A B S T R AC T BACKGROUND The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established. We compared chemoradiotherapy followed by surgery with surgery alone in this patient population. METHODS We randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. RESULTS From March 2004 through December 2008, we enrolled 368 patients, 366 of whom were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy–surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy–surgery group versus 69% in the surgery group (P<0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy– surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy–surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P = 0.003). CONCLUSIONS Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation [KWF Kankerbestrijding]; Netherlands Trial Register number, NTR487.)

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Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

ContextCarcinoma of the esophagus traditionally has been
treated by surgery or radiation therapy (RT), but 5-year overall
survival rates have been only 5% to 10%. We previously reported
results of a study conducted from January 1986 to April 1990 of
combined chemotherapy and RT vs RT alone when an interim analysis
revealed significant benefit for combined therapy.ObjectiveTo report the long-term outcomes of a previously
reported trial designed to determine if adding chemotherapy during RT
improves the survival rate of patients with esophageal carcinoma.DesignRandomized controlled trial conducted 1985 to 1990 with
follow-up of at least 5 years, followed by a prospective cohort study
conducted between May 1990 and April 1991.SettingMulti-institution participation, ranging from tertiary
academic referral centers to general community practices.PatientsPatients 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.InterventionsCombined 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.Main Outcome MeasuresOverall survival, patterns of failure, and
toxic effects.ResultsCombined 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%). Persistence of
disease (despite therapy) was the most common mode of treatment
failure; however, it was less common in the groups receiving combined
therapy (34/130 [26%]) than in the group treated with RT only (23/62
[37%]). Severe acute toxic effects also were greater in the combined
therapy groups. There were no significant differences in severe late
toxic effects between the groups. However, chemotherapy could be
administered as planned in only 89 (68%) of 130 patients (10% had
life-threatening toxic effects with combined therapy vs 2% in the RT
only group).ConclusionCombined therapy increases the survival of
patients who have squamous cell or adenocarcinoma of the esophagus,
T1-3 N0-1 M0, compared with RT alone.

https://jamanetwork.com/journals/jama/articlepdf/189737/JOC81619.pdf

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

Summary Background In a previous meta-analysis, we identified a survival benefit from neoadjuvant chemotherapy or chemoradiotherapy before surgery in patients with resectable oesophageal carcinoma. We updated this meta-analysis with results from new or updated randomised trials presented in the past 3 years. We also compared the benefits of preoperative neoadjuvant chemotherapy compared with neoadjuvant chemoradiotherapy. Methods To identify additional studies and published abstracts from major scientific meetings, we searched Medline, Embase, and Central (Cochrane clinical trials database) for studies published since January, 2006, and also manually searched for abstracts from major conferences from the same period. Only randomised studies analysed by intention to treat were included, and searches were restricted to those databases citing articles in English. We used published hazard ratios (HRs) if available or estimates from other survival data. We also investigated treatment effects by tumour histology and relations between risk (survival after surgery alone) and effect size. Findings We included all 17 trials from the previous meta-analysis and seven further studies. 12 were randomised comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1854), nine were randomised comparisons of neoadjuvant chemotherapy versus surgery alone (n=1981), and two compared neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy (n=194) in patients with resectable oesophageal carcinoma; one factorial trial included two comparisons and was included in analyses of both neoadjuvant chemoradiotherapy (n=78) and neoadjuvant chemotherapy (n=81). The updated analysis contained 4188 patients whereas the previous publication included 2933 patients. This updated meta-analysis contains about 3500 events compared with about 2230 in the previous meta-analysis (estimated 57% increase). The HR for all-cause mortality for neoadjuvant chemoradiotherapy was 0·78 (95% CI 0·70–0·88; p Interpretation This updated meta-analysis provides strong evidence for a survival benefit of neoadjuvant chemoradiotherapy or chemotherapy over surgery alone in patients with oesophageal carcinoma. A clear advantage of neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy has not been established. These results should help inform decisions about patient management and design of future trials. Funding Cancer Australia and the NSW Cancer Institute.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(11)70142-5.pdf

Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis

Background We performed a multi-institutional randomized trial comparing preoperative chemotherapy followed by surgery with surgery alone for patients with local and operable esophageal cancer. Methods Preoperative chemotherapy for patients randomly assigned to the chemotherapy group included three cycles of cisplatin and fluorouracil. Surgery was performed two to four weeks after the completion of the third cycle; patients also received two additional cycles of chemotherapy after the operation. Patients randomly assigned to the immediate-surgery group underwent the same surgical procedure. The main end point was overall survival. Results Of the 440 eligible patients with adequate data, 213 were assigned to receive preoperative chemotherapy and 227 to undergo immediate surgery. After a median possible study time of 55.4 months, there were no significant differences between the two groups in median survival: 14.9 months for the patients who received preoperative chemotherapy and 16.1 months for those who u...

Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer

Background Uncontrolled studies suggest that a combination of chemotherapy and radiotherapy improves the survival of patients with esophageal adenocarcinoma. We conducted a prospective, randomized trial comparing surgery alone with combined chemotherapy, radiotherapy, and surgery. Methods Patients assigned to multimodal therapy received two courses of chemotherapy in weeks 1 and 6 (fluorouracil, 15 mg per kilogram of body weight daily for five days, and cisplatin, 75 mg per square meter of body-surface area on day 7) and a course of radiotherapy (40 Gy, administered in 15 fractions over a three-week period, beginning concurrently with the first course of chemotherapy), followed by surgery. The patients assigned to surgery had no preoperative therapy. Results Of the 58 patients assigned to multimodal therapy and the 55 assigned to surgery, 10 and 1, respectively, were withdrawn for protocol violations. At the time of surgery, 23 of 55 patients (42 percent) treated with preoperative multimodal therapy who c...

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Napoleon Keeling

Papers

A comparison of multimodal therapy and surgery for esophageal adenocarcinoma.