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Originally published as JCO Early Release 10.1200/JCO.2004.08.080 on October 4 2004 © 2004 American Society of Clinical Oncology. Quality of Life in Ovarian Cancer Patients: Comparison of Paclitaxel Plus Cisplatin, With Cyclophosphamide Plus Cisplatin in a Randomized StudyFrom the University Health Network, Princess Margaret Hospital, Toronto; National Cancer Institute of Canada Clinical Trials Group, Queen's University Cancer Research Institute, Kingston, Ontario; QOL Consulting, Vancouver, British Columbia; Tom Baker Cancer Centre, Calgary, Alberta, Canada; Chinese University of Hong Kong, Hong Kong, China; and Institut Jules Bordet, Brussels, Belgium Address reprint requests to Andrea Bezjak, MD, Princess Margaret Hospital/University Health Network, 610 University Avenue, Suite 5-911, Toronto, ON M5G 2M9, Canada; e-mail: andrea.bezjak{at}rmp.uhn.on.ca
PURPOSE: Formal quality-of-life (QOL) assessments may contribute important information on patient symptoms. Despite many trials of systemic chemotherapy in ovarian cancer, reports of its effect on QOL are few. PATIENTS AND METHODS: QOL was assessed in an Intergroup randomized trial comparing paclitaxel plus cisplatin to cyclophosphamide plus cisplatin in women with advanced ovarian cancer. One hundred fifty-two eligible patients accrued in Canada completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and a trial-specific checklist at baseline (after surgical debulking) and at regular intervals during and after chemotherapy. Mean change scores over time in the two arms were calculated.
RESULTS: Compliance with QOL questionnaire completion was excellent (81% to 93%). In general, deterioration was seen in the QOL domains immediately after chemotherapy (day 8 of cycle 1), followed by clinically meaningful improvements compared with baseline (change scores CONCLUSION: Improvement from baseline in QOL measures was seen in both treatment arms. The greater neurologic and muscle toxicity of paclitaxel did not adversely influence QOL. QOL data can contribute useful information on the experience of symptoms and their time course, which may assist patients and physicians in their discussion about the anticipated effects of therapy.
Quality of life is of great importance in assessing the impact of therapy in patients with locally advanced cancers. Women with advanced epithelial ovarian cancer frequently are treated with, and demonstrate a response to chemotherapy, but have only a modest chance of long-term survival; only approximately 10% to 20% of women with advanced disease are progression free 5 years after their diagnosis.1-3 Numerous randomized studies comparing various chemotherapy regimens have been completed in the last two decades. Results from these trials have been summarized in several recent meta-analyses or systematic reviews.1-3 They concluded that platinum-containing combination regimens were superior to the same regimen without platinum, that carboplatin and cisplatin were similarly efficacious, and that there was some evidence that platinum combination treatment was superior to single-agent platinum. As a result, cisplatin plus cyclophosphamide emerged as the standard of care to which new regimens would be compared. Subsequent to these trials, a series of studies have been completed that examined the benefits of adding paclitaxel to first-line therapy. Four trials compared first-line paclitaxel versus nonpaclitaxel therapy and yielded conflicting results.4-7 In two studies (Gynecologic Oncology Group 111, Intergroup trial4,5) the paclitaxel arm was clearly superior in terms of progression-free and overall survival. In the remaining two studies (Gynecologic Oncology Group 132, International Collaborative Ovarian Neoplasm Group 36,7), no such advantage to the experimental arm could be documented. Many have sought to explain these discordant observations without convincing success. Because the positive trials were the first to be done, the majority of the ovarian cancer community has moved to adopt paclitaxel plus a platinum compound as the standard of care, and certainly the standard for the next generation of studies. Despite the fact that numerous comparative therapeutic studies have been completed, there are relatively few reports of comparisons of the quality-of-life (QOL) effects of these differing therapies. As noted, given that most women with advanced ovarian cancer are not cured and many regimens have similar efficacy, differences in QOL may help determine which regimen is preferred. Furthermore, systematic documentation of the QOL experience of patients enrolled onto clinical trials may assist in providing information to future nontrial patients regarding the expected effects of therapy as they make their