Metastatic Pancreatic Cancer Second-Line Treatment Options: Is the Difference Only in Cost?

Serkan Yıldırım1 & A. P. Erdoğan2 & M. Karateke3 & C. Yılmaz4 & A. Özveren5 & G. Bulut6 & F. Ekinci2 & E. Almuradova3

Abstract

İntroduction Although pancreatic cancer ranks seventh in cancer-related deaths, it is an extremely fatal disease, and more than 330,000 people die from this disease worldwide. Although there are many first-line treatment studies in the literature, there are almost no prospective studies regarding second-line therapy. Therefore, there is no standard approach in the second-line treatment of pancreatic cancer. We decided to conduct this study to investigate second-line treatments with problems such as cost, treatment efficacy, and toxicity.
Methods Patients older than 18 years old who applied to Ege University Hospital medical oncology department with a diagnosis of metastatic pancreatic cancer, who received first-line chemotherapy due to their illness, and who had progressed afterwards were included in the study. The files of the patients who applied between 2013 and 2017 were examined.
Results Our study’s primary endpoint was progression-free survival, and it was found that the median progression-free survival was 3.2 months in the Xelox patients, 3.7 months in the gemcitabine-nab paclitaxel patients, and 3.5 months in the other regimens. When the secondary endpoint was evaluated, overall survival, the median overall survival was 5.9 months in the Xelox patients, 5.3 months in the gemcitabine-nab paclitaxel patients, and 4.8 months in the other regimens.
Conclusion As a result, second-line treatments were compared, and no statistically significant difference was found between them. For this reason, the side effects of previously used drugs and the side effects of new drugs to be used, as well as their costs, should be evaluated when choosing a treatment.

Keywords Pancreatic cancer . Secondline . Chemotherapy

Introduction

Although pancreatic cancer ranks seventh in cancer-related deaths, it is a fatal disease, and more than 330,000 people die from this disease worldwide (1). The 5-year survival rate in pancreatic cancer is approximately 7–8% (2, 3). The majority of patients is not suitable for operation at the time of diagnosis (4). Recurrence rates are very high, even in patients with curative surgery. Chemotherapy is usually the only appropriate treatment for metastatic disease. Gemcitabine-based and 5-FU-based options are available as chemotherapy. Firstly, gemcitabine was used as a single agent for a long time (5). In later periods, FOLFIRINOX and gemcitabine-nab paclitaxel regimens have been used more in first-line treatment due to their contribution to progression-free survival and more prolonged overall survival (6, 7).
Although there are many first-line treatment studies in the literature, there are almost no prospective studies regarding second-line therapy. Therefore, there is no standard approach in the second-line treatment of pancreatic cancer. Because of the poor prognosis of the patients, many patients cannot reach the second-line treatment. Most of those who reach secondline treatment can come to treatment with much weariness due to previous chemotherapy toxicity. For this reason, the second-line chemotherapy decision should be made on a patient basis, and personal preferences and goals should be considered. Besides, cost should be considered while giving second-line treatment in this disease, where survival can be predicted to be poor.
We decided to conduct this study to investigate second-line treatments with problems such as cost, treatment efficacy, and toxicity.

Material-Method

Our study is a single-center retrospective analysis. Patients older than 18 years old referred to Ege University Hospital medical oncology department with a diagnosis of metastatic pancreatic cancer, who received first-line chemotherapy, and had a progression afterward were included in the study. The files of the patients who applied between 2013 and 2017 were examined. Ethics committee approval was obtained for the study.
In our study, the primary endpoint was progression-free survival, and the secondary endpoint was overall survival. Progression-free survival was defined as the time from the start of second-line chemotherapy to progression or death, and overall survival was defined as the time from the onset of second-line chemotherapy to death.
Data analysis was performed using the IBM SPSS Statistics (IBM Corp. Armonk, NY, USA) for Windows, version 20.0. Numerical variables were expressed as mean and standard deviation or median (minimum-maximum) values, where appropriate. General characteristics of subgroups were compared using a Mann-Whitney U test. The PFS and OS rates were estimated by the Kaplan-Meier method and compared with the log-rank test. A p value of ≤ 0.05 was considered statistically significant.

Results

A total of 83 patients were included in the study. These patients had previously received first-line chemotherapy for metastatic pancreatic cancer and subsequently progressed. While 57 of 82 patients were female, 26 were male. Fifty-four patients received Xelox, 11 of them Gemcitabine-nab paclitaxel, and the remaining 18 patients received other regimens. These other regimes were platinum-gemcitabine for three patients, Folfirinox for six patients, Capesitabine for four patients, Xeliri for two patients, Folfox for one patient, and Fam for one patient. While 77 of the cases had a histopathological diagnosis, six were diagnosed clinically and radiologically. Thirty three of 77 cases had cancer originating from the pancreatic head, 25 from the body, and 19 from the tail region. The mean age of all patients was 59.4 years, the mean age of those taking Xelox was 60.3, the mean age of those who received gemcitabine-nab paclitaxel was 55.1, and the mean age of the patients who received other regimens was 59.2 (Table 1).
Our study’s primary endpoint was progression-free survival, and it was found that the median progression-free survival was 3.2 months in the Xelox patients, 3.7 months in the gemcitabine-nab paclitaxel patients, and 3.5 months in the other regimens. When these regimens were compared with each other, no statistically significant difference is found in progression-free survival (Fig. 1).
When the secondary endpoint was evaluated, overall survival,the median overall survival was 5.9 months in the Xelox patients, 5.3 months in the gemcitabine-nab paclitaxel patients, and 4.8 months in the other regimens. When these regimens were compared with each other, no statistically significant difference is found (Fig. 2).

Discussion

Significant studies have been conducted in the treatment of metastatic pancreatic cancer in recent years. As in all cancers, personalized treatments according to their molecular features have come to the fore in pancreatic cancer. In pancreatic cancer, the use of PARP inhibitors such as olaparip in maintenance therapy has had a positive effect on the disease in case of a BRCA germline or somatic mutation or somatic mutation in the homologous recombination repair (HRR) genes (8). Although PARP inhibitors are not second-line therapy, immunotherapy has recently been shown to be effective in dMMR (MSI-H biological footprint) tumors as in all cancer types. Checkpoint inhibitors such as pembrolizumab have been used in several patients with dMMR, including pancreatic cancer (9, 10). In the Keynote-158 study, an objective response occurred in 4 of the 22 pancreatic cancer patients, one of which was complete, and this response lasted an average of 13.4 months (11). Similarly, TRK inhibitors, loratrectinib and entrectinib, were found to be effective in TRK fusion gene-positive cancers regardless of histology. This fusion protein can also be detected in pancreatic adenocarcinomas (12, 13) (Tables 2 and 3).
Although immunotherapy, PARP inhibitors, and TRK inhibitors are used in treatment, they can be applied only in a small group of patients (12, 13). The vast majority of patients is treated with conventional chemotherapy. Although there is no standard treatment in second-line therapy, using chemotherapy in patients whose performance status is suitable for chemotherapy has been proven in a prospective study to contribute to survival more compared to best supportive care (14). Which drugs to use may vary according to the previous treatment.
In our study, a total of 83 patients who received second-line treatment were examined. These 83 patients were studied in three groups according to the treatment they received. The progression-free survival of the Xelox group was a median of 3.2 months, and the overall survival was a median of 5.8 months. The gemcitabine-nab paclitaxel group’s progression-free survival was 3.7 months, and overall survival was a median of5.3 months. Other regimens’ progression-free survival median was 3.5 months, and overall survival was a median of 4.8 months. Neither regimen made a statistically significant difference in either progression-free survival or overall survival.
Liposomal irinotecan is a molecule that can remain in the circulation longer than standard irinotecan and, therefore, can be uptaken more by tumor cells (15). This agent can be used in the second-line treatment of pancreatic cancer. In the NAPOLI-1 study, which is a phase 3 study, gemcitabinerefractory patients were randomly assigned to liposomal irinotecan plus Fluorouracil-Leucovorin and Fluorourasilleucovorin alone. Combination therapy statistically significantly prolonged overall survival and progression-free survival (16). In the NAPOLI-1, the median of progression-free survival was 3.1 months and overall survival

6.1 months.

Our study has weaknesses such as not using liposomal irinotecan, being retrospective, and, therefore, not homogenous patient selection. However, the result achieved is crucial. Almost no regimen was superior to another in second-line therapy. In the liposomal irinotecan study, the patients’ overall survival and progression-free survival were numerically close to the results of our study. Therefore, cost should be considered in addition to side effects when determining second-line treatment for patients.

Conclusion

In conclusion, second-line treatments were compared, and no statistically significant difference was found between them. For this reason, the side effects of the drugs used previously and the sideeffects ofthe new drugs tobe used, aswell astheir costs, should be evaluated when choosing a treatment.

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