Chemotherapy with or without targeted therapy

Gemcitabine versus fluorouracil (5-FU): 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 vs. 2% with 5-FU; P = .003).[1][Level of evidence A1]

FOLFIRINOX (leucovorin, 5-FU, irinotecan, and oxaliplatin) versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group performance status score of 0 or 1.[4][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 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 (leucovorin, 5-FU, irinotecan, and oxaliplatin) versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group performance status score of 0 or 1.[4][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 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 (leucovorin, 5-FU, irinotecan, and oxaliplatin) versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group performance status score of 0 or 1.[4][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 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 (HR for disease progression, 0.47; 95% CI, 0.37–0.59; P < .001).

FOLFIRINOX (leucovorin, 5-FU, irinotecan, and oxaliplatin) versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group performance status score of 0 or 1.[4][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 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 (leucovorin, 5-FU, irinotecan, and oxaliplatin) versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group performance status score of 0 or 1.[4][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 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.

NALIRIFOX (5-FU, irinotecan sucrosofate [also called nanoliposomal irinotecan], and oxaliplatin) versus gemcitabine and nab-paclitaxel: The multicenter, open-label, phase III NAPOLI 3 study (NCT04083235) included 770 patients with confirmed pancreatic ductal adenocarcinoma who had not been treated previously for metastatic disease. The patients were randomly assigned 1:1 to receive NALIRIFOX (irinotecan sucrosofate [50 mg/m2], oxaliplatin [60 mg/m2], leucovorin [400 mg/m2], and 5-FU [2,400 mg/m2] as an intravenous infusion over 46 hours on days 1 and 15 of cycles lasting 28 days) or nab-paclitaxel (125 mg/m2) and gemcitabine (1,000 mg/m2 given intravenously on days 1, 8, and 15 of cycles lasting 28 days). The primary end point was OS from randomization to death due to any cause, for NALIRIFOX versus gemcitabine/nab-paclitaxel. Secondary end points included PFS and overall response rate by RECIST version 1.1.[5]Based on this trial, NALIRIFOX is a standard first-line treatment option for patients with advanced pancreatic cancer.

NALIRIFOX (5-FU, irinotecan sucrosofate [also called nanoliposomal irinotecan], and oxaliplatin) versus gemcitabine and nab-paclitaxel: The multicenter, open-label, phase III NAPOLI 3 study (NCT04083235) included 770 patients with confirmed pancreatic ductal adenocarcinoma who had not been treated previously for metastatic disease. The patients were randomly assigned 1:1 to receive NALIRIFOX (irinotecan sucrosofate [50 mg/m2], oxaliplatin [60 mg/m2], leucovorin [400 mg/m2], and 5-FU [2,400 mg/m2] as an intravenous infusion over 46 hours on days 1 and 15 of cycles lasting 28 days) or nab-paclitaxel (125 mg/m2) and gemcitabine (1,000 mg/m2 given intravenously on days 1, 8, and 15 of cycles lasting 28 days). The primary end point was OS from randomization to death due to any cause, for NALIRIFOX versus gemcitabine/nab-paclitaxel. Secondary end points included PFS and overall response rate by RECIST version 1.1.[5]Based on this trial, NALIRIFOX is a standard first-line treatment option for patients with advanced pancreatic cancer.

The median OS was 11.1 months (95% CI, 10.0–12.1) in the NALIRIFOX group and 9.2 months (95% CI, 8.3–10.6) in the nab-paclitaxel/gemcitabine group (HR, 0.83; 95% CI, 0.7–0.99; P = .036). The median follow-up was 16.1 months.[5][Level of evidence A1]

