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Randomized Study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group Comparing Quality of Life in Patients With Ovarian Cancer Treated With Cisplatin/Paclitaxel Versus Carboplatin/Paclitaxel

From the Department of Obstetrics and Gynecology, Medical University Graz, Graz, Austria; Department of Gynecology and Obstetrics, Universitätsklinikum Schleswig-Holstein, Campus Kiel; Department of Gynecology and Gynecologic Oncology, Dr Horst Schmidt Klinik (HSK), Wiesbaden, Germany

Address reprint requests to Elfriede R. Greimel, PhD, Department of Obstetrics and Gynecology, University Graz, Auenbruggerplatz 14, 8036 Graz, Austria; e-mail: elfriede.greimel{at}meduni-graz.at

	ABSTRACT

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PURPOSE: The objective of this study was to compare the quality of life (QoL) of ovarian cancer patients treated with paclitaxel/carboplatin (TC) versus paclitaxel/cisplatin (PT) and to determine the impact of treatment toxicity on the various QoL domains.

PATIENTS AND METHODS: In this phase III trial, 798 patients with ovarian cancer stages IIB-IV were randomly assigned to receive TC or PT. The primary end point was progression-free survival; secondary end points included toxicity, QoL, and response to treatment. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 before treatment, within 3 days before the second and the fourth chemotherapy cycle, and 3 weeks after completion of chemotherapy.

RESULTS: Previously reported data showed that patients undergoing TC or PT did not differ in progression-free survival and overall survival. However, the TC arm was superior, indicating a better overall QoL compared with the PT arm. Controlling for toxicity and age, a significant treatment by assessment time interaction was found for four QoL functioning scales and three symptoms scales. Patients in the TC arm showed better means scores after treatment on overall QoL (P = .012), physical functioning (P = .012), role functioning (P = .005), and cognitive functioning (P = .024), compared with the PT arm. Concerning symptom experience, patients undergoing TC showed less nausea and vomiting (P < .001), less appetite loss (P < .001), and less fatigue (P = .033) after completion of treatment compared with patients undergoing PT.

CONCLUSION: The TC regimen achieved better QoL outcomes compared with the PT regimen. Thus, clinicians may consider replacing cisplatin with carboplatin when treating ovarian cancer patients with chemotherapy.

	INTRODUCTION

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Ovarian cancer is the most malignant tumor of the female tract with 192,000 estimated new cases and 114,000 cancer deaths worldwide.¹ Because of inadequate screening tools and a lack of early clinical symptoms, the majority of women are diagnosed with International Federation of Gynecology and Obstetrics stage III or IV disease. Only 20% to 25% of patients are cured, and the majority of patients develop a relapse within the first 5 years after initial diagnosis.² Median survival for patients following recurrence is approximately 2 years.³ Standard treatment for patients with advanced ovarian carcinoma is cytoreductive surgery aiming to remove the visible tumor tissue, followed by combination chemotherapy.⁴

During the past 20 years, the chemotherapy regimens used to treat advanced ovarian cancer have undergone two major advances in efficacy. First, the introduction of platinum-based agents, and second, the introduction of taxanes. Randomized trials showed that carboplatin in combination with cyclophosphamide is better tolerated than cisplatin in combination with cyclophosphamide with no loss of efficacy.^5,6 The first combination of a platinum agent with paclitaxel as first-line therapy in ovarian cancer utilized cisplatin. The paclitaxel/cisplatin (PT) regimen showed better results in terms of progression-free survival and overall survival when compared with regimens that do not contain taxanes.⁷ Caroboplatin, an analog of cisplatin, has less nonhematologic toxicity. The feasibility and tolerability of paclitaxel plus carboplatin (TC) has been tested in several phase I/II studies.^8-10 Two large prospectively randomized noninferiority phase III trials comparing these treatment regimens in terms of toxicity and efficacy showed no significant difference between the two treatment arms concerning survival outcomes.^3,11 However, the TC regimen was better tolerated and had less toxicity than the PT regimen.

