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Journal of Clinical Oncology, Vol 25, No 17 (June 10), 2007: pp. 2490-2491 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.9314
Docetaxel for Advanced Gastric Cancer?Department of Internal Medicine II, University Hospital, Friedrich-Schiller-University Jena, Germany; Coordinating Centre for Clinical Trials, Martin-Luther-University Halle-Wittenberg, Germany
Department of Internal Medicine II, University Hospital, Friedrich-Schiller-University Jena, Germany
Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
Department of Internal Medicine II, University Hospital, Friedrich-Schiller-University Jena, Germany To the Editor: We congratulate Dr Van Cutsem and colleagues for the publication of V325.1 Taxanes have emerged as a class of chemotherapeutic agents with important antineoplastic activity in a variety of solid tumors, such as breast, lung, and prostate cancer. Therefore, it was an intriguing question whether they induce a similar therapeutic benefit in patients with gastric cancer. V325 was performed to answer this question. The results of this trial show—for the patients treated with docetaxel, cisplatin, and fluorouracil (DCF) compared with cisplatin and fluorouracil (CF)—a significant prolongation of the primary end point time-to-progression (TTP; 5.6 v 3.7 months, P < .001; hazard ratio, 1.47). However, this translated into a small difference in median survival of only 0.6 months (9.2 v 8.6 months). In addition, a prolongation of time to 5% deterioration of global quality of life and time to definite worsening of Karnofsky performance status could be demonstrated for the patients treated with DCF. We would like to discuss two points in the context of this trial. Is TTP indeed an appropriate primary end point for phase III clinical trials in advanced gastric cancer today, and could (or should) it replace overall survival as primary end point in future trials? At present, this is a controversial issue. While some investigators have selected TTP,2 others have used overall survival3,4 as primary end point in recent randomized phase III trials. We do very well understand the reasons to choose TTP as primary end point of a trial. It has a sound biologic rationale, it is independent from subsequent lines of therapy, and it requires a shorter duration of follow-up. Although we are aware of the widespread use of this end point in cancer clinical trials,5 we would like to emphasize that TTP is a surrogate end point. The use of surrogate end points is justified if the end point of interest is too difficult and/or too expensive to measure routinely.6 An established condition for their use is that they bear a clear statistical relationship with the true end point.6 Thus, a prolongation of TTP indicates a patient benefit only if at least one of the following conditions are met: if it is associated with maintained or improved quality of life and/or performance status and/or if it is associated with improved survival. Can we be sure that a prolongation of TTP in patients with advanced gastric cancer, which may be achieved at the price of relevant toxicity, is always correlated with a clinically meaningful benefit in quality of life or improvement in performance status? We cannot. TTP is a questionable surrogate for quality of life or performance status. Furthermore, the use of any surrogate for these end points is unnecessary. Both, a patient's quality of life and performance status can inexpensively and precisely be directly assessed. For quality of life, validated questionnaires, such as the European Organisation for Research and Treatment of Cancer or Functional Assessment of Cancer Therapy instruments,7,8 are available. Imaging procedures are unable to deliver any further relevant information in this context. The correlation between TTP and survival, as well as the impact of second- and more lines of therapy on survival, are established for other tumors, such as those in colorectal cancer.9,10 However, gastric cancer has a different biology, and both the impact of second (and further) lines of therapy on survival, and the question of whether TTP is sufficiently correlated with survival to qualify as an acceptable surrogate are unresolved issues in patients with advanced gastric cancer at present. The correlations between response rate and TTP and response rate and survival in advanced gastric cancer have been analyzed in a recent publication by Ichikawa and Sasaki.11 In an attempt