ABSTRACT: The 5-year overall survival of patients with pancreatic cancer is approximately 5%, with potentially resectable disease representing the curable minority. Although surgical resection remains the cornerstone of treatment, local and distant failure rates are high after complete resection, and debate continues as to the appropriate adjuvant therapy. Many oncologists advocate for adjuvant chemotherapy alone, given that high rates of systemic metastases are the primary cause of patient mortality. Others, however, view locoregional failure as a significant contributor to morbidity and mortality, thereby justifying the use of adjuvant chemoradiation. As in other gastrointestinal malignancies, neoadjuvant chemoradiotherapy offers potential advantages in resectable patients, and clinical investigation of this approach has shown promising results; however, phase III data are lacking. Further therapeutic advances and prospective trials are needed to better define the optimal role of adjuvant and neoadjuvant treatment in patients with resectable pancreatic cancer.
Pancreatic cancer is the fourth leading cause of cancer-related death in the United States and accounts for roughly 40,000 deaths each year. Patients generally present with locally advanced or metastatic disease that precludes cure, since symptoms frequently prompt the diagnosis in the absence of effective screening strategies. Even among patients who present with localized disease, the 5-year overall survival (OS) is approximately 20%, but potentially higher in patients with complete surgical resection (R0) and uninvolved lymph nodes.[2,3] Local and/or distant recurrence is common following resection, highlighting the importance of adjuvant therapy.[4,5] Despite the use of neoadjuvant and adjuvant therapies, little progress has been made in the last three decades, and the search for more efficacious treatment continues. In this article, we review the data surrounding the use of chemotherapy (CT) and chemoradiotherapy (CRT) in patients with resectable pancreatic cancer.
Early Adjuvant Therapy Trials
The 1985 GITSG trial
An early randomized controlled trial for resectable pancreatic cancer, designed by the Gastrointestinal Tumor Study Group (GITSG), laid the foundation for the adoption of CRT in the United States (Table 1). Forty-three patients were enrolled in this clinical trial comparing outcomes of surgery alone to CRT. All patients underwent curative resection of pancreatic adenocarcinoma without evidence of intraperitoneal disease. Split-course radiotherapy (RT) was administered to a total dose of 40 Gy, with a 2-week treatment break. CT consisted of fluorouracil(Drug information on fluorouracil) (5-FU) delivered as a bolus infusion (500 mg/m2) during the first 3 days of each RT course and weekly thereafter for a planned course of 2 years. Improvements in median disease-free survival (DFS) and OS with CRT were observed: 11 months vs 9 months, and 20 months vs 11 months, respectively. Two-year OS was 42% in the CRT group vs 15% in the surgery-alone arm.
The GITSG trial closed prematurely following enrollment of 43 of an intended 100 patients, due to slow accrual over the 8-year enrollment period. The RT approach in this trial was considered low-dose and antiquated by contemporary standards due to the use of a split-course technique and the use of large treatment fields, which encompassed the entire pancreas/pancreatic bed and the celiac, pancreaticosplenic, peripancreatic, and retroperitoneal regional lymph nodes. Additionally, the inclusion of both CRT and adjuvant CT after surgery evaluated two treatment variables, making it difficult to discern the true effect of either treatment alone. In the CRT arm, there were issues of compliance, with 32% of patients assigned to CRT receiving inappropriate radiation and 25% of patients failing to initiate treatment within 10 weeks post surgery, the protocol-specified time limit. Despite these limitations and failure to reach the desired patient accrual, the GITSG trial demonstrated a benefit for CRT, which became standard adjuvant therapy, particularly in the United States.
In Europe, the use of adjuvant CRT underwent further assessment by the European Organization for Research and Treatment of Cancer (EORTC), who designed a trial comparing the use of surgery and adjuvant CRT to surgery alone in 218 patients with resected pancreatic head (n = 114) or periampullary (n = 104) carcinomas. RT, as in the GITSG trial, was delivered in a split course to 40 Gy, with a 2-week treatment break. CT was delivered by continuous infusion (25 mg/kg) but only during RT (for the first 5 days of each RT course). Long-term follow-up of the EORTC trial demonstrated no difference in 5-year OS with CRT use: 25% (CRT) vs 22% (surgery alone). Post-hoc analysis of pancreatic head lesions failed to demonstrate a benefit with CRT, with a median OS of 1.3 years for CRT vs 1 year for surgery alone.
This trial has been criticized for its heterogeneous patient population, which included patients with both pancreatic and periampullary primary tumors. Periampullary carcinomas have been associated with a significantly better prognosis compared with pancreatic cancer; the two entities thus represent truly different diseases and potentially dilute any evidence of benefit from adjuvant CRT. Similar to the GITSG trial, older RT techniques—split course and low total dose—were used. Also, more than 20% of patients in the CRT arm did not receive the intended treatment due to postoperative complications and/or patient refusal. Finally, although a small subset, patients undergoing non-curative resection were still eligible for enrollment. The discordant results of the EORTC and GITSG trials have led some investigators to attribute the OS benefit seen in the GITSG trial to adjuvant CT administration rather than to RT.
