Neoadjuvant chemotherapy with vincristine, bleomycin and methotrexate combined with radiotherapy in advanced head and neck squamous cell carcinoma

From September 1980 to August 1981, 25 patients with advanced head and neck squamous cell carcinoma were treated at the Centro Oncologico, Trento, by a chemo-radiotherapeutic combination. The treatment protocol consisted of 4-6 courses of VBM (vincristine, bleomycin and methotrexate) followed by conventional radiotherapy (65 Gy). Only to VBM responders (15 patients) were administered 10 cycles of vincristine-methotrexate. At the end of induction chemotherapy an overall response of 60% (12% complete, 48% partial) was obtained. At the end of radiotherapy the responses were 52.5% complete and 35.5% partial, for an overall response of 88%. The overall survival at 60 months was 8%. This combined approach, in spite of the satisfactory immediate local response rate, does not offer advantages for survival in comparison to conventional treatment modalities.     

Combination chemotherapy with high-dose methotrexate, bleomycin, and cisplatin in management of head and neck squamous cell carcinoma

Fifty-nine patients with stage IV head and neck squamous cell cancer were treated with an intensive induction chemotherapy consisting of high-dose methotrexate-leucovorin, bleomycin, and cisplatin. Forty-five patients had recurrent disease following surgery and/or radiation therapy. The response rate in this group was 22%, with a median response duration of 10 weeks and a median survival of 19 weeks. The median survival in responders was 20 weeks and in nonresponders 18 weeks. Fourteen previously untreated patients (13 T4 and one T2) received identical chemotherapy followed by radiation and/or surgery. The response to chemotherapy in previously untreated patients was impressively higher (93%). These patients had a median survival of 48 weeks, and 30% survived 2 years. The initial chemotherapy did not compromise the succeeding radiation therapy or surgery. Toxicities were frequent, but generally well tolerated. It is concluded that prior surgery and/or radiation therapy compromises the efficacy of subsequent chemotherapy in head and neck cancer. Responses to intensive chemotherapy prior to surgery and/or radiation therapy are excellent in patients with T4 tumors and provides a basis for further intensive treatment in attempts to augment cure rates.     

Combination chemotherapy with cisplatin, bleomycin, and methotrexate in patients with advanced head and neck cancer

Twenty-six patients with advanced head and neck cancer, 22 of whom had failed prior surgery and/or radiotherapy, were treated with a combination regimen of cis-diamminedichloroplatinum II, bleomycin, and methotrexate. There were no complete responses. Nine patients achieved a partial response (35%). Three of the four (75%) patients without prior therapy achieved a partial response while only 6 of the 22 patients (27%) with prior surgery and/or radiation therapy obtained a partial response. The median response duration was 3 months. Patients with a partial response did not live significantly longer than those who did not live significantly longer than those who did not respond. Toxic reactions were frequent: there were three episodes of sepsis secondary to leukopenia and two cases of bleomycin pulmonary toxicity. Mucositis was noted in 40% and nausea and vomiting in 60% of patients. We conclude that this triple-drug regimen has little value in the treatment of patients with advanced squamous cell carcinoma of the head and neck who have failed prior surgery and radiotherapy.     

Neoadjuvant chemotherapy with cisplatin, methotrexate, bleomycin and vincristine (CABO) in patients with stage III and IV squamous cell carcinoma of the head and neck

Forty-six patients with Stage III-IV previously untreated squamous cell carcinoma of the head and neck were treated with neoadjuvant chemotherapy with cisplatin, methotrexate, bleomycin and vincristine. The overall response rate was 70%, with a 9% complete response rate. The most frequent side effects were myelosuppression, nausea and vomiting, alopecia, neurotoxicity and stomatitis. Definitive local therapy consisted of surgery alone in 13 cases, surgery plus radiation in another 13, and radiotherapy alone in 14. Six patients, four of whom died, received no definitive local therapy and two were lost to follow-up. The median disease-free survival time was 10.5 months, and the most frequent cause of failure was local regional relapse (85%). Median survival time was 13 months and there were eight long-term survivals (median 48 months). Response to chemotherapy was independent of all analysed prognostic factors. Disease-free survival and survival were significantly influenced by the presence or absence of lymph nodes. Our results do not support the routine use of neoadjuvant chemotherapy with cisplatin, methotrexate, bleomycin, and vincristine in patients with advanced cell carcinoma of the head and neck.     

