Stage I and Stage II Pancreatic Cancer Treatment
Treatment Options for Stages I and II Pancreatic Cancer
Postoperative chemoradiation therapy
Treatment Options Under Clinical Evaluation for Stages I and II Pancreatic Cancer
Current Clinical Trials
Treatment Options for Stages I and II Pancreatic Cancer
Treatment options for stages I and II pancreatic cancer include the following:
- Surgery: radical pancreatic resection including:
- Whipple procedure (pancreaticoduodenal resection).
- Total pancreatectomy when necessary for adequate margins.
- Distal pancreatectomy for tumors of the body and tail of the pancreas.[1,2]
- Postoperative chemoradiation therapy: radical pancreatic resection followed by 5-fluorouracil (5-FU) chemotherapy and radiation therapy.[3-7]
- Postoperative chemotherapy: radical pancreatic resection followed by chemotherapy (gemcitabine or 5-FU/leucovorin).
Complete resection can yield 5-year survival rates of 18% to 24%, but ultimate control remains poor because of the high incidence of both local and distant tumor recurrence.[9-11][Level of evidence: 3iA]
Approximately 20% of patients present with pancreatic cancer amenable to local surgical resection, with operative mortality rates of approximately 1% to 16%.[12-16] Using information from the Medicare claims database, a national cohort study of more than 7,000 patients undergoing pancreaticoduodenectomy between 1992 and 1995 revealed higher in-hospital mortality rates at low-volume hospitals (<1 pancreaticoduodenectomy per year) versus high-volume hospitals (>5 per year) (16% vs. 4%, respectively; P < .01).Postoperative chemoradiation therapy
The role of postoperative therapy (chemotherapy with or without chemoradiation therapy) in the management of this disease remains controversial because much of the randomized clinical trial data available are statistically underpowered and provide conflicting results.[3-7]
Evidence (postoperative chemoradiation therapy):
Several phase III trials examined the potential overall survival (OS) benefit of postoperative adjuvant 5-FU–based chemoradiation therapy:
- Gastrointestinal Study Group (GITSG): A small randomized trial conducted by the GITSG in 1985 compared surgery alone with surgery followed by chemoradiation.[Level of evidence: 1iiA];[Level of evidence: 2A]
- The investigators reported a significant but modest improvement in median-term and long-term survival over resection alone with postoperative bolus 5-FU and regional split-course radiation given at a dose of 40 Gy.
- European Organization for the Research and Treatment of Cancer (EORTC): An attempt by the EORTC to reproduce the results of the GITSG trial failed to confirm a significant benefit for adjuvant chemoradiation therapy over resection alone;[Level of evidence: 1iiA] however, this trial treated patients with pancreatic and periampullary cancers (with a potentially better prognosis).
- A subset analysis of the patients with primary pancreatic tumors indicated a trend toward improved median, 2-year, and 5-year OS with adjuvant therapy compared with surgery alone (17.1 months, 37%, and 20%, respectively, vs. 12.6 months, 23%, and 10%, respectively; P = .09 for median survival).
- An updated analysis of a subsequent European Study for Pancreatic Cancer (ESPAC 1) trial examined only patients who underwent strict randomization after pancreatic resection. The patients were assigned to one of four groups (observation, bolus 5-FU chemotherapy, bolus 5-FU chemoradiation therapy, or chemoradiation therapy followed by additional chemotherapy).[6,7][Level of evidence: 1iiA]
- With a 2 × 2 factorial design reported at a median follow-up of 47 months, a median survival benefit was observed for only the patients who received postoperative 5-FU chemotherapy. However, these results were difficult to interpret because of a high rate of protocol nonadherence and the lack of a separate analysis for each of the four groups in the 2 × 2 design.[6,7,17][Level of evidence: 1iiA]
- U.S. Gastrointestinal Intergroup: The U.S. Gastrointestinal Intergroup has reported the results of a randomized phase III trial (Radiation Therapy Oncology Group (RTOG)-9704) that included 451 patients with resected pancreatic cancers who were assigned to receive either postoperative infusional 5-FU plus infusional 5-FU and concurrent radiation or adjuvant gemcitabine plus infusional 5-FU and concurrent radiation.[Level of evidence: 1iiA] The primary endpoints were OS for all patients and OS for patients with pancreatic head tumors.
