Sequential strategy: improving efficacy of treatment

To date, the optimum sequential chemotherapy strategy remains an unanswered question in the management of advanced pancreatic cancer. Because of a lack of relative clinical trials, no clear evidence is available for second-line chemotherapy after FOLFIRINOX or gemcitabine plus nab-paclitaxel first-line regimens. Moreover, the benefit of FOLFIRINOX, followed by gemcitabine plus nab-paclitaxel versus the reverse sequence, also remains unknown. Recent data from a non-randomized cohort study suggest that the administration of nab-paclitaxel and gemcitabine in patients refractory to the FOLFIRINOX regimen might be a successful strategy to delay tumor progression, as documented by a disease control rate of 58%.76 Median PFS and OS from the start of second-line therapy were 5.1 and 8.8 months, respectively. However, these exciting results were associated with a high rate of toxicity; grades 3 and 4 toxicity occurred in 40% of the patients, mostly neutropenia and neurotoxicity. Moreover, a retrospective study using the same sequence observed similar results.77 Therefore, to reduce cumulative toxic effects, optimize dose intensity, and increase efficacy, further investigation in therapeutic sequences is needed.


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Maintenance therapy in advanced disease: new life for an old idea

With the success of more effective regimens in patients with advanced disease, questions concerning how best to manage the treatment-free interval prior to disease progression have been raised. Therapeutic strategies, such as maintenance therapy, may represent potential means to improve clinical outcomes in advanced pancreatic cancer. Although well established for the treatment of certain hematologic malignancies, maintenance therapy has only recently been tested as a treatment paradigm for metastatic pancreatic adenocarcinoma. In the Pancreatic AdenoCarcinoma Trials – 12 (PACT-12) trial, 55 patients without evidence of progression after 6 months of initial chemotherapy (mostly, gemcitabine combinations) were randomized to sunitinib or observation.78 Median OS was 9.2 months in the observation group versus 10.6 months in the sunitinib group, which was not statistically significant (HR 0.71; 95% CI 0.40–1.26; P = 0.11) and precluded strong conclusions; however, the 1- and 2-year survival rates were 35.7% and 7.1% in the observation arm and 40.7% and 22.9% in the sunitinib arm, suggesting that a subset of patients may benefit from maintenance therapy. Although sunitinib proved inactive in second-line therapy of pancreatic cancer, the intriguing results of the PACT-12 trial suggest that this drug may impact the disease course when administered as maintenance treatment in patients achieving disease control with first-line chemotherapy. Alternatively, it is likely that as more active agents against pancreatic cancer become available, maintenance therapy may potentially achieve even more exciting results.

OS prediction for second-line chemotherapy: better patient selection

Currently, the vast majority of clinical trials evaluating second-line regimens have used the Eastern Oncology Cooperative Group or Karnofsky performance status score and other “pragmatic parameters” (eg, age, duration of first-line therapy) to select candidates. This selection not only generates considerable heterogeneity in survival in patients who receive second-line chemotherapy between studies but also is unable to determine which patients might benefit from second-line chemotherapy. A retrospective study from the CONKO study group revealed that a prognostic score which included Karnofsky performance status, carbohydrate antigen 19-9 levels at start of second-line therapy, and the duration of first-line therapy was able to identify three subgroups in the second-line setting.79 The modified Glasgow Prognostic Score – a systemic inflammation-based prognostic system which incorporated CRP and albumin – has also been shown to be reliable indicator of OS in the setting of second-line therapy.65 In a prospective population-based cohort study, Vienot et al developed and validated a prognostic nomogram and score to predict OS in patients with advanced pancreatic cancer who received second-line chemotherapy in routine clinical practice using a broad spectrum of parameters (age, smoking status, liver metastases, performance status, pain, jaundice, ascites, duration of first-line, and type of second-line regimen).80 This score classified patients into low-, intermediate-, and high-risk groups with median OS of 11.3, 3.6, and 1.4 months, respectively. Although the study did not evaluate albumin or serum CRP because of the high rate of missing data, this prognostic nomogram and score represents the most comprehensive scoring system reported thus far, which accurately predicts OS prior to the administration of second-line chemotherapy and may help clinicians in their therapeutic decisions. In addition, this tool may be beneficial for better selection of patients for treatment, for stratified random assignment to ensure well-balanced treatment groups, and for the potential optimization of clinical trial design. Furthermore, the development of risk-adapted strategies for second-line management in the future could be considered in the different risk groups identified.

