Quality of life (QOL) outcomes from a randomized trial of cisplatin versus cisplatin plus paclitaxel in advanced cervical cancer: A Gynecologic Oncology Group study

Gynecologic Oncology 101 (2006) 296 – 304 www.elsevier.com/locate/ygyno

Quality of life (QOL) outcomes from a randomized trial of cisplatin versus cisplatin plus paclitaxel in advanced cervical cancer: A Gynecologic Oncology Group study Richard P. McQuellon a,*, Howard T. Thaler b,c, David Cella d,e, David H. Moore f a

Psychosocial Oncology, Comprehensive Cancer Center of Wake Forest University, Department of Internal Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1082, USA b Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA c GOG Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA d Psychiatry and Behavioral Science Research, Institute for Health Services Research and Policy Studies, Northwestern University, Evanston, IL 60208, USA e Center on Outcomes, Research and Education, Evanston Northwestern Healthcare, Evanston, IL 60201, USA f Department of Obstetrics/Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA Received 26 April 2005 Available online 10 January 2006

Abstract Objective. Chemotherapy can profoundly affect patients’ quality of life (QOL), yet few clinical trials in advanced cervical cancer have included QOL outcomes. Our purpose was to assess the impact of cisplatin (C) versus cisplatin plus paclitaxel (CP) on overall QOL and pain in cervical cancer patients. Methods. QOL was assessed using FACT-Cx, consisting of the Functional Assessment of Cancer Therapy (FACT-G) plus a cervix cancerspecific subscale, the Brief Pain Inventory-Short Form (BPI-SF), and a neurotoxicity subscale. Time points were: baseline (prior to randomization) and prior to chemotherapy cycles 2, 3, and 4. Results. Overall (FACT-G) scores did not differ significantly between arms at the fourth assessment (C = 70.3 (19.6); CP = 72.8 (17.4)). Scores were stable over time and considerably lower than the general population norms. The BPI-SF revealed a decline in pain scores in both arms from the first to fourth assessments. The CP arm produced a significantly higher response rate and progression-free survival (PFS) but not overall survival (OS). Greater myelosuppression was reported in the combination arm. The rate of QOL drop-out for any reason was higher for C (53%) compared to CP (38%) (P < 0.05). At the fourth time point, 60% of living patients in both arms completed a QOL assessment. Conclusion. There was no significant difference in overall QOL scores between treatment arms or serially. Combined with QOL results, the significant increase in response and PFS in the CP arm and the higher drop-out rate in the C arm suggest a better outcome for the combination regimen despite its increased myelosuppression. D 2005 Elsevier Inc. All rights reserved. Keywords: Quality of life; FACT-Cx; Advanced cervical cancer; Cisplatin chemotherapy

Introduction Assessment of quality of life (QOL) is important for evaluating the full impact of cancer therapies on the wellbeing of patients. The inclusion of QOL as an outcome in clinical trials allows cancer researchers to compare different

* Corresponding author. Fax: +1 336 716 5687. E-mail address: [email protected] (R.P. McQuellon). 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.10.039

treatments for more than the traditional endpoints of response rate, progression-free survival (PFS), and overall survival. This is especially important in advanced disease when one treatment offers a modest survival benefit over another at the expense of increased toxicity. If two treatments produce similar short-term impairment of patients’ QOL but one has a clear survival advantage, that regimen may become the treatment of choice. However, advances in the treatment of cancer that result in small incremental survival benefit using combinations of chemotherapeutic agents can be quite debilitating with regard

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to toxicity and overall QOL. In recent years, interest in patient QOL has increased and such endpoints are being integrated into clinical trials, providing potential for broadening treatment decisions based upon QOL data [1]. The US

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Food and Drug Administration currently requests that new cancer drugs be evaluated with regard to their impact on overall QOL in addition to their potential for extending survival [2].

Fig. 1. (Two-sided) GOG patient reporting form (FACT-G + BPI).

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Fig. 1 (continued).

