Topoisomerase I Inhibitors in the Treatment of Head and Neck Cancer

July 1, 2001

Traditionally, the role of chemotherapy in the treatment ofsquamous carcinoma of the head and neck has been confined to patients with

ABSTRACT: Traditionally, the role of chemotherapy in the treatment ofsquamous carcinoma of the head and neck has been confined to patients withrecurrent or metastatic disease who are deemed incurable with surgery orradiation therapy. Over the past decade, however, the role of chemotherapy haschanged dramatically. The use of primary combined chemoradiation to preservefunction or to enhance survival in patients with unresectable disease has becomea standard approach. As the use of chemotherapy in squamous carcinoma of thehead and neck has expanded, investigators have been interested in identifyingnew active agents. Topoisomerase I inhibitors, a new class of drugs, have beenfound to be active in a number of solid and hematologic malignancies. Threetopoisomerase I inhibitors have been investigated in the treatment of metastaticor recurrent squamous carcinoma of the head and neck: 9-aminocamptothecin(9-AC), topotecan (Hycamtin), and irinotecan (CPT-11, Camptosar). Neither 9-ACnor topotecan has demonstrated clinically significant activity in the treatmentof 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 a1-year survival rate of 30.2%. The response and toxicity appear to be dosedependent. Further investigation of irinotecan in combination with other activeagents and radiotherapy is warranted. [ONCOLOGY 15(Suppl 8):47-52, 2001]

Introduction

The term "head and neck cancer"refers to tumors arising from theepithelial lining of the oral cavity, larynx, pharynx, and paranasal sinuses. Inaddition, cancers arising from the major and minor salivary glands are usuallyincluded in this classification. Approximately 45,000 new cases of squamouscarcinoma 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 moreprevalent in males. The major risk factors associated with head and neck cancerare smoking and alcohol abuse. In addition, viral associations include humanpapillomavirus and Epstein-Barr virus.

Outcome for patients with squamous carcinoma of the head andneck is dependent on the stage at presentation.[2] While approximately one-thirdof patients are diagnosed at an early stage (T1, N0, M0 or T2, N0, M0), the vastmajority present with locally advanced disease (T3, T4, or N+). Only a smallnumber of patients will have metastatic disease at the time of diagnosis (1% to5%).[3,4] The cure rate is between 70% and 90% for patients with early-stagedisease and 20% to 70% for those with locally advanced disease, depending ontumor size, stage, and primary site. Unfortunately, patients who present withmetastatic disease have a poor prognosis; median survival for patients treatedwith standard treatment regimens is about 6 months, with a1-year survival rate of 20%.

Chemotherapy:The Changing Role

Historically, head and neck cancer has been a disease treated bysurgery or radiation therapy, or both. Chemotherapy has been reserved forpatients who have failed primary treatment. For early-stage disease,single-modality treatment with either radiation therapy or surgery producesequally high cure rates. Thus, the decision regarding which modality to use isbased on the relative morbidity.[5,6] For example, radiation is often used totreat 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 unduelong-term sequelae of radiation therapy. Clinical research efforts have focusedon strategies to optimize functional outcome and to prevent second primarytumors.

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

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

During the 1980s and 1990s, numerous phase II studiesdemonstrated that use of chemoradiation might provide a reasonablefunction-sparing alternative for patients with locally advanced disease.Subsequently, phase III studies were undertaken to determine whetherchemoradiation 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 thelarynx were randomly assigned to receive a total laryngectomy with postoperativeradiation, or induction chemotherapy with three cycles of cisplatin (Platinol)and fluorouracil (5-FU) followed by radiation (66-76 Gy), with surgicalsalvage therapy for nonresponders or those with recurrences.[8] Survival in bothtreatment arms was equivalent (68%). A total of 64% of patients treated withinduction chemotherapy and radiation were able to preserve their larynx.

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

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

Numerous phase III trials have confirmed the efficacy ofchemoradiation, which has now become the standard of care. As an example, Calaiset al reported data from a randomized trial in stage III/IV oropharyngealcarcinoma.[10] Patients received radiotherapy alone (70 Gy/7 wk) vs concomitantradiotherapy and carboplatin (Paraplatin) at 70 mg/m2/d × 4 days and 5-FU at600 mg/m2/d by continuous infusion × 4 days, with cycles administered on days1, 22, and 43. The addition of chemotherapy resulted in improved 3-yearactuarial survival rates (51% vs 31%, P = .002) and locoregional control (66% vs42%). In the Eastern Cooperative Oncology Group (ECOG) 1392 three-arm trial,radiation alone was compared with radiation and concomitant cisplatin at 100mg/m2 on days 1, 22, and 43 vs split-course radiation with concomitant cisplatinand 5-FU × 3 cycles. The results of this trial showed a statisticallysignificant improvement in 3-year survival with concurrent administration ofcisplatin plus radiation (20% vs 37%, P = .016).[11]

