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Urology course Prostate cancer

7. Prostate cancer (PC)


Statistically, it is the most common cancer of men (exceeding the lung and colon cancer) and it represents 32% of all cancers. Its occurrence is correlated with the natural phenomenon of aging. It is very rare in men under 40 years, but it reaches its maximum frequency in the eighth decade of life. We have to mention that the incidence of occult cancers (shown in autopsy) is much higher than those manifested clinically. The latter ones are characterized by a large variability in their natural evolution (and therefore the potential for metastasis), leading to various controversies regarding appropriate therapy attitude, depending on the evolution of the disease. Therefore, the treatment that may evolve from a simple monitoring to aggressive surgery (total prostatectomy) depends on the age of the patient, grading and the clinical stage and last but not least on the protocols and therapy possibilities of each medical center. INCIDENCE The incidence, namely the rate of morbidity / year / 100.000 population ranges from 1.3 in China, 3.4 in Japan and 30 in Germany. In the U.S.A, this rate is 60 in the white population and 95 in the black population. In Europe, it is the second cause of death after lung cancer and bronchitis, approximately at the same level with colorectal tumors. In Germany, there are 40.000 new cases / year. 40-60% of men of 70 years suffer of prostate cancer, mostly well-differentiated, of small dimensions. These prostate cancers found incidentally at autopsy are known as latent prostate cancers. Prostate cancer grows slowly; the doubling time of tumor mass is 2-4 years. The increased incidence of occult cancers may be explained by the fact that this cancer may occur in advanced ages, and as it grows slowly, it does not manifest clinically, as the individuals die from other morbid causes associated. ETIOPATHOGENESIS Epidemiological studies emphasize the involvement of factors in the etiology of PC:

Urology course Prostate cancer

Genetic predisposition (if a sibling or parent suffers of PC, the risk of PC is at least double); Hormone causes (the involvement of steroid hormone is clear because PC does not occur in eunuchs; cancer cells depend on hormones and increase rapidly in the presence of androgens; castration causes a dramatic regression in the evolution of cancer. Neoplasia occurs in the active prostate glands, not in those inactive by age). On the other hand, in patients with prostate cancer we may notice aberrations in the steroid metabolism; Environmental and diet factors (the second and third generation of Japanese living in America have the same incidence of PC as the rest of the population, while in Japan it is only 10% of the incidence in the U.S.); Local infections (due to the direct relationship between prostate gland and urethra, it is possible that some viral or venereal infections to be involved in prostate cancer; these data are controversial). PATHOLOGY According to the studies of McNeal, the prostate, a gland, is divided into several areas (fig. 6.1), into the rectum, related to its anterior part, is found in the peripheral area, the origin for 75% of all prostate b a c carcinomas. In less than 5% of cases, prostate cancer originates in the central area, which is located around channels of the ejaculation (fig. 7.1), seminal
transition zone; d - fibro-muscle stroma

which open at the level Fig. 7.1. Prostate after McNeal a. peripheral zone; b central zone; c colicullus. Around the proximal urethra, the transitional area is found, the place of origin of BPH. About 20% of all prostate cancers occur in this area.

Urology course Prostate cancer

Prostate glands have their own channels that open in the seminal colicullus channels that are covered with cubic epithelial cells. Around the prostate gland, there is a stroma rich in connective tissue. In 98% of the cases, prostate cancer originate in the glandular epithelium, and the remaining of 2% originate in the epithelium of the tubes of the prostate gland. Very rarely we may also find sarcomas, which originate in the stroma of the glandular tissue, especially in young people. Local-regional evolution. Prostate cancer grows in the direction of the apex of the prostate gland. Following the development of the prostate cancer, the prostate capsule is infiltrated, the perineural spaces being particularly affected at the entry and exit of the nerves. The capsular penetration and seminal vesicles are signs indicating locally advanced prostate cancer. Metastasis. The most comon metastasis of prostate cancer are at the lymph node and bone. The obturator lymph nodes represent the first station. In case of radical prostatectomy, they are the lymph nodes indicating the lymphatic invasion or its absence. The pre-sacral and inguinal lymph nodes are the next lymph node stop, then the common iliac lymph nodes and then paraaortic lymph nodes (fig. 7.2). The mediastinal and supraclavicular lymph nodes are subsequently infiltrated. Hematogenous metastases are usually found at the level of the skeleton (osteoblastic metastases), they are found in 85% of the Fig. 7.2. Limphnode groups interested in PC patients dying of this condition. Visceral metastases are rare; the lung, liver and adrenal glands may be involved. Generally, hematogenous metastasis follows the lymph metastasis. Most PC develop heterogeneous and multicentric.

