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.     

Treatment of advanced Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide (ABVD) after failure of MOPP therapy.

From June 19, 1975 to December 22, 1976, twenty-seven patients with advanced Hodgkin's disease who failed MOPP (nitrogen mustard, vincristine, procarbazine and prednisone) were treated with adriamycin, bleomycin, vinblastine, and imidazole carboxamide, (ABVD). Complete response (CR) was achieved in 22% of patients and partial response was achieved in 15%. No response was observed in 63% of patients. With a median duration of follow-up for CR patients of only 10.5 months, two of the six CR patients have already relapsed. In this series of patients ABVD was not an effective curative regimen for patients with Hodgkin's disease who have failed MOPP.     

Toxicity of aggressive multimodality therapy including cisplatinum, bleomycin and methotrexate with radiation and/or surgery for advanced head and neck cancer

A combined modality regimen employing induction chemotherapy with cisplatinum, bleomycin and methotrexate followed by surgery and/or radiation therapy was initiated in patients with advanced squamous cell carcinoma of the head and neck. In the first 23 patients treated with this program there was a 90% response rate to induction chemotherapy (9% CR and 81% PR). Toxicity associated with radiotherapy, but not surgery, was increased with 11 of 23 patients (48%) who experienced some toxicity during or immediately after radiotherapy. Mucositis was worse than expected and severe delayed mucositis was seen in 2 patients, one or whom required hospitalization. Late complications, possibly related to therapy included one myocardial infarction and one episode of hypoglycemia, both of which were fatal. One other patient voluntarily failed to take prescribed oral leucovorin, dying of unrescued methotrexate toxicity during adjuvant therapy, a questionable suicide. Further follow-up and analysis of failure will be necessary to determine if the value of a combined modality regimen in producing an increased cure rate and long term survival will out weight increased toxicity.     

Chemotherapy of advanced head and neck cancer with methotrexate, bleomycin, and cis-diamminedichloroplatinum II in an effective outpatient schedule.

Thirty-one patients with advanced cancer of the head and neck, twenty-six of whom had failed prior irradiation, were treated with an out-patient chemotherapy regimen combining methotrexate, bleomycin, and cis-diamminedichloroplatinum (II). The overall response rate among evaluable patients was 61%, with 22.5% complete remission. If 6 additional patients not completing 3 weeks of treatment are included, the response rate was 51.4%. The median duration of partial remission was 3 months, but none of the complete remitters has relapsed with a follow-up of two to twenty months (median six). Response rate was not dependent on performance status, prior irradiation, or primary site. Toxicity was mild. The remission rate and duration suggest that this regimen may be superior to single agents, and as effective as more complicated and toxic regimens using higher doses of the same drugs.     

Favorable long-term survival following induction chemotherapy with cisplatin, fluorouracil, and leucovorin and concomitant chemoradiotherapy for locally advanced head and neck cancer.

BACKGROUND: The majority of patients with head and neck cancer die of locoregional recurrence of disease following surgery and/or radiotherapy. PURPOSE: Our purpose was to administer induction chemotherapy, perform surgery, and administer concomitant chemoradiotherapy in rapid sequence and to evaluate their impact on locoregional and distant tumor control. METHODS: Sixty-four patients with previously untreated, locoregionally advanced head and neck cancer received two cycles of cisplatin, bleomycin, and methotrexate (PBM) (33 patients) or cisplatin, fluorouracil (5-FU), and leucovorin (PFL) (31 patients). PFL was given to patients who were unable to receive bleomycin. Local therapy consisted of surgery and/or concomitant chemoradiotherapy with 5-FU, hydroxyurea, leucovorin, and radiotherapy (FHX-L), all administered every other week. RESULTS: Complete and overall induction response rates were 21% and 79%, respectively, for PBM and 29% and 81%, respectively, for PFL. At completion of local therapy, 81% of the patients were disease-free. With a median follow-up of 35 months, the median survival and time to progression are 22 and 17 months, respectively, for PBM and have not been reached for PFL. Locoregional recurrence of disease is 30% for PBM and 26% for PFL. Distant disease progression is 24% for PBM and only 3% for PFL. CONCLUSIONS: The sequencing of induction chemotherapy and concomitant chemoradiotherapy is feasible and results in a high local control rate and in an encouraging survival rate with PFL. The high distant failure (i.e., outside the head and neck area) rate of PBM suggests insufficient systemic activity for that regimen. IMPLICATIONS: Concomitant FHX-L chemoradiotherapy may improve regional control rates of advanced head and neck cancer. Effective systemic therapy may be needed to control systemic micrometastases. PFL, but not PBM, appears to be suitable to accomplish that goal.     