NALIRIFOX (5-FU, irinotecan sucrosofate [also called nanoliposomal irinotecan], and oxaliplatin) versus gemcitabine and nab-paclitaxel: The multicenter, open-label, phase III NAPOLI 3 study (NCT04083235) included 770 patients with confirmed pancreatic ductal adenocarcinoma who had not been treated previously for metastatic disease. The patients were randomly assigned 1:1 to receive NALIRIFOX (irinotecan sucrosofate [50 mg/m2], oxaliplatin [60 mg/m2], leucovorin [400 mg/m2], and 5-FU [2,400 mg/m2] as an intravenous infusion over 46 hours on days 1 and 15 of cycles lasting 28 days) or nab-paclitaxel (125 mg/m2) and gemcitabine (1,000 mg/m2 given intravenously on days 1, 8, and 15 of cycles lasting 28 days). The primary end point was OS from randomization to death due to any cause, for NALIRIFOX versus gemcitabine/nab-paclitaxel. Secondary end points included PFS and overall response rate by RECIST version 1.1.[5]Based on this trial, NALIRIFOX is a standard first-line treatment option for patients with advanced pancreatic cancer.

The median PFS was 7.4 months in the NALIRIFOX group and 5.6 months in the nab-paclitaxel/gemcitabine group (HR, 0.69; 95% CI, 0.58–0.83; P < .0001).

NALIRIFOX (5-FU, irinotecan sucrosofate [also called nanoliposomal irinotecan], and oxaliplatin) versus gemcitabine and nab-paclitaxel: The multicenter, open-label, phase III NAPOLI 3 study (NCT04083235) included 770 patients with confirmed pancreatic ductal adenocarcinoma who had not been treated previously for metastatic disease. The patients were randomly assigned 1:1 to receive NALIRIFOX (irinotecan sucrosofate [50 mg/m2], oxaliplatin [60 mg/m2], leucovorin [400 mg/m2], and 5-FU [2,400 mg/m2] as an intravenous infusion over 46 hours on days 1 and 15 of cycles lasting 28 days) or nab-paclitaxel (125 mg/m2) and gemcitabine (1,000 mg/m2 given intravenously on days 1, 8, and 15 of cycles lasting 28 days). The primary end point was OS from randomization to death due to any cause, for NALIRIFOX versus gemcitabine/nab-paclitaxel. Secondary end points included PFS and overall response rate by RECIST version 1.1.[5]Based on this trial, NALIRIFOX is a standard first-line treatment option for patients with advanced pancreatic cancer.

The overall response rate was 42% in the NALIRIFOX group and 36% in the nab-paclitaxel/gemcitabine group (P = .11). The median duration of response was 7.3 months in the NALIRIFOX group and 5 months in the nab-paclitaxel/gemcitabine group (HR, 0.67; 95% CI, 0.48–0.93).

NALIRIFOX (5-FU, irinotecan sucrosofate [also called nanoliposomal irinotecan], and oxaliplatin) versus gemcitabine and nab-paclitaxel: The multicenter, open-label, phase III NAPOLI 3 study (NCT04083235) included 770 patients with confirmed pancreatic ductal adenocarcinoma who had not been treated previously for metastatic disease. The patients were randomly assigned 1:1 to receive NALIRIFOX (irinotecan sucrosofate [50 mg/m2], oxaliplatin [60 mg/m2], leucovorin [400 mg/m2], and 5-FU [2,400 mg/m2] as an intravenous infusion over 46 hours on days 1 and 15 of cycles lasting 28 days) or nab-paclitaxel (125 mg/m2) and gemcitabine (1,000 mg/m2 given intravenously on days 1, 8, and 15 of cycles lasting 28 days). The primary end point was OS from randomization to death due to any cause, for NALIRIFOX versus gemcitabine/nab-paclitaxel. Secondary end points included PFS and overall response rate by RECIST version 1.1.[5]Based on this trial, NALIRIFOX is a standard first-line treatment option for patients with advanced pancreatic cancer.

There were 369 patients (>99%) with any adverse event in the NALIRIFOX group and 376 patients (99%) with any adverse event in the nab-paclitaxel/gemcitabine group. The most common grade 3 to 4 toxicities in the NALIRIFOX group were diarrhea (20%), hypokalemia (15%), neutropenia (14%), and nausea (12%). The most common grade 3 to 4 toxicities in the nab-paclitaxel/gemcitabine group were neutropenia (25%) and anemia (17%). Of note, hematological toxicities (i.e., neutropenia, anemia, thrombocytopenia) were lower in the NALIRIFOX group than the nab-paclitaxel/gemcitabine group. Peripheral neuropathy was noted in 3% of patients in the NALIRIFOX group compared with 6% of patients in the gemcitabine/nab-paclitaxel group.