Urology course Prostate cancer

The "grading" system most commonly used is the Gleason system, which notes from 1 to 5, based on glandular appearance (and not smear!), two most frequent focal tumors. The score resulted is interpreted as follows: 2-4 well differentiated, 5-7 moderately differentiated, 8-10 poorly differentiated. It is one of the most important clinical indicators for assessing PC prognosis. The stage of the PC staging is determined according to the TNM system of UICC. TNM staging system T - tumor Tx- primary tumor cannot be identified T0 - no primary tumor T1 tumor not clinically apparent T1a - tumor found incidentally at histological examination, representing <5% of the tissue obtained through TURP T1b - tumor discovered incidentally at the histological examination, representing > 5% of the tissue obtained through TURP T1c - impalpable tumor, identified by biopsy (elevated PSA) T2 tumor localized in the prostate T2a the tumor occupies half or less of a lobe T2b the tumor occupies more than half of one lobe, but not both T2c the tumor occupies both lobes T3 extracapsular extended tumor T3a - extracapsular (unilateral or bilateral) extension with microscopic bladder neck invasion T3b the tumor invades the seminal vesicles T4 the tumor is fixed or invades the adjacent structures others than the seminal vesicles: external sphincter, rectum, elevator muscle of the anus or pelvis. N - Lymph nodes Nx - the lymph nodes cannot be evaluated N0 - no metastases in the regional lymph nodes N1 metastasis in regional lymph nodes

Urology course Prostate cancer

M - Metastasis Mx - the existence of metastases cannot be evaluated M0 - no distant metastases M1 - distant metastases M1a - metastasis to lymph nodes other than the regional lymph nodes M1b. - Bones Mlc - Other tissues or organs Symptoms Currently, PC is most commonly found in asymptomatic phase or by elevated PSA, or DRE. These investigations should be applied to all patients over 45 years, as screening. Thanks to the aggressive screening policies in countries like USA, Austria, England, France, the mortality due to this pathology decreased. At the same time, PC may also be discovered incidentally on the pathological examination of the tissue obtained by transurethral resection of the prostate adenoma, for example. The localized PC rarely generates symptoms. Sometimes, the occurrence of bone metastases orients the clinical examination toward a suffering prostate, where cancer, by then asymptomatic, is detected. Sometimes, even from the early stages of disease, the development of the tumoral process in the cervical - trigonal region leads to the occurrence of the dysectasia syndrome, characterized by dysuria, pollakiuria and urination pain. In the prostate cancer it is usual that dysuria worsens rapidly, the patient sometimes suffering of acute urinary retention or chronic incomplete retention with bladder distension, in a few months. Initially, terminal hematuria, then total hematuria, but low-intensity and persistent, is frequently added to the dysectasia syndrome in PC, unlike prostate adenoma. Some patients may present hemospermia. Very rarely, PC occurs in a hemorrhagic syndrome due to fibrinolysis. In extended prostate cancer, the general condition is also influenced;patients lose weight, paleness due to anemia also occurs, sometimes due to persistent hematuria less abundant, but persistent, as well as by the inhibitory action of the neoplastic process on the bone marrow.

