Radiotherapy for Gastrointestinal Malignancies

Manisha Palta¹, Christopher Willett², and Brian Czito²

¹Duke Regional Hospital, Durham, NC, USA

²Duke University Medical Center, Durham, NC, USA

Case study 121.1

A 65-year-old female presents with painless jaundice and diarrhea for 1 month. Labs show an elevation in liver function tests and total bilirubin of 13.4. Computed tomography (CT) scan reveals a 2 cm lesion in the pancreatic head. Endoscopic retrograde cholangiopancreatography demonstrates a common bile duct stricture, and a metal stent is placed. Endoscopic ultrasound demonstrates a 1.9 cm pancreatic head mass and fine-needle aspiration shows adenocarcinoma. CT scan confirms no involvement of major vessels and no evidence of distant metastases. The patient undergoes pancreaticoduodenectomy, revealing pT1N0 poorly differentiated adenocarcinoma with negative margins.

1. Which of the following would be the most appropriate next step in management?

Gemcitabine
5FU-based chemotherapy
Chemoradiotherapy (CRT) with a 5FU-based regimen
No adjuvant therapy

Although surgical resection remains the cornerstone of treatment, local and distant failure rates are high, and debate continues as to the appropriate adjuvant therapy. Retrospective analyses indicate high rates of both local and distant failure. 50–80% local failure rates following surgery alone prompted evaluation of optimized adjuvant therapy. The Gastrointestinal Tumor Study Group (GITSG) laid the foundation for the adoption of CRT in the United States, showing an improvement in disease-free (DFS) and overall survival (OS). In Europe, the use of adjuvant CRT underwent further assessment, with the European Organization for Research and Treatment of Cancer (EORTC) and European Study Group for Pancreatic Cancer-1 (ESPAC-1) trials showing no benefit and, in the case of the ESPAC-1 trial, a possible detriment with adjuvant CRT.

In parts of Europe, the EORTC and ESPAC-1 trials were judged to provide sufficient evidence to exclude the routine use of adjuvant CRT in favor of adjuvant CT. Further trials in Europe have focused on identifying the optimal adjuvant CT regimen. The CONKO-001 trial evaluated the role of gemcitabine after Whipple and found an improvement in DFS and OS with adjuvant gemcitabine compared to observation. The ESPAC-3 trial compared adjuvant gemcitabine to 5FU with folinic acid after surgery. No differences were seen in DFS or OS, but gemcitabine had a more favorable toxicity profile and remains the standard adjuvant regimen in parts of Europe. The ongoing ESPAC-4 trial is currently randomizing patients with pancreatic and periampullary tumors to adjuvant gemcitabine or gemcitabine–capecitabine therapy.

While adjuvant CT has remained the standard in parts of Europe, CRT has remained a standard in the United States. In addition to the GITSG trial, two large retrospective series compared outcomes with CRT compared to no adjuvant therapy after surgical resection, showing a survival benefit with CRT. Further insight as to the role of radiation therapy will be gained through the ongoing Radiation Therapy Oncology Group (RTOG) 0848–EORTC trial, which randomizes patients with resected pancreatic head adenocarcinoma (stratified based on CA 19-9, nodal, and margin status) to gemcitabine or gemcitabine–erlotinib for five cycles. If no progression is seen on restaging after completion of CT, patients are further randomized to receive an additional cycle (for a total of six cycles) of previously administered CT versus CRT (50.4 Gy) using modern techniques and central RT quality assurance, with concurrent capecitabine or 5FU. Although options 1–3 are supported by available data, given the high rates of local failure and the data from the GITSG and large retrospective series, the authors advocate for adjuvant CRT.

2. If this patient was initially found to have encasement of the celiac axis with abdominal pain despite narcotics, which of the following would be the most appropriate next step in management?

Gemcitabine
5FU-based CT
CRT with a 5FU-based regimen
Attempted surgical resection
FOLFIRINOX

Data regarding the appropriate management of patients with locally advanced pancreatic cancer are conflicting. A number of randomized trials have compared CT and CRT. The GITSG trial found a 2-month OS improvement with CRT when compared to CT alone, while an Eastern Cooperative Oncology Group (ECOG) and Fédération Francophone de Cancérologie Digestive (FFCD) trial showed no difference and survival detriment, respectively, with CRT. A more contemporary publication from the ECOG randomized patients to CT or CRT, with both arms utilizing gemcitabine. Despite failing to meet accrual goals, this trial showed a statistically significant improvement in median OS from 9 to 11 months in patients receiving CRT. Data from a randomized trial in the metastatic setting compared treatment with gemcitabine to a regimen of oxaliplatin, irinotecan, leucovorin, and 5FU (FOLFIRINOX). Median survival was 6.8 months in the gemcitabine group and 11.1 months in the FOLFIRINOX group. Median survival in this randomized trial is the longest seen in the published literature for patients with metastatic pancreatic cancer. There are, as of yet, no randomized data evaluating the efficacy of FOLFIRNOX in patients with locally advanced disease although this may be reasonable in select situations. In this case, options 1–3 are reasonable and supported by available data. In many situations, a course of CT upfront, followed by CMT in patients who do not progress, is reasonable. The authors advocate for option 3 given local tumor-related symptoms.