Treatment of squamous-cell carcinoma of the head and neck with cisplatin and 5-fluorouracil

Seventy patients with squamous-cell carcinoma of the head and neck were treated with a 24-hour infusion of cisplatin, followed by a 5-day continuous infusion of 5-fluorouracil (5-FU). Among 31 patients without prior treatment, stage III (six patients) and IV (25 patients), there were seven complete responses (CRs) and 19 partial responses (PRs) for an overall response rate of 84%. In the group of 30 patients with recurrent disease after surgery and/or radiotherapy, there were five CRs and ten PRs (total response rate of 50%). Among nine patients who failed prior chemotherapy, there were two CRs and one PR. Performance status and stage had minor effects on response frequency. The projected survival in the no prior treatment group was 59% at 22 months while the median survival of the recurrent cancer group was nine months. Compared to our previous study using cisplatin-vincristine-bleomycin (COB) chemotherapy, our present regimen has a higher CR rate (P less than .008). Durations of response and survival in the present study appear to be longer in the unresectable group and the recurrent cancer group. Toxicity was generally mild. The use of dexamethasone, diphenhydramine, droperidol, and perphenazine as antiemetics prophylactically resulted in 28% of treatment cycles associated with vomiting. This compares favorably with our previous 79% incidence of vomiting. This regimen appears to be more effective than our previous regimen and can be given with less toxicity.     

The role of intratumour therapy with electroporation and bleomycin in the management of advanced squamous cell carcinoma of the head and neck.

OBJECTIVES: To determine the safety and efficacy of electroporation with bleomycin in patients with advanced squamous cell carcinoma of the head and neck. METHODS: Two open-label, multicenter, single-arm Phase II studies of intratumour electroporation therapy. Sixty-two patients with 86 squamous cell carcinoma tumours of the head and neck were enrolled. Twenty-five patients were treated with bleomycin alone. Fifty-four patients (17 initially treated with bleomycin alone) were treated with electroporation and bleomycin therapy. Local tumour response was measured. RESULTS: In the bleomycin alone group, one tumour showed a partial response and 36 tumours showed no response to treatment. In the bleomycin with electroporation groups, 17 tumours showed complete response, 22 tumours showed partial response and 30 failed to achieve more than a 50% reduction in tumour size (no response). Bleomycin with electroporation had a significantly (p<0.001) greater number of patients showing a partial or complete response to the therapy when compared to bleomycin alone. Thirteen adverse events were reported which included five episodes of local bleeding, six local infections, one local tongue swelling and one cardiac arrhythmia. CONCLUSIONS: Fifty-seven percent of squamous cell carcinomas of the head and neck demonstrated a partial or complete response to intratumour electroporation with bleomycin suggesting that further work investigating its use as a treatment for local control of these lesions should be pursued.     

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.     

Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously untreated patients with advanced squamous cell cancers of the head and neck

Induction chemotherapy, followed by surgery and/or radiotherapy was utilized in patients with advanced squamous cell carcinoma of the head and neck. During these trials, the authors observed that response to chemotherapy predicts further response to subsequent radiotherapy. This study was comprised of 57 patients with 60 separate neoplasms who demonstrated less than complete response (partial or no response) to initial treatment with a combination chemotherapy containing cisplatin. Subsequently radiotherapy, either 5000 rad preoperatively or 6600 rad as definitive therapy, was employed. Forty-one of the 42 tumors with initial partial response to chemotherapy also responded to radiotherapy (97.6%). Only one of the 18 tumors that initially failed to respond to chemotherapy subsequently responded to radiotherapy (5.5%). This observation suggests that patients with head and neck cancer sensitive to initial chemotherapy share parameters that are also radiation sensitive.     

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.     

Cisplatin, bleomycin, and methotrexate (PBM) chemotherapy in locally advanced and metastatic head and neck cancer

Twenty-two patients with locally advanced or metastatic head and neck tumors received a total of 84 courses of a combination of cisplatin, bleomycin, and Methotrexate (PBM) for a median of four courses per patient (range, 1-7). Among these 22 patients there were four patients (18%) who achieved complete remission (CR) and 13 patients (60%) who had a partial remission (PR). The overall remission rate (CR + PR) thus reached 78%; five patients (22%) progressed while on therapy. The mean duration of objective response (CR + PR) was 8 months; CR lasted a median of 18 months (range, 2-48). Survival was not influenced by tumor histology or by previous surgery. The presence of locoregional disease did adversely affect survival from the onset of chemotherapy (P = 0.1). The rate of survival was also affected by primary tumor site; patients with nasopharyngeal primaries survived longer than all other patients (22 vs. 11 months, P = 0.06). Toxicity to chemotherapy consisted mainly of nausea and vomiting and stomatitis. Three patients developed fever while leukopenic. One patient experienced irreversible renal damage, and another suffered from bleomycin-induced pulmonary fibrosis. The high response rate obtained in our group of patients did not have a substantial impact on overall survival. Aggressive, multimodality approaches should be considered in the treatment of these patients when possible.     

Factors that affect response to chemotherapy and survival of patients with advanced head and neck cancer.

A review of 164 patients with far advanced head and neck cancer, treated by a cytotoxic chemotherapy over a ten year period, at WAyne State University, Detroit, Michigan, was done in an attempt to determine factors that may influence the response to chemotherapy and subsequent survival. Response rate to methotrexate was 28%, 5-FU 31%, and porfiromycin 13%. Improved responses were noted with combination chemotherapy. Patients who failed to first line therapy rarely responded to other single agent or combination chemotherapy. Those who did not have prior surgery and/or radiotherapy had better results from drug therapy. Patients with good performance status at the time of initial chemotherapy, had better response to treatment (32% vs. 13% PR & CR) and longer survival (28 weeks vs. 9 weeks, p = 0.01) when compared to those with poor status. Patients who responded to chemotherapy have better survival compared to nonresponders (29 weeks vs. 16 weeks, p = 0.002). This information may prove helpful in future planning of multidisciplinary approach in the treatment of patients with 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.     

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.     

Phase-II study of cis-diammine-dichloro platinum (cis-platinum), bleomycin and methotrexate for advanced squamous cell carcinoma of head and neck

Summary Twenty-one patients with head and neck carcinomas relapsing after radiotherapy were treated with a combination of cis-platinum, bleomycin, and methotrexate. Four patients (19%) achieved a partial response. Toxicity was significant in selected cases; three patients developed WBC counts less than 1,000/mm³ and one of these patients died with sepsis. Severe mucositis was present in three of the twenty-one patients. Considering the toxicity of this combination and the limited therapeutic activity with the dose and schedule used in this study, this regimen is not recommended for the treatment of squamous head and neck carcinomas relapsing after radiotherapy.     

Induction chemotherapy with a new regimen alternating cisplatin, fluorouracil with mitomycin, hydroxyurea and bleomycin in carcinomas of nasopharynx or other sites of the head and neck region.