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.[6][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.[6][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.[6][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.[6][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.[6][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 neuropathy 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.[6][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 plus 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.[6][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 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.[7][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.[7][Level of evidence A1]

The addition of erlotinib modestly prolonged survival when combined with 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.[7][Level of evidence A1]

The corresponding median survival rate for patients receiving erlotinib was 6.2 months versus 5.9 months for patients receiving placebo. The 1-year survival rate for patients receiving erlotinib was 23% versus 17% for patients receiving placebo.

Irinotecan sucrosofate with or without 5-FU and leucovorin: The NAPOLI-1 trial (NCT01494506) evaluated the role of irinotecan sucrosofate in patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapies.[8] Irinotecan sucrosofate is an encapsulated formulation of irinotecan designed to increase intratumoral levels of irinotecan and its active metabolite. In this study, a total of 417 patients were randomly assigned to receive either irinotecan sucrosofate monotherapy (120 mg/m2 every 3 weeks; n = 151), 5-FU and leucovorin (n = 149), or irinotecan sucrosofate (80 mg/m2 every 2 weeks plus 5-FU) and leucovorin (n = 117).[8][Level of evidence B1]

Irinotecan sucrosofate with or without 5-FU and leucovorin: The NAPOLI-1 trial (NCT01494506) evaluated the role of irinotecan sucrosofate in patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapies.[8] Irinotecan sucrosofate is an encapsulated formulation of irinotecan designed to increase intratumoral levels of irinotecan and its active metabolite. In this study, a total of 417 patients were randomly assigned to receive either irinotecan sucrosofate monotherapy (120 mg/m2 every 3 weeks; n = 151), 5-FU and leucovorin (n = 149), or irinotecan sucrosofate (80 mg/m2 every 2 weeks plus 5-FU) and leucovorin (n = 117).[8][Level of evidence B1]

Median OS was 6.1 months (95% CI, 4.8–8.9) in patients who received irinotecan sucrosofate with 5-FU and 4.2 months (95% CI, 3.6–4.9) in patients who received 5-FU and leucovorin (P = .012). Median OS was 4.9 months (95% CI, 4.2–5.6) for patients who received irinotecan sucrosofate monotherapy, compared with 4.2 months (95% CI, 3.6–4.9) for those who received 5-FU and leucovorin (unstratified HR, 0.99; P = .94). On multivariate analysis, irinotecan sucrosofate plus 5-FU and leucovorin was associated with improved OS (HR, 0.58; 95% CI, 0.42–0.81).

Irinotecan sucrosofate with or without 5-FU and leucovorin: The NAPOLI-1 trial (NCT01494506) evaluated the role of irinotecan sucrosofate in patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapies.[8] Irinotecan sucrosofate is an encapsulated formulation of irinotecan designed to increase intratumoral levels of irinotecan and its active metabolite. In this study, a total of 417 patients were randomly assigned to receive either irinotecan sucrosofate monotherapy (120 mg/m2 every 3 weeks; n = 151), 5-FU and leucovorin (n = 149), or irinotecan sucrosofate (80 mg/m2 every 2 weeks plus 5-FU) and leucovorin (n = 117).[8][Level of evidence B1]

Grade 3 or 4 adverse events occurred most frequently in the patients who received irinotecan sucrosofate plus 5-FU and leucovorin and included neutropenia (27%), diarrhea (13%), vomiting (11%), and fatigue (14%).

Irinotecan sucrosofate with or without 5-FU and leucovorin: The NAPOLI-1 trial (NCT01494506) evaluated the role of irinotecan sucrosofate in patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapies.[8] Irinotecan sucrosofate is an encapsulated formulation of irinotecan designed to increase intratumoral levels of irinotecan and its active metabolite. In this study, a total of 417 patients were randomly assigned to receive either irinotecan sucrosofate monotherapy (120 mg/m2 every 3 weeks; n = 151), 5-FU and leucovorin (n = 149), or irinotecan sucrosofate (80 mg/m2 every 2 weeks plus 5-FU) and leucovorin (n = 117).[8][Level of evidence B1]

Despite differences in survival and toxicity between regimens, quality of life was not significantly different between treatment groups.

