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Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3210-3216 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.3956 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
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 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, Mail Stop 426, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jajani{at}mdanderson.org
Purpose Therapy of patients with advanced gastric or gastroesophageal junction cancer should provide symptom relief and improve quality of life (QOL) because most patients are symptomatic at baseline. Using validated instruments, we prospectively assessed QOL (even after completion of protocol treatment) as one of the secondary end points of the V325 phase III trial. Patients and Methods Four hundred forty-five patients randomly received either docetaxel 75 mg/m2 and cisplatin 75 mg/m2 each on day 1 plus fluorouracil 750 mg/m2/d continuous infusion on days 1 to 5 every 3 weeks (DCF) or cisplatin 100 mg/m2 on day 1 plus fluorouracil 1,000 mg/m2/d continuous infusion on days 1 to 5 every 4 weeks (CF). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and, where available, the EuroQOL EQ-5D questionnaire were administered every 8 weeks from baseline until progression and then every 3 months. Time to definitive deterioration of QOL parameters was analyzed. Results The proportions of patients having assessable EORTC QLQ-C30 and EQ-5D questionnaires at baseline were 86.0% and 78.7% with DCF, respectively, and 89.7% and 92.8% with CF, respectively. Time to 5% deterioration of global health status (primary end point) significantly favored DCF over CF (log-rank test, P = .01). QOL was preserved longer for patients on DCF than those on CF for all time to deterioration analyses, demonstrating the statistical superiority of DCF compared with CF. Conclusion V325 represents the largest trial with the longest prospectively controlled evaluations of QOL during protocol chemotherapy and follow-up in patients with advanced gastric or gastroesophageal junction cancer. In V325, advanced gastric or gastroesophageal junction cancer patients receiving DCF not only had statistically improved overall survival and time to tumor-progression, but they also had better preservation of QOL compared with patients receiving CF.
The multinational, randomized, phase III V325 trial evaluated the efficacy and safety of docetaxel, fluorouracil, and cisplatin (DCF) compared with cisplatin and fluorouracil (CF) in 445 patients with advanced gastric cancer.1 All efficacy results favored DCF over CF, with DCF resulting in longer time to progression (hazard ratio [HR] = 1.473; 95% CI, 1.189 to 1.825; log-rank test, P = .0004), higher response rate (36.7% v 25.4%, respectively;  2 test P = 0.016), and longer survival (HR = 1.293; 95% CI, 1.041 to 1.606; log-rank test, P = .0201). Grade 3 or 4 nonhematologic toxicities occurred in 69% of patients in the DCF arm and in 59% of patients in the CF arm. Higher rates of grade 3 or 4 neutropenia, complicated neutropenia, and grade 3 or 4 diarrhea were associated with DCF; more stomatitis occurred with CF. Quality of life (QOL) is particularly important to patients with advanced cancer because most are symptomatic when diagnosed and the disease is incurable. Even when treatment improves overall or progression-free survival, this benefit can often be counterbalanced by the burden of treatment and/or its potential effects on patients’ QOL. Theoretically, treatment may either improve QOL (by palliating symptoms, preventing progressive deterioration of QOL by stabilizing symptoms, and preventing new symptoms) or have a negative impact on QOL (an undesirable outcome). In V325, analysis of patient-reported QOL was a predefined secondary end point to investigate whether the better efficacy with DCF was counterbalanced first by the toxicity of the regimen and second by the impact of the regimen on patient QOL. The results of the QOL analyses are described in this report.
We have described the design of this phase II/III trial elsewhere1; briefly, the phase III trial design is summarized in the following sections.
