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), however, of long-term control and survival in operated patients receiving IORT, although such data are contaminated, with 24% of patients receiving preoperative and postoperative EBRT. Nonetheless, preoperative chemotherapy with surgery and IORT gave a 5-year local control of 23.3%, although IORT is unlikely to become mainstream treatment outside specialized centers undertaking this modality because of the limited number of appropriate patients.

Neoadjuvant Chemoradiotherapy, Chemotherapy, And Biologic Treatment

Broadly speaking, medical treatments are either directed at known borderline resectable disease, with the aim of downsizing a tumor in contact with or encasing vascular structures, or to patients with staged resectable disease. The presumption of both is acceptance of the rationale for neoadjuvant chemoradiotherapy (nCRT). Early studies implied the advantage of CRT in advanced pancreatic cancer (Moertel et al, 1969, 1981), hence the extrapolation to neoadjuvant regimens. These can be categorized into studies using 5-FU (Table 63A.4) or gemcitabine (Table 63A.5) as the radiosensitizing agent.

Overall, great heterogeneity exists between studies, with mixing of preoperative and postoperative chemoradiation, lack of standardized regimens, and in some cases poor outcome data. However, a few points are worthy of discussion. First, the majority of these studies are from the United States and use multimodal therapy, which is less common in Europe. Patients are restaged after nCRT; hence, a prognostically better subgroup is the result. In addition, current histologic assessment would change the assessments of R0 resection in some of these studies. Of those receiving nCRT, the rate of tumor resection is less than 60% for those receiving 5-FU–based treatment, but it is up to 85% in those receiving gemcitabine-based therapy. Gemcitabine-based neoadjuvant therapy would appear safe and is likely to be the emerging central agent in these modalities. The addition of biologic agents would appear counterintuitive at the moment, but the literature base is currently lacking. Hence this field is in need of powered trials. A randomized, multicenter study (ESPAC-5) is being planned.

Palliative Chemotherapy

Until the landmark study by Burris and colleagues (1997), 5-FU had been considered the gold standard of palliative chemotherapy despite its poor response rates, but gemcitabine has subsequently been shown to be more beneficial than 5-FU when used as monotherapy in advanced pancreatic cancer (Carmichael et al, 1996; Casper et al, 1994; Hertel et al, 1990; Huang et al, 1991). Better response rates, longer median and 1-year survival, and enhanced clinical benefit response were achieved. The cornerstone study exploring these advantages (Burris et al, 1997) randomized patients with advanced pancreatic cancer to receive either 5-FU or gemcitabine. Those receiving gemcitabine had a modest but significant increase in median survival (5.56 vs. 4.41 months; P = .0025) and improved clinical benefit (23.8% vs. 4.8%; P = .0022). A follow-on study by the same group showed advantage for patients with advanced pancreatic cancer previously treated with 5-FU in whom there had been disease progression. The patients were subsequently given gemcitabine (Rothenberg et al, 1996), and a 27% clinical benefit response was achieved for a median of 14 weeks, with an overall median survival of 3.85 months. The Eastern Cooperative Oncology Group randomized 322 patients with advanced pancreatic cancer to receive solo gemcitabine or gemcitabine followed by 5-FU (Berlin et al, 2002). This regimen achieved a nonsignificant rise in median survival, although it did show a significantly improved progression-free survival for gemcitabine plus 5-FU (P = .022).

Overall, combining 5-FU with gemcitabine has little to offer over monotherapy with gemcitabine (Berlin et al, 2002; Crown et al, 1991; DeCaprio et al, 1991; Di Costanzo et al, 2005; Hansen et al, 1988; Maisey et al, 2002; Riess et al, 2005). Alternately, combining gemcitabine with platinum compounds has a better overall response rate and to some extent better median and progression-free survival (Alberts et al, 2003; Cascinu et al, 2003; Colucci et al, 2002; Heinemann et al, 2000, 2006; Philip et al, 2001; Poplin et al, 2006); however, it is associated with more toxicity side effects. The same is true for most other cytotoxic agents.

Combination of gemcitabine with capecitabine has shown promise in Phase II (Scheithauer et al, 2003) and Phase III (Herrmann et al, 2007) trials. The largest Phase III trial to date (Cunningham et al, 2009) has recently reported and is summarized in Table 63A.6. In this study, 533 patients were randomized to either gemcitabine (G) or gemcitabine and capecitabine (GC). Those receiving GC had significantly better objective response rates (19.1% GC vs. 12.4 G; P = 0.034) and progression-free survival (HR, 0.78; 95% CI, 0.66 to 0.93). Although not reaching significance, a trend toward increased overall survival was reported for GC. Median survival and 1-year survival for GC and G were 7.1 months versus 6.2 months and 24.3% versus 22%, respectively. This study also includes a meta-analysis of this report and directly comparable Phase II and III trials (Herrmann et al, 2007; Scheithauer et al, 2003), all of which show a significant survival benefit from gemcitabine combined with capecitabine (HR, 0.86; 95% CI 0.75 to 0.98; P = .02). The initial excitement regarding combining gemcitabine with biologic agents—such as erlotinib, an epidermal growth-factor receptor tyrosine kinase inhibitor, or bevacizumab, monoclonal antibody to vascular endothelial growth factor A—have not shown the expected promise in recent phase III trials and appear no better than combination gemcitabine and capeciabine (see Table 63A.6).

