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Health-Related Quality of Life in Patients Treated for Anaplastic Oligodendroglioma With Adjuvant Chemotherapy: Results of a European Organisation for Research and Treatment of Cancer Randomized Clinical Trial

Martin J.B. Taphoorn, Martin J. van den Bent, Murielle E.L. Mauer, Corneel Coens, Jean-Yves Delattre, Alba A. Brandes, Peter A.E. Sillevis Smitt, Hans J.J.A. Bernsen, Marc Frénay, Cees C. Tijssen, Denis Lacombe, Anouk Allgeier, Andrew Bottomley

From the Department of Neurology, Medical Center Haaglanden/Westeinde Ziekenhuis, the Hague; Department of Neurology, Daniel den Hoed Cancer Center/Erasmus University Hospital, Rotterdam; Department of Neurology, Canisius Wilhelmina Ziekenhuis, Nijmegen; Department of Neurology, Elisabeth Ziekenhuis, Tilburg, the Netherlands; Quality of Life Unit, and Data Center, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Department of Neurology, Centre Hospitalier Universitaire Pitié-Salpétrière, Paris; Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France; and Medical Oncology Department, Bellaria-Maggiore Ospedale, Bologna, Italy

Address reprint requests to Martin J.B. Taphoorn, MD, Medical Center Haaglanden/Westeinde Ziekenhuis, Department of Neurology, PO Box 432, the Hague, the Netherlands, 2501 CK; e-mail: m.taphoorn{at}mchaaglanden.nl

	ABSTRACT

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Purpose: Little is known about the health-related quality of life (HRQOL) of patients treated for anaplastic oligodendrogliomas. The impact of combined procarbazine, CCNU (lomustine), and vincristine (PCV) chemotherapy after radiotherapy (RT) compared with RT alone on HRQOL in the randomized European Organisation for Research and Treatment of Cancer (EORTC) 26951 trial was studied.

Patients and Methods: Adult patients with anaplastic oligodendrogliomas received RT alone or RT plus PCV chemotherapy. HRQOL was assessed with the EORTC Quality of Life Questionnaire C30 and Brain Cancer Module. Seven prespecified HRQOL end points were selected. We hypothesized that chemotherapy would impair HRQOL during treatment but that there would be a similar HRQOL between treatment arms once off treatment. Assessments were performed at randomization, at the end of RT, and then every 3 to 6 months until progression.

Results: A total of 368 patients were randomly assigned to one of the two arms; overall, 58% were male, and the median age was 49 years. Compliance with HRQOL was 78% at baseline and dropped to 55% to 72% up to 2.5 years post-RT. Baseline scores demonstrated considerable impairments in HRQOL for both treatment groups. The longitudinal analysis showed a significant increase in nausea/vomiting in the RT plus PCV chemotherapy arm during and shortly after chemotherapy. Because of a difference in baseline scores for fatigue and physical functioning, the differences between treatment arms during PCV did not reach significance. The nonselected scales of appetite loss and drowsiness demonstrated significant differences between treatment arms during chemotherapy in favor of the RT arm. The long-term results showed no difference between arms.

Conclusion: The major impact of PCV on HRQOL is on nausea/vomiting, loss of appetite, and drowsiness during and shortly after treatment. There are no long-term effects of PCV chemotherapy.

	INTRODUCTION

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The treatment of brain tumor patients, as with any other patients with cancer, is not merely aimed at enhancing survival but also at relief of symptoms and maintenance or improvement of the patient's well-being. Consequently, health-related quality of life (HRQOL), a multidimensional concept that incorporates physical, psychological, and social aspects, has become a major secondary end point in cancer trials.^1,2 Particularly in patients with cancer who cannot be cured, which includes the majority of brain tumor patients, HRQOL is a relevant end point. With increasing treatment modalities for brain tumor patients that may increase toxic effects on brain functioning, measurement of HRQOL is especially warranted. Apart from being a useful measure in clinical trials, HRQOL may supply prognostic information and thereby support clinical decision making in the individual patient.^3,4

Oligodendrogliomas, a subset of glial neoplasms, are relatively chemosensitive tumors compared with their larger astrocytic counterpart.⁵ In recurrent anaplastic oligodendroglial tumors, combination treatment with procarbazine, lomustine, and vincristine (PCV) chemotherapy was effective in 60% to 70% of patients, who had a median time to progression of 12 to 18 months.^6,7 In view of these results, the use of adjuvant PCV chemotherapy for newly diagnosed anaplastic oligodendroglioma was studied in two randomized clinical trials with recently reported results.^8,9