It is estimated that 10,370 women in the United States will develop cervical cancer in 2005 and that 3710 will die of the disease [3]. In addition to advancing the study of traditional response and survival outcomes, treatment of advanced carcinoma

of the cervix also provides opportunity to assess patient-reported QOL. Especially important is the benefit analysis of short-term chemotherapy-induced interference with QOL relative to a longterm gain of potential increased survival in an incurable disease.

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Quality of life of patients with advanced cervical cancer has been reported as poor and generally lower than published norms [4]. One prospective study assessing QOL of female cancer patients reported follow-up data at 6 –8 weeks after initiating treatment [5]. The sample included patients with breast (n = 65), cervical (n = 79), ovarian (n = 64), and endometrial (n = 40) cancer. During treatment, women with gynecologic cancers had lower physical functioning scores when compared to those with breast cancer, and cervical cancer patients had lower role functioning relative to breast cancer patients. Additionally, all patients had a high level of impairment of the various QOL dimensions during treatment. For all women, global QOL and emotional functioning were mostly affected during and after treatment. Capelli et al. [6] assessed QOL among 115 ovarian, cervical, and endometrial cancer patients using the SF-36, a measure developed and standardized using a sample from the general population. While they do not report solely on cervical cancer patients, they did observe that women with progressive/ recurrent disease had significantly lower scores on all QOL scales when compared with same-aged healthy subjects. Among the cervical cancer patients, 19% had stage III or IV disease. It is not surprising that patients with recurrent cervical cancer would score lower on overall and dimension-specific QOL measures when compared with a healthy control group. In contrast to these studies, Ota and colleagues [7] reported on one patient treated with paclitaxel for recurrent adenocarcinoma of the cervix whose QOL scores were favorable during and after treatment. Currently, median survival for patients with advanced carcinoma of the cervix is reported as less than 6 months, with fewer than 20% surviving 1 year [8]. Women with advanced cervical cancer are known to experience pain and QOL deficits as a result of disease progression. With no curative options, it is important to develop treatment strategies that minimize toxicity and maximize QOL in the short term (less than 3 months). This can be a delicate balance, because even though chemotherapy may produce unwanted side effects (including nausea, diarrhea, and malaise), it may also ameliorate symptoms of pain by shrinking tumors that are impinging on vital organs. The purpose of this study was to integrate QOL assessment into a phase III Gynecologic Oncology Group (GOG) treatment protocol comparing cisplatin (C) versus cisplatin plus paclitaxel (CP) for advanced cervical cancer. Clinical results indicated that there was a significant difference between these two treatments favoring CP for objective response rate and PFS, with no difference in overall survival [9]. In this paper, we report on overall QOL and pain experience among patients undergoing chemotherapy for advanced cervical cancer. The QOL endpoints were viewed as a general evaluation of treatment effect upon patients. Methods Eligibility The treatment trial opened to patient accrual in August, 1997 and closed in March, 1999. Patients were enrolled on the study from 46 GOG member

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institutions. Eligibility requirements included: histologically proven Stage IVB, recurrent or persistent squamous cell carcinoma of the cervix not responsive to curative treatment with surgery and/or radiation therapy; lesions measurable by physical examination, radiography, computer tomography, or magnetic resonance imaging; and GOG performance status of 0 – 2. Other requirements were as previously described [9]. Patients provided written informed consent consistent with all Federal, state, and local (Institutional Review Board) requirements. Random allocation was to either single agent cisplatin at an intravenous dose of 50 mg/m2 at the rate of 1 mg per minute, or to paclitaxel intravenously at a dose of 135 mg/m2 as a 24-h infusion followed immediately by cisplatin at a dose of 50 mg/m2. Patients who received paclitaxel were pre-medicated with dexamethasone, diphenhydramine, and an H2 receptor antagonist. Both groups received a prophylactic antiemetic regimen along with adequate intravenous hydration and electrolyte replacement. Treatment cycles were repeated at 21day intervals, to a total of six cycles unless disease progression or toxicity prohibited further therapy.

