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Originally published as JCO Early Release 10.1200/JCO.2006.05.6929 on March 26 2007 © 2007 American Society of Clinical Oncology. Health-Related Quality of Life in Younger Patients With Chronic Lymphocytic Leukemia Treated With Fludarabine Plus Cyclophosphamide or Fludarabine Alone for First-Line Therapy: A Study by the German CLL Study Group
From the Department of Internal Medicine I, University of Cologne, Cologne; and Institute of Medical Statistics and Epidemiology and Institute of Psychosomatic Medicine, Technical University, Munich, Germany Address reprint requests to Michael Hallek, MD, Klinik I für Innere Medizin, Klinikum der Universität zu Köln, Kerpener Strasse 62, D-50924 Köln, Germany; e-mail: michael.hallek{at}uni-koeln.de
Purpose To date, only a few studies have evaluated the health-related quality of life (HRQOL) of patients with chronic lymphocytic leukemia (CLL) receiving chemotherapy. Therefore, the German CLL Study Group assessed HRQOL in younger patients with advanced CLL receiving first-line chemotherapy with fludarabine or fludarabine plus cyclophosphamide (FC). Patients and Methods Three hundred seventy-five patients younger than 66 years with advanced CLL were randomly assigned to receive either fludarabine alone (fludarabine 25 mg/m2/d for 5 days intravenously [IV], repeated every 28 days) or FC (fludarabine 30 mg/m2/d for 3 days IV plus cyclophosphamide 250 mg/m2/d for 3 days, repeated every 28 days). Six courses of treatment were planned to be administered. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 was sent to all patients at baseline and after 6, 12, and 24 months. Results Eighty-nine percent of 362 included patients completed at least one questionnaire (163 fludarabine- and 158 FC-treated patients). Comparing the baseline levels of 249 CLL patients with the general German population, significant differences in nearly all HRQOL scales were assessed between the two groups. A multivariate analysis showed no significant differences in all HRQOL scales between both arms. In both treatment arms, symptoms such as fatigue, insomnia, and appetite loss improved to lower levels after the end chemotherapy. Except for lower physical status, no significant difference in HRQOL between male and female patients was evaluated. Conclusion Fludarabine-based treatment seems to improve HRQOL little to moderately in younger patients with advanced CLL. No significant difference between fludarabine- and FC-treated patients was observed.
The assessment of health-related quality of life (HRQOL) has become one of the major end points besides overall survival within clinical trials in hematology and oncology. Chronic lymphocytic leukemia (CLL) of the B-cell type is an indolent lymphoma with a variable course of disease, with overall survival times ranging from less than 2 years to more than 15 years.1-3 Because several phase III trials have shown that fludarabine is superior to chlorambucil or polychemotherapy with cyclophosphamide, doxorubicin, and prednisone with regard to response rates and progression-free survival, purine analogs have become the standard first-line therapy in younger patients with advanced CLL.4-6 However, none of these studies was able to show a prolongation of overall survival. Despite the fact that CLL is the most common leukemia in the Western world, HRQOL has rarely been evaluated within large clinical trials. The impact of chemotherapy on HRQOL in CLL patients is not yet clear.7 Therefore, we evaluated the HRQOL of previously untreated younger patients who were randomly assigned to receive either fludarabine alone or the combination therapy of fludarabine plus cyclophosphamide (FC) for advanced CLL within in a phase III trial of the German CLL Study Group (GCLLSG). HRQOL was assessed using the questionnaire of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30).8 The clinical results of the study were published elsewhere.9 Here, we report the results of HRQOL assessment of both treatment arms and compared these results with the HRQOL of the general population in Germany.10
Clinical Trial From July 1999 until July 2003, 375 patients from Germany and Austria were enrolled onto the CLL4 trial of the GCLLSG (entitled Fludarabine Versus FC in First Line Therapy of Younger Patients up to 65 Years With Advanced CLL). Diagnosis of CLL had to be confirmed according to the guidelines of the National Cancer Institute (NCI) –Sponsored Working Group.11 Only previously untreated patients with advanced Binet stage C or B with symptoms that required therapy or patients in Binet stage A suffering from severe B symptoms were included. The stage of the disease was assessed according to the Binet or Rai classification,2,3 with requirement of treatment assessed according to the NCI criteria.11 Severe organ dysfunction, concomitant or previous neoplasm, and autoimmune hemolytic anemia or thrombocytopenia were exclusion criteria. Thirteen patients were excluded from analysis because of violation of inclusion criteria. Eleven patients were lost to follow-up. The protocol was approved by the Ethics Committee of the medical faculty of the Ludwig-Maximilians-University of Munich, and all patients signed an informed consent form. Patients were randomly assigned to receive either fludarabine alone (25 mg/m2 administered intravenously (IV) daily over 30 minutes for 5 days) or FC (fludarabine 30 mg/m2 administered IV daily over 30 minutes for 3 days plus cyclophosphamide 250 mg/m2 administered IV daily over 30 minutes for 3 days). Both regimens were repeated every 28 days, and a maximum of six courses was administered in each arm. The clinical response was defined according to the revised guidelines of the NCI-sponsored workshop.11
