research delving into the molecular physiology of the prostate gland has also
from 691 prostate cancer cases and 640 spouse control subjects showing a twofold uncovered specic DNA sequences that may be related to the occurrence and
increased risk in men with a family history of prostate cancer in a single rst-degree progression of prostate cancer. It is well known that prostate cancer cells, like their
relative. There was a vefold risk if there were two affected relatives, and the relative normal counterparts, are usually sensitive to androgens, and their growth depends on
risk rose to 11 for three rst-degree relatives with prostate cancer. androgen-stimulated cell division. Prostate cell growth is controlled by the interaction
of circulating androgens, such as testosterone and dihydrotestosterone, with the
androgen receptor. The androgen receptor gene contains a polymorphic CAG repeat
sequence that encodes the portion of the receptor involved in DNA transcription. The
length of the CAG repeat sequence was found to be inversely proportional to the
In a Canadian study, the frequency of prostate cancer detected in men who had a activity of the androgen receptor; therefore, shorter CAG repeat sequences may be
rst-degree relative with a history of prostate cancer was 2.6 times greater than for related to prostate cancer growth. 48
men without such a history. 40 Aprikian et al., 41 in a study of 2,968 patients, noted that
prostate cancer was detected in 40% (1,300 patients) of men with a family history of
prostate cancer, compared with 29% of 769 men without a family history ( p < . 0001). In
a review of the epidemiology of prostate cancer, Giovannucci 33 Giovannucci et al., 49 in an analysis of the activity of the androgen receptor in men with
prostate cancer, found that a shorter CAG repeat sequence in the androgen receptor
gene predicts higher grade and more advanced stage of prostate cancer at diagnosis,
reported that approximately 9% of cases may be attributed directly to a family history, as well as metastasis and mortality from the disease. Other studies found that the
although this may be as high as 43% among men younger than 55 years of age. prevalence of short CAG repeats is higher
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Chapter 65 Low-Risk Prostate Cancer 1285
TABLE 65.3 PARTIAL LIST OF PROSTATE CANCER SUSCEPTIBILITY GENES AND CANDIDATE GENES
5-hydroxy-3-methylglutaryl-coenzyme
A reductase inhibitors (statins). Data
Gene Location Alterations Proposed Phenotypic Consequences
for the effects of statin use on
RNASEL/HPC1 1q24-25 Base substitutions Encodes endoribonuclease Early subsequent risk of prostate cancer
Four-base deletion leading to premature age at diagnosis
are conicting, with some
truncation
observational cohort studies and
ELAC2/HPC2 17p11 Base insertion leading to premature Unknown
retrospective analyses
termination Base
substitutions
MSR1 8p22-23 Base substitutions Encodes subunit of class A macrophage-scavenger
suggesting a
receptor reduced risk of advanced prostate
AR Xq11-12 Polymorphic polyglutamine (CAG) and Encodes androgen receptor, and androgen dependent transcription cancer, 55 reduced risk of death from
polyglycine (GGC) repeats factor prostate cancer, 56 and lower rates of
CYP17 10q24.3 Base substitutions in transcriptional Encodes cytochrome P-450c17 , and enzymes that relapse following radiotherapy 57 or
promoter (T C transition leading to a new catalyzes key reactions in sex-steroid biosynthesis radical prostatectomy (RP). 58 However,
Sp1 recognition site) several large meta-analyses failed to
SRD5A2 2p23 Base substitutions Encodes the predominant 5- - reductase in the prostate, converts identify a relationship between statin
testosterone to dihydrotestosterone
use and prostate cancer risk, 59,60
AMACR 5p13.2 Missense mutations Unknown
BRCA2 13q12-13 Various Possible link to higher Gleason score and stage at
diagnosis
Some studies correlated smoking with increased risk of prostate cancer, 68 whereas
another study did not nd a signicant correlation. 69 In one analysis of 359 patients, 70 a
Other Risk Factors greater tumor-specic mortality rate among smokers than nonsmokers with stage A
Chronic or recurrent inammation may have a role in the development of prostate and D tumors was observed. No occupational factors have been conrmed as risks,
cancer, as has been recognized in many other human cancers. Although various but some evidence suggests that occupational exposure to cadmium and some
microbial organisms have been identied to infect prostate tissue, the specic aspects of farming may increase risks moderately, although these factors would
offending pathogen causing prostatitis has not been isolated. However, the specic account for only a small proportion of the total cases. Japanese men exposed to
cause may not be necessary, as it is the host inammatory response to an infection atomic bomb explosions in Hiroshima and Nagasaki have not had a signicantly
rather than the infectious agent itself that may lead to prostate cancer. In one large higher incidence of prostatic cancer. 71
populationbased study, prostate cancer risk was increased in men with a history of
gonorrhea or syphilis (odds ratio, 1.6; 95% condence interval, 1.2 to 2.1). 54 A criticism
of such epidemiologic studies is the bias that men with symptomatic prostatitis
compared with men without it are more likely to seek out care with urologists, have an
increased serum PSA test, and have prostate biopsies. 53
NATURAL HISTORY
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