QOL procedure and compliance Patients were to complete QOL assessments consisting of 64 questions at four time points: at baseline (prior to randomization), and prior to treatment cycles 2, 3 and 4. Since a distinguishing feature of this study was to assess the effects of disease and treatment via the patient’s own experience (as opposed to investigator-rated), every effort was made to minimize patient burden by developing a questionnaire that was detailed, yet easy to complete (Fig. 1). In the event treatment was delayed, assessments were requested by week 4 (for delay of cycle 2), by week 7 (for delay of cycle 3), and by week 10 (for delay of cycle 4). All patients alive at each time point, including those who had progressed, were to complete the assessments.

Assessment instruments Functional Assessment of Cancer Therapy-G (FACT-G) The general version of the Functional Assessment of Cancer Therapy (FACT-G) is a 29-item self-report questionnaire that consists of five subscales: physical (PWB), functional (FWB), social/family (SFWB), emotional (EWB) well-being, and relationship with doctor (RWD). Each item is rated on a Likerttype scale from 0 (not at all) to 4 (very much). The range of scores on the FACT-G is 0 to 108 (27 items  4). The FACT-G was developed and validated to measure QOL in cancer patients and was designed for use in clinical trials [10] (note: the current form, Version 4 of the FACT-G, no longer includes the two-item RWD subscale). Although it can be adapted for use in an interview format, it was utilized in this study as a self-report tool easily completed in 5 – 10 min. Patients were asked to rate how they feel today and over the previous 7 days. The FACT-G subscale scores can be aggregated into a total QOL score, with a higher score indicating better QOL. Cronbach’s alpha for each subscale has been reported as follows: PWB (0.82); FWB (0.80); SFWB (0.69); EWB (0.74); RWD (0.65); and total FACT-G (0.89). Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) FACT-Cx is the FACT-G plus a cervix cancer-specific subscale. The cervix subscale consists of 15 questions developed from interviews with patients and clinicians involved with cervical cancer. The range of scores on the Cx subscale is 0 to 60 (15 items  4). A Trial Outcome Index (TOI) representing PWB + FWB + the Cx subscale was used as a measure of treatment impact on physical symptoms and functioning. Brief Pain Inventory-Short Form (BPI-SF) The BPI-SF is a 14-item instrument designed to assess pain in patients with cancer and other diseases. The BPI-SF measures intensity of pain (5-item sensory dimension, each item scored as 0 – 10) plus two questions regarding current medications and medication relief, and interference of pain in the patient’s life (7-item reactive dimension, each item scored as 0 – 10) [11]. The BPI has demonstrated both reliability and validity across cultures and

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R.P. McQuellon et al. / Gynecologic Oncology 101 (2006) 296 – 304 subsequent evaluations, or to drop out of the treatment study entirely. We were aware that, even among patients who completed protocol therapy, there could be a subset who chose to opt out of the QOL component. Data that are not missing at random require a method of analysis that avoids biasing results. The Pattern-Mixture Model is an effective method to avoid this potential bias since it accounts for the fact that the cohort of participating patients at each assessment point is dynamic [13]. We defined patients as either Completers or Drop-Outs. A Completer was defined as a patient who provided any QOL assessment at the fourth time point and a Drop-Out was defined as any other patient; namely, one who did not provide an assessment at the fourth time point whether or not they remained alive or receiving protocol therapy. In both cases, this was without regard for their previous compliance at assessment points 1 – 3. A separate mixed model analysis of variance was computed for Completers and Drop-Outs. The mixed model analysis of variance assumes that each patient within a group has an individual time trend summarized by an intercept and slope. Each group has its own mean and variance for these parameters, which can be compared. Time trends and treatment effects were thus assessed separately for Completers and for Drop-Outs. Results were then combined in the Pattern-Mixture Model by the delta method. Statistical significance was taken as P < 0.05.

Table 1 Patient characteristics (n = 264) Characteristic

C (n = 134)

Race White African American Hispanic Asian American Filipino Performance status 0 1 2 Site of disease Pelvis Distant Both Grade 1 2 3 Unspecified Prior radiotherapy Mean age—years (range) Treatment Median no. cycles (range) Not treated

CP (n = 130)

No.