Irinotecan sucrosofate with or without 5-FU and leucovorin: The NAPOLI-1 trial (NCT01494506) evaluated the role of irinotecan sucrosofate in patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapies.[8] Irinotecan sucrosofate is an encapsulated formulation of irinotecan designed to increase intratumoral levels of irinotecan and its active metabolite. In this study, a total of 417 patients were randomly assigned to receive either irinotecan sucrosofate monotherapy (120 mg/m2 every 3 weeks; n = 151), 5-FU and leucovorin (n = 149), or irinotecan sucrosofate (80 mg/m2 every 2 weeks plus 5-FU) and leucovorin (n = 117).[8][Level of evidence B1]

The benefit of using irinotecan sucrosofate rather than unencapsulated irinotecan has not been established because the regimen for the control arm of this study was 5-FU/leucovorin. Additionally, the value of using irinotecan sucrosofate after FOLFIRINOX in the first-line setting is not clear.

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 an OFF regimen or BSC.[2]; [3][Level of evidence C1] The OFF regimen consisted of leucovorin (200 mg/m2) followed by 5-FU (2,000 mg/m2 [24 hours 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 an OFF regimen or BSC.[2]; [3][Level of evidence C1] The OFF regimen consisted of leucovorin (200 mg/m2) followed by 5-FU (2,000 mg/m2 [24 hours 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 an OFF regimen or BSC.[2]; [3][Level of evidence C1] The OFF regimen consisted of leucovorin (200 mg/m2) followed by 5-FU (2,000 mg/m2 [24 hours 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 an OFF regimen or BSC.[2]; [3][Level of evidence C1] The OFF regimen consisted of leucovorin (200 mg/m2) followed by 5-FU (2,000 mg/m2 [24 hours 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.

FOLFOX (leucovorin, 5-FU, and oxaliplatin) versus 5-FU/leucovorin after gemcitabine chemotherapy: The prospective, multicenter PANCREOX trial included 108 patients with advanced pancreatic cancer who had previously received first-line gemcitabine-based chemotherapy. Patients were randomly assigned to receive 5-FU/leucovorin without oxaliplatin (n = 54) or with oxaliplatin (n = 54), administered as modified FOLFOX-6 (mFOLFOX-6).[9][Level of evidence C1] With a target accrual of 128 patients, the study closed prematurely because of slow accrual.

FOLFOX (leucovorin, 5-FU, and oxaliplatin) versus 5-FU/leucovorin after gemcitabine chemotherapy: The prospective, multicenter PANCREOX trial included 108 patients with advanced pancreatic cancer who had previously received first-line gemcitabine-based chemotherapy. Patients were randomly assigned to receive 5-FU/leucovorin without oxaliplatin (n = 54) or with oxaliplatin (n = 54), administered as modified FOLFOX-6 (mFOLFOX-6).[9][Level of evidence C1] With a target accrual of 128 patients, the study closed prematurely because of slow accrual.

After a median follow-up of 8.8 months, the median PFS was 3.1 months in the mFOLFOX-6 arm and 2.9 months in the infusional 5-FU arm (HR, 1.00; 95% CI, 0.66–1.53, P = .989).

FOLFOX (leucovorin, 5-FU, and oxaliplatin) versus 5-FU/leucovorin after gemcitabine chemotherapy: The prospective, multicenter PANCREOX trial included 108 patients with advanced pancreatic cancer who had previously received first-line gemcitabine-based chemotherapy. Patients were randomly assigned to receive 5-FU/leucovorin without oxaliplatin (n = 54) or with oxaliplatin (n = 54), administered as modified FOLFOX-6 (mFOLFOX-6).[9][Level of evidence C1] With a target accrual of 128 patients, the study closed prematurely because of slow accrual.

