Second-line treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials.

BACKGROUND There is currently no standard of care for the second-line treatment of advanced pancreatic cancer. The aim of this analysis was to compare the different therapeutic approaches in this setting. METHODS We carried out a systematic analysis of second-line studies in advanced pancreatic cancer that have progressed on or following gemcitabine and published or presented from 2000 to 2012. RESULTS Forty-four clinical trials (t) were identified; of which 34 met the inclusion criteria treating an aggregate total of 1503 patients (n). Patients who received treatments (t: 33; n: 1269) had a median overall survival (OS) of 6 months compared with 2.8 months for patients who received best supportive care only (t: 2; n: 234) (P = 0.013). The gemcitabine and platinum-based combination (t: 5; n: 154) provided a median progression-free survival and OS of 4 and 6 months compared with 1.6 and 5.3 for the rest of the regimens (t: 29; n: 1349) (P = 0.059 and 0.10, respectively) and 2.9 and 5.7 for the combination of 5-fluorouracil and platinum agents (t: 12; n: 450) (P = 0.60 and 0.22, respectively). CONCLUSION(S) Although not conclusive, these data showed that the advantage of second-line chemotherapy in pancreatic cancer is very limited and there is a need for more studies.

[1]  D. Hedley,et al.  Phase II trial of erlotinib in advanced pancreatic cancer (PC). , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  F. Tas,et al.  Performance status of patients is the major prognostic factor at all stages of pancreatic cancer , 2013, International Journal of Clinical Oncology.

[3]  V. Heinemann,et al.  Systemic treatment of advanced pancreatic cancer. , 2012, Cancer treatment reviews.

[4]  Derek S. Chan,et al.  The Pancreas Cancer Microenvironment , 2012, Clinical Cancer Research.

[5]  V. Velculescu,et al.  Genetic Basis of Pancreas Cancer Development and Progression: Insights from Whole-Exome and Whole-Genome Sequencing , 2012, Clinical Cancer Research.

[6]  Y. Ko,et al.  Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104) , 2012, Gut.

[7]  A. Hinke,et al.  Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). , 2011, European journal of cancer.

[8]  B. Dörken,et al.  Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. , 2011, European journal of cancer.

[9]  Pierre Michel,et al.  FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. , 2011, The New England journal of medicine.

[10]  M. Reni,et al.  Salvage Therapy with Mitomycin and Ifosfamide in Patients with Gemcitabine-Resistant Metastatic Pancreatic Cancer: A Phase II Trial , 2011, Chemotherapy.

[11]  M. Tempero,et al.  A multinational phase II study of liposome irinotecan (PEP02) for patients with gemcitabine-refractory metastatic pancreatic cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  L. Weiner,et al.  Phase II and Coagulation Cascade Biomarker Study of Bevacizumab With or Without Docetaxel in Patients With Previously Treated Metastatic Pancreatic Adenocarcinoma , 2011, American journal of clinical oncology.

[13]  D. Mavroudis,et al.  Second-line chemotherapy with Capecitabine (Xeloda) and Docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial , 2011, Cancer Chemotherapy and Pharmacology.

[14]  B. Chauffert,et al.  Combination 5-fluorouracil, folinic acid and cisplatin (LV5FU2-CDDP) followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: final results of a randomised strategic phase III trial (FFCD 0301) , 2010, Gut.

[15]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[16]  P. Bejarano,et al.  A phase II trial of nab-paclitaxel (NP) in patients with advanced pancreatic cancer (PC) who have progressed on gemcitabine (G)-based therapy. , 2010 .

[17]  D. Park,et al.  A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer , 2009, British Journal of Cancer.

[18]  C. Grávalos,et al.  Phase II trial of second-line chemotherapy in metastatic pancreas cancer with the combination of oxaliplatin (Ox) and capecitabine (Cp). , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  Xiaobai Li,et al.  Fixed-Dose-Rate Gemcitabine in Combination with Oxaliplatin in Patients with Metastatic Pancreatic Cancer Refractory to Standard-Dose-Rate Gemcitabine: A Single-Institute Study , 2009, Oncology.

[20]  J. Schlesselman,et al.  Phase II Study of Docetaxel and Gefitinib as Second-Line Therapy in Gemcitabine Pretreated Patients with Advanced Pancreatic Cancer , 2009, Oncology.

[21]  M. Pino,et al.  Capecitabine and Celecoxib as Second-Line Treatment of Advanced Pancreatic and Biliary Tract Cancers , 2009, Oncology.

[22]  B. Dörken,et al.  Second-Line Therapy in Refractory Pancreatic Cancer. Results of a Phase II Study , 2009, Oncology Research and Treatment.

[23]  A. Novarino,et al.  Oxaliplatin, 5-Fluorouracil, and Leucovorin as Second-Line Treatment for Advanced Pancreatic Cancer , 2009, American journal of clinical oncology.

[24]  Jeffrey W. Clark,et al.  Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  Godefridus J Peters,et al.  Gemcitabine chemoresistance in pancreatic cancer: Molecular mechanisms and potential solutions , 2009, Scandinavian journal of gastroenterology.

[26]  K. Hess,et al.  Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second‐line therapy for patients with advanced pancreatic cancer , 2008, Cancer.

[27]  J. Neoptolemos,et al.  Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer: results of secondary end points analyses , 2008, British Journal of Cancer.

[28]  M. Tempero,et al.  A phase II study of bevacizumab (BEV) plus erlotinib (ERL) in patients with gemcitabine (GEM)-refractory metastatic pancreatic cancer (MPC) , 2008 .

[29]  B. Dörken,et al.  A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study , 2008 .