%

No.

%

92 29 11 1 1

69 22 8 1 1

75 47 6 2 0

58 36 5 2 0

64 59 11

48 44 8

59 54 17

45 42 13

66 49 19

49 37 14

52 61 17

40 47 13

5 4 90 67 38 28 1 1 123 92 46 (22 – 84)

8 6 78 60 42 32 2 2 118 91 48 (21 – 77)

4 (0 – 10) 4

5 (0 – 11) 1

Results Demographics and patient characteristics are reported in Table 1. There were no statistically significant differences between patients on either treatment arm, although the number of patients with pelvic versus distant disease was 66 and 49, respectively, on the C arm and 52 and 61, respectively, on the CP arm.

languages, and has been used to study the effectiveness of pain treatment [12]. A score of 6 on any single item is generally considered to be clinically significant.

Quality of life

Neurotoxicity subscale A 6-item subscale was included to capture specific neurotoxic adverse effects associated with paclitaxel and/or cisplatin chemotherapy. The range of scores on this subscale is 0 to 24 (6 items  4). Results of this scale are not reported here.

Of 264 eligible patients, 252 (96%) completed the baseline QOL assessment. A majority of patients (139/233 patients alive at that time point = 60%, or 139/264 eligible patients who began protocol therapy = 53%) completed the QOL assessment at the fourth time point. There were more Completers in the CP arm compared to the C arm (77 versus 62). Overall QOL scores were stable among Completers with no difference between arms (scores not reported here).

Statistical analysis Patients participating in clinical trials, whose disease status worsens over time, are more likely than those whose disease status improves, to miss

Table 2 Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) mean scores (SD) at four time points Assessment

PWBa SFWBb EWBc FWBd FACT-Cxe TOIf FACT-Gg a b c d e f g

Assessment #1 (baseline) (n = 252)

Assessment #2 (pre-cycle 2) (n = 216)

Assessment #3 (pre-cycle 3) (n = 177)

Assessment #4 (pre-cycle 4) (n = 139)

C (n = 130)

C (n = 108)

C (n = 85)

C (n = 62)

CP (n = 122)

CP (n = 108)

CP (n = 92)

CP n = 77)

Mean

(SD)

Mean

(SD)

Mean

(SD)

Mean

(SD)

Mean

(SD)

Mean

(SD)

Mean

(SD)

Mean

(SD)

17.7 20.8 14.2 13.5 35.5 66.5 66.0

(6.9) (5.3) (5.4) (7.0) (6.6) (15.2) (18.2)

17.4 20.5 14.7 14.2 36.5 68.3 66.8

(6.6) (5.3) (5.6) (6.4) (6.9) (14.7) (16.6)

17.0 21.9 16.0 14.2 35.4 66.7 69.0

(6.7) (5.0) (5.5) (7.3) (7.5) (17.8) (19.0)

17.0 20.5 16.2 13.8 36.3 66.9 67.5

(6.7) (5.1) (5.3) (6.4) (7.0) (16.3) (18.4)

17.7 22.1 16.6 14.6 35.7 68.1 70.9

(6.7) (4.9) (5.1) (7.2) (6.8) (17.5) (20.0)

17.6 20.6 16.6 14.4 36.6 68.5 69.2

(6.1) (5.4) (5.2) (7.0) (6.5) (14.8) (19.1)

17.9 21.4 16.0 15.4 36.6 69.6 70.3

(7.1) (5.0) (5.1) (7.2) (6.8) (16.7) (19.6)

18.2 21.0 17.5 14.7 36.2 69.3 72.8

(6.1) (5.0) (4.8) (6.9) (6.8) (15.1) (17.4)

PWB = physical well-being. SFWB = social/family well-being. EWB = emotional well-being. FWB = functional well-being. FACT-Cx = Functional Assessment of Cancer Therapy-Cervix. TOI = Trial Outcome Index. FACT-G = Functional Assessment of Cancer Therapy-General.