Overall response rate and quality of life was not significantly different in the two arms.

FOLFOX (leucovorin, 5-FU, and oxaliplatin) versus 5-FU/leucovorin after gemcitabine chemotherapy: The prospective, multicenter PANCREOX trial included 108 patients with advanced pancreatic cancer who had previously received first-line gemcitabine-based chemotherapy. Patients were randomly assigned to receive 5-FU/leucovorin without oxaliplatin (n = 54) or with oxaliplatin (n = 54), administered as modified FOLFOX-6 (mFOLFOX-6).[9][Level of evidence C1] With a target accrual of 128 patients, the study closed prematurely because of slow accrual.

The overall incidence of grade 3 or 4 adverse events was 63% in the mFOLFOX-6 arm and 11% in the 5-FU/leucovorin arm. However, more patients in the mFOLFOX-6 arm withdrew from the study because of adverse events than did patients in the 5-FU/leucovorin arm (20% vs. 2%).

FOLFOX (leucovorin, 5-FU, and oxaliplatin) versus 5-FU/leucovorin after gemcitabine chemotherapy: The prospective, multicenter PANCREOX trial included 108 patients with advanced pancreatic cancer who had previously received first-line gemcitabine-based chemotherapy. Patients were randomly assigned to receive 5-FU/leucovorin without oxaliplatin (n = 54) or with oxaliplatin (n = 54), administered as modified FOLFOX-6 (mFOLFOX-6).[9][Level of evidence C1] With a target accrual of 128 patients, the study closed prematurely because of slow accrual.

Based on this study, no benefit was seen with the addition of oxaliplatin, administered in the mFOLFOX-6 regimen, versus infusional 5-FU/leucovorin among patients with advanced pancreatic cancer after first-line gemcitabine-based chemotherapy. These results may suggest that oxaliplatin-based regimens for metastatic pancreatic cancer may yield the greatest benefit in the first-line setting.

Gemcitabine/paclitaxel versus gemcitabine after FOLFIRINOX failure or intolerance: The prospective, open-label, phase III GEMPAX study (NCT03943667) included 211 patients with metastatic pancreatic cancer that progressed during or within 3 months of completing first-line FOLFIRINOX (including FOLFIRINOX treatment as adjuvant therapy) or were intolerant of this therapy. Patients were randomly assigned to one of the following treatment arms:[10]The following results were observed:

Gemcitabine/paclitaxel versus gemcitabine after FOLFIRINOX failure or intolerance: The prospective, open-label, phase III GEMPAX study (NCT03943667) included 211 patients with metastatic pancreatic cancer that progressed during or within 3 months of completing first-line FOLFIRINOX (including FOLFIRINOX treatment as adjuvant therapy) or were intolerant of this therapy. Patients were randomly assigned to one of the following treatment arms:[10]The following results were observed:

Gemcitabine/paclitaxel: Gemcitabine (1,000 mg/m2) and solvent-based paclitaxel (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle.

Gemcitabine/paclitaxel versus gemcitabine after FOLFIRINOX failure or intolerance: The prospective, open-label, phase III GEMPAX study (NCT03943667) included 211 patients with metastatic pancreatic cancer that progressed during or within 3 months of completing first-line FOLFIRINOX (including FOLFIRINOX treatment as adjuvant therapy) or were intolerant of this therapy. Patients were randomly assigned to one of the following treatment arms:[10]The following results were observed:

Gemcitabine alone: Gemcitabine (1,000 mg/m2) on days 1, 8, and 15 of a 29-day cycle.

