On behalf of the Scottish Gynaecological Cancer Trials Group
Affiliations of authors: Cancer Research U.K. Department of Medical Oncology, Glasgow, U.K. (PAV, JP, AH); Christie Hospital, Manchester, U.K. (GCJ); Sammons Cancer Center, Dallas, TX (AG); Hammermith Hospital, London, U.K. (HG); Weston Park Hospital, Sheffield, U.K. (RC); Belfast City Hospital, Northern Ireland, U.K. (RA); Aberdeen Royal Infirmary, Aberdeen, U.K. (DP); Royal Marsden Hospital, London, U.K. (SBK)
Correspondence to: Paul A. Vasey, MD, Division of Oncology, Joyce Tweddell Bldg., Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia (e-mail: paul_vasey{at}health.qld.gov.au)
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ABSTRACT |
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INTRODUCTION |
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However, in metastatic breast cancer, docetaxel, a semisynthetic taxane with pharmacologic and pharmacokinetic advantages over paclitaxel (710), has shown superiority over anthracyclines and paclitaxel in randomized trials (11,12). Docetaxel has also been evaluated in ovarian cancer. Phase II trials have indicated a level of efficacy comparable to that of paclitaxel (13), and, in paclitaxel-resistant patients, docetaxel retains an important degree of clinical activity (14). The feasibility of a docetaxelcarboplatin combination treatment for ovarian cancer was confirmed in a large feasibility study (15), and the recommended three-weekly dose was docetaxel at 75 mg/m2 of body surface area and carboplatin to an area under the plasma concentrationtime curve (AUC) of 5. Independent results from the United States showed a high clinical response rate and good tolerability for docetaxel at 60 mg/m2 plus carboplatin to an AUC of 6 when administered every 3 weeks (16).
In light of these promising findings, a randomized phase III study, SCOTROC (Scottish Randomised Trial in Ovarian Cancer) 1, was begun to compare efficacy, tolerability, and quality of life outcomes of docetaxelcarboplatin with paclitaxelcarboplatin as initial chemotherapy for stage IcIV ovarian and/or peritoneal cancers.
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PATIENTS AND METHODS |
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Between October 8, 1998, and May 8, 2000, 1077 patients from 83 international centers were randomly assigned to treatment with docetaxelcarboplatin (n = 539) or with paclitaxelcarboplatin (n = 538). The two treatment arms were well matched with respect to demographic and disease characteristics (Table 1). The patients progress through the trial is shown in Fig. 1.
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The study had full multicenter ethics committee approval, and all patients gave written informed consent. Randomization took place within 6 weeks of surgery, and patients were allocated to treatment by a minimization algorithm that used the following criteria: extent of residual disease, center, FIGO stage, performance status, tumor grade, interval debulking intention, CA-125 level available before treatment, and presence or absence of primary peritoneal cancer.
Treatment
Six cycles of chemotherapy were planned with intervals of 3 weeks between cycles and with the first cycle starting within 2 weeks of randomization. Docetaxel at 75 mg/m2 was administered as a 1-hour intravenous infusion. Paclitaxel at 175 mg/m2 was administered as a 3-hour intravenous infusion. In both arms, administration of the taxane was immediately followed by a 1-hour intravenous infusion of carboplatin to an AUC of 5, with the initial dose calculated according to the method described by Calvert (mg = [glomerular filtration rate + 25] x 5) (17), by use of 51Cr-EDTA (edetic acid) to measure the glomerular filtration rate (18). This dose remained fixed for all cycles, unless toxicity necessitated a reduction.
All patients received oral dexamethasone at either 8 mg twice daily for 3 days, starting the day before docetaxel, or at 20 mg administered 12 and 6 hours before paclitaxel. One hour before paclitaxel administration, patients also intravenously received 10 mg of chlorpheniramine (or 50 mg of diphenhydramine) and 50 mg of ranitidine (or 300 mg of cimetidine). Antiemetics used were either 3 mg of granisetron or 8 mg of ondansetron.
Cycles were repeated in the absence of progressive disease or prohibitive toxicity. If maximal tumor cytoreduction had not been achieved during primary surgery, further surgery was permitted between cycles 3 and 4. Patients who underwent this interval cytoreductive surgery then continued chemotherapy postoperatively for three more cycles. After six cycles, patients with a partial or complete response but with elevated CA-125 levels could continue with single-agent carboplatin to an AUC of 7 for up to three additional cycles; continuing the taxaneplatinum combination was prohibited. Patients completing first-line therapy ceased all cytotoxic treatments until progression.