Chemotherapy-induced toxicities can have a significant impact on a patient's ability to carry out normal activities of daily living and quality of life (QoL).¹² The major clinical symptom of hematologic toxicity is anemia that severely affects patients' QoL.^13,14 Anemia commonly occurs in cancer patients undergoing myelosuppressive chemotherapy.^15-18 Chemotherapy-induced leucopenia and thrombocytopenia are the most common dose-limited toxicities of myelosuppressive chemotherapy. Adverse gastrointestinal events are also common with paclitaxel but particularly under cisplatin therapy. Nausea and vomiting are the major complaints among cisplatin-treated patients.^19,20 Peripheral neuropathy is one of the principal toxic effects of platinum and taxane chemotherapy, both are standard drugs for ovarian cancer treatment that interfere with self-care activities, physical and role activities, and QoL.²¹

Innovative treatment regimens often do not result in substantial differences in survival. The acceptance of new cancer therapies is sometimes dependent on their QoL consequences. Thus, tolerability of treatment and QoL should be an important focus in research. This article reports on the results of a large clinical trial comparing TC with PT. The primary objective was to determine the treatment efficacy in terms of the proportion of patients without disease progression. Secondary end points included toxicity, response to treatment, and QoL. Previously reported data showed no survival differences among patients treated with TC or PT. However, the TC regimen was associated with a higher frequency of hematologic toxicity but a lower frequency of gastrointestinal and neurologic toxicity compared with the PT regimen.¹¹

The objective of the QoL assessment within this trial was to determine the impact of the TC regimen versus the PT regimen on patients' QoL. QoL is a multidimensional concept including physical, emotional, social, and daily-life functioning as well as symptoms related to disease and treatment from the patient's perspective.²² A preliminary analysis of the QoL data showed that overall QoL was significantly better in the TC regimen than in the PT regimen.¹¹ As treatment-related adverse effects may negatively impact QoL, we determine the effect of hematologic and nonhematologic toxicity on patients' QoL and symptom experience.

	PATIENTS AND METHODS

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In this phase III trial, 798 patients with histologically confirmed ovarian cancer stages IIB-IV (International Federation of Gynecology and Obstetrics) were enrolled from 1995 to 1997. Patients who underwent radical debulking surgery were randomly assigned to receive TC or PT. Computer-generated randomization lists were prepared for each study center before the start of the trial using permuted blocks of randomly varying size. Randomization was done by fax to the study office using a registration form. The investigator was informed by fax about the treatment arm.

In the TC arm, paclitaxel (185 mg/m²) was administered intravenously over 3 hours followed by carboplatin (dose in milligrams = area under the curve x [GFR + 25]) administered intravenously over 30 to 60 minutes. In the PT arm paclitaxel (same dose and schedule) plus cisplatin 75 mg/m² was administered intravenously, both given over six courses every 3 weeks. The study was designed in accordance with good clinical practice guidelines, German drug laws, and the Declaration of Helsinki. German and Austrian centers participated in this study, and the local ethics committee of each participating center approved the study. This study was also certified by the German Cancer Society. All patients provided written informed consent before participating in the study.

QoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire (QLQ-C30) version 2.0. It consists of 30 items comprising five functional scales (physical, role, emotional, social, cognitive), three symptom scales (fatigue, nausea/vomiting, pain), an overall QoL scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The QLQ-C30 has been psychometrically validated cross-culturally. All scales and single items meet the standards for reliability.²³

QoL assessment was scheduled at baseline (pretreatment), within 3 days before the second and the fourth chemotherapy cycles, 3 weeks after completion of six cycles of chemotherapy (post-treatment), and at every 6 months follow-up. The protocol specified that all centers had an initiation visit including display of all study materials, aim of the study protocol, and detailed information about study administration, including QoL assessment. In each center, a trained nurse or physician was identified to administer the QoL forms. Patients were verbally instructed and assistance was provided in filling out the questionnaire, if needed. QoL assessments were not obtained if patients were too ill and unable to read or write. The compliance with the study procedures was monitored regularly by monitors visiting each center every 2 to 6 months, depending on the number of recruited patients. During these visits, missing QoL forms were regularly discussed and administrators were reminded to improve compliance. The questionnaire completion rate was calculated for patients enrolled in the trial at all assessment points.

