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Gemcitabine Plus Cisplatin in Advanced Pancreatic Cancer

Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN

To the Editor:

We read with interest the trial results reported by Heinemann et al¹ regarding whether cisplatin adds efficacy to gemcitabine for advanced pancreatic cancer. Based on the primary end point, it seems to be a negative phase III trial of a gemcitabine combination for pancreatic cancer; yet the conclusions read as if this were a positive trial. The authors state that "[The] results support the efficacy and safety of an every-2-weeks treatment with gemcitabine plus cisplatin."¹ However, the primary end point of the trial was overall survival, and the difference in survival rates in the two arms did not reach statistical significance. In addition, the toxicity in the combination arm was notable for 22% grade 3 to 4 nausea versus 6% in the gemcitabine-alone arm. In a disease where cachexia is a major cause of morbidity and mortality, this symptom is not insignificant.

If the authors wished to consider an improvement in survival from 6 months to 7.5 months significant, they should have powered the study appropriately. However, they clearly stated in their methods that the study was powered to detect an improvement in survival from 5 to 8 months. This reflects two key errors. First, the anticipated effect of adding cisplatin was clearly overestimated, especially in light of a prior negative phase III study of a similar combination.² Second, the inclusion of patients with locally advanced disease rather than strictly stage IV patients may have led to an underestimation of survival in the gemcitabine arm, as patients with locally advanced disease on average survive longer than stage IV patients—10 months in both arms in this study. Therefore, future studies should be limited to either patients with locally advanced or stage IV disease, but not both. It is also important that investigators adhere to their trial design and preset measures of success. To use secondary end points or post hoc analyses to derive a "positive" result undermines the study and its applicability to general practice. In the trial conducted by Heinemann and colleagues,¹ an argument is made that the trial was underpowered and a different end point (disease control rate) should have been used. Stating that the study was underpowered infers that the study was inappropriately designed. Given the toxicity and limited efficacy of our therapeutic options for pancreatic cancer, it is critical that we continue to appropriately design trials and maintain meaningful end points so that only truly beneficial therapies are brought forward for general use.

Unfortunately, barring a dramatic and unexpected effect of cisplatin, this study was not sufficiently powered to reach the primary end point. Therefore, the study does not support the addition of a gemcitabine-cisplatin combination to our armamentarium for advanced pancreatic cancer, despite the conclusions of the authors.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

REFERENCES

1. Heinemann V, Quietzsch D, Gieseler F, et al: Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 24:3946-3952, 2006[Abstract/Free Full Text]

2. Colucci G, Giuliani F, Gebbia V, et al: Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: A prospective, randomized phase III study of the Gruppo Oncologia dell'Italia Meridionale. Cancer 94:902-910, 2002[CrossRef][Medline]

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