Inclusion and Exclusion Criteria
Treatment
QOL: Patient Questionnaires The EORTC QLQ-C30 questionnaire is a validated, cancer-specific instrument designed for prospective clinical trials.2 The questionnaire incorporates five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea/vomiting), a global health status/QOL scale, and six single items assessing additional symptoms commonly reported by cancer patients (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The EQ-5D questionnaire is a relatively simple instrument, comprising five questions and a visual analog scale.3
Questionnaire Administration
Statistical Methods
To be considered assessable, a questionnaire must have been completed Following the EORTC guidelines,4 the 30 items of the QLQ-C30 scales were transformed into the 15 scales mentioned earlier. A linear transformation was used to obtain scales ranging from 0 to 100, with a high score indicating a high level of functioning for the functional and global scales and, conversely, a high level of symptomatology for the symptoms scales. Missing items within a scale were handled according to the EORTC recommendations.4 The primary end point of the QOL assessment was time to definitive deterioration from baseline by 5% on the global health status/QOL scale. Secondary end points were time to definitive deterioration of global health status/QOL from baseline by 10%, 20%, and 30%; physical functioning by 5%, 10%, 20%, and 30%; and social functioning, pain, and nausea/vomiting by 10%, 20%, and 30% (for each parameter). These scales were obtained from two items of the QLQ-C30 questionnaire; for example, the scale for nausea/vomiting was derived from item 14 (question about the intensity of nausea) and from item 15 (question about the intensity of vomiting). Four scores were possible and ranged from 1 (not at all) to 4 (very much). Following the EORTC guidelines, the minimum relative observed deterioration possible was 16.6%, corresponding to a worse score of one grade (or more) on at least one item from which the scale was derived. For the scale assessing appetite loss, only the time to definitive deterioration by 30% (actually 33%) was analyzed, corresponding to a worse score of one unit (or more) for the question about appetite. Time to definitive deterioration by 5%, 10%, 20%, and 30% of the EQ-5D visual analog scale was another secondary end point. For all time to definitive deterioration analyses, treatment effect (plus CI) was estimated using a Cox model, with treatment as the only covariate. Deterioration was considered to be definitive if there was no subsequent improvement above the defined threshold before further anticancer therapy was administered. If a definitive deterioration was observed after a missing value, it was assumed that the deterioration occurred at the time of the missing value. Death was considered as an event in the absence of definitive deterioration if it occurred within 12 weeks of the last assessment. Otherwise, the patient was considered lost to follow-up and censored at the date of last assessment. The QOL schedule of assessment was dependent on whether progressive disease was reported by the investigator (assessment every 8 weeks) or not (assessment every 3 months). During the 3-monthly assessment period, if a definitive deterioration was observed more than 12 weeks from the last nondeteriorated assessment, the date of deterioration was set at the last assessment date plus 12 weeks to avoid prolonging the time to deterioration when assessments were not regularly performed. Patients receiving further antitumor therapy before definitive worsening were censored at the date of their last assessment before therapy. Baseline comparability was assessed by the two-sample Wilcoxon test. A repeated measure analysis was performed on the global health status/QOL parameter, physical functioning, social functioning, appetite loss, pain, and nausea/vomiting scales.
Patients and Assessable Questionnaires A total of 445 patients from 72 centers in 16 countries were enrolled and treated (DCF, n = 221; CF, n = 224). General baseline characteristics of the patient groups were similar (Table 1).
The proportion of patients with assessable QLQ-C30 questionnaires at baseline was 86.0% with DCF and 89.7% with CF (Table 2). The main cause of nonassessability was completion of the questionnaire between random assignment and first infusion with DCF (7.5% of patients) and translation unavailable with CF (4.5%). The rate of assessable questionnaires decreased over time (Table 2), as expected. The availability of forms was similar between the two treatment groups.
The proportion of patients with assessable EQ-5D questionnaires at baseline was 78.7% with DCF and 92.8% with CF (Table 2). The main cause of nonassessbility was also completion between random assignment and first infusion (DCF, 11%; CF, 3.2%). There were no differences between the groups at baseline in the QLQ-C30 global health status/QOL, functional, or symptom subscales or in the EQ-5D (Table 3).
Treatment Comparison Time to 5% definitive deterioration of global health status/QOL (primary end point) significantly favored DCF over CF (P = .012), with an advantage of more than 2 months in median time to definitive deterioration with DCF (6.5 months) versus CF (4.2 months; HR = 1.45; 95% CI, 1.08 to 1.93; log-rank test, P = .01; Fig 1). For all other thresholds (10%, 20%, and 30%), time to definitive deterioration of global health status/QOL from baseline occurred consistently and significantly favored DCF compared with CF (log-rank test, P = .007 to .03).
The Kaplan-Meier probability curves for the lowest defined level of deterioration of all secondary parameters are shown in Figure 2, whereas HRs and 95% CIs for time to deterioration in all QOL analyses between the treatment arms are illustrated in Figure 3. For the physical functioning parameter, time to deterioration by 5% was not significantly different between the arms (P = .1349); however, deterioration by 10%, 20%, and 30% occurred significantly later with DCF than CF (P = .017, .025, and .02, respectively). For the social functioning parameter, all analyses showed a significant advantage with DCF of a median of  2.6 months (log-rank test, P = .0008, .002, and .001 for the 10%, 20%, and 30% thresholds, respectively) compared with CF. Time to deterioration analyses also significantly favored DCF over CF for the nausea/vomiting parameter (log-rank test, P = .006, .003, and .005 for the 10%, 20%, and 30% thresholds, respectively) and the pain parameter (log-rank test, P = .026, .016, and .011 for the 10%, 20%, and 30% thresholds, respectively). Time to deterioration of appetite loss by 30% occurred significantly later (a median of 2 months later, approximately) with DCF than with CF (log-rank test, P = .020).
