Radiation (XRT) alone Versus Radiation + Chemotherapy (XRT+C)

Radiation alone has such a poor cure rate for esophagus cancer that many studies have evaluated combining radiation with chemotherapy (which probably improves the cure rates) or combine external beam radiation with intracavitary radiation (HDR, where the benefit is less clear.) We generally follow the protocol as per RTOG 94-05 (which used 5FU/Platinol/Radiation and is comparing doses of 50Gy versus 64.8Gy.) Key aspects of the protocol. The study was recently published and showed that  5000 was as good or better than the high dose:

Initial Course (50.4 Gy) Target Volume: RT will begin on the first day of week 1. The superior and inferior borders of the field will be 5 cm beyond the tumor and the lateral borders of the field will be 2 cm beyond the lateral borders of the tumor as defined by endoscopic U/S, esophagram, or CT (whichever is larger). The peri-esophageal nodes will be included. A barium swallow will also be obtained at the time of simulation to confirm the location of the esophagus. If the primary tumor is above the carina (proximal esophagus), the supraclavicular nodes will be included in the initial (50.4 Gy) RT field. A localized photon or electron boost to the supraclavicular fossa (SCF) is allowed if the SCF dose is < 50.4 Gy (specified at 3 cm depth from the anterior skin surface). The daily fraction size will be 1.8 Gy/day x 28 fractions.

Cone-Down (14.4 Gy) Target Volume: will be performed in a similar manner, however, the superior and inferior field will be decreased to 2 cm beyond the tumor. The lateral field will remain 2 cm beyond the lateral borders of the tumor as defined by CT or esophageal U/S, whichever is larger. A dose of 14.4 Gy (1.8 Gy x 8 fractions) will be delivered. The maximum dose to the spinal cord will be limited to 45 Gy.

Cisplatin: In both treatment arms, cisplatin (75 mg/m²) will be given by bolus and will be delivered on the first day of weeks 1 and 5. Four weeks following the completion of RT, this will be repeated (first day of post-RT weeks 1 and 5).

5-Fluorouracil: In both treatment arms, 5-fluorouracil (1000 mg/m²/24 hrs) will be delivered on days 1-4 of weeks 1 and 5. Four weeks following the completion of RT this will be repeated (first day of post-RT weeks 1 and 5).

Some other key studies:  

JAMA 1999 May 5;281(17):1623-7

Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group.

Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, Al-Sarraf M, Byhardt R, Russell AH, Beitler JJ, Spencer S, Asbell SO, Graham MV, Leichman LL

Department of Radiation Oncology, New York University, NY, USA. Jay.Cooper@Med.NYU.edu

Patients had squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, adequate renal and bone marrow reserve, and a Karnofsky score of at least 50. Interventions Combined modality therapy (n = 134): 50 Gy in 25 fractions over 5 weeks, plus cisplatin intravenously on the first day of weeks 1, 5, 8, and 11, and fluorouracil, 1 g/m2 per day by continuous infusion on the first 4 days of weeks 1, 5, 8, and 11. In the randomized study, combined therapy was compared with RT only (n = 62): 64 Gy in 32 fractions over 6.4 weeks.  Combined therapy significantly increased overall survival compared with RT alone. In the randomized part of the trial, at 5 years of follow-up the overall survival for combined therapy was 26% (95% confidence interval [CI], 15%-37%) compared with 0% following RT. In the succeeding nonrandomized part, combined therapy produced a 5-year overall survival of 14% (95% CI, 6%-23%).

Int J Radiat Oncol Biol Phys 1999 Feb 1;43(3):517-23

Final report of Intergroup Trial 0122 (ECOG PE-289, RTOG 90-12): Phase II trial of neoadjuvant chemotherapy plus concurrent chemotherapy and high-dose radiation for squamous cell carcinoma of the esophagus.

Minsky BD, Neuberg D, Kelsen DP, Pisansky TM, Ginsberg RJ, Pajak T, Salter M, Benson AB 3rd

Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. minskyb@mskcc.org

Forty-five patients with clinical Stage T1-4N0-1M0 squamous cell carcinoma were entered on a prospective single-arm study, of which 38 were eligible. Patients received 3 monthly cycles of 5-FU (1000 mg/m2/24 h x 5 days) and cisplatin (100 mg/m2 day 1; neoadjuvant segment) followed by 2 additional monthly cycles of 5-FU (1000 mg/m2/24 h x 5 days) and cisplatin (75 mg/m2 day 1) plus concurrent 6480 cGy (combined modality segment). The median follow-up in surviving patients was 59 months. RESULTS: For the 38 eligible patients, the primary tumor response rate was 47% complete, 8% partial, and 3% stable disease. The first site of clinical failure was 39% local/regional and 24% distant. For the total patient group, there were 6 deaths during treatment, of which 9% (4/45) were treatment related. The median survival was 20 months. Actuarial survival at 3 years was 30%, and at 5 years, 20%. CONCLUSION: This intensive neoadjuvant approach does not appear to offer a benefit compared with conventional doses and techniques of combined modality therapy. However, high dose radiation (6480 cGy) appears to be tolerable, and is being tested further in Intergroup Trial INT 0123.

Int J Radiat Oncol Biol Phys 1998 Sep 1;42(2):269-76

Combined chemoradiotherapy vs. radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group.