Dose and/or Schedule Modifications
We delayed treatment for up to 2 weeks if the neutrophil count was less than 1.5 x 109 neutrophils per liter and the platelet count was less than 100 x 109 platelets per liter on day 1 of each cycle. Prophylactic antibiotics in all subsequent cycles were recommended for complicated grade 4 neutropenia. The dose of docetaxel was reduced to 60 mg/m2 or that of paclitaxel to 135 mg/m2 for subsequent cycles in the event of prolonged or complicated grade 4 neutropenia. If this degree of hematologic toxicity reoccurred despite the dose reduction, we recommended granulocyte colony-stimulating factor at 300 mg/day for all subsequent cycles. We allowed the use of granulocyte colony-stimulating factor for persistent neutropenic fever. Carboplatin was reduced to an AUC of 4 for complicated grade 4 thrombocytopenia.
We also allowed treatment to be delayed for 2 weeks for mucositis of grade 3 or higher and skin toxicity of grade 2 or higher. In the event that liver function deteriorated or that neurotoxicity to grade 3 or higher occurred, we recommended that the taxane be discontinued. Patients could continue carboplatin alone if further chemotherapy was indicated.
For clinically significant hypersensitivity reactions to taxanes, the infusion was stopped, symptoms were treated, and patients were reinfused within 3 hours without further premedication if appropriate. Less severe reactions were managed by slowing down the infusion, observing the patient until recovery, and then reinfusing at the initial rate.
Clinical Assessments
Before entry, patients underwent a physical examination, electrocardiogram, chest x-ray, abdominopelvic computed-tomography scan, full blood count, biochemical profile, CA-125 assay, and documentation of renal function via isotopic measurement, as previously described (18).
Patients had weekly full blood counts during chemotherapy, and the physical examination and assessments of ECOG performance status, biochemistry, and CA-125 level were repeated before each cycle. Response was assessed with a computed-tomography scan after cycles 3 and 6, and this procedure was also recommended if CA-125 had increased or plateaued. The CA-125 response was classified according to the method of Rustin (19).
A complete response was defined as the complete disappearance of all measurable (in two dimensions) and evaluable disease, with no new lesions appearing, no disease-related symptoms, and no evidence of nonevaluable disease, including normalization of CA-125 level and other abnormal laboratory values. A partial response was defined as a 50% or greater decrease from baseline in the sum of products of perpendicular diameters of all bidimensionally measurable lesions, with no clinically significant increase in size of evaluable lesions and with no new lesions. For a unidimensionally measurable tumor, a partial response was defined as a decrease of 50% or more in the sum of the largest diameters of all lesions. It was not necessary for all lesions to have regressed. Stable and/or no change was defined as a tumor that did not qualify for a complete response, a partial response, or progressive disease or had an unknown status. Progressive disease was defined as 1) a 25% or greater increase in the size of at least one bidimensionally or unidimensionally measurable lesion, 2) a clear worsening from previous assessment of any evaluable disease (note that worsening of existing nonevaluable disease did not constitute progression), 3) the reappearance of any lesion that had disappeared, with the exception of ascitic or pleural fluid that was drained and recurred within 3 months of drainage, or 4) the appearance of any new lesion and/or site.
Toxic effects were documented by use of the National Cancer Institute Common Toxicity Criteria (NCICTC, version 2.0). Quality of life was prospectively evaluated before each cycle, at 6 months, and every 4 months for up to 2 years by use of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (version 3.0), and EORTC QLQ-OV28 (version 1) (20). In some centers, patients undertook a neurotoxicity assessment (21) that consisted of 12 questions and five neurologic tests (producing a neurotoxicity score [NScore]) at baseline, after cycles 3 and 6, at 6 months, and every 4 months for up to 2 years.
Follow-up for each patient occurred every 2 months, until the CA-125 level increased plus symptoms appeared or until radiologically defined disease progression. Physical examinations were given and CA-125 levels were determined every 2 months. Computed tomography scans were recommended in patients with no symptoms but increasing levels of markers. Follow-up intervals were extended after 2 years according to each center's local policy. Centers assessing NScore and quality-of-life data collected data until progression or up to a maximum of 2 years after treatment.