CONCLUSION

If disease progression occurs after administration of first-line therapy, survival remains short for patients with pancreatic cancer, and the outcome with second-line chemotherapy remains unsatisfactory, with a low response rate. The current treatment options vary in terms of drugs and dosages with different survival benefits. The only way to move forward in meaningful ways will be to identify new and more effective therapeutic alternatives that emerge from phase I/II clinical trials. Any therapy should be individualized and based on performance status, comorbidities, expected toxicities, and patient preference. More broadly, with a greater understanding of pancreatic cancer tumor biology, coupled with the growing availability of non-cytotoxic agents and interest by academia and pharmaceutical companies to meet the challenge, better systemic treatments of pancreatic cancer beyond conventional chemotherapy are anticipated in the near future. Due to the heterogeneity of pancreatic cancer per se, each novel therapy may exclusively be limited to a distinct subset of individuals. In addition, there is a need to assess biomarkers that might identify the patient subsets that will most likely benefit from second-line therapy.

Acknowledgments

This work was supported by the National Science Foundation for Distinguished Young Scholars of China (grant no 81625016) and the Shanghai Sailing Program (grant no 17YF1402500).

Author contributions

All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.


Jie Hua1–4*, Si Shi1–4*, Dingkong Liang1–4, Chen Liang1–4, Qingcai Meng1–4, Bo Zhang1–4, Quanxing Ni1–4, Jin Xu1–4, Xianjun Yu1–4

1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Pancreatic Cancer Institute, Fudan University, Shanghai, People’s Republic of China; 4Shanghai Pancreatic Cancer Institute, Shanghai, People’s Republic of China 


References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.

2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.

3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.

4. Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet. 2016;388(10039):73–85.

5. Neuzillet C, Tijeras-Raballand A, Bourget P, et al. State of the art and future directions of pancreatic ductal adenocarcinoma therapy. Pharmacol Ther. 2015;155:80–104.

6. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403–2413.

7. Conroy T, Desseigne F, Ychou M, et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825.

8. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nabpaclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–1703.

9. Dahan L, Bonnetain F, Ychou M, et al; Fédération Francophone de Cancérologie Digestive. 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). Gut. 2010;59(11):1527–1534.

10. Oettle H, Riess H, Stieler JM, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014;32(23):2423–2429.

11. Wang-Gillam A, Li CP, Bodoky G, et al; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545–557.

12. Gill S, Ko YJ, Cripps C, et al. PANCREOX: a Randomized phase III study of fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy. J Clin Oncol. 2016;34(32):3914–3920.

13. Ciuleanu TE, Pavlovsky AV, Bodoky G, et al. A randomised Phase III trial of glufosfamide compared with best supportive care in metastatic pancreatic adenocarcinoma previously treated with gemcitabine. Eur J Cancer. 2009;45(9):1589–1596.

14. Pelzer U, Schwaner I, Stieler J, 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. Eur J Cancer. 2011;47(11):1676–1681.

15. Androulakis N, Syrigos K, Polyzos A, et al; Hellenic Oncology Research Group. Oxaliplatin for pretreated patients with advanced or metastatic pancreatic cancer: a multicenter phase II study. Cancer Invest. 2005;23(1):9–12.

16. Boeck S, Weigang-Köhler K, Fuchs M, et al. Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial. Ann Oncol. 2007;18(4):745–751.

17. Morizane C, Okusaka T, Furuse J, et al. A phase II study of S-1 in gemcitabine-refractory metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2009;63(2):313–319.

