Adjuvant Chemoradiation

Surgical resection is the only curative treatment for patients with PC, yet only 10% to 15% of patients have a resectable tumor at the time of diagnosis. Moreover, after surgery, the 5-year survival is less than 20%. In this context, adjuvant chemotherapy, with or without radiotherapy, is the recommended approach after surgery to improve both locoregional control and overall survival (OS).

Several trials have analyzed the efficacy of CRT after pancreaticoduodenectomy ( Table 1 ). The Gastrointestinal Tumor Study Group (GITSG) was the first to document that adjuvant CRT after surgical resection prolonged survival. In this study, radiation was administered in combination with bolus 5-fluorouracil (5-FU) and was followed by maintenance 5-FU. Although the study was terminated prematurely because of a low rate of accrual, a survival advantage was demonstrated for the patients who received the combination treatment in comparison with patients who were treated with surgery alone. A subsequent nonrandomized study by the GITSG confirmed the support for the use of adjuvant CRT, rather than either radiation therapy alone or surgery alone, for patients with resectable disease.

The European Organization for Research and Treatment of Cancer conducted a trial in which 218 patients with pancreatic and nonpancreatic periampullary adenocarcinoma were randomized to either observation alone or to a combination of radiotherapy and 5-FU (administered as a continuous infusion) after potentially curative resection. No additional postradiation chemotherapy was administered. The preliminary analysis did not find a significant benefit to adjuvant chemoradiation; however, a subsequent statistical reanalysis demonstrated a significant survival improvement with the combination treatment for patients with pancreatic head cancers.

In contrast, the controversial results of the European Study Group for Pancreatic Cancer (ESPAC-1) suggested a detrimental effect on survival with adjuvant CRT compared with adjuvant chemotherapy or surgery alone. In this 4-arm trial, 541 patients were randomized, based on a 2 × 2 factorial design, to one of the following arms: (1) Observation, (2) concomitant CRT alone with 500 mg/m ² of 5-FU IV bolus during the first 3 days of radiation therapy and repeated after a planned 2-week break, (3) chemotherapy alone with leucovorin, 20 mg/m ² bolus plus 5-FU, 425 mg/m ² administered for 5 consecutive days and repeated every 28 days for 6 cycles, or (4) CRT followed by chemotherapy. No difference was found in survival between patients assigned to CRT (median survival, 15.5 months) versus observation (median survival, 16.1 months; P = .24). A trend to a survival advantage for those patients treated with chemotherapy alone (median survival, 17.4 months) versus observation alone (15.9 months; P = .19) was described. Despite criticisms of the study design, including criticism of the enrollment criteria and radiation therapy techniques, the authors concluded that adjuvant CRT did not offer any OS advantage, whereas a potential benefit existed for adjuvant chemotherapy alone after surgical resection.

To determine if the addition of gemcitabine to adjuvant 5-FU chemoradiation improved survival for patients with resected PC, 451 patients were randomized to either 5-FU (250 mg/m ² per day) or gemcitabine (1000 mg/m ² weekly) for 3 weeks before CRT and for 12 weeks after CRT therapy (Intergroup/RTOG 97-04 phase III trial). Chemoradiation with a continuous infusion of 250 mg/m ² per day 5-FU during radiation therapy was the same for all patients. In this phase III trial, patients with pancreatic head tumors had a median survival of 20.5 months in the gemcitabine groups versus a 16.9 months in the 5-FU group ( P = .09). Grade 4 hematologic toxicity was reported in 1% of the fluorouracil group and 14% of the gemcitabine group ( P <.001) without a difference in febrile neutropenia or infection. Although the survival improvement was not significant, the authors concluded that the addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected PC. A long-term follow-up of this trial was recently published. The 5-year results of this study demonstrate that the previously observed improvement in 3-year OS with the addition of gemcitabine to adjuvant fluorouracil-based CRT for patients with pancreatic head tumors was not seen at 5 years: OS was 22% with gemcitabine versus 18% with 5-FU. A trend toward significance in improvement of OS in the gemcitabine arm was seen on a multivariate analysis ( P = .08).

Several institutions have prospectively or retrospectively demonstrated the utility of adjuvant CRT compared with surgery alone. The Johns Hopkins Hospital–Mayo Clinic Collaborative Study recently reported a large collaborative analysis of 1092 patients who underwent resection with curative intent. Compared with the OS for those undergoing surgery alone, the OS was longer for recipients of CRT (median OS 21.1 vs 15.5 months; P >.001). In the multivariate analysis, after adjusting for different variables, OS remained superior for patients treated with adjuvant CRT compared with those who received surgery alone.

The European Organization for Research and Treatment of Cancer’s phase II trial assessed the toxicity of gemcitabine followed by gemcitabine concurrent with radiation. The results showed that adjuvant gemcitabine followed by the combination of gemcitabine and radiation (50.4 Gy) was feasible and only slightly more toxic than gemcitabine alone, pointing to a further evaluation of this multimodal approach in a phase III trial.

Adjuvant Chemotherapy

To test the hypothesis that gemcitabine after resection improves disease-free survival, the CONKO-001 study randomized 368 (354 were elegible for intent-to-treat-analysis) patients with completely resected PC to 6 cycles of gemcitabine or surgery alone. The study demonstrated a significant improvement in its primary endpoint of disease-free survival for patients receiving postoperative gemcitabine (13.4 vs 6.9 months; P <.001) but without an improvement in OS (22.1 vs 20.2 months; P = .06). However, the recently reported 5-year results demonstrated a significant improvement in OS with a median and 5-year survival rate of 22.8 months and 21% in the gemcitabine arm and 20.2 months and 9% in the surgery alone arm ( P = .005).