Several other Phase III trials of novel agents are in progress or have recently closed, notably TeloVac, RC-57, and IPC-BAYPAN. Also under development is the VIP study, a Phase II, randomized, multicenter trial comparing gemcitabine and vandetanib with solo gemcitabine in advanced pancreatic cancer.

It is vital to remember that patients with advanced pancreatic cancer are looking for improvement in quality of life, which should not be sacrificed for modest increases in survival.

Palliative Radiotherapy

Much of the poor reputation of palliative radiotherapy may be unjustified in the modern era. This is because of a recent dramatic shift in radiotherapy delivery techniques from fractional or low doses (e.g., 2 Gy over 6 weeks with a radiation holiday of 2 weeks in the middle) to a continuous-course fraction with a higher overall dose (e.g., 50.4 Gy compared with 40 Gy in fractionated low-dose EBRT). This has the advantage of faster completion of treatment and better overall local control (Lim et al, 2003; Regine et al, 2006). Radiation field size has decreased with the use of intensity-modulated radiation therapy (IMRT), in which smaller fields are targeted by “pencil” beams to reduce the traditional scatter effect to surrounding tissues (Bai et al, 2003; Ben-Josef et al, 2004; Crane et al, 2001; Landry et al, 2002; Milano et al, 2004). This has the added advantage of potentially reducing side effects of combination agents.

Stereotactic radiotherapy (CyberKnife; Accuray, Sunnyvale, CA) uses focused radiotherapy with controlled organ movement via implanted metallic markers. Unfortunately, both Phase I (25 Gy, 15 patients) (Koong et al, 2004) and Phase II trials (45-Gy IMRT with a 25 Gy stereotactic boost, 19 patients) (Koong et al, 2005) have failed to show any great effect, with median survivals of 11 and 7.6 months, respectively. Median time to progression with sole 25-Gy stereotactic radiation was 2 months. Despite the lack of evidence for this technique, which involves a specialized setup, it is gaining some popularity as a result of recent high-profile cases.

Palliative Chemoradiotherapy

Palliative radiotherapy has been used in conjunction with chemotherapeutic agents, mainly 5-FU, which allows radiosensitization of tissues. Early work by Moertel and colleagues (1969) suggested a survival advantage for those patients given CRT (35 to 40-Gy EBRT + 5-FU) over those given only EBRT (35 to 40 Gy), with a median survival of 10.4 versus 6.3 months and a 1-year survival of 22% versus 6.3%, respectively. Several small, historic trials have addressed the role of 5-FU and EBRT and show median survival times of 10 to 15 months (Gunderson et al, 1987; Haycox et al, 1998; Ikeda et al, 2001), although these studies may be subject to patient selection bias. The larger GITSG trial (Moertel et al, 1981) randomized 194 patients with advanced pancreatic cancer to either ERBT (60 Gy), ERBT + 5-FU (40 Gy), or EBRT + 5-FU (60 Gy). Concomitant EBRT with 5-FU increased median survival from 23 to 42 weeks. Unfortunately, none of these trials had a control arm. A smaller, follow-on GITSG trial (1988) of 48 advanced pancreatic cancer patients randomized to either 5-FU plus 54-Gy EBRT with follow-on streptozotocin, mitomycin-C, and 5-FU (SMF) versus SMF only. The combination regimen was seen to increase median survival from 32 weeks in the SMF group to 42 weeks in the combination SMF group.

Contrary to this, the Eastern Cooperative Oncology Group (Klaassen et al, 1985) randomized 91 patients to either 5-FU plus 40-Gy EBRT versus 5-FU alone and found no difference in survival in either arm. At present, there seems to be little difference between chemotherapy based on 5-FU and the radiosensitizer EBRT in the treatment of advanced pancreatic cancer (Haycox et al, 1998). A recent multicenter, randomized, Phase II trial by Wilkowski and colleagues (2009) failed to elicit any advantage of CRT regimens. In this trial, 95 patients were randomized to either 5-FU with 50-Gy EBRT (RT–5-FU arm); gemcitabine and cisplatin with 50-Gy EBRT (RT-GC arm), or gemcitabine and cisplatin with 50-Gy EBRT with follow-on gemcitabine and cisplatin (RT-GC + GC arm). Median survivals of 9.6, 9.3, and 7.3 months for RT–5-FU, RT-GC, and RT-GC + GC, respectively, with corresponding progression-free survival at 4, 5.6, and 6 months. The authors conclude that such CRT is no better than solo gemcitabine.

Overall, despite the success of gemcitabine in the adjuvant setting, there would appear to be significant side effects, especially in terms of toxicity, when combined with radiotherapy. As yet there is no clear way forward, but palliative CRT seems to have few advantages over solo chemotherapy for advanced, unresectable pancreatic carcinoma.