Despite attempted curative resection of localized adenocarcinoma of the pancreas, most patients experience a recurrence and die of their disease. The Gastrointestinal Tumor Study Group, European Organisation for Research and Treatment of Cancer, and European Study Group for Pancreatic Cancer trials have suggested the benefit of adjuvant therapy. However, the relatively few randomized trials available have not established a definite standard of care due to study limitations. Although these trials, and the recently published Charité Onkologie (CONKO)-001 trial, have shown a definite advantage of adjuvant chemotherapy, the most effective chemotherapy and the role of radiation therapy remain unclear. This review will discuss the data available from reported trials of adjuvant and neoadjuvant therapy in pancreatic cancer, address the issues leading to the ongoing controversies, and consider future directions for clinical trials.
Pancreatic cancer remains the least curable of all cancers. Over 37,000 people in the United States were diagnosed with pancreatic cancer in 2005; only 2% to 3% can expect to live 5 years or more using current treatment techniques. Complete surgical removal of the cancer is considered a sine qua non for a cure to pancreatic cancer, although prolonged disease-free survival can very rarely be achieved in patients with localized pancreatic cancer who receive chemoradiation without surgery.
In this issue of
, Drs. Keedy and Berlin provide a capable review of key clinical trials shaping current thinking surrounding the adjuvant therapy of pancreatic cancer. They conclude (appropriately, in my view) that adjuvant chemotherapy represents a standard of care, and that the role of adjuvant chemoradiation remains uncertain. However, their articleentitled "Adjuvant Therapy for Pancreatic Cancer: To Treat or Not to Treat?"might be more aptly entitled "Adjuvant Therapy for Pancreatic Cancer: Can We Treat It Better?" as cure rates remain only 15% to 20% when applied to this select patient population.
How might we improve curative therapy for pancreatic cancer? To begin with, patient selection has been highly variable among the world's best adjuvant pancreatic cancer studies. There are many reasons for this. First, studies to date have not required state-of-the-art imaging (triphasic, highresolution, three-dimensional reconstructed computed tomography [CT], endoscopic ultrasound). Second, the decision as to who is resectable has generally been left to the discretion of individual surgeons as opposed to prospective rules. Third, a lack of independent pathologic review may lead to the inclusion of cancers other than adenocarcinoma of the pancreas (eg, other periampullary cancers) into clinical trials.
Additionally, pathologic criteria for study entry into adjuvant trials have varied. For example, the Gastrointestinal Tumor Study Group (GITSG) trial cited by the authors excluded node-positive patients, the European Organisation for Research and Treatment of Cancer (EORTC) trial excluded patients with T3 or T4 primary lesions, and the Charité Onkologie (CONKO)-001 trial excluded patients with postoperative tumor marker values (CA 19.9 or carcinoembryonic antigen [CEA]) greater than 2.5 times normal.
Many studies (eg, the European Study Group for Pancreatic Cancer [ESPAC]-1 trial) did not require mandatory CT restaging prior to initiation of adjuvant treatment. Finally, selection biases likely exist as to who is considered postoperatively for protocol entry. As mentioned by the authors, 20% to 30% of patients even at high-volume centers never receive adjuvant therapy for a variety of reasons (postoperative complications, comorbid conditions, patient/physician attitudes, etc). In community practice, this number may be as high as 60%. Thus, patient populations between major trials may vary considerably, hindering comparative analysis.
Although surgery provides the foundation for cure in pancreatic cancer, its efficacy is limited. The goal of surgery in localized pancreatic cancer is to achieve an R0 resection (no residual macroscopic or microscopic disease). Patients who have undergone an R1 resection (residual microscopic disease) experience similar overall survival to those with de novo presentation of locally advanced disease (ie, 9- to 12-month median survival, and a 5-year survival rate close to 0%). Typically, 20% to 30% of patients in adjuvant clinical trials for pancreatic cancer have had an R1 resection. Local recurrence rates folowing pancreaticoduodenectomy only for pancreatic cancer range from 50% to 85%. Systemic recurrence rates are as high as 90%, usually occurring within months from surgery.
Five-year disease-free survival of resected pancreatic cancer without additional therapy is generally 10% or less (note the median disease-free interval of 6.9 months and 5-year overall survival of 5.5% for the observation arm of the CONKO-001 trial). Given the inverse relationship between surgical morbidity/mortality and surgical volume for pancreaticoduodenectomy, patients who undergo this procedure at low-volume centers may actually have a higher risk of death than cure if surgery is the only therapeutic modality employed.
