Adjuvant Chemoradiotherapy

Early studies examining the role of combined external-beam radiotherapy (EBRT) with 5-fluorouracil (5-FU) as a radiosensitizing agent in advanced, unresectable pancreatic adenocarcinoma showed an increased median survival over that of solo EBRT (Douglas et al, 1979; Moertel et al, 1981). Subsequently, combination chemoradiotherapy (CRT) was used in patients who had undergone potentially curative resection for pancreatic adenocarcinoma. The Gastrointestinal Tumor Study Group trial 9173 (Kalser & Ellenberg, 1985) randomized 43 patients to either CRT (40-Gy EBRT, combined with 5-FU and follow-on 5-FU) or no adjuvant treatment after potentially curative pancreatic resection; recruitment was slow and only 43 patients were enrolled after 8 years instead of the intended 150. Median, 2-year, and 5-year survival rates were all increased in the treatment group (Table 63A.1). This trial had several problems, chief among them being poor compliance and inadequate quality assurance, with only 9% of patients completing the intended 2 years of chemotherapy; 32% had violations of the radiation therapy. To increase numbers, another 30 patients were entered into the treatment group without randomization (Douglas et al, 1987). Several subsequent studies have all shown similar advantages (Conlon et al, 1996; Neoptolemos et al, 1998; Yeo et al, 1998), although all were underpowered.

Two studies, however, have countered these results. Bakkevold and colleagues (1993) prospectively randomized 61 patients who had undergone radical pancreatic resections (including 14 patients with periampullary lesions) to adjuvant combination chemotherapy with 5-FU, adriamycin, and mitomycin-C versus observation; no postoperative EBRT was used. Although the median survival and 2-year survival were increased in the treatment groups, the overall long-term cure rate was unaffected (see Table 63A.1).

Later, on behalf of the European Organisation for Research and Treatment of Cancer (EORTC), Klinkenbijl and colleagues (1999) randomized 218 patients following potentially curative resection for pancreatic cancer to CRT (40-Gy EBRT and 5-FU, no follow-on 5-FU) or no adjuvant treatment. This included 114 patients with pancreatic head cancer and 93 with periampullary cancer. Of the patients with pancreatic head cancers, no significant increase in median survival was found between the two groups (see Table 63A.1).

These early studies set the scene for the European Study Group for Pancreatic Cancer (ESPAC) to conduct a randomized trial of adjuvant chemotherapy and chemoradiotherapy in resected pancreatic cancer. The design was as a 2 × 2 factorial trial in which patients were randomized twice to either chemotherapy (bolus 5-FU for six cycles) or no chemotherapy or to chemoradiation (fractionated 20-Gy EBRT plus an intravenous bolus of 5-FU) or no chemoradiation. This totaled 549 patients from 61 cancer centers in 11 countries, thus making it, at the time, the largest adjuvant therapy trial in pancreatic cancer ever completed. A total of 289 patients were randomized into the 2 × 2 factorial design, and 261 additional patients were randomized to either chemotherapy or chemoradiation versus observation outside the original design (ESPAC-1 plus).

ESPAC-1 has been criticized largely because of confusion over the 2 × 2 trial design; nonetheless, data from both patient datasets are relevant (Neoptolemos et al, 2001, 2004) and are suggestive of the benefit of chemotherapy (Table 63A.2 and Fig. 63A.1), evident in resection margin–positive (R1) as well as resection margin–negative (R0) patients. Two subsequent meta-analyses have confirmed this advantage, suggesting a reduction in risk of death in postresection pancreatic cancers of 25% (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.64 to 0.90; P = .001) (Stocken et al, 2005) and an advantage of postresectional chemotherapy in patients with an R0 margin over those with an R1 margin (Butturini et al, 2008). Moreover, the reported that survival advantage for adjuvant chemotherapy was maintained when adjusted for quality of life over the 24-month period after resection (Carter et al, 2009).

FIGURE 63A.1 Results from ESPAC-1 2 × 2 factorial design. CRT, chemoradiotherapy; CT, chemotherapy.

(Modified from Neoptolemos JP, et al, 2004: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200-1210.)