Gemcitabine/paclitaxel versus gemcitabine after FOLFIRINOX failure or intolerance: The prospective, open-label, phase III GEMPAX study (NCT03943667) included 211 patients with metastatic pancreatic cancer that progressed during or within 3 months of completing first-line FOLFIRINOX (including FOLFIRINOX treatment as adjuvant therapy) or were intolerant of this therapy. Patients were randomly assigned to one of the following treatment arms:[10]The following results were observed:

There was no significant difference in OS among patients who received gemcitabine/paclitaxel (6.4 months after a median follow-up of 13.4 months) or gemcitabine alone (5.9 months after 13.8 months of follow-up) (HR, 0.87; 95% CI, 0.63–1.20; P = .4095). However, OS was improved in the following subgroups of patients who received gemcitabine/paclitaxel: (1) patients aged 65 years or younger (HR, 0.66; 95% CI, 0.44–0.99), and (2) patients with CA 19-9 levels of 59 times the upper limit of normal or higher at baseline (HR, 0.64; 95% CI, 0.42–0.97).[10][Level of evidence B1]

Gemcitabine/paclitaxel versus gemcitabine after FOLFIRINOX failure or intolerance: The prospective, open-label, phase III GEMPAX study (NCT03943667) included 211 patients with metastatic pancreatic cancer that progressed during or within 3 months of completing first-line FOLFIRINOX (including FOLFIRINOX treatment as adjuvant therapy) or were intolerant of this therapy. Patients were randomly assigned to one of the following treatment arms:[10]The following results were observed:

PFS was 3.1 months in the gemcitabine/paclitaxel group and 2.0 months in the gemcitabine-alone group (HR, 0.64; 95% CI, 0.47–0.89, P = .0067). The objective response rate was 17.1% in the gemcitabine/paclitaxel group and 4.2% in the gemcitabine-alone group (P = .008).

Gemcitabine/paclitaxel versus gemcitabine after FOLFIRINOX failure or intolerance: The prospective, open-label, phase III GEMPAX study (NCT03943667) included 211 patients with metastatic pancreatic cancer that progressed during or within 3 months of completing first-line FOLFIRINOX (including FOLFIRINOX treatment as adjuvant therapy) or were intolerant of this therapy. Patients were randomly assigned to one of the following treatment arms:[10]The following results were observed:

Third-line therapies were given to 32.1% of patients in the gemcitabine/paclitaxel group and 46.5% of patients in the gemcitabine-alone group.

Gemcitabine/paclitaxel versus gemcitabine after FOLFIRINOX failure or intolerance: The prospective, open-label, phase III GEMPAX study (NCT03943667) included 211 patients with metastatic pancreatic cancer that progressed during or within 3 months of completing first-line FOLFIRINOX (including FOLFIRINOX treatment as adjuvant therapy) or were intolerant of this therapy. Patients were randomly assigned to one of the following treatment arms:[10]The following results were observed:

The overall incidence of grade 3 or greater treatment-related adverse events was 58% in the gemcitabine/paclitaxel group and 27.1% in the gemcitabine-alone group. In the gemcitabine/paclitaxel group, 13% of patients experienced serious treatment-related adverse events, versus 7.1% of patients in the gemcitabine-alone group. The most common grade 3 or greater treatment-related adverse events among patients in the gemcitabine/paclitaxel group versus those in the gemcitabine-alone group were anemia (15.2% vs. 4.3%), thrombocytopenia (19.6% vs. 4.3%), neutropenia (15.9% vs. 15.7%), peripheral neuropathy (12.3% vs. 0%), and asthenia (10.1% vs. 2.9%). There was one grade 5 adverse event associated with gemcitabine/paclitaxel therapy, which was attributed as acute respiratory distress.

Gemcitabine/paclitaxel versus gemcitabine after FOLFIRINOX failure or intolerance: The prospective, open-label, phase III GEMPAX study (NCT03943667) included 211 patients with metastatic pancreatic cancer that progressed during or within 3 months of completing first-line FOLFIRINOX (including FOLFIRINOX treatment as adjuvant therapy) or were intolerant of this therapy. Patients were randomly assigned to one of the following treatment arms:[10]The following results were observed:

Based on this study, no OS benefit was seen with second-line gemcitabine/paclitaxel over gemcitabine alone. However, there was an OS benefit in certain subgroups (patients aged 65 years or younger and patients with high CA 19-9 levels at baseline). PFS and objective response rate were significantly higher in the gemcitabine/paclitaxel group. Thus, combination therapy with gemcitabine/paclitaxel can be considered for the appropriate patient, recognizing the higher rate of treatment-related adverse events.