Statistical Analysis
The primary study end point was progression-free survival. The study was designed with an 80% power to detect a difference of 25% in median progression-free survival (from 17 to 21.25 months) at the two-sided 5% level of statistical significance. This required 1050 patients with a minimum follow-up of 1 year.
Progression-free and overall survival were analyzed with the Cox model, incorporating study pretreatment factors used in randomization. Responses were compared by use of Fisher's exact test. The MannWhitney U test was used for safety analyses; for some toxic effects, the U test was supplemented by Fisher's exact test. All analyses for efficacy were performed on an intent-to-treat basis, and all patients were included for analysis wherever possible.
EORTC quality-of-life instrument measures were calculated (22) and grouped into the following four families of end points: global health status, functional scales, symptom scales, and neurotoxicity. The latter consisted of the NScore and the neurotoxicity scale from questionnaire QLQ-OV28. Analysis was further split into the following three time periods: acute effects (on treatment), persistent effects (change between 6 months and baseline), and long-term effects (change over follow-up period). For each patient, the standardized area under the curve (36) compared with baseline was calculated; this end point was compared between the arms by use of the Wilcoxon two-sample test. Multiple testing within each family and/or time point combination was corrected for by the Hochberg (23) procedure. Multiple imputation (24) was applied to assess the robustness of the results to missing data. All statistical tests were two-sided.
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RESULTS |
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There were no statistically significant differences between arms for taxane and carboplatin dose intensity, cumulative dose, or the proportions of patients receiving carboplatin after completing the taxanecarboplatin combination. Eighty-two (15%) of the 539 patients receiving docetaxelcarboplatin and 114 (21%) of the 538 patients receiving paclitaxelcarboplatin withdrew from the protocol before completion, mostly because of toxicity. Neurotoxicity prompted the early withdrawal of 31 patients receiving paclitaxelcarboplatin but only of four patients receiving docetaxelcarboplatin. In the docetaxelcarboplatin arm, the most common reason for early withdrawal was hypersensitivity (12 patients). Sixty-eight (13%) of the 538 patients in the paclitaxelcarboplatin arm and 59 (11%) of the 539 patients in the docetaxelcarboplatin arm went on to receive an additional three cycles of carboplatin treatment (AUC of 7).
Survival
At the time of analysis, 686 patients had progressed or died (343 on each study arm). The median was 23 months, and 98% of living patients had a minimum 1 year's follow-up. The median progression-free survival for the docetaxelcarboplatin arm was 15.0 months (95% confidence interval [CI] = 13.3 to 16.6) and for the paclitaxelcarboplatin arm was 14.8 months (95% CI = 13.5 to 16.1) (hazard ratio [HR] for docetaxelpaclitaxel = 0.97, 95% CI = 0.83 to 1.13; P = .707) (Fig. 2, A). The 2-year survival rates associated with docetaxelcarboplatin treatment and paclitaxelcarboplatin treatment were 64.2% (95% CI = 59.9% to 68.5%) and 68.9% (95% CI = 64.6% to 73.2%), respectively (HR for docetaxelpaclitaxel = 1.13, 95% CI = 0.92 to 1.39; P = .238) (Fig. 2, B).
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There was no statistically significant difference in clinical or CA-125 response rates, and 300 patients in the docetaxelcarboplatin arm and 296 patients in the paclitaxelcarboplatin arm were evaluable. Clinical response rates were 58.7% in the docetaxelcarboplatin arm and 59.5% in the paclitaxelcarboplatin arm (difference = 0.8%, 95% CI = 8.6 to 7.1; P = .868) (Table 2). The complete response rate was 28% in both arms. CA-125 responses could be evaluated in 68% of patients. Such responses occurred in 75.8% of the patients in the docetaxelcarboplatin arm and in 76.8% of the patients in the paclitaxelcarboplatin arm (difference = 1.0%, 95% CI = 7.2 to 5.1; P = .794).
