The American Cancer Society estimates that 28,900 new cases of

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1 2224 Phase II Study of Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Patients with Squamous Cell Carcinoma of the Upper Respiratory or Alimentary Passages of the Head and Neck Scott H. Okuno, M.D. 1 James A. Mailliard, M.D. 2 Vera J. Suman, Ph.D. 1 John H. Edmonson, M.D. 1 Edward T. Creagan, M.D. 1 Suresh Nair, M.D. 3 Ralph Levitt, M.D. 4 John W. Kugler, M.D. 5 1 Mayo Clinic and Mayo Foundation, Rochester, Minnesota. 2 Nebraska Oncology Group, Creighton University, University of Nebraska Medical Center and Associates, Omaha, Nebraska. 3 Geisinger Clinic and Medical Center CCOP, Danville, Pennsylvania. 4 MeritCare Hospital CCOP, Fargo, North Dakota. 5 Illinois Oncology Research Association CCOP, Peoria, Illinois. Conducted as a trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service Grants CA-15083, CA-25224, CA-37404, CA-63849, CA-35448, CA , CA-35113, CA-35195, CA-35269, CA-35415, CA-60276, and CA from the National Cancer Institute Department of Health and Human Services. Additional participating institutions include: Carle Cancer Center, Urbana, IL (Alan K. Hatfield, M.D.); Duluth CCOP, Duluth, MN (James E. Krook, M.D.); Toledo Community Hospital Oncology Program CCOP, Toledo, OH (Paul L. Schaefer, M.D.); Scottsdale CCOP, Scottsdale, AZ (Tom R. Fitch, M.D.); Sioux Community Cancer Consortium, Sioux Falls, SD (Loren K. Tschetter, M.D.); CentraCare Clinic, St. Cloud, MN (Harold E. Windschitl, M.D.). Address for reprints: Scott H. Okuno, M.D.,Mayo Clinic, 200 First Street SW, Rochester, MN 55905; Fax: (507) ; okuno.scott@mayo. edu Received February 14, 2001; revision received November 12, 2001; accepted December BACKGROUND. The chemotherapy drugs methotrexate, vinblastine, doxorubicin, and cisplatin have shown activity in patients with recurrent or metastatic squamous cell carcinoma arising from the upper respiratory or alimentary passages of the head and neck. This study was undertaken to assess the antitumor activity and toxicity profile of the drug combination methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) in this patient population. METHODS. Patients with histologically confirmed unresectable, recurrent, or metastatic squamous cell carcinoma arising from the upper respiratory or alimentary passages of the head and neck were treated with MVAC over a 4-week cycle. The doses were as follows: 30 mg/m 2 of methotrexate on Days 1, 15, and 22; 3 mg/m 2 of vinblastine on Days 2, 15, and 22; 30 mg/m 2 of doxorubicin on Day 2; and 70 mg/m 2 of cisplatin on Day 2. The total cumulative dose of doxorubicin was not to exceed 450 mg/m 2. Treatment was discontinued after four cycles for those whose disease remained stable. Patients were evaluated for chemotherapy response, progression free survival, and survival. RESULTS. Thirty-six patients were accrued onto this study between April 1993 and February One patient (3%) with a history of cardiac heart failure was declared ineligible. Severe leukopenia (leukocyte count 2000 cells/m 3 ) was observed in 55% of the patients during the first cycle of treatment and in 81% of the patients during the entire course of their treatment. The overall objective response rate over the first 4 cycles of treatment was 46% (90% confidence interval [CI], 33 60%). Two of the 18 patients who responded had a complete response. The median time to progression was 19 weeks, and 1-year progression free survival rate was 17% (95% CI, 8 36%). The median survival was 49 weeks, and the 1-year survival rate was 43% (95% CI, 29 63%). Among the 22 patients with unresected residual or recurrent disease, the median time to progression was 11 weeks, and 1-year progression free survival rate was 14% (95% CI, 5 39%), and median survival was 24 weeks, and the 1-year survival rate was 36% (95% CI, 21 63%). Among the 13 patients with metastatic disease, the median time to progression was 26 weeks, and the 1-year progression free survival rate was 23% (95% CI, 9 62%), the median survival was 54 weeks, and the 1-year survival rate was 54% (95% CI, 33 89%). CONCLUSIONS. Methotrexate, vinblastine, doxorubicin, and cisplatin is an active chemotherapy regimen in patients with recurrent or metastatic squamous cell cancer arising from the upper respiratory or alimentary passages of the head and neck. Cancer 2002;94: American Cancer Society. DOI /cncr KEYWORDS: head and neck carcinoma, squamous cell, chemotherapy, methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). The American Cancer Society estimates that 28,900 new cases of head and neck carcinoma will occur in 2002 and 7400 patients will die in 2002 because of their head and neck carcinoma. 1 Mortality 2002 American Cancer Society