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

Standard Chemotherapy Agents

As chemoradiation has become a standard treatment option forpatients with locally advanced disease, interest in identifying new activeagents in squamous carcinoma of the head and neck has intensified. Initialstudies of new chemotherapy agents are usually conducted in metastatic orrecurrent disease. This allows investigators to establish the efficacy of a newagent prior to incorporation into more complex combined-modality treatmentregimens. A number of chemotherapy agents have demonstrated single-agentresponse rates of at least 10% to 15% in recurrent or metastatic squamouscarcinoma of the head and neck. These include paclitaxel (Taxol), docetaxel(Taxotere), cisplatin, carboplatin, 5-FU, methotrexate, ifosfamide (Ifex), andvinblastine.[15-17]

The use of combination therapy results in a statisticallysignificant increase in the response rate to a range of 30% to 40%.[18,19] Whilesome evidence suggests a survival advantage for single-agent chemotherapy vsbest supportive care, there is no conclusive evidence that survival withmultidrug chemotherapy regimens using currently available drugs is superior tothat of single-agent therapy in the treatment of metastatic or recurrentsquamous carcinoma of the head and neck.[20] Improved survival for recurrent ormetastatic squamous carcinoma of the head and neck will require theidentification of new, more active agents.

Topoisomerase I Inhibitors

Topoisomerases are nuclear enzymes involved in a wide array ofcellular functions including DNA replication, RNA transcription, andrecombination.[21] Because topoisomerase function is vital for tumor growth,investigators have developed topoisomerase inhibitors for use as antineoplasticagents. The first topoisomerase I inhibitor evaluated in humans wascamptothecin. This agent was associated with unacceptable toxicity[22];therefore, further development was halted. Continued interest in topoisomerase Iinhibitors resulted in development of camptothecin analogs with improvedtoxicity profiles. These include topotecan (Hycamtin), 9-aminocamptothecin(9-AC), and irinotecan (CPT-11, Camptosar). These three inhibitors have all beenevaluated in the treatment of metastatic or recurrent head and neck cancer.

Topotecan

Topotecan is a water-soluble camptothecin analog with activityin recurrent ovarian and small-cell lung carcinoma.[23] The most commonlyreported toxicity of single-agent topotecan is myelosuppression. Bothneutropenia and thrombocytopenia are prominent.[23,24] Three phase II studieshave been conducted to evaluate the efficacy of topotecan in squamous cellcarcinoma of the head and neck.

The ECOG conducted a phase II trial of weekly infusionaltopotecan in patients with metastatic or locally recurrent disease.[25]Eligibility criteria included bidimensionally measurable squamous carcinomaconsidered incurable with surgery or radiation therapy. Patients were stratifiedinto the following two cohorts based on extent of previous treatment:chemotherapy-naive patients and chemotherapy failures (patients who had notresponded to one regimen for recurrent or metastatic disease).

Patients were treated with topotecan at 1.5 mg/m2 as a 24-hourcontinuous infusion. Therapy was given weekly for 4 weeks followed by a 1-weekrest, with cycles repeated every 5 weeks. Dose modifications were required forgrade 2 or greater neutropenia or thrombocytopenia and clinically meaningfulgrade 3 or 4 nonhematologic toxicities. Response was assessed using standardcriteria. Patient survival was measured from date of study entry. A two-stagedesign with early stopping rules was applied to both patient cohorts.

Thirty-two patients were entered in the study (16chemotherapy-naive and 16 chemotherapy failures). All patients were evaluablefor toxicity. One patient in each cohort was ineligible and excluded fromanalysis. Two patients were not evaluable for response because repeat tumormeasurements were not obtained. Toxicity was mild with no therapy-relateddeaths. The most prominent toxicity was myelosuppression: five patientsexperienced grade 3 or 4 neutropenia, three had grade 3 infection, six had grade3 or 4 anemia, and one experienced grade 3 thrombocytopenia. Nonhematologictoxicity was minimal. No responses were seen in either cohort. Median survivalrates were 4.6 and 3.2 months in the chemotherapy-naive and previously treatedarms, respectively. One-year survival rates were 33% for chemotherapy-naivepatients and 13% for previously treated patients.

