RTOG Protocol No:	8501	Protocol Status:
SWOG Protocol No:	8598	Opened:	January 2, 1986
NCCTG Protocol No:	88-40-51	Closed:	April 20, 1991

Title:

Phase III Prospective Trial for Localized Cancer of the Esophagus: Comparing Radiation as a Single Modality to the Combination of Radiation Therapy and Chemotherapy.

Patient Population:

Patients with squamous cell or adenocarcinoma of the thoracic esophagus, with no evidence of disseminated cancer, negative bone scan, WBC > 4000/mm³, platelets > 100,000/mm³, creatinine < 1.5 mg%, BUN < 22 mg%.

Objectives:

To determine whether overall survival and patterns of recurrence differ in patients receiving combination RT and chemotherapy vs. RT alone.

Schema:

S	1. Weight loss in last 6 months	R	A. Chemotherapy + RT (Both chemo and
	> 10 lbs.		RT to start on day 1)
T	vs.	A	CCDP - 75 mg/m2 - first day of wks
	< 10 lbs.		1,5,8,11
R		N
	2. Lesion Size		5-FU - 1000 mg/m2 x 4 days wks 1,5,8,11
A	> 5 cm	D
	vs.		RT - 2 Gy x 5 days/wk x 3 weeks (30 Gy)
T	< 5 cm	O	followed by boost of 2 Gy x 5 days/wk x 2
			wks (20 Gy)
I	3. Histology	M
	Squamous		B. Radiation Alone/Closed May, 1990
F	vs.	I	2 Gy x 5 days/wk x 5 wks (50 Gy)
	Adenocarcinoma
Y		Z	BOOST - 2 GY x 5 DAYS/WK X 1.4 WKS
			(14 GY)
		E

Study Chairs:	Arnold M. Herskovic, M.D. (RTOG)	Patients Entered During:
	Claudia Perez-Tamayo, M.D. (SWOG)	Randomized Phase 1/2/85 to 4/30/90
	Jeffrey S. Brindle, M.D. (NCCTG)
		RTOG	80

Reference: Thomas Jr. C, Berkey B, Minsky B, et al. Recursive Partitioning Analysis (RPA) Of Pre-Treatment Variables For 416 Patients With Loco-Regional Esophageal Cancer Treated With Concomitant Chemoradiotherapy (CT-RT) On Intergroup And Radiation Therapy Oncology Group (RTOG) Trials. Proc Am Soc Thera Rad Oncol (ASTRO), New Orleans, LA, Int J Radiat Oncol Biol Phys, [54] (2) pg. 131, Abs. #221, 2002.

Purpose/Objective: Specific aims of this analysis were to analyze the relative contributions of uniformly collected pre-treatment patient (pt) and tumor-related variables to survival and to identify terminal nodes via RPA that could be utilized as stratification variables for future phase 3 trials.

Materials/Methods: From two Intergroup trials (85-01, N=130; 94-05, N=218) and one RTOG trial (92-07, N=68), we identified 416 pts who were treated with concomitant cisplatin-based CT-RT and were analyzed for survival by RPA in order to define prognostic classes. The following pre-treatment factors were evaluated: histology, age, weight loss, KPS, gender, race, T-stage, tumor location and size, N-stage, and degree of dysphagia. The entire dataset was considered as the initial node. The criteria for split points was the smallest p-value less than unadjusted 0.05.

Results: Of 416 pts, 336 (81%) were dead at the time of the analysis. RPA identified only one significant split: pre-treatment weight loss in the prior 6 months <10% vs. > 10% (Figure). Within the <10% weight loss cohort we observed a trend toward improved survival in pts with a KPS 90-100 compared to those with a KPS 50-80 (p=0.098).

Conclusions: Unlike our experience with malignant glioma, brain metastases, and locally advanced non-small cell lung cancer, RPA failed to identify novel prognostic information that could be incorporated into the stratification scheme of future CT-RT trials for esophageal cancer. The lack of endoscopic ultrasound as an adjunct to the initial staging work-up precludes an accurate determination of T-stage and should be incorporated into the staging algorithm of future cooperative group trials. Furthermore, our analysis may validate % weight loss as a stratification variable for esophageal cancer. Finally, this parameter may be utilized when comparing pt. cohorts that have been treated with definitive CT-RT versus those pts. where surgery has been a component of therapy.

This Abstract was supported by grant number RTOG U10 CA21661, CCOP U10 CA37422, Stat U10 CA32115 from the National Cancer Institute (NCI). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCI.

