Chemotherapy of advanced colorectal cancer. A randomized trial of sequential methotrexate and 5-fluorouracil

Fifty-five patients with advanced colorectal cancer were entered into a randomized controlled clinical trial to evaluate order of administration and sequential methotrexate (MTX) and 5-fluorouracil (5-FU) therapy. Patients were randomized to receive either MTX, 250 mg/m2, followed 1 h later by 5-FU, 600 mg/m2, or 5-FU followed 1 h later by MTX in the same doses. Fifty-four patients were evaluable for response, of whom 15 (28%) achieved objective partial tumor response. There were no significant differences between the two sequences in response rate, time to treatment failure, or survival duration. The results of this study do not indicate a clinically significant difference between the two sequences tested, in which MTX preceded or followed 5-FU by 1 h. Determination of the value of these drugs given sequentially at longer intervals must await appropriate controlled trials.     

A prospective randomized trial of methotrexate versus cisplatin in the treatment of recurrent squamous cell carcinoma of the head and neck

A prospective randomized study was conducted to determine the relative effectiveness, toxicity and tolerance of methotrexate (MTX) versus cisplatin (DDP) in patients with recurrent head and neck squamous cell carcinoma. Forty-four patients were randomized to receive either MTX, 40 mg escalated to 60 mg/m2 IV push weekly, or DDP, 50 mg/m2 6 hour infusion days 1 and 8 every 4 weeks. All patients had objectively measurable disease and a performance status greater than 60% (Karnofsky scale). All had been treated with surgery and/or radiotherapy. No patients had prior chemotherapy. Prior treatment, performance status, and site of primary disease were comparable in both groups. Complete and partial objective responses were achieved in 23.5% of the MTX group and 28.6% of the DDP group (P = 0.51). Median duration of response was 84 days in the MTX group and 92 days in the DDP group. Median survival of patients was 6.1 months with MTX and 6.3 months with DDP. Mucositis was noted in 38% of patients in the MTX group (P = 0.001) compared to none in the DDP group. Vomiting occurred in 87% of patients in the DDP group (P less than .0001) compared to 10% of patients in the MTX group. This study demonstrates that in the treatment of recurrent head and neck squamous cell carcinoma, MTX and DDP are equally effective, although MTX appears to be better tolerated.     

Cisplatin and 5-fluorouracil chemotherapy in advanced or recurrent squamous cell carcinoma of the head and neck

Fifty-three patients with advanced or recurrent squamous cell carcinoma of the head and neck (SCCHN) were treated with bolus cisplatin (CDDP) and 96-hour infusion of 5-fluorouracil (5-FU). Twenty-six patients with advanced disease (21 T4 and/or N3) and no prior therapy (NPT) received 2 to 3 cycles of chemotherapy prior to surgery and/or radiation. There were four complete responses (CR) and 12 partial responses (PR) to chemotherapy for an overall response rate of 61%. In 20 patients with locally recurrent or disseminated disease there was one CR and six PR for an overall response rate of 35%. All but one responding patient in both groups showed clear evidence of tumor response after the initial cycle of chemotherapy. Two of the five complete responders required at least three courses to achieve CR. Disease-free survival was poor: only five of 26 patients in the NPT group remain alive and free of disease 8 to 28 months from initial therapy. CDDP and 5-FU is an active combination for SCCHN, but survival benefit remains to be proven.     

A Northern California Oncology Group randomized trial of leucovorin plus 5-fluorouracil versus sequential methotrexate, 5-fluorouracil, and leucovorin in patients with advanced colorectal cancer who failed treatment with 5-fluorouracil or 5-fluorodeoxyuridine alone

The current study was initiated to confirm preliminary reports that 20% or more of patients with colorectal cancer who fail treatment with 5-fluorouracil (FUra) will respond to treatment with either leucovorin plus FUra or with sequential methotrexate, FUra, leucovorin. One hundred two patients with advanced, measureable colorectal cancer who failed treatment with FUra and/or 5-fluorodeoxyuridine (FUdR) were randomized to treatment with either high-dose leucovorin plus FUra (Arm B) or sequential methotrexate, FUra, leucovorin (Arm C). In this interim report, 92 patients were evaluable for toxicity and 89 patients were evaluable for response. Grade 3 or 4 nonhematologic toxicity which was primarily gastrointestinal was experienced by 25% of patients on both treatment arms during at least 1 treatment cycle. Hematologic toxicity was minimal. Among 43 evaluable patients on Arm B, there were 2 complete responses (5%) and 1 minor response (3%). Among 46 evaluable patients on Arm C, there was 1 complete response (2%), 1 partial response (2%), and 6 minor responses (14%). The median time to treatment failure was 2.2 months on Arm B and 3.5 months on Arm C. The median survival was 8.3 months on Arm B and 8.7 months on Arm C. Colorectal cancers that are resistant to FUra are cross-resistant to both experimental combinations.     

