Given the limited improvement adjuvant therapy has had on outcomes in resected pancreatic cancer and the aggressive nature of this disease, there has been increasing interest in the potential of neoadjuvant treatment to improve survival. Neoadjuvant therapy is attractive for a number of theoretical reasons. Giving treatment and assessing response preoperatively would hopefully identify potential “nonresponders” to chemotherapy prior to surgery, and patients with aggressive tumors who progress despite neoadjuvant treatment might avoid a high-morbidity operation. Additionally, neoadjuvant therapy could increase the chance of achieving a margin-negative resection as well as negative lymph node involvement, both of which have been shown to have positive prognostic value on long-term outcome following surgery. Finally, retrospective studies have shown that nearly 25% of patients who undergo resection never complete adjuvant therapy, presumably due to prolonged postoperative recovery.[20,21] Giving therapy preoperatively would ensure that all patients receive a complete course of multimodality treatment.
Unlike adjuvant therapy, which has been evaluated by several large, multicenter, randomized controlled clinical trials, the majority of work in the neoadjuvant arena has been done by single-institution phase II studies, most notably from the University of Texas M. D. Anderson Cancer Center (Table 2). Initial studies examining the effect of preoperative chemoradiation using 5-FU-based platforms in combination with intraoperative radiation therapy suggested that the primary benefit of neoadjuvant chemoradiation was in improved locoregional control.[22,23]
As with adjuvant treatment, trials in neoadjuvant therapy were guided by advances in systemic therapeutics, leading to the evaluation of gemcitabine(Drug information on gemcitabine)-based treatments. Two well-designed phase II studies from M. D. Anderson examining gemcitabine-based chemotherapy and chemoradiation were published in 2008. Investigators for both trials used standardized pretreatment staging, surgery, pathologic assessment of margin status, and grade of treatment effect so that internal comparisons could be made. In Evans et al, 86 patients with resectable pancreatic cancer at time of enrollment underwent neoadjuvant gemcitabine-based chemoradiation, which was comprised of weekly iv gemcitabine (400 mg/m2) for seven doses plus external beam radiation therapy for five days/week for a total of 30 Gy. Patients were restaged by CT scan 4 to 6 weeks after therapy completion. Surgery was considered delayed if it occurred more than eight weeks after completion of chemoradiation. Of the 86 patients enrolled, 12 (14%) did not undergo resection due to medical comorbidities or disease progression in either the liver or peritoneum. Of the 64 patients who underwent resection, median overall survival was 34 months, with a five-year survival rate of 33%. The median time to recurrence was 13.2 months in 37 patients, and only 11% of recurrences were to the local tumor bed. For all 86 patients enrolled in the study, the median overall survival was 22.7 months, with a five-year survival rate of 27%.
Since most patients who experienced recurrence had metastatic spread to either distant organs or the peritoneal cavity, these same investigators designed a complementary study to determine whether the addition of systemic chemotherapy to preoperative chemoradiation might improve outcomes. In this phase II trial, 90 patients with potentially resectable pancreatic cancer at the time of enrollment received combination gemcitabine and cisplatin(Drug information on cisplatin) chemotherapy plus external beam radiation (Gem-Cis-XRT) consisting of gemcitabine (750 mg/m2) and cisplatin (30 mg/m2) every two weeks for four doses, followed by a three-week rest period. After this, patients underwent four weekly infusions of lower-dose gemcitabine (400 mg/m2) plus external beam radiation, for a total dose of 30 Gy. After therapy was completed, patients were restaged as in the previous study. Surgical resection occurred within eight weeks of chemoradiation, or else it was considered delayed. Of the 90 patients enrolled, 79 (88%) completed chemo-chemoradiation, 62 (78%) of these went to surgery, and 52 (66%) underwent resection. The median survival of the 52 patients who underwent resection was 31 months. Because identical inclusion, staging, and grading criteria were used for the two studies, these results were internally compared and it was determined that adding preoperative systemic chemotherapy to chemoradiation did not significantly benefit survival.