Quality-of-Life Instrument: EORTC QLQ-C30 The validity and test-retest reliability of the questionnaire has previously been demonstrated by several studies.12-14 The first HRQOL questionnaire at baseline was handed out by the treating physician. The following three questionnaires at 6, 12, and 24 months after random assignment were mailed to the patients, with a cover letter explaining the procedure for filling out the questionnaire. As previously published,15 changes in HRQOL scores between 5 and 10 points were interpreted as little change, differences between 10 and 20 points were interpreted as moderate change, and differences of more than 20 points were interpreted as very large change.
Statistical Analysis Raw scores for scales were evaluated by addition of the specific items, which were included in one scale and set into relation to the number of items.8 Raw scores were then transformed to a linear scale ranging from 0 to 100, with a high score in global health and all functional scales correlating with a good HRQOL; however, for all symptom scales and single items, a high score correlated with a high burden of symptoms. The formula for the linear transformation into functioning scales and symptom scales was as follows: Score = [(raw score – 1)/range] x 100. The transformation formula for functioning scales was as follows: Score = {1 –[(raw score – 1)/range]} x 100. If single items were missing for calculation of scale scores, all completed items were used for calculation if at least half of the items from the scale were answered. If less than half of the items from the scale were answered, then that score was missing for the patient. The multivariate analysis of HRQOL and other variables for both treatment arms was performed with a linear mixed model. No interaction terms were built, but a term for random intercept was included. Restricted maximum likelihood method was selected as the method of calculation. The default setting of the iteration parameters was used. To exclude differences that might occur by chance, the Bonferroni correction was applied.
Treatment arms were compared using the
The clinical results showing the superiority of FC compared with fludarabine alone with regard to response and progression-free survival were published elsewhere.9
Compliance of HRQOL Assessment
Comparison of HRQOL Between CLL Patients and Healthy Controls To evaluate the differences in HRQOL between healthy people and CLL patients, previously published reference values on the EORTC-C30 questionnaire of the general German population10 were compared with the baseline HRQOL data of CLL patients included in our study (Table 3). Data of the general German population were sex and age adjusted for this analysis.
To assess the deviation from HRQOL reference ranges, which were obtained from the normal German population, the z scores for global health status as well as the functioning scales and fatigue symptom scale were calculated (Fig 1). The comparison with reference data shows that CLL patients had a significantly impaired HRQOL on all functioning scales as well as fatigue, nausea, and all single-items scales with the exception of pain. The most prominent differences were observed in role functioning (range of differences in scores, –20 to –22) and in fatigue (range of differences in scores, +23 to +24). Emotional and social functioning as well as dyspnea, insomnia, appetite loss, and financial impact showed moderate differences between the two groups.
Comparison of HRQOL in Patients Treated With Fludarabine and FC No significant difference in HRQOL at baseline was assessed between the treatment arms. Figures 2 through  7 and Tables 4 through 9 show the most prominent results in functioning and symptom scales. Twelve months after random assignment, a significantly higher scoring level in role functioning was assessed in the FC arm compared with the fludarabine arm (score, 72 v 64, respectively; P = .04; Fig 4, Table 6). Moreover, scores of nausea and vomiting were significantly elevated in the FC arm compared with the fludarabine arm at months 0 and 6 (scores, 14 v 5 and 12 v 7, respectively; P < .001 and P = .03, respectively), which correlates with the clinical data.9 Because of the median time of 2 weeks from the delivery of the questionnaire to the date of completion, several patients had just received the first treatment course when the baseline questionnaire was completed. After 24 months, significantly lower scores of appetite loss were reported in the FC arm compared with the fludarabine arm (score, 5 v 18, respectively; P = .004). Scores on dyspnea were significantly lower with FC treatment compared with fludarabine after 12 months as well (score, 23 v 33, respectively; P = .03).
