Postoperative chemotherapy

FOLFIRINOX: In the randomized, open-label, phase III PRODIGE-24 trial (NCT01526135), 493 patients with R0/R1 resections were randomly assigned 1:1 to receive six cycles of gemcitabine (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) or 12 cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, and 5-FU 2,400 mg/m2 over 46 hours every 2 weeks).[23,24][Level of evidence A1]

FOLFIRINOX: In the randomized, open-label, phase III PRODIGE-24 trial (NCT01526135), 493 patients with R0/R1 resections were randomly assigned 1:1 to receive six cycles of gemcitabine (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) or 12 cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, and 5-FU 2,400 mg/m2 over 46 hours every 2 weeks).[23,24][Level of evidence A1]

With a median follow-up of 69.7 months, the median disease-free survival (DFS) was 21.4 months (95% CI, 17.5–26.7) in the FOLFIRINOX group and 12.8 months in the gemcitabine group (95% CI, 11.6–15.2) (HR, 0.66; 95% CI, 0.54–0.82; P < .001).

FOLFIRINOX: In the randomized, open-label, phase III PRODIGE-24 trial (NCT01526135), 493 patients with R0/R1 resections were randomly assigned 1:1 to receive six cycles of gemcitabine (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) or 12 cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, and 5-FU 2,400 mg/m2 over 46 hours every 2 weeks).[23,24][Level of evidence A1]

The median OS was 53.5 months (95% CI, 43.5–58.4) in the FOLFIRINOX group and 35.5 months (95% CI, 30.1–40.3) in the gemcitabine group (HR, 0.68; 95% CI, 0.54–0.85; P = .001). The 5-year OS rate was 43.2% in the FOLFIRINOX group and 31.4% in the gemcitabine group.

FOLFIRINOX: In the randomized, open-label, phase III PRODIGE-24 trial (NCT01526135), 493 patients with R0/R1 resections were randomly assigned 1:1 to receive six cycles of gemcitabine (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) or 12 cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, and 5-FU 2,400 mg/m2 over 46 hours every 2 weeks).[23,24][Level of evidence A1]

Toxicity was higher with combination therapy; 75.9% of patients who received FOLFIRINOX had grade 3 or 4 toxicities, compared with 52.9% of those who received gemcitabine, with similar rates of neutropenia (although 62.2% of patients on FOLFIRINOX received granulocyte colony-stimulating factor). Thirty-three percent of patients who received FOLFIRINOX stopped treatment prematurely, compared with 21% of patients who received gemcitabine alone.

Gemcitabine and capecitabine: The European Study for Pancreatic Cancer (ESPAC-4 [NCT00058201]) trial randomly assigned 732 patients with resected pancreatic cancer to receive either six cycles of gemcitabine alone (1,000 mg/m2 given weekly for 3 weeks of every 4 weeks) or oral capecitabine (1,660 mg/m2 given for 21 days followed by 7 days of rest [one cycle]).[25][Level of evidence A1]

Gemcitabine and capecitabine: The European Study for Pancreatic Cancer (ESPAC-4 [NCT00058201]) trial randomly assigned 732 patients with resected pancreatic cancer to receive either six cycles of gemcitabine alone (1,000 mg/m2 given weekly for 3 weeks of every 4 weeks) or oral capecitabine (1,660 mg/m2 given for 21 days followed by 7 days of rest [one cycle]).[25][Level of evidence A1]

With a median follow-up of 43.2 months, the median OS for patients in the gemcitabine/capecitabine group was 28.0 months (95% CI, 23.5–31.5) compared with 25.5 months for the gemcitabine-alone group (95% CI, 22.7–27.9; HR, 0.82; P = .032). Treatment with gemcitabine/capecitabine yielded an improvement in the estimated 5-year OS rate from 16.3% with gemcitabine alone to 28.8% with gemcitabine/capecitabine.

Gemcitabine and capecitabine: The European Study for Pancreatic Cancer (ESPAC-4 [NCT00058201]) trial randomly assigned 732 patients with resected pancreatic cancer to receive either six cycles of gemcitabine alone (1,000 mg/m2 given weekly for 3 weeks of every 4 weeks) or oral capecitabine (1,660 mg/m2 given for 21 days followed by 7 days of rest [one cycle]).[25][Level of evidence A1]

There was no significant difference in overall rates of grade 3/4 toxicities between treatment arms. Compared with gemcitabine alone, capecitabine was associated with higher rates of grade 3/4 diarrhea (5% vs. 2%), neutropenia (38% vs. 24%), and hand-foot syndrome (7% vs. 0%).

Gemcitabine and capecitabine: The European Study for Pancreatic Cancer (ESPAC-4 [NCT00058201]) trial randomly assigned 732 patients with resected pancreatic cancer to receive either six cycles of gemcitabine alone (1,000 mg/m2 given weekly for 3 weeks of every 4 weeks) or oral capecitabine (1,660 mg/m2 given for 21 days followed by 7 days of rest [one cycle]).[25][Level of evidence A1]

There was no significant effect on the quality of life in the treatment groups.