treatment choices. The QOL literature is more scant in ovarian cancer than in other common malignancies,8,9 with relatively few publications detailing QOL effects of chemotherapy,10,11 and others exploring specific QOL issues, including fatigue12 and survivorship issues.13 A recently published randomized trial of cisplatin plus paclitaxel versus carboplatin plus paclitaxel14 includes QOL results in 679 patients with advanced ovarian cancer, also using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30); tumor efficacy was comparable, but the toxicity profile was better with carboplatin, with small but significant differences in QOL scores in favor of that regimen. This article reports the results of QOL assessments obtained at baseline and throughout therapy in Canadian women with a diagnosis of advanced epithelial ovarian cancer enrolled onto an Intergroup multicenter trial of paclitaxel plus cisplatin (TP) versus cyclophosphamide plus cisplatin (CP). Specifically, we compared the QOL experience between the two study arms. The results of the study, indicating improved progression-free and overall survival with paclitaxel plus platinum, were reported in May 2000.5 Since that date, an update of more mature survival information shows a continued significant survival advantage to the paclitaxel arm (relative hazard of death, 0.75; 95% CI, 0.63 to 0.90).15
Randomized Trial The Intergroup phase III comparison of TP and CP in advanced epithelial ovarian cancer (National Cancer Institute of Canada Clinical Trials Group [NCIC CTG] OV.10/EORTC 55931) was a joint study of the EORTC Gynecological Cancer Cooperative Group, NCIC CTG, Nordic Gynecological Cancer Study Groups, and Scottish Gynecologic Cancer Trials Group. The primary objective of the study was to determine whether the substitution of paclitaxel given during 3 hours for cyclophosphamide in combination with cisplatin would improve the progression-free survival of first-line therapy of advanced ovarian cancer. Secondary end points included response rate, overall survival, toxicity, QOL, and cost effectiveness. Patients with epithelial ovarian carcinoma, International Federation of Gynecology and Obstetrics stages IIb, IIc, III, and IV were randomly assigned to receive six cycles of either TP (paclitaxel 175 mg/m2 administered during a 3-hour infusion and cisplatin 75 mg/m2 administered intravenously every 3 weeks) or CP (cyclophosphamide 750 mg/m2 and cisplatin 75 mg/m2 administered intravenously every 3 weeks). A total of 680 patients (668 eligible) were accrued in a 16-month period from 1994 to 1995. As noted, the study demonstrated that TP produced significantly superior survival compared with the standard CP arm.
Quality of Life Assessment
QOL assessments were to be done at baseline and on day 1 (prechemotherapy) of each cycle of chemotherapy, on day 8 of cycle 1, and every 3 months after the completion of treatment until disease progression or for a total of 2 years after the end of chemotherapy, whichever came first. Although the study called for six cycles of chemotherapy, patients with an incomplete response could be offered another one to three cycles at the discretion of their oncologist; QOL information was collected on day 1 of those cycles as well.
Statistical Analyses Questionnaire completion rates at baseline and during the protocol treatment were calculated for all patients enrolled onto the study. Mean baseline scores for each of the domains and items in the core and trial-specific questionnaires for each of the treatment groups were first calculated. At each assessment point postbaseline and for each domain and item, the change score from baseline was then calculated as the difference between the score at this time point and the baseline score for all patients who had scores recorded at both this time and baseline. The mean change score for all patients at a given time was calculated and compared between the two treatment groups using the Wilcoxon rank sum test. A positive change in mean scores for the functional domains (physical, role, cognitive, emotional, and social) as well as the global QOL score indicated improvement, whereas a positive change in mean scores for the symptom domains from the core questionnaire and the symptom items from the trial-specific check list indicated worsening. As a secondary analysis of several domains and issues of interest (global QOL, muscle pain, and sensation in fingers or toes), growth curves18 were constructed using repeated measures analysis. Because the patients from the Nordic and Scottish groups did not participate in the QOL study and a large portion of EORTC patients did not complete the baseline questionnaires (40% rate of completion), only the patients enrolled by NCIC CTG were included in the comparative analyses.