2 Methotrexate, Vinblastine, Doxorubicin, and Cisplatin for Head and Neck Carcinoma/Okuno et al rates have been decreasing since the early 1980s. The standard curative treatment options for patients with head and neck carcinoma is usually surgery or radiation therapy. The treatment of patients with recurrent or metastatic head and neck carcinoma, however, is palliative and has not consistently demonstrated an improvement in overall survival. 2,3 Multiple chemotherapy agents and combination have been used in patients with head and neck carcinoma. As single agents, methotrexate, vinblastine, doxorubicin, and cisplatin have shown activity in patients with recurrent or metastatic squamous cell carcinoma arising from the upper respiratory or alimentary passages of the head and neck. 4 9 In addition, doxorubicin is an active agent in resistant head and neck carcinoma when it is combined with cisplatin or cyclophosphamide. 10,11 The drug combination methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) has been used in advanced bladder carcinoma and in gynecologic tumors with significant activity and acceptable toxicities This study was undertaken by the North Central Cancer Treatment Group (NCCTG) to assess the antitumor activity and toxicity profile of MVAC in patients with head and neck carcinoma. Patient Characteristics Patients 18 years of age or older with histologic confirmation of unresectable, recurrent, or metastatic squamous cell carcinoma (including undifferentiated carcinoma) arising from the upper respiratory or alimentary passages of the head and neck were eligible. An exception to the requirement for histologic confirmation was made in the case of a patient with a previously histologically confirmed primary carcinoma and a clinical diagnosis of new or progressive pulmonary metastasis with no other tumor area assessable to biopsy. The patients were required to have Eastern Cooperative Oncology Group performance score of 0 2 and have measurable or assessable indicator lesion. A measurable lesion is a lesion with clearly defined bidimensional measurements whose largest tumor dimension is at least 1.0 cm on physical examination or chest X-ray, at least 3.0 cm on computed tomography scan, magnetic resonance imaging scan, or ultrasound, or at least 5.0 cm on radioisotope liver scan. An assessable lesion is a lesion on physical examination or imaging study that can be assessed in terms of changes in size but cannot be clearly measured in two dimensions. (Note: The definitions of measurable and assessable disease and the criteria for objective tumor response used in this study are that which were used in NCCTG clinical trials prior to their adoption of the Response Evaluation Criteria in Solid Tumors [RECIST] criteria). Contraindication to study entry included a leukocyte count of less than 3600 cells/mm 3 ; platelet count less than 100,000 cells/mm 3 ; serum creatinine greater than 1.5 times the upper limit of institutional normal (ULN); total bilirubin greater than or equal to 0.9 mg/dl above ULN, serum calcium greater than or equal to 1.9 mg/dl above ULN, major surgery within the 4 weeks of registration; abdominal exploration or biopsy within 3 weeks of registration, any prior chemotherapy; prior radiation therapy to greater than 15% of functioning bone marrow within 30 days of registration or greater than 30% of the bone marrow irradiated to a dose in excess of 2500 centigrays cgy at any time prior to registration; weight loss greater than 10% within the last 3 months before registration; myocardial infarct, angina pectoris, congestive heart failure, or significant myocardial dysfunction within the last 4 months before registration; bilateral bundle branch block or any medication for cardiac-related problems at any time before registration; hypercalcemia requiring more than simple hydration; estimated daily caloric intake of less than 1200 calories; second malignant disease of the type that might make the origin of the metastasis questionable; and active infection. Pregnant and lactating women were not eligible for this trial. The trial was