A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: Preliminary results

Abstract

Background A phase III randomized comparison of radiotherapy alone versus combination chemotherapy and concurrent continuous‐course radiotherapy was performed at the Cleveland Clinic Foundation. Methods Between March 1990 and June 1995, 100 patients with resectable stage III and IV squamous cell head and neck cancer were randomized to either Arm A: radiotherapy alone, 68–72 Gy at 1.8–2.0 Gy per day; or to Arm B: the identical radiotherapy with concurrent chemotherapy. Chemotherapy consisted of 5‐fluorouracil, 1000 mg/m2/day, and cisplatin 20 mg/m2/day, both given as continuous intravenous infusions over 4 days beginning on day 1 and day 22 of the radiotherapy. At 50–55 Gy, patients were clinically reassessed. If a response was evident, radiotherapy was completed. In non‐responding patients, however, radiotherapy was terminated and surgery recommended. After completion of all treatment, salvage surgery was performed, if possible, for any residual primary or nodal disease or for any subsequent locoregional recurrence. Results Except for an overrepresentation of T1 patients on Arm A, the treatment arms were equivalent. Toxicity was greater in the patients on Arm B with a higher incidence of grade III and IV neutropenia, thrombocytopenia, cutaneous reaction, and mucositis. Feeding tubes were also required more often, and weight loss was greater on the chemotherapy arm. No toxic deaths occurred. With a median follow‐up of 36 months, the Kaplan‐Meier 3‐year projections of relapse‐free survival are 52% for Arm A and 67% for Arm B (p = .03), and the likelihood of developing hematogenous metastases is 21% for Arm A and 10% for Arm B (p = .04). Although overall survival is not significantly different, overall survival with successful primary site preservation was 35% for Arm A and 57% for Arm B (p = .02). This difference remains statistically significant in the subsets of patients with laryngeal and hypopharyngeal primaries but not in patients with oropharyngeal primaries. Conclusions Continuous‐course radiotherapy and concurrent combination chemotherapy is an intensive, toxic but tolerable treatment regimen, which, when compared with radiotherapy alone, can produce an improvement in relapse‐free survival, a decrease in distant metastases, and an improvement in overall survival with successful primary site preservation. © 1997 John Wiley & Sons, Inc. Head Neck 19: 567–575, 1997.

Changes in Survival in Head and Neck Cancers in the Late 20th and Early 21st Century: A Period Analysis

“…In the late 1990s, several trials comparing radiation therapy alone with concurrent chemotherapy plus radiation therapy, with or without surgery, in head and neck cancers other than nasopharyngeal cancer were published. One of the first, published in 1997, showed similar overall survival rates but longer survival with organ preservation in patients undergoing combined therapy [19]. Another study, published in 1999, showed an improvement in the overall survival rate, as has a recent meta-analysis [3,4].…”

Pharmacokinetic Analysis and Phase 1 Study of MRX-1024 in Patients Treated with Radiation Therapy with or without Cisplatinum for Head and Neck Cancer

“…However, other studies of concurrent chemotherapy and RT for head and neck cancer have also recorded such high rates of mucositis (5). Adelstein et al reported a phase 3 trial in which 100 patients were randomized to radiation alone versus radiation with concurrent chemotherapy in locally advanced head and neck cancer and noted severe mucosal injury in 24% of patients randomized to radiation alone compared with 84% in those treated with concurrent chemotherapy and radiation (44). Because radiation dose, fraction size, field size, and technique, along with dose, schedule, and type of chemotherapy, can all influence mucositis (2-5), it is difficult to make strong conclusions about the rates of mucosal injury in the current phase 1 study, except to note that they seem compelling enough to warrant further evaluation in phase 2 studies.…”

Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison

“…Secondly, those with T4 lesions made up only 33% of the patients in Adelstein et al's study compared to 56% in our study. These differences in patient factors and the inability to deliver the planned doses of cytotoxics could have resulted in a significantly poorer outcome of our patients with a 3-year overall survival rate of 40% when compared to 60% in Adelstein et al's study (Adelstein et al, 1997).…”

“…Of significance was that primary-site resection was not required in any patient for tumour control. The same group went on to a phase III randomised study comparing radiation therapy alone vs concurrent CDDP/5FU and continuous course radiotherapy in 100 patients with resectable stage III and IV SCHNC (Adelstein et al, 1997). Salvage surgery was planned for patients whose disease was not responding or progressing when re-evaluated at 55 Grays (Gy).…”