to clarify the correlation between TTP and survival, we reanalyzed this data. As a result, we could find a poor correlation of TTP and overall survival of r = 0.40 for all treatment protocols and r = 0.26 for modern regimens, which included irinotecan, docetaxel, paclitaxel, or oxaliplatin. Although preliminary, these data do not support the use of TTP as primary end point in trials for patients with advanced gastric cancer. Both, magnitude and quality of the patient benefit from a prolongation of TTP—as observed in V325—are unclear. Is the patient population of the trial representative for the overall population of patients with gastric cancer? In V325, the median age of the included patients was 55 years (range, 25 to 79 years). In contrast, the median age at diagnosis is 70 years for males and 75 years for females in Germany,12 and 67 and 72 years, respectively in the United States.13 Thus, as in many cancer therapy clinical trials,14,15 the patient population of V325 was significantly younger as compared with the average population of patients with gastric cancer. Particularly when considering the greater toxicity of DCF in patients older than 65 years of age (incidence of grade 3 and 4 infections 20% v 9% for DCF v CF, respectively), and that infections were the main cause of toxic deaths in both treatment arms, caution is required when using DCF in a standard (elderly) population of patients with advanced gastric cancer. We do not know what the rate of toxic deaths would have been for DCF if the patients included in this trial would have met the median age of 70 years, as in the average population of gastric cancer patients. Thus, results of V325 are only valid for a patient population similar to that of the trial cohort. Further data to evaluate the risk/benefit ratio for the use of DCF in elderly patients with advanced gastric cancer is required. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS Supported by the Coordinating Centre for Clinical Trials, Martin-Luther-University, Halle-Wittenberg, Germany, and the Ministry for Education and Research, Grant No. BMBF/FKZ: 01GH 0105 KKS-Halle. 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. Al Batran S, Hartman J, Probst S, et al: A randomized phase III trial in patients with advanced adenocarcinoma of the stomach receiving first-line chemotherapy with fluorouracil, leucovorin and oxaliplatin (FLO) versus fluorouracil, leucovorin and cisplatin (FLP). J Clin Oncol 24:182s, 2006 (LBA 4016) 3. Cunningham D, Rao D, Starling N, et al: Randomised multicenter phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: The REAL-2 trial. J Clin Oncol 24:182s, 2006 (abstr 4017) 4. 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 (JCOG9205). J Clin Oncol 21:54-59, 2004[CrossRef] 5. Johnson JR, Williams G, Pazdur, R.: End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 21:1404-1411, 2003 6. Ellenberg SS, Hamilton JM: Surrogate endpoints in clinical trials: Cancer. Stat Med 8:415-425, 1989[Medline] 7. Vickery CW, Blazeby JM, Conroy T, et al: Development of an EORTC disease-specific quality of life module for use in patients with gastric cancer. Eur J Cancer 37:966-971, 2001[CrossRef][Medline] 8. Eremenco SL, Cashy I, Webster K et al: FACT-Gastric: A new international measure of Quol in gastric cancer. J Clin Oncol 22:759s, 2004 (abstr 8123) 9. Miller LL, Elfring GL, Gruia, et al: A case for time to progression (TTP) as the primary (1°) efficacy endpoint in first line metastatic colorectal cancer therapy: Correlation of TTP and overall survival (OS). J Clin Oncol 22:245s, 2004 (abstr 3503) 10. Grothey A, Sargent D, Goldberg RM, et al: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan and oxaliplatin in the course of treatment. J Clin Oncol 22:1209-1214, 2004 11. Ichakawa W, Sasaki Y: Correlation between tumor response to first-line chemotherapy and prognosis in advanced gastric cancer patients. Ann Oncol 17:1665-1672, 2006 12. German Cancer Registry Robert-Koch Institut. http://www.rki.de 13. US National Cancer Institute. www.seer.cancer.gov 14. Hutchins LF, Unger JM, Crowley IJ, et al: Underrepresentation of patients 65 years of age or older in cancer –treatment trials. N Engl J Med 341:2061-2067, 1999 15. Lewis JH, Kilgore ML, Goldman DP, et al: Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol 21:1383-1389, 2003
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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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