approved by the institutional of review boards of all participating institutions, and written form consent was obtained from each patient before study entry. Patients and Methods We administered MVAC over a 4-week cycle. Dosages were as follows: 30 mg/m 2 of methotrexate on Days 1, 15, and 22; 3 mg/m 2 of vinblastine on Days 2, 15, and 22; 30 mg /m 2 of doxorubicin on Day 2; and 70 mg/m 2 of cisplatin on Day 2; methotrexate, vinblastine, doxorubicin were given intravenous push to a Y-injection site of 0.9% sodium chloride running intravenously. Cisplatin was given intravenously over a 2-hour period and 1000 ml of D5/0.45 sodium chloride with 25 g of mannitol. The chemotherapy dose of doxorubicin was not to exceed 450 mg/m 2. The patients who responded to treatment continued on therapy until disease progression was documented. Patients who were responding to treatment but developed central nervous system metastasis could remain on study and receive radiation therapy. Treatment was discontinued after four cycles for those whose disease remained stable. Treatment and Evaluation Within 14 days before registration and before the start of a cycle of treatment, patients underwent a complete medical examination including measurement of the indicator lesion, hematologic and chemistry group

3 2226 CANCER April 15, 2002 / Volume 94 / Number 8 readings (leukocyte count, platelet count, hemoglobin, creatinine, total bilirubin, serum glutamic oxaloacetic transaminase, calcium, and alkaline phosphatase), and toxicity assessment using the National Cancer Institute Common Toxicity Criteria (NCI CTC). Leukocyte and platelet counts also were obtained weekly during the course of treatment. An electrocardiogram and a chest X-ray were obtained within 14 days before registration. Electrocardiograms were repeated as clinically indicated and chest X-rays were repeated before each treatment cycle if abnormal or every 3 months while on treatment if normal. Computed tomography scans of the abdomen were performed before the start of the third cycle of treatment and as clinically indicated. After completion of treatment but before the documentation of a progression, patients underwent medical examinations that included a tumor assessment, chest X-ray, and toxicity assessment, every other month the first year after registration, every 2 months the second year after registration, and every 6 months thereafter until progression. Patients who refused further treatment or discontinued treatment because of toxicity were followed up annually for progression and death. It was recommended that treatment be terminated if a patient experienced severe (NCI CTC Grade 3 or higher) cardiac dysrhythmia, pericarditis, cardiac function, or neural sensory deficit or if a patient s serum creatinine increased to more than two times their pretreatment level. The guidelines for dose reductions on Days 15 and 22 included the following recommendations: 1) methotrexate and vinblastine dosages should be reduced by 50% on that day and subsequent administrations if on that day the leukocyte count was cells/mm 3 or the platelet count was 75,000 89,999 cells/mm 3 ; 2) methotrexate and vinblastine should not be administered on that day if on that day the leukocyte count was less than 2000 cells/mm 3 or the platelet count was less than 75,000 cells/mm 3 ; and 3) methotrexate should not be administered that day if Grade 2 or higher stomatitis was observed or if creatine levels exceeded 1.5 times baseline levels. The guidelines for dose reductions at the end of the 4-week treatment cycle (Day 29), included decreasing methotrexate and cisplatin doses on subsequent cycles by 50% if creatine levels were times that of baseline; decreasing cisplatin doses on subsequent cycles by 50% if a Grade 2 neurosensory toxicity was observed; not administrating methotrexate on the first day of the next cycle if Grade 2 or higher stomatitis was observed; and delaying treatment until leukocyte counts reached 3500 cells/mm 3 and platelet counts reached 100,000 cells/mm 3. During the course of the 28-day treatment cycle if the leukocyte counts were cells/mm 3 or platelet counts were 25,000 74,999 cells/mm 3 for 7 or more consecutive days, it was recommended that methotrexate, vinblastine, doxorubicin doses be reduced by 20%. For leukocyte or platelet values below these levels for 7 or more consecutive days, it was recommended that methotrexate, vinblastine, and doxorubicin