PRINCIPLES OF CHEMOTHERAPY

IN HEAD AND NECK CANCER

 Principle of Chemotherapy
• Aims :
– eradication of systemic cancer cells
– increase of locoregional control when used with
surgery or radiotherapy
• Macroscopic or microscopic metastases
Macro  have clinical or radiologic evidence of tumor
spread.
Micro  clinically unrecognizable small metastatic
tumor deposits, which, if untreated, will become
macroscopic.
 Introduction
Head and neck cancer
(HNC) 5% (or 40,000
patients) of malignancies
in the United States

Indonesia 2013 Top 10

Cancer

Infodatin. Kemenkes 2016

 Cell Cycle

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Classification of chemotherapy drug
TABLE 98-1. Chemotherapy agents

Class of drugs Examples

Alkylating agents Nitrogen mustard, cyclo-phosphoamide,

chlorambucil, melphalan, nitrosourea, cisplatin
Antimetabolites Methotrexate, 5-fluorouracil, cytosine
arabinoside, hydroxyurea, gemcitabine
Natural products
Vinca alkaloids Vincristine, vinblastine, vinorelbine
Antibiotics Doxorubicin, bleomycin, dactinomycin,
mitomycin C, etoposide
Taxanes Paclitaxel, docetaxel
Topoisomerase Irinotecan, topotecan
inhibitors
Hormones Tamoxifen, leuprolide
Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 The Cell Cycle And Cell Proliferation

Potential implications for the treatment HNC

Vinca Alkaloids :
(Vincristine and vinblastine) :
M
major sytolitic effect through
induction of mitotic arrest
Bleomycine : G2
G1
most active during G0
premitotic or G2 phase
R
Antimetabolits :
(Methotrexate and 5-FU) : Active
against rapidly proliferating cells S
during S-phase by inhibition
synthesis DNA)
Alkylating Agent : Irradiations :
(Cisplatine) : Induced cell cycle
block in G2 and R phase (involved Damage DNA by direct and indirect
effect (S-phase more radioresistent)
p34cdc-2 as a primary targets by
cross link DNA)

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 DEVELOPMENT AND APPLICATION OF
CHEMOTHERAPY
• Primary goal : increase the cure rate
• Second goal :
– decrease long-term sequelae of radical surgery or
radiation therapy
– to allow for organ preservation.
• Treated with chemotherapy recurrent:
– unresectable disease who have failed surgery or
radiation th/
– metastatic disease
Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
Active chemotherapy drugs in H&N cancer

• Cisplatin • Hydroxyurea
• Carboplatin • Doxorubicin
• Methotrexate • Cyclophosphamid
• 5-Fluorouracil e
• Paclitaxel • Ifosfamide
• Docetaxel
• Gemcitabine
• Bleomycin
• Vinorelbine
• Irinotecan
Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Methotrexate
Methotrexate
(binding to enzyme
dihydrofolate reductase)
Dihydrofolate Tetrahydrofolate

Celullar depletion of
reduce folate

Inhibition of DNA synthesis

 Active only during the S phase of the cell cycle

 Toxic reactions : myelosuppression, mucositis, dermatitis, nausea,
vomiting, diarrhea, hepatic fibrosis, renal injury (high-dose
schedules prevented with urinary alkalinization and vigorous hydration)

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
• Minimized side effects by supplying reduced folates
in the form of leucovorin within 36 hours after
exposure to the drug.
• As a single agent, given in weekly doses of 50 mg/m2
• High-dose regimens of ≥ 1 g/m2,  require
“leucovorin rescue” therapy within 36 hours.
• Partial response rates : 10% - 30%
• Response duration : 1 - 6 months

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Cisplatin
• The most frequently used drug in treating H&N
cancer.
• Results from intracellular binding of its activated,
positively charged form with a nucleophilic site on
DNA to form bifunctional covalent links that interfere
with normal DNA function2.
• Daily doses : 60 to 120 mg/m2 (2 to 6 hours)

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
• Toxic reactions :
– Renal toxicity  mild to moderate azotemia and
electrolyte wasting, particularly of magnesium.
– nausea and vomiting, peripheral neurotoxicity,
ototoxicity, and cumulative myelosuppression if
several cycles of the drug are administered.
• Single-agent doses : 60 to 120 mg/m2 every 3 - 4
weeks
• Partial response rates : 15% to 30%
• Monthly doses exceeding 120 mg/m2

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Carboplatin
• Carboplatin is an analogue of cisplatin that causes
less nephrotoxicity, ototoxicity, and neuropathy,
although it is more myelosuppressive.
• Dosage using AUC 6

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 5-Fluorouracil
• An S phase–specific uracil analogue
• Activated by means of two major intracellular
pathways:
– sequential phosphorylation
– incorporation into RNA or activation to 5-
fluorodeoxyuridine monophosphate, which blocks
the enzyme thymidylate synthase and blocks the
conversion of uridine into thymidine compounds

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
• Cells are depleted of thymidine and are not capable
of synthesizing DNA
• Major side effects : myelosuppression, mucositis,
dermatitis, and diarrhea
• Used as a single-agent IV bolus in patients with H&N
cancer, limited activity (less than 20%)

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Paclitaxel and Docetaxel

• Paclitaxel stabilizes tubulin polymers, preventing cell

division.
– The optimal dose and schedule is not yet defined
for head and neck cancer.
– Response rate : 40%
• Docetaxel (Taxotere) is a semisynthetic taxane from
the European yew tree  response rates = 25% -
30%.

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Hydroxyurea

– Inhibits the enzyme ribonucleotide reductase and

depletes the cell of DNA precursors.