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FACT and subscale scores are reported in Table 2. There were no statistically significant differences in scores at any assessment point between treatment groups on the FACT-G or any subscale. The mean (standard deviation [SD]) change in the TOI and the total FACT-G scores for all patients who had both a baseline and final assessment was as follows: C (n = 56) and CP (n = 74), respectively: +2.12 (13.41) and +2.50 (16.69); and 1.49 (13.63) and +1.36 (14.04). In both treatment arms, FACT-G and TOI scores remained stable over the treatment course. The only subscale that changed (improved) significantly was EWB (C = +1.45 (5.37), P = 0.05; CP = +2.15 (4.22), P < 0.0001). In general, the pattern across subscale scores was stable in both treatment arms. Of particular interest is the relative stability between arms and over time as measured by the FACT-Cx subscale, which was designed to assess disease- and treatment-related symp-

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toms in patients with cervical cancer. From baseline to the fourth assessment, the mean score in the C arm (n = 60) increased by 1.14 (5.83) points, while in the CP arm (n = 76), it declined by 0.97 (7.57) points among patients who had provided both assessments. Neither was statistically significant. Pain Mean scores for pain intensity, pain interference, and pain at its worst are displayed as Figs. 2a, b, and c. Average pain scores among patients on both regimens at baseline, with the exception of pain at its worst, were below 5.0. Pain intensity represents the average of the first five items of the BPI and pain interference is the average of the seven pain interference items. Pain at its worst signifies patients’ rating of their pain experience over the previous 24 h. At the second and third

Fig. 2. Brief Pain Inventory (BPI) Scores for Pain Intensity (PINTEN) (a); Pain interference (PINTER) (b); Pain at its worse in past 24 h (PWORST) (c).

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assessment time points, there were small mean differences of 0.4 to 0.5 points in all three measures between arms favoring CP. The pattern of change within each treatment regimen appeared to be similar. In the C arm, pain scores decreased from baseline to the fourth assessment point as follows: intensity (n = 58) = 0.082 (2.69), P = 0.02; interference (n = 58) = 0.92 (2.82), P = 0.02; pain at its worst (n = 57) = 1.18 (3.37), P = 0.01. In the CP arm, mean pain scores also decreased, as: intensity (n = 72) = 0.75 (2.74), P = 0.02; interference (n = 72) = 0.45 (2.98), P = 0.21; pain at its worst (n = 72) = 1.00 (3.77), P = 0.03. Performance status and toxicity Performance status was similar in the two regimens (Table 1). There were differences in reported toxicities favoring the C arm [9]. The most frequently reported toxicity in both regimens was myelosuppression. Grade 3– 4 anemia and grade 3– 4 neutropenia were more common in the CP arm. Completers and drop-outs The number of patients supplying the baseline assessment was 130 and 122, respectively. Three additional patients (1 on the C arm, 2 on the CP arm) missed the baseline assessment but supplied at least one subsequent assessment. The number completing the fourth assessment (Completers) was 62 and 77, respectively, for the C versus CP arms. The overall completion rates of 47% for the C arm and 62% for the CP arm represent the number of assessments provided at the fourth time point over the number ever evaluable for QOL.1 Patients who did not provide any QOL data at the fourth assessment point, regardless of the reason, were designated as Drop-Outs. The drop-out rate was significantly higher in the C arm (P = 0.023). Among Completers in both regimens, there was overall improvement in scores for pain intensity (P = 0.001) and pain interference (P = 0.009). The FACT-Cx showed significant improvement in the EWB subscale (P < 0.001) and no significant trend for any of the other subscale scores. For Drop-Outs in both treatment arms, there was significant worsening over time in PWB (P < 0.001), FWB (P = 0.010), and the TOI (P = 0.001), and borderline significant worsening in BPI scores for pain intensity (P = 0.081) and pain interference (P = 0.054). At no assessment time point was there a significant difference in QOL scores between treatment regimens. Applying the Pattern-Mixture Model to Completers and

1 The number of patients who dropped out of the QOL component of the study as reported by Moore et al. (50 of 133 patients in the C arm and 33 of 128 in the CP arm) is based on a slightly different definition of Completer versus Drop-Out. In that paper, the number of Drop-Outs was calculated by subtracting the number of Completers from the number of patients alive at the time of the fourth and final QOL assessment. In the current analyses, we chose to define as Drop-Outs patients who failed to complete the fourth assessment, including those who died prior to that time.

