RTOG Protocol No: 9207	Protocol Status:
	Opened:	June 22, 1992
	Closed:	February 14, 1995

Title:

A Phase I/II Trial for Localized Cancer of the Esophagus: External Beam Irradiation, Esophageal Brachytherapy and Combination Chemotherapy

Patient Population:

Patients at least 18 yrs. of age, KPS >60, with squamous cell carcinoma or adenocarcinoma of the esophagus, with T1-2, Nx-N1, M0, and no evidence of disseminated cancer. Patients had no prior chemotherapy or radiation therapy and no prior malignancy within 5 years of study entry.

Objectives:

To determine the toxicity of chemotherapy, external beam irradiation and esophageal brachytherapy (EB) given at a high and low dose rate in a potentially curable group of patients with adenocarcinoma or squamous cell carcinoma of the esophagus. Also to determine the patterns of recurrence for patients treated with combination chemotherapy, external beam, and EB given at a high and low dose rate.

Schema:

R	Chemotherapy
E		CDPD - 75 mg/m2 - first day of weeks 1,5,8,11
G		5-FU - 1000 mg/m2 x 4 days, weeks 1,5,8,11
I
S	Radiotherapy
T	External beam		50.0 Gy/25 fractions/5 weeks starting day 1
E
R	Esophageal		- HDR 5.0 Gy, weeks 8 and 9 (once a week x 2)
	Brachytherapy* OR
			- LDR 20.0 Gy at week 8 (once) (closed 12/22/94)

Brachytherapy must be given concurrently with 5-FU during week 8

* Each institution declared a single dose rate (either HDR or LDR [discontinued 12/22/94)) before a patient could be registered to this protocol. All patients entered on this protocol by a given institution were to be treated at that dose rate.

Study Chairs:	Laurie E. Gaspar, M.D., (Radiation Oncology)
	Arnold M. Herskovic, M.D., (Radiation Oncology)
	Walter Kocha, M.D., (Medical Oncology)

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: Gaspar, L. E., et al. A Phase I/II Study of External Beam Radiation, Brachytherapy and Concurrent Chemotherapy for Patients with Localized Carcinoma of the Esophagus (RTOG 9207) Final Report. Cancer 88 (5): 988-995, 2000.

Background: A multiinstitutional, prospective study of the Radiation Therapy Oncology Group (RTOG) was designed to determine the feasibility and toxicity of chemotherapy, external beam radiation, and esophageal brachytherapy (EB) in a potentially curable group of patients with adenocarcinoma or squamous cell carcinoma of the esophagus. A preliminary analysis indicated a 17% 1-year actuarial risk of treatment-related fistulas. A final analysis of this study was considered important to determine the median survival time, local control, and late toxicity associated with this treatment regimen.

Methods: Planned treatment was 50 grays (Gy) of external beam radiation (25 fractions given over 5 weeks) followed 2 weeks later by EB (either high-dose-rate 5 Gy during Weeks 8, 9, and 10, for a total of 15 Gy, or low-dose-rate 20 Gy during Week 8). Chemotherapy was given during Weeks 1, 5, 8, and 11, with cisplatin 75 mg/m(2) and 5-fluorouracil 1000 mg/m(2)/24 hours in a 96-hour infusion.

Results: Of the 49 eligible patients, 45 (92%) had squamous histology and 4 (6%) had adenocarcinoma. Forty-seven patients (96%) completed external beam radiation plus at least 2 courses of chemotherapy, whereas 34 patients (69%) were able to complete external beam radiation, EB, and at least 2 courses of chemotherapy. The estimated survival rate at 12 months was 49%, with an estimated median survival of 11 months. Life-threatening toxicity or treatment-related death occurred in 12 (24%) and 5 (10%) cases, respectively. Treatment-related esophageal fistulas occurred in 6 cases (12% overall, 14% of patients starting EB) at 0.5-6.2 months from the first day of brachytherapy, leading to death in 3 cases.

Conclusions: In this study, severe toxicity, including treatment-related fistulas, occurred within 7 months of brachytherapy. Based on the 12% incidence of fistulas, the authors continue to urge caution in employing EB, particularly when used in conjunction with chemotherapy.

Reference: Gaspar, L., et al. Swallowing Function and Weight Change Observed in a Phase I/II Study of External Beam Radiation, Brachytherapy and Concurrent Chemotherapy in Localized Cancer of the Esophagus (RTOG 9207). American Radium Society, 2000.

Background: A multi-institutional, prospective study was completed utilizing chemotherapy, external beam irradiation and esophageal brachytherapy (EB) in a potentially curable group of patients with carcinoma of the esophagus.

Swallowing function and weight were assessed prior to and following treatment.

Materials and Methods: Planned treatment was 50Gy external beam radiation (25 fractions/5 weeks) followed 2 weeks later by EB (either HDR 5 Gy weeks 8, 9 and 10 for a total of 10-15 Gy). Chemotherapy was given weeks 1,5,8 and 11 with Cisplatin (DDP) 75 mg/m2 and 5-FU 1000 mg/m2 24 hrs, 96 hour infusion. Swallowing was graded from 1 (able to set any solids) to 4 (complete obstructions to solids and liquids). Weight "loss" or weight "gain" was defined as a gain change in 3 month post- to pre-therapy weight < 5% or > 5%, respectively.

Results: Estimated survival rate at 12 months was 49%, with an estimated 11 month median survival rate. Swallowing prior to treatment was graded as Grade 1 in 14 patients. Grade 2 in 22 patients, Grade 3 in 9 patients, Grade 4 in 4 patients. The best-improved dysphagia score following treatment in 29 evaluable patients was Grade 1 in 24 patients, Grade 2 in 4 patients, Grade 3 in 1 patient, Grade 4 in 0 patients. Post-treatment weights in 42 evaluable patients was categorized as a loss, gain or stable in 29 (69%), 4 (9.5%) and 9 (21.5%) patients, respectively. Dysphagia score was highly correlated with weight change.

Conclusions: Swallowing function following brachytherapy and concurrent chemoradiation therapy is satisfactory in the majority of surviving patients. Dysphagia grade was an important factor with respect to weight change. Future plans are to compare this to other prospective studies which utilized chemoradiation without brachytherapy.