The time to deterioration analyses of the visual analog scale of the EQ-5D showed consistent results to those of the QLQ-C30 global health status/QOL analysis for the deterioration by 5% (log-rank test, P = .008; Figs 2 and 3), 10% (log-rank test, P = .01), and 20% (log-rank test, P = .012; Fig 3), with a later deterioration of at least 3.2 months for these three analyses. For the time to deterioration by 30%, the difference between arms was not significant (log-rank test, P = .09; Fig 3).
When choosing chemotherapy with potentially toxic agents, patients with incurable cancers often consider both length of survival and QOL. The V325 trial is the largest randomized, controlled trial that formally and systematically assessed QOL in patients with advanced gastric cancer or gastroesophageal junction. The EORTC QLQ-C30 questionnaire is a validated cancer-specific QOL instrument practical for use in prospective clinical trials.2 As reported previously,1 the V325 trial of patients with advanced gastric cancer or gastroesophageal junction, more than 95% of whom had metastatic disease, showed a significant survival advantage for patients treated with DCF compared with CF (HR = 1.29; log-rank test, P = .02). There was more grade 3 to 4 neutropenia, febrile neutropenia and/or neutropenic infection, and diarrhea with DCF than CF, but there was more grade 3 to 4 stomatitis with CF. In addition, more DCF-treated patients (62%) experienced grade 3 to 4 serious adverse events than CF-treated patients (45%). Despite this, most analyses of QOL favored the DCF arm. The primary QOL end point, time to 5% definitive deterioration of global health status/QOL, was significantly longer by more than 2 months with DCF than with CF (log-rank test, P = .01). Results of secondary QOL analyses were all consistent with the primary end point, highlighting the robustness of the results. Despite a higher rate of complicated neutropenia, QOL was better for patients in the DCF arm than for patients receiving CF. This was more evident in the later part of the follow-up and coincided with late advantages also seen in overall survival and time to progression. Furthermore, although the rates of certain adverse events were similar with DCF or CF, a difference emerged when the impact of these events was analyzed relative to QOL. For example, nausea/vomiting, regardless of cause and grade, occurred at a similar rate in the two treatment arms, yet the time to definitive deterioration of nausea/vomiting was significantly longer in DCF-treated patients. Rather than being contradictory, these results indicate that the definitive worsening of these events (as reported by the patient) evolved earlier with CF than DCF, impacting negatively on the CF-treated patients’ QOL. Three published comparative studies have evaluated QOL with different chemotherapy combinations for advanced gastric cancer.5-7 A phase III study by Webb et al7 comparing epirubicin, cisplatin, and fluorouracil (ECF) with fluorouracil, doxorubicin, and methotrexate showed better global QOL with ECF at 24 weeks (P = .04) but reported no differences between the arms for all other QOL parameters assessed. The second study compared ECF with mitomycin, cisplatin, and fluorouracil (MCF)6 and reported that QOL scores were maintained with ECF but declined with MCF, with global QOL score, physical functioning, emotional functioning, and fatigue better at 3 and 6 months for ECF and cognitive functioning better at 6 months compared with MCF. Despite the finding in these studies that ECF had the better safety profile, notably in the study by Ross et al,6 QOL data did not show a large advantage in favor of ECF. Of note, the proportion of patients with assessable EORTC QLQ-C30 questionnaires at baseline in the V325 study was more than 85%, whereas the rate of patients with baseline available questionnaires was 71.5% in the study by Ross et al6 and 72.7% in the study by Webb et al.7 In a third randomized study of 61 patients in which QOL was assessed with the EORTCQLQ-C30 instrument, chemotherapy resulted in improved QOL compared with patients who received only best supportive care.5 In many clinical trials, QOL is measured for only as long as patients receive study treatment. This strategy has a positive impact on the compliance rate but neglects the effects of long-term toxicity and QOL. The V325 trial continued to evaluate QOL after treatment had stopped. As a consequence, compliance decreased over time. As can be expected in clinical trials of advanced diseases, a substantial number of patients often progress/deteriorate and withdraw from the study. Although the compliance rate of V325 was generally good, especially during treatment, the number of patients withdrawing as a result of disease progression was considerable. The usual high attrition rate is a complicating factor in repeated-measures analysis of variance and interpretation of QOL data because it can be related to the treatment received. It can be argued that analyses based on available QOL data may erroneously lead to the conclusion that a less effective treatment is superior with respect to QOL; if only patients in sufficiently good condition complete the questionnaires, then better QOL data could come from the treatment arm experiencing poorer survival. For this reason and also because there is no gold standard for handling missing data in variance analysis, we chose the parameter of time to definitive deterioration of global health status/QOL by 5% as the primary end point of the QOL analysis following the methodology described by Awad et al.8 Because a