RTOG Protocol No:	9405	Protocol Status:
Intergroup Protocol No:	0123	Opened:	June 12, 1995
ECOG Protocol No:	R9405	Closed:	July 1, 1999
NCCTG Protocol No:	91-40-51

Title: An Intergroup Randomized Comparison of Combined Modality Therapy for Carcinoma of the Esophagus

Patient Population:

Histologically proven squamous cell or adenocarcinoma; stages T1-4, Nx, M0; Karnofsky Performance Status >60; WBC >4,000/mm; platelets >150,000/mm; Hgb >10 gm%; creatinine <upper normal limit; no TE fistula; must have abdominal CT; no evidence of disseminated cancer; no prior chemotherapy; chest RT; no tumor extension within 2 cm proximal to the stomach.

Objectives:

1. To compare, the outcomes (survival and failure patterns) of therapy with conventional dose RT (50.4 Gy) and 5-FU/CDDP (4 cycles) versus high dose RT (64.8 Gy) and 5-FU/CDDP combined chemotherapy (4 cycles).

2. To compare the tolerance and quality of life in patients receiving these therapies.

Schema:

*Chemotherapy

CDDP - 75 mg/m² - day 1 of wks 1 and 5; then repeat 4 weeks after the end of RT

5-FU - 1000 mg/m² - days 1-4 of wks 1 and 5; then repeat 4 wks after the end of RT

Study Chairs:	Bruce Minsky, M.D.(Radiation Oncology)	Total Patients Entered: 236
	David Kelsen, M.D. (Medical Oncology)
	Robert Ginsberg, M.D. (Surgical Oncology)
	Todd Wasserman, M.D. (Quality of Life)
	Thomas Pisansky, M.D. (ECOG, Radiation Oncology)
	Al Benson, M.D. (ECOG, Medical Oncology)
	Richard Feins, M.D. (ECOG, Surgical Oncology)
	James A. Martenson, M.D. (NCCTG, Radiation Oncology)
	Paul Schaefer, M.D. (NCCTG, Medical Oncology)

Reference: Minsky B, Pajak T, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) Phase III Trial of Combined-Modality Therapy for Esophageal Cancer: High-Dose Versus Standard-Dose Radiation Therapy. J Clin Oncol 20 (5):1167-1174, 2002.

Purpose: To compare the local/regional control, survival, and toxicity of combined-modality therapy using high-dose (64.8 Gy) versus standard-dose (50.4 Gy) radiation therapy for the treatment of patients with esophageal cancer.

Patients and Methods: A total of 236 patients with clinical stage T1 to T4, N0/1, M0 squamous cell carcinoma or adenocarcinoma selected for a nonsurgical approach, after stratification by weight loss, primary tumor size, and histology, were randomized to receive combined-modality therapy consisting of four monthly cycles of fluorouracil (5-FU) (1,000 mg/m²/24 hours for 4 days) and cisplatin (75 mg/m² bolus day 1) with concurrent 64.8 Gy versus the same chemotherapy schedule but with 2) concurrent 50.4 Gy. The trial was stopped after an interim analysis. The median follow-up was 16.4 months for all patients and 29.5 months for patients still alive.

Results: For the 218 eligible patients, there was no significant difference in median survival (13.0 v 18.1 months), 2-year survival (31% v 40%), or local/regional failure and local/regional persistence of disease (56% v 52%) between the high-dose and standard-dose arms. Although 11 treatment-related deaths occurred in the high-dose arm compared with two in the standard-dose arm, seven of the 11 deaths occurred in patients who had received 50.4 Gy or less.

Conclusion: The higher radiation dose did not increase survival or local/regional control. Although there was a higher treatment-related mortality rate in the patients assigned to the high-dose radiation arm, it did not seem to be related to the higher radiation dose. The standard radiation dose for patients treated with concurrent 5-FU and cisplatin chemotherapy is 50.4 Gy.

