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Journal of Clinical Oncology, Vol 25, No 34 (December 1), 2007: pp. 5528-5529 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.9980
Doubts About Whether Docetaxel, Cisplatin, Plus Fluorouracil Has Any Benefit in Advanced Gastric CancerMelbourne Oncology Group, Cabrini Health; and Department of Medicine, Monash University, Victoria, Australia To the Editor: The recently reported claims by Ajani et al1,2 for better preservation of quality of life (QOL) and for improved clinical benefit for docetaxel, cisplatin, plus fluorouracil (DCF) over cisplatin plus fluorouracil (CF) in advanced gastric cancer in the V-325 Study seem questionable. As reported in the original phase III study,3 50% of patients receiving DCF were taken off therapy either because of adverse events from treatment or because of the patient's withdrawal of consent, and not because of progressive disease. More cycle delays occurred with the DCF than the CF treatment (64% v 42%, respectively), and lethargy, a key contributor to performance status, was the major reason for these dose delays. In addition, more patients required dose reductions for the DCF than for the CF regimen (41% v 36%, respectively). The rates of grade 3 to 4 stomatitis, diarrhea, neutropenia, and febrile neutropenia in the study were substantial in both arms, with 69% of patients receiving DCF and 59% receiving CF having at least one grade 3 to 4 treatment-related adverse event. Forty-six percent of patients receiving DCF had a grade 3 or 4 event in the last cycle of treatment before their consent was withdrawn, compared with 42% for those receiving CF. With all of these figures, it seems inconceivable that a regimen with such extraordinarily high toxicity could lead to improved (preservation) of quality of life and clinical benefit, as claimed by the Ajani et al,1 when they clearly acknowledged that DCF caused an increase in toxicity compared with CF.3 How else then could this apparent improved preservation of quality of life be explained if it is not due to a clearly more toxic chemotherapy regimen? The answer may well be the premedication and post-treatment dose of dexamethasone4 used. Patients receiving DCF received a total dose of 88 mg of dexamethasone with each course of chemotherapy. This compares with a total premedication dose of only 40 mg of dexamethasone for patients receiving CF. The patients receiving DCF had a median of six courses of therapy and so would probably have received a total of 528 mg of dexamethasone over the six courses of therapy, compared with a maximum of only 160 mg of dexamethasone for the patients receiving CF who had a median of four courses of chemotherapy. It is well established that corticosteroids can significantly improve quality of life in patients with advanced preterminal cancer. Not only do they reduce the mean intensity of pain, they improve appetite and daily activity, and reduce depression and analgesic consumption.5,6 These are precisely the measures that were being assessed in the quality-of-life and Karnofsky performance status assessments used by Ajani et al in their two manuscripts claiming palliative benefit for DCF over CF.1,2 It is also extremely important to know when the patients completed the quality-of-life assessment forms. If they were done on the day of chemotherapy treatment before administration of chemotherapy, then patients receiving DCF would already have received 16 mg of dexamethasone in the previous 24 hours, compared with no dexamethasone in patients receiving CF. This large premedication dose of dexamethasone would have a substantial affect on the patients' perceived quality of life and performance status because of its ability to reduce nausea, vomiting, and pain, and increase the sense of well-being and performance status.5,6 In addition, because dexamethasone can cause fluid retention and weight gain, the more than three-fold increase in total premedication dose of dexamethasone given to the patients receiving DCF would have helped mask any weight loss and loss of appetite. When one considers that the overall survival benefit for DCF versus CF was only 0.6 months for this group of selected young patients with high baseline performance status, and that the CIs for survival for the two regimens were overlapping, then it is hard to see any advantages at all for the use of this highly toxic regimen of DCF in advanced gastric cancer. Many of the authors of the studies declared potential financial conflicts of interest, and it would be interesting to see an independent analysis and interpretation of the data. Ilson, the writer of the associated editorial,7 and who also declared a potential financial conflict of interest with the sponsoring company of the studies, was not convinced enough by the data to advocate that DCF should become our optimal first-line therapy in advanced gastric cancer. As well conducted as the V-325 Study may have been, I do not believe that the conclusions are justified by the data provided and because of the enormous differences in doses of dexamethasone given between the two treatment regimes over the study period. These differences are not commented on in any of the recent articles.1-3 I do not believe that the expensive and toxic regimen of DCF represents progress in the treatment of advanced gastric and gastroesophageal cancer. The only meaningful benefit of DCF for treated patients may well be the dexamethasone. Author's Disclosures of potential Conflicts of Interest The author(s) indicated no potential conflicts of interest. REFERENCES
1. Ajani JA, Moiseyenko VM, Tjulandin S, et al: Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: The V-325 Study Group. J Clin Oncol 25:3205-3209, 2007 2. Ajani JA, Moiseyenko VM, Tjulandin S, et al: Quality of life with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a phase III trial for advanced gastric or gastroesophageal adenocarcinoma: The V-325 Study Group. J Clin Oncol 25:3210-3216, 2007 3. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al: Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: A report of the V325 Study Group. J Clin Oncol 24:4991-4997, 2006 4. Ajani JA, Fodor MB, Tjulandin SA, et al: Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol 23:5660-5667, 2005 5. Bruera E, Roca E, Cedaro L, et al: Action of oral methylprednisolone in terminal cancer patients: A prospective randomized double-blind study. Cancer Treat Rep 69:751-754, 1985[Medline] 6. Popiela T, Lucchi R, Giongo F: Methylprednisolone as palliative therapy for female terminal cancer patients: The Methylprednisolone Female Preterminal Cancer Study Group. Eur J Cancer Clin Oncol 25:1823-1829, 1989[CrossRef][Medline] 7. Ilson DH: Docetaxel, cisplatin, and fluorouracil in gastric cancer: Does the punishment fit the crime? J Clin Oncol 25:3188-3190, 2007 Related Reply
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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