Urology course Prostate cancer

CLINICAL EXAMINATION Digital rectal examination has a major role in the diagnosis of PC, which may detect the lesion even before clinical manifestation. In the beginning, the tumor lesion is represented by an intra-prostate nodule, difficult to differentiate from an inflammatory one. The prostate nodule inflammation protrudes at the surface of the gland and has precise limits; the cancerous nodule is inserted in the gland, tough, well-defined and painless. Sometimes the whole lobe or entire gland is affected, which in case of tumor is hard, with irregular surface, painless, well confined. Most of the times, the median ditch is maintained. In advanced stages, the gland is fixed on tissues and bones surrounding sacral excavation. In this phase, at the DRE, a hard, woody mass is found, occupying all the pelvis, where the prostate cannot be detected; frozen pelvis. Any hard, painless prostate nodule requires clarification by biopsy. DIAGNOSIS 1. Transrectal ultrasound. Today there are special ultrasound probes with appropriate frequency of 7,5 MHz or more for rectal or vaginal examination. Typically, the PC node occurs as a hypoechogenic area. This sign is not specific, since HBP, blood vessels, cysts, inflammatory processes appear as hypoechogenic areas. If they are located in the peripheral area of the prostate, they should also be investigated by biopsy. The main advantage of the transrectal prostate biopsy compared to the supra-symphyseal or transurethral biopsy is that of sampling ultrasound guided biopsies, by adjusting the needle guidance system for transrectal ultrasound probe, which allows adequate sampling of biopsies from suspicious areas. This will enable pathologist to determine the stage and grading, which are the most important factors in determining prognosis. The limit of the transrectal ultrasound is the lower accuracy of magnetic resonance imaging (MRI) in assessing extracapsular extension, failure to appreciate the regional lymph node invasion and make differential diagnosis with other hypoecogenic images due to adenoma or prostatitis (specificity 78-99%). 2. Prostatic biopsy puncture needles have been much improved by adapting them to biopsy guns. Prostate biopsy. It may be transrectal, transperineal or transurethral biopsy.

Urology course Prostate cancer

Transrectal biopsy. It is carried out by means of transrectal ultrasound (fig.

7.3). Currently, it is the most used technique in asymptomatic patients with elevated PSA. 12 biopsies are performed under ultrasound guidance. In addition, the ultrasound guidance may identify hypoechogenic areas (pathognomonic for PC) that are not detected in DRE and may guide the biopsies to the
Fig. 7.3. Transrectal prostate biopsy.

transition area located above the prostate and that is not accessible

to DRE. Rarely, it may be performed without ultrasound guidance. The palpating finger (index) feels the node and the biopsy needle is inserted in the lesion. Tru-Cut biopsy needles (Travenol) are used. Transperineal biopsy. It is performed with the same type of needle, but only 3. PSA values. Prostate specific antigen (PSA) is a glycoprotein secreted by prostate, which prevents sperm clotting. PSA may be determined from serum by radio- or immunoassay methods, with elevated values both in HBP and in PC. But appearance of the PC tissue increases the serum value of PSA 10 times more than the same quantity of BPH tissue. However, 20% of the PC found are accompanied by normal levels of PSA. Generally, the maximum normal value of PSA is 3,2 ng / ml. PSA is an extremely useful value for incipient and early prostate cancer diagnosis. PSA has a special value in the control and monitoring therapy. We may conclud that PSA is a useful marker for post-therapy screening and tracking. Thus, the total acid phosphatase, prostatic acid phosphatase and alkaline phosphatase are no longer used in the diagnosis and therapy monitoring of the prostate cancer. preceded by local anesthesia.

Urology course Prostate cancer

4. CT examination is not an appropriate examination to evidence PC metastases in lymph nodes. CT may detect these lymphatic invasions only in the case of massive node invasion, with lymph nodes having a diameter larger than 1.5 cm. Even in assessing local tumor invasion (T staging) CT is an investigation with modest results. 5. Bone scintigraphy. It is the most important investigation for highlighting bone metastases. Sensitivity of the method in detecting these metastases is approximately 100%. All processes of bone healing after fractures, inflammation, etc., may cause similar changes in osteoblastic metastases. 6. Magnetig resonance imaging (MRI). An expensive and time-consuming investigation. It is superior both to transrectal ultrasound in assessing extracapsular invasion, and to the CT in assessing lymph nodes invasion, especially when MRI with endo-rectal probe is performed. It is restricted to young patients, where the preservation of the peri-prostate vascular-nervous packages is needed (their bilateral intraoperatory cutting generates erectile dysfunction). 7. UIV and renal ultrasound show urethral obstruction by the infiltration of terminal ureters at the level of the bladder, in a PC with local invasion. The most important diagnostic measure before radical prostatectomy is a local lymphadenectomy for the nodes in the obturator fossa (6-9 lymph nodes on each side). If these nodes are invaded, we may assume with a probability of 90% that there are distance lymphatic metastases. DIFFERENTIAL DIAGNOSIS There are other prostate disorders that may mimic a PC such as prostate adenoma, chronic prostatitis, prostatic tuberculosis, fibrosis caused by previous biopsies, cysts and prostate stones. The occurrence of PSA decreased the number of patients undergoing prostate biopsy. 1. Prostate adenoma is usually associated with a long history of obstructive symptoms and the prostate volume is usually higher than in CP. 2. Prostatic tuberculosis is often associated with damages of epididymis, history of pulmonary tuberculosis, fever and sterile pyuria. 3. Chronic prostatitis has a long history, and leukocytes are identified in urine or prostatic secretion. 4. Prostate cysts or stones are easily identified at transrectal ultrasound.