Since the usurpation of 5-FU as the gold standard of chemotherapy for pancreas cancer, current focus has centered on the use of gemcitabine as a radiosensitizer and also on the use of biologic agents. The Radiation Therapy Oncology Group (RTOG) (Regine et al, 2006) conducted a Phase III trial, study 9704, of 538 patients (443 analyzed, with 388 having cancer in the head of the pancreas) based on chemoradiation (50.4-Gy EBRT with 5-FU) combined with either 5-FU or gemcitabine, 3 weeks before CRT and 12 weeks after. Although both the median and 3-year survival rates were increased in the group receiving gemcitabine, these increases were not significant. Analysis of the 388 patients with pancreatic head cancer suggested a 21% reduction in risk of death in the gemcitabine arm (HR, 0.79; 95% CI, 0.63 to 0.99; P = .047). Although this was suggestive of the advantage of gemcitabine, a greater proportion of T3 tumors and higher toxicity were reported in this arm. In response, the EORTC 40013 Phase III trial plans to randomize 538 patients after R0 pancreatic resection to either gemcitabine or two cycles of gemcitabine followed by CRT (gemcitabine and 50.4-Gy EBRT).

A phase III trial of postoperative cisplatin, interferon alpha-2b, and 5-FU combined with external radiation treatment versus 5-FU alone for patients with resected pancreatic adenocarcinoma randomized 110 patients after pancreatectomy to either 5-FU, cisplatin, interferon-α₂β, and EBRT (50.4 Gy) with two follow-on cycles of 5-FU post-CRT (arm A) or 5-FU/folinic acid (arm B). Median overall survival of patients treated in arm A was 32.1 months (95% confidence interval [CI], 22.8 to 42.2) compared with 28.5 months (95% CI, 19.5 to 38.6) for arm B. Unfortunately, this underpowered trial was not able to address satisfactorily the significance of adjuvant chemoradiation plus interferon. Further trials are required to confirm these effects.

Finally, RTOG0848 is opening a Phase III trial, recruiting 950 patients with resected adenocarcinoma of the pancreas, including intraductal papillary mucinous neoplasms (IPMNs), to either five cycles of gemcitabine or five cycles of gemcitabine with erlotinib. Patients with no progression will receive either one further cycle of chemotherapy or one cycle of chemotherapy followed by EBRT plus either 5-FU or capecitabine.

Overall, the use of chemoradiation remains controversial, but many U.S. centers continue to support adjuvant chemoradiotherapy as standard treatment (Twombly, 2008).

Adjuvant Chemotherapy

ESPAC-1 has provided the clearest evidence to date that adjuvant chemotherapy is advantageous (see Table 63A.2) when based on regimens of biomodulated 5-FU. The advance made by ESPAC-1 has driven forward the next generation of adjuvant chemotherapy trials, notably ESPAC-3 (v2) and ESPAC-4 in addition to translational run-offs (ESPAC-T plus and ESPAC-4T).

Evidence that emerged during the 1990s showed the usefulness of gemcitabine in pancreatic cancer, initially in the setting of advanced disease (Berlin et al, 2002; Burris et al, 1997; Carmichael et al, 1996; Casper et al, 1994; Hertel et al, 1990; Huang et al, 1991; Rothenberg et al, 1996). Recently, a large, multicenter, Phase III randomized trial of 386 patients was undertaken to determine the influence of adjuvant gemcitabine versus observation following resection of pancreatic cancer on disease-free survival (CONKO-001) (Oettle et al, 2007; Neuhaus et al, 2008). Median disease-free survival for the gemcitabine group was 13.4 months compared with 6.9 months for the observation arm (P < .001); these data are summarized in \xEF”\xBFTable 63A.3\xEF”\xBF\xEF”\xBF\xEF”\xBF. The estimated disease-free survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group versus 7.5% and 5.5% in the observation group, respectively. In addition, a significant improvement in median overall survival of 24.2 months was reported with gemcitabine compared with observation alone (20.5 months; P = .02). Estimated overall survival at 3 and 5 years was 34% and 22.5% for gemcitabine patients versus 20.5% and 11.5% for observation patients, respectively. These results were suggestive of prolonged disease-free survival in patients undergoing R0 or R1 resection for pancreatic cancer. These earlier studies formed the basis for the ESPAC-3 study.