Changes in HRQOL after chemotherapy were analyzed in 208 patients for whom both baseline scores and follow-up scores were available (Table 10). After 12 months, a small but significant improvement in global health status (+9; P = .04) and a moderate improvement in emotional function (+10; P = .02) were assessed in the FC arm compared with no change in the fludarabine arm. Role functioning and social functioning improved 1 year after random assignment to FC (+6 and +7, respectively), but the difference was not significant. Nausea and vomiting, which were more common with FC therapy, decreased significantly after 12 months (–9; P = .03). In both treatment arms, fatigue, insomnia, and appetite loss improved little to moderately after completion of therapy.
An analysis comparing HRQOL changes between month 24 and baseline was performed for both treatment arms but showed no significant differences, which might be a result of the lower number of patients available for follow-up at 24 months compared with the follow-up time of 22 months. Additionally, we performed a multivariate linear mixed model analysis evaluating HRQOL ranges by treatment arm after 6, 12, and 24 months that included sex, age, Binet stage, Eastern Cooperative Oncology Group performance status, hemoglobin count, number of treatment courses, response, and the presence of grade 3 or 4 toxicity as covariates. No significant difference between both treatment arms was observed. To exclude differences that might occur by chance, a Bonferroni correction was applied. No significant differences after correction were found.
Comparison of HRQOL in Male and Female CLL Patients
Because CLL is still an incurable disease with conventional chemotherapy, maintenance of quality of life is one of the major aims in treatment of CLL. Although HRQOL has been widely evaluated in patients with solid tumors, results regarding the assessment of HRQOL in indolent lymphomas such as CLL are still poor. Therefore, the aim of our trial was to evaluate the HRQOL in younger patients with CLL over a 2-year period after initiation of fludarabine-based first-line therapy. This analysis is the first one presenting results of HRQOL in CLL patients treated within a randomized trial. The compliance with HRQOL evaluation in our study at baseline was 69% and remained stable during 2 years of follow-up. A previous HRQOL study in CLL patients reported a similar compliance rate.7 It is remarkable that this analysis was performed by a single center compared with our multicenter phase III study. However, in other malignant entities, compliance rates of up to 90% have been reported within phase III trials.16,17 Previously, it has been shown that higher compliance rates in cancer patients were obtained if data collection was integrated in routine care and if further technical instruments such as touch screen computers were used.18 Because of the large number of participating centers (n = 137) and the lack of additional staff and technical support, the compliance rate at baseline was lower in our study than in previous studies on HRQOL. The distribution of patient characteristics and clinical outcome with regard to compliance only showed a significant difference in the mean number of administered courses and response rates. Responders were more likely to fill out their questionnaires at follow-up. HRQOL rates were also compared between responders and nonresponders in this trial (data not shown). Except for improved role functioning in responders, no significant differences in HRQOL were observed between the two groups. The United Kingdom CLL Study Group evaluated HRQOL with the EORTC QLQ-C30 questionnaire as well within the CLL4 trial comparing chlorambucil versus fludarabine alone versus FC.19 In this study, significantly improved role functioning, emotional functioning, and global health status were found in responders. Another trial evaluating HRQOL in patients with multiple myeloma reported that physical functioning and global