In light of the high risk of distant recurrence following surgery for localized pancreatic cancer, it is clear that this is a systemic disease from the outset, irrespective of whether complete surgical resection is achieved. It is not a question of whether systemic therapy should be given, but how best to do it. All of the major randomized trials cited in this review showed a survival advantage for the use of chemotherapy alone (either fluorouracil [5-FU]-based treatment or single-agent gemcitabine [Gemzar]) vs observation as adjuvant treatment for pancreatic cancer (remembering that the EORTC trial did not employ chemotherapy postchemoradiation and is considered by some to be statistically underpowered to show a survival advantage for treatment). The Radiation Therapy Oncology Group (RTOG) 9704 trial suggests an advantage for gemcitabine over infusional 5-FU as adjuvant therapy. The ESPAC-3 trial, which directly compares gemcitabine with bolus 5-FU/leucovorin, will provide a more definitive answer to this question.
Therapeutic advance in pancreatic cancer depends upon improved systemic therapy. Although chemotherapy combinations have produced only marginal incremental success in advanced pancreatic cancer, they appear to work best for good-performance patients with minimum disease volumeexactly the situation postresection. To date, epidermal growth factor inhibitors (bevacizumab [Avastin], cetuximab [Erbitux], erlotinib [Tarceva]) have also produced only marginal gain in pancreatic cancer, but over 20 new drugs employing a variety of molecular strategies are currently in clinical trials for pancreatic cancer. The potential for prediction of drug response exists via techniques such as molecular profiling, tumor xenografts, and genetically manipulated animal models. Also, the recent report of the use of antitumor vaccination as part of adjuvant therapy for pancreatic cancer postchemoradiation by Laheru and colleagues heralds the potential addition of immunotherapy to our systemic approach to pancreatic cancer.
Unlike systemic therapy, the ultimate role of radiation therapy as part of adjuvant treatment for pancreatic cancer is uncertain. The goal of radiation therapy as adjuvant treatment is to reduce the rate of local recurrence. The logic behind its use is straightforward. Patients have a high incidence of local recurrence even with chemotherapy in resected pancreatic cancer (in the CONKO-001 trial, 34% in gemcitabine-treated patients vs 41% in the observation arm). Recurrence rates in patients with R1 resections are typically even higher, in excess of 60%. Improved local control could improve cure rates in the case of isolated local recurrence; even if systemic recurrence takes place, it could reduce significant morbidity from local complications (eg, pain, biliary/gastric outlet obstruction, vascular occlusion/thrombosis).
5-FU-based chemoradiation after curative surgery for resected pancreatic cancer has significant toxicity. In the RTOG 9704 trial, the incidence of grade 3/4 toxicity was over 60% in the 5-FU arm, and almost 80% in the gemcitabine arm, including a 14% rate of grade 4 hematologic toxicity. Gastrointestinal toxicity (anorexia, nausea/vomiting, diarrhea, mucositis) can be both severe and difficult to control, even in experienced centers. A dedicated staff and supportive care strategy are essential to successful adjuvant chemoradiation for pancreatic cancer.
The role of radiation therapy in the adjuvant treatment of pancreatic cancer invariably sparks passionate debate. Proponents cite the aforementioned logic behind radiation therapy, its utility in other gastrointestinal malignancies (eg, rectal cancer), and technical issues (dose, schedule, quality control) associated with therapy delivery in the major European (EORTC and ESPAC-1) trials. The ESPAC-1 had an astonishing 62% local failure rate; Abrams and colleagues showed in the RTOG 9704 experience that suboptimal delivery of radiation therapy can be a more significant prognostic factor than the identity of the adjuvant chemotherapeutic agent. Detractors cite the formidable toxicity associated with chemoradiation (eg, in RTOG 9704) and the inability of standard chemoradiation, compared with chemotherapy only, to improve disease-free or overall survival in resected pancreatic cancer.
The beauty of radiation therapy is very much "in the eye of the beholder." It may be that sophisticated chemoradiation, given with skillful supportive care, is an asset in the adjuvant treatment of pancreatic cancer; ineffective or toxic chemoradiation that compromises systemic treatment is likely a liability to a successful outcome.
The future of adjuvant therapy for pancreatic cancer will be characterized by more optimism, more standardized patient selection, and better supportive care. Future options for the adjuvant treatment of pancreatic cancer include resequencing therapeutic modalities (eg, Moutardier et al), novel approaches to local control (eg, the Virginia Mason chemoradiation protocol), and improved systemic agents. The future forecast for the adjuvant treatment of pancreatic cancer calls for "increasing sunshine."
Vincent J. Picozzi, MD, MMM
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