[30]  R. Goldberg,et al.  A phase II trial of sunitinib (S) in previously-treated pancreas adenocarcinoma (PAC), CALGB 80603 , 2008 .

[31]  M. Reni,et al.  PEFG (Cisplatin, Epirubicin, 5-Fluorouracil, Gemcitabine) Regimen as Second-Line Therapy in Patients With Progressive or Recurrent Pancreatic Cancer After Gemcitabine-Containing Chemotherapy , 2008, American journal of clinical oncology.

[32]  G. Gallick,et al.  Gemcitabine Resistance in Pancreatic Cancer: Picking the Key Players , 2008, Clinical Cancer Research.

[33]  Alona Muzikansky,et al.  Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  R. Labianca,et al.  Increased survival using platinum analog combined with gemcitabine as compared to single-agent gemcitabine in advanced pancreatic cancer: pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a German multicenter study. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[35]  M. Miyazaki,et al.  Treatment with an oral fluoropyrimidine, S-1, plus cisplatin in patients who failed postoperative gemcitabine treatment for pancreatic cancer: a pilot study , 2007, International Journal of Clinical Oncology.

[36]  V. Georgoulias,et al.  A Multicenter Phase II Study of Docetaxel in Combination with Gefitinib in Gemcitabine-Pretreated Patients with Advanced/Metastatic Pancreatic Cancer , 2007, Oncology.

[37]  J. K. Lee,et al.  Irinotecan monotherapy as second-line treatment in advanced pancreatic cancer , 2007, Cancer Chemotherapy and Pharmacology.

[38]  E. Roman,et al.  Phase II trial of capecitabine and docetaxel as second line therapy for locally advanced and metastatic pancreatic cancer , 2007 .

[39]  G. Colucci,et al.  Second-line chemotherapy in advanced pancreatic carcinoma: a multicenter survey of the Gruppo Oncologico Italia Meridionale on the activity and safety of the FOLFOX4 regimen in clinical practice. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[40]  P. Murawa,et al.  Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group , 2023, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  F. Lordick,et al.  Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[42]  T. Boulikas,et al.  Liposomal cisplatin combined with gemcitabine in pretreated advanced pancreatic cancer patients: a phase I-II study. , 2006, Oncology reports.

[43]  M. Ducreux,et al.  Oxaliplatin combined with 5-FU in second line treatment of advanced pancreatic adenocarcinoma. Results of a phase II trial. , 2006, Gastroenterologie clinique et biologique.

[44]  A. Brandes,et al.  Raltitrexed–eloxatin salvage chemotherapy in gemcitabine-resistant metastatic pancreatic cancer , 2006, British Journal of Cancer.

[45]  F. Gay,et al.  Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced pancreatic adenocarcinoma: a phase II study , 2006, British Journal of Cancer.

[46]  Y. Hao,et al.  DEPLETION OF HEAT SHOCK PROTEIN-70 (HSP70) CAUSES APOPTOSIS IN PANCREATIC CANCER CELLS , 2005 .

[47]  E. Felekouras,et al.  Second-line treatment with oxaliplatin, leucovorin and 5-fluorouracil in gemcitabine-pretreated advanced pancreatic cancer: A phase II study , 2005, Investigational New Drugs.

[48]  R. Labianca,et al.  Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  H. Burris,et al.  Phase II trial of oral rubitecan in previously treated pancreatic cancer patients. , 2005, The oncologist.

[50]  K. Syrigos,et al.  Oxaliplatin for Pretreated Patients with Advanced or Metastatic Pancreatic Cancer: A Multicenter Phase II Study , 2005, Cancer investigation.

[51]  A. Manni,et al.  Combined Irinotecan and Oxaliplatin in Patients with Advanced Pre-Treated Pancreatic Cancer , 2004, Oncology.

[52]  H. Burris,et al.  A randomized phase III study of rubitecan (ORA) vs. best choice (BC) in 409 patients with refractory pancreatic cancer report from a North-American multi-center study. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  S. Cosimo,et al.  Pilot study of celecoxib and infusional 5‐fluorouracil as second‐line treatment for advanced pancreatic carcinoma , 2004, Cancer.

[54]  Miklos Pless,et al.  Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  W. Scheithauer,et al.  Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma , 2003, British Journal of Cancer.

[56]  Barbara L. Smith,et al.  Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  R. Goldberg N9741: a phase III study comparing irinotecan to oxaliplatin-containing regimens in advanced colorectal cancer. , 2002, Clinical colorectal cancer.

[58]  D. Girling Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial , 2002, The Lancet.

[59]  P. Homel,et al.  Irinotecan combined with gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (G-FLIP) is an effective and noncrossresistant treatment for chemotherapy refractory metastatic pancreatic cancer. , 2001, The oncologist.

[60]  D. Huhn,et al.  Paclitaxel as weekly second-line therapy in patients with advanced pancreatic carcinoma , 2000, Anti-cancer drugs.

[61]  D. Winchester,et al.  Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985-1995, using the National Cancer Database. , 1999, Journal of the American College of Surgeons.

[62]  Christian Jacques,et al.  Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer , 1998, The Lancet.

[63]  S Marsoni,et al.  The phase II trial. , 1985, Cancer treatment reports.

[64]  L. Schwartz,et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). , 2009, European journal of cancer.

[65]  H. Ueno,et al.  A phase II study of S-1 in gemcitabine-refractory metastatic pancreatic cancer , 2008, Cancer Chemotherapy and Pharmacology.

[66]  H. Burris,et al.  Assessing clinical benefit in the treatment of pancreas cancer: gemcitabine compared to 5-fluorouracil. , 1997, European journal of cancer.