Urology course Prostate cancer

5. The differential diagnosis of Paget's disease is taken into consideration in asymptomatic patients with bone metastases who present increased values acid phosphatase and alkaline phosphatase. STAGING The assessment of the clinical stage of cancer can be made by DRE, transrectal ultrasound, computed tomography or magnetic resonance imaging. DRE (fig. 7.4) may assess the extracapsular extension, seminal vesicle attachment, extension to pelvic wall or the rectum. The examination depends on the experience of the examiner; it cannot identify the T stage and it cannot clearly differentiate the prostate conditions described above. Transrectal ultrasound may diagnose 60% of the PC because of their hypoechogenic aspect (40% are isoechogenic or hyperechogenic) and it also serves to the eco-guiding of the biopsies (the guidance allows adequate sampling of biopsies of suspicious areas, which allows the pathologist to assess the stage and grading, the most important factors in determining the prognosis). The limit transrectal ultrasound is accuracy, lower magnetic resonance imaging (MRI) in assessing the extracapsular extension, node failure and to the with
Fig. 7.4. Digital rectal examination

appreciate the regional lymph invasion differential diagnosis

other hypoechogenic images due to adenoma or prostatitis (specificity 78-99%). TREATMENT

1. Treatment of localized PC (T1 ,T2, NX N0 ,M0) 1.a. Monitoring of the patient (Watchful waiting - WW). Watchful waiting may be considered in patients with localized PC, but with a reduced life expectancy or elderly patients with less aggressive tumors.

Urology course Prostate cancer

The current treatment for T1 and T2 stages is the radical prostatectomy or radiotherapy, both with a long-term survival of 80-90% and mortality less than 1%. 1.b. Total prostatectomy may be transperitoneal and / or retropubic. Laparoscopic lymph node dissection allows perineal approach in obese patients, without the need for another suprapubic incision. In this intervention, besides the removal of the prostate, the seminal vesicles will also be removed and the bilateral lymphadenectomy will be performed. The survival rate from 10 to 15 years, in T2 patients, is 68%, respectively 62% respectively. Similar results (in terms of oncology) with open radical prostatectomy were obtained by laparoscopic radical prostatectomy, or even robotics. The immediate complications of total prostatectomy are intraoperative bleeding, injury of the obturator nerve, the ureter or rectum. Immediate postoperative complications include: venous thrombosis, pulmonary embolism, symptomatic pelvic lymphocele, wound or urinary tract infections, etc.. The incidence of these complications is less than 3%. Long-term complications are urinary incontinence and erectile dysfunction. PSA level after radical prostatectomy should be 0 ng / ml at about 6 weeks. Otherwise, it is considered tumor residue or metastasis (PSA remains high or increases rapidly after prostatectomy) or tumor recurrence (PSA to 0 ng / ml and then increases). Other surgical techniques which may be applied to these patients, but that have no intention of oncology treatment are represented by cryotherapy or ablation with high frequency ultrasound (HIFU), perineal or transrectal techniques. 1.c. Radiotherapy. Brachytherapy and external conformational therapy seem to have similar results with the surgery. Since in this case, the staging is only clinical and imaging (not pathological), the comparative studies between the two methods are difficult to perform. Transperineal brachytherapy is the transperineal implantation in prostate of radioactive seed under ultrasound control (fig. 7.5). It is reserved for the patients with small prostate, low PSA and low Gleason score.

Urology course Prostate cancer

Conformational external therapy is a new technique that, due to threedimensional determination of the tumor and surrounding tissue, the radiation dose is administered directly on the targeted tumor tissue, protecting the surrounding tissues. Doses of 74-80 Gy are used in short sessions, 5 days per week for 6-7 weeks.