In the European Organization for Research and Treatment of Cancer (EORTC) 26951 study, patients with anaplastic oligodendroglioma were randomly assigned after surgery to either radiotherapy (RT) alone or to RT followed by adjuvant PCV. Although the difference in overall survival was not significant, the progression-free survival in the adjuvant PCV treatment arm was significantly longer than in the standard treatment arm (23.0 v 13.2 months, respectively; P = .0018).⁹ The HRQOL results of this trial are reported here. HRQOL was a secondary end point of the trial, and we assumed that adjuvant PCV treatment would have a temporarily negative impact on HRQOL during and shortly after PCV.

	PATIENTS AND METHODS

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Treatment
In this multicenter EORTC study, adult patients (aged 16 to 70 years) with anaplastic oligodendroglioma or anaplastic mixed oligoastrocytoma were enrolled after surgery. Patients were randomly assigned to receive either RT alone (59.4 Gy in 33 fractions of 1.8 Gy) or the same RT plus PCV chemotherapy (six cycles, standard dosage PCV, repeated every 6 weeks). The details on trial conduct and clinical outcome have been reported elsewhere.⁹

Procedures
Two HRQOL measures were selected: the EORTC Quality of Life Questionnaire C30 (QLQ-C30, version 3) and the EORTC QLQ-Brain Cancer Module (QLQ-BN20).^10,11 Both tools have robust psychometric properties that result from rigorous testing and from development of their use in several international clinical cancer trials.¹² Both instruments were available in the language of all participating patients.¹³

The items on both measures were scaled and scored by using the recommended EORTC procedures.¹⁴ Raw scores were transformed to a linear scale that ranged from 0 to 100, in which a higher score represented a higher level of functioning or an improved level of symptoms. If at least half of the items in the scale were completed, the scale score was calculated with only those items for which values existed.

The results are presented in accordance with recent guidelines for reporting HRQOL.² Differences of at least 10 points (on a 0 to 100 scale) were classified as the minimum clinically meaningful change in the mean value of a HRQOL parameter.¹⁵ Mean changes of < 10 effect points were considered no change or clinically irrelevant. Mean changes of > 20 points were classed as large effects.

The baseline HRQOL assessments were performed at random assignment. Follow-up assessments were performed at regular intervals, (ie, at the end of RT, then every 3 months for the first year after radiotherapy, then at 6-month intervals until recurrence of disease).

Only HRQOL forms completed before or on the day of progression of the disease or before or on the last day of study for patients who did not progress were selected for the analysis. The time windows for acceptable HRQOL forms were defined as follows: baseline HRQOL assessments had to be taken no more than 6 weeks from random assignment but no sooner than 1 week after surgery and before the start of RT; HRQOL assessments at the end of RT had to be taken no more than 2 weeks before the end of radiotherapy and no more than 1.5 months after the end of RT; thereafter, adjacent time windows were used to gather the maximum information available (not > 1.5 months from the target time point for assessments collected every 3 months and not > 3 months from the target time point for assessments collected every 6 months).

HRQOL was a mandatory aspect of this clinical trial protocol to ensure optimal compliance for HRQOL data.

Statistical Analysis
HRQOL was a secondary study end point. HRQOL comparison was performed using Statistical Analysis Software (version 9.1; SAS Institute, Cary, NC) based on the intent-to-treat principle.

We hypothesized that adjuvant chemotherapy would impair HRQOL during chemotherapy treatment compared with the no treatment arm after RT but that there would be similar HRQOL once off treatments. The null hypothesis was that there is no difference in HRQOL between the treatment regimens, and the alternative hypothesis was that there is a difference, which may be in either direction.

To reduce errors from multiple testing, seven key scales for the primary analysis (ie, fatigue, overall HRQOL, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting) were preselected based on past clinical experience. We excluded one scale from the final analysis, namely, financial impact of treatment, because this was an unlikely influence in this trial. The remaining HRQOL variables then were examined on an exploratory basis. To correct for multiple comparisons and to avoid type I errors, the level of statistical significance was set at P = .01. The treatment comparison was performed at each time point.

A mixed model with an undefined covariance structure was fitted to the longitudinal HRQOL data (each selected score) to test for differences between the two treatment groups. All patients with at least one valid HRQOL form were included in the analysis (N = 351). Differences in mean scores at each time point and differences in mean changes from baseline were tested.