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Five patients (three in the paclitaxelcarboplatin arm and two in the docetaxelcarboplatin arm) did not start any treatment and were excluded from toxicity analyses. Three patients in the paclitaxelcarboplatin arm and one patient in the docetaxelcarboplatin arm were treated on the opposite arm and were analyzed for toxicity according to the treatment they actually received. The incidence of grade 34 neutropenia (94% versus 84%, difference = 11%, 95% CI = 7% to 14%; P<.001) and of complicated neutropenia (grade 4 neutropenia for more than 7 days or with fever; P<.001) was statistically significantly higher in the docetaxelcarboplatin arm than in the paclitaxelcarboplatin arm (Table 3). Two patients died as a result of toxicity in the docetaxelcarboplatin arm, whereas one died in the paclitaxelcarboplatin arm. Similar low rates of grade 34 nonhematologic toxicity (occurring in 5% of patients) were observed for both regimens (Table 4). Overall, we observed more gastrointestinal toxicities, peripheral edema, allergic reactions, and nail changes in the docetaxelcarboplatin arm and more arthralgia, myalgia, alopecia, and abdominal pain in the paclitaxelcarboplatin arm.
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Treatment with docetaxelcarboplatin was associated with statistically significantly lower incidences of neurosensory (45% versus 78%; P<.001) and neuromotor (9% versus 16%; P = .001) toxicity than treatment with paclitaxelcarboplatin. Rates of grade 24 neurosensory toxicity were 11% in the docetaxelcarboplatin arm and 30% in the paclitaxelcarboplatin arm (difference = 19%, 95% CI = 15% to 24%; P<.001). In addition, grade 24 neuromotor toxicity was statistically significantly (P<.001) less frequent in the docetaxelcarboplatin arm (3%) than in the paclitaxelcarboplatin arm (7%; difference = 4%; 95% CI = 1% to 7%). These data are presented in Table 5.
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Quality-of-life data were available for 974 patients and consisted of 6582 assessments; NScore data were available for 538 patients and consisted of 1854 assessments. (Only 64% of patients at the centers where this end point was analyzed completed the NScore assessment questionnaire because only a fixed number of NScore questionnaires was available at each site, and these questionnaires were not replaced when they ran out.) The completion rate was highest during therapy and lowest during follow-up, but the pattern of missing data over time did not differ markedly between treatment arms.
Global quality-of-life scores did not differ between treatment arms during either therapy or follow-up, with scores increasing from baseline in both arms. During therapy, there were no differences between treatment arms for virtually all the functional scores (performance, role, emotional, cognitive, and social functioning; body image; and attitude toward disease and treatment), apart from the body image quality-of-life variable, which deteriorated more in the paclitaxelcarboplatin arm than in the docetaxelcarboplatin arm (Table 6). Symptom scores showed that pain and gastrointestinal symptoms decreased more in the docetaxelcarboplatin arm and that hair loss, weakness, and aches and pains increased more in the paclitaxelcarboplatin arm. For neurotoxicity, the quality-of-life score deteriorated and the NScore increased more in the paclitaxelcarboplatin arm than in the docetaxelcarboplatin arm.
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DISCUSSION |
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Although preclinical studies indicated that docetaxel might be superior to paclitaxel, this study did not demonstrate a progression-free or overall survival advantage for docetaxelcarboplatin treatment over paclitaxelcarboplatin treatment, although the relatively short follow-up precludes a definitive statement on overall survival. These outcome data are consistent with those reported in other studies of treatment with paclitaxelcarboplatin in a heterogeneous mixture of chemotherapy-naive ovarian cancer patients (25,26). Longer survival times reported in other trials may reflect their inclusion of populations expected to do relatively well, e.g., patients with no residual disease after primary surgery (4). In addition, the broad definition of progressive disease in this trial is likely to produce shorter progression-free times than the definitions used in other studies.
Peripheral neurotoxicity [predominantly sensory but can progress to motor weakness (27)] is the principal nonhematologic toxicity of paclitaxel and may manifest early in the course of treatment (28). Reduced neurotoxicity without decreased antitumor efficacy has been shown when paclitaxel was combined with carboplatin rather than with cisplatin in major clinical trials in ovarian cancer (4,5); however, neurotoxicity is still experienced by many patients. Our data point to further improvement when paclitaxel is replaced by docetaxel. Neurotoxicity is infrequently reported during docetaxel therapy unless cumulative doses exceed 600 mg/m2 (29). During this trial, neurotoxicity was more problematic than myelosuppression and was the leading reason for early withdrawal in the paclitaxelcarboplatin arm. Our 30% rate of clinically significant neurotoxicity for the paclitaxelcarboplatin arm is higher than previously reported and may be attributable to our comprehensive approach to neurotoxicity monitoring.