Drop-Outs revealed overall worsening of PWB (P = 0.002) and a modest improvement in EWB (P = 0.032), but showed no significant trend for any other outcome measure and no significant differences between arms. Discussion As part of the study’s clinical endpoints, Moore et al. [9] reported greater toxicity in the CP arm and no significant difference in survival between the treatment regimens. However, the addition of paclitaxel to cisplatin did not appear to negatively impact QOL as measured by the FACT-Cx. There were no statistically significant differences between the treatment regimens relative to overall QOL and the TOI. The mean change in the FACT-G score in both treatment arms was not statistically significant, and such small differences are likely not clinically significant [14]. Among patients who completed protocol therapy, regardless of treatment arm, QOL was stable, with results at the fourth assessment point slightly favoring the CP regimen. This seems somewhat counterintuitive given the potential for increased toxicity with a second drug. There was a significant increase in response rate and PFS, and a higher percentage of Completers, favoring the CP arm. It is likely that data were not missing at random and that more patients remained on the CP arm despite increased toxicity because the treatment was slowing disease progression. It is likely that patients having a longer ‘‘remission’’ experience better EWB; indeed, in this study, there was improved EWB among Completers. The differential drop-out rate favoring the CP arm suggests that this was not random, but was related to slower disease progression and perhaps to the treatment itself. Even the application of rigorous statistical methodology cannot confirm this interpretation, although it does seem reasonable. In non-small cell lung cancer, as in advanced cervical cancer, the issue of maintaining QOL during the treatment period is an important one. Bonomi and colleagues measured QOL in a clinical trial comparing two dose levels of paclitaxel (135 mg/m2 and 250 mg/m2) plus cisplatin (75 mg/m2) versus etoposide (100 mg/m2) plus cisplatin (75 mg/m2) for traditional clinical endpoints including toxicity and survival, as well as quality of life [15]. A statistically significant survival advantage was reported with the combination paclitaxel regimen compared to etoposide plus cisplatin (median survival 9.9 months versus 7.6 months; 1-year survival 38.9% versus 31.8%, P = 0.048). Toxicity was similar across all treatment arms and QOL declined over the 6-month course of treatment similarly in all regimens. Since survival favored paclitaxel and cisplatin, and there were no increased QOL deficits with the comparison arms, that trial clearly favored the paclitaxel combination. This clear outcome is in contrast to our results where QOL endpoints were similar and there was no apparent survival benefit of the combination regimen. The present study did not collect data on pain management methods by individual practitioners or treatment site. However, in all likelihood, our sample is representative of patients receiving treatment for advanced cervical cancer and therefore