Missing data is a common problem in HRQOL analyses. The missingness mechanism was investigated to check the reliability of the use of a mixed model. The mixed model is valid under the missing completely at random (MCAR) or missing at random (MAR) assumptions. Missing data occurred when patients did not complete all or some items of the questionnaires at the time of a scheduled HRQOL assessment. Missing data also occurred when patients dropped out from the HRQOL assessment because of progression, death, or end of their period of clinical follow-up. The MAR setting appeared acceptable. A number of sensitivity analyses (ie, complete cases, unconditional mean imputation) were conducted. The results confirmed that the MCAR setting is not appropriate.

The percentages of patients who experienced at least a 10, 20, 30, or more point worsening at any time point compared with baseline in each selected scale were reported. The percentages were computed on the total number of patients with a baseline HRQOL assessment and with at least one additional follow-up HRQOL form.

A subgroup analysis was performed on patients who started RT and received at least two cycles of chemotherapy (108 of 185 patients). For these patients, HRQOL assessments from the start of chemotherapy to the end of chemotherapy plus 2 months, but before progression, were selected; a washout period of about 2 months was expected. The maximal worsening from baseline during that period was analyzed in this subgroup. For comparison, the same analysis was repeated in the same subgroup of 108 patients in the RT plus PCV arm without restricting HRQOL assessments to the period when the patients were on chemotherapy. Moreover, the maximal worsening from baseline also was analyzed in the RT-only arm (182 patients).

	RESULTS

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HRQOL: Compliance and Baseline Scores
Compliance overall at baseline was 78% (288 patients) but dropped to 50% at 3 years after the end of RT (Table 1). Because there were few assessable patients after the end of RT plus 2.5 years follow-up, the analysis was stopped after this time point. Fisher's exact tests for a compliance difference between the two treatment arms revealed no significant differences at baseline nor at follow-up time points.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Baseline and follow-up graphical data at each point of assessment for both treatment arms of three preselected health-related quality-of-life scales: (A) fatigue; (B) nausea/vomiting; and (C) physical functioning. RT, radiotherapy; PCV, procarbazine/lomustine.

When analyzing the change in fatigue and physical functioning from baseline, however, the results showed reduced differences between the two treatments arms. At baseline, patients in the RT plus PCV arm had a higher mean level of fatigue (39.5 v 36.6) and a lower mean level of physical functioning (71.5 v 77.9) compared with the RT arm. Therefore, the difference in mean changes from baseline in fatigue (3.1 v –4.8; P = .0319) and physical functioning (–3.8 v 0.5; P = .3227) at the end of chemotherapy was neither statistically nor clinically significant anymore.

At the 1-year time point and at all assessments afterward, no significant or clinically meaningful differences were observed (at a level of significance of .01) on any of the seven scales.

Regarding changes in HRQOL over time, improvements (mean changes of > 10 points) from baseline were observed in overall HRQOL and social functioning. These were observed in both treatment groups with a delay of > 1.5 years after the completion of RT.

Other HRQOL Scales: Exploratory Analysis
There was a statistically and clinically significant increase in appetite loss in the RT plus PCV arm compared with the RT alone arm during and after chemotherapy (at the end of RT plus 3, 6, 9, or 12 months after the end of RT; Tables 5 and 6; Fig 2A to B). At 6 and 9 months, the mean scores were 30.4 and 28, respectively, in the RT plus PCV arm versus 12.6 and 6.9, respectively, in the RT arm (P < .00001). There was also a statistically and clinically significant increase in drowsiness in the RT plus PCV arm compared with the RT alone arm at the end of radiotherapy plus 6 months (P = .0028). The mean score was 30.8 in the RT plus PCV arm and 18 in the RT arm. The long-term results (after 1 year) showed no difference between arms.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Baseline and follow-up graphical data for both treatment arms of two nonselected health-related quality-of-life scales: (A) appetite loss; and (B) drowsiness. RT, radiotherapy; PCV, procarbazine/lomustine.

The impact of baseline patient and tumor characteristics on the dropout was investigated, as was the impact of the value of the HRQOL score at each time point on the drop-out at the next time point. Of these factors, institution, type of surgery, endothelial abnormalities, necrosis, and genetic status had a significant impact on the drop-out mechanism. Also, several HRQOL scores at time point one had a significant impact on drop-out at time point two. These results confirmed that missing HRQOL data are not MCAR. Such results were expected, as one of the reasons to drop out from HRQOL assessment was progression.