An additional European trial conducted by the European Study Group for Pancreatic Cancer (ESPAC) aimed to further explore the question of appropriate adjuvant therapy for "macroscopically" resected pancreatic cancers. In this ESPAC-1 study, 541 patients with pancreatic adenocarcinoma underwent surgery and received CRT, CT, CRT followed by CT, or no further treatment. Although planned as a 2×2 randomization design, only 285 patients were randomized to one of the above treatment arms. The remainder were, per patient or physician preference, randomized only for CRT (vs no CRT) or CT (vs no CT) in an attempt to enhance patient accrual. RT was delivered in a manner similar to that used in the GITSG and EORTC trials, and bolus 5-FU (425 mg/m2) chemotherapy was administered along with leucovorin (LV) (20 mg/m2). On initial analysis, outcomes from all three cohorts (2×2 factorial, CT vs no CT, and CRT vs no CRT) were analyzed collectively, specifically evaluating patients who received CRT or no CRT and CT or no CT. No difference in survival was seen in patients who received CRT compared with patients who did not receive CRT. In the CT arm, however, a 35% reduction in death was seen in the group who received CT compared with those who received no CT, with a difference in median survival of 19.7 months vs 14 months. Long-term results of the patients randomized in the 2×2 schema were subsequently reported. This analysis suggested a survival detriment in patients receiving CRT, who had a 5-year OS of 10%, compared with 20% in those who did not receive CRT. However, in patients receiving CT, an improvement in OS continued to be seen at 5 years: 21% (CT) vs 8% (no CT).
A number of problems are associated with the interpretation of these data. First, the complex trial design has the potential for bias, since patients and/or physicians could select randomization for one treatment variable. Also, as in the aforementioned trials, the RT technique used was, by contemporary standards, considered outdated, employing split course and low total dose. No details of RT delivery or central quality assurance for RT, surgery, or pathology were available. In addition, many treatment violations occurred, as only 62% of patients received full CRT treatment and only 42% of patients in the CT arms completed the predefined regimen. Although many have attempted to draw conclusions from the updated publication, the 2×2 cohort of the study was not powered to detect OS differences. Patients receiving CRT in the ESPAC trial experienced poorer survival outcomes compared with those in other reported CRT series, and patients who had received prior chemotherapy and/or radiation therapy were still eligible for enrollment. Despite these critiques, some have speculated that the detriment seen in the CRT group may have resulted from delayed administration of systemic therapy.
Another common critique of all of the early trials of adjuvant therapy is their lack of restaging after surgical resection and prior to the initiation of adjuvant therapy to evaluate the presence of persistent or metastatic disease. The time between initial staging and the commencement of adjuvant treatment can be as long as 3 to 4 months, during which a significant minority of patients would be expected to develop radiographically apparent metastases. Without interval restaging, these patients might inappropriately receive CRT. Although these 3 trials formed the foundation for adjuvant treatment approaches to resectable pancreatic cancer, perhaps because each trial was fraught with flaws, there continues to be little consensus regarding "most appropriate" treatment. A relative dichotomy in adjuvant treatment approaches for resectable pancreatic cancer has emerged between the United States and parts of Europe, with adjuvant CRT frequently implemented in the United States and adjuvant chemotherapy alone used in parts of Europe.
Trials of Adjuvant Gemcitabine(Drug information on gemcitabine)-Based Chemotherapy
In parts of Europe, the EORTC and ESPAC-1 trials were felt to provide sufficient evidence to exclude the routine use of adjuvant CRT in favor of adjuvant CT alone. The Charite Onkologie (CONKO) trial from Germany randomly assigned 368 patients with R0 or R1 resection either to treatment with six cycles of adjuvant gemcitabine (Gemzar) (three weekly infusions of 1000 mg/m2) or to observation. Patients with a carbohydrate antigen 19-9 (CA 19-9) or carcinoembryonic antigen (CEA) level greater than 2.5 times the upper limit of normal were excluded. Low rates of grade 3-4 toxicities were seen in the gemcitabine arm, with the majority of these being hematologic toxicities. The primary study endpoint of DFS was significantly improved to 13.4 months with gemcitabine, compared with 6.9 months for surgery alone. This improvement was seen in both the R0 and R1 subgroups. At initial publication there was no difference in OS; however, with longer follow-up, median and 5-year OS were both improved in patients receiving gemcitabine (23 months vs 20 months, and 21% vs 9%, respectively). These findings were supported by a smaller randomized study from Japan, which again demonstrated a DFS benefit for adjuvant gemcitabine compared to surgery alone. This well-conceived and implemented trial established gemcitabine as the adjuvant chemotherapy of choice.
At the same time the CONKO trial was enrolling patients, ESPAC-3, the largest randomized controlled trial in pancreatic cancer to date, enrolled 1088 patients with pancreatic adenocarcinoma who were undergoing R0 or R1 resection. Patients were randomly assigned to six cycles of adjuvant gemcitabine (three weekly infusions of 1000 mg/m2) or six cycles of bolus 5-FU/LV (5-FU, 425 mg/m2; LV, 20 mg/m2). Patients receiving 5-FU/LV experienced significantly higher rates of grade 3-4 gastrointestinal toxicity (stomatitis and diarrhea), whereas patients receiving gemcitabine experienced significantly higher rates of grade 3-4 hematologic toxicity. At a median follow-up of 34.2 months, there was no difference between the two groups in the primary endpoint of OS. Given its favorable toxicity profile, in many parts of Europe gemcitabine alone is considered the standard adjuvant treatment in patients with resectable pancreatic cancer. The focus of future European adjuvant therapies for resectable pancreatic cancer has centered primarily on finding the ideal combination of systemic agents. The ongoing ESPAC-4 trial is accruing patients with resected pancreatic cancer for randomization to gemcitabine alone vs gemcitabine/capecitabine; the trial is expected to close in 2014.