Effective chemotherapy for advanced carcinoma of the cervix with bleomycin, cisplatin, vincristine, and methotrexate

This study was designed as a Phase II clinical trial in advanced recurrent or metastatic squamous cell carcinoma of the cervix with a combination of bleomycin (B: 10 u/m2/d) and cisplatin (P: 20 mg/m2/d) administered for five consecutive days in intravenous infusion for 7 hours and vincristine (V: 1 mg/m2) and methotrexate (M: 40 mg/m2) administered only on day one of each cycle which was repeated every 28 days up to a maximum of 6 times. Over a period of 2 years, 15 evaluable patients with measurable disease received at least 3 courses of therapy. Six had recurrent disease and nine had distant metastases. All had previous radiation therapy. There were two dropouts after the first course due to nausea and vomiting which was practically universal. Other side effects included: mild paresthesias of the extremities (89%), stomatitis (41%), diarrhea (17%), moderate pancytopenia and hypomagnesemia which was reduced from 65% to 17% when magnesium sulfate 10% was administered with cisplatin. Sixty-six percent of the evaluable patients achieved remission (7 partial and 3 complete) usually before the fourth course of therapy. The disease-free interval was of 29.7 +/- 15 weeks in all responders (40.6 +/- 15.5 weeks in complete responders). The mean survival from the start of BPVM therapy was of 55.8 +/- 33.3 weeks in responders and of only 14 +/- 2.9 weeks in nonresponders (P less than 0.01). It is concluded that BPVM is an effective combination chemotherapy in advanced squamous cell carcinoma of the cervix. These results should be confirmed in a Phase III trial.     

Sequential methotrexate and 5-fluorouracil with bleomycin and cisplatin in the chemotherapy of advanced squamous cancer of the head and neck

A bolus intravenous dose of 5-fluorouracil of 600 mg/M2 was added exactly 1 hour after methotrexate administration in an established combination program including bleomycin and cisplatin for advanced squamous cell cancer of the head and neck. Results were no better than those observed previously with the three drugs, and hematologic and mucosal toxicities were slightly worse. The overall response rate was 41% in 34 patients with recurrent or metastatic disease, with only 6% complete remissions. Median time to disease progression for responding patients was 14 weeks, compared with 10 weeks for nonresponders. Partial response had little impact on survival. Among 12 patients with far-advanced disease confined above the clavicles without prior radiotherapy, 9 (75%) achieved partial remission, but the median survival, even with later surgery or irradiation, was only 34 weeks.     

Induction chemotherapy with cisplatin, bleomycin and methotrexate in advanced head and neck cancer--lack of therapeutic gain

Seventy patients with stage IV head and neck cancer were treated by two courses of induction chemotherapy followed by surgery plus postoperative irradiation (7) or radical radiotherapy (62). One patient renounced to further treatment after chemotherapy. Each chemotherapy course consisted of methotrexate (40 mg/m2 days 1 and 14), bleomycin (10 mg/m2 days 1, 7 and 14), and cisplatin (50 mg/m2 day 4). Three patients did not complete the two courses of chemotherapy planned due to bad tolerance whereas the rest of the patients tolerated chemotherapy well. 2 CR (3%) and 35 PR (50%) were achieved for an overall response rate to chemotherapy of 53%. 35 (50%) CR were achieved with the whole treatment schedule. The 5-year disease-free survival is 26% for the whole group of patients. The prior response to chemotherapy neither influenced the complete responses to treatment nor the relapse-free survival. The addition of this chemotherapy to conventional treatment was of no value.     

Combined chemotherapy of head and neck squamous cell carcinomas with methotrexate,bleomycin, and hydroxyurea

Summary Thirty-two patients with squamous cell carcinoma of head and neck not amenable to surgery or radiotherapy were treated with a combination of methotrexate 0.6 mg/kg IV weekly, bleomycin 15 mg IV weekly, and hydroxyurea 1,000 mg/m² three oral doses weekly. Eleven complete responses and ten partial responses of more than 50% were observed. The mean duration was 43 weeks for complete responses and 35 weeks for partial responses. Toxicity consisted in leukopenia, thrombocytopenia, nausea, vomiting, stomatitis, and cutaneous alterations. Only one patient suffered reversible lung toxicity.These results suggest that a combination of three drugs in squamous cell head and neck cancer may be more effective than a combination of bleomycin and methotrexate only.     