health status were correlated with response to therapy.20 Scoring results from this trial were similar with regard to global health status, role functioning, and emotional functioning compared with previously published data on HRQOL in CLL patients.7,19 Compared with the Austrian study, higher scores for physical functioning and cognitive functioning were assessed in our trial, which is a result of the lower median patient age of 59 years compared with 68 years.7 The younger patients included in our study seemed to have lower values for their social functioning than patients in other trials.7,19 One explanation is the fact that younger patients are more likely to feel disabled in fulfilling their profession because of their disease. However, as has been shown earlier, there are cultural differences in HRQOL between different European countries21; these differences need to be considered when clinical trial results on HRQOL are compared. Most of the patients with CLL were not severely physically impaired by the disease, but they did show very large differences in role functioning and fatigue compared with healthy controls as well as moderate differences in social functioning and emotional functioning. Similar results have been obtained within a phase II study comparing CLL patients with healthy controls.22 Functioning scales and symptom scales showed no significant impairment at month 6 after the end of chemotherapy, except for nausea and vomiting and diarrhea. Because patients did not receive an HRQOL questionnaire at interim staging in this analysis, we cannot exclude the possibility that HRQOL might be more impaired as a result of therapy-related adverse effects during chemotherapy. A phase II trial evaluating HRQOL after oral administration of fludarabine showed no significant impairment of HRQOL after three and six courses of chemotherapy, which might also be related to a response shift reflecting the patients' adaptation to their disease.22 Most of the HRQOL scores yielded no significant difference between the two treatment arms 6 months after random assignment, indicating that the more intensive combination regimen did not affect the functioning levels, although FC was associated with significantly more adverse effects, especially myelotoxicity. One year after random assignment, global health status and emotional functioning were little improved after FC treatment. Because FC induced higher response rates and longer progression-free survival, it can be assumed that an improvement in response to therapy correlates with at least a small improvement in HRQOL. Similar results were obtained from a study from the French Cooperative Group on CLL; patients treated with the more effective regimen of fludarabine or cyclophosphamide, doxorubicin, vincristine, and prednisone had a benefit in terms of quality-adjusted time without symptoms or toxicity.23 Because the follow-up questionnaires of patients who received a lower number of treatment courses and who were more often nonresponsive to therapy were more frequently missing, this patient group is a bit under-represented in our analysis. Therefore, a conclusion on HRQOL in CLL patients with nonresponse or who could not tolerate therapy is difficult to make. Using a multivariate linear mixed model, no significant difference between both treatment arms in all HRQOL scores was observed. The earlier mentioned differences between both arms were relatively small. When viewed in relation to other parameters such as age, stage, sex, response to therapy, and incidence of toxicities, HRQOL differences between both treatment arms disappeared. Our comparative analysis on HRQOL in male and female patients showed initially significant differences in physical functioning as well as appetite loss and constipation, which was reported previously.7 However, the sex-specific difference in emotional functioning, as previously reported,7,24 was not confirmed by our data. Interestingly, at the follow-up periods, nearly