Fig. 7.5. Brachyteraphy tehnique and the aspect of intraprostatic seeds

It is estimated that 10-year survival is 68% for T 1 and 52% for T2. In case of effective radiation therapy, PSA levels should reach 0.5 ng / ml; level reached in a long interval of up to 3 years. At the same time, the increase of PSA in these patients is tumor recurrence. The increasing of PSA after the radiation therapy always shows failure. PSA above 30 ng / ml before radiotherapy is usually associated with modest results. The complications of radiation therapy depend on total dose, tumor volume, spatial distribution of the dose and schedule of the radiotherapy used. The use of external conformational therapy or brachytherapy reduced these complications. They consist of intestinal distress (rectorrhagy, tenesmus, diarrhea, incontinence for feces, rectal stricture or bowel obstruction), urological distress (dysuria, cystitis, hematuria, urethral stricture), erectile dysfunction and pelvic lymphatic edema of the pelvic limbs. The major complications, as rectal or bladder fistulae (2-4%) require surgical treatment. There is no cure in stage T3 or T4. However, today, according to some authors, total prostatectomy in stage T3 N0 M0 is followed by relatively good survival results at 5 years. If local lymph nodes are invaded, surgery is ineffective, the tumor cannot be completely excised, and local or systemic recurrence rate is very high.

Urology course Prostate cancer

Relapse-free survival after radiotherapy is modest, 54% at 5 years and 36% at 10 years. 2. Treatment of locally advanced PC with or without metastases (T3, T4, N1, M1) Prostate carcinomas are heterogeneous tumors composed of hormone sensitive and hormone resistant cells. The degree of hormone sensitivity will determine the initial response to androgen deprivation. Although dihydrotestosterone (DHT) is the active metabolite necessary for the normal prostate cell growth, PC may use other hormone precursors for its growth (ex. those from the adrenal gland). After deprivation,
LH

androgen approximately

40% of the patients experience the cessation of the disease progression, while 20% of the cancers will continue to grow and evolve. Treatment results are modest, proliferation over time they of certain become ineffective due to the hormone resistant tumor cells. The average survival time of patients with metastases is 2 years. Approximately 80% of them die within the first 5
Fig.7.6 Hypothalamus-pituitary-gonadal axis

years.

Hormone therapy (fig 7.6) Estrogens. Until recently, estrogens (diethylstilbestrol - DES) and orchiectomy have been the most important alternatives to hormone therapy. DES, at a dose of 3

Urology course Prostate cancer

mg/day, acts by suppressing LH and probably, also by a minor effect (little known) in cancer cells. The efficacy of estrogen use is similar to orhiectomy, but combining the two methods (orchiectomy + estrogen) is not superior and life expectancy does not change. Estrogens tend now to be abandoned because 20-30% of the patients present lethal cardiac or pulmonary complications, as thromboembolism, peripheral edema and fluid retention, in the first 3 months (at the mentioned dose). Painful gynecomastia is another complication that is resolved by radiotherapy. Orchiectomy is the cheapest and safest method of blending testicular androgens. At present, local anesthesia may be given, requiring 1-2 days of hospitalization. It is difficult for patients to accept it, because it is psychologically traumatizing. Usually, surgery is accompanied by hot flashes, which decrease at the administration of Cyproterone acetate, DES (diethylstilbestrol) 1 mg twice / week or monthly injections of depot progesterone preparations. LH-RH agonists. Also known as analogues (leuprorelin, goserelina, buserelin, etc.) work by stimulating the production of pituitary gonadotropins, for 2-3 weeks, then inhibiting it. Their effecacy is similar to the estrogens and orhiectomy (they reduce testosteronemia to the castrating level) and they are administered as subcutaneous injections or as depot at 1, 2, 3 or 6 months. Side effects include hot flashes 50%, nausea 5% and gynecomastia 3%. Currently, depot preparations of gosereline (Zoladex) or difereline, with monthly administration (3,75 mg) and more recently at 3 months (1 l, 25mg) are manufactured. LH-RH antagonists In contrast to LH-RH agonists, LH-RH antagonists bind rapidly to LH-RH receptors in the pituitary gland, resulting in rapid decrease in LH, FSH and testosterone. Studies on this type of hormone therapy are still at beginning. There are no such forms as depot as for LH-RH agonists. As representatives, we may mention abarelix, degarelix. Antiandrogens include drugs that act either a) by the inhibition of androgen synthesis, or b) by blocking their action in the target organ. a) androgen synthesis inhibitors include spironolactone, aminoglutethimide and ketoconazole and block the synthesis both at testicular and adrenal level. Ketoconazole, imidazole derivative, initially conceived as antifungal, has significant side effects

