International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationAdjuvant 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
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 This relates mainly to issues of surgical quality in INT0116 and also to concerns regarding the now-outdated chemoradiation regimen that was used.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
References (13)
- et al.
Gastric surgical adjuvant radiotherapy consensus report: Rationale and treatment implementation
Int J Radiat Oncol Biol Phys
(2002) - et al.
3D conformal radiotherapy for gastric cancer—results of a comparative planning study
Radiother Oncol
(2005) - et al.
A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF)
Ann Oncol
(1994) - et al.
Chemo-radiotherapy for localized pancreatic cancer: Increased dose intensity and reduced acute toxicity with concomitant radiotherapy and protracted venous infusion 5-fluorouracil
Int J Radiat Oncol Biol Phys
(1998) - et al.
IMRT for postoperative treatment of gastric cancer: Covering large target volumes in the upper abdomen: A comparison of a step-and-shoot and an arc therapy approach
Int J Radiat Oncol Biol Phys
(2004) - et al.
IMRT for adjuvant radiation in gastric cancer: A preferred plan?
Int J Radiat Oncol Biol Phys
(2005)
Cited by (29)
The Feasibility of Quality Assurance in the TOPGEAR International Phase 3 Clinical Trial of Neoadjuvant Chemoradiation Therapy for Gastric Cancer (an Intergroup Trial of the AGITG/TROG/NHMRC CTC/EORTC/CCTG)
2023, International Journal of Radiation Oncology Biology PhysicsA new approach to delineating lymph node target volumes for post-operative radiotherapy in gastric cancer: A phase II trial
2015, Radiotherapy and OncologyCitation Excerpt :Thus, our strategy appears comparable to the strategies employed in these previous studies, at least. Over the past decade, Tepper and Gunderson’s [3] guide for defining gastric cancer CTVs has been applied in many studies, including trials and studies of 3-D treatment methods [5,6,10,19,20]. Nonetheless, detailed CTVs definitions (especially for LN stations) have not been clarified for 3-D therapy.
Role of (chemo)-radiotherapy in resectable gastric cancer
2014, Clinical OncologyCitation Excerpt :The complexity of gastric radiotherapy planning was illustrated by the fact that 35% of plans in INT0116 had major or minor errors at initial review, requiring correction before starting therapy. Similarly, the uncertainties around target delineation also lead to inevitable discrepancies in contouring, and this has been shown in the context of both phase II and III trials where detailed guidelines were provided [41,42] (the contouring atlas and protocol are available from the corresponding author ). Leong et al. recently reported that 35% of radiotherapy plans contained major or minor protocol violations in a prospective phase II trial of adjuvant CRT, again occurring despite provision of a detailed contouring atlas and planning guidelines.
Postoperative chemotherapy followed by conformal concomitant chemoradiotherapy in high-risk gastric cancer
2012, International Journal of Radiation Oncology Biology PhysicsCitation Excerpt :Arcangeli et al. (21) reported 40% 5-year overall survival after postoperative concomitant hyperfractionated radiotherapy and 5-FU protracted venous infusion. Recently, Leong et al. (22) reported in a multicentric prospective study 62% 3-year overall survival after one cycle of epirubicine, cisplatin, and 5-FU (ECF) followed by 3D conformal radiotherapy with concurrent infusional 5-FU and two additional cycles of ECF. Sixty-six percent of patients developed Grade 3/4 neutropenia.
Gastric Cancer
2011, Current Problems in CancerCitation Excerpt :In a 10-year follow-up to the Intergroup 0116 trial, PCRT sustained a benefit for chemoradiation with HR for survival (HR = 1.32, P = 0.004) and disease-free survival (HR = 1.51, P < 0.001) favoring chemoradiation, with the exception of women and diffuse histology.75 Other support in the development of recommendations for postoperative therapy includes Leong et al,76 who treated 54 R0 resected patients, with adjuvant therapy consisting of 1 cycle of epirubicin, cisplatin, and 5-FU, followed by radiotherapy with concurrent infusional 5-FU, and then 2 additional cycles of epirubicin, cisplatin, and 5-FU. Three-year overall survival rate was estimated at 61.6%.
Supported by a research grant from the Royal Australian and New Zealand College of Radiologists.
Conflict of interest: none.