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Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3205-3209 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.4968 Clinical Benefit With Docetaxel Plus Fluorouracil and Cisplatin Compared With Cisplatin and Fluorouracil in a Phase III Trial of Advanced Gastric or Gastroesophageal Adenocarcinoma: The V-325 Study Group
From The University of Texas M.D. Anderson Cancer Center, Houston, TX; N.N. Petrov Research Institute of Oncology, St Petersburg; N.N. Blokhin Cancer Research Center; Russian Scientific Centre of Radiology, Moscow, Russia; Fundación Arturo López Pérez; Hospital Clínico Universidad de Chile, Santiago, Chile; C.H. de Pontevedra, Pontevedra, Spain; Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; Hospitais da Universidade de Coimbra, Coimbra, Portugal; Taipei Veterans General Hospital, Taipei, Taiwan; Sanofi-aventis, Antony, France; and the Leuven University Hospital, Leuven, Belgium Address reprint requests to Jaffer A. Ajani, MD, Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Box 426, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jajani{at}mdanderson.org
Purpose: For patients with advanced gastric or gastroesophageal cancer (AGGEC) providing clinical benefit with improved palliation is highly desirable. However, a prospective evaluation of clinical benefit in AGGEC patients has never before been reported in a phase III setting. Patients and Methods: In a multinational trial (V325), 445 patients were randomly assigned and treated with either docetaxel plus cisplatin and fluorouracil (DCF) or cisplatin and fluorouracil (CF). Clinical benefit was prospectively evaluated in this trial as a secondary end point. The primary measure for clinical benefit analysis was time to definitive worsening by one or more categories of Karnofsky performance status (KPS). Secondary clinical benefit end points included time to 5% definitive weight loss, time to definitive worsening of appetite by one grade, pain-free survival (defined as time to first appearance of pain), and time to first cancer pain-related opioid intake. Clinical benefit assessments were recorded at each clinic visit. Results: Clinical benefit assessments were performed in more than 75% of patients throughout V325. DCF significantly prolonged time to definitive worsening of KPS compared with CF (median, 6.1 v 4.8 months; hazard ratio, 1.38; 95% CI, 1.08 to 1.76; log-rank P = .009). Although time to definitive weight loss and time to definitive worsening of appetite favored DCF, the results were not statistically significant. Pain-free survival and time to first cancer pain-related opioid intake were comparable. Conclusion: To our knowledge, V325 is the first phase III trial to report clinical benefit in AGGEC patients. Clinical benefit was assessed beyond protocol-specific chemotherapy. The addition of D to CF not only significantly improved clinical benefit but also improved quality of life, time to progression, and overall survival compared with CF.
Patients with advanced gastric or gastroesophageal cancer (AGGEC) experience deterioration of symptoms and quality of life (QOL) as their cancer progresses. In a prospective study of patients with AGGEC, 84% had disease-related symptoms at enrollment, including 26.5% with National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 to 4 symptoms, and more than 50% experienced more than 5% weight loss within the last 3 months prior to registration.1 An objective of effective palliative therapy is to preserve or improve symptoms and QOL, along with overall survival (OS). Evaluation of clinical benefit, defined as preventing deterioration of Karnofsky performance status (KPS), worsening of pain, and progressive weight loss, is highly desirable but has not been reported in previous phase III studies of AGGEC to our knowledge.
A multinational, randomized phase III study (V325) evaluated the impact of adding docetaxel to a reference regimen of cisplatin plus fluorouracil (CF) in advanced gastric cancer patients.1 All efficacy results significantly favored docetaxel plus CF (DCF) over CF alone, with a longer time to progression (TTP; hazard ratio [HR], 1.47; 95% CI, 1.19 to 1.82; log-rank P < .001), longer OS (HR, 1.29; 95% CI, 1.0 to 1.6; log-rank P = .02), and higher overall response rate (ORR; 37% v 25%; For palliative treatments, clinical benefit measurements may also be a relevant indicator of efficacy, as they demonstrate the impact of therapy on tumor-related symptoms.3 The V325 study was designed to include predefined clinical benefit end points and the results are reported herein.
The design of this phase III trial has been described elsewhere.1,2,4 Briefly, chemotherapy-naïve patients age  18 years with metastatic or locally recurrent gastric adenocarcinoma, KPS higher than 70, and adequate hematologic, renal, and hepatic functions were enrolled. Patients were randomly assigned to receive once every 3 weeks docetaxel (Taxotere; Sanofi-aventis, Bridgewater, NJ) 75 mg/m2 (day 1) plus cisplatin 75 mg/m2 (day 1) and fluorouracil 750 mg/m2/d continuous infusion (days 1 to 5; DCF), or once every 4 weeks cisplatin 100 mg/m2 (day 1) and fluorouracil 1,000 mg/m2/d continuous infusion (days 1 to 5; CF).