definitive deterioration can often be captured before a patient's deterioration in physical status affects compliance, this methodology is less affected by missing data than the classical repeated-measures analysis of variance. This methodology is similar to other time to event analyses, such as the time to progression, but has been adapted to the analysis of QOL and is less impacted by the missing data than a classical analysis of variance. It allows keeping patients in the analysis even if some of their questionnaires are missing as long as they have assessable questionnaires afterwards. In addition, if a patient died within 12 weeks of the last assessment, the death was considered an event, and missing questionnaires afterwards were not considered as missing values, which is in contrast to an analysis of variance. When a patient deteriorated and did not have an assessment after that point, the patient was considered as definitively deteriorated because it is assumed that the reason for the missing data was the worsening of the patient's QOL. This approach has been shown to be sensitive when true differences in QOL exist.9-11 Of note, even though the methodology was not the same, Ross et al6 also used QOL parameter deterioration, with scores evaluated at 3 and 6 months. Another factor to consider in the design of trials evaluating QOL is how to schedule completion of the questionnaire. During treatment in the V325 study, all assessments were performed before the patient received the next chemotherapy cycle. The reasons for this are many. Logistically, it is easier to assess QOL during a scheduled hospital visit; capturing the toxicity at its maximum would potentially require one or more extra hospital visits by patients just to complete a questionnaire, adding to a patient's burden; and any antitumor effect is most easily recognized before a new treatment cycle, and thus, this scheduling provides a more accurate time point for comparison. In summary, the V325 randomized phase III trial resulted in a significantly better preservation of QOL for patients treated with DCF than patients treated with CF. In V325, better preservation of QOL occurred as a result of a significantly higher level of efficacy imparted by the addition of docetaxel to CF compared with CF alone despite a higher incidence of some toxicities as a result of the addition of docetaxel to CF. Clearly, the quantity and quality of life are important outcomes, and ideally, treatment should enhance both. Research on QOL provides a qualitative and quantitative basis to integrate these elements into the decision-making process. The QOL results of the V325 study consistently favored DCF over CF, supporting the benefit of DCF in patients with advanced gastric or gastroesophageal junction adenocarcinoma.
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: Lucile Awad, Sanofi-aventis Leadership: N/A Consultant: Jaffer A. Ajani, Sanofi-aventis; Manuel Constenla, Sanofi-aventis; Corrado Boni, Sanofi-aventis; Eric Van Cutsem, Sanofi-aventis Stock: N/A Honoraria: Jaffer A. Ajani, Sanofi-aventis; Sergei Tjulandin, Sanofi-aventis; Manuel Constenla, Sanofi-aventis; Corrado Boni, Sanofi-aventis Research Funds: Jaffer A. Ajani, Sanofi-aventis; Sergei Tjulandin, Sanofi-aventis; Manuel Constenla, 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: Lucile Awad Administrative support: Lucile Awad 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: Lucile Awad Data analysis and interpretation: Jaffer A. Ajani, Lucile Awad Manuscript writing: Jaffer A. Ajani, Lucile Awad Final approval of manuscript: Jaffer A. Ajani
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. Fayers P, Aaronson N, Bjordal K, et al: EORTC QLQ-C30 Scoring Manual. Brussels, Belgium, European Organisation for Research and Treatment of Cancer, 1995 3. Kind P: The EuroQol instrument: An index of health-related quality of life, in Spilker B (ed): Quality of Life and Pharmacoeconomics in Clinical Trials (ed 2). Philadelphia, PA, Lippincott-Raven, 1996, pp 191-201 4. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organisation for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993 5. 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 6. 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 7. Webb A, Cunningham D, Scarffe JH, et al: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261-267, 1997 8. Awad L, Zuber E, Mesbah M: Applying survival data methodology to analyze quality of life data, in Mesbah M, Cole BF, Ting Lee M-L (eds): Statistical Methods for Quality of Life Studies: Design, Measurements and Analysis. Boston, MA, Kluwer Academic Publishers, 2002 9. Cunningham D, Pyrhönen 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] 10. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998[CrossRef][Medline] 11. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355:1041-1047, 2000[CrossRef][Medline] Submitted July 23, 2006; accepted October 30, 2006.
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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
15 days before random assignment for the baseline assessment and more than 10 days after the start of the latest infusion for assessments during the treatment period; this allowed assessment of the patient's QOL after recovery from potential acute toxicities of the drug. Questionnaires without an assessment date or those completed after the cutoff date or after further antitumor therapy were not assessable. If more than one questionnaire was received from a patient within a defined window, the mean of the assessable values was taken. 