– Administered orally

– Major side effect : myelosuppression.

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Other Drugs

– Bleomycin  combination with cisplatin or

methotrexate. Potentially fatal interstitial
pneumonitis limits its cumulative usage.

– Gemcitabine (antimetabolite)  response rate of

13%

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Combination chemotherapy
• In head and neck cancer  methotrexate or
cisplatin.
• Cisplatin + 5-FU continuous IV infusion 4- to 5-day
 active combination (synergistic in vitro)
• Recurrent disease  response rates : 20% - 70%
• Neoadjuvant :
– setting with locally advanced, nonmetastatic
disease, response rates : 60% - 80%, with 10 - 40
complete responses
Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
Conclusions about combination regiments
1. Combinations produce statistically significantly
higher response rates than single agents, including
methotrexate.
2. Cisplatin and infusional 5-FU produce higher
response rates than single agents or other
combinations.
3. In no comparison groups (single agent or
combinations) was survival meaningfully increased.
4. The toxicities of cisplatin and infusional 5-FU in
terms of nausea and vomiting were significantly
higher than with single agents.

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Induction (Neoadjuvant) Chemotherapy

Advantages and disadvantages of induction chemotherapy

for locally advanced head and neck cancer
Advantages
– Drug delivery to cancer cells is unimpaired.
– Macroscopic response may predict for response of
microscopic disease. Prompt elimination of
micrometastases may aid in cure.
– Tumor may be downsized, allowing for more
successful surgery or radiation therapy with less
radical treatment.
– Patient performance status at surgery may be
improved.
Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
Disadvantages
– Original extent of tumor may be obscured.
– Performance status may decline.
– Tumor may increase during chemotherapy.
– Duration, toxicity, and cost of treatment are
increased.

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Concomitant Chemoradiotherapy
Benefits of chemoradiotherapy

• Drugs and irradiation may be active against different

tumor cell subpopulations based on cell cycle
specificity, pH, and oxygen supply. Cells resistant to
one modality of treatment may be eradicated by the
other.
• Combination therapies may increase tumor cell
recruitment from G0 into radiation therapy–
responsive cell cycle phase.
• Tumor shrinkage may decrease interstitial pressure
and therefore increase drug and oxygen delivery.

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
• Early eradication of tumor cells prevents
emergence of drug or radiation resistance.
• Cell-cycle synchronization increases the
effectiveness of both therapies.
• Chemotherapy inhibits repair of sublethal
radiation damage and inhibits recovery from
potentially lethal radiation damage.

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
• A benefit chemotherapy agents : 5-FU, bleomycin,
methotrexate, cisplatin, and mitomycin C
• Chemotherapy is generally given on the days of
radiation, but rapidly alternating chemotherapy and
radiation therapy also appear to be of benefit.
• Concomitant chemotherapy and radiotherapy  for
patients with unresectable disease.

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Chemotherapy emergencies
• Divided into those characterized by severe
symptomatic side effects or organ-specific toxicities
With most chemotherapy drugs, granulocytopenia
and thrombocytopenia are regularly observed

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Complications Chemotherapy

Complication Management

Nausea/vomiting Antiemetics, fluids, relaxation, support

Diarrhea Treat infection (Clostridium difficile), antidiarrheals
Alopecia None versus scarf, turban, prosthesis (wig)
Mucositis Mouth care, narcotics
Myelosuppression
Neutropenia Granulocyte colony-stimulating factor, IV antibiotics,
and hospitalization if febrile
Thrombocytopenia Platelet transfusion if <20/mL or bleeding at <50/mL
Anemia Treat bleeding, erythropoietin, transfusions
Nephrotoxicity Hydration, support, dialysis
Electrolyte wasting Repletion
Neurotoxicity Mainly supportive
Allergic reaction Antihistamine, steroids, epinephrine
Pulmonary toxicity Support, steroids, treat specific cause
Hepatotoxicity Mainly supportive
Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Emergencies Chemotherapy related
Emergency Signs and Symptoms Treatment

Neutropenic Fever, chills, Hospitalization

fever Infections symptoms antibiotics, ± granulocyte
plus absolute neutrophil stimulating factor
count <500

Thrombo- Platelet count <20, petechiae, Transfuse, find source of

cyclopenia/overt bleeding bleeding, avoid aspirin
bleeding and nonsteroidal
anti inflammatory drugs

Allergic Rash, hives, stridor, Antihistamine, steroids

reaction hypotension epinephrine

Extravasation Redness, swelling, Subcutaneous

pain epinephrine
hyaluronidase
Overdose Drug dependent Supportive, antidote if
available
Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
 Conclusion
• Standard chemotherapy : methotrexate, cisplatin, or
paclitaxel, administered to symptomatic patients with
recurrent or metastatic H&N cancer. Treatment intent is
palliative.
• Combination chemotherapy in recurrent disease  improved
response rates without a major impact on survival.
• Neoadjuvant chemotherapy for locoregionally advanced H&N
cancer  high overall and complete response rates, but its
impact on survival is minimal.
• Larynx preservation is feasible with chemotherapy, but
administration of neoadjuvant chemotherapy should
otherwise be confined to an investigational setting.

Bruce Brockstein, MD, Janardan D. Khandekar, MD, Ballenger Head and Neck cancer, chapter 57: 1321-59
• Concomitant chemoradiotherapy for locoregionally advanced
H&N cancer  for patients with unresectable disease.
• Chemotherapy has a definite role in metastatic
lymphoepithelioma. Concomitant cisplatin and radiotherapy
 treatment of locoregionally advanced nasopharyngeal
cancer.
• Participation in clinical trials should be strongly encouraged
for all patients.
Thank you