be reduced by 40%. If leukocyte nadir was greater than or equal to 3000 cells/mm 2, platelet nadir was greater than or equal to 75/mm 2, and no severe toxicities were observed on methotrexate, vinblastine, and doxorubicin, doses could be increased by 10%. Statistical Consideration The primary endpoint of this study was the objective regression rate over the first four cycles of treatment. A patient was considered to have had a complete regression (CR) if there was a total disappearance of all evidence of tumor noted on 2 consecutive evaluations at least 4 weeks apart. Patients with palpable hepatomegaly were considered to have had a partial regression (PR) if at least a 30% reduction in the sum of the linear measurements below the right and left costal margins in the midclavicular lines and below the xyphoid process was noted on 2 consecutive evaluations at least 4 weeks apart. Patients with bidimensional indicator lesions were considered to have had a PR if there was at least a 50% reduction in the sum of the products of the largest perpendicular dimensions of the indicator lesion on 2 consecutive evaluations at least 4 weeks apart. Patients with assessable disease were considered to have had tumor regression if a definite decrease in the size of the indicator lesion was documented on 2 consecutive evaluations at least 4 weeks apart. A patient was considered to have progressed if new lesions appeared; the indicator lesion significantly increased in size; or significant clinical deterioration occurred that could not be attributed to treatment or other medical conditions. A significant increase in the size of the indicator lesion was defined as at least a 25% increase in size compared with its pretreatment size for a patient with measurable disease who did not meet the criteria for CR or PR; a definite increase in the size of the indicator lesion compared with its pretreatment size for a patient with assessable disease who did not meet the criteria for tumor regression; an increase in size of the indicator lesion at the point of its maximum reduction that was at least 50% of the size of its maximum reduction for a patient with measurable disease who did meet the criteria for CR of PR; and a definite increase in size of the indicator lesion at the point of its maximum reduction for patients with assessable disease who met the criteria for tumor regression. Patients were con-

4 Methotrexate, Vinblastine, Doxorubicin, and Cisplatin for Head and Neck Carcinoma/Okuno et al sidered to have stable disease if they failed to meet the criteria for CR, PR, tumor regression, or progression. A three-stage design was implemented to test the hypothesis that had a true proportion of objective regressions over the first 4 cycles of treatment is at most 0.20, where the smallest proportion of objective regressions over the first 4 cycles of treatment that would suggest this treatment regimen warrants further study is This study design was as follows. Accrue 15 eligible patients. If two or fewer objective regressions were observed, accrual would be terminated. If 3 or more objective regressions were observed, 10 additional patients were accrued and evaluated for response. If 6 or fewer objective regressions were observed among all 25 patients accrued, accrual would be terminated. If not, 10 additional patients were accrued and evaluated for response. If 11 or more objective regressions were observed among these 35 patients, this was to be regarded as sufficient antitumor activity in this patient population to consider further testing of this regimen in subsequent trials unless significant toxicity was encountered. This design was chosen to provide a power of 86% for detecting a true objective proportion of 0.40 at a significance level of The objective regression proportion was estimated as the number of eligible patients who had begun treatment and achieved a CR, PR, or regression divided by the total number of eligible patients who had begun treatment. A 90% confidence interval (CI) for the objective regression proportion was constructed using the Duffy and Santner approach. For those who achieved a response, the duration of response was defined as the time from the date the response was first documented to the date of progression. Time to progression was defined as the time from registration to disease progression. Patients who died without documentation of progression were considered to have progressed