all differences in HRQOL between the sexes disappeared. Because the data on marital and educational status were not available, we cannot exclude the possibility of an influence of the sociodemographic factors on HRQOL. Although several trials on cancer patients have shown that partnership and higher income had a positive effect on quality of life of cancer patients,25,26 two German trials showed that, at least in the German population, partnership and educational status did not affect HRQOL.27,28 In conclusion, fludarabine-based chemotherapy results in a small to moderate improvement of HRQOL in CLL patients. The disease-associated symptoms of fatigue, insomnia, and appetite loss improved little to moderately after chemotherapy, at least in patients who responded to therapy. No significant differences in HRQOL between both treatment arms were observed. The HRQOL in CLL patients is significantly impaired compared with the general population, especially regarding role functioning, social functioning, and fatigue symptoms. Because CLL is still an incurable disease with conventional chemotherapy, measurement of HRQOL ought to have an important role in future clinical trials.29 Despite more effective treatment options for CLL patients, HRQOL seems to improve only moderately. Therefore, additional supportive therapy is warranted in CLL patients in the future.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Barbara F. Eichhorst, Medac Schering Onkologie; Michael Hallek, Medac Schering Onkologie Testimony: N/A Other: N/A
Conception and design: Barbara F. Eichhorst, Raymonde Busch, Ingrid Kuhn-Hallek, Michael Hallek Administrative support: Barbara F. Eichhorst, Tanja Obwandner Collection and assembly of data: Barbara F. Eichhorst, Tanja Obwandner, Ingrid Kuhn-Hallek Data analysis and interpretation: Barbara F. Eichhorst, Raymonde Busch, Tanja Obwandner, Peter Herschbach Manuscript writing: Barbara F. Eichhorst Final approval of manuscript: Barbara F. Eichhorst, Raymonde Busch, Tanja Obwandner, Ingrid Kuhn-Hallek, Peter Herschbach, Michael Hallek
Study office: A. Westermann, K. Posse, D. Glogger. Statistics: K. Klein, Aberl, C. Ilgen. The following investigators participated in this study (in alphabetical order of cities, institutions, and names of participating physicians): Ansbach: S. Müller. Aschaffenburg: M. Weslau. Arnstadt: C. Müller. Augsburg: Zentralklinikum: J. Dani, P. Seufert. Aurich: Kreiskrankenhaus: W. Langer. Bad Hersfeld: Kreiskrankenhaus, Majunke. Bad Mergentheim: Caritas Krankenhaus: E. Hartung. Bad Saarow-Pieskow: Humaine-Klinikum: P. Frenzel, H. Fuss. Bad Salzuflen: R. Weinert. Bayreuth: A. Hübner. Bergisch Gladbach: H. Culmann. Berlin: Clinic of the Humboldt University Charité Mitte: J. Eucker, O. Sezer; Evangelisches Waldkrankenhaus Spandau: J. Potenberg; Robert-Rössle-Klinik: B. Dörken; University Hospital Benjamin Franklin: A. Krackhardt; University Hopsital Charité, Campus Virchow-Clinic: S. Srock; A. Dietzmann; A. Kirsch; A. Koschuth; H. Seibt-Jung; F. Strohbach, K. Zuchold. Bietigheim-Bissingen: Krankenhaus: G. Dietrich. Bremen: Evangelische Diakonissenanstalt: C. Diekmann. Chemnitz: M. Grundeis. Cottbus: U. von Grünhagen. Dresden: S. Dörfel. Düsseldorf: Krankenhaus Düsseldorf-Benrath: B. Günther. Eisenach: St Georg Klinikum: B. Ismer. Emden: Hans-Susemihl-Krankenhaus: H. Becker. Erfurt: H. Franke; U. Hauch; J. Weniger; Helios-Klinikum: K. Härtwig, M. Herold. Erlangen: M. Eckart. Eschweiler: St Antonius Hospital: S. Schäfer. Essen: Evangelisches Krankenhaus Essen-Werden: W. Heit; University Hospital: G. Brittinger, U. Dührsen, J. Dürig, H. Müller-Beisenhirtz; R. Rudolph. Esslingen: Städtische Kliniken: R. Eckert. Forchheim: R. Thiemann. Frankfurt Oder: Klinikum: W. Stein. Freiburg: Reiber. Garmisch-Partenkirchen: Kreiskrankenhaus: H. Lambertz. Gerlingen: H.-R. Schmitt. Germering: J. Mittermüller. Gießen: G. Schliesser. Göppingen: Klinik am Eichert: B. Maier-Bay. Göttingen: University Hospital: C. Binder. Greifswald: Ernst-Moritz-Arndt University Hospital: G. Dölken, B. Kallinich, M. Wimmer; B. Meyer. Güstrow: H. Eschenburg. Hagen: Katholisches Krankenhaus: W. Lindemann. Halle: H.