H&N overview of chemotherapy

Question 1

What is the role of chemotherapy in the treatment

of head and neck cancers?

Answer 1

● For patients undergoing treatment with curative intent,
chemotherapy is used concurrent with radiation therapy
to improve locoregional control of disease, either as
definitive chemoradiation therapy or as chemoradiation
therapy after complete surgical resection (adjuvant
therapy). Induction chemotherapy (multidrug regimen
given before definitive chemoradiation) is another ac-
cepted use of chemotherapy for head and neck cancer.
● For patients with recurrent or metastatic disease not
amenable to curative therapy, chemotherapy is used as a
palliative treatment to help control disease and improve
cancer-related symptoms.

Question 2

True or False. Head and neck squamous cell carcinoma is unusually sensitive to chemotherapy
for a solid tumor.

Answer 2

True

Question 3

For squamous cell carcinoma of the head and
neck, chemotherapy (5-fluorouracil [5-FU]) and
cisplatin) has been demonstrated to result in
overall response rates up to 90%. What percentage
of patients will have complete responses, and
what percentage of these complete responses can
be considered a cure?

Answer 3

● Complete response: 20 to 50%
● Cure: ~ 0%; chemotherapy cannot be used with curative
intent.

Question 4

Studies have shown that patients who have not
been treated with prior surgery and/or radiation
respond to chemotherapy almost twice as often as
patients who had. What might explain this?

Answer 4

● Better performance status before treatment
● Intact blood supply to the tumor
● Prior radiation may select for clonal populations of
chemo-resistant cells.

Question 5

What class of chemotherapeutic agents target
DNA and cause cross-linking, double-strand
breaks, or substitutions, thereby interfering with
DNA replication and ultimately causing mutation
and/or cell death?

Answer 5

Alkylating agents

Question 6

What inorganic platinum chemotherapeutic agent results in DNA cross-links, denaturation of strands, covalent bonds with DNA bases, and DNA intra-
strand cross-links?

Answer 6

Cisplatin

Question 7

What common side effects are associated with

cisplatin administration?

Answer 7

Nephrotoxicity, ototoxicity, neurotoxicity, nausea/vomiting,

electrolyte disturbances, myelotoxicity

Question 8

Name the second generation platinum agent that binds with DNA to create interstrand and intra-strand cross-links and protein-DNA cross-links that ultimately result in interruption of the cell cycle
and apoptosis.

Answer 8

Carboplatin

Question 9

What class of chemotherapeutic agents inhibits
accurate DNA replication by imitating naturally
occurring metabolites imperative to DNA replication? What are some examples?

Answer 9

Antimetabolites
● Methotrexate: Binds to dihydrofolate reductase, which is necessary for de novo synthesis of thymidine and purine
synthesis
● 5-FU: Irreversibly binds to thymidylate synthetase,
blocking conversion of uridine to thymidine, thereby
preventing DNA synthesis

Question 10

Cultured Streptomyces spp. produce compounds
that function as antibiotic chemotherapeutic
agents. What agent in this class results in (1)
intercalation between base pairs; (2) forms complexes with iron, thus reducing oxygen to superoxide and hydroxyl radicals which result in DNA
strand breaks; (3) DNA cross-linking, alkylation, and oxygen radicals?

Answer 10

Antitumor antibiotics
● Doxorubicin
● Bleomycin
● Mitomycin

Question 11

What class of chemotherapeutic agents binds to
free tubulin dimers and therefore results in disruption of microtubule polymerization or de-
polymerization and ultimate disruption of the cell cycle? What are some examples?

Answer 11

Alkaloids
● Vincristine: Binds irreversibly to microtubules and spindle
proteins in S phase and interferes with the mitotic spindle
→ arrest in metaphase
● Vinblastine: Binds to tubulin and inhibits microtubule
formation, disrupts mitotic spindle → arrest in M phase

Question 12

What class of chemotherapeutic agents causes
stabilization of microtubules, thereby inhibiting
the normal cell cycle by preventing microtubule
disassembly and arrest at the G2/M phase and
apoptosis? What are some examples?