Patient Population Between 1994 and 1995, 680 patients were accrued onto the study; 160 of these (152 eligible) were accrued in Canada by NCIC CTG participating institutions. Table 1 shows the demographic and clinical characteristics of the overall population, as well as the Canadian subset, by treatment arm. They were comparable with the exception of baseline performance status. Fewer Canadian patients with baseline ECOG performance status of 0 were randomly assigned than in the overall study population. Most patients (93%) had a laparotomy before study entry, and had residual disease more than 1 cm (suboptimally debulked, 67%) before beginning treatment. The most frequent sites of disease at time of random assignment were pelvis (66%), ascites (43%), nodes (24%), pleural effusion (24%), liver (20%), and abdomen (17%).
Compliance With QOL Completion Tables 2 and 3 show the compliance, by study arm, for completion of QOL questionnaires during therapy at the protocol-prescribed intervals for NCIC CTG patients. Eight of the 160 Canadian patients were ineligible for the study, leaving 152 eligible patients included in the QOL analysis. Compliance for NCIC CTG patients was excellent (81% to 93%) at all time points, aside from day 8 in cycle 1 for which QOL data were logistically more difficult to collect, and was not enforced for the entire duration of the study. Because of a higher proportion of patients completing all cycles of chemotherapy in the TP arm (88% TP patients completed at least six cycles versus 77% of CP patients), there was a somewhat greater number of patients providing on-treatment QOL information in this arm in comparison with the CP arm.
Effect of Treatment on QOL The mean and standard deviation of the baseline scores for each domain and item are given in Table 4. Patients in both study arms showed impairment at baseline of global QOL, role function, and social function, as well as a significant burden of symptoms, particularly fatigue, loss of appetite, sleep problems, pain, swelling in abdomen, and stomach cramps. The baseline QOL scores were comparable between the two arms, with the exception of more frequent urination in the CP arm (mean, 25.7 versus 13.9; P = .03) and marginally better social functioning in the CP arm (mean, 54.9 versus 44.2; P = .05).
Tables 5, 6, and 7 list the mean change scores from baseline by treatment arm for each domain and item during therapy and up to 24 months after completion of treatment. For most items, the pattern of change in mean scores is similar over time in both study arms, with few instances of significant differences observed. In general, there was deterioration seen in the QOL domains immediately after chemotherapy (day 8 of cycle 1), followed by clinically meaningful improvements compared with baseline (change scores  10) in both arms in a number of domains and items. Improvement was observed by cycle 2 of chemotherapy, and included global QOL (Fig 1), emotional function, social function, fatigue, pain, sleep, constipation, appetite, abdominal swelling, and abdominal cramps. Improvements in global QOL (change scores ranging from 10 to 20) persisted for the duration of follow-up; there was a marginal advantage in global QOL in patients in the CP arm during chemotherapy, which was not seen in the postchemotherapy period.
Although both cisplatin and paclitaxel may be associated with neurotoxicity, there were significant differences in the change scores for both muscle pain and neurotoxicity (sensation in fingers or toes), with worse symptoms during chemotherapy in the TP arm. Although muscle pain tended to improve (lower scores) in the CP arm, it worsened (higher scores) over the same time frame in the TP arm. These differences were both clinically and statistically significant. As shown in Fig 2, the differences in muscle pain disappeared toward the end of chemotherapy. Sensory changes followed a similar pattern (Fig 3). Increases in mean change scores reflective of more severe symptoms were seen in the TP arm early during treatment (by cycle 3). Although symptoms also increased in the CP arm, these occurred later (by cycle 8) and were less severe. With follow-up after completion of therapy, the differences between arms seemed to disappear after a year, as shown in Fig 3.
Growth curves of the three domains and issues of specific interest (global QOL, muscle pain, and sensation in fingers or toes) confirmed the above-mentioned conclusions: there were no differences between the two study arms at any of the time points within the first year for global QOL (Fig 1B); worse muscle pain for TP at the 3-month time point only; and worse sensation in fingers or toes at 3, 6, 9, and 12 months (data beyond 12 months were not included).