Smith TJ, Ryan LM, Douglass HO Jr, Haller DG, Dayal Y, Kirkwood J, Tormey DC, Schutt AJ, Hinson J, Sischy B

Morristown Memorial Hospital, NJ, USA.

Squamous carcinoma of the thoracic esophagus has an extremely poor prognosis. This study, EST-1282, was undertaken by the Eastern Cooperative Oncology Group (ECOG) to determine whether the combined use of 5-fluorouracil (5-FU), mitomycin C, and radiation therapy improved the disease-free survival and overall survival of patients with carcinoma of the esophagus, compared to those who received radiation therapy alone. Two- and 5-year survivals were 12% and 7% in the radiation alone arm and 27% and 9% in the chemoradiation arm. Patients treated with chemoradiation had a longer median survival (14.8 months), compared to patients receiving radiation therapy alone (9.2 months). This difference was statistically significant. The same pattern of survival was noted in almost all subgroups independent of whether surgical resection was performed.

N Engl J Med 1992 Jun 11;326(24):1593-8

Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus.

Herskovic. 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. 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 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).

J Clin Oncol 1997 Jan;15(1):277-84

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

al-Sarraf M. 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 and fluorouracil (5FU) 1,000 mg/m2/d on days 1 to 4 every 4 weeks with RT and every 3 weeks post-RT. 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%.

Int J Radiat Oncol Biol Phys 1998 Mar 15;40(5):1049-59

Neoadjuvant concurrent chemoradiotherapy followed by definitive high-dose radiotherapy or surgery for operable thoracic esophageal carcinoma.

Murakami . forty patients with operable squamous cell carcinoma of the thoracic esophagus were enrolled in a study of neoadjuvant concurrent chemoradiotherapy followed by definitive high-dose radiotherapy (CRT group) or surgery (CRT-S group). Neoadjuvant chemoradiotherapy consisted of 44 Gy in 40 fractions for 4 weeks (2.2 Gy/2 Fr/day) through 10-MVX rays, with 2 courses of cisplatin (80-100 mg/body, mean: 60 mg/m2, Day 1, bolus injection) and 5-fluorouracil (500-1000 mg/body/day, mean: 400 mg/m2, Days 1-4, continuous infusion). Overall survival at 2 and 3 years for CRT vs. CRT-S Group was 72%, 64% vs. 75%, 38%, respectively. No treatment-related mortality was observed. The rate of the 'esophagus conservation' was 65% (Stage 0: 1 of 1, 100%; Stage I: 11 of 12, 92%; Stage II: 8 of 17, 47%; Stage III: 6 of 10, 60%). CONCLUSION: Our results demonstrated that almost all early disease (Stage 0-I) and about half of advanced disease (Stage II-III) could be conserved, their esophagus treated by the multidisciplinary approach centering on high-dose radiotherapy and concurrent chemotherapy.

Arch Otolaryngol Head Neck Surg 2000 Feb;126(2):205-8

Thirty-four patients with carcinoma of the cervical esophagus treated with chemoradiation therapy.

Burmeister BH, Dickie G, Smithers BM, Hodge R, Morton K

Queensland Radium Institute, South Brisbane, Australia.

Patients received 3 different chemotherapy regimens. Two of the regimens used a combination of cisplatin and fluorouracil. The high-dose cisplatin regimen was a large dose of cisplatin (80 mg/m2) given on days 1 and 22 followed by a 96-hour infusion of fluorouracil (800 mg/m2) from days 2 to 5 and from days 23 to 26. The low-dose cisplatin regimen was cisplatin, 20 mg/m2, from days 1 to 5 and from days 22 to 26 and the same 96-hour infusion of fluorouracil. The third regimen used fluorouracil alone. The mean radiation dose administered was 61.2 Gy in 29.6 fractions during 41.8 days using 4- or 6-mV photons and a shrinking field technique. RESULTS: The results of treatment have shown a high rate of local control, although some patients developed metastases. The local complete response rate following treatment was 91%, and the rate of local control of disease was 88%. The projected actuarial 5-year survival rate was 55%.

J Clin Oncol 2000 Feb;18(3):455-62

Outcome of patients receiving radiation for cancer of the esophagus: results of the 1992-1994 Patterns of Care Study.

Coia LR, Minsky BD, Berkey BA, John MJ, Haller D, Landry J, Pisansky TM, Willett CG, Hoffman JP, Owen JB, Hanks GE

Department of Radiation Oncology, Community Medical Center, Toms River, NJ 08755, USA. lcoia@sbhcs.com

400 patients with squamous cell (62%) or adenocarcinoma (37%) of the thoracic esophagus who received radiation therapy (RT) as part of primary or adjuvant treatment. Patients were staged according to a modified 1983 American Joint Committee on Cancer staging system. Fifteen percent of patients had clinical stage (CS) I disease, 40% had CS II disease, and 30% had CS III disease. Twenty-six percent of patients underwent esophagectomy. Seventy-five percent of patients received chemotherapy; 84% of these received concurrent chemotherapy and radiation (CRT). Preoperative CRT resulted in a nonsignificantly higher 2-year survival rate compared with definitive CRT alone (63% v 39%; P =.11), whereas 2-year survival by planned treatment rather than treatment given was 47.7% for preoperative CRT and 35.4% for definitive CRT (P =.23). Definitive CRT compared with definitive RT alone resulted in significantly higher 2-year survival (39% v 20.6%; P =.027) and lower 2-year local regional failure (30% v 57.9%; P =. 0031).