Jay S. Cooper

Combined Chemotherapy and Radiotherapy Compared with Radiotherapy Alone in Patients with Cancer of the Esophagus

BACKGROUND The efficacy of conventional treatment with surgery and radiation for cancer of the esophagus is limited. The median survival is less than 10 months, and less than 10 percent of patients survive for 5 years. Recent studies have suggested that combined chemotherapy and radiation therapy may result in improved survival. METHODS This phase III prospective, randomized, and stratified trial was undertaken to evaluate the efficacy of four courses of combined fluorouracil (1000 mg per square meter of body-surface area daily for four days) and cisplatin (75 mg per square meter on the first day) plus 5000 cGy of radiation therapy, as compared with 6400 cGy of radiation therapy alone, in patients with squamous-cell carcinoma or adenocarcinoma of the thoracic esophagus. The trial was stopped after the accumulated results in 121 patients demonstrated a significant advantage for survival in the patients who received chemotherapy and radiation therapy. RESULTS The median survival was 8.9 months in the radiation-treated patients, as compared with 12.5 months in the patients treated with chemotherapy and radiation therapy. In the former group, the survival rates at 12 and 24 months were 33 percent and 10 percent, respectively, whereas they were 50 percent and 38 percent in the patients receiving combined therapy (P less than 0.001). Seven patients in the radiotherapy group and 25 in the combined-therapy group were alive at the time of the analysis. The patients who received combined treatment had fewer local (P less than 0.02) and fewer distant (P less than 0.01) recurrences. Severe and life-threatening side effects occurred in 44 percent and 20 percent, respectively, of the patients who received combined therapy, as compared with 25 percent and 3 percent of those treated with radiation alone. CONCLUSIONS Concurrent therapy with cisplatin and fluorouracil and radiation is superior to radiation therapy alone in patients with localized carcinoma of the esophagus, as measured by control of local tumors, distant metastases, and survival, but at the cost of increased side effects.

A radiation therapy oncology group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003

Abstract Purpose: The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial. The objective of this randomized trial was to test the efficacy of hyperfractionation and two types of accelerated fractionation individually against standard fractionation. Methods and Materials: Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1.2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive. Results: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control ( p = 0.045 and p = 0.050 respectively) than those treated with standard fractionation. There was also a trend toward improved disease-free survival ( p = 0.067 and p = 0.054 respectively) although the difference in overall survival was not significant. Patients treated with accelerated fractionation with split had similar outcome to those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation. However, there was no significant increase of late effects. Conclusions: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.

Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501)

In 2004, level I evidence was established for the postoperative adjuvant treatment of patients with selected high‐risk locally advanced head and neck cancers, with the publication of the results of two trials conducted in Europe (European Organization Research and Treatment of Cancer; EORTC) and the United States (Radiation Therapy Oncology Group; RTOG). Adjuvant chemotherapy‐enhanced radiation therapy (CERT) was shown to be more efficacious than postoperative radiotherapy for these tumors in terms of locoregional control and disease‐free survival. However, additional studies were needed to identify precisely which patients were most suitable for such intense treatment.

Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study.

PURPOSE The present intergroup phase III randomized study compared combined chemotherapy (CT) plus radiotherapy (RT) treatment versus RT only in patients with locally advanced esophageal cancer. MATERIALS AND METHODS Two courses of chemotherapy during 50 Gy RT followed by additional two courses of the same CT, versus 64 Gy RT alone were investigated. CT consisted of cisplatin 75 mg/m2 on day 1 [corrected] and fluorouracil (5FU) 1,000 mg/m2/d on days 1 to 4 every 4 weeks with RT and every 3 weeks post-RT. The main objective of the study was to compare overall survival between the two randomized treatment groups. Patients were stratified by tumor size, histology, and degree of weight loss. RESULTS Sixty-two assessable patients were randomized to receive RT alone, and 61 to the combined arm. Patients characteristics were as follows: squamous cell cancer, 90% versus 85%; weight loss greater than 10 lb, 61% versus 69%; and tumor size, > or = 5 cm, 82% versus 80% on the RT and CT-RT arms, respectively. Systemic side effects, which consisted of nausea, vomiting, and renal and myelosuppression, occurred more frequently on the combined arm, while local side effects were similar in both groups. With a minimum follow-up time of 5 years for all patients, the median survival duration was 14.1 months and the 5-year survival rate was 27% in the combined treatment group, while the median survival duration was 9.3 months with no patients alive at 5 years in the RT-alone group (P < .0001). Additional patients (69) were treated with the same combined therapy and were analyzed. The results of the last group confirmed all of the results obtained with combined CT-RT in the randomized trial, with a median survival duration of 17.2 months and 3-year survival rate of 30%. CONCLUSION We conclude that cisplatin and 5FU infusion given during and post-RT of 50 Gy is statistically superior to standard 64-Gy RT alone in patients with locally advanced esophageal cancer.

Laryngeal Cancer in the United States: Changes in Demographics, Patterns of Care, and Survival

Background: Survival has decreased among patients with laryngeal cancer during the past 2 decades in the United States. During this same period, there has been an increase in the nonsurgical treatment of laryngeal cancer.