There is a growing appreciation of the importance of quality-of-life measures in cancer patients because the goals of therapy are to improve the quality as well as the duration of life. Generic quality-of-life measures do not adequately address disease- and treatment-related issues in ovarian cancer, and the OV28 instrument has been developed specifically for this unmet need (20). The improvements in quality-of-life parameters in the docetaxelcarboplatin arm, compared with the paclitaxelcarboplatin arm, as shown by validated instruments specific to ovarian cancer patients, are therefore of considerable interest. During therapy, pain and gastrointestinal quality-of-life scores decreased more in the docetaxelcarboplatin arm, whereas hair loss, weakness, and aches and pains increased more in the paclitaxelcarboplatin arm. Body image also deteriorated more in the paclitaxelcarboplatin arm at 6 months and on long-term follow-up than in the docetaxelcarboplatin arm; the two groups also differed with respect to neurotoxicity and NScore. It should be noted that the gastrointestinal quality of life score relates more to symptoms of disease (bloating, abdominal pain, feeling full) than the side effects of treatment, which is why it tends to improve during treatment.
The results of Osabe et al. (35) provide a basis for interpreting the differences between the two patient groups; broadly, that report suggested that patients regard differences of between 5 and 10 in EORTC quality-of-life scales as small, 1020 as moderate, and greater than 20 as large. By these criteria, the differences between the arms with regard to hair loss and aches and pains and quality of life neurotoxicity (acute/persistent) are moderate; the remaining differences are all small.
The difference in mean NScore between successive grades of the NCICCTC toxicity scale is approximately 3.0 (data on file, Cancer Research U.K. Trials Unit, Glasgow, U.K.); this difference can be used to interpret the clinical significance of the mean difference between the arms in the acute (mean difference = 1.76), persistent (mean difference = 1.73) and long-term (mean difference = 1.00) time periods. These results clarify the effect of neurotoxicity on quality of life, which has been poorly elucidated to date through the use of validated and reliable instruments (27); support earlier results that showed a low incidence of neuropathy in ovarian cancer patients who received docetaxel (16,17); and concur with the observation that neurotoxicity is less severe with docetaxel than with paclitaxel and is not dose-limiting (30).
Neurotoxicity data from SCOTROC 1 have been independently incorporated into a retrospective study evaluating quality-of-life effects of chemotherapy-induced neuropathy compared with other symptoms of ovarian cancer and its treatment (31). Key findings of this study were that clinically significant neuropathy was experienced by 57% of cisplatin-treated patients and 62% of paclitaxel-treated patients, reducing quality of life by 17% to 24%. By analyzing preliminary SCOTROC data, it was estimated (31) that severe chemotherapy-induced neuropathy reduced quality of life by 10% to 20%.
Statistically significantly more grade 34 neutropenia but no increased mortality was associated with docetaxelcarboplatin treatment compared with paclitaxelcarboplatin. Although there were higher incidences of complicated myelotoxicity with docetaxelcarboplatin, overall rates were low (approximately 10%) and did not compromise dose delivery or safety. In addition, the widespread use of prophylactic antibiotics and the availability of colony-stimulating factors allowed for the safe administration of myelosuppressive chemotherapy; furthermore, another study (17) suggested that the reduction of docetaxel to 60 mg/m2 was unlikely to affect survival.
The research efforts of the Scottish Gynaecological Cancer Trials Group have shifted toward the evaluation of sequential chemotherapy regimens consisting of four cycles of single-agent carboplatin at a higher AUC of 7 followed by four cycles of docetaxel-based therapy. The results of ongoing feasibility trials of this approach [SCOTROC 2 program (32,33)] will be analyzed together to form the basis of a future phase III trial that will explore the merits of this type of sequential treatment relative to conventionally delivered concurrent chemotherapy.
In conclusion, treatment with docetaxelcarboplatin should be viewed as an alternative to treatment with paclitaxelcarboplatin for newly diagnosed stage IcIV ovarian cancer. Treatment with docetaxelcarboplatin provides a similar level of progression-free survival to treatment with paclitaxelcarboplatin while reducing the level of neurotoxicity and improving the level of treatment-related quality of life.