Reference: Thomas Jr. C, Berkey 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: Kachnic L, et al. One-Year Follow-Up Reveals No Difference In Quality of Life Between High Dose And Conventional Dose Radiation: A Quality of Life Assessment of RTOG 94-05. Int J Radiat Oncol Biol Phys 51:97, 2001.

Purpose: This study evaluated and compared the quality of life (QOL) outcomes for patients with esophageal cancer receiving combined modality therapy (CMT) with conventional dose radiation (RT) vs. high dose RT as used in RTOG study 94-05.

Materials and Methods: Between June 12, 1995 and July 1, 1999, 236 patients with cT1-4NxM0 esophageal cancers were randomized on RTOG 94-05 to conventional dose (CD) CMT: 50.4 Gy RT + concurrent 5-FU and cisplatin administered on weeks 1 and 5 and repeated 4 weeks post RT vs. high dose (HD) CMT: 64.8 Gy RT + the same chemotherapy. QOL was assessed using the Functional Assessment of Cancer Therapy (FACT) - Head & Neck (version 2). This questionnaire was administered to patients pre-treatment, post-treatment, at 8 months from the start of CMT, at 1 year and at 6-month intervals to year 5.

Results: Of 209 eligible protocol patients, 169 (81%) participated in the pre-treatment QOL component of RTOG 94-05 (83 in the HD arm and 86 in the CD arm). The principle reason for non-participation was institutional error. The distribution of pre-treatment characteristics by participation in QOL assessment was similar in both treatment arms. African-Americans, patients with >10% weight loss, and patients with low performance status were significantly less likely to complete QOL forms (p=0.04, P=0.01 and P=0.004 respectively). Baseline QOL parameters were similar in the two treatment arms. Pulmonary symptoms were the most significant pre-treatment dysfunction reported. Female gender and >10% pre-treatment weight loss correlated with pre-treatment total QOL scores. Women reported lower overall QOL as well as worse physical and emotional well-being in the HD arm as compared to the CD arm (p=0.07, P=0.01 and P=0.03 respectively). Patients with >10% weight loss reported decreased QOL in nearly all domains in both treatment groups, although more pronounced in the 64.8 Gy arm. Treatment arm assignment, age, performance status, tumor size and histology did not significantly correlate with overall pre-treatment QOL. At treatment completion, 96 patients (46%) completed QOL forms (46 HD, 50 CD); non-participation was due to death in 17, delayed completion in 23 and missing in 33. QOL was worse post-treatment in both arms with total QOL scores significantly lower than baseline in the HD arm (p=0.05). Similarly, women reported lower QOL on the 64.8 Gy arm (overall QOL P=0.06, physical well-being P=0.06, relationship with physician P=0.02 and emotional well-being P=0.02). Among the various QOL domains, pre-treatment weight loss of >10% only significantly correlated with decreased family well-being on the HD arm (p=0.04). Seventy-three patients (35%) participated in QOL assessment at 8 months post CMT (40 HD, 33 CD); the principle reason for non-participation was patient death. QOL scores were similarly restored to baseline in the two treatment arms, with head and neck symptoms reported as improved. Pre-treatment weight loss remained a significant predictor for overall QOL, as well as for social and family well being. Gender had no significant effect on QOL at 8 months. Fifty-seven patients were available for QOL participation at 1 year (25 HD, 32 CD) with no significant differences in QOL scores between the two treatment arms. Preliminary analysis at 2 years showed no local control or survival benefit for the high dose arm.

Conclusion: In this randomized trial of RT dose escalation, functional and symptomatic scores of QOL were decreased after CMT in both treatment arms with total QOL scores significantly poorer than baseline in the high dose group. This early decrease in QOL for the 64.8 Gy arm was restored to baseline after 8 months, and at 1 year there were no significant differences in QOL scores between the two treatment arms. Therefore, for patients treated with CMT for esophageal cancer who remain alive at 1 year, RT dose escalation to 64.8 Gy appears to be as well tolerated as the conventional 50.4 Gy arm from the patient's perspective.