Vinblastine, bleomycin and cisplatin for recurrent or metastatic squamous cell carcinoma of the head and neck

Forty-two patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with vinblastine, bleomycin, and cisplatin. All patients had received prior surgery, radiation or chemotherapy and all had measurable disease. Forty-five percent of the patients responded with a median duration of response of eight months and median survival of nine months. Six patients (14%) were complete responders and had a median duration of response of 12 months and median survival of 24+ months. Thirteen patients (31%) were partial responders and had a median duration of response of seven months and survival of 13 months. Toxicity was mild with nausea and vomiting occurring in all patients after cisplatin. There were two cases of bleomycin-induced pulmonary fibrosis and two cases of mild renal insufficiency (creatinine clearance level, 45 cc/min). This regimen compares favorably with other published regimens for advanced head and neck cancer.     

Multidrug chemotherapy using bleomycin, methotrexate, and cisplatin combined with radical radiotherapy in advanced head and neck cancer

Thirty-one patients with Stage III-IV head and neck squamous cell cancer were treated by three courses of combination chemotherapy using bleomycin, methotrexate, and cisplatin followed by a radical course of radiation and in two cases by surgery. Of 29 evaluable patients, 4 (14%) achieved complete remission (CR) with chemotherapy and 13 (45%) had a partial response (PR). With the addition of radiotherapy and surgery, the CR rate increased to 72%. At 30 months the actuarial survival of all evaluable patients was 61% and of complete responders, 76%. Patients with nasopharyngeal cancer had an actuarial survival of 80% at 30 months, whereas patients with squamous malignancies at other sites in the head and neck region had an actuarial survival of only 37%. Side effects were tolerable. It is concluded that complete responders to combination chemotherapy and radiotherapy have a survival benefit at 30 months. The combined approach is most effective in nasopharyngeal cancer.     

Combination chemotherapy with vinblastine, bleomycin, and cis-diamminedichloroplatinum (II) in squamous cell carcinoma of the head and neck

Forty-five patients with advanced squamous cell carcinoma of the head and neck, 23 of whom had received no prior therapy, were given the combination of vinblastine, 4 mg/m2 intravenously (IV) on Day 1; bleomycin, 15 mg/day intramuscularly on Days 1-7; and cis-diamminedichloroplatinum (II), 60 mg/m2 with mannitol diuresis on Day 8. The regimen was repeated at three-week intervals, for a maximum of three cycles. Among the 23 patients without prior surgery or radiation, there were 5 complete responses and 12 partial responses, a 74% response rate; whereas, among the 22 with prior therapy, there were 2 complete responses and 8 partial responses, a response rate of 45%. Nineteen of 23 previously untreated patients were subsequently given radiation, 1 had surgery, and 1 had surgery plus radiation. Twelve of these 19 patients are currently free of disease, with a median duration of ten months from initial response. Four of the 22 previously treated patients received radiation and 2, surgery; 4 of these 6 patients are without evidence of disease. Renal dysfunction with elevation of serum creatinine occurred in 5 patients, a leukocyte count of less than 3,000/mm3 in 3, a platelet count of less than 100,000/mm3 in 2, skin changes in 11, hearing loss in 1, and both peripheral neuropathy and pulmonary changes in 1 patient. This combination of agents has substantial activity in untreated patients and may be useful as initial therapy in advanced head and neck malignancies by diminishing the incidence of local recurrence and distant metastasis.     