- A 5-year update of RTOG-9704 reported that patients with pancreatic head tumors (n = 388) had a median survival and 5-year OS of 20.5 months and 22% survival rate with gemcitabine, versus 17.1 months and 18% with 5-FU (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.67–1.05; P = .12).
- Univariate analysis showed no difference in OS; however, on multivariate analysis, patients on the gemcitabine arm with pancreatic head tumors experienced a trend toward improved OS (P = .08). Distant relapse remained the predominant site of first failure (78%).
- A secondary analysis of RTOG-9704 explored the correlation of adherence to protocol-specified radiation with patient outcomes.
- Radiation therapy adherence was scored as per protocol (n = 216) and less than per protocol (n = 200). The major deviation seen was deviation in field size and field placement.
- For all pancreatic sites, median survival for patients per protocol was significantly longer than patients treated less than per protocol (1.74 years vs. 1.46 years; P = .008).
- On multivariate analysis, treatment per protocol correlated more strongly with median survival than assigned treatment arm (P = .014). However, this is an exploratory analysis that cannot control for potential unknown confounders.
The EORTC/U.S. Gastrointestinal Intergroup RTOG-0848 phase III adjuvant trial evaluating the impact of chemoradiation after completion of a full course of gemcitabine with or without erlotinib is currently enrolling patients.Postoperative chemotherapy
Evidence (postoperative chemotherapy):
- Charité Onkologie (CONKO)-001: Results have also been reported from CONKO-001, a multicenter phase III trial of 368 patients with resected pancreatic cancer who were randomly assigned to receive six cycles of adjuvant gemcitabine versus observation.[Level of evidence: 1iiDii] In contrast to the previous trials, the primary endpoint was disease-free survival (DFS).
- Median DFS was 13.4 months in the gemcitabine arm (95% CI, 11.4–15.3) and 6.9 months in the observation arm (95% CI, 6.1–7.8; P < .001). However, there was no significant difference in OS between the gemcitabine arm (median 22.1 months, 95% CI, 18.4–25.8) and the control arm (median 20.2 months, 95% CI, 17–23.4).
- At the American Society of Clinical Oncology annual meeting in 2008, the investigators, with longer follow-up, reported a significant improvement in OS that favored gemcitabine (median survival 22.8 months vs. 20.2 months; P = .005; 5-year survival 21% vs. 9%).
- ESPAC-3: The ESPAC-3 (NCT00058201) trial randomly assigned 1,088 patients who had undergone complete macroscopic resection to either 6 months of 5-FU (425 mg/m2) and leucovorin (20 mg/m2) on days 1 to 5 every 28 days or 6 months of gemcitabine (1,000 mg/m2) on days 1, 8, and 15 every 28 days.[Level of evidence: 1iiA]
- Median OS was 23.0 months (95% CI, 21.1– 25.0) for patients treated with 5-FU plus leucovorin and 23.6 months (95% CI, 21.4–26.4) for those treated with gemcitabine (HR = 0.94; 95% CI, 0.81–1.08; P = .39).
Additional trials are still warranted to determine more effective adjuvant therapy for this disease.Treatment Options Under Clinical Evaluation for Stages I and II Pancreatic Cancer
Treatment options under clinical evaluation include the following:
- Gemcitabine and capecitabine (ESPAC-4).
- Gemcitabine and erlotinib (CONKO-005).
- Gemcitabine and erlotinib with or without 5-FU/capecitabine-based chemoradiation (RTOG-0848).
- Preoperative chemotherapy and/or radiation therapy.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I pancreatic cancer and stage II pancreatic cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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