Sixty-six patients with locally advanced (Stages III and IV) carcinoma of the head and neck were treated with three cycles of induction chemotherapy, consisting of cisplatin, fluorouracil (FU) infusion, bleomycin, mitomycin, and hydroxyurea, followed by radiotherapy and/or surgery. There were 48 men and 18 women with a median age of 55 years (range, 18 to 75 years) and Karnofsky performance status of 80 (range, 40 to 90). Primary site was nasopharynx (28 patients), followed by larynx (12) and others (26). Forty-one (62%) patients were presented with Stage IV disease. The response rate to induction chemotherapy was 27% complete response, 50% partial response, 20% stable disease, and 3% progressive disease. There was no significant difference in response rate between patients with cancer of nasopharynx or other sites (P greater than 0.1). Survival was 61% at 24 months. Patients with cancer of nasopharynx had a better survival than those with other primaries (P = 0.033). Toxicities from chemotherapy included alopecia (73%), nausea/vomiting (66%), leukopenia (54%), stomatitis (36%), anemia (32%), thrombocytopenia (16%), and diarrhea (9%). Grade IV toxicity was not observed. Induction chemotherapy with this new regimen resulted in a high response rate but may not be superior to cisplatin and FU alone. It can be safely combined with radiotherapy as a potentially curative therapy in squamous cell carcinoma of the head and neck. Chemotherapy followed by radiation therapy may yield survival similar to radical surgery in laryngeal and other head and neck cancers.     

Bleomycin and cis-platinum with or without mitomycin C in 110 previously untreated patients with head and neck cancer

Between November 1979 and October 1981, 110 consecutive patients with previously untreated, biopsy-proven squamous cell carcinoma of the head and neck, were treated by chemotherapy prior to scheduled surgery and/or radiotherapy. Two regimens of chemotherapy were used. The first 57 patients received cis-platinum, 20 mg/m2/day for 5 consecutive days and bleomycin 5 mg/m2/day as a continuous infusion over the same 5 days every 3 weeks (Regimen A). The next 53 patients received the same schedule and dose of cis-platinum, bleomycin 2.5 mg/m2 every 12 hours for the same 5 consecutive days and mitomycin C6 mg/m2 on day 1 of each cycle every 3 weeks (Regimen B). The number of courses administered prior to surgery and/or radiotherapy ranged from 1-4 depending on the otorhinolaryngologist's assessment of the optimal time for locoregional treatment. The overall response rate in regimen A was 78% (45/57) compared to 90% for regimen B (48/53). Complete responses were seen in 10/57 (18%) and 13/53 (25%) patients in regimens A and B, respectively. Eight of 57 patients in regimen A and 6/53 in regimen B refused further treatment and follow-up, and 7/53 patients in regimen B chose to pursue chemotherapy (in which methotrexate replaced bleomycin) rather than undergo surgery and/or radiotherapy. Five of these seven patients are surviving disease-free from 7-12 months. In regimen A, 31/57 patients are surviving with a median survival exceeding 15 months. In regimen B, 46/53 patients are surviving up to 14 months. Nausea and vomiting induced by cis-platinum were the major side effects, seen to a variable degree in all patients. No cis-platinum-induced renal toxicity was observed with the 5-day regimen and none of the patients had symptomatic bleomycin-induced pneumonitis. One patient had a bleomycin-induced skin rash which did not require discontinuation of therapy.     

Intra-arterial mitomycin C and intravenous bleomycin as induction chemotherapy in advanced head and neck cancer--a phase II study

Fifty-six patients with previously untreated, unresectable squamous cell carcinomas of the head and neck region were treated with repeated intra-arterial chemotherapy with mitomycin C using a selective or super-selective angiographic technique, and bleomycin given i.v., followed by radical radiotherapy. In addition, restricted tumour-reductive surgery was done in 18 of these patients. The response rate (CR + PR) after completion of the integrated treatment was 89%, with 63% of the patients showing CR. The toxicity of this regimen was, however, far from negligible. The median survival for this series of patients with advanced head and neck cancers is 19 months, and 17 are still alive after 16 + -66 + months.     

