Treatment of Early-Stage Pancreatic Cancer
Treatment of Early-Stage Pancreatic Cancer
Pancreatic cancer is the fourth leading cause of cancer death, and it is estimated that over 43,000 people would be diagnosed with and over 36,000 people would die of pancreatic cancer in the United States in 2010. Surgical resection remains the only chance for possible cure, but only 15% to 20% of patients newly diagnosed with pancreatic cancer are considered for surgical resection. Of these, the median five-year survival rate is still less than 20%, with most resections resulting in recurrent disease.[4,5] This suggests that even seemingly resectable pancreatic cancer has microscopic systemic spread before operative intervention occurs. Both adjuvant and neoadjuvant therapies have been studied in an effort to improve survival for patients with resectable pancreatic cancer.
Early trials of adjuvant therapy in pancreatic cancer had multiple limitations including small sample size, population heterogeneity, and inability to distinguish between components of combined modality treatment. The first randomized controlled trial of adjuvant therapy in pancreatic cancer was designed by the Gastrointestinal Tumor Study Group (GITSG), and found that adjuvant 5-FU plus radiation, followed by two years of weekly 5-FU maintenance therapy had better outcomes than surgery alone (Table 1). Of note, a split-course radiation therapy regimen of 40 Gy was used, which is considered to be substandard by modern techniques. The trial was continued as a registry since real-time disclosure led to difficulties in randomizing patients to the surgery-alone arm; a total of 32 patients were registered on the combined modality arm. Later review combining these 32 patients with the 43 patients in the original study showed continued benefit of adjuvant chemoradiation. Although this trial has been criticized for its small size, slow accrual rate, inferior (by modern standards) radiotherapy, and inability to distinguish between the benefit of chemotherapy and that of chemoradiation, it nevertheless served as a significant first step in establishing a place for adjuvant therapy in the treatment of resected pancreatic cancer.
For nearly fifteen years, the GITSG trial provided the only evidence-based rationale for adjuvant therapy in pancreatic cancer—until the European Organization for Research and Treatment of Cancer (EORTC) presented a phase III clinical trial comparing chemoradiation (20 Gy split-course radiation and infusional 5-FU 25 mg/kg) with observation alone in a population of 218 patients with both pancreatic head and periampullary tumors. This trial was criticized for studying only chemoradiation in a heterogeneous population with an inferior (by modern standards) radiotherapy regimen; however it did reveal a nonsignificant trend favoring chemoradiation in the subset of patients with pancreatic head tumors. The European Study Group for Pancreas cancer-1 (ESPAC-1) trial was published in 2004 with the intent of distinguishing between the benefit of chemotherapy and chemoradiation. The ESPAC-1 trial had a complex 2 × 2 factorial design in which 289 patients were randomized to one of four treatment groups: observation alone, chemotherapy, chemoradiation, or chemoradiation followed by chemotherapy. An additional 256 patients were allocated to one of two randomizations: either chemotherapy vs observation or chemoradiation vs observation. The study authors concluded that adjuvant chemotherapy had a beneficial effect on overall survival (median survival 20.1 months vs 15.5 months in those who received chemotherapy vs those who did not, HR for death 0.71, P = .009), but that chemoradiation was actually associated with a decreased survival (median survival 15.9 months vs 17.9 months in those who received chemoradiation vs those who did not, HR for death 1.28, P = .05). It should be noted, however, that the study was not powered to compare the four individual groups. Additionally, the split-course radiation therapy used in this trial is not current practice, so these results cannot be applied to modern techniques that give higher doses of radiation in a more protracted, but continuous, time course.
In 2008, two retrospective, non-randomized, single-institution analyses further suggested a benefit from adjuvant chemoradiation. The Johns Hopkins Hospital evaluated a prospectively collected cohort of patients who underwent either adjuvant chemoradiation with 5-FU, or observation alone. Of this cohort, patients who received adjuvant therapy had improved median, two-year, and five-year survival compared with those treated with surgery alone (21.2 vs 14.4 months; 43.9% vs 31.9%; 20.1% vs 15.4%, respectively; P < .001). The Mayo Clinic also performed a retrospective review of 472 patients who underwent R0 resection of invasive pancreatic cancer from 1975 to 2005. Of the 472 patients, 274 patients received adjuvant external beam radiation using multiple techniques; 98% of these patients also received concurrent 5-FU based chemotherapy. The study found that the patients who received adjuvant chemoradiation had improved median, two-year, and five-year overall survival compared with patients who received surgery alone (25.2 months vs 19.2 months, 50% vs 39%, and 28% vs 17%, respectively; P = .001), with an absolute survival benefit of 11%. As with other retrospective studies, there was inherent bias since only the patients who did well enough postoperatively to receive adjuvant therapy were included in the analysis. However, these data are interesting and should be seen as hypothesis-generating in designing future trials in adjuvant therapy in pancreatic cancer.