Robert and colleagues from Birmingham, Alabama published finalresults of their phase II trial of topotecan at 1.5 mg/m2 for 5 days, repeatedevery 3 weeks.[26] Of 26 patients enrolled in the study, 23 were evaluable fortoxicity and 22 were evaluable for response. Once again, the most commontoxicity was myelosuppression with neutropenia reported in 42% of cycles. Ninepatients required blood transfusions. The overall response rate was 13% with onecomplete response and two partial responses.

The Southwest Oncology Group (SWOG) conducted a phase II trialof topotecan in metastatic and recurrent squamous carcinoma of the head and neckusing the same dose and schedule.[27] Toxicity was similar to that seen in theBirmingham report. Twenty-nine patients were entered in the trial, only 21 ofwhom were eligible for response assessment. None of these 21 had an objectiveresponse to therapy.

In conclusion, three phase II trials evaluating the efficacy oftwo different schedules of topotecan in the treatment of squamous carcinoma ofthe head and neck have been conducted. The aggregate results of these trialsindicate minimal activity for topotecan in therapy for squamous carcinoma of thehead and neck (Table 1).

9-aminocamptothecin

9-aminocamptothecin is a poorly soluble camptothecin analog thathas been evaluated in a broad range of solid and hematologic tumors. Initialpreclinical trials indicated that prolonged therapeutic drug levels were neededto demonstrate efficacy.[24] Thus, 9-AC was initially evaluated as a 72-hourinfusion, with treatment repeated every 2 to 3 weeks. More prolonged infusionshave also been investigated.

Only one study of 9-AC has been conducted in squamous carcinomaof the head and neck. Lad et al reported the results of a phase II trial of 9-ACin patients with metastatic and recurrent disease. Fourteen patients wereenrolled in the study. Five patients had induction chemotherapy as part ofprimary treatment. All patients had bidimensionally measurable disease and anECOG performance status of 0 to 2. Patients were administered 9-AC at 850 mg/m2via 72-hour continuous infusion, with treatment repeated every 14 days. Grade3/4 toxicity was modest, with neutropenia in five patients, anemia in four, andnausea in three. The response rate was 0% with a median survival of 6 months(see Table 1).[28]

Irinotecan

Irinotecan is a topoisomerase inhibitor that was developed inattempts to identify a water-soluble camptothecin derivative with enhancedantitumor activity and a tolerable toxicity profile.[29,30] Irinotecan hasminimal inherent activity; however, the SN38 metabolite produced byde-esterification is 1,000 times more potent than the parent compound. In vitroand animal studies demonstrated substantial antitumor activity in several commonsolid tumors. Results from phase I studies evaluating a variety of doses andschedules have been reported. The major dose-limiting toxicity ismyelosuppression with neutropenia as the most prominent hematologic toxicity.Irinotecan can produce significant nonhematologic toxicities including severediarrhea and abdominal cramping. Aggressive antidiarrheal therapy has allowedthe safe utilization of this agent. Clinical studies in humans have demonstratedsignificant antitumor efficacy in colorectal, cervical, ovarian, non-small-cell,and small-cell lung carcinoma.[30,31]

Phase II Study of Irinotecan

We undertook a phase II study to evaluate the efficacy andtolerability of irinotecan in patients with metastatic or recurrent head andneck carcinoma. Eligibility criteria included histologic confirmation ofsquamous carcinoma of the head and neck. Patients had not previously receivedchemotherapy for their metastatic or recurrent disease. Patients who hadreceived chemotherapy as part of initial primary therapy were consideredchemotherapy-naive if their last chemotherapy dose had been more than 6 monthsprior to recurrence.

Patients were required to have an ECOG performance status of 0or 1, a life expectancy of 12 weeks, good organ system function, serumcreatinine of less than 2 mg/dL, SGOT ≤ three times the upper limit of normal,bilirubin level less than 1.5 mg/dL, granulocyte count ³1,500/mL, and plateletcount > 100,000/mL. All patients provided informed consent. The study wasapproved by the institutional review board.

The first 22 patients were treated with irinotecan at 125 mg/m2via a 90-minute infusion. Treatment was repeated weekly for 4 consecutive weeksfollowed by a 2-week rest. This 6-week period was considered one cycle. Patientswith clinically significant grade 3 or 4 toxicity had the irinotecan dosemodified to 100 mg/m2 and 75 mg/m2 for the first and second episodes oftoxicity, respectively. Patients were reevaluated for disease status after each6-week cycle. Patients with stable or responding disease were allowed tocontinue to a maximum of nine treatment cycles, while those with progressivedisease were discontinued from the study.