Biochemical modulation of 5-fluorouracil: A randomized comparison of sequential methotrexate, 5-fluorouracil and leucovorin versus sequential 5-fluorouracil and leucovorin in patients with advanced symptomatic colorectal cancer

BACKGROUND: The optimal chemotherapy for advanced colorectal carcinoma isnot known. Two regimens, both based upon biochemical modulationof 5-FU, were compared in a randomized multicenter trial. PATIENTS AND METHODS: A total of 202 symptomatic patients were randomly allocatedto receive either sequential methotrexate, 250 mg/m², duringthe first 2 hours and 5-FU, 500 mg/m², at hours 3 and 23 followedby leucovorin rescue initiated at hour 24 (15 mg x 8) (MFL)or sequential 5-FU 500 mg/m² followed by leucovorin 60 mg/m²30–40 minutes later, on days 1 and 2 (FLv). Treatmentswere repeated every 14 days for eight courses and then every3 to 4 weeks. Four patients were unevaluable. RESULTS: The two treatments were equally effective with respect to objectiveresponse rates (complete (CR) + partial (PR), MFL 17%, FLv 21%),subjective response rates (symptom relief in the absence ofsevere adverse effects, 45% vs. 37%), and survival (median 7.5vs. 9 months). All responses lasted at least 4 months. Overall,toxicity was low and comparable between the groups, but serioustoxicity was more common in the MFL group. CONCLUSIONS: Since FLv is easier to administer and carries less risk forserious toxicity, it should be recommended as a first-line treatmentbefore MFL. On either regimen, about 40% of symptomatic patientscan expect palliation, i.e., symptomatic relief without severeadverse effects, for at least 4 months. biochemical modulation, chemotherapy, colorectal cancer, 5-fluorouracil, subjective response     

Phase II trial of carboplatin plus cisplatin in recurrent and advanced squamous cell carcinoma of the head and neck

Cisplatin is one of the most active chemotherapeutic agents for the treatment of squamous carcinoma of the head and neck; however, neurotoxicity and nephrotoxicity are dose-limiting. The analog, carboplatin, is a promising new agent with similar activity but a different spectrum of toxicity. To evaluate if a therapeutic advantage could be achieved with acceptable toxicity, a combination of carboplatin 350 mg/m2 and cisplatin 50 mg/m2 were administered every 28 days to patients with recurrent or metastatic disease who had received no prior chemotherapy. Of 24 patients enrolled in this study, 21 were assessable for response and toxicity. Five partial responses were observed (24%; 95% confidence interval [Cl], 4.9% to 38.6%). No complete response occurred. Two of these patients received definitive radiotherapy and achieved complete responses. The median survival of all patients was 24 weeks. Hematologic toxicity was dose-limiting necessitating a decrease in the starting dose of carboplatin to 300 mg/m2. Nonhematologic toxicity was infrequent and mild. Significant renal impairment occurred in only two patients. Although treatment with the combination of carboplatin and cisplatin is feasible, we found no therapeutic advantage in terms of an increased response or survival.     