Answer 12

Taxanes
● Docetaxel
● Paclitaxel

Question 13

What chimeric monoclonal antibody targeting
EGFR, which is overexpressed in head and neck
squamous cell carcinoma, has proven to be
effective for this pathology?

Answer 13

Cetuximab

Question 14

What recombinant humanized monoclonal anti-

body targets EGFR and is currently being investigated in head and neck cancer?

Answer 14

Bevacizumab

Question 15

What are the potential pros and cons of induction
or chemotherapy followed by definitive treatment
in head and neck squamous cell carcinoma?

Answer 15

Pros:
● Decrease the size of the tumor prior to definitive
management
● Increase the response to locoregional definitive manage-
ment (both radiation and surgery may be more effective
for smaller tumors)
● Theoretically decreases the risk for distant metastases
● Assess tumor response to chemotherapy (also a surro-
gate marker for radiosensitivity)
Cons:
● Difficulty identifying tumor extent
● Inability to tolerate definitive management due to toxicities
● Increased cost and complexity of treatment
● Decreased compliance with treatment

Question 16

Phase II trials demonstrated considerable promise
for the use of an induction/neoadjuvant approach
to head and neck squamous cell carcinoma. What
were the results of subsequent phase III trials?

Answer 16

Controversial. Initial phase III studies demonstrated no
survival advantage. However, more recent phase III trials,
including agents such as docetaxel, cisplatin, and 5-FU,
demonstrated both a progression-free survival and overall
survival advantage (European Organization for Research
and Treatment of Cancer [EORTC] 24971; TAX 324).

Question 17

The Head and Neck Contracts Program, run by the
National Cancer Institute, and the Head and Neck
Intergroup Study 0034 both demonstrated that
adjuvant chemotherapy after primary surgery or
radiation has the potential to reduce what key
oncologic outcome measure?

Answer 17

● Distant metastases
● Did not impact overall survival
● Can be considered “maintenance” chemotherapy

Question 18

What are some of the attributes that define high-risk disease in head and neck cancer patients that benefits from adjuvant chemotherapy?

Answer 18

● Positive surgical margins
● Extracapsular extension
● T3/T4 primary disease
● Higher nodal stage
● Perineural invasion
● Angiolymphatic invasion
● Involvement of level IV or V lymph nodes

Question 19

What is the rationale for using chemotherapy and
radiation therapy together to treat head and neck
squamous cell carcinoma?

Answer 19

Each modality functions independently from the other, but
together they result in synergistic chemotherapeutic
radiosensitization.

Question 20

Phase III trials have demonstrated improved disease-free survival for patients undergoing adjuvant chemoradiation therapy for high-risk disease.
What factors conferred a high-risk status for these
studies?

Answer 20

● Positive surgical margins

● Extracapsular extension

Question 21

Which agents have shown a survival advantage for

concurrent chemotherapy as single agents?

Answer 21

● Cisplatin (low-dose daily; high-dose every 3 weeks)
● Carboplatin
● 5-FU

Question 22

Aggressive, multiagent chemotherapy has been
added to radiation therapy for head and neck
cancer and has resulted in a locoregional control
rate in some studies of > 90%. In this cohort of
patients, what is the most likely oncologic failure?

Answer 22

Distant metastases. May suggest a role for induction
chemotherapy.
Note: Controversy is ongoing as to whether the benefit of
multiagent chemotherapy outweighs the risks. Therefore,
single-agent chemoradiation therapy remains the standard
of care for this approach.

Question 23

What clinical outcome has driven research into
definitive chemoradiation strategies for head and
neck cancer? Name two studies that provided
evidence to support this approach.

Answer 23

Organ preservation
Department of Veterans Affairs Laryngeal Cancer Study
Intergroup Radiation Oncology Group (RTOG) 91–11