Urology course Prostate cancer

including: hepatotoxicity, gastrointestinal intolerance, gynecomastia and hypocalcaemia. It is indicated that fast-acting drug in patients with bone pain and spinal cord compression. b) androgen antagonists act through a competitive mechanism of blocking the androgen receptor. They may be steroid anti-androgens (cyproterone acetate 200 300 mg/day Androcur) or non-steroid antiandrogens (flutamide - Eulexine 3x250 mg / day, nilutamida - 2x150mg/zi, bicalutamide - Casodex 50-100 mg / day). The advantage of these drugs is to preserve libido in most patients. Maximum androgen blockade (CAB = complete androgen blockade) is an antiandrogen in association with orchiectomy or LH-RH analogue. This association is based on the idea that hormonal treatment failure is due to inadequate suppression of adrenal androgens and not to the selection of the hormone resistant cancer cells. Recent studies have not demonstrated the superiority of the method in terms of increased survival or quality of life. Minimal androgen blockade is the combination of a minimum non-steroid antiandrogen 5 reductase inhibitor (finasteride). By this combination the testosterone level is low, without significant effects on sexual function. The anti-cancer drugs may be used in metastasis hormone-resistant PC. Various types of anti-cancer drugs have been studied: taxanes, mitoxantrone in combination with corticosteroids, estramustin phosphate, cisplatin or carboplatin, etc. Suramin, an anti-parasitic agent, is currently the subject of several studies. It works by blocking growth factors (b FGF and EGF), having anti-enzymatic effects, cytotoxic effects on PC cells and suppression effect on the corticosuprarenal gland, all resulting in a decrease of plasma androgens. It determines a reduction in the oral tissue, which persists on average 4-11 months (at 33-50% of hormone resistant patients). PSA decreases by 75% to 29% of men receiving such treatment. Recent phase III trials have shown encouraging results on the effects of the treatment with certain Sipuleucel-T (Provenge) vaccines in patients suffering of hormone resistant PC with metastases.

Urology course Prostate cancer

The palliative treatment refers to the patients with bone metastases and to the patients with subvesical obstruction. In the first case, we use radiotherapy or recently, the administration of strontium 89. The patients with subvesical obstruction are treated with orchiectomy, CAB and / or transurethral resection, with the intention of removing the largest possible amount of the tumor tissue, leaving a prostate lodge type cavity after the resection, being mandatory to keep the striated sphincter. CONCLUSIONS Prostate cancer is a disease of older man. It is the most common urological malignant tumor and it is the second as a cause of cancer death in men, after bronchial carcinoma. Prostate cancer is an extremely slow growing adenocarcinoma that grows very slowly and whose early forms noticed in the autopsy of the men over 70 years are found in half of the autopsies. The aggression of the tumor is closely correlated with its volume. From a tumor volume (ex. 0,5 cm3), there is a clinically manifested tumor that may be palpated at DRE. Up to a volume of 4 cm 3, the tumor is almost always limited to the prostate. At higher volumes, it penetrates the capsule and it metastasizes first to the lymph nodes (lymphatic metastases), and then the bones (hematogenous metastases). By the digital rectal examinations, we may discover prostate tumors clinically relevant. Early detection of prostate cancer was much improved by determining the level of the prostate specific antigen PSA. Transrectal ultrasound is the diagnostic method that may be used to diagnose prostate cancer in early stage. The diagnosis of PC is determined by histopathological examination of a tissue fragment taken by prostate biopsy, ultrasound guided. PC limited to the organ will be treated by radical prostatectomy. Radiation therapy does not have a curative, but palliative role. PC with metastases will be treated by one of the various forms of anti-androgenic therapy.

Urology course Prostate cancer

PSA is an organ-specific marker. After total prostatectomy, it becomes a tumorspecific marker, very useful in monitoring the evolution of surgery. Based on serum PSA values, the effect of radiotherapy or hormone therapy is monitored. PC cannot be cured by means of current chemotherapy and immunotherapy. In these cases, palliative measures will be applied to calm down pain.

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