A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma

Seventy-four previously untreated patients with metastatic colorectal adenocarcinoma were prospectively randomized into one of three treatment regimens: (1) 5-fluorouracil (5-FU) 450 mg/m2 as an intravenous (IV) bolus daily for five days or toxicity, then 200 mg/m2 IV bolus every other day for six doses; (2) methotrexate (MTX) 50 mg/m2 in normal saline by IV infusion over four hours followed by an IV bolus of 5-FU 600 mg/m2. This was administered weekly for 4 weeks and then every 2 weeks. (3) Leucovorin 500 mg/m2 in a two-hour IV infusion of normal saline with 5-FU 600 mg/m2 as an IV bolus one hour after the Leucovorin began every week for 6 weeks. The combined complete and partial response rates in the three regimens were 11%, 5%, and 48%, respectively (P = .0009). The median duration of response in the 5-FU and Leucovorin regimen was 10 months. There was no statistically significant difference between the treatment regimens with respect to survival time (P = .6). Toxicity in the 5-FU and Leucovorin regimen was predominantly diarrhea (13 of 30 patients, 40%). In this regimen, eight of 13 patients (52%) who developed diarrhea not only required a dose reduction of 5-FU, but also hospitalization for IV hydration. The predominant toxicity in the 5-FU alone regimen and the 5-FU and MTX regimen was leukopenia. One drug-related death occurred in each regimen.     

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.     

A comparison of carboplatin plus methotrexate versus methotrexate alone in patients with recurrent and metastatic head and neck cancer

Patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN) were stratified by performance status, extent of disease, and prior radiotherapy and subsequently randomized to receive carboplatin (CBDCA; Bristol-Myers, Wallingford, CT) administered intravenously (IV) monthly, initially at doses of 400 mg/m2 in combination with methotrexate (MTX) given IV weekly at doses of 40 mg/m2 or MTX alone at the same dose/schedule. Significant dose-limiting myelosuppression required CBDCA dose reductions to 300 mg/m2 and, subsequently, 200 mg/m2. Nonhematological toxicities were not significant. Our study objective was to determine whether CBDCA plus MTX produce a substantial improvement in response rate over single-agent MTX. A response rate of 50% (complete [CR] plus partial response [PR]) for CBDCA plus MTX compared with 25% for MTX was specified as the difference to be detected. We employed a two-stage study design for randomized trials that allowed for early termination of studies involving relatively ineffective treatment regimens. With this design, the study could be closed after the first stage (20 patients entered onto each treatment arm) if the number of responders to CBDCA plus MTX were not superior to MTX. Five of 20 patients responded to treatment in each arm, and we were able to conclude that the addition of CBDCA to MTX is unlikely to result in a twofold increase in response rate compared with MTX alone in this group of patients. This two-stage design represents a simple and efficient method of testing the relative efficacy of new combinations containing at least one active agent against a suitable control arm in this disease. It addresses scientific and ethical issues of continuing testing with relatively ineffective treatments, and at the same time provides a reliable method for identifying very active regimens likely to represent significant therapeutic advances.     

Advanced colorectal carcinoma. A prospective randomized trial of sequential methotrexate, 5-fluorouracil, and leucovorin versus 5-fluorouracil alone

One hundred and twenty-five previously untreated patients bearing metastatic or advanced recurrent (inoperable) colorectal carcinoma and measurable disease were prospectively randomized. Those in arm A received 5-fluorouracil (5-FU), 1,200 mg/m2 i.v. infusion over 2 h, while those in arm B received methotrexate (MTX), 200 mg/m2 i.v. (push injection), followed 20 h later by 5-FU, 1,200 mg/m2 i.v. infusion over 2 h, plus calcium leucovorin (LV), 25 mg i.m. every 6 h for eight doses beginning 24 h after MTX administration. Cycles were repeated every 15 days. All patients receiving treatment were evaluable for toxicity and survival, and 118 patients were evaluable for response. The objective regression rate (complete plus partial response) was 12% (7 of 58) in arm A and 28% (17 of 60) in arm B (p = 0.049). No change was observed in 24% (14 of 58) in arm A and in 35% (21 of 60) in arm B (p = 0.28), while progressive disease was registered in 64% (37 of 58) and 37% (22 of 60) in arms A and B, respectively (p = 0.006). Median duration of response was 3 months in arm A and 5 months in arm B (p = 0.39). The median survival was 8.3 months in arm A and 11.2 months in arm B (p = 0.25). No statistically significant differences were found when objective regression and survival were related to site of primary tumor, performance status, and number of involved organs. There were two drug-related deaths in arm B due to severe myelosuppression followed by mucositis and sepsis. Of nonhematologic toxicities, diarrhea was more frequently observed in arm B, as were mucositis and infectious complications. Our results indicate that the sequential schedule MTX-5-FU-LV with 20-h intervals between MTX and 5-FU is superior in terms of objective regression to 5-FU alone given at the dose and schedule used in the present study. However, MTX-5-FU-LV did not have a significant impact on survival.     