After assessment of the first 22 patients (cohort 1), it wasdetermined that toxicity was excessive. The initial irinotecan dose wasdecreased to 75 mg/m2 over a 90-minute infusion given for 2 consecutive weeksfollowed by a 1-week rest (cohort 2). This 3-week period was considered a cycle.Response to treatment was evaluated every two cycles. Patients with stable orresponding disease continued treatment for a maximum of nine cycles, and thosewith progressive disease were removed from the study. Patients who tolerated the75 mg/m2 dose were allowed to have the dose escalated to 100 mg/m2.

For both patient cohorts, toxicity was evaluated using commontoxicity criteria, and response was assessed using standard response criteria.Patients were encouraged to complete a minimum of 6 weeks of therapy prior todiscontinuing treatment.

All patients enrolled in this trial had received previoustherapy. For the 22 patients in cohort 1, previous therapy includedsurgery/radiotherapy in 13 patients, chemotherapy/radiotherapy in 4, surgeryonly in 2, radiation only in 1, and p53 therapy in 2 patients. For the 16patients in cohort 2, previous therapy included surgery/radiotherapy in 6,chemotherapy/radiotherapy in 4, surgery/radiotherapy/chemotherapy in 2, surgeryonly in 1, and radiation only in 1 patient(s).

Toxicity

Twenty of 22 patients enrolled at dose level 1 (cohort 1) wereeligible for toxicity assessment. Toxicities included grade 3 nausea/vomiting intwo patients, grade 3 diarrhea in five patients, grade 3 neutropenia in threepatients, and hospitalization for gastrointestinal toxicity or neutropenia forfive patients. Twelve patients required at least one dose modification.

Fourteen of 16 patients entered at dose level 2 (cohort 2) wereeligible for toxicity assessment. Grade 3 or 4 toxicities included grade 3nausea/vomiting in two patients, grade 3 diarrhea in one patient, andhospitalization for gastrointestinal toxicity or neutropenia for three patients;grade 3 neutropenia did not occur. Eight patients had a dose increase after thefirst cycle. Toxicities appeared to be much better tolerated at the lower doselevel.

Response

For cohort 1, 19 patients were eligible for assessment ofresponse (Table 2). One patient had a complete response and four had partialresponses. In addition, one patient had a minor response and eight achievedstable disease. The overall response rate (complete plus partial response) forcohort 1 was 26.3% (95% confidence interval [CI] = 9.1%-51.2%). Among 14patients in cohort 2 who were eligible for response determination, two had apartial response. Four patients had stable disease. The overall response rate(complete plus partial response) for cohort 2 was 14.2% (95% CI = 1.8%-42.8%).

Although the number of patients is small, it appears that thelower dose was associated with a lower rate of response. The overall responserate for 33 evaluable patients at both dose levels was 21.2% (95% CI = 9%-38.9%).Median survival for all evaluable patients was 214 days (95% CI = 146-365days) with a 1-year survival rate of 30.2%. The Kaplan-Meier survival curve isshown in Figure 1.

Of note, eight patients in cohort 1 and four patients in cohort2 experienced stable disease. Patients with stable disease were allowed tocontinue on therapy. All patients in cohort 1 who had stable disease wereremoved from the study after two treatment cycles without evidence ofprogression. This was presumably due to the significant toxicity noted at thisdose level.

All four patients with stable disease in cohort 2 continuedtherapy until disease progression occurred. Progression was noted in threepatients after four treatment cycles and in one patient after eight treatmentcycles. Thus, while the response rate at the lower dose level was lower, therewas an increase in the percentage of patients with stable disease who were ableto continue therapy without undue toxicity. The high rate of stable disease maybe clinically significant.

Conclusions

Topoisomerase I inhibitors have demonstrated clinicallymeaningful activity in a number of solid tumors. Their role in the treatment ofsquamous carcinoma of the head and neck has therefore been investigated. Both9-AC and topotecan have failed to demonstrate any substantial clinical activityin patients with recurrent, locally advanced, or metastatic disease. Irinotecan,however, has demonstrated modest clinical activity. Further investigation ofthis agent in the treatment of squamous carcinoma of the head and neck isindicated.

The toxicity of irinotecan at higher doses is substantial inthis frail patient population. Preliminary data indicate that lower doses ofsingle-agent irinotecan are better tolerated but less effective. The judicioususe of irinotecan in combination with other agents known to be active insquamous carcinoma of the head and neck may be one way to capitalize on theefficacy of irinotecan while potentially avoiding the toxicity of the higherdose regimens. A phase II trial of weekly irinotecan in combination withcisplatin is planned.

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