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Topoisomerase I Inhibitors in the Treatment of Head and Neck Cancer

Topoisomerase I Inhibitors in the Treatment of Head and Neck Cancer

ABSTRACT: Traditionally, the role of chemotherapy in the treatment of squamous carcinoma of the head and neck has been confined to patients with recurrent or metastatic disease who are deemed incurable with surgery or radiation therapy. Over the past decade, however, the role of chemotherapy has changed dramatically. The use of primary combined chemoradiation to preserve function or to enhance survival in patients with unresectable disease has become a standard approach. As the use of chemotherapy in squamous carcinoma of the head and neck has expanded, investigators have been interested in identifying new active agents. Topoisomerase I inhibitors, a new class of drugs, have been found to be active in a number of solid and hematologic malignancies. Three topoisomerase I inhibitors have been investigated in the treatment of metastatic or recurrent squamous carcinoma of the head and neck: 9-aminocamptothecin (9-AC), topotecan (Hycamtin), and irinotecan (CPT-11, Camptosar). Neither 9-AC nor topotecan has demonstrated clinically significant activity in the treatment of metastatic or recurrent squamous carcinoma of the head and neck. In contrast, irinotecan has demonstrated a modest overall response rate of 21.2% (95% confidence interval [CI] = 9%-38.9%), with a median survival of 214 days and a 1-year survival rate of 30.2%. The response and toxicity appear to be dose dependent. Further investigation of irinotecan in combination with other active agents and radiotherapy is warranted. [ONCOLOGY 15(Suppl 8):47-52, 2001]


The term "head and neck cancer"
refers to tumors arising from the
epithelial lining of the oral cavity, larynx, pharynx, and paranasal sinuses. In
addition, cancers arising from the major and minor salivary glands are usually
included in this classification. Approximately 45,000 new cases of squamous
carcinoma of the head and neck are diagnosed annually in the United States.[1]
It occurs predominantly in the sixth and seventh decades of life and is more
prevalent in males. The major risk factors associated with head and neck cancer
are smoking and alcohol abuse. In addition, viral associations include human
papillomavirus and Epstein-Barr virus.

Outcome for patients with squamous carcinoma of the head and
neck is dependent on the stage at presentation.[2] While approximately one-third
of patients are diagnosed at an early stage (T1, N0, M0 or T2, N0, M0), the vast
majority present with locally advanced disease (T3, T4, or N+). Only a small
number of patients will have metastatic disease at the time of diagnosis (1% to
5%).[3,4] The cure rate is between 70% and 90% for patients with early-stage
disease and 20% to 70% for those with locally advanced disease, depending on
tumor size, stage, and primary site. Unfortunately, patients who present with
metastatic disease have a poor prognosis; median survival for patients treated
with standard treatment regimens is about 6 months, with a
1-year survival rate of 20%.

The Changing Role

Historically, head and neck cancer has been a disease treated by
surgery or radiation therapy, or both. Chemotherapy has been reserved for
patients who have failed primary treatment. For early-stage disease,
single-modality treatment with either radiation therapy or surgery produces
equally high cure rates. Thus, the decision regarding which modality to use is
based on the relative morbidity.[5,6] For example, radiation is often used to
treat early larynx cancers with the intent being to preserve voice quality.
Surgery may be used to treat a small oral cavity lesion in order to avoid undue
long-term sequelae of radiation therapy. Clinical research efforts have focused
on strategies to optimize functional outcome and to prevent second primary

Owing to the high cure rates, treatment strategies for
early-stage disease have remained relatively unchanged over the past decade. In
contrast, treatment options for locally advanced disease have changed
dramatically.[7] In the past, patients were categorized according to whether
their tumor could be resected surgically. Resectability has been defined by the
treating surgeon, and, with improvements in operative techniques, this
definition has changed over time. Nonetheless, there remains a cohort of
patients whose disease is bulky and for whom resection is unlikely to produce a
cure; these patients are considered unresectable.

Historically, patients deemed resectable underwent surgery and
postoperative radiation therapy to prevent local recurrence. Surgery for tumors
of the larynx, hypopharynx, or base of the tongue often required total
laryngectomy or total glossectomy. This resulted in marked functional deficits
and an adverse effect on quality of life.

During the 1980s and 1990s, numerous phase II studies
demonstrated that use of chemoradiation might provide a reasonable
function-sparing alternative for patients with locally advanced disease.
Subsequently, phase III studies were undertaken to determine whether
chemoradiation adversely affected survival.