18. Sudo K, Yamaguchi T, Nakamura K, et al. Phase II study of S-1 in patients with gemcitabine-resistant advanced pancreatic cancer. Cancer Chemother Pharmacol. 2011;67(2):249–254.

19. Yi SY, Park YS, Kim HS, et al. Irinotecan monotherapy as second-line treatment in advanced pancreatic cancer. Cancer Chemother Pharmacol. 2009;63(6):1141–1145.

20. Ko AH, Tempero MA, Shan YS, et al. A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer. Br J Cancer. 2013;109(4):920–925.

21. Boeck S, Wilkowski R, Bruns CJ, et al. Oral capecitabine in gemcitabine-pretreated patients with advanced pancreatic cancer. Oncology. 2007;73(3–4):221–227.

22. Hosein PJ, de Lima Lopes G Jr, Pastorini VH, et al. A phase II trial of nab-Paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013;36(2):151–156.

23. Pelzer U, Stieler J, Roll L, et al. Second-line therapy in refractory pancreatic cancer. results of a phase II study. Onkologie. 2009;32(3):99–102.

24. Tsavaris N, Kosmas C, Skopelitis H, et al. Second-line treatment with oxaliplatin, leucovorin and 5-fluorouracil in gemcitabine-pretreated advanced pancreatic cancer: a phase II study. Invest New Drugs. 2005;23(4):369–375.

25. Novarino A, Satolli MA, Chiappino I, et al. Oxaliplatin, 5-fluorouracil, and leucovorin as second-line treatment for advanced pancreatic cancer. Am J Clin Oncol. 2009;32(1):44–48.

26. El-Hadaad HA, Wahba HA. Oxaliplatin plus 5-fluorouracil and folinic acid (OFF) in gemcitabine-pretreated advanced pancreatic cancer: a phase II study. J Gastrointest Cancer. 2013;44(3):313–317.

27. Yoo C, Hwang JY, Kim JE, 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. Br J Cancer. 2009;101(10):1658–1663.

28. Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008;113(8):2046–2052.

29. Cantore M, Rabbi C, Fiorentini G, et al. Combined irinotecan and oxaliplatin in patients with advanced pre-treated pancreatic cancer. Oncology. 2004;67(2):93–97.

30. Reni M, Pasetto L, Aprile G, et al. Raltitrexed-eloxatin salvage chemotherapy in gemcitabine-resistant metastatic pancreatic cancer. Br J Cancer. 2006;94(6):785–791.

31. Demols A, Peeters M, Polus M, et al. Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced pancreatic adenocarcinoma: a phase II study. Br J Cancer. 2006;94(4):481–485.

32. Ettrich TJ, Perkhofer L, von Wichert G, et al. DocOx (AIO-PK0106): a phase II trial of docetaxel and oxaliplatin as a second line systemic therapy in patients with advanced pancreatic ductal adenocarcinoma. BMC Cancer. 2016;16:21.

33. Kim HJ, Yun J, Kim HJ, et al. Phase II study of palliative S-1 in combination with cisplatin as second-line chemotherapy for gemcitabine-refractory pancreatic cancer patients. Oncol Lett. 2012;3(6):1314–1318.

34. Stathopoulos GP, Boulikas T, Vougiouka M, Rigatos SK, Stathopoulos JG. Liposomal cisplatin combined with gemcitabine in pretreated advanced pancreatic cancer patients: a phase I–II study. Oncol Rep. 2006;15(5):1201–1204.

35. Ulrich-Pur H, Raderer M, Verena Kornek G, et al. Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma. Br J Cancer. 2003;88(8):1180–1184.

36. Reni M, Panucci MG, Passoni P, et al. Salvage chemotherapy with mitomycin, docetaxel, and irinotecan (MDI regimen) in metastatic pancreatic adenocarcinoma: a phase I and II trial. Cancer Invest. 2004;22(5):688–696.

37. Ko AH, Dito E, Schillinger B, Venook AP, Bergsland EK, Tempero MA. Excess toxicity associated with docetaxel and irinotecan in patients with metastatic, gemcitabine-refractory pancreatic cancer: results of a phase II study. Cancer Invest. 2008;26(1):47–52.

