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Second-Line Therapy for Gemcitabine-Refractory Pancreatic Cancer: Is There a Standard?: Page 3 of 3

Second-Line Therapy for Gemcitabine-Refractory Pancreatic Cancer: Is There a Standard?: Page 3 of 3

Discussion

In the past decade, gemcitabine has been established as the treatment of choice in the first-line setting for advanced pancreatic cancer based on clinical benefits. Currently, gemcitabine is also being used more frequently as adjuvant chemotherapy after pancreatic resection as a single agent or in combination with 5-FU and radiation, based on data from the CONKO[6] and Radiation Therapy Oncology Group (RTOG 9704) studies.[38] Growing evidence suggests that sequential polychemotherapy can extend median survival by up to 16 months in selected patients.[39] Therefore, the role of second-line chemotherapy needs to be better defined in patients with gemcitabine-refractory metastatic pancreatic cancer and those who have failed adjuvant gemcitabine therapy.

Given the fact that gemcitabine was approved for metastatic pancreatic cancer on the basis of clinical benefits, second-line trials should evaluate outcomes other than response rate or survival. For a well-designed study, researchers should consider using clinical benefits such as quality of life, symptom control, analgesic use, and weight gain as primary endpoints, and a valid, reliable scale for clinical benefit in this population. However, since the US Food and Drug Administration may not approve another drug for pancreatic cancer based on clinical benefits, most pharmaceutical companies will shy away from using such parameters as endpoints.

Cancer therapies are very expensive and provide modest benefits in second-line treatment for pancreatic cancer. Therefore, an economic evaluation should also be undertaken, and any benefit in favor of new therapy should be balanced by the additional cost.

Development of predictive or prognostic markers in pancreatic cancer can help us determine Table 3who may benefit from second-line treatment. Performance status, serum level of C-reactive protein, and peritoneal dissemination were identified as important prognostic factors in patients with gemcitabine-refractory pancreatic cancer.[40] These factors should be considered in determining the treatment following first-line chemotherapy. In an Italian/Swiss multicenter retrospective survey,[41] multivariate analysis in 160 gemcitabine-resistant pancreatic cancer patients revealed that performance status at the beginning of second-line therapy and response to first-line treatment are important determinants of survival in second-line chemotherapy. Excision repair cross-complementation 1 (ERCC1) expression in platinum-treated patients was also highly predictive of better survival.

More research on molecular markers or certain metabolic enzymes that can predict clinical outcome would be helpful as well. For example, data presented in the annual GI ASCO meeting in 2007 showed that certain polymorphic variants of gemcitabine can predict sensitivity to gemcitabine-based therapy.[42]

Gemcitabine-Refractory Pancreatic Cancer in the Metastatic Setting

It is unclear at this time what percentage of patients who fail gemcitabine-based therapy for metastatic pancreatic cancer will go on to receive second-line chemotherapy. In some trials, up to 57% of patients who progress on gemcitabine subsequently receive second-line treatment.[5]

The data on second-line chemotherapy compared to best supportive care is lacking in pancreatic cancer. Only one small randomized trial showed a benefit of second-line chemotherapy compared to best supportive care. In this trial, patients with gemcitabine-refractory pancreatic cancer who received oxaliplatin, 5-FU, and leucovorin had a longer median survival compared to best supportive care.[7] Further studies are needed to compare cytotoxic chemotherapy to palliative measures such as celiac axis block, stenting of blocked ducts, or palliative radiation and best supportive care. Since progression-free and overall survival in second-line treatment of pancreatic cancer is usually short, cost-effectiveness should also be considered in the analysis.

Current phase II and III trials in this setting are using either 5-FU or capecitabine in their standard-treatment arm, most likely because of the difficulty of randomizing patients with good performance status to best supportive care only.

In this article, we have reviewed small phase I and II studies that have been reported primarily in abstract form. Most of these studies suffer from similar deficiencies secondary to small patient numbers and heterogeneous populations. The reports provide limited details about patients enrolled, their treatment history, and their response to first-line therapy, all of which is important in predicting overall survival in general.[12] Some of the patients in these trials received gemcitabine as an adjuvant treatment, while others received it in the metastatic setting, and authors have used different definitions of refractory disease. Most studies used response rate as a primary endpoint without taking into consideration clinical benefits or costs. Based on these data, it is difficult to draw a valid conclusion regarding standard second-line therapy in the metastatic setting.

Gemcitabine-Refractory Pancreatic Cancer in the Adjuvant Setting

As noted above, gemcitabine is commonly used in the adjuvant setting as a single agent or in combination with 5-FU and radiation, based on data from the CONKO[6] and Radiation Therapy Oncology Group (RTOG 9704) studies.[38] Unfortunately, the majority of patients will experience disease progression. Progression-free survival was 13.4 months in the treatment arm of the CONKO trial, and overall survival was 18.8 months in the gemcitabine arm in the RTOG trial. Therefore, we need to establish a better therapeutic guideline for patients who fail gemcitabine as an adjuvant treatment. The term “refractory to gemcitabine” in the adjuvant setting for pancreatic cancer is not clearly defined, compared to colon cancer where patients are considered refractory to the FOLFOX regimen (5-FU, leucovorin, oxaliplatin) if they relapse within 1 year of treatment.

From the clinical trials in this review, it is unclear what percentage of patients received gemcitabine as an adjuvant treatment. The main difference in the adjuvant setting is that patients who relapse after adjuvant gemcitabine therapy often have good performance status and will be able to receive further chemotherapy. The data for rechallenging these patients with gemcitabine are very limited.

Conclusions

For pancreatic cancer patients whose disease is refractory to gemcitabine, second-line therapy has not been clearly shown to affect survival. There are still many questions that need to be answered: Does the patient suffer from treatment-related toxicities without any survival or clinical benefit, and at what cost? Are we giving patients false hope and creating suffering by giving them chemotherapy? Why are we combining chemotherapeutic agents in the second-line setting when there is no survival or clinical benefit from single agents?

In conclusion, more randomized studies formally investigating the role of second-line therapy in advanced pancreatic cancer are warranted, since more patients will now be receiving gemcitabine as an adjuvant treatment. Stratification based on an ideal prognostic system before randomization will be crucial to the success of such studies. Development of novel therapeutic agents is important in the second-line setting, but we first need to answer the fundamental question: Do patients gain anything from active treatment?

Ideally, studies should compare active treatment against best supportive care, but these studies may be difficult to accomplish in the United States. Incorporating clinical benefits as primary endpoints along with cost-effectiveness analysis should be part of future clinical trials as well. With better patient selection and better endpoints, we can hopefully improve clinical outcomes for those with advanced pancreatic cancer in second-line settings, without giving patients false hope.

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Disclosures

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

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