A randomized study of methotrexate,bleomycin, hydroxyurea with versus without cisplatin in patients with previously untreated and recurrent squamous cell carcinoma of the head and neck

The value of a combination of methotrexate, bleomycin and hydroxyurea with us. without cisplatin was randomly examined in 62 evaluable patients with previously untreated (44 patients) and recurrent (18 patients) squamous cell carcinoma of the head and neck. Methotrexate (30 mg/m²) and bleomycin (15 mg) were given intravenously weekly, hydroxyurea (1000 mg/m²) per os 3 times per week for 4 weeks. Cisplatin (60 mg/m²) was added on Day 1 every month. A higher overall response rate was observed with the cisplatin-containing regimen (66%, included 17% complete) as compared with 27% (3% complete) with the 3-drug combination (P value 0.0025). The cisplatin-containing regimen was more active in both previously untreated patient group and in the group of recurrent patients. Toxicity was more pronounced in the cisplatin regimen and necessitated frequently reduced drug dosages. No survival difference was observed between the treatment groups. Median survival in previously untreated patients was 16.2 months and 7.2 months in patients who failed conventional local treatment. It is concluded that a cisplatin-containing regimen is more effective in advanced head and neck carcinoma than the same combination without cisplatin.     

Mitomycin-C, methotrexate, bleomycin and cis-diamminedichloroplatinum II in the chemotherapy of advanced squamous cancer of the head and neck

Thirty-four patients with advanced squamous cancer of the head and neck were treated with an outpatient regimen combining mitomycin-C, cis-diamminedichloroplatinum (II), methotrexate and bleomycin. Five had complete remissions and 15 partial remissions, for an overall response rate of 59%. Responses were noted on 11 of 13 patients (85%) with disease above the clavicles without prior irradiation. Median duration of partial remission was four months. Response rate was independent of age, performance status, presence of distant metastases and primary site. Hematologic toxicity was substantially more severe with this program than had been observed in a prior study using the same regimen without mitomycin-C. Since neither complete nor partial response rates, nor response durations improved with the addition of mitomycin, we conclude that it adds little to the efficacy of the other three agents.     

Results and failures with or without cisplatin containing induction chemotherapy in the treatment of squamous cell carcinoma of the head and neck

This prospective randomised study was undertaken to assess the effects and effectiveness of cisplatin in a pre-operative setting. Thirty-eight patients were treated with stage II-IVa (AJCC) squamous cell cancer of the oral cavity and oropharynx. Nineteen patients received a combination of bleomycin, vincristine, methotrexate (BVM; group I.), 19 received BVM and cisplatin (group II). Patients underwent surgery within 3 weeks after chemotherapy. Biopsy and surgical specimens were compared. A clinical complete response was seen in five patients in group I (26.3%) and in four patients in group II (21.1%). Partial response was noted in 11 patients in group I (57.8%) and in 13 patients in group II (68.4%). There was no statistical difference in clinical response between the two groups. Microscopic response was better in the cisplatin treated group. Median follow up of patients is 52 (36-70) months. Disease free survival showed a significant difference, favouring the no cisplatin group (P = 0.03). There was no significant difference in overall survival (P > 0.6). Cisplatin in combination with BVM showed significantly higher levels of microscopic response, but the lower disease free survival is mostly due to a higher rate of regional neck failure.     

Induction chemotherapy in advanced squamous head and neck carcinoma with high-dose cis-platinum and bleomycin infusion.

Forty patients with advanced head and neck cancer were treated with combined Cis-platinum-Bleomycin chemotherapy. Cis-diammine dichloroplatinum (DDP) 120 mg/m2 iv was given after prehydration, with mannitol diuresis on Day 1. On Day 3, an initial loading dose of Bleomycin 15 mg/m2 was given by rapid iv push followed by continuous 24 hour intravenous infusion of Bleomycin 15 mg/m2 Day 3 through Day 10. DDP 120 mg/m2 iv was administered again on Day 22. The patients were evaluated for tumor response and resectability between Day 29 to Day 35. Of 39 patients who were evaluable, there were 8 complete responses or CR (20%) and 22 partial responses or PR (56%), for a major response rate of 76%. Nineteen patients had surgery (14 patients whose lesions were initially inoperable and 5 patients who were initially operable). Chemotherapy toxicity in 40 patients included alopecia (40), vomiting (39), mucositis (11), skin rash (10), fever (17), weight loss of more than 5 lbs. (25), WBC less than 3,000 (2), platelets less than 100,000 (1), peak serum creatinine of 2 mg% (3), severe-hearing loss (1), hypersensitivity reaction (2). Surgical complication in 19 patients were pharyngocutaneous fistulae (2), wound dehiscence (1), meningitis and brain abscess (1). There was one death secondary to nephrotoxicity. This particular combination chemotherapy when given as initial treatment, appears very effective in reduction of tumor bulk. Long-term follow-up and randomization is necessary to determine effect upon survival.     

