Clinical Investigation
Adjuvant Chemoradiation for Gastric Cancer Using Epirubicin, Cisplatin, and 5-Fluorouracil Before and After Three-Dimensional Conformal Radiotherapy With Concurrent Infusional 5-Fluorouracil: A Multicenter Study of the Trans-Tasman Radiation Oncology Group

Presented in part as an oral presentation at the 49th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Los Angeles, CA, October 31, 2007.
https://doi.org/10.1016/j.ijrobp.2009.11.042Get rights and content

Purpose

The INT0116 study has established postoperative chemoradiotherapy as the standard of care for completely resected gastric adenocarcinoma. However, the optimal chemoradiation regimen remains to be defined. We conducted a prospective, multicenter study to evaluate an alternative chemoradiation regimen that combines more current systemic treatment with modern techniques of radiotherapy delivery.

Methods and Materials

Patients with adenocarcinoma of the stomach who had undergone an R0 resection were eligible. Adjuvant therapy consisted of one cycle of epirubicin, cisplatin, and 5-FU (ECF), followed by radiotherapy with concurrent infusional 5-FU, and then two additional cycles of ECF. Radiotherapy was delivered using precisely defined, multiple-field, three-dimensional conformal techniques.

Results

A total of 54 assessable patients were enrolled from 19 institutions. The proportion of patients commencing Cycles 1, 2, and 3 of ECF chemotherapy were 100%, 81%, and 67% respectively. In all, 94% of patients who received radiotherapy completed treatment as planned. Grade 3/4 neutropenia occurred in 66% of patients with 7.4% developing febrile neutropenia. Most neutropenic episodes (83%) occurred in the post-radiotherapy period during cycles 2 and 3 of ECF. Grade 3/4 gastrointestinal toxicity occurred in 28% of patients. In all, 35% of radiotherapy treatment plans contained protocol deviations that were satisfactorily amended before commencement of treatment. At median follow-up of 36 months, the 3-year overall survival rate was estimated at 61.6%.

Conclusions

This adjuvant regimen using ECF before and after three-dimensional conformal chemoradiation is feasible and can be safely delivered in a cooperative group setting. A regimen similar to this is currently being compared with the INT0116 regimen in a National Cancer Institute–sponsored, randomized Phase III trial.

Introduction

The US Intergroup trial (INT0116) has established combined chemoradiotherapy as an integral component of standard adjuvant therapy for high-risk, completely resected adenocarcinoma of the stomach (1). This trial demonstrated a major survival advantage to the use of combined modality therapy postoperatively, with 3-year survival improving from 41% to 50%. However, postoperative adjuvant chemoradiotherapy has not been universally adopted as standard of care in all countries. This relates mainly to issues of surgical quality in INT0116 and also to concerns regarding the now-outdated chemoradiation regimen that was used. The chemotherapy regimen of bolus 5-FU and leucovorin that was used in INT0116 had minimal effect on regional and distant failure (1), clearly indicating the need for more effective systemic therapies. Furthermore, radiotherapy target volumes in INT0116 were designed with minimal use of CT planning, and most patients were treated with simple parallel-opposed, anteroposterior–posteroanterior (AP-PA) field arrangements resulting in large radiation treatment volumes (2). Despite the simple nature of the techniques, there was a protocol deviation rate of 35%. With present-day three-dimensional (3D) planning systems, it is now possible to deliver radiation using multiple-field techniques that conform more accurately to the high-risk volume and with substantial sparing of critical normal tissues; however this will greatly increase the potential risks for protocol interpretation errors.

The implementation of adjuvant chemoradiation in Australia proved challenging due to concerns about treatment related toxicity, and debate regarding the optimal chemotherapy regimen and the optimal technique of radiotherapy delivery. In 2002, the Trans-Tasman Radiation Oncology Group (TROG) launched a prospective, multicenter study to evaluate the feasibility, on a national level, of an alternative regimen of adjuvant chemoradiation, based on the results of a single-institution pilot study (3). This regimen used epirubicin, cisplatin, and 5-fluorouracil (ECF) as the systemic component, given before and after chemoradiation. The chemoradiation component combined modern 3D conformal radiotherapy techniques with continuous infusional 5-FU. The toxicity rates observed in this pilot study compared favorably to those reported in INT0116, and 81% of patients were able to complete all planned treatment. The aims of this TROG study were to detail the acute toxicity associated with this chemoradiation regimen, and to determine compliance with the chemotherapeutic and radiotherapeutic components of protocol treatment. Additional aims were to educate radiation oncologists and to standardize the approach to modern 3D conformal radiotherapy for gastric cancer, which was essential before we could initiate further multicenter studies.

Section snippets

Patients

Eligible patients were those with histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction, who had undergone a complete R0 resection with negative margins. Because the purpose of the trial was to evaluate the feasibility of adjuvant chemoradiation, surgery did not form part of this trial, and the extent of surgical lymph node dissection was not mandated in the protocol. Additional eligibility criteria included the following: tumor Stage T3 to T4 and/or N1 to N3

Patient characteristics

Nineteen institutions participated in this trial between July 2003 and October 2006. A total of 56 patients were enrolled in the study, of whom 54 were assessable. Of the 2 patients who were excluded from the analysis, 1 patient was ineligible and another patient withdrew from the trial before commencing protocol treatment. Patient characteristics are listed in Table 1. The median age was 57 years (range, 26–73 years). The majority of patients had locally advanced disease, with 50% of tumors

Discussion

The finding that postoperative chemoradiation improved survival in patients with resectable gastric cancer was met with both excitement and apprehension among oncologists who treat gastrointestinal malignancies. On one hand, the INT0116 results were seen as a major advance after decades of investigation that had yielded little improvement in the 5-year survival rates for gastric cancer. On the other hand, clinicians were suddenly faced with the dilemma of implementing an unfamiliar treatment

Conclusion

Our study demonstrates that this adjuvant regimen combining ECF with chemoradiation is feasible and can be safely delivered in a cooperative group setting. It also showed tha,t despite detailed protocol instruction, compliance with the intended radiation technique was achieved only with real-time central review. This illustrates the ongoing need for real-time review, as well as accreditation exercises for complex 3D radiotherapy techniques. Because this study was conducted in all states of

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Supported by a research grant from the Royal Australian and New Zealand College of Radiologists.

Conflict of interest: none.

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