Very-high-dose cisplatin with bleomycin infusion as initial treatment of advanced head and neck cancer

Fifty-one patients with locally advanced squamous cancer of the head and neck (SCHN) were treated with up to three cycles of very-high-dose cisplatin, 187.5 mg/m2 (administered over five days) in hypertonic saline, and bleomycin infusion, 60 U/m2 (administered over five days), prior to definitive local therapy, in an attempt to improve complete remission (CR) and overall response rates. After chemotherapy, patients underwent surgery if the tumor was resectable for cure, (unless the operation involved total laryngectomy), and/or locoregional radiation therapy. Twelve patients (24%) achieved CR and 23 (45%) partial remission (PR) for an overall response rate of 69%. Thirty-nine of the 51 patients are evaluable following chemotherapy and locoregional treatment, and 28 (72%) have achieved disease-free status. Seven of these 28 (25%) have subsequently relapsed. Eleven of the 51 patients (22%) have died at median follow-up of 10+ months (3+ to 24+). Nausea and vomiting (94%) was the most severe acute toxicity. Myelosuppression was mild and nephrotoxicity was effectively prevented by the 3% saline diuresis. Bleomycin was withheld in 12 of 49 (24%) because of deterioration in pulmonary function tests. Ototoxicity in 12 of 49 (25%) and neurotoxicity in 19 of 49 (39%) were the most significant long-term toxicities. Very-high-dose cisplatin and bleomycin in this study was an effective chemotherapy regimen, but not more so than more conventional doses of cisplatin. Toxicity from both drugs was significant.     

Docetaxel and cisplatin: An active regimen in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck

Background: Docetaxel and cisplatin are among the most active antitumor agents in head and neck cancer, and phase I studies found the combination of the two drugs to be feasible. The EORTC ECSG performed a multicenter phase II study in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck to evaluate the antitumor efficacy and toxicity of this combination.Patients and methods: Eligibility criteria included written informed consent, a WHO performance status <2, life expectancy of >12 weeks, and adequate bone marrow, liver and renal function. Neoadjuvant pretreatment with cisplatin-based chemotherapy or prior radiotherapy were allowed. Patients were ineligible if pretreated with taxoids, had CNS involvement, concurrent malignancy, peripheral neuropathy, or no measurable disease. Treatment consisted of docetaxel 100 mg/m2 (one-hour i.v. infusion), followed by cisplatin 75 mg/m2 (three-hour i.v. infusion), repeated every three weeks. Supportive care included hydration, 5HT3- antagonists, and corticosteroids.Results: Forty-four patients (median age 55 years, range 35–76) entered the trial; 41 patients were eligible, 164 cycles of treatment were evaluable for toxicity, and 31 patients for response. Fourteen patients had undergone prior surgery, 15 had received radiotherapy, and five had had chemotherapy. A median number of four treatment cycles (range 1–6) was given. Hematologic and non-hematologic toxicities were common, but hypersensitivity reactions and fluid retention were very infrequent due to corticosteroid prophylaxis. Four patients were taken off the study due to toxicity, and one toxic death occurred due to pneumonia. Among 41 eligible patients, objective responses as confirmed by independent review included six complete remissions and 16 partial remissions, resulting in an overall response rate of 53.7% (95% confidence interval: 37.4%–69.3%). Responses occurred in locally advanced, recurrent and metastatic disease, both in pre- and non-pretreated patients. Of 22 evaluable, non-pretreated patients with locally advanced or metastatic disease, five achieved complete responses, and 14 partial responses. Observed among nine evaluable pretreated patients with locally advanced or metastatic head and neck cancer were one complete response and two partial responses.Conclusion: The combination of docetaxel and cisplatin is feasible and active in locally advanced, recurrent, and metastatic squamous cell carcinoma of the head and neck.