on the date of their death. Survival time was defined as the time from registration to death. Time to event distributions were estimated using the Kaplan Meier method. RESULTS Thirty-six patients were accrued onto the study between April 1993 and February One patient (3%) with a history of cardiac heart failure was declared ineligible as he was taking medications for this condition. The pretreatment characteristics of the 35 patients are presented in Table 1. Twenty-two patients (63%) had unresected residual or recurrent disease. Eight patients (23%) were not irradiated or surgically treated before entry. Two patients (6%) had been biopsied only. The remaining 25 patients (71%) had TABLE 1 Patient Characteristics at Entry Characteristic MVAC (n 35) (%) Median age (yrs, range) 59 (24 77) Male gender 26 (74) Race White 32 (91) Black 2 (6) Other 1 (3) Site of primary disease Larynx 8 (23) Hypopharynx 6 (17) Nasopharynx 6 (17) Oral cavity/floor of mouth 6 (17) Tongue 4 (11) Oropharynx 2 (6) Sinus 1 (3) Face 1 (3) Unknown 1 (3) Performance score 0 12 (34) 1 20 (57) 2 3 (9) Dominant disease Visceral 12 (34) Nonvisceral 23 (66) Disease status Unresected residual 7 (20) Recurrent 15 (43) Metastatic 13 (37) Indicator lesion Measurable 19 (54) Assessable 16 (46) Prior surgery None 8 (23) Minimal 2 (6) Extensive 1 (3) Prior RT None 10 (29) 5000 cgy completed 6 months before entry 1 (3) 5000 cgy completed 6 months before entry 5 (15) 5000 cgy completed 6 months before entry 19 (54) MVAC: methotrexate, vinblastine, doxorubicin, cisplatin; cgy: centigray. been irradiated for a total dose of at least 5000 cgy or had extensive surgery. Approximately two-thirds of the study patients had nonvisceral dominant disease. The overall objective regression rate over the first 4 cycles was 46% (90% CI, 33 60%). There were 8 PRs among the 19 patients with measurable disease and 2 CRs and 6 tumor regressions among the16 patients with assessable disease. The median duration of response was 7.7 months (range, 8 weeks to 5.3 years). Table 2 displays the response data in terms of disease status at study entry. There were 12 patients with recurrent disease at study entry whose indicator lesion was in a prior radiated field 5 patients had tumors

5 2228 CANCER April 15, 2002 / Volume 94 / Number 8 TABLE 2 Response by Disease Status at Study Entry Type of disease CR PR REG Primary Site (in order of response duration) Duration of response (mos) Unresected residual (n 7) Nasopharynx, oral cavity, sinus, tongue 4.4, 6.7, 60.7, 63.7 Recurrent (n 15) Larynx, hypopharynx, floor of mouth, larynx nasopharynx 1.9, 4.2, 7.3, 8.0, 8.3 Metastatic (n 13) Larynx, hypopharynx, tongue, nasopharynx, hypopharynx, oropharynx hypopharynx 5.0, 5.7, 6.0, 8.9, 11.6, 13.3, 13.9 CR: complete regression; PR: partial regression; REG: tumor regression. that responded to treatment, and 3 patients had tumors that remained stable. All but 2 of the 16 patients who achieved a response completed the 4 cycles of treatment. Both of these patients terminated treatment after 3 cycles. One patient developed sepsis secondary to chemotherapy-induced neutropenia and then died. The other patient went off study to receive radiation therapy. Among the 14 patients who achieved a response and completed 4 cycles of treatment, 5 patients continued to receive treatment (per protocol) for 1 3 additional cycles. The reasons the other nine patients did not continue to receive additional cycles of the study therapy included desire to receive alternative therapy (three patients), refusal (two patients), progression documented at fourth cycle evaluation (two patients), stroke (one patient), and severe toxicity (one patient). Of the four patients who completed four cycles of treatment with an objective response of stable disease, three patients maintained stable disease throughout the 4 cycles and one patient was found to have progressed at the fourth cycle evaluation. Only one of three patients who maintained stable disease throughout four cycles of treatment entered the observation phase (per protocol). The other two patients refused to enter the observational phase to receive alternative therapy. The 15 patients who did not complete 4 cycles of treatment failed to receive a response because of progression (8 patients), death (4 patients), clinical deterioration (1 patient), toxicity (1 patient), and refusal (1 patient). The causes of these early deaths were aspiration