Chemotherapy with or without targeted therapy

FOLFIRINOX versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.[6][Level of evidence A1] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m2], irinotecan [180 mg/m2], leucovorin [400 mg/m2], and fluorouracil [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).

FOLFIRINOX versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.[6][Level of evidence A1] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m2], irinotecan [180 mg/m2], leucovorin [400 mg/m2], and fluorouracil [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 overall survival (OS) was 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group (hazard ratio [HR]death, 0.57; 95% confidence interval [CI], 0.45–0.73; P < .001).

FOLFIRINOX versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.[6][Level of evidence A1] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m2], irinotecan [180 mg/m2], leucovorin [400 mg/m2], and fluorouracil [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).

Median progression-free survival (PFS) was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (HRdisease progression, 0.47; 95% CI, 0.37–0.59; P < .001).

FOLFIRINOX versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.[6][Level of evidence A1] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m2], irinotecan [180 mg/m2], leucovorin [400 mg/m2], and fluorouracil [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).

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).

FOLFIRINOX versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.[6][Level of evidence A1] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m2], irinotecan [180 mg/m2], leucovorin [400 mg/m2], and fluorouracil [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).

Based on this trial, FOLFIRINOX is considered a standard treatment option for patients with advanced pancreatic cancer.

Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international, phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma. Patients had a Karnofsky Performance Status of at least 70 and had not previously received chemotherapy for metastatic disease.[7][Level of evidence A1] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1,000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).

Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international, phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma. Patients had a Karnofsky Performance Status of at least 70 and had not previously received chemotherapy for metastatic disease.[7][Level of evidence A1] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1,000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1,000 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).

Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international, phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma. Patients had a Karnofsky Performance Status of at least 70 and had not previously received chemotherapy for metastatic disease.[7][Level of evidence A1] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1,000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).

Median PFS 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).

Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international, phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma. Patients had a Karnofsky Performance Status of at least 70 and had not previously received chemotherapy for metastatic disease.[7][Level of evidence A1] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1,000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).

Nab-paclitaxel/gemcitabine was more toxic than gemcitabine. The most common grade 3 toxicities in the nab-paclitaxel/gemcitabine group were neutropenia (38%), fatigue (17%), and neuropathy (17%); febrile neutropenia occurred in 3% of patients. In the gemcitabine-alone group, the most common grade 3 toxicities were neutropenia (27%), fatigue (1%), and neuropathy (1%); febrile neutropenia occurred in 1% of patients.

Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international, phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma. Patients had a Karnofsky Performance Status of at least 70 and had not previously received chemotherapy for metastatic disease.[7][Level of evidence A1] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1,000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).

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.

Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international, phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma. Patients had a Karnofsky Performance Status of at least 70 and had not previously received chemotherapy for metastatic disease.[7][Level of evidence A1] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1,000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).

Based on this trial, nab-paclitaxel/gemcitabine is a standard treatment option for patients with advanced pancreatic cancer.

Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international, phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma. Patients had a Karnofsky Performance Status of at least 70 and had not previously received chemotherapy for metastatic disease.[7][Level of evidence A1] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1,000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).

Quality-of-life data were not measured for this regimen, and this study did not address the efficacy of nab-paclitaxel/gemcitabine versus FOLFIRINOX.

Gemcitabine versus 5-FU: Gemcitabine has demonstrated activity in patients with pancreatic cancer and is a useful palliative agent.[8-10] 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 (the 1-year survival rate was 18% with gemcitabine compared with 2% with 5-FU; P = .003).[9][Level of evidence A1]

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 with the combination of gemcitabine and erlotinib (100 mg/d) in patients with advanced or metastatic pancreatic carcinomas.[11][Level of evidence A1]

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 with the combination of gemcitabine and erlotinib (100 mg/d) in patients with advanced or metastatic pancreatic carcinomas.[11][Level of evidence A1]

The addition of erlotinib modestly prolonged survival when combined with gemcitabine versus gemcitabine alone (HR, 0.81; 95% CI, 0.69–0.99; P = .038).

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 with the combination of gemcitabine and erlotinib (100 mg/d) in patients with advanced or metastatic pancreatic carcinomas.[11][Level of evidence A1]

The median and 1-year survival rates for patients who received erlotinib were 6.2 months and 23%. The median and 1-year survival rates for patients who received placebo were 5.9 months and 17%.

Platinum analogue or fluoropyrimidine versus single-agent gemcitabine: Many phase III studies have evaluated a combination regimen with either a platinum analogue (cisplatin or oxaliplatin) or fluoropyrimidine versus single-agent gemcitabine.[12,13]

Platinum analogue or fluoropyrimidine versus single-agent gemcitabine: Many phase III studies have evaluated a combination regimen with either a platinum analogue (cisplatin or oxaliplatin) or fluoropyrimidine versus single-agent gemcitabine.[12,13]

None of these phase III trials have demonstrated a statistically significant advantage favoring the use of combination chemotherapy in the first-line treatment of metastatic pancreatic cancer.

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 Charité Onkologie (CONKO)-003 investigators randomly assigned patients requiring a second line of chemotherapy to either the OFF regimen or BSC.[14,15][Level of evidence C1] 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.

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 Charité Onkologie (CONKO)-003 investigators randomly assigned patients requiring a second line of chemotherapy to either the OFF regimen or BSC.[14,15][Level of evidence C1] 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.

The median survival 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).

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 Charité Onkologie (CONKO)-003 investigators randomly assigned patients requiring a second line of chemotherapy to either the OFF regimen or BSC.[14,15][Level of evidence C1] 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 OS was 9.09 months for the sequence of gemcitabine/OFF and 7.90 months for gemcitabine/BSC.

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 Charité Onkologie (CONKO)-003 investigators randomly assigned patients requiring a second line of chemotherapy to either the OFF regimen or BSC.[14,15][Level of evidence C1] 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.

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.