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.


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.


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.


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 


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