The ESPAC-3 phase III randomized trial was designed to determine whether fluorouracil or gemcitabine is superior in terms of OS as adjuvant treatment after resection of PC. A total of 1088 patients were randomized to receive either gemcitabine or 5-FU plus folinic acid. In contrast with the findings for nonresected advanced PC, there was no significant difference in OS between patients treated with postoperative adjuvant 5-FU plus folinic acid and patients who were treated with gemcitabine. However, gemcitabine showed a superior toxicity profile with fewer treatment-related serious adverse events (7.5%) compared with 14% of patients receiving 5-FU plus folinic acid ( P <.001). The lower toxicity and the ease of administration of gemcitabine in a weekly treatment schedule led to consideration of this treatment as the standard of care for most patients (see Table 1 ).

Although a growing body of literature indicates a benefit of adjuvant treatment in localized PC after a potentially curative resection, the vast majority of tumors recur and the patients succumb to their disease a short time after diagnosis.

To summarize, strong evidence from randomized trials suggest that adjuvant chemotherapy (gemcitabine or 5-FU) is the standard treatment option. However, there remains controversy regarding the role of adjuvant CRT. Future clinical trials exploring different adjuvant chemotherapy or chemoradiation schedules, as well as the integration of novel cytotoxic and targeted agents, could elucidate which is the best option to improve the outcome for patients with resected PC. The ESPAC-4 trial is evaluating the addition of the oral fluropyrimidine, capecitabine, to gemcitabine after resection of localized PC. The RTOG0848 trial will analyze whether both erlotinib and fluoropyrimidine-based chemoradiation improves the survival of patients treated with gemcitabine as adjuvant treatment for patients with resected head of PC.

Preoperative Chemoradiation

Neoadjuvant, or preoperative, therapy has been used to improve survival in resectable PC. There are several reasons to consider a neoadjuvant approach, such as:

• 1
  

  Early treatment of micrometastasis disease;

  
  
• 2
  

  Extension of potentially curative treatment to patients with borderline disease;

  
  
• 3
  

  Increasing the rates of negative margin resections and decrease local failure rates; and

  
  
• 4
  

  Improving the selection of patients for whom resection will not offer a survival benefit.

A rigorous meta-analysis of 56 phase I and II trials studying the effect of neoadjuvant therapy was completed. Interestingly, for patients with resectable tumors who received neoadjuvant therapy, resection frequencies and survival after neoadjuvant therapy were similar to those patients with primarily resected tumors treated with adjuvant therapy, showing no advantage of neoadjuvant therapy for patients with resectable tumors. However, among patients with initially staged unresectable tumors, one third were resected after neoadjuvant therapy, with survival comparable with those patients with initially resectable tumors.

Recently, a large pancreatic series from the California Cancer Surveillance Program for Los Angeles County retrospectively identified 458 patients with nonmetastatic PC who underwent definitive pancreatic resection and received systemic chemotherapy. In contrast with the conclusions of the meta-analysis, patients who received neoadjuvant therapy presented a lower rate of lymph node positivity (45%) and improved OS (34 months) compared with the adjuvant group of patients (65% [ P = .11] and 19 months [ P = .003], respectively). In the multivariate analysis, neoadjuvant therapy remained an independent predictor of improved survival ( P = .013). The authors suggested that this strategy should be considered an acceptable alternative to the initial surgery treatment in operable PC.

To summarize, although neoadjuvant CRT can be administered safely, the recommended practice for resectable disease outside the clinical trial setting should be surgery followed by adjuvant chemotherapy with or without radiation.

Single Agent

The standard treatment for patients with advanced metastatic or recurrent PC is systemic chemotherapy. However, responses rates (RR) to the current available drugs are low and treatment should be considered palliative. For many years, the most active chemotherapeutic agent used in the treatment for patients with advanced PC has been 5-FU. In different phase II studies, patients treated with 5-FU achieved a RR from 0% to 20% with a median survival of 4 to 5 months. The modulation of 5-FU with other agents, such as leucovorin, did not show clear evidence of increased RR in phase II studies. Many subsequent studies were developed to evaluate different 5-FU combinations; however, in randomized phase III studies, the survival of patients treated with 5-FU alone was not different from that of patients treated with more aggressive and more toxic chemotherapeutic regimens.

In 1997, a randomized phase III clinical trial compared gemcitabine with 5-FU in 126 patients with advanced metastatic PC who had not received prior systemic therapy ( Table 3 ). Patients were randomized to receive gemcitabine (800 mg/m ² as a 30-minute intravenous injection weekly for 3 consecutive weeks followed by 1 week of rest) or 5-FU (600 mg/m ² once a week). Although the RR was 5.4% for gemcitabine and 0% for 5-FU, a positive clinical benefit response (a combination of performance status, analgesic usage, and measurements of pain) was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU–treated patients ( P = .002). There was an overall disease control rate (partial response plus stable disease) of 45% with gemcitabine versus 19% with 5-FU. The median times-to-tumor progression were 3.8 and 1.9 months and the median survival durations were 5.7 and 4.4 months for gemcitabine and 5-FU–treated patients, respectively ( P = .002). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Because of these results, gemcitabine was approved as first-line treatment of metastatic PC in the United States and many other countries and currently is considered the standard agent for the treatment of this disease.

Table 3

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