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NOTES |
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Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology (San Francisco, CA, May 1215, 2001) and the 38th Annual Meeting of the American Society of Clinical Oncology (Orlando, FL, May 1821, 2002).
Over the last 5 years, Dr. Kaye has participated in occasional advisory boards for both Aventis, the manufacturer of docetaxel, and Bais, BMS, the manufacturer of paclitaxel. Dr. Paul is currently conducting research sponsored by Aventis. Dr. Coleman is a speaker and an advisory board member for Aventis. Dr. Gordon is conducting research sponsored by Aventis and is a member of the speakers bureau for Aventis. Dr. Vasey has previously conducted research funded by Aventis and has received honoraria for speaking engagements.
We thank all the members of the SCOTROC team at the Cancer Research U.K. trials Unit in Glasgow for their efforts in processing the data and also acknowledge Drs Robert Brown (Head of Laboratory Research, Department of Medical Oncology, Glasgow) and Jonathan Davis (Consultant Gynecologic Oncologist, Stobhill Hospital, Glasgow) for their work in setting up the surgical and biological studies. Many thanks to Lucinda Billingham, Senior Statistician at the Cancer Research U.K. Clinical Trials Unit at the University of Birmingham, U.K., for her help with the quality of life and neurotoxicity study analyses. Finally, the authors would like to acknowledge and thank all clinicians who entered patients into this study. They are:
Adams M., Velindre NHS Trust Hospital, U.K., Aebi S., Inselspital, Switzerland, Alexopoulos C., Evangelismos Hospital, Greece, Andel J., General Hospital Steyr, Austria, Arango H., Morton Plant Mease Health Care, USA, Atkinson R., Belfast City Hospital, U.K., Bauer J., Centre Hospitalier University Vaudois, Switzerland, Bonaventura T., Newcastle Mater Misericordiae Hospital, Australia, Bowman A., Western General Hospital, U.K., Briggs P., Monash Medical Centre, Australia, Buck M., Sir Charles Gairdner Hospital, Australia, Calvert H., Newcastle General Hospital, U.K., Carson L., Fairview University Medical Center, USA, Chan S., Nottingham City Hospital, U.K., Coleman R., Weston Park Hospital NHS Trust, U.K., Cosin J., Fairview University Medical Center, USA, Crawford S., Airedale General Hospital, U.K., Cruickshank D., South Cleveland Hospital, U.K., Cruickshank M., Aberdeen Royal Infirmary, U.K., Dady P., Wellington Hospital, New Zealand, Daniel F., Derriford Hospital, U.K., Davis J., Stobhill Hospital, U.K., Davy M., Royal Adelaide Hospital, Australia, Duncan L., Sammons Cancer Center, USA, Earl H., Addenbrookes NHS Trust, U.K., Egli F., Kantonsspital Chur, Switzerland, Elia M., Raigmore Hospital, U.K., Evans B., Auckland Hospital, New Zealand, Fehrenbacher L., Kaiser Permanente Medical Center, USA, Fennelly D., St Vincent's Hospital, Eire, Findlay M., Wellington Hospital, New Zealand, Fitzharris B., Christchurch Hospital, New Zealand, Fountzilas., G, Kyanoys Stavros General Clinic, Greece, Friedlander M., Prince Of Wales Hospital, Australia, Gabra H., Western General Hospital, U.K., Ganju V., Monash Medical Centre, Australia, Georgoulis V., University Hospital of Heraklio Crete, Greece, Gordon A., Sammons Cancer Center, USA, Graham J., Bristol Oncology Centre/Taunton & Somerset Hospital, U.K., Grant P., Mercy Hospital, Australia, Gre'nman S., Turku University Hospital, Finland, Grennan T., Kaiser Permanente Medical Center, USA, Harnett P., Westmead Hospital, Australia, Harper P., Guy's Hospital, U.K., Henle A., General Hospital Bregenz, Austria., Hess D., Kantonsspital, Switzerland, Highley M., Ninewells Hospital, U.K., Hindley A., Royal Preston