This trial was undertaken primarily to determine if TP offered superior progression-free and overall survival outcomes compared with a standard of CP in women with newly diagnosed advanced epithelial ovarian cancer. The results were convincing in demonstrating highly significant increases in both progression-free and overall survival for the study arm (TP; approximately 4- and 10-month increases of median survivals, respectively).5 QOL measures were undertaken to provide a longitudinal view of patient-reported symptoms, both disease and treatment related, as well as providing a general assessment of global well-being and functional status of patients treated with both regimens. If this study had demonstrated therapeutic equivalence between the two regimens, the QOL data would have been critical to the decision-making process in recommending one regimen over another. Even though the difference in efficacy was pronounced, the QOL data can still play a useful role in describing the impact of treatment in terms that might help inform patients about the experience of therapy. Our data show that over the course of treatment, both regimens are associated with a meaningful improvement in most of the domains and symptoms of QOL. The persistence of improvement while enrolled onto the study suggests that this is due to the palliative effect of chemotherapy on the tumor, which one would assume would continue until the time of clinical relapse. Despite the shorter progression-free survival with CP, the global QOL improvements were just as prompt during therapy as those seen with TP. With respect to the impact of toxicity, the results of our study suggest that QOL information was consistent with the reported toxicity19: more neurosensory effects and myalgia were documented in the TP arm. The completeness of the longitudinal measures of these symptoms up to 24 months after treatment provides some reassurance that, with time, both arms come together in the magnitude of these effects: neurosensory changes were similar (as measured by mean change scores from baseline) by about 12 months after treatment was complete. Differences in myalgia between the arms disappeared by about 3 months after therapy. Furthermore, despite the differences in the individual symptom experience between the arms, there was no apparent adverse impact of these on the main domains of QOL: mean scores for global QOL, and physical, emotional, social, and role functions were similar over time in both arms. Both of these observations (the recovery from significant treatment-related symptoms and the lack of apparent impact on global functioning) are clinically useful data that were not previously documented, and that may assist both the woman and the physician in the discussion about the anticipated effects of the proposed chemotherapy treatments. As in any QOL analysis, the data need to be interpreted bearing in mind potential study limitations. Limitations of this study are that it represents QOL information only from the Canadian subset of patients (ie, 22% of patients accrued in the study). Although these patients were comparable in their baseline characteristics with the patients accrued in other countries, some confounding variables unique to the Canadian centers (eg, supportive care measures employed) may have had an impact on the QOL scores. The baseline QOL scores and symptoms may have been due to the effect of surgery rather than ovarian cancer itself; thus, improvements in QOL and symptoms may have occurred even in the absence of chemotherapy. Only patients still participating in the study (who have not experienced disease progression) are providing QOL data, and as time goes by, this becomes a small proportion of the initial patient cohort. Thus, maintenance of QOL improvement is not seen in all patients entering onto the study. However, one should not assume that the QOL improvements are confined only to responders; in an analysis of QOL data from a breast cancer study, we have demonstrated a gradient effect of QOL response and tumor response, with QOL improvements seen also in patients with stable disease.20 Since this study was completed, additional randomized studies have been conducted with the substitution of carboplatin for cisplatin in the paclitaxel regimen.14,21,22 Those trials have not shown any differences in efficacy between the two platinums, but have consistently demonstrated less neurotoxicity in the carboplatin plus paclitaxel arms as measured by traditional toxicity grading. For these reasons, carboplatin plus paclitaxel is widely regarded as the current standard of care. Nevertheless, our results demonstrate QOL benefits of both chemotherapeutic regimens.
The authors indicated no potential conflicts of interest.
We thank Eric Bacon for his excellent statistical assistance, Keith James, MD, for the coordination of the study, and the many patients, clinical research associates, and investigators who contributed to the study.