The role of low dose cisplatin plus 5-fluorouracil for treatment of recurrent and/or advanced squamous cell carcinoma of the head and neck

To improve survival rate in advanced head and neck cancer, we scheduled 90 patients to receive low dose cisplatin plus 5-fluorouracil regimen as neoadjuvant(NAC), concurrent(CC), adjuvant(AC), and second line chemotherapy (SC) setting. Our regimen consisted of cisplatin (CDDP 5 mg/m2/1 hr infusion on days 1-5, 8-12, 15-19, 22-26) and 5-fluorouracil (5-FU 200 mg/m2/24 hr infusion or oral administration of tegaful-uracil (UFT-E) 400 mg/body on days 1-28). The concurrent chemoradiotherapy consisted of conventional irradiation with 1.6-2.0 Gy/day on five days per week up to a total dose around 60Gy, and CDDP 3 mg/m2 by intravenous infusion over 1 hour plus 5-FU 150 mg/m2 by intravenous infusion over 24 hours per day on five days per week. For SC, 24 patients evaluable for response, 4 CR and 6 PR with RR of 42% were achieved. For NAC, 14 patients were evaluated for response, 2 CR and 7 PR were achieved. CC was indicated for locally unresectable cases. Of the 33 patients evaluable for response were 17 CR and 9 PR with RR of 79%. Dose limiting toxicities for chemotherapy were anemia and leukopenia and chemoradiotherapy was mucositis. Our treatment modality showed marginal toxicity and good response. Moreover, our regimen could be given in an outpatient setting safely so quality of life for patients was identical. We concluded that for advanced head and neck cancer, these treatment options were effective for second line and adjuvant setting. Chemoradiotherapy with this regimen also gave a impact for improving local control and survival period for locally unresectable cases.     

Prospective randomized study of cyclophosphamide, epirubicin, and 5-fluorouracil versus cyclophosphamide, adriamycin, and 5-fluorouracil in advanced or recurrent breast cancer

Background  Treatment with cyclophosphamide, adriamycin, and 5-fluorouracil (CAF), a widely used, potent regimen is sometimes restricted by the myelotoxicity and myocardiotoxicity of adriamycin (ADR). In a prospective randomized controlled study of patients with advanced or recurrent breast cancer, the efficacy and toxicity of a CEF regimen, in which epirubicin (EPI) was substituted for ADR, was compared with CAF. Methods  138 female patients under 75 years of age who had unresectable or recurrent breast cancer during the period from October, 1989 to September, 1991, were randomized to one of two treatment regimens. The first regimen consisted of cyclophosphamide 100 mg p.o. d1-14, adriamycin 30 mg/m^p2 i.v. d1, 8 and 5-fluorouracil 500 mg/m^p2 i.v. d1, 8 (CAF). In the second regimen, EPI 30 mg/m^p2 i.v. d1, 8 was substituted for ADR (CEF). Both regimens were delivered q4 weeks. Results  Of 138 patients, 105 (CEF 56, CAF 49) were evaluable for response and survival, and all were evaluable for toxicity (CEF 68, CAF 70). The median course of lots CEF and CAF was 3 cycles. Response rates (complete response plus partial response) with CEF and CAF were 35.7% (20/56) and 36.7% (1 8/49), respectively. Adverse effects were similar in the two groups, but severe leukopenia (CEF 36.8%, CAF 64.3%) and hepatic toxicity (CEF 1.5%, CAF 12.9%) were encountered more frequently with CAF than with CEF. The duration of 50% survival was 135.9 weeks for CEF and 172.1 weeks for CAF (not significant). Conclusion  At an equal dose of EPI and ADR response rates and survival of the CEF group were similar to those of the CAF group, but adverse effects were fewer in the CEF group.     

Simultaneous versus sequential combined technique therapy for squamous cell head and neck cancer

Forty-eight patients with locally confined (M0) squamous cell head and neck cancer were prospectively randomized to receive either simultaneous (SIM) or sequential (SEQ) combined technique therapy with a 5-fluorouracil infusion, a cisplatin bolus injection, and radiation therapy. Patients with residual resectable disease underwent surgery after induction therapy, whereas those achieving a complete response to induction did not require surgery. Patients on the two treatment arms were equivalent in all measured variables, including disease extent. Toxicities of the SIM and SEQ arms also were equivalent except for mucositis and the resultant weight loss, which were more severe on the SIM arm (P = 0.002). With a follow-up time ranging from 9 to 41 months, seven of the 24 SIM patients and 14 of the 24 SEQ patients are considered treatment failures. The relapse-free survival is significantly better on the SIM arm (P = 0.03), although an overall survival advantage has not yet been demonstrated (P = 0.13). The achievement of a complete response after induction therapy correlates with both the relapse-free (P = 0.0005) and overall (P = 0.05) survival, and the likelihood of an induction complete response also is significantly better for those treated with the SIM schedule (P = 0.02). Eighteen patients did not require surgery after achieving an induction complete response. Relapse-free survival does not appear to be compromised in this patient subset.     

The activity of a single-agent 5-fluorouracil infusion in advanced and recurrent head and neck cancer

Although chemotherapy regimens using cisplatin (CDDP) and 5-fluorouracil (5-FU) infusion have shown significant activity in advanced and recurrent head and neck cancer, their use requires normal renal function. The use of 5-FU infusion alone has not been evaluated in these tumors. Retrospective analysis revealed 11 patients who received 5-FU infusion alone because of poor renal function: 7 patients with recurrent disease who were previously treated with surgery and/or radiation therapy and 4 patients who received 5-FU as preoperative induction therapy for advanced disease were treated. The infusion dose consisted of 1000 mg/M2/24 hours for 96 hours for patients with previous radiation and 120-hour infusions for patients without previous radiation. The courses were repeated at 3-week intervals. Eight of 11 (72%) demonstrated a response (1 complete response [CR] and 7 partial responses [PRs]. Responses occurred in 4 of 4 (all PRs) patients with previously untreated epidermoid cancer, 1 patient with recurrent adenocystic cancer, and 3 of 6 patients with recurrent epidermoid cancer not previously treated with chemotherapy. Three patients, with no prior systemic or local therapy, who were clinical partial responders to 5-FU infusion went on to surgery and radiotherapy. Their responses were maintained for 18, 14, and 46+ months, respectively. The predominant toxicities were stomatitis (6/11, 55%) and leukopenia (2/11 patients). In this retrospective analysis, 5-FU infusion alone demonstrated good activity in head and neck cancer with tolerable toxicity. Since the number of patients is small and were selected on the basis of renal function, prospective evaluation is essential.     

A randomized trial of cisplatin (CACP) + 5-fluorouracil (5-FU) infusion and CACP + 5-FU bolus for recurrent and advanced squamous cell carcinoma of the head and neck

One of the most active chemotherapeutic regimens for treatment of advanced and recurrent head and neck cancer is cisplatin (CACP) + 5-fluorouracil (5-FU) infusion with a response rate of 90% in advanced, previously untreated patients and 70% in patients with recurrent disease. Forty-four patients from two Wayne State University-affiliated hospitals were entered into a randomized trial of CACP (100 mg/m2) day 1 and 24-hour infusion of 5-FU (1000 mg/m2) days 1 through 4 versus CACP (100 mg/m2) day 1 and bolus 5-FU (600 mg/m2) day 1 and day 8. Thirty-eight patients were evaluable for three induction courses. Response for the infusion arm was 72% (4/18 complete response [CR] + 9/18 partial response [PR]). Response for the bolus arm was 20% (2/20 CR + 2/20 PR). The difference in response was statistically significant by chi-square analysis (P less than 0.01). Seventy percent of the patients on the bolus arm experienced leukopenia with several episodes of grades 3 and 4 leukopenia. In addition, 50% of the patients on the bolus arm experienced thrombocytopenia. Stomatitis was more frequent on the infusion arm but it was mild and reversible. The complete responders on either arm have a median survival of 120+ weeks; partial responders, 30 weeks. Cisplatin + 5-FU infusion produces a superior response as initial chemotherapy for three courses compared with CACP and 5-FU bolus.     

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.     

A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract

One hundred eight patients with recurrent or metastatic transitional cell carcinoma of the urothelial tract were randomized to receive cisplatin (C) 80 mg/m2 on day 1 every 4 weeks, or methotrexate (M) 50 mg/m2 on days 1 and 15 plus C 80 mg/m2 on day 2 every 4 weeks (C + M). Fifty-three eligible patients were randomized to C + M and 55 to C. In the C + M arm, 45% of patients responded (complete response [CR], 9%) and 31% (CR, 9%) in the C arm (P = .18). In the C arm, 20 patients failing or relapsing after C received M. Two patients responded, and four with progressive disease (PD) and one with a previous partial response (PR) showed no change. The median survival was 8.7 months (C + M arm) and 7.2 months (C arm), P = .7. Relapse-free survival was not significantly different, but C + M was associated with a significantly increased time to disease progression (median, 5.0 months, v 2.8 months for C arm). The response of untreated patients (37%) was not different from those with prior treatment (39%). On the C + M arm, 92% of patients and 96% of patients on the C arm received 85% or more of the scheduled C dose. Significantly more grade 3 or 4 hematological toxicity (27% v 2%; P = .01) and mucositis (20% v 0%; P = .0005) occurred in patients on the C + M arm. Although the initial response rates seen on the combination arm look superior, and the time to disease progression is increased, these effects have not translated into a clinically important increase in the duration of survival and were associated with increased toxicity.     

Bleomycin infusion followed by cyclophosphamide, methotrexate, and 5-fluorouracil in advanced squamous carcinoma of the head and neck

Twenty-seven patients with squamous cell carcinoma of the head and neck were treated with bleomycin 7.5 U/m2/day continuous infusion X 3 days (days 1-4, 8-11), followed by cyclophosphamide 300 mg/m2, methotrexate 30 mg/m2 and 5-fluorouracil 300 mg/m2 on days 5 and 12 (bleo-CMF). Treatment was repeated every 28 days. All but two had a performance status of 0-2 and all but 3 patients had received prior surgery, radiotherapy, and/or chemotherapy. Of 24 evaluable patients, 1 had a complete remission (1.9 months) and 4 had partial remissions (3.7, 3.9, 3.9, 4.1 months, respectively) for an overall response rate of 21%. If one excludes 7 patients with prior chemotherapy, the response rate is 5 of 17 (29%). All responders had received both radiotherapy and surgery. The median survival was 4.4 months for the responders and 3.5 months for the nonresponders. Marked hematologic toxicity occurred in eight patients, and contributed to the death of two. Severe pulmonary toxicity occurred in two patients and caused the death of one. Bleo-CMF did not produce a higher response rate than historical single-agent trials and caused significant toxicity. Furthermore, there was no important difference in the survival of responders and nonresponders.     

A prospective evaluation of 5-fluorouracil plus cisplatin in advanced squamous-cell cancer of the head and neck

Recent studies have shown improved efficacy of chemotherapy in patients with advanced squamous-cell cancer of the head and neck. Our purpose was to evaluate prospectively the activity of cisplatin plus 5-fluorouracil (5FU) in 37 patients with advanced stage IV squamous-cell cancer of the head and neck. There were two groups. Group 1 consisted of 19 previously untreated patients with either T4 or N3 disease. They received 100 mg/m2 cisplatin (days 1 and 28) and 120-hour infusion of 1,000 mg/m2/24 hours 5FU (days 1 to 5 and 28 to 32). They subsequently were offered preoperative radiotherapy (RT) and surgery. Group 2 consisted of 18 previously treated patients. They received 5FU and cisplatin in the same dosage every 28 days for either recurrent or metastatic disease. It was found that in group 1 there was an 84% response rate (five complete responses (CR) and 11 partial responses (PR) ). Three of those with PR achieved a CR after RT. Seven patients have had RT plus surgery and are disease free at 8 to 27 month follow-up. Six patients (one CR, five PR) refused surgery and progressed within 4 months. In group 2 there was an 11% response rate after two cycles (two PR), three patients had a minimal response (MR, less than 50% response) and received a mean of four cycles of treatment. Three patients with stable disease received a mean of four cycles of chemotherapy until progression. Two of 11 patients who had received previous chemotherapy plus RT showed an MR; nine of these patients had shown a response to their previous chemotherapy. Only one of 14 patients who had RT plus chemotherapy had a PR, and three had MR. Of five patients who had previous surgery, only one had a PR. All five had received chemotherapy as well. It was concluded that 5FU plus cisplatin is an effective combination in previously untreated patients. In previously treated patients with recurrent disease, there is a substantially lower response rate.