Complete Cases Analysis
Only few patients had a HRQOL assessment at each time point. Therefore, the complete cases analysis was performed on all patients who had a HRQOL measurement at the end of RT plus > 2.5 years (n = 111). The delayed progression in the RT plus PCV arm resulted in a smaller number of compliers but a better HRQOL status in the RT arm than in the RT plus PCV arm, which biased the analysis.

Imputation of Unconditional Mean
Missing data were replaced by the mean computed from the observed data at each time point. However, the results are not reliable under MAR.

Additional Analyses
Additional analyses were performed to try to better assess the negative impact of the adjuvant chemotherapy on HRQOL of patients (all seven preselected HRQOL scores).

Percentage of Patients With > 10-Point Worsening
The percentages of patients who experienced a > 10-, 20-, 30-point, or more worsening at any time point compared with baseline in each selected scale were similar in both groups for all HRQOL scales except for nausea/vomiting. The percentages of patients with an increase from baseline of nausea/vomiting of > 10, 20, and 30 were much higher in the RT plus PCV arm (Table 7). It was also higher for greater levels of increase.

	DISCUSSION

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In this large set of anaplastic oligodendroglioma patients, baseline HRQOL scores were substantially impaired, to the same extent as was observed in glioblastoma patients, compared with reference values.^16,17 This underlines the serious impact of the disease itself on HRQOL.

The further decline in HRQOL during and after chemotherapy treatment was present mainly in nonpreselected scales, which suggests that patients during and shortly after PCV treatment had more appetite loss and were more drowsy than patients in the RT-only arm. In the preselected scales, it was not as pronounced as was expected beforehand. Apart from a temporary and statistically significant, but not clinically meaningful, difference in nausea/vomiting between treatment arms in favor of the RT-only arm, no differences were noticed for the other six selected scales.

Next to the well-known hematologic toxicity of PCV chemotherapy, even in the standard dosage regimen, PCV chemotherapy is assumed to induce considerable fatigue, nausea/vomiting, malaise, and weight loss. In particular, these adverse effects cause PCV chemotherapy to be less well tolerated than temozolomide chemotherapy.^6,7,18

These findings were observed despite the use in this trial of standard-dosage PCV rather than a dose-intense regimen, as was given in the concurrent North American randomized trial in anaplastic oligodendroglioma patients.⁸ Unfortunately, HRQOL was not a secondary measure in that study, but one might have anticipated a more negative impact on HRQOL during dose-intense PCV treatment than we observed with standard dosage. Moreover, patients in the PCV plus RT arm who receive less than the planned six PCV cycles (mainly because of hematologic toxicity) do not drop out of the HRQOL analysis, provided there is no tumor progression. The negative impact of PCV treatment on HRQOL is diluted by these patients who stop PCV. However, a further analysis of our data regarding this possible diluting effect did not reveal that scores of additional scales differed between treatment arms.

The timing of completion of the HRQOL questionnaires during and after PCV treatment is likely to have influenced the scores, especially on the nausea/vomiting scale. Patients had to complete the questionnaire after the completion of two, four, and six PCV cycles, respectively. The HRQOL questionnaire, however, refers only to the preceding week and not to the complete 6-week cycle duration. In the PCV schedule, procarbazine is administered on days 8 through 21, and the patients are seen in the outpatient clinic approximately 3 weeks later. Procarbazine use especially gives rise to severe subjective toxicity, which will have subsided after 2 to 3 weeks. The rather liberal time windows set in this study for HRQOL questionnaires to be acceptable for analysis may have diluted the negative impact of PCV treatment on HRQOL.

The observation that RT did not negatively affect HRQOL during and shortly after treatment is in line with our preceding study in glioblastoma patients.¹⁷ Another positive finding is that, over time, patients reported improvements in overall HRQOL and in social functioning. Clearly, these results are biased by including only patients without tumor recurrence in the analysis, because patients with a poor performance status have a decreased prognosis.¹⁹

In future studies of patients with brain tumors, HRQOL can only be taken as a useful end point if careful attention is paid to items such as compliance, critical selection of HRQOL scales, and more strict time limits for HRQOL assessment that consider the maximum impact of treatment.