Clinical Benefit Assessments
Primary clinical benefit end point was time to definitive worsening of KPS. Performance status was assessed using the KPS (where 0 = dead and 100 = normal, no evidence of disease). Worsening was defined as a definitive decrease in performance status by
Secondary clinical benefit end points were time to definitive weight loss, time to definitive worsening of appetite, pain-free survival, and time to first cancer pain-related opioid intake. Definitive weight loss was defined as a decrease in weight of
Statistical Analysis
Overall, 445 patients from 72 centers in 16 countries were treated (DCF, 221; CF, 224). General patient baseline characteristics and treatment-related safety and efficacy end points have been reported previously.1 Clinical benefit assessments were performed in more than 75% of patients throughout the V325 study. Table 1 shows compliance until cycle 11 for the KPS analysis; participation in clinical benefit end points was approximately 100% at baseline and more than 80% during study treatment.
Clinical Benefit DCF significantly prolonged time to definitive worsening of KPS versus CF (median 6.1 v 4.8 months; HR, 1.38; 95% CI, 1.08 to 1.76; P = .009; Fig 1, Table 2). The 1-year estimated probability of patients not showing a definitive worsening of KPS was 33.1% with DCF versus 15.8% with CF.
The median time to definitive 5% weight loss was 5.8 months with DCF versus 4.4 months with CF (P = .078; Fig 2A, Table 2). The corresponding 1-year estimated probability of patients not showing a definitive 5% weight loss was 40.6% and 25.3%, respectively. The median time to definitive worsening of appetite was 7.5 months with DCF and 6.2 months with CF (P = .114; Fig 2B, Table 2). The 1-year estimated probability of no definitive worsening of appetite was 40.9% and 28.8% for DCF and CF, respectively.
Pain-free survival was similar between the treatment groups (median 10.3 months with DCF v 9.5 months with CF; Fig 2C, Table 2), as was the time to first cancer pain-related opioid intake (median not reached in both arms; Fig 2D, Table 2).
In addition to efficacy end points, such as TTP, assessments of surrogate secondary end points of QOL and clinical benefit are important in prospective phase III studies in AGGEC. QOL surrogate end points enable us to study patients' perceptions and clinical benefit analyses provide additional assessments that are otherwise ignored in routine analyses. However, such end points have been infrequently studied.6,7 In the V325 study, QOL was better with DCF because of the demonstrated higher efficacy of DCF over CF2; conversely, in studies reporting no efficacy improvements for the experimental arm over the reference arm, QOL did not improve.8-10 This suggests that higher efficacy may be essential for improvement in surrogate end points such as QOL and clinical benefit. The V325 study in AGGEC patients (of whom > 95% had metastatic disease) showed a significant TTP and OS advantage and improved QOL for DCF over CF, albeit with increased diarrhea and complicated neutropenia.1 The V325 efficacy and QOL results1,2 are supported by the predefined clinical benefit analysis reported here, which favored DCF treatment over CF. DCF significantly prolonged maintenance of KPS and provided superior (though nonsignificant) results over CF in the appetite and weight-loss analyses. Cancer pain and opioid intake were similar between the groups. To our knowledge, clinical benefit has only been reported previously in small phase II studies. In one phase II study of chemotherapy-naïve patients with advanced gastric cancer receiving fluorouracil and leucovorin,3 60% of patients met the clinical benefit response criteria (at least one positive primary measurement, pain or KPS, and another stable primary measurement, or if both primary measurements were stable, a positive secondary measurement [7% weight loss]). Median survival was significantly longer in clinical benefit responders than in nonresponders. The authors suggested that clinical benefit response reflected the biologic and symptom-related response to treatment, and may be a useful alternative to WHO criteria in evaluating response to chemotherapy in patients with gastric cancer.3 Another phase II study11 in chemotherapy-naïve patients with advanced gastric cancer treated with paclitaxel and fluorouracil defined clinical benefit as a sustained improvement (> 4 weeks) in at least one clinical benefit parameter (KPS, weight gain, pain intensity, or analgesic consumption) without worsening in another. Of 29 assessable patients, 19 showed an objective tumor response and 15 showed an improvement in at least one clinical benefit parameter. In 14 patients, there was agreement between clinical benefit and tumor response, suggesting that tumor shrinkage alone does not necessarily translate into clinical benefit or good palliation. However, comparative trials (either phase II or III) have not reported assessments of clinical benefit. Clinical benefit as an indicator of treatment response has also been used in pancreatic and colorectal cancer trials.12-14 In a gemcitabine trial of patients with fluorouracil-refractory pancreatic cancer, rigorous assessment of cancer-related symptoms provided an objective evaluation of response, despite low WHO response rates.12 In a study of patients with metastatic colorectal cancer, clinical benefit end points similar to those in this study were used to show that patients treated with second-line irinotecan had an improved OS and fewer tumor-related symptoms than