Chemotherapy of advanced head and neck squamous carcinoma with cisplatin, fluorouracil and bleomycin administered in an outpatient schedule

From May 1983 to September 1984, 48 consecutive patients with locally advanced, recurrent and/or metastatic head and neck squamous carcinoma were treated with cisplatin 60 mg/m2 i.v. on day 1, fluorouracil 10 mg/kg i.v. push from day 1 to day 4 and bleomycin 10 mg/m2 i.v. from day 1 to day 4, every 3 weeks. In the 44 evaluable patients complete remission was observed in 4, partial remission in 9, stable disease in 19, and progression in 12, for a 29.5% response rate. When the analysis was limited to the 21 patients with PS greater than 70 and no previous chemotherapy or radiotherapy, the response rate was 48%. Toxicity was acceptable, and no treatment related deaths occurred. Overall median survival (all eligible patients) was 7 months. Although further studies with this combination in poor risk patients (previously treated or with PS less than 70) do not appear to be indicated, a more accurate assessment in good risk patients might be warranted.     

Therapy of recurrent squamous cell carcinoma of the head and neck using combination vincristine, bleomycin, and methotrexate. A Southwest Oncology Group Study

Fifty-six patients with squamous cell carcinoma of the head and neck were treated with the combination of vincristine, bleomycin, and methotrexate (VBM) on an every 2-week schedule. The overall CR + PR rate was 20%. Median response duration was 10 weeks. The toxicity during this trial was comparable to previously reported VBM regimens. The response rate was less than or no better than those previously reported for VBM or methotrexate alone. Therefore, this regimen offers nothing over methotrexate alone or other VBM regimens.     

Paclitaxel, cisplatin, and 5-fluorouracil for patients with advanced or recurrent squamous cell carcinoma of the head and neck

BACKGROUND: The combination of cisplatin and 5-fluorouracil (5-FU) is considered standard therapy for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Paclitaxel has exhibited single-agent activity in patients with this disease. The authors conducted this study to evaluate the feasibility and efficacy of combining paclitaxel with cisplatin and 5-FU for patients with advanced or recurrent SCCHN. METHODS: Patients with recurrent, metastatic, or locally advanced SCCHN who had measurable or evaluable disease and no prior chemotherapy were eligible. The starting dose level consisted of paclitaxel 135 mg/m(2) on Day 1, cisplatin 75 mg/m(2) on Day 2, and 5-FU 1 gm/m(2)/day on Days 2-6. Due to Grade 4 mucositis, dose level 1 of 5-FU was reduced to 800 mg/m(2)/day on Days 2-6 (for 7 patients), and subsequently the 5-FU dose was adjusted to 1 gm/m(2)/day on Days 2-5 (for 17 patients). RESULTS: Twenty-five patients were enrolled, with a median age of 60 years and a median Southwest Oncology Group performance status of 1. Of the 25 patients, 16 had recurrent disease, 3 had metastatic disease at diagnosis, and 6 had untreated locally advanced SCCHN. Ninety-nine courses of therapy were administered, with a median of 5 courses. Major toxicities were neutropenia and mucositis. Significant neurotoxicity or nephrotoxicity were not observed. There were two treatment-related deaths (one each due to mucositis and neutropenic pneumonia), and these precluded further dose escalation. Fifteen of the 25 patients (60%) achieved a major response. Of significance is the response rate of 58% (11 of 19 patients) in those with recurrent or metastatic disease who had a duration of response ranging from 3 to 19+ months. Two of these 19 patients continue to be in remission of 19+ and 15+ months' duration, respectively. The median survival for patients with recurrent or metastatic disease was 6 months (range, 1-26 months), with a 1-year survival rate of 37%. CONCLUSIONS: The dose and schedule for the combination of paclitaxel, 5-FU, and cisplatin as determined in this study are feasible, with encouraging outcomes and activity in patients with recurrent or metastatic SCCHN. The results of this trial warrant larger-scale evaluation to determine the role of this combination in the management of patients with this disease.