pneumonia secondary to tracheoesophageal fistula on Day 8, renal failure on Day 8, cardiopulmonary arrest secondary to hypotension on Day 12, and head trauma/coma on Day 30. Patients were followed up until death or a minimum of 5 years was reached. At last contact, 3 patients are still alive and progression free years after registration, 9 patients had died without having documented progression; and 23 patients had progressed and died. Two of the three patients still alive achieved a response (one CR and one PR) and then received FIGURE 1. The distributions of overall survival times and progression free survival times among the 35 eligible patients. radiation therapy. The other patient still alive remained stable while on MVAC and then went on to surgery. Overall, the 1-year PFS rate was 17% (95% CI, 8 36%), and the 1-year survival rate was 43% (95% CI, 29 63%; see Fig. 1). Among the 21 patients with unresected residual disease or recurrence disease, the median time to progression was 11 weeks with a 1-year progression free survival rate of 14% (95% CI, 5 39%), and the median survival time was 24 weeks with a 1-year survival rate of 36% (95% CI, 21 63%; see Fig. 2). Among the 13 patients with metastatic disease, the median time to progression was 26 weeks with a 1-year progression free rate of 23% (95% CI, 9 62%), and the median survival time was 54 weeks (see Fig. 3). Toxicities Severe leukopenia (leukocyte count less than 2000 cells/mm 3 ) was observed in 55% of patients during the first cycle of treatment and 81% of patients during the entire course of treatment. Severe thrombocytopenia (platelet count 50,000 cell/mm 3 ) was observed in only 1 patient (3%) during the first cycle of treatment and in 2 patients (7%) during the entire course of

6 Methotrexate, Vinblastine, Doxorubicin, and Cisplatin for Head and Neck Carcinoma/Okuno et al TABLE 3 Severe Toxicities Reported Type MVAC (n 35) (%) FIGURE 2. The distributions of overall survival times and progression free survival times among the 21 patients with unresected or recurrent disease. Lethargy Severe 9 Any 77 Nausea Severe 17 Any 63 Vomiting Severe 14 Any 49 Stomatitis Severe 9 Any 46 Anorexia Severe 3 Any 29 Diarrhea Severe 6 Any 14 Neurosensory Severe 0 Any 14 Infection Severe 6 Any 11 Headache Severe 3 Any 6 Dyspnea Severe 3 Any 3 MVAC: methotrexate, vinblastine, doxorubicin, cisplatin. FIGURE 3. The distributions of overall survival times and progression free survival times among the 13 patients with metastatic disease. treatment. One patient after three cycles developed sepsis secondary to chemotherapy induced neutropenia and died. Severe (Grade 3 or higher) neurosensory toxicity was not reported, and Grade 2 neurosensory toxicity was reported in only one patient. Grade 2 or higher stomatitis was observed in 26% of the patients during the treatment course. Other severe nonhematologic toxicities included nausea, vomiting, and lethargy (Table 3). A patient was considered to have completed a full dose of an agent on a particular cycle if at least 90% of the initial dose of that agent was administered on that cycle. A full dose of methotrexate and vinblastine was given to less than 25% of the patients in each of the 4 treatment cycles. The percentage of patients who received a full dose of doxorubicin decreased from 100% in the first cycle to 44% in the 4th cycle of treatment. Greater than 80% of the patients received a full dose of TABLE 4 No. of Patients Who Received at Least 90% of Initial Dose Agent Cycle Methotrexate 6/35 5/26 4/24 1/18 Vinblastine 6/35 5/26 5/24 4/18 Doxorubicin 35/35 18/26 13/24 8/18 Cisplatin 35/35 24/26 22/24 15/18 cisplatin in the first 4 cycles of treatment (Table 4). Table 5 displays by agent and cycle of treatment the median dose and range of dosages administered. DISCUSSION The combination regimen MVAC initially was used in the management of bladder cancer with impressive response rates. 16 The NCCTG studied this regimen in women with advanced cervical carcinoma and observed a 66% response rate, with a 21% complete