In a trial by the Veterans Affairs Laryngeal Cancer Study Group,
332 patients with locally advanced (stage III/IV) squamous carcinoma of the
larynx were randomly assigned to receive a total laryngectomy with postoperative
radiation, or induction chemotherapy with three cycles of cisplatin (Platinol)
and fluorouracil (5-FU) followed by radiation (66-76 Gy), with surgical
salvage therapy for nonresponders or those with recurrences.[8] Survival in both
treatment arms was equivalent (68%). A total of 64% of patients treated with
induction chemotherapy and radiation were able to preserve their larynx.

Similarly, the European Organization for the Research and
Treatment of Cancer (EORTC) randomly assigned patients with hypopharynx cancer
to surgery followed by radiation or induction treatment with cisplatin and 5-FU
followed by radiation with surgical salvage therapy for recurrence.[9] At 3
years, 42% of patients receiving induction chemotherapy and radiation retained a
"functional larynx." Median survival was 44 months for patients
receiving function-sparing therapy vs 25 months for those undergoing surgery
with postoperative radiation (P = NS). Thus, tissue-sparing therapy using
induction chemotherapy followed by radiation did not compromise survival for
patients with either laryngeal or hypopharyngeal primary tumors.

For patients with unresectable squamous carcinoma of the head
and neck, the rate of long-term survival using radiation therapy alone was less
than 20%. Over the past two decades, the use of combined chemoradiation therapy
has been evaluated in such patients in the hopes of improving cure rates.
Because squamous carcinoma of the head and neck has historically been a
locoregional disease process, investigators hypothesized that chemotherapy used
as a radiation sensitizer to enhance radiation effectiveness might result in
improved local control and overall survival.

Numerous phase III trials have confirmed the efficacy of
chemoradiation, which has now become the standard of care. As an example, Calais
et al reported data from a randomized trial in stage III/IV oropharyngeal
carcinoma.[10] Patients received radiotherapy alone (70 Gy/7 wk) vs concomitant
radiotherapy and carboplatin (Paraplatin) at 70 mg/m2/d × 4 days and 5-FU at
600 mg/m2/d by continuous infusion × 4 days, with cycles administered on days
1, 22, and 43. The addition of chemotherapy resulted in improved 3-year
actuarial survival rates (51% vs 31%, P = .002) and locoregional control (66% vs
42%). In the Eastern Cooperative Oncology Group (ECOG) 1392 three-arm trial,
radiation alone was compared with radiation and concomitant cisplatin at 100
mg/m2 on days 1, 22, and 43 vs split-course radiation with concomitant cisplatin
and 5-FU × 3 cycles. The results of this trial showed a statistically
significant improvement in 3-year survival with concurrent administration of
cisplatin plus radiation (20% vs 37%, P = .016).[11]

In addition to the recently published phase III trials—three
meta-analyses, two literature-based and one patient-based—evaluating the role
of chemotherapy in the primary treatment of head and neck cancer have been
reported.[12-14] All three identified a survival advantage for patients
receiving concomitant chemoradiation. The Bourhis data showed a 19% relative
risk reduction and an 8% absolute survival benefit at 5 years (P = .0001). Thus,
both randomized phase III trials and three meta-analyses have demonstrated
superior survival and local control rates for patients treated with concomitant

Standard Chemotherapy Agents

As chemoradiation has become a standard treatment option for
patients with locally advanced disease, interest in identifying new active
agents in squamous carcinoma of the head and neck has intensified. Initial
studies of new chemotherapy agents are usually conducted in metastatic or
recurrent disease. This allows investigators to establish the efficacy of a new
agent prior to incorporation into more complex combined-modality treatment
regimens. A number of chemotherapy agents have demonstrated single-agent
response rates of at least 10% to 15% in recurrent or metastatic squamous
carcinoma of the head and neck. These include paclitaxel (Taxol), docetaxel
(Taxotere), cisplatin, carboplatin, 5-FU, methotrexate, ifosfamide (Ifex), and

The use of combination therapy results in a statistically
significant increase in the response rate to a range of 30% to 40%.[18,19] While
some evidence suggests a survival advantage for single-agent chemotherapy vs
best supportive care, there is no conclusive evidence that survival with
multidrug chemotherapy regimens using currently available drugs is superior to
that of single-agent therapy in the treatment of metastatic or recurrent
squamous carcinoma of the head and neck.[20] Improved survival for recurrent or
metastatic squamous carcinoma of the head and neck will require the
identification of new, more active agents.


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