Hospital, U.K., Horowitz I., The Emory Clinic, USA, Hui L., Kaiser Permanente Medical Center, USA, Iveson T., Salisbury District Hospital/Royal South Hants Hospital, U.K., Jalkanen J., Helsinki University Central Hospital, Finland, Jayson G., Christie Hospital NHS Trust, U.K., Joffe J., Huddersfield Royal Infirmary, U.K., Junor E., Beatson Oncology Centre Glasgow, U.K., Kainz C., Vienna University Medical School, Austria, Kato D., Kaiser Permanente Medical Center, USA, Kaye S., Beatson Oncology Centre Glasgow, U.K., Kennedy I., Waikato Hospital, New Zealand, Kennedy J., Glasgow Royal Infirmary, U.K., Klimek M., Maria Sklodowska-Curie Memorial Oncology Institute, Poland, Komulainen M., Kuopio University Hospital, Finland, Kuoppala T., Tampere University Hospital, Finland, Laking G., Wellington Hospital, New Zealand, Lamont A., Southend Hospital, U.K., Lang A., General Hospital Feldkirch, Austria, Ledermann J., Royal Free Hospital/Whittington Hospital/UCL Medical School, U.K., Leikermoser R., General Hospital Elisabethinen Linz, Austria, Leong D., Newcastle Mater Misericordiae Hospital, Australia, Lewis C., Prince Of Wales Hospital, Australia, Loh K., The Queens Medical Center Research, USA, Long J., Waikato Hospital, New Zealand, Macleod P., Derriford Hospital, U.K., Maenpaa J., Tampere University Hospital, Finland, Malamos N., Helena-Venizelou Hospital, Greece, Marth C., Univ-Clinic Innsbruck, Austria, Mathis G., General Hospital Hohenems, Austria, Mattmann S., Kantonsspital, Switzerland, Mavroudis D., University Hospital of Heraklio Crete, Greece, McGuire W., Mercy Medical Center, USA, Minford J., Sammons Cancer Center, USA, Neesham D., Royal Women's Hospital, Australia, Osborne R., Dorset Cancer Centre, U.K., Parkin D., Aberdeen Royal Infirmary, U.K., Pasquinelli-Egli V., Inselspital, Switzerland, Peintinger F., General Hospital Bruck/Mur, Austria, Perey L., Centre Hospitalier Univ Vaudois, Switzerland, Perren T., St James's University NHS Trust, U.K., Phillips K., Mercy Hospital, Australia, Poole C., CRC Institute for Cancer Studies, U.K., Puistola U., Oulu University Hospital, Finland, Quinn M., Royal Women's Hospital, Australia, Rankin E., Ninewells Hospital, U.K., Rathmell A., South Cleveland Hospital, U.K., Reed N., Beatson Oncology Centre Glasgow, U.K., Richardson G., Monash Medical Centre, Australia, Rochat J., Kaiser Permanente Medical Center, USA, Rustin G., Mount Vernon Hospital, U.K., Rysz B., Maria Sklodowska-Curie Memorial Oncology Institute, Poland, Salmi T., Turku University Hospital, Finland, Schuetz P., Hospital Lainz, Austria, Sessa C., Ospedale San Giovanni, Switzerland, Sevelda P., Hospital Lainz, Austria, Skailes G., Royal Preston Hospital, U.K., Smyth J., Western General Hospital, U.K., Sorosky J., University of Iowa, USA, SoU.K.op M., Glasgow Royal Infirmary, U.K., Steiner R., Kantonsspital Chur, Switzerland, Stuart N., Ysbyty Gwynedd Hospital, U.K., Stummvoll W., Krankenhaus Der Barmherzigen, Austria, Symonds P., Leicester Royal Infirmary, U.K., Tan L., Hinchingbrooke Hospital, U.K., Tatman J., Kaiser Permanente Medical Center, USA, Thurlimann B., Kantonsspital, Switzerland, Twiggs L., Fairview University Medical Center, USA, Vasey P., Beatson Oncology Centre Glasgow, U.K., Verrill M., Newcastle General Hospital, U.K., Volgger B., Univ-Clinic Innsbruck, Austria, Walker E., Crosshouse Hospital, U.K., Wilkinson P., Christie Hospital NHS Trust, U.K., Yliskoski M., Kuopio University Hospital, Finland, Yosef H., Beatson Oncology Centre Glasgow, U.K., Zielinski J., Oncology Centre Institute, Poland.
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Manuscript received June 2, 2004; revised September 16, 2004; accepted October 1, 2004.
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