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provides insight as to what patients might expect as their disease progresses. An important question facing clinicians is ‘‘What is normal?’’ Viewing our results in context with those of a population-based sample can address this issue [16]. It has been generally assumed that patients with advanced cervical cancer have significant QOL deficits. Comparing QOL scores from this study to published normative values using the FACT supports this observation. FACT norms for the general population have recently been published [17]. The FACT-G general population mean score is 80.1 (SD = 18.1), which is considerably higher than the 66.0 (SD = 18.2) and 66.8 (SD = 16.6) reported for the C and CP arms, respectively. Even though most patients had a performance status 1, they initiated chemotherapy with considerable QOL deficits, particularly in the areas of functional and physical well-being, where normative scores are 18.5 (SD = 6.8) and 22.7 (SD = 5.4), respectively, compared to approximately 14 and 17 for our study population. Functioning prior to treatment was compromised. Even at the fourth time point, when patients in both treatment arms had achieved an improved FACT-G score of approximately 70, there was a 10-point deficit relative to the normative value of 80.1. A difference of this magnitude is generally considered clinically significant [14]. Further, for those patients who discontinued protocol treatment, there was significant worsening of physical and functional well-being likely due to disease progression and perhaps due to short-term effects of treatment. There was an upward trend in overall QOL from baseline to the final assessment. While the change in overall scores was small, 4.3 and 5 in C and CP, respectively, it may be clinically significant. However, overall QOL scores on the FACT-G were still considerably lower than the 80.1 (SD = 18.1) found in the general population. For Drop-Outs in either arm, both physical and functional well-being deteriorated significantly over the course of treatment. This may be a result of progressive disease or adverse effect of protocol therapy. While overall QOL scores did not improve significantly in this study among Completers, they did remain stable and EWB actually improved. Further, there was an improved objective response rate favoring the CP combination. This study provides empirical data on the impact of these two treatment regimens on QOL, with those on the CP arm reporting no greater QOL deficits and a higher completion rate compared to the C arm. In addition, Completers in both arms reported fewer pain symptoms. These data support the observation that adding paclitaxel to cisplatin does not diminish patient QOL, and that the combination arm may be preferred for management of patients with advanced cervical cancer. Acknowledgments This study was supported by the National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517).

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The following Gynecologic Oncology Group institutions participated in this study: University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, Wayne State University School of Medicine, University of Minnesota Medical School, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group, P.C., University of California at Los Angeles, University of Washington Medical Center, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University School of Medicine, Wake Forest University School of Medicine, Albany Medical College, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-PresbyterianSt. Luke’s Medical Center, University of Kentucky, Community Clinical Oncology Program, The Cleveland Clinic Foundation, State University of New York at Stony Brook, Eastern Pennsylvania GYN/ONC Center, P.C., Washington University School of Medicine, Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Texas M.D. Anderson Cancer Center, University of Massachusetts Medical Center, Medical University of South Carolina, Women’s Cancer Center, University of Oklahoma Health Sciences Center, University of Virginia Health Science Center, University of Chicago, Tacoma General Hospital, Thomas Jefferson University Hospital, Case Western Reserve University, Tampa Bay Cancer Consortium, North Shore University Hospital, Brookview Research, Inc., and Ellis Fischel Cancer Center. The authors acknowledge Caron Modeas for assistance in preparing and editing the manuscript. References [1] Moinpour CM, Lyons B, Grevstad PK, et al. Quality of life in advanced non-small-cell lung cancer: results of a Southwest Oncology Group randomized trial. Qual Life Res 2002;11(2):115 – 26. [2] Beitz J, Gnecco C, Justice R. Quality of life endpoints in cancer clinical trials: the U.S. Food and Drug Administration perspective. Monogr Natl Cancer Inst 1996;20:7 – 9. [3] Jemal A, Murray T, Ward E, et al. Cancer statistics. CA Cancer J Clin 2005;55:10 – 30. [4] Nair MG. Quality of life in cancer of the cervix patients. Int Clin Psychopharmacol 2000;15(Suppl 3):47 – 9. [5] Greimel E, Thiel I, Peintinger F, Cegnar I, Pongratz E. Prospective assessment of quality of life of female cancer patients. Gynecol Oncol 2002;85:140 – 7. [6] Capelli G, DeVincenzo RI, Addamo A, Bartolozzi F, Braggio N, Scambia G. Which dimensions of health-related quality of life are altered in patients attending the different gynecologic oncology health care settings? Cancer 2002;95(12):2500 – 7. [7] Ota S, Sugiyama T, Ushijima K, et al. Remission of metastatic cervical adenocarcinoma with weekly paclitaxel. Int J Gynecol Cancer 2001;11(2):167 – 8. [8] Omura GA, Blessing JA, Vaccarello L, et al. Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 1997;15(1):165 – 71. [9] Moore DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin

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