The sample size calculation was based on the primary end point. The trial had sufficient power to detect differences in the QoL scales. The primary and secondary end points were analyzed considering an overall level of P < .05. The QLQ-C30 scales and single items were linearly transformed to 0 to 100 and analyzed according to the procedures recommended by the EORTC QoL Group.²⁴ Higher scores on the functioning scales and the overall QoL scale indicate a higher level of functioning and a better QoL. Higher scores on the symptom scales or single item scales represent a higher level of symptoms or problems.

As suggested by Osoba et al²⁵ a difference of less than 10 points on a 100-point QoL scale was classified as no change or of small clinical relevance; a difference of 10 to 20 points was considered as moderate; a difference of 20 points or more indicated large effects. For example, an increase of 10 points on a functional scale would mean a moderate improvement, whereas a decrease of 10 points would be interpreted as moderate worsening. Likewise, a rise in a symptom score indicates deterioration; whereas, a reduced score means improvement of the specific symptom. Mean chance scores were calculated as the difference between baseline and post-treatment. A positive mean change score for the functioning scales indicated improvements; whereas, a negative mean change score for the symptom scales indicated worsening.

At baseline, the study sample was compared with reference samples using clinically meaningful differences. Reference data were taken from an international references sample in locally advanced cervical cancer²⁶ and a normative references sample for a general female population, including 1,139 German women.²⁷

For the comparative analysis, differences in the level of QLQ-C30 scores were analyzed by means of a two factorial multivariate analysis of covariance for repeated measures. Hematologic toxicity (thrombocytopenia, anemia, leukopenia, febrile neutropenia, neutropenia), isolated anemia, neurotoxicity (peripheral sensory neuropathy, central neuropathy), gastrointestinal toxicity (constipation, diarrhea, mucositis/stomatitis, nausea, vomiting), and pain (myalgia/artralgia) were used as covariates. Hematologic toxicity was dichotomized in grades 0 to 2 v 3 to 4. Nonhematologic toxicity parameters were dichotomized in grades 0 to 1 v 2 to 4. Age was also considered as a covariate, since advanced age is a recognized risk factor for the development of chemotherapy-related myelosupression, presumably because of progressive deterioration of renal function with aging and the natural reduction in cellular reserves in the bone marrow.²⁸

Multivariate analyses of variance were carried out separately for each assessment time to compare the two treatment arms with respect to the various QoL scales and symptoms scales.

	RESULTS

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In this trial, a total of 798 patients with ovarian cancer stages IIB-IV undergoing surgery were enrolled and randomly assigned to receive TC combination (n = 407) or PT combination (n = 391). Fifteen of 798 patients were excluded because of violation of inclusion criteria. A total of 397 patients were enrolled in the TC arm, 386 patients were enrolled in the PT arm (Fig 1). Three hundred sixty-six patients in the TC arm and 357 patients in the PT arm provided QoL baseline assessments. QoL compliance rate varied between 92% at baseline and 62% and 59%, respectively, after completion of chemotherapy. Eighteen patients responded to less than half of the questions and 39 patients had missing toxicity data. Patients who were excluded as a result of missing data (mainly because of administration failure to hand out QoL forms) were compared with patients who provided complete QoL data.

View larger version (30K): [in this window] [in a new window]   Fig 1. Compliance by study arm for completion of Quality of Life (QoL) questionnaire (QLQ-C30). Percent compliance of trial participants by treatment arm; analyses restricted until cycle 6. TC, paclitaxel/carboplatin; PT, paclitaxel/cisplatin.

Figure 2 shows the QoL mean scores for the treatment groups at baseline compared with reference values in a clinical sample²⁶ and in a general sample of 1,139 German women.²⁷ Ovarian cancer patients in our trial showed lower baseline mean scores in overall QoL, physical functioning, and role functioning and experienced a higher level of fatigue, dyspnoea, and appetite loss than patients with locally advanced cervical cancer. The differences were of moderate clinical importance (10 to 20 points) except for role functioning and appetite loss (> 20 points). Compared with normative reference data in a general female population, ovarian cancer patients in our trial had lower mean scores in all QoL functioning scales (except for cognitive functioning) and higher scores in most symptom scales. These differences were of small or moderate clinical importance.