38. Zaniboni A, Aitini E, Barni S, et al. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012;69(6):1641–1645.

39. Sonbol MB, Firwana B, Wang Z, et al. Second-line treatment in patients with pancreatic ductal adenocarcinoma: a meta-analysis. Cancer. 2017;123(23):4680–4686.

40. Rothenberg ML, Benedetti JK, Macdonald JS, et al. Phase II trial of 5-fluorouracil plus eniluracil in patients with advanced pancreatic cancer: a Southwest Oncology Group study. Ann Oncol. 2002;13(10):1576–1582.

41. Kim YJ, Bang S, Park JY, Park SW, Chung JB, Song SY. Phase II study of 5-fluorouracil and paclitaxel in patients with gemcitabine-refractory pancreatic cancer. Cancer Chemother Pharmacol. 2009;63(3):529–533.

42. Katopodis O, Polyzos A, Kentepozidis N, 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. Cancer Chemother Pharmacol. 2011;67(2):361–368.

43. Soares HP, Bayraktar S, Blaya M, et al. A phase II study of capecitabine plus docetaxel in gemcitabine-pretreated metastatic pancreatic cancer patients: CapTere. Cancer Chemother Pharmacol. 2014;73(4):839–845.

44. Ge F, Xu N, Bai Y, et al. S-1 as monotherapy or in combination with leucovorin as second-line treatment in gemcitabine-refractory advanced pancreatic cancer: a randomized, open-label, multicenter, phase II study. Oncologist. 2014;19(11):1133–1134.

45. Ueno M, Okusaka T, Omuro Y, et al. A randomized phase II study of S-1 plus oral leucovorin versus S-1 monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer. Ann Oncol. 2016;27(3):502–508.

46. Ohkawa S, Okusaka T, Isayama H, et al. Randomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer. Br J Cancer. 2015;112(9):1428–1434.

47. Ioka T, Komatsu Y, Mizuno N, et al. Randomized phase II trial of irinotecan plus S-1 in patients with gemcitabine-refractory pancreatic cancer. Br J Cancer. 2017;116(4):464–471.

48. Cereda S, Reni M, Rognone A, et al. Salvage therapy with mitomycin and ifosfamide in patients with gemcitabine-resistant metastatic pancreatic cancer: a phase II trial. Chemotherapy. 2011;57(2):156–161.

49. Braghiroli MI, de Celis Ferrari AC, Pfiffer TE, et al. Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas. Ecancermedicalscience. 2015;9:563.

50. Moore MJ, Goldstein D, Hamm J, et al; National Cancer Institute of Canada Clinical Trials Group. 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. J Clin Oncol. 2007;25(15):1960–1966.

51. Renouf DJ, Tang PA, Hedley D, et al. A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer. Eur J Cancer. 2014;50(11):1909–1915.

52. Kulke MH, Blaszkowsky LS, Ryan DP, et al. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007;25(30):4787–4792.

53. Ko AH, Bekaii-Saab T, Van Ziffle J, et al. A multicenter, open-label phase II clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma. Clin Cancer Res. 2016;22(1):61–68.

54. Ko AH, Venook AP, Bergsland EK, et al. A phase II study of bevacizumab plus erlotinib for gemcitabine-refractory metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2010;66(6):1051–1057.

55. Javle MM, Shroff RT, Xiong H, et al. Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer. 2010;10:368.

56. Ignatiadis M, Polyzos A, Stathopoulos GP, et al. A multicenter phase II study of docetaxel in combination with gefitinib in gemcitabine-pretreated patients with advanced/metastatic pancreatic cancer. Oncology. 2006;71(3–4):159–163.

57. Brell JM, Matin K, Evans T, et al. Phase II study of docetaxel and gefitinib as second-line therapy in gemcitabine pretreated patients with advanced pancreatic cancer. Oncology. 2009;76(4):270–274.