Reference: Cooper JS, et. al. Chemoradiotherapy Significantly Improves the Cure Rate of Locally Advanced Esophageal Cancer Long-Term Follow-Up of a Prospective Randomized Intergroup Trial (RTOG 85-01). JAMA, 281:1623-1627, 1999.

Context: Carcinoma of the esophagus traditionally has been treated by surgery or radiation therapy, but 5-year overall survival rates have been low.

Objective: To determine if adding chemotherapy to radiation therapy improves the survival rate of these patients.

Design: A prospective, randomized trial was conducted between 1/86 and 4/90. Between 5/90 and 4/91 a separate non-randomized, prospectively accrued cohort was treated according to the "investigational arm" of the randomized trial.

Setting: Multi-institutional, Intergroup organized. A total of 87 institutions, ranging in nature from tertiary, academic referral centers to general community practices, located throughout the United States.

Patients: Patients had squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, adequate renal and bone marrow reserve and a Karnofsky score at least 50. All patients acknowledged informed consent in writing. 129 patients had their treatment selected by random chance, stratified by the size of their primary tumor, its histopathologic type and their amount of weight loss; subsequently 73 consecutive patients were treated uniformly by combined modality therapy. 10 have been excluded from analysis.

Interventions: Standard therapy = Radiation therapy (RT) only: 64 Gy in 32 fractions over 6.5 weeks. Investigational therapy = combined modality therapy (CTX/RT): 50 Gy in 25 fractions over 5 weeks plus 2 cycles of cisplatin, 75 mg/m2 IV days 1 & 29, and 5-fluorouracil, 1 gm/m2/d continuous infusion days 1-4 & 29-32. Two additional cycles of the same chemotherapy were given 3 weeks apart after RT was completed.

Main outcome measures: 1. Overall survival (OS). 2. Patterns of failure. 3. Toxicity

Results: Results are reported on an intention-to-treat basis. CTX/RT significantly increased overall survival as compared to RT. In the randomized part of the trial, at the 5-year mark the OS for CTX/RT was 26% (15-37%, 95% C.I.) as compared to 0% following RT. In the succeeding non-randomized part, CTX/RT produced a 5-year OS of 14% (6-23%, 95% C.I.). Persistence of disease (despite therapy) was the most common mode of treatment failure; however, it was less common in the groups treated by CTX/RT than in the group treated by RT. Severe acute toxicity also was greater in the CTX/RT groups, but later in the trial some of the effect was abrogated. There were no significant differences in grade 3+ late toxicity between the groups. However, chemotherapy could be administered as planned in only 68% (89/130) of patients.

Conclusion: CTX/RT increases the survival of patients who have squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, as compared with RT alone.

Reference: O. Streeter, et al. Does Race Influcence Survival for Esophageal Cancer Patients Treated on the Radiation and Chemotherapy Arm of RTOG 85-01? Int J Radiat Oncol Biol Phys 44 (5): 1047-1052, 1999

Purpose: In reported retrospective non-randomized trials of treatment of esophageal carcinoma, blacks have a lower survival from esophageal cancer than whites. None of these studies has accounted for the extent of disease, or the methods and quality of treatment. We reviewed the data that included only patients treated on the chemoradiation arm of the RTOG 85-01 esophageal carcinoma trial to see if there were differences in overall survival between black and white patients receiving the same standard of care.

Methods and Materials: One hundred-nineteen patients, 37 blacks and 82 whites were evaluated who met the criteria for receiving chemoradiation of 5000 cGy and four courses of Cisplatin (75 mg/m2) and Fluorouracil (1000 mg/m2 for 4 days).

Results: Blacks had squamous histology only, with 86% of blacks having weight loss of 10 lbs. or more compared to 56% of whites (p = 0.001). In addition, blacks had larger tumors and more difficulty eating (p = 0.010). Overall, there was no difference in the Kaplan-Meier median survival estimate by race (p = 0.2757). Only when we limited the analysis to the "squamous histology" subgroup, stratified according to age >70 vs. <70 years (p = 0.0002), and nodal status (p = 0.0177) in a Cox regression model analysis, did race appear to be a significant factor (p = 0.0012). However, using the entire database, the age effect was found to be a "bimodal" effect, wherein the "youngest" (< age 60 years) and "oldest" patients (age > 70 years) did poorly. Because of the dramatic differences in the age and histology distributions between blacks and whites, this issue could not be resolved in the subset of squamous only who received chemoradiation.

Conclusions: The increasing incidence of adenocarcinoma among white patients without a corresponding increase of this histology in blacks reflects a difference in diet and or lifestyle compared to blacks that deserves additional study. When treated aggressively with chemoradiation, race did not appear to be a statistically significant factor for overall survival.