patients receiving best supportive care.14 Although chemotherapy can prolong survival and improve QOL in patients with gastric cancer, the precise magnitude of the benefit is difficult to estimate.15 Clinical benefit as an additional evaluation of treatment response may assist physicians in assessing the impact of therapies on tumor-related symptoms, thereby aiding informed treatment decision making. In conclusion, to our knowledge, the V325 study represents the first prospective phase III trial in patients with AGGEC where clinical benefit in multiple categories has been studied and it has been evaluated for up to 14 months (a period well beyond the administration of protocol chemotherapy). The results of the clinical benefit analyses, demonstrating benefit for DCF over CF, are consistent with the other important advantages in TTP, OS, ORR, and QOL reported for DCF over CF.1,2
Although all authors completed the disclosure declaration, the following authors or their 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: Cindy Marabotti, Sanofi-aventis Leadership: N/A Consultant: Jaffer A. Ajani, Sanofi-aventis; Corrado Boni, Sanofi-aventis; Eric Van Cutsem, Sanofi-aventis Stock: N/A Honoraria: Corrado Boni, Sanofi-aventis Research Funds: Jaffer A. Ajani, Sanofi-aventis; Vladimir M. Moiseyenko, Sanofi-aventis; Alejandro Majlis, Sanofi-aventis; Miguel Fodor, Sanofi-aventis; Eric Van Cutsem, Sanofi-aventis Testimony: N/A Other: N/A
Conception and design: Jaffer A. Ajani, Eric Van Cutsem Financial support: Cindy Marabotti Administrative support: Cindy Marabotti Provision of study materials or patients: Jaffer A. Ajani, Vladimir M. Moiseyenko, Sergei Tjulandin, Alejandro Majlis, Manuel Constenla, Corrado Boni, Adriano Rodrigues, Miguel Fodor, Yee Chao, Edouard Voznyi, Eric Van Cutsem Collection and assembly of data: Jaffer A. Ajani, Vladimir M. Moiseyenko, Sergei Tjulandin, Alejandro Majlis, Manuel Constenla, Corrado Boni, Adriano Rodrigues, Miguel Fodor, Yee Chao, Edouard Voznyi, Cindy Marabotti, Eric Van Cutsem Data analysis and interpretation: Jaffer A. Ajani, Eric Van Cutsem Manuscript writing: Jaffer A. Ajani, Vladimir M. Moiseyenko, Sergei Tjulandin, Alejandro Majlis, Manuel Constenla, Corrado Boni, Adriano Rodrigues, Miguel Fodor, Yee Chao, Edouard Voznyi, Cindy Marabotti, Eric Van Cutsem Final approval of manuscript: Jaffer A. Ajani
Numerous individuals from many institutions participated to complete this study. The representative authors are grateful for everyone's efforts.
Supported by Sanofi-aventis. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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, Moiseyenko VM, Tjulandin S, et al: Better quality of life with docetaxel, cisplatin, and 5-fluorouracil compared to cisplatin and 5-fluororuacil: A controlled phase III trial for patients with advanced gastric adenocarcinoma. J Clin Oncol 2007 [in press] 3. Lin YC, Liu HE, Wang CH, et al: Clinical benefit and response in patients with gastric cancer to weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV). Anticancer Res 19:5615-5620, 1999[Medline] 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. Osoba D, Murray N, Gelmon K, et al: Quality of life, appetite, and weight change in patients receiving dose-intensive chemotherapy. Oncology 8:61-65, 1994 6. Ohtsu A, Shimada Y, Shirao K, 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, 2003 7. 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 Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18:2648-2657, 2000 8. Dank M, Zaluski J, Barone C, et al: Randomized phase III trial of irinotecan (CPT-11) + 5-FU/folinic acid (FA) vs CDDP + 5-FU in 1st line advanced gastric cancer patients. J Clin Oncol 23:308s, 2005 (abstract 4003) 9. Cunningham D, Nao S, Starling N, et al: Randomised multicentre 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 24:18s, 2006 (LBA 4017)[CrossRef] 10. Ross P, Nicolson M, Cunningham D, et al: Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20:1996-2004, 2002 11. Murad AM, Petroianu A, Guimaraes RC, et al: Phase II trial of the combination of paclitaxel and 5-fluorouracil in the treatment of advanced gastric cancer: A novel, safe, and effective regimen. Am J Clin Oncol 22:580-586, 1999[CrossRef][Medline] 12. Rothenberg ML, Moore MJ, Cripps MC, et al: A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 7:347-353, 1996 13. Chung HW, Bang SM, Park SW, et al: A prospective randomized study of gemcitabine with doxifluridine versus paclitaxel with doxifluridine in concurrent chemoradiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 60:1494-1501, 2004[CrossRef][Medline] 14. Cunningham D, Pyrhonen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998[CrossRef][Medline] 15. Glimelius B, Ekstrom K, Hoffman K, et al: Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8:163-168, 1997[CrossRef][Medline] Submitted December 19, 2006; accepted March 21, 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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ABSTRACT
INTRODUCTION
2 test P = .01). More grade 3 to 4 neutropenia (82% v 57%), febrile neutropenia and/or neutropenic infection (29% v 12%), diarrhea (19% v 8%), and serious adverse events occurred with DCF than with CF (62% v 45%), and more grade 3 to 4 stomatitis (27% v 21%) occurred with CF. Nevertheless, QOL was superior with DCF versus CF,
15 days before random assignment). Worsening was considered definitive if no later improvement above the defined threshold was observed during the study and before any further anticancer therapy. 