View larger version (50K): [in this window] [in a new window]   Fig 2. Baseline scores for the Quality of Life Questionnaire (QLQ-C30) by treatment group, advanced cervical cancer reference values and normative reference values. TC, paclitaxel/carboplatin; PT, paclitaxel/cisplatin.

QoL of patients assigned to the two treatment arms were also compared at the two intermediate assessment points using multivariate analyses of variance. Before the second cycle of chemotherapy, patients treated with TC had significantly better overall QoL scores (P = .046) and less nausea/vomiting (P = .002) but more dyspnea (P = .004). These effects were statistically significant but not clinically relevant. Before the fourth chemotherapy cycle, the treatment effects were even stronger, indicating significantly better overall QoL (P = .006), emotional functioning (P = .041), social functioning (P = .027), less nausea/vomiting (P < .001), and less appetite loss (P = .028) in the TC arm compared with the PT arm. These differences were significant on a statistical level but not on a clinical level.

	DISCUSSION

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This randomized trial was undertaken to compare two chemotherapy regimens in terms of progression-free and overall survival outcomes as well as toxicity. The results showed that the TC regimen was not statistically significantly different from those of the PT regimen concerning survival outcomes, but the toxicity patterns were different. Hematologic toxicity was significantly more frequent in the TC arm, with neutropenia and leukopenia as the predominant side effects. In the PT arm, nonhematologic toxicity, specifically nausea and vomiting, was observed in more than twice as many patients than in the TC arm. As reported in the original paper, patients receiving TC showed better overall QoL compared with patients receiving PT at any assessment point.¹¹ At baseline, there were no significant differences between the two treatment arms in any of the QoL scores. We also compared the QoL baseline scores with reference data for patients with locally advanced cervical cancer²⁶ and with normative reference data for a general population of 1,139 German women.²⁷ Patients with ovarian cancer participating in this study had lower QoL scores than cervical cancer patients. As expected, the QoL was worse when compared with females of the German reference sample. Ovarian cancer patients had radical surgery within 6 weeks of random assignment. This may have affected patients' QoL at baseline since they may not have been completely recovered from surgery. During treatment, QoL differences between the study sample and the reference samples decreased. After completion of chemotherapy, clinically meaningful differences in QoL diminished for most scales, indicating that women who have had treatment for ovarian cancer regain QoL function similar to women in the general population.

The QoL of patients was affected differently depending on the chemotherapy combination they received. As previously reported, patients undergoing PT had significantly lower overall QoL scores compared with patients undergoing TC.¹¹ In our analysis, the same pattern was found for several QoL functioning scales and symptoms scales, indicating better QoL and less symptom experience in the TC group compared with the PT group. Throughout the treatment, the TC regimen was superior to the PT regimen in terms of QoL. These findings are consistent with previous studies, indicating that patients receiving cisplatin had lower overall QoL scores, more appetite disturbance, and nausea and vomiting.²⁹

In this study, we included toxicity scores as covariates to find out how much chemotherapy-induced toxicity and which toxicity parameters affect patients' QoL. Hematologic toxicity was statistically significant more frequently in the TC regimen. However, patients treated with TC showed better QoL after treatment compared with patients treated with PT, indicating that these toxicity parameters did not have an adverse impact on QoL. Although neutropenia can be life threatening, in our study its impact on QoL seems to be low. This can be explained by the fact that these side effects are rarely accompanied with clinical symptoms such as febrile neutropenia and infections.