Long-Term Results of RTOG 91-11: A Comparison of Three Nonsurgical Treatment Strategies to Preserve the Larynx in Patients With Locally Advanced Larynx Cancer

PURPOSE To report the long-term results of the Intergroup Radiation Therapy Oncology Group 91-11 study evaluating the contribution of chemotherapy added to radiation therapy (RT) for larynx preservation. PATIENTS AND METHODS Patients with stage III or IV glottic or supraglottic squamous cell cancer were randomly assigned to induction cisplatin/fluorouracil (PF) followed by RT (control arm), concomitant cisplatin/RT, or RT alone. The composite end point of laryngectomy-free survival (LFS) was the primary end point. RESULTS Five hundred twenty patients were analyzed. Median follow-up for surviving patients is 10.8 years. Both chemotherapy regimens significantly improved LFS compared with RT alone (induction chemotherapy v RT alone: hazard ratio [HR], 0.75; 95% CI, 0.59 to 0.95; P = .02; concomitant chemotherapy v RT alone: HR, 0.78; 95% CI, 0.78 to 0.98; P = .03). Overall survival did not differ significantly, although there was a possibility of worse outcome with concomitant relative to induction chemotherapy (HR, 1.25; 95% CI, 0.98 to 1.61; P = .08). Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT (HR, 0.58; 95% CI, 0.37 to 0.89; P = .0050) and over RT alone (P < .001), whereas induction PF followed by RT was not better than treatment with RT alone (HR, 1.26; 95% CI, 0.88 to 1.82; P = .35). No difference in late effects was detected, but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy (30.8% v 20.8% with induction chemotherapy and 16.9% with RT alone). CONCLUSION These 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS. Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone. New strategies that improve organ preservation and function with less morbidity are needed.

Late effects of radiation therapy in the head and neck region.

The head and neck region is composed of numerous structures, each with an inherent response to radiation that is largely governed by the presence or absence of mucosa, salivary glands, or specialized organs within that site. Irradiated mucocutaneous tissues demonstrate increased vascular permeability that leads to fibrin deposition, subsequent collagen formation, and eventual fibrosis. Irradiated salivary tissue degenerates after relatively small doses, leading to markedly diminished salivary output. This, in turn, effects the teeth by promoting dental decay which, in turn, effects the integrity of the mandible. Details of these changes are presented, including their pathophysiology, clinical syndromes, and potential treatment.

Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implications based on the RTOG experience.

The development of second malignant tumors (SMTs), in patients who have had their first tumor treated successfully, represents a serious limitation of current therapeutic strategies for head and neck cancers. To improve our understanding of the current magnitude of the problem and the various factors that might influence its importance, we reviewed the Radiation Therapy Oncology Groups (RTOG) prospectively collected registry of all head and neck patients seen in participating member institutions between February 1977 and April 1980. A total of 928 patients were identified who had squamous cell carcinomas of the head and neck region, no prior or coincident history of another malignant tumor, and whose planned treatment consisted of radiation therapy only. A total of 110 second, independent, malignant tumors occurred in these patients. Overall, the estimated risk of developing a second tumor within 3 years of radiotherapy was 10%, within 5 years 15%, and within 8 years 23%. Minor differences in frequency were observed for different primary sites. These SMTs unquestionably influenced subsequent survival adversely. Analysis of the database also revealed that the extent of the primary tumor influenced the risk of a second; most occurred in patients who presented with the smallest primary tumors because of their better survival. Our data indicate that preventive medicine should have its greatest impact in those patients who are treated for an early stage primary tumor.

The palliation of brain metastases in a favorable patient population: a randomized clinical trial by the Radiation Therapy Oncology Group.

Abstract The palliative effectiveness of a short, intensive course of brain irradiation (3000 rad in 2 weeks) was compared to that of a high-dose course (5000 rad in 4 weeks) in a randomized RTOG clinical trial. Eighty percent of the 255 evaluable patients had lung primaries, 7% breast, and 13% other or unknown primaries. Patients with evidence of extra-cranial metastases, uncontrolled primaries, or Class IV Neurologic Function (NFIV) were excluded. Forty-one percent of NFII and 71 % of NFIV patients improved in neurologic function class. For NFII patients, a significantly greater improvement rate was obtained with the short course than with the long course. Otherwise there were no significant differences between the two regimens with respect to palliation of symptoms, improvement rate, median time to progression, cause of death, or median survival. We conclude that 3000 rad in two weeks is at least as effective as 5000 rad in four weeks in the palliation of brain metastases, even in this relatively favorable patient population.

Original contributionSecond malignancies in patients who have head and neck cancer: Incidence, effect on survival and implications based on the RTOG experience

The development of second malignant tumors (SMTs), in patients who have had their first tumor treated successfully, represents a serious limitation of current therapeutic strategies for head and neck cancers. To improve our understanding of the current magnitude of the problem and the various factors that might influence its importance, we reviewed the Radiation Therapy Oncology Groups (RTOG) prospectively collected registry of all head and neck patients seen in participating member institutions between February 1977 and April 1980. A total of 928 patients were identified who had squamous cell carcinomas of the head and neck region, no prior or coincident history of another malignant tumor, and whose planned treatment consisted of radiation therapy only. A total of 110 second, independent, malignant tumors occurred in these patients. Overall, the estimated risk of developing a second tumor within 3 years of radiotherapy was 10%, within 5 years 15%, and within 8 years 23%. Minor differences in frequency were observed for different primary sites. These SMTs unquestionably influenced subsequent survival adversely. Analysis of the database also revealed that the extent of the primary tumor influenced the risk of a second; most occurred in patients who presented with the smallest primary tumors because of their better survival. Our data indicate that preventive medicine should have its greatest impact in those patients who are treated for an early stage primary tumor.