-J. Hurtz, A. Oppenhorst, R. Rohrberg, M. Schmidt; C. Spohn. Hamburg: Allgemeines Krankenhaus: B. Seyfarth; University Hospital Eppendorf: M. Brügmann, M. de Wit, G. Schuch. Hamm: Evangelisches Krankenhaus: Fouth, E. Lange, C. Voss; St Marienhospital: H. Dürck. Hannover: B. Gaede. Heidelberg: University Hospital: M. Hensel. Heilbronn: Städtisches Klinikum: K.-H. Koniczek; P. Porowski. Herrsching: H. Dietzfelbinger. Hildesheim: W. Freier. Hövelhof: M. Schneider. Holzminden: Evangelisches Krankenhaus: F. Burghardt. Homburg Saar: University Hospital Saarland: J. Marell, N. Murawski, H. Schmitt. Idar-Oberstein: Städtisches Krankenhaus: A. Fauser, D. Linck. Ingolstadt: P. Maubach. Jena: S. Hahnfeld. Kaiserlautern: Westpfalzklinikum: J. Kirsch, H. Link; R. Hansen. Karlsruhe: Städtisches Klinikum: M. Haag, M. Schmier; St Vicentius Krankenhaus: G. Göckel, J. Metzger. Kassel: S. Siehl, U. Söhling. Kempten: Klinikum Kepmpten Oberallgäu: O. Prümmer. Kiel: University Hospital: M. Kneba,S. Matutat, M. Ritgen, Köln: University Hospital: V. Diehl, T. Elter, G. Fingerle-Rowson, R. Schnell, H. Schulz; T. Kim. Kronach: M. Strauch. Landshut: U. Vehling-Kaiser. Leer: Kreiskrankenhaus: G. Köchling; L. Müller. Lemgo: Klinikum Lippe-Lemgo: H. Middeke. Ludwigsburg: Ulshöfer. Magdeburg: Städtisches Klinikum Krankenhaus Altstadt: E. Kettner; Otto-von-Guericke University Hospital: A. Franke, C. Maas, S. Mewes, K. Wieker, M. Wiermann. Mannheim: University Hospital: O. Maywald, M. Schatz. Mönchengladbach: Grabenhorst. München: Krankenhaus München-Schwabing: D. Adorf; University Hospital Großhadern: M. Bergmann, R. Forstpointner, A. Golf, E. Hiller, H.-J. Kolb, N. Lang; University Hospital Rechts der Isar: G. Fischer, I. Ringshausen, F. Schneller; W. Abenhardt; M. Kimmich. Mönchengladbach: U. Grabenhorst. Münster: University Hospital:M. Kropff. Muhr am See: B. Göttler. Neunkirchen: P. Schmidt. Norderstedt: R. Hoffmann. Nordhausen: Südharz Krankenhaus: K. Dachselt. Nürnberg: Klinikum Nord: C. Falge, A. Lechner, K. Schäfer-Eckart, G. Schmidt. Offenbach: H. Balló. Oldenburg: B. Ottembra, D. Reschke. Ostfildern: Paracelsus-Krankenhaus: U. Abele. Pasewalk: Asklepios Klinik: T. Ehlert. Plauen: Vogtlandklinikum: V. Schirmer. Potsdam: Klinikum Ernst von Bergmann: K. Akrivakis, A. Gerhardt, R. Pasold, F. Rothmann; A. Sauer. Regensburg: Krankenhaus Barmherzige Brüder: E.-D. Kreuser, C. Steinbrecher. Rosenheim: Klinikum: C. Hempfling. Rostock: University Hospital: B. Krammer-Steiner, A. Steffen, S. Wilhelm; V. Lackner. Saarbrücken: Caritas-Klinik St. Theresia-Rastpfuhl: A. Rotter; G. Jacobs, J. Schimke. Schwerin: Klinikum: D. Hähling. Siegen: St Marien-Krankenhaus: T. Gaska. Stuttgard: Diakonissenkrankenhaus: K. Kaesberger; Katharinenhospital: S. Krauss; Marienhospital: B. Schmid; Robert-Bosch-Krankenhaus: W. Aulitzky; H.Fiechtner; E. Höring, M. Respondek. Trier: Krankenanstalt Mutterhaus der Borromäerinnen: B. Meuter, C. Peter; B. Rendenbach. Tübingen: University Hospital: O. Aichele, D. Benz; M. Haen. Ulm: University Hospital: H. Döhner, J. Greiner, A. Kröber, E. Leupolt, S. Stilgenbauer. Vechta: St. Marienhospital: J. Diers. Weilheim: Perker. Wendlingen: T. Kamp. Wien: Hanusch Krankenhaus: G. Hopfinger; University Hospital: U. Jäger. Worms: O. Burkhard, B. Reimann. Würzburg: University Hospital: M.-E. Goebler, R. Grossmann, H. Rückle-Lanz; R. Schlag. Wuppertal: Klinikum St Antonius: M. Sandmann. Zittau: M. Schulze.
published online ahead of print at www.jco.org on March 26, 2007. Supported by Grant No. 70-2353 from Deutsche Krebshilfe, Bonn, Germany, and by a grant from Medac Schering Onkologie, Munich, Germany. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. All statistical tests were two sided. Statistical significance was defined as P < .05. The analysis was performed with SPSS V12.0 (SPSS Inc, Chicago, IL). 