Supported by a core grant from the National Cancer Institute of Canada, and in part by funding from Bristol Myers-Squibb and the EORTC Data Centre. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Advanced Ovarian Cancer Trialists Group: Chemotherapy for advanced ovarian cancer, in The Cochrane Library Issue 2, Chichester, UK, John Wiley and Sons Ltd, 2004 2. The Ovarian Cancer Meta-Analysis Project: Cyclophosphamide plus cisplatin versus cyclophosphamide, doxorubicin and cisplatin chemotherapy of ovarian carcinoma: A meta-analysis. J Clin Oncol 9:1668-1674, 1991[Abstract] 3. Covens A, Carey M, Bryson P, et al: Systematic review of first-line chemotherapy for newly diagnosed postoperative patients with stage II, III, or IV epithelial ovarian cancer. Gynecol Oncol 85:71-80, 2002[CrossRef][Medline]
4. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1-6, 1996
5. Piccart MJ, Bertelsen K, James K, et al: Randomized Intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced ovarian cancer. J Natl Cancer Inst 92:699-708, 2000
6. Muggia FM, Braly PS, Brady MF, et al: Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: A Gynecologic Oncology Group Study. J Clin Oncol 18:106-115, 2000 7. The International Collaborative Ovarian Neoplasm (ICON) Group: Paclitaxel plus carboplatin versus standard chemotherapy with either single agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: The ICON3 randomised trial. Lancet 360:505-515, 2002[CrossRef][Medline] 8. Montazeri A, McEwan J, Gillis CR: Quality of life in patients with ovarian cancer: Current state research. Support Care Cancer 4:169-179, 1996[CrossRef][Medline] 9. Bezjak A: Quality of life in women with cancer, in Kabanagh J, Singletary E, Einhorn N, et al (eds): Cancer in Women. Malden, MA, Blackwell, 1998, pp 610-632 10. Schink JC, Weller E, Harris LS, et al: Outpatient Taxol and carboplatin chemotherapy for suboptimally debulked epithelial carcinoma of the ovary results in improved quality of life: An Eastern Cooperative Oncology Group phase II study (E2E93). Cancer J 7:155-164, 2001[Medline] 11. Lakusta CM, Atkinson MJ, Robinson JW, et al: Quality of life in ovarian cancer patients receiving chemotherapy. Gynecol Oncol 81:490-495, 2001[CrossRef][Medline] 12. Holzner B, Kemmler G, Meranger V, et al: Fatigue in ovarian carcinoma patients: A neglected issue? Cancer 97:1564-1572, 2003[CrossRef][Medline] 13. Wenzel LB, Donnelly JP, Fowler JM, et al: Resilience, reflection, and residual stress in ovarian cancer survivorship: A Gynecologic Oncology Group study. Psychooncology 11:142-153, 2002[CrossRef][Medline]
14. Du Bois A, Luck H-J, Meier W, et al: A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95:1320-1330, 2003
15. Piccart M, Bertelsen K, Stuart G, et al: Long-term follow-up confirms a survival advantage of the paclitaxel-cisplatin regimen over the cyclophosphamide-cisplatin combination in advanced ovarian cancer. Ann Oncol 13:109, 2002 (suppl 5) 16. Osoba D, Zee B, Pater J, et al: Psychometric properties and responsiveness of EORTC Quality of Life Questionnaire (QLQ-C30) in patients with breast, ovarian and lung cancer. Qual Life Res 3:353-364, 1994[CrossRef][Medline] 17. Fayers P, Aaronson N, Bjordal K, et al: EORTC Scoring Manual (ed 2). Brussels, Belgium, EORTC Quality of Life Study Group, 1999 18. Zee B: Growth curve model analysis for quality of life data. Stat Med 17:757-766, 1998[CrossRef][Medline] 19. Bacon M, James K, Zee B: A comparison of the incidence, duration and degree of the neurological toxicities of cisplatin-paclitaxel (PT) and cisplatin-cyclophosphamide (PC). Int J Gynecol Cancer 13:428-434, 2003[CrossRef][Medline]
20. Geels P, Eisenhauer E, Bezjak A, et al: The palliative effect of chemotherapy: Objective tumor response correlates with symptom improvement in patients with metastatic breast cancer. J Clin Oncol 18:2395-2405, 2000 21. Ozols RF, Bundy BN, Fowler J, et al: Randomized phase III study of cisplatin (CIS)/paclitaxel (PAC) versus carboplatin (CARBO)/PAC in optimal stage III epithelial ovarian cancer (OC): A Gynecologic Oncology Group Trial (GOG 158). Proc Am Soc Clin Oncol 18:356a, 1999 (abstr 1373)
22. Neijt JP, Engelholm SA, Tuxen MK, et al: Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 18:3084-3092, 2000 Submitted August 12, 2003; accepted September 1, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