ESPAC-3 initially was designed with three arms: six cycles of 5-FU versus six cycles of gemcitabine versus observation, with a recruitment target of 330 patients. With the publication of the ESPAC-1 results, a definite survival advantage for adjuvant chemotherapy after resection of pancreatic ductal adenocarcinoma was apparent over observation alone; the trial design was therefore amended, with the observation arm being dropped. The recruitment targets for the remaining two arms were increased to 515 patients each for a total of 1030 patients with pancreatic ducal adenocarcinoma, and the trial was renamed ESPAC-3 (v2). ESPAC-1 had been underpowered to determine the role of adjuvant therapy in less common malignancies such as bile duct cancers and ampullary tumors; therefore the observation arm of ESPAC-3 was continued for these patients. The trial closed after having recruited 1583 patients, with 1088 having ductal adenocarcinoma. Overall, no difference was found between 5-FU/FA and gemcitabine by treatment (P = .39), treatment effect by R status (P = .56), or by progression-free survival (P = .44). However, significant advantages were found from the use of gemcitabine, notably its significantly reduced side effects and toxicity profiles (Neoptolemos et al, 2009a, 2009b); thus the current recommendation for adjuvant chemotherapy in pancreatic ductal adenocarcinoma is gemcitabine (see Table 63A.3).

Currently, interest lies in the use of capecitabine, a prodrug for 5-FU. It is sequentially metabolized into active 5-FU by enzymes highly expressed in both liver and tumor, notably the last enzyme in this cascade, thymidine phosphorylase. This has four potential advantages: 1) systemic side effects are reduced, 2) high concentrations are achieved in the vicinity of the tumor, 3) oral capecitabine has a pharmacokinetic profile similar to that of a continuous systemic infusion 5-FU, and 4) patients tolerate it better than 5-FU. Unfortunately, the effects of solo capecitabine seem minimal: clinical response in 24% and tumor response in 7% (Cartwright et al, 2002). Better responses have been observed when capecitabine and gemcitabine were combined. Eighty-three patients were randomized to either biweekly gemcitabine or biweekly gemcitabine and daily oral capecitabine for a duration of 6 months (Scheithauer et al, 2003). Although no increase was seen in median survival, a 33% increase in clinical benefit response was reported in the combination group.

This effect will be explored in the forthcoming ESPAC-4 study, which aims to recruit 1080 patients who have undergone curative resection for pancreatic ductal adenocarcinoma within the previous 12 weeks. Randomization will be either to six cycles of gemcitabine or to six cycles of gemcitabine plus 24 weeks of capecitabine. The primary end point is length of survival with secondary end points of toxicity, quality of life, 2-year survival, 5-year survival, and relapse-free survival.

The effects of combining chemotherapeutic agents are measured against the solo effects of the current gold standard drugs. Bakkevold and colleagues (1993) randomized patients who had undergone pancreatic resection to FAM (5-FU, adriamycin, and mitomycin-C) or observation. Although a significant increase was reported in median survival (23 vs. 11 months; P = .04), no increase in 3- or 5-year survivals was reported. Excessive toxicity was noted, and only 56% of the treatment group completed the six courses of chemotherapy (see Table 63A.3). Takada and colleagues (2003) enrolled 508 patients with mixed pancreatobiliary cancers (173 with pancreatic cancer) and randomized them to either surgery alone or surgery with combined mitomycin-C and 5-FU. The 5-year survival rates were 18 months and 11.5 months, respectively. Of note was the use of oral 5-FU, which has lower efficacy as a result of first-pass hepatic metabolism when compared with intravenous administration.

Kosuge and colleagues (2006) undertook a multicenter, randomized trial of surgery versus surgery and combination cisplatin and 5-FU. They concluded that although cisplatin and 5-FU were safe and well tolerated, the combination conferred no clear survival benefit over monotherapy (see Table 63A.3). As yet, no convincing evidence shows any benefit of combination chemotherapy over standard monotherapy based on either or both of these agents (Magee et al, 2002), and good evidence shows increased severity of side effects in combined regimens (Ghaneh et al, 1999).

Intraoperative Radiotherapy

The effect of EBRT on the pancreatic bed is limited by the immediacy of radiosensitive structures; the use of intraoperative radiotherapy (IORT) should reduce this effect. Studies that have explored IORT are small and have heterogenous populations, such that conclusions are hard to reach (Coquard et al, 1997; Fossati et al, 1995; Hiraoka et al, 1990; Reni et al, 2001; Shibamoto et al, 1996; Showalter et al, 2009; Zerbi et al, 1994). RTOG gave 20 Gy of IORT with EBRT (a total of 50.4 Gy) to 51 patients with advanced pancreatic cancer. Results showed a disappointing median survival of 9 months (Tepper et al, 1991). Sindelar and Kinsella (1986) similarly showed a median survival of only 12 months in patients treated with surgery or surgery and IORT. There are reports (Valentini et al, 2009