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    Pancreatic Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Stage III Pancreatic Cancer Treatment

    Table 8. Randomized Studies in Stage III Pancreatic Cancer: Median Survival continued...

    Taken together, the FFCD and GERCOR studies provide support for gemcitabine-based chemotherapy for at least 3 months, followed by chemoradiation in the absence of metastatic disease. This approach has yet to be validated in a prospective phase III trial.

    Chemotherapy

    Chemotherapy is the primary treatment modality for patients with locally advanced pancreatic cancers. Although gemcitabine has long been considered the standard regimen, newer chemotherapy regimens have recently emerged.

    Evidence: (chemotherapy):

    1. Gemcitabine versus 5-FU: Gemcitabine has demonstrated activity in patients with pancreatic cancer and is a useful palliative agent.[12,13,14] A phase III trial of gemcitabine versus 5-FU as first-line therapy in patients with advanced or metastatic adenocarcinoma of the pancreas reported a significant improvement in survival among patients treated with gemcitabine (1-year survival was 18% with gemcitabine compared with 2% with 5-FU; P = .003).[13][Level of evidence: 1iiA]
    2. Gemcitabine alone versus gemcitabine and erlotinib: The National Cancer Institute of Canada performed a phase III trial (CAN-NCIC-PA3 [NCT00026338]) that compared gemcitabine alone versus the combination of gemcitabine and erlotinib (100 mg/day) in patients with advanced or metastatic pancreatic carcinomas.[15][Level of evidence: 1iiA]
      • The addition of erlotinib modestly prolonged survival when combined with gemcitabine versus gemcitabine alone (hazard ratio [HR] = 0.81; 95% CI, 0.69 to 0.99; P = .038).
      • The corresponding median and 1-year survival rates for patients who received erlotinib versus placebo were 6.2 months and 5.9 months, and 23% versus 17%, respectively.
    3. Platinum analog or fluoropyrimidine versus single-agent gemcitabine: Many phase III studies have evaluated a combination regimen with either a platinum analog (cisplatin or oxaliplatin) or fluoropyrimidine versus single-agent gemcitabine.[16,17]
      • Not one of these phase III trials has demonstrated a statistically significant advantage favoring the use of combination chemotherapy in the first-line treatment of metastatic pancreatic cancer.
    4. Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma (Karnofsky Performance Status of ≥70) who had not previously received chemotherapy for metastatic disease.[18][Level of evidence: 1iiA] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).
      • The median OS was 8.5 months in the nab-paclitaxel/gemcitabine group compared with 6.7 months in the gemcitabine group (HRdeath, 0.72; 95% CI, 0.62-0.83; P < .001).
      • Median progression-free survival was 5.5 months in the nab-paclitaxel/gemcitabine group and 3.7 months in the gemcitabine group (HRdisease progression, 0.69; 95% CI, 0.58-0.82; P < .001).
      • Nab-paclitaxel/gemcitabine was more toxic than gemcitabine. The most common grade 3 toxicities were neutropenia (38% in the nab-paclitaxel/gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% in the nab-paclitaxel/gemcitabine group vs. 1% in the gemcitabine group), and neuropathy (17% in the nab-paclitaxel/gemcitabine group vs. 1% in the gemcitabine group). Febrile neutropenia occurred in 3% of the nab-paclitaxel/gemcitabine group versus 1% in the gemcitabine group. In the nab-paclitaxel/gemcitabine group, the median time from grade 3 neuropathy to grade 1 or resolution was 29 days. Of patients with grade 3 peripheral neuropathy, 44% were able to resume treatment at a reduced dose within a median of 23 days after onset of a grade 3 event.
      • On the basis of this trial, nab-paclitaxel plus gemcitabine is a standard treatment option for patients with advanced pancreatic cancer.
      • Quality of life data have not yet been published regarding this regimen, and this study does not address the efficacy of nab-paclitaxel/gemcitabine versus FOLFIRINOX.
    5. FOLFIRINOX versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an ECOG performance status score of 0 or 1.[19][Level of evidence: 1iiA] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m2], irinotecan [180 mg/m2], leucovorin [400 mg/m2], and 5-FU [400 mg/m2] given as a bolus followed by 2,400 mg/m2 given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).
      • The median OS was 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group (HRdeath = 0.57; 95% CI, 0.45-0.73; P < .001).
      • Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (HR for disease progression = 0.47; 95% CI, 0.37-0.59; P < .001).
      • FOLFIRINOX was more toxic than gemcitabine; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of quality of life, versus 66% in the gemcitabine group (HR = 0.47; 95% CI, 0.30-0.70; P < .001).
      • On the basis of this trial, FOLFIRINOX is considered a standard treatment option for patients with advanced pancreatic cancer.
    6. 5-FU, leucovorin, and oxaliplatin (OFF regimen) versus best supportive care (BSC): Second-line chemotherapy after progression on a gemcitabine-based regimen may be beneficial. The CONKO-003 investigators randomly assigned patients in the second line of chemotherapy to either the OFF regimen or BSC.[20]; [21][Level of evidence: 3iA] The OFF regimen consisted of leucovorin (200 mg/m2) followed by 5-FU (2,000 mg/m2[24-hour continuous infusion] on days 1, 8, 15, and 22) and oxaliplatin (85 mg/m2 on days 8 and 22). After a rest of 3 weeks, the next cycle was started on day 43. The trial was terminated early because of poor accrual, and only 46 patients were randomly assigned to either the OFF regimen or BSC.
      • Median survival on second-line chemotherapy was 4.82 months (95% CI, 4.29-5.35) with the OFF treatment regimen and 2.30 months (95% CI, 1.76-2.83) with BSC alone (HR = 0.45; 95% CI, 0.24-0.83).
      • Median OS was 9.09 months for the sequence of gemcitabine (GEM)-OFF and 7.90 months for GEM-BSC.
      • The early closure of the study and the very small number of patients made the P values misleading. Therefore, second-line chemotherapy with the OFF regimen may be falsely associated with improved survival.
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