Besides traditional chemotherapy models, chemoradiation using a combination of gemcitabine and bevacizumab(Drug information on bevacizumab), a humanized IgG1 monoclonal antibody that binds to vascular endothelial growth factor-A (VEGF-A), has also been explored in small sample sizes, although the results, in terms of the tolerability of this combination and its effect on post-operative complications have been mixed;[26,27] of note, a recent study of bevacizumab plus gemcitabine in the metastatic setting showed no clear survival benefit compared to gemcitabine alone.
Current trials in neoadjuvant therapy include the before-mentioned ACOSOG Z5041, as well as a European prospective randomized phase II trial that is examining neoadjuvant chemoradiation vs surgery in resectable and borderline resectable patients and that integrates adjuvant therapy into both arms. Phase III clinical trials comparing neoadjuvant therapy to adjuvant treatment or observation alone have not yet been done.
The incorporation of neoadjuvant therapy into multimodality treatment for resectable pancreatic cancer has had intriguing results, and this suggests a role for improved localized control. The median survival rates for resected patients in the studies by Evans et al and Varadhachary et al compare favorably with median survival rates in trials of adjuvant therapy; however, this may be due to the “weeding out” of patients with rapidly progressive disease prior to surgery. Although improved locoregional control alone does not necessarily translate into improved survival in a disease in which outcomes are determined by systemic spread, this issue warrants further exploration especially as better systemic therapies are developed.
Borderline Resectable Pancreatic cancer
Advances in CT imaging technology have recently led to the classification of a group of tumors that have a high likelihood of resection with positive surgical margins. This group, which has been termed “borderline resectable,” has been identified as a discrete entitywhose management is as yet undefined. The National Comprehensive Cancer Network defines as “borderline resectable” those tumors that meet any of the following criteria: abutment of the superior mesenteric artery; severe unilateral superior mesenteric vein or portal vein impingement; gastroduodenal artery encasement to its origin; or invasion of the transverse mesocolon.[30,31] Since it is estimated that this group may comprise as much as one-third of patients presenting with locally advanced pancreatic cancer, a consensus definition of borderline resectable pancreatic cancer was recently developed by the American Hepato-Pancreato-Biliary Association (AHPBA) and may be useful in the development of future trials exploring both adjuvant and neoadjuvant treatments (Table 3).
Advances in radiographic staging, surgical technique, and perioperative care have reduced the morbidity and mortality of pancreaticoduodenectomy;[33,34] however, survival rates following resection have seen only minor improvement since the publication of the original GITSG trial in 1985. Comparison across trials remains problematic, as there is variation in the population studied, eligibility criteria, and chemotherapy and radiotherapy techniques—all factors that influence outcomes. In 2009, a Consensus Conference sponsored by the American Hepato-Pancreato-Biliary Association set forth an expert consensus statement supporting the use of adjuvant therapy. Although the authors were in agreement that a six-month course of systemic chemotherapy with gemcitabine or 5-FU should be part of any adjuvant treatment, they also stated that “there is no single adjuvant regimen of chemotherapy or chemoradiotherapy that can claim unequivocal superiority to others.” The fact that it was not possible for an expert consensus statement to specify a standard of care regimen is a reflection of the heterogeneity of patient population, interventions, and outcomes across the past studies of adjuvant therapy.
Based on current data, it is clear that some form of adjuvant therapy is beneficial, and most forthcoming studies are using gemcitabine-based platforms. Single-institution trials of neoadjuvant therapy have been done using predefined, consistent parameters for defining disease and treatment with the intention of improving our ability to make inter-trial comparisons, and it is hoped that as neoadjuvant therapy moves into phase III studies, this paradigm will continue. Utilization of a common language and standardized practices across future trials will be key in providing clear and comparable results. Advances in the adjuvant setting are driven by advances in systemic therapy, and new therapeutic options are needed to make progress in the treatment of this deadly and difficult disease.
Financial Disclosure: Dr. Berlin receives research support from OSI, Bayer, Pfizer, Amgen, Genenetech, Abbott, and Novartis, and he has ad boards with Amgen, AstraZeneca, Enzon, Genentech, Abbott, Clovis, Otsuka, and sanofi-aventis. Drs. Cardin and Castellanos have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.