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Journal of Clinical Oncology, Vol 25, No 17 (June 10), 2007: pp. 2491-2493 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.1369
In ReplyDepartment of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX I thank Wagner et al for their interest in V325 and for points they have raised. I welcome every opportunity to discuss any aspects of V325 that have1 and have not yet been published. However, before doing that, I want to clarify one important point: the addition of docetaxel to cisplatin plus fluorouracil (DCF) versus CF—because the median cumulative doses of cisplatin and fluorouracil administered in both arms was similar (Figs 1 and 2), —resulted in a 23% reduction in the risk of death, doubling of the 2-year survival rate (DCF, 18% v CF, 9%), and a significant two-sided log-rank P value (P = .020; hazard ratio = 1.293; 95% CI, 1.04 to 1.61). Yes, we are all trained to first look at the median survival differences (as Wagner et al have done) but the difference at the median is only one point on the curves, which represent the entire study observation duration and 100 points. The two-sided, log-rank P value calculates the area between the curves in their entirety. It is true that the difference at the median is small (as we mentioned in our article1) but we do need to recognize how differences are being calculated, what the P values represent, the risk reduction, and other advantages provided by the addition of docetaxel to CF in V325.
Is time to progression (TTP) a valid primary end point for a study like V325, ask Wagner et al? V325 was a pivotal registration trial unlike other trials.2-4 TTP is an acceptable primary end point for the European Health Authorities, whereas overall survival (OS) is the requested primary end point for the US Health Authorities. Based on these considerations, the V325 sample size was calculated and the study was powered (95% power and two-sided test) to be able to demonstrate an advantage, if any, for both end points: TTP as designated primary end point and OS as a major secondary end point. V325, in reality, had two primary end points: TTP and OS with highest levels of statistical stipulations used for advanced gastroesophageal cancer trials published. It has not yet been established, although believed by some, that postfirst-line protocol anticancer therapy can dilute the treatment effect on OS. Therefore, it can be argued that TTP assesses the net added benefit of the experimental therapy compared with a reference therapy. Incidentally, 32% of patients in the DCF arm received second-line anticancer therapy compared with 41% of patients in the CF arm (including 10.3% of patients who received taxanes; Table 1). Despite this, OS was significantly in favor of DCF.
With regards to important points about quality of life (QOL) and clinical benefit mentioned by Wagner et al, DCF (having surpassed its TTP objective and significantly prolonging OS) did preserve the QOL better than CF5 did and provided improved clinical benefit as well.6 With regards to toxicity, it is interesting to note that the QOL of patients who did and who did not develop complicated neutropenia within the DCF arm was not different.7 In addition, the higher rate of complicated neutropenia did not induce a higher rate of fatal infection in the DCF arm (seven patients or 3.2% toxic deaths with DCF and eight patients or 3.6% with CF). The conclusion of Wagner et al about poor correlation between TTP and OS is based on a meta-analysis that is potentially biased because TTP is unavailable for more than one half of the studies.8 Although nonparametric methodology was used in their analysis, the Spearman correlation does not adequately assess the relationship between TTP and OS because it fails to account for patient censoring. Furthermore, these studies were conducted under different protocols where the definition of the TTP can vary considerably and may include death as a component of the end point (as was the case in V325). Their second point is about the median age of the patient population. V325 was truly a global trial: eight European countries (including Germany), six South American countries, the United States, and Taiwan participated. A total of 72 worldwide sites enrolled patients. The median age represented in V325 is, unfortunately, the modern reality. The age for gastroesophageal cancer diagnosis is getting lower. Only 25% of patients in V325 were 65 years of age or older.
V325 has demonstrated beneficial contributions of docetaxel to patients with advanced gastric or gastroesophageal cancer but its addition to other active agent(s) (CF as an example in V325) can result in higher rate of complicated neutropenia. If the anticipated rate of complicated neutropenia is V325 met all its premier end points and it represents one of the modern trials with high statistical rigor and exemplary methodology and I hope that future trials in this arena will only surpass the standards set by V325. So, when you ask [Docetaxel for advanced gastric cancer?] I reply, yes, because docetaxel improves patient outcome and we can build on this understanding. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: N/A Leadership: N/A Consultant: Jaffer A. Ajani, sanofi-aventis Stock: N/A Honoraria: N/A Research Funds: Jaffer A. Ajani, sanofi-aventis Testimony: N/A Other: N/A
ACKNOWLEDGMENTS Jaffer A. Ajani is writing on behalf of everyone who contributed to the completion of V325. REFERENCES
1. Van Cutsem E, Moisyenko VM, Tjuladin 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. Ohtsu A, Shimada Y, Shirea V, et al: Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JACOG9205). J Clin Oncol 21:54-59, 2004[CrossRef] 3. Vanhoefer U, Rougier P, Wilke H, et al: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18:2648-2657, 2000 4. Cunningham D, Rao S, Starling N, et al: Randomized multicenter phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced esophagogastric cancer: The REAL 2 trial. J Clin Oncol 24:182s, 2006 (LBA 4017) 5. Ajani JA, Moiseyenko VM, Tjulandin S, et al: Better quality of life with docetaxel plus cisplatin and 5-fluorouracil compared to cisplatin and 5-fluorouracil: A controlled phase II trial (V-325) for patients with advanced gastric or gastroesophageal adenocarcinoma. J Clin Oncol doi:10.1200/JCO.2006.10.4968 6. Ajani JA, Moiseynko VM, Tjulandin S, et al: Improved clinical benefit with docetaxel plus 5-fluorouracil and cisplatin v 5-flurouracil plus cisplatin in advanced gastric or gastroesophageal cancer in a phase III trial. J Clin Oncol (in press) 7. Ajani A, Moiseyenko V, Tjulandin SA, et al: Changes from baseline health-related quality of life (HRQOL) analysis: No compromise by adding docetaxel to a cisplatin-based regimen in advanced gastric cancer patients, including those experiencing febrile neutropenia (FN) or neutropenic infection (NI). Ann Oncol 17:ix314, 2006 (suppl 9; abstr 1098) 8. Ichikawa W, Sasaki Y: Correlation between tumor response to first-line chemotherapy and prognosis in advanced gastric cancer patients. Ann Oncol 17:1665-1672, 2006 9. Aapro MS, Cameron DA, Pettengell R, et al: European Organisation for Research and Treatment of Cancer guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer 42:2433-2453, 2006[CrossRef][Medline] 10. National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology, 2006. http://www.nccn.org 11. Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 update of recommendations for the use of white blood cell growth factors: An evidence-based clinical practice guideline. J Clin Oncol 24:3187-3205, 2006 This article has been cited by other articles:
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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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20%, then primary prophylaxis with growth factors is recommended.
