From 12% to 15% of the approximately 45,000 patients diagnosed with pancreas adenocarcinoma undergo a potentially curative resection each year in North America, translating into roughly 5,000 to 7,000 patients who are candidates for adjuvant therapy. About 80% of these patients will relapse and succumb to their disease with a median survival with adjuvant therapy now approaching 2 years. While the absolute benefit of adjuvant therapy for resected pancreas adenocarcinoma remains a subject of debate, and while there is clear need for improvement, there is no longer any debate that adjuvant therapy improves survival—it clearly does!
Earlier Trials
The original historical precedent for adjuvant therapy for resected pancreas adenocarcinoma dates back over 25 years to the results of a small phase III trial by the Gastrointestinal Tumor Study Group (GITSG) trial, which showed a benefit to adjuvant fluorouracil (5-FU)-based chemoradiation and subsequent systemic 5-FU over observation.1
A subsequent series of trials from the European Study Group for Pancreatic Cancer (ESPAC) investigators have contributed much to the field. The initial ESPAC-1 trial, reported in 2004,2 provided a clear signal in an adequately powered randomized trial that systemic therapy—in this case, bolus 5-FU and leucovorin given on days 1 to 5 monthly for 6 months—improved overall survival over observation in the adjuvant setting. The other main conclusion from the ESPAC-1 trial was that adjuvant chemoradiation not only did not offer any survival benefit, but may have led to inferior outcomes, possibly in part by delaying systemic therapy.
These latter conclusions have been heavily challenged, reflecting concerns regarding the complex ESPAC-1 statistical design, use of older-style split-course radiation, and limited bolus 5-FU exposure, along with other quality control concerns related to surgery, radiation, and chemotherapy. Nonetheless, the notion that adjuvant chemoradiation does not add benefit in the adjuvant setting has been embraced by the non-U.S. pancreatic community, and over the past decade, adjuvant systemic therapy alone has increasingly become a standard option in most parts of the world.
CONKO-001 Study
More recently, the initial report of the CONKO-001 study in 20073 and the results of the ESPAC-3 trial4 have firmly entrenched the value of systemic adjuvant therapy for resected pancreas cancer. Specifically, the ESPAC-3 trial compared bolus 5-FU and leucovorin to gemcitabine and concluded that the two systemic options are essentially equivalent. However, the toxicity profile favored gemcitabine over bolus “Mayo Clinic–style” 5-FU and leucovorin.
The now updated and mature survival results from the CONKO-001 trial, reported by Oettle et al in JAMA5 and reviewed in this issue of The ASCO Post, provide long-term outcome data for patients with resected pancreas adenocarcinoma who received gemcitabine adjuvant therapy compared to placebo in the setting of a well-designed contemporary trial. The results provide concrete support for adjuvant gemcitabine, with a doubling in median disease-free survival (13.4 vs 6.7 months) and improved overall survival for gemcitabine vs placebo (hazard ratio = 0.76, 95% confidence interval = 061–0.95, P = .01), along with improved 5-year and 10-year overall survival for the treated group.
Current Options
Where do these collective data leave us in 2013? First, adjuvant systemic therapy should be recommended to all patients with resected pancreas adenocarcinoma who have a reasonable postoperative recovery. There are almost no patients in whom adjuvant therapy should not be considered, except perhaps a small subset of patients with resected intraductal papillary mucinous neoplasia with a small amount of invasive disease, where the utility of adjuvant therapy has not been rigorously studied; in this setting, decisions should be made on a case-by-case basis.
Second, either systemic therapy alone with gemcitabine (or 5-FU) or along with adjuvant chemoradiation are acceptable options. Third, the role of adjuvant chemoradiation following resection of pancreas adenocarcinoma remains very much an unanswered question without prospective modern era data to support using or not using such an approach. Opinion is heated in both directions. Several large single-institution retrospective data sets indicate a benefit to adjuvant chemoradiation with improved survival and improved locoregional tumor control over surgery alone.
The current ongoing Radiation Therapy Oncology Group (RTOG) 0848 study is designed to provide a definitive answer to the value of chemoradiation in the adjuvant setting following gemcitabine-based therapy. This study incorporates modern principles of chemoradiation delivery, including real-time quality assurance measures. The RTOG 0848 trial has enrolled about one-third of planned patients, so results are not likely to accrue until later this decade.
Looking Ahead
Major questions in the adjuvant setting going forward are whether adding a second drug to gemcitabine adds benefit and whether non–gemcitabine-based regimens have a role, along with further study of neoadjuvant therapy. ESPAC-4 is examining the addition of capecitabine to gemcitabine. A soon-to-open adjuvant study will evaluate albumin-bound paclitaxel (nab-paclitaxel [Abraxane]) and gemcitabine compared to gemcitabine in the adjuvant setting. This trial follows on the recently reported positive results in the metastatic disease setting demonstrating improved survival with addition of nab-paclitaxel to gemcitabine, and in Europe, a trial evaluating FOLFIRINOX (5-FU, leucovorin, irinotecan, oxaliplatin) compared to gemcitabine is underway.
To date, no molecularly targeted agent has been established to have a role in the adjuvant therapy of pancreas adenocarcinoma, although studies are evaluating the addition of erlotinib (Tarceva) to gemcitabine (CONKO-005, RTOG 0848). A randomized phase II study did not suggest any utility for the addition of either bevacizumab (Avastin) or cetuximab (Erbitux) to gemcitabine in the adjuvant treatment of pancreas cancer.
Other directions of study in adjuvant pancreas cancer include an evaluation of various immunotherapeutic approaches. One example is that of a phase III trial that has recently completed recruitment with pending results evaluating a “hyperacute” vaccine (algenpantucel-L) using two allogeneic pancreatic cancer tumor cell lines compared to standard therapy. Other immune approaches have evaluated KRAS vaccines.
Conclusions
To summarize, adjuvant therapy for pancreas adenocarcinoma works, with a magnitude of risk reduction similar to the benefit observed for adjuvant therapy in other solid tumor malignancies, however, we clearly have much work to do. It is hoped that some of the improved outcomes that have been observed in the treatment of metastatic pancreas cancer will translate to the adjuvant setting, with results from ongoing trials likely to accrue over the next 2 to 5 years. In addition, a major focus going forward will be a more wide-scale investigation of neoadjuvant therapy. ■
Dr. O’Reilly is a gastrointestinal medical oncologist at Memorial Sloan-Kettering Cancer Center, New York.
Disclosure: Dr. O’Reilly is a consultant for Celgene.
References
1. Gastrointestinal Tumor Study Group: Treatment of locally unresectable carcinoma of the pancreas: Comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst 80:751-755, 1988.
2. Neoptolemos JP, Stocken DD, Friess H, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200-1210, 2004.
3. Oettle H, Post S, Neuhaus P, et al: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. JAMA 297:267-277, 2007.
4. Neoptolemos JP, Stocken DD, Bassi C, et al: Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: A randomized controlled trial. JAMA 304:1073-1081, 2010.
5. Oettle H, Neuhaus P, Hochhaus A, et al: Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial. JAMA 310:1473-1481, 2013.