Nonhematologic toxicities, such as nausea and vomiting, were more often reported in the PT arm. These side effects seem to affect patients' QoL to a greater extent than hematologic toxicity. Peripheral neuropathy is the principal toxic effect of chemotherapy for ovarian cancer patients that interferes with self-care activities, mobility, and QoL. This was taken into account in our analysis by dichotomizing neurotoxicity, representing the limit for the impairment of activities of daily living. The most affected domains in our analysis were reduced physical functioning, role functioning, and emotional functioning. Additionally, neurotoxicity had a significant impact on the symptoms scales fatigue and pain. Neurotoxicity is known to persist in some patients for a long time after completion of first-line therapy. This side effect is important with regard to QoL during the treatment-free interval of these patients and during re-introduction of therapy on platinum-sensitive tumors in case of a relapse. Results from a phase III study in the second-line treatment showed that the addition of paclitaxel to platinum improves survival in comparison with platinum without paclitaxel, reinforcing the significance of chemotherapy-induced neurotoxicity and its influence on QoL during the course of disease.³⁰ Wenzel et al³¹ found that one-third of patients undergoing cisplatin and paclitaxel experienced long-term toxicity, such as numbness or tingling. Although, in this study, we were unable to confirm this because of the lack of follow-up data.

A possible limitation of the study is the use of a generic QoL measure without a cancer-specific instrument. Therefore, the effect of specific symptoms that only apply to ovarian cancer patients might have been underestimated. A cancer site–specific measure may have been more sensitive to treatment-related changes; thus, even more effects could have been shown with an ovarian cancer specific instrument. The EORTC ovarian cancer module was under development and, at the time of patient recruitment, not available.

Another limitation of this study is the drop-out rate of patients who did not comply with the planned schedule of QoL assessment or returned incomplete forms. This is a well-known phenomenon that the proportion of patients providing QoL data becomes smaller and smaller in longitudinal studies.³² To avoid sample bias, we compared study participants with patients who were excluded because of missing QoL forms in terms of the clinical outcomes and QoL baseline scores. Patients who provided QoL assessments did not differ in their baseline characteristics from those who provided QoL data. Surprisingly, hematologic toxicity was significantly lower in the subgroup not responding to subsequent QoL measures. Other toxicity scores were also slightly lower in patients who participated in the study. Furthermore, there were no differences in terms of stage of disease and survival outcomes, which may have been a threat to the validity of our results.

Since carboplatin and cisplatin have equal efficacy in ovarian cancer patients, the results of this study are clinically useful and may assist physicians and patients in the discussion of anticipated treatment effects and their impact on QoL. Given the fact that the TC regimen achieved better QoL outcomes compared with the PT regimen, clinicians may consider replacing cisplatin with carboplatin when treating ovarian cancer patients with chemotherapy.

	Authors' Disclosures of Potential Conflicts of Interest

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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.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Jacobus Pfisterer Bristol-Meyers Squibb (A) Bristol-Meyers Squibb (B); Bristol-Meyers Squibb (B) Andreas du Bois Bristol-Meyers Squibb (A) Bristol-Meyers Squibb (B); Bristol-Meyers Squibb (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Elfriede R. Greimel, Vesna Bjelic-Radisic, Jacobus Pfisterer, Felix Hilpert, Andreas du Bois Administrative support: Jacobus Pfisterer, Felix Hilpert, Andreas du Bois Provision of study materials or patients: Jacobus Pfisterer, Felix Hilpert, Andreas du Bois Collection and assembly of data: Jacobus Pfisterer, Andreas du Bois Data analysis and interpretation: Elfriede R. Greimel, Vesna Bjelic-Radisic, Jacobus Pfisterer, Felix Hilpert, Fedor Daghofer, Andreas du Bois Manuscript writing: Elfriede R. Greimel, Vesna Bjelic-Radisic, Jacobus Pfisterer, Felix Hilpert, Fedor Daghofer, Andreas du Bois Final approval of manuscript: Elfriede R. Greimel, Vesna Bjelic-Radisic, Jacobus Pfisterer, Felix Hilpert, Fedor Daghofer, Andreas du Bois

 

	Acknowledgment

 
We thank monitoring staff, C. Biberger, M. Borinin, B. Kirchherr, C. Renné, P. Schantl, and the study secretaries and data managers, S. Conze, G. Elser, and M. Polzin. Special thanks to Bristol-Myers Squibb for providing paclitaxel as the study drug. We also thank all participating centers for recruiting patients for this clinical trial.

	NOTES

 
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted April 15, 2005; accepted November 4, 2005.

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