Gemcitabine and capecitabine: The European Study for Pancreatic Cancer (ESPAC-4 [NCT00058201]) trial randomly assigned 732 patients with resected pancreatic cancer to receive either six cycles of gemcitabine alone (1,000 mg/m2 given weekly for 3 weeks of every 4 weeks) or oral capecitabine (1,660 mg/m2 given for 21 days followed by 7 days of rest [one cycle]).[25][Level of evidence A1]

Based on these findings, the adjuvant combination of gemcitabine and capecitabine is the standard of care after a resection for pancreatic cancer.

S-1: The Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01) study was a phase III, multicenter, noninferiority trial conducted in Japan that randomly assigned 385 patients to receive either gemcitabine (1,000 mg/m2 weekly for 3 weeks of every 4 weeks) for six cycles or S-1 (tegafur, gimeracil, and oteracil potassium) (given orally twice a day for 4 weeks followed by a 2-week break).[26][Level of evidence A1]

S-1: The Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01) study was a phase III, multicenter, noninferiority trial conducted in Japan that randomly assigned 385 patients to receive either gemcitabine (1,000 mg/m2 weekly for 3 weeks of every 4 weeks) for six cycles or S-1 (tegafur, gimeracil, and oteracil potassium) (given orally twice a day for 4 weeks followed by a 2-week break).[26][Level of evidence A1]

The prespecified criteria for early discontinuation was met at interim analysis for efficacy with all of the protocol treatments completed. On early interim analysis, the HRmortality was 0.57 (95% CI, 0.44–0.72; P for noninferiority < .001; P for superiority < .001). These results were associated with a 5-year OS rate of 24.4% in the gemcitabine group and 44.1% in the S-1 group.

S-1: The Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01) study was a phase III, multicenter, noninferiority trial conducted in Japan that randomly assigned 385 patients to receive either gemcitabine (1,000 mg/m2 weekly for 3 weeks of every 4 weeks) for six cycles or S-1 (tegafur, gimeracil, and oteracil potassium) (given orally twice a day for 4 weeks followed by a 2-week break).[26][Level of evidence A1]

Grade 3 or 4 leukopenia, neutropenia, and liver transaminitis were observed more frequently in the gemcitabine group, and stomatitis and diarrhea were experienced more frequently in the S-1 group.

S-1: The Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01) study was a phase III, multicenter, noninferiority trial conducted in Japan that randomly assigned 385 patients to receive either gemcitabine (1,000 mg/m2 weekly for 3 weeks of every 4 weeks) for six cycles or S-1 (tegafur, gimeracil, and oteracil potassium) (given orally twice a day for 4 weeks followed by a 2-week break).[26][Level of evidence A1]

Among Japanese patients, adjuvant chemotherapy with S-1 can be a new standard of care for resected pancreatic patients. Additional studies are needed to validate these results in patients of other races and ethnicities.

S-1: The Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01) study was a phase III, multicenter, noninferiority trial conducted in Japan that randomly assigned 385 patients to receive either gemcitabine (1,000 mg/m2 weekly for 3 weeks of every 4 weeks) for six cycles or S-1 (tegafur, gimeracil, and oteracil potassium) (given orally twice a day for 4 weeks followed by a 2-week break).[26][Level of evidence A1]

The pharmacokinetics and pharmacodynamics of S-1 may be different between Eastern and Western patient populations because grade 3/4 gastrointestinal toxicities, especially diarrhea, have been reported more commonly in the Western patient population. S-1 is not currently approved by the U.S. Food and Drug Administration for use in the United States.

Gemcitabine: Charité Onkologie (CONKO)-001 was 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.[22][Level of evidence B1] In contrast to the previous trials, the primary end point was DFS.

Gemcitabine: Charité Onkologie (CONKO)-001 was 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.[22][Level of evidence B1] In contrast to the previous trials, the primary end point was DFS.

With a median follow-up of 136 months, long-term follow-up of the CONKO-001 study demonstrated a significant improvement in OS that favors gemcitabine (median survival, 22.8 months vs. 20.2 months; HR, 0.76; 95% CI, 0.61–0.95, P = .01). Gemcitabine compared with observation alone yielded improved survival rates at 5 years of 20.7% for the gemcitabine arm versus 10.4% for the observation-alone arm, and the survival rates at 10 years were 12.2% for the gemcitabine arm versus 7.7% for the observation-alone arm.[27][Level of evidence A1]

Gemcitabine or 5-FU: The ESPAC-3 trial (NCT00058201) 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.[3][Level of evidence A1]

Gemcitabine or 5-FU: The ESPAC-3 trial (NCT00058201) 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.[3][Level of evidence A1]

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).