Finally, taking into account the clinical results from this study that indicated that early PCV chemotherapy postpones tumor recurrence, HRQOL assessment should not stop once progression occurs. The impact of tumor progression on HRQOL and on clinical symptoms should provide us more insight into the potential benefit of early (aggressive) treatment, because this might keep patients in a stable condition for a longer time.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions Appendix REFERENCES

 
Conception and design: Martin J.B. Taphoorn, Martin J. van den Bent, Murielle E.L. Mauer, Corneel Coens, Andrew Bottomley

Administrative support: Martin J. van den Bent, Jean-Yves Delattre, Alba A. Brandes, Peter A.E. Sillevis Smitt, Hans J.J.A. Bernsen, Marc Frénay, Cees C. Tijssen, Denis Lacombe, Anouk Allgeier

Provision of study materials or patients: Martin J.B. Taphoorn, Martin J. van den Bent, Jean-Yves Delattre, Alba A. Brandes, Peter A.E. Sillevis Smitt, Hans J.J.A. Bernsen, Marc Frénay, Cees C. Tijssen

Collection and assembly of data: Martin J.B. Taphoorn, Murielle E.L. Mauer, Corneel Coens, Denis Lacombe, Anouk Allgeier, Andrew Bottomley

Data analysis and interpretation: Martin J.B. Taphoorn, Martin J. van den Bent, Murielle E.L. Mauer, Corneel Coens, Andrew Bottomley

Manuscript writing: Martin J.B. Taphoorn, Martin J. van den Bent, Murielle E.L. Mauer, Corneel Coens, Andrew Bottomley

Final approval of manuscript: Martin J.B. Taphoorn, Martin J. van den Bent, Murielle E.L. Mauer, Corneel Coens, Jean-Yves Delattre, Alba A. Brandes, Peter A.E. Sillevis Smitt, Hans J.J.A. Bernsen, Marc Frénay, Cees C. Tijssen, Denis Lacombe, Anouk Allgeier, Andrew Bottomley

	Appendix

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This study was conducted by the European Organisation for Research and Treatment of Cancer, a not-for-profit foundation under Belgian Law.

	NOTES

 
Supported by Grants No. 5U10CA11488-30 through 5U10CA11488-34 from the National Cancer Institute. Supported in part by the European Organisation for Research and Treatment of Cancer Charitable Trust.

Presented in part at the 13th Annual Conference of the International Society for Quality of Life Research, Lisbon, Portugal, October 10-14, 2006, and at the 11th Annual Meeting of the Society for Neurooncology, Orlando, FL, November 17-19, 2006.

The corresponding author (M.J.B.T.) had full access to all data in the study and had the final responsibility for the decision to submit for publication.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions Appendix REFERENCES

 
1. Fairclough DL: Design and analysis of quality of life studies in clinical trials. London, England: Chapman and Hall/CRC, 2002

2. Bottomley A, Flechtner H, Efficace F, et al: Health related quality of life outcomes in cancer clinical trials: On behalf of the EORTC Data Center and Quality of Life Group. Eur J Cancer 41:1697-1709, 2005[CrossRef][Medline]

3. Kramer JA, Curran D, Piccart M, et al: Identification and interpretation of clinical and quality of life prognostic factors for survival and response to treatment in first-line chemotherapy in advanced breast cancer. Eur J Cancer 36:1498-1506, 2000[CrossRef][Medline]

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5. Kleihues P, Cavenee WK: Tumours of the nervous system. WHO classification of tumours. Lyon, France, IARC Press, 2000

6. Cairncross G, Macdonald D, Ludwin S, et al: Chemotherapy for anaplastic oligodendroglioma. J Clin Oncol 12:2013-2021, 1994[Abstract/Free Full Text]

7. van den Bent MJ, Kros JM, Heimans JJ, et al: Response rate and prognostic factors of recurrent oligodendroglioma treated with procarbazine, CCNU and vincristine chemotherapy. Neurology 51:1140-1145, 1998[Abstract/Free Full Text]

8. Cairncross JG, Berkey B, Shaw E, et al: Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Treatment Oncology Group trial 9402. J Clin Oncol 24:2707-2714, 2006[Abstract/Free Full Text]

9. van den Bent MJ, Carpentier AF, Brandes AA, et al: Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: A randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 24:2715-2722, 2006[Abstract/Free Full Text]

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14. Fayers P, Aaronson NK, Bjordal K, et al: EORTC QLQ-C30 scoring manual (ed 3). Brussels, Belgium: EORTC publications, 2001

15. Osoba D, Rodrigues G, Myles J, et al: Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 16:139-144, 1998[Abstract/Free Full Text]

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Submitted May 23, 2007; accepted September 11, 2007.

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