7 2230 CANCER April 15, 2002 / Volume 94 / Number 8 TABLE 5 Median and Range of Dose Administered Agent 1(n 35) (range) 2(n 26) (range) Cycle 3(n 24) (range) 4(n 18) (range) Methotrexate 60 (28 92) 59 (19 101) 38 (15 93) 38 (15 81) Vinblastine 6 (3 10) 6 (2 10) 5 (1 11) 5 (2 9) Doxorubicin 30 (27 31) 30 (19 34) 29 (15 37) 25 (15 37) Cisplatin 70 (66 72) 70 (49 72) 69 (49 74) 69 (35 75) response rate. 15 Currently, MVAC is one of the arms in the Gynecology Oncology Group three-arm study in women with advanced cervical carcinoma. Building on the experience with MVAC, the NCCTG proceeded with this study of MVAC in advanced head and neck carcinoma during an era when the main active agents used for head and neck carcinoma were methotrexate, cisplatin, and 5-fluorouracil. Despite newer chemotherapy agents such as the taxanes, gemcitabine, and vinorelbine, use of chemotherapy for patients with recurrent unresectable squamous cell carcinoma of the head and neck has not clearly demonstrated an improvement in overall survival compared to observation. 17 Single agents against squamous cell carcinomas of the head still demonstrate a response rate of approximately 20 40%. Combination chemotherapy regimens for advanced disease have shown higher responses with response rates up to 70%. 3,18,19 These regressions, however, have been generally short-lived, limited to 3 4 months and have not significantly altered survival, which is approximately 4 8 months. In this study, the MVAC regimen has demonstrated significant activity and prolonged progression free survival with some long-term survivors for patients with unresectable metastatic squamous cell carcinomas of the head and neck. Three of the six patients with nasopharynx disease responded to treatment, which is comparable to the objective response rate of 45% (95% CI, 26 64%) observed in the other 29 patients on this study whose primary disease was not nasopharynx. Patients with locally recurrent disease tended to fair worse than patients with metastatic disease in terms of progression free survival and overall survival. Patient population mix and subsequent therapies in part may account for the results in this study. Despite the administrative and toxicity profile complexity of the MVAC regimen, our response rate of 46% and 1-year survival rate of 43% compares favorably with recent studies using paclitaxel/cisplatin/5- fluorouracil and paclitaxel/ifosfamide/cisplatin regimens with 1-year survival rates of 37% and 41%, respectively. 20,21 What is lacking in our study, as well as in other studies, are data on quality of life. When regimens have similar survival rates, quality-of-life data are an important element in the treatment decision-making process. This MVAC regimen should be compared with the standard regimens (5-fluorouracil, cisplatin, or taxane-based therapy) in both locally recurrent and unresectable metastatic patients in terms of response, survival, and quality of life. REFERENCES 1. Jemal A, Thomas A, Murray T. Cancer statistics, CA Cancer J Clin 2002;52: Hussain M, Benedetti J, Smith RE, et al. Evaluation of 96- hour infusion fluorouracil plus cisplatin in combination with alpha interferon for patients with advanced squamous cell carcinoma of the head and neck. Cancer. 1995;76: Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous cell carcinoma of the head and neck; a Southwest Oncology Group study. 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8 Methotrexate, Vinblastine, Doxorubicin, and Cisplatin for Head and Neck Carcinoma/Okuno et al Saxman SB, Loehrer PJ, Propert K, et al. Long-term follow-up of phase III intergroup study of MVAC vs cisplatin in metastatic urothelial carcinoma [meeting abstract]. Proc Annu Meet Am Soc Clin Oncol. 1996;15:A Long HJ, Langdon RM Jr., Cha SS, et al. Phase II trial of methotrexate, vinblastine, doxorubicin, and cisplatin in advanced/recurrent endometrial carcinoma. Gynecol Oncol. 1995;58: Sternberg CN, Yogoda A, Scher HL, et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium: efficacy and patterns of response and relapse. Cancer. 1989;64: Vokes EE, Athanasiadis I. Chemotherapy for squamous cell carcinoma of head and neck: the future is now. Ann Oncol. 1996;7: Eisenberger M, Kransnow S, Elenberg S, et al. A comparison of carboplatin plus methotrexate versus methotrexate alone in patients with recurrent and metastatic head and neck cancer. J Clin Oncol. 1989;17: Clavel M, Vermorken JB, Cognetti F, et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol. 1994;5: Hussain M, Gadgeel S, Kucuk O, Du W, Salwen W, Ensley J. Paclitaxel, cisplatin, and 5-fluorouracil for patients with advanced or recurrent squamous cell carcinoma of the head and neck. Cancer. 1999;86: Shin DM, Glisson BS, Khuri FR, et al. Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma. J Clin Oncol. 1998; 16: