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Journal of Clinical Oncology, Vol 25, No 34 (December 1), 2007: pp. 5529-5530 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.0061
In ReplyThe University of Texas M.D. Anderson Cancer Center, Houston, TX We thank Dr Haines for his letter expressing skepticism of the positive results of the V-325 study published in four peer-reviewed articles.1-4 He brings out many important issues that are worthy of discussion. When V-325 was conceived, we recognized that the total corticosteroid dose in the two arms would be different: patients on the docetaxel, cisplatin, plus fluorouracil (DCF) arm were to receive more corticosteroids than those in the cisplatin plus fluorouracil (CF) arm. However, at no time did we believe that the efficacy, toxicity, quality of life (QoL), or clinical benefit (CB) could be influenced by the differences in the corticosteroid dose, or that there were any confounding factors. So, what about the potential influence of corticosteroids on these parameters, as Haines has claimed? A number of issues should be clarified. The two studies5,6 cited by Haines to support his assertion that the corticosteroids influenced efficacy, QoL, and CB of DCF in V-325 investigated a small number of terminally ill patients (one of the two studies is a randomized trial of 40 patients). The randomized study5 was conducted before 1985 and had a 14-day treatment schema with a cross-over design, and the rigor, breadth, and the duration of assessments (14 days) should not be compared with those of V-325. The patient population is entirely different (the studies cited by Haines did not investigate patients with advanced gastroesophageal cancer). V-325 was a registration trial that was designed and discussed thoroughly with many regulatory agencies before its launch. The protocol was not once believed to contain any confounding factors. In addition, in the V-325 study, the information for the QoL questionnaire and CB parameters were completed before the administration of corticosteroid premedications. Only 8% of the assessable QoL questionnaires in the DCF arm and 5% in the CF arm were not completed before the start of steroid premedications. Therefore, the corticosteroid premedications for docetaxel could not have had any impact on the QoL or CB results in V-325. I emphasize that the methodology2 and the quality of study execution of V-325 have not yet been surpassed. We believe that the claim made by Haines is not supported by the literature and by the V-325 data. However, I must give him the benefit of the doubt by examining some issues in greater detail. The QoL3 and CB4 assessments extended well beyond the duration of protocol therapy, meaning that data on QoL and CB (and efficacy) were assessed even when patients were not receiving protocol-specific doses of corticosteroids. QoL was assessed for approximately 56 weeks and CB was assessed for more than 40 weeks. Each time, the QoL was assessed at least 10 days after the last cycle of chemotherapy, and CB was assessed before each cycle of chemotherapy (and after the patient discontinued therapy). This information is clearly stated in both reports. Thus there was no influence of corticosteroids on these assessments. If we carefully examine Figure 1 in all three published reports1,3,4 and Figure 2 in the efficacy report,1 it should be amply clear that the benefit of adding docetaxel to CF was more pronounced after 20 weeks (median duration of the administration of DCF was 19 weeks) for all efficacy and ancillary end points studied in V-325. DCF conferred considerable sustained and delayed advantage to a number of patients that cannot be explained by the administration of extra corticosteroids. We also performed a prespecified analysis on fluid retention and 14.9% of patients receiving DCF versus 4.0% of patients receiving CF experienced fluid retention. It is unlikely that this small difference influenced the time to definitive weight loss (as a component of CB).4 With regard to dose delays, one cycle delay occurred in 64% of patients receiving DCF versus 42% of patients receiving CF, and it represents 24.4% of the total number of cycles (289 of 1,186 cycles) in the DCF arm and 18.4% of cycles (167 of 906) in the CF arm. Moreover, 8.2% of cycles (97 of 1,186 cycles) were delayed due to toxicity for patients receiving DCF and 6.5% of cycles (59 of 906 cycles) were delayed for patients receiving CF. However, Haines seems to suggest that a greater number of these 64% of patients with cycle delay had a delay because of lethargy, but only 9.5% of patients receiving DCF and 3.1% of patients receiving CF had dosing delay due to lethargy. The main reason for cycle delay was not toxicity but "other reasons" that corresponded to personal issues, logistic issue, errors in scheduling, and patient preferences (38.9% of patients with cycle delay in the DCF arm and 26.8% in the CF arm). Regarding consent withdrawal, 46% of patients receiving DCF had a grade 3/4 event in the last cycle compared with 42% of patients receiving CF. Therefore, the reason for consent withdrawal in DCF was not due to higher toxicity in DCF but it was possibly due to so-called chemotherapy fatigue from a longer duration of therapy. It is a well-known phenomenon in oncology practices that patients request treatment-free intervals after several months of the same therapy. The longer the duration of chemotherapy and the more frequently it is given, the more likelihood there is of a patient's request for a break (chemotherapy fatigue). The safety profile of DCF corresponds to an intensive therapy. V-325 was a proof-of-principle trial that established the contribution of docetaxel in patients with untreated, advanced gastroesophageal cancer. DCF, as constituted in V-325, should be given only to patients that are carefully selected by physicians who are knowledgeable about the regimen and, more importantly, about this particular patient population; these physicians should also have an excellent infrastructure in place. The V-325 investigators and others have already begun to modify DCF to improve its safety profile (Table 1 7-11), and it has also been considered a desirable direction by others.12
With regard to the median age of the study population, we have previously explained that this study accrued in four continents and the median age of patients with gastroesophageal cancers is declining.13 With regard to the difference in the median survival time, Haines and Ilson12 are correct that the difference in the median survival between DCF and CF was only 2 weeks. However, the P values (P < .001 for time to progression and P < .02 for overall survival) calculated by the log-rank test are not representing only the median differences (ie, just a single point on the survival curve). The P values are related to the area between the curves. In V-325, a fraction of patients in the DCF arm experienced considerable delayed benefit (doubling of the 2-year survival rate). We should learn to pay more attention to the hazard ratio. There was a 22% reduction in the risk of death for patients who received DCF compared with CF. This simply means that not all patients are likely to benefit from a new treatment, but we do not know how to select this subset at the outset. We recognize that most oncologists tend to look at the median difference and ignore what the P value means. I agree that safer and more effective or individualized therapies are needed. We have a lot of hard work ahead of us. Haines also makes puzzling comments about the conflicts of interest and about independent data review. All authors have declared their conflicts of interest as required by the Journal of Clinical Oncology and also in many other settings. He should also know that all V-325 analyses performed were prespecified in the statistical plan of the protocol and prenegotiated with several regulatory agencies. In addition, the health authorities are provided with the raw data of the results of a registration trial, and in some countries, the health authorities perform their own analyses before approving a new anticancer treatment, which was the case for V-325. Fourteen independent audits were conducted in various countries, including one in the United States by the US Food and Drug Administration. Asking for more than that may not be appropriate or resource-conscious. In conclusion, I believe Haines raises many doubts about the results of the V-325 study; however, his conclusions are not based on the objective published V-325 data and are not supported by the literature either. Author's Disclosures of potential Conflicts of Interest Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Jaffer A. Ajani, sanofi-aventis (U) Stock Ownership: None Honoraria: None Research Funding: Jaffer A. Ajani, sanofi-aventis Expert Testimony: None Other Remuneration: None
REFERENCES
1. 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 2. 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 3. 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 4. 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 5. Bruera E, Roca E, Cedaro L, et al: Action of oral methylprednisolone in terminally ill cancer patients: A prospective randomized double-blind study. Cancer Treat Rep 69:751-754, 1985[Medline] 6. Popiela T, Lucchi R, Giongo F: The methylprednisolone as palliative therapy for female terminal cancer patients. Eur J Cancer Clin Oncol 25:1823-1829, 1989[CrossRef][Medline] 7. Hejna M, Zacherl J, Ba-Ssalamah A, et al: Phase II study of docetaxel in combination with oxaliplatin in patients with metastatic or locally advanced esophagogastric cancer previously untreated with chemotherapy for advanced disease: Results of the CECOG-Study ES-GAS.1.2.001. J Clin Oncol 25:204s, 2007 (suppl; abstr 4527) 8. Al-Batran S, Hartmann JT, Hofheinz T, et al: Modified FOLFOX in combination with docetaxel for patients with metastatic adenocarcioma of the stomach or gastroesophageal junction: A multicenter phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). J Clin Oncol 25, 2007 (suppl; abstr 4545) 9. Aljani JA, Phan A, Ho, L, et al: Phase I/II trial of docetaxel plus oxaliplatin and 5-fluorouracil (D-FOX) in patients with untreated, advanced gastric of gastroesophageal cancer. J Clin Oncol 25:225s, 2007 (suppl; abstr 4612) 10. Tebbutt N, Sourjina T, Strickland A, et al: ATAX: Randomized phase II study evaluating weekly docetaxel-based chemotherapy combinations in advanced esophago- gastric cancer, final results of an AGITG trial. J Clin Oncol 25:204s, 2007 (suppl; abstr 4528) 11. Lorenzen S, Hentrich M, Haberi C, et al: Split-dose docetazel, cisplatin and leucovorin/fluorouracil as first-line therapy in advanced gastric cancer and adenocarcinoma of the gastroesophageal junction: results of a phase II trial. Ann Oncol 18:1673-1679, 2007 12. Ilson DH: Docetaxel, cisplatin, and fluorouracil in gastric cancer: Does the punishment fit the crime? J Clin Oncol 25:3188-3190, 2007 13. Ajani J: Docetaxel for advanced gastric cancer? J Clin Oncol 25:2491-2493, 2007 Related Correspondence
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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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