58. Wu Z, Gabrielson A, Hwang JJ, et al. Phase II study of lapatinib and capecitabine in second-line treatment for metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2015;76(6):1309–1314.

59. Van Cutsem E, Vervenne WL, Bennouna J, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27(13):2231–2237.

60. Astsaturov IA, Meropol NJ, Alpaugh RK, et al. Phase II and coagulation cascade biomarker study of bevacizumab with or without docetaxel in patients with previously treated metastatic pancreatic adenocarcinoma. Am J Clin Oncol. 2011;34(1):70–75.

61. O’Reilly EM, Niedzwiecki D, Hall M, et al; Cancer and Leukemia Group B. A Cancer and Leukemia Group B phase II study of sunitinib malate in patients with previously treated metastatic pancreatic adenocarcinoma (CALGB 80603). Oncologist. 2010;15(12):1310–1319.

62. Dragovich T, Laheru D, Dayyani F, et al. Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001). Cancer Chemother Pharmacol. 2014;74(2):379–387.

63. Bodoky G, Timcheva C, Spigel DR, et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs. 2012;30(3):1216–1223.

64. Chung V, McDonough S, Philip PA, et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol. 2017;3(4):516–522.

65. Hurwitz HI, Uppal N, Wagner SA, et al. Randomized, double-blind, phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J Clin Oncol. 2015;33(34):4039–4047.

66. Hurwitz H, Van Cutsem E, Bendell J, et al. Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies. Invest New Drugs. Epub 2018 Mar 6.

67. Wolpin BM, Hezel AF, Abrams T, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2009;27(2):193–198.

68. Arcaroli J, Quackenbush K, Dasari A, et al. Biomarker-driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer. Cancer Med. 2012;1(2):207–217.

69. Carvajal RD, Tse A, Shah MA, et al. A phase II study of flavopiridol (Alvocidib) in combination with docetaxel in refractory, metastatic pancreatic cancer. Pancreatology. 2009;9(4):404–409.

70. Pino MS, Milella M, Gelibter A, et al. Capecitabine and celecoxib as second-line treatment of advanced pancreatic and biliary tract cancers. Oncology. 2009;76(4):254–261.

71. Chawla SP, Chua VS, Fernandez L, et al. Advanced phase I/II studies of targeted gene delivery in vivo: intravenous Rexin-G for gemcitabine-resistant metastatic pancreatic cancer. Mol Ther. 2010;18(2):435–441.

72. Ramanathan RK, Abbruzzese J, Dragovich T, et al. A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination. Cancer Chemother Pharmacol. 2011;67(3):503–509.

73. Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9:21.

74. Bachet JB, Gay F, Maréchal R, et al. Asparagine synthetase expression and phase I study with L-asparaginase encapsulated in red blood cells in patients with pancreatic adenocarcinoma. Pancreas. 2015;44(7):1141–1147.

75. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: pancreatic adenocarcinoma, V.3.2017. Available from: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed December 10, 2017.

76. Portal A, Pernot S, Tougeron D, et al. Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort. Br J Cancer. 2015;113(7):989–995.

77. Zhang Y, Hochster H, Stein S, Lacy J. Gemcitabine plus nab-paclitaxel for advanced pancreatic cancer after first-line FOLFIRINOX: single institution retrospective review of efficacy and toxicity. Exp Hematol Oncol. 2015;4:29.

78. Reni M, Cereda S, Milella M, et al. Maintenance sunitinib or observation in metastatic pancreatic adenocarcinoma: a phase II randomised trial. Eur J Cancer. 2013;49(17):3609–3615.

79. Sinn M, Dälken L, Striefler JK, et al. Second-line treatment in pancreatic cancer patients: who profits? – Results from the CONKO study group. Pancreas. 2016;45(4):601–605.

80. Vienot A, Beinse G, Louvet C, et al. Overall survival prediction and usefulness of second-line chemotherapy in advanced pancreatic adenocarcinoma. J Natl Cancer Inst. 2017;109(10).

Source: OncoTargets and Therapy.
Originally published August 6, 1028.