Annals of Oncology Advance Access originally published online on August 20, 2007
Annals of Oncology 2007 18(10):1691-1697; doi:10.1093/annonc/mdm331
© 2007 European Society for Medical Oncology
melanoma |
Results of a multicenter randomized study to evaluate the safety and efficacy of combined immunotherapy with interleukin-2, interferon-
2b and histamine dihydrochloride versus dacarbazine in patients with stage IV melanoma
1 Department of Medical Oncology, Christie Hospital, Manchester, UK
2 Department of Dermatology, University of Kiel, Kiel, Germany
3 Department of Medical Oncology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
4 Departments of Oncology, Umeå University Hospital, Umeå, Sweden
5 Department of Oncology, McGill University, Montreal, Canada
6 EpiCept Corporation, San Diego, CA, USA
7 Dept of Virology, University of Göteborg, Göteborg
8 Departments of Surgery, Umeå University Hospital, Umeå, Sweden
* Correspondence to: Peter Naredi, Department of Surgery, Umeå University Hospital, S-90185 Umeå, Sweden. Tel: +46 90 7851153; Fax: +46 90 7851156; E-mail: peter.naredi{at}surgery.umu.se
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionConflict of interest statementAcknowledgementsReferences |
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Background: The safety and efficacy of immunotherapy with histamine dihydrochloride (HDC), interleukin-2 (IL-2) and interferon-
2b (IFN) compared with dacarbazine (DTIC) in adult patients with stage IV melanoma was evaluated. Patients and methods: Two hundred and forty-one patients were randomized to either receive repeated 4-week cycles of IFN [3 MIU, s.c., once daily for 7 days], IL-2 (2.4 MIU/m2, s.c., twice a day for 5 days) and HDC (1 mg, s.c., twice a day for 5 days) or DTIC 850 mg/m2 i.v. every 3 weeks. The primary endpoint was overall survival.
Results: Median survival was longer for patients receiving HDC/IL-2/IFN (271 days) than for patients receiving DTIC (231 days), but this did not achieve statistical significance. Four patients receiving HDC/IL-2/IFN and nine receiving DTIC experienced at least one grade 4 adverse event. Striking differences in overall survival were observed between countries participating in the study.
Conclusion: Treatment with HDC/IL-2/IFN was safely administered on an outpatient basis, but this immunotherapeutic regimen did not improve upon the response rate and overall survival seen with DTIC.
Key words: clinical trials, dacarbazine, histamine dihydrochloride, immunotherapy, interferon alpha, interleukin-2, melanoma, phase III
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionConflict of interest statementAcknowledgementsReferences |
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Stage IV melanoma is associated with a 5–11 month median survival duration and, despite response rates ranging from 10–50%, available treatments have failed to improve upon this and are associated with significant toxicity. The lack of efficacious treatments for advanced melanoma requires that new approaches be tested.
Currently, there are two agents approved for use in stage IV melanoma patients: dacarbazine (DTIC) in Europe and the USA and high-dose intravenous interleukin-2 (IL-2) in the USA. DTIC provides a 10–17% tumor response rate, but these responses are generally of short duration, and there is no evidence suggesting that DTIC has a significant impact on overall survival in this patient population [1–3].
The impact of high-dose IL-2 on the overall survival of patients with stage IV melanoma is not known. Pooled data from eight studies report a median survival of 11.4 months. IL-2 administered at high doses is associated with severe systemic side-effects [4]. Single-agent interferon-alpha (IFN) therapy, as well as single-agent IL-2 treatment, yields response rates of approximately 15% in metastatic melanoma with infrequent long-term responders and occasional long-term survivors [5]. The combination of IFN and IL-2 has been reported to increase response rates [6] but this has not been confirmed in a randomized phase III trial [7].
Immunosuppression within and around tumors has been implicated as a major factor in preventing better clinical outcomes using cytokines such as IL-2 and IFN [8, 9]. One mechanism by which tumors may suppress T-cell and natural killer (NK)-cell function is through the recruitment of monocyte/macrophages (MO) to the tumor site. These cells produce reactive oxygen species (ROS), which can cause down-regulation of the CD3
transduction antigen in NK and T cells along with significant NK-cell and T-cell apoptosis. Histamines inhibit ROS production in MO, and thereby protect NK-cells and T-cells from functional inhibition and apoptosis. The use of histamine dihydrochloride (HDC) as a counter-suppressive agent in combination with IL-2 and/or IFN has been under investigation in several phase 2 and 3 clinical trials [10–16].
The basis for this trial was in vitro and in vivo studies suggesting that the combination of HDC and IL-2 yields a more efficient lymphocyte-mediated destruction of several human malignant target cells [17–21] than either compound used as a single agent; these in vitro findings are supported by clinical studies in melanoma demonstrating that cytotoxic lymphocytes are more efficiently activated by systemic treatment with HDC/IL-2 in vivo than by monotherapy with IL-2 [22]. A recent randomized trial in acute myeloid leukemia (AML) demonstrated a statistically significant improvement in long-term leukemia-free survival for patients treated post-consolidation with HDC and IL-2 compared with the no-treatment control patients [16].
Clinical experience from a randomized phase 3 study in stage IV melanoma patients reported that the combination of histamine plus IL-2 improved the overall survival of stage IV melanoma patients with liver metastases versus IL-2 alone (9.4 vs. 5.1 months) but there was no survival benefit for the overall population [12]. A second confirmatory phase 3 study failed to show any survival benefit for patients with liver metastases (P. Naredi). In a phase II study in stage IV melanoma patients combining HDC/IL-2/IFN, the median survival exceeded 11 months and complete responses were seen, including in patients with liver metastases [14]. The present study was designed to test this outpatient combination immune-based treatment regimen containing low-dose IL-2, low-dose IFN and histamine compared with DTIC alone in stage IV melanoma patients.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionConflict of interest statementAcknowledgementsReferences |
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patients and eligibility
Inclusion criteria were: age >18 years; histologically proven American Joint Committee on Cancer (AJCC) stage IV melanoma; life expectancy of
3 months; clinically adequate bone marrow, kidney, cardiac and liver function (hemoglobin >10.0 g/dl, white blood cell count (WBC) >2.5 x 109 cells/L, absolute neutrophil count (ANC) >1.5 x 109 cells/L, platelet count >100 x 109/L, partial thromboplastin time (PTT or activated partial thromboplastin time in Australia) within normal limits, creatinine clearance >60 ml/min, serum bilirubin <1.5 times the upper limit of normal (ULN), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <3 times the ULN, fasting serum glucose <160 mg/dl; Karnofsky status score of 70). All patients signed an informed consent. Patients were excluded if any of the following conditions applied: prior treatment with DTIC or IL-2 (except IL-2 used as an adjuvant >1 year before enrollment in this study); abnormal cardiac function assessed by resting ECG; any other concurrent systemic anti-neoplastic therapy; ongoing active other malignancy (except in situ carcinoma of the cervix, localized squamous or basal cell skin carcinomas); metastatic central nervous system (CNS) malignancy at randomization (patients with stable, treated brain metastases were eligible); documented history of asthma treated within the past 5 years; medical, sociological or psychological impediment to compliance with protocol; pregnancy or breast-feeding; positive serum HIV test or history of autoimmune disease; active peptic ulcer disease or a history of prior bleeding ulcer disease.
study design
Patients were stratified on the basis of liver metastases at baseline (present or absent) and then randomized to either HDC/IL-2/IFN or to DTIC. Site-specific randomization codes were produced electronically for each stratified group, and site personnel called a central randomization desk. Randomization was conducted in consecutive sequence within each center. This study was not blinded because of the physiologic effects of HDC (such as flushing). The study was approved by the Institutional Ethics Review Boards.
Histamine dihydrochloride 1 mg (Ceplene, Maxim Pharmaceuticals, San Diego, CA, USA) was administered twice daily on days 1–5 of each week of the 4-week treatment cycle. HDC was administered by slow subcutaneous injection over a period of not less than 10 min and not more than 30 min. IL-2 (ProleukinTM, Chiron Corporation, Emeryville, CA, USA) was administered subcutaneously at a dosage of 2.4 MIU/m2 twice daily for days 1–5 of weeks 1 and 2 of each treatment cycle. IFN (interferon-2b, Intron-ATM, Schering Plough, Kenilworth, NJ, USA) was administered subcutaneously at a daily dose of 3 MIU for days 1–7 of each week of the treatment cycle. Before the first cycle a priming dose of IFN for 5–7 days was given. Intravenous DTIC 850 mg/m2 was delivered on day 1 of each 3-week cycle. DTIC was administered according to standard practice in each institution and was obtained from commercial stock.
The duration of treatment for patients receiving HDC/IL-2/IFN was expected to be 12 months, except in the event of progressive disease or adverse effect (AE) resulting in study discontinuation. Duration of treatment for patients who received DTIC and achieved a response was left to the discretion of the investigator.
study endpoints
The intent-to-treat (ITT) population comprised all randomized patients and the intent-to-treat liver metastases (ITT-LM) subgroup was defined as all randomized patients who had liver metastases at baseline. The primary efficacy endpoint was overall survival in the ITT population calculated as the number of days from randomization to death. Those patients without a documented date of death at the time of data cut-off were censored at the last date on which the patient was known to be alive.
Secondary efficacy endpoints were overall survival in the ITT-LM population, progression-free survival, objective response rate and duration of response. Progression-free survival was calculated as the number of days from randomization to the first documentation of progressive disease (PD) or death. Those patients without documented PD or death at the time of data cut-off were censored at the date of the last assessment of disease response. Objective tumor response rate was calculated as the number of patients with a confirmed complete response (CR) or partial response (PR) divided by the number of patients randomized. Assessment for a response occurred every 12 weeks after randomization with confirmation of the response 4 weeks later. The duration of the objective response was calculated as the number of days from the first documentation of CR or PR until the first documentation of PD or death. Only patients with a confirmed CR or PR were included in the analysis.
statistics
The primary analysis compared the overall survival in the two treatment groups using the stratified log-rank test, stratified by the presence or absence of liver metastases at baseline. The null hypothesis was that distribution of overall survival be the same in the two treatment groups. All P values reported are two-sided. Kaplan-Meier curves were used to summarize the survival distributions in the treatment groups, and the median of the survival distributions with 95% confidence interval (CI) was tabulated by treatment group.
A sample size of 96 patients in each group was required to provide 80% power to detect a 50% increase in median survival time (7.0–10.5 months) between the two treatment groups, with a type I error of 0.05. To allow for an expected drop-out rate of 20%, enrollment of 240 patients (120 per group) was planned to maintain the desired power.
Kaplan-Meier estimates of the survival rate in each treatment group were calculated at 6, 12, 18, 24, 30 and 36 months, along with 95% CI. The treatment groups were compared at each time point by using an approximate z test. The secondary endpoints of progression-free survival and duration of objective response were analyzed by using the same methods as for the primary analysis of overall survival. For duration of response, only those patients with an objective tumor response (confirmed CR or PR) were included in the analysis. The investigator's assessment of response was used to determine each patient's best overall response. The Fisher exact test was used to compare the treatment groups for objective tumor response rates and for comparison of prognostic factors between countries.
safety analysis
All patients who received at least 1 dose of study drug were included in the safety analyses. Endpoints for assessment of safety included monitoring the occurrence, frequency and severity of AE [according to Cancer and Leukemia Group B (CALGB) expanded common toxicity criteria] and their causal relationship to study drugs. Laboratory values, vital signs, results of physical examinations and ECG, dose adjustments and treatment withdrawals for safety reasons were included in the assessment of safety.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionConflict of interest statementAcknowledgementsReferences |
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patient characteristics
A total of 241 patients were randomized from February 1998 to October 2000 (119 to HDC/IL-2/IFN and 122 to DTIC) at 43 centers in Australia (66 patients), Canada (23 patients), Germany (52 patients), Israel (4 patients), Sweden (45 patients) and the United Kingdom (51 patients). Follow-up continued until June 2002, after which the trial database was locked.
The two treatment groups were similar with regard to sex, race, age, WHO performance status, lactate dehydrogenase (LDH) and location of disease. There were no significant differences in key prognostic factors or demographic characteristics between the two study groups (Table 1).
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Patient participation by treatment cycle was defined as receipt of at least one dose in a given cycle. Participation by cycle was similar between the two treatment groups after the first evaluation at week 12. However, there was a higher drop-out rate in the HDC/IL-2/IFN group after the first cycle (29% vs. 12% for DTIC). Five patients in the HDC/IL-2/IFN and one patient in the DTIC arm completed 12 months of treatment and three patients (all in the HDC/IL-2/IFN arm) went on with extended treatment for a further 6 months.
efficacy
The primary measure of efficacy was the duration of survival in the ITT population.
Although median survival was longer in the group receiving HDC/IL-2/IFN [271 (216–330, 95% CI) days versus 231 (157–291) days for the DTIC group], no statistically significant differences were seen in the Kaplan-Meier estimates for the ITT population (P = 0.94, stratified log-rank test, Fig. 1).
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Analysis comparing the Kaplan-Meier estimate of the percentage of ITT patients alive in the two treatment groups revealed a statistically significant higher survival rate at 6 months after randomization (P = 0.028) in the group receiving HDC/IL-2/IFN. However, this trend was not retained for later time periods.
The ITT-LM population was prospectively identified as a subset of the overall study population that would be considered in the primary analysis of the study. Although median survival was longer in the group receiving HDC/IL-2/IFN [211 (175–272) days versus 154 (114–256) days for the DTIC group], no statistically significant differences were seen (P = 0.70, Fig. 2).
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The results of the multivariate regression analyses for the ITT and ITT-LM populations are presented in Table 2. In the ITT population, baseline performance status and serum LDH were statistically significant predictors of survival. In the ITT-LM population, only serum LDH was a statistically significant predictor of survival. In neither the ITT nor ITT-LM populations did the treatment effect vary according to LDH level (LDH > ULN P = 0.43, LDH
ULN P = 0.47 for ITT; LDH > ULN P = 0.55 and for LDH ULN P = 0.90 for ITT-LM).
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Of the 241 patients in the ITT population, 235 (98%) had either died or experienced disease progression at the time of data cut-off. The difference between the Kaplan-Meier estimates of duration of progression-free survival for the two treatment groups showed a trend but was not statistically significant; 92 (88–95) days versus 83 (76–87) days for HDC/IL-2/IFN and DTIC, respectively, P = 0.18).
In the ITT population, no statistically significant differences were seen between the two treatment groups in best tumor response (Table 3). Fifteen (13%) of the patients receiving HDC/IL-2/IFN and 17 (15%) of the patients receiving DTIC achieved a CR or PR. The duration of objective response in the ITT population was longer for HDC/IL-2/IFN at 310 (178–NA) days than for DTIC [219 (171–290), P = 0.44].
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Striking differences in median survival were seen among the participating countries (P = 0.003, log-rank test, Table 4, Fig. 3). Germany (median 482 days, P = 0.001), Canada (336 days, P = 0.045) and Australia (230 days, P = 0.045) all had longer median survival than the United Kingdom (178 days). In Canada, Sweden and the United Kingdom, the median duration of survival was higher for the group receiving HDC/IL-2/IFN; however, in Germany and Australia, the median duration of survival was higher for the group receiving DTIC, with large variances in the medians between countries. Despite uniform entry criteria patients in different countries were entered at different stages of their disease (Table 4). Australia and Germany had significantly fewer patients with elevated LDH than Sweden and Canada. Germany also had significantly fewer patients with stage M1c than Sweden and the United Kingdom. Performance status also varied with Australia and Germany, despite the lowest frequency of patients with elevated LDH and/or stage M1c, having the highest frequency of patients considered to have performance status 1.
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In contrast to other phase 3 trials in melanoma we permitted the entry of patients with ocular melanoma. In this group of 37 patients median survival was longer for those receiving HDC/IL-2/IFN [325 (174–611) days versus 220 (118–283) days for the DTIC group, P = 0.14].
safety
The percentage of patients experiencing any AE was similar between the two treatment groups (99% for the HDC/IL-2/IFN group and 97% for the DTIC group), as was the percentage of patients who died on study or within 28 days of the last dose of study drug (10% for the HDC/IL-2/IFN group and 10% for the DTIC group, all patients died from melanoma). Most AE experienced by patients in both groups were mild or moderate in severity. The percentage of patients who discontinued because of an AE was also similar between the two groups (23% for the HDC/IL-2/IFN group and 20% for the DTIC group). Fatigue, lethargy, nausea and vomiting were the most common AEs in the HDC/IL-2/IFN arm while abdominal pain and hepatobiliary abnormalities were the most common in the DTIC population (Table 5).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionConflict of interest statementAcknowledgementsReferences |
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Stage IV melanoma patients have a poor prognosis and DTIC remains the standard treatment despite no demonstrable overall survival advantage. In this randomized study comparing DTIC to an outpatