Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer.

PURPOSE: To compare two published schedules of cisplatin plus fluorouracil (5-FU) infusion and radiation as either sequential or concomitant treatment for toxicity and efficacy in patients with unresectable head and neck cancer. PATIENTS AND METHODS: This was a randomized trial between cisplatin 100 mg/m2 over 15 minutes on day 1 plus 5-FU 1.0 g/m2 by continuous infusion on days 1 to 5, repeated every 3 weeks for three cycles, followed by 70 Gy of radiation in 7 to 8 weeks, versus cisplatin 60 mg/m2 over 15 minutes on day 1 plus 5-FU 800 mg/m2 by continuous infusion on days 1 to 5 plus radiation 2 Gy on days 1 to 5, repeated every other week for seven cycles. Unresectable head and neck squamous cancer patients not previously treated with radiation or chemotherapy and with a performance status of 0 to 2 were stratified by tumor (T) and node (N) groupings and performance status and randomized. RESULTS: Two hundred fifteen patients were entered and 214 analyzed, 107 on each arm. After all treatment, overall response rates were different (P = .003), with similar complete response rates, but more partial responses and fewer patients with no change or progression with concomitant treatment. Cox regression analysis for progression-free survival identified concomitant treatment (P = .003), Radiation Therapy Oncology Group (RTOG) stage III grouping (P < .0001), performance status (P = .0002), concomitant treatment (P = .003), and treating institution (P = .006) as significant. The sequential and concomitant treatments showed similar distant failure patterns (10% and 7%, respectively), but divergent regional failure rates (55% and 39%). Severe and worse toxic events were similar between the treatment programs, but radiation-induced mucositis combined with cisplatin-induced water-losing nephropathy, in the concomitant arm only, demanded more supportive care. Survival duration was similar between the treatment arms, but significantly more patients in the sequential arm died of their cancer (P = .011). CONCLUSION: Concomitant treatment offered improved disease control, predominantly of regional disease, but benefit was dependent on the experience of the treating institution. Translation of this benefit into improved survival is not yet evident, with an excess of deaths from other causes in the concomitant arm.

Combined simultaneous cisplatin/fluorouracil chemotherapy and split course radiation in head and neck cancer.

Fifty-three patients with stage III (eight patients, 15%), stage IV (36 patients, 68%), or recurrent disease (nine patients, 17%) entered a study of simultaneous cisplatin, 60 mg/m2 day 1, fluorouracil (5-FU) infusion, 800 mg/m2 days 1 to 5, and radiation, 2 Gy days 1 to 5, every other week for a total of seven cycles (70 Gy in 13 weeks). Patient acceptance was high, with only two patients (4%) refusing to complete therapy. The median actual dose delivered was 88% of the planned dose for cisplatin, 78% for 5-FU, and 70 Gy for radiation. Weight loss of 10% or more and severe mucositis were the most common side effects (53% and 48% incidence, respectively). All patients were followed at least 1 year (median, 51 months). While the complete response rate (55%) seemed no better than that reported in other series, freedom of progression of regional disease (73%), and the survival of all patients (median, 37 months) were substantially improved. Only 33% of partial responders have failed regionally, while 15% of complete responders have failed regionally (P greater than .10), which indicates that clinical assessment of response was unreliable. Stage, the presence of N3 disease, and delivery of less than the median actual dose received of 5-FU (but not cisplatin) were significantly associated with failure. This regimen is feasible and tolerable in this difficult patient population. It generally requires no special forced feeding techniques. Survival results from this limited institution study appear better than those using sequential multimodality therapies. With such favorable regional control, this approach may offer an alternative in the future to radical surgery and radiation in resectable disease. More definitive evaluation seems warranted.

Surgical complications in patients with head and neck cancer receiving chemotherapy.

We evaluated postoperative complications in a randomized series of patients with head and neck cancer who received preoperative chemotherapy. Forty-two patients with advanced squamous carcinoma of the head and neck were randomized to receive either high-dose methotrexate with leucovorin calcium rescue (23 patients) or no chemotherapy (19 patients) prior to definitive conventional treatment. The two groups of patients were balanced by sex, disease site, stage, histologic grade, and prior therapy. Sixteen of the 23 patients receiving preoperative chemotherapy had postoperative complications, whereas only eight of 19 patients not receiving chemotherapy had postoperative complications. Surgical complications included wound infections, orocutaneous fistulas, and flap necrosis.

Improved control in advanced head and neck cancer with simultaneous radiation and cisplatin/5-FU chemotherapy.

Chemotherapy with cisplatin plus 5-FU infusion was given simultaneously with radiation therapy; both were administered every other week. Twenty-seven patients with stage IV disease and three with stage III disease were treated; 57% had T4, 33% had N3, and 10% had M1 disease. Of these patients, 17 (57%) achieved complete response and the rest achieved partial response. However, whether or not a clinically complete response occurred had no effect on subsequent risk for disease recurrence. With a median follow-up of 16 months (range, 6-35), only 11 patients (37%) have had disease recurrence and eight (27%) have died. Of those patients who recurred, six failed in distant sites only, one developed a second head and neck primary, and four (36% of all failures) failed regionally. Normally, greater than 50% of patients who are initially controlled (usually less than 60% of stage IV patients) would have failed within the first 12 months and greater than or equal to 75% of these would be expected to fail regionally. Nine patients who had received previous treatment or who had M1 disease accounted for six of the recurrences and four of the deaths. Because of the excellent local control, we have cautiously limited surgery to conserve laryngeal, tongue, and mandibular function in selected cases. Neither immediate nor long-term toxicity from radiation appeared increased. Although no patient with such advanced disease can be considered cured at this time, these results seem to represent a substantial improvement in the quality of life and degree of local control over other approaches. Controlled trials of the sequencing of radiation and chemotherapy in head and neck cancer appear indicated.

A randomized trial of adjuvant chemotherapy in head and neck cancer.

Ninety-five patients with squamous cell carcinoma of the head and neck were entered into a randomized study testing a two-week course of induction chemotherapy with methotrexate and leucovorin given prior to regional therapy. In addition, following regional therapy, patients randomized to chemotherapy were to receive similar methotrexate courses every three months for one year. Poor tolerance to this regimen after radiation and surgery led to a change in the chemotherapy following regional therapy to a combination of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin every three weeks for four cycles after the first 35 patients had been entered. Nine cases were ineligible and four lacked any follow-up data, leaving 82 analyzable cases. Using Cox regression analysis, no differences in the percentage of patients achieving disease control, the relapse-free survival, or the overall survival were identified between any treatment group. As has been described in many pilot studies of induction chemotherapy of head and neck cancer, chemotherapy responders had a more favorable disease-free survival than chemotherapy nonresponders in the total group of patients receiving adjuvant chemotherapy. However, correcting for imbalances in the expected three year disease-free survival of these patients, based on their disease site and stage, erased this difference, indicating tumor response to this regimen of chemotherapy is not an independent factor affecting disease outcome. The division of patients into arbitrary prognostic categories based on the expected outcome for each specific tumor site and stage proved to be a useful method for balancing treatment groups, given the multiple site-stage combinations within the upper aerodigestive tract. The defined prognostic categories were the single most sensitive predictors of relapse-free and overall survival.

A randomized comparison of high-dose infusion methotrexate versus standard-dose weekly therapy in head and neck squamous cancer.

Forty-seven patients with recurrent or metastatic head and neck squamous cancer were entered into a prospectively controlled study comparing high-dose infusion methotrexate with leucovorin against standard-dose methotrexate without leucovorin. Patients were stratified for prior treatment and hematogenous metastases prior to randomization. Patients received either methotrexate (1,500 mg/m2) infused over 24 hours with leucovorin or 40 mg/m2 intramuscularly. Each treatment was given weekly for the first six weeks and followed a dose escalation schedule to toxicity. After six weeks patients received the high-dose regimen every two weeks and the low-dose schedule continued weekly. One patient was ineligible and four had inadequate follow-up to assess response (less than two weeks). Forty-two patients were evaluable for survival and 37 for response. Six of 19 patients (32%) treated with high-dose infusion responded (one complete response) and four of 18 patients (22%) receiving standard dosage responded (P = .52). Treatment with high-dose methotrexate resulted in an improved duration of disease control over standard dosage with the respective median times to progression of 11 weeks and five weeks (P = .04). These differences were most marked in good performance status patients (P = .007) and those without hematogenous dissemination (P = .02). Toxicity, however, was also significantly worse in the high-dose treatment group (P = .01) and survival was identical between treatments (4.2 months). The authors conclude that any treatment advantage to high-dose methotrexate may be attributable to its greater toxicity rather than to a selective therapeutic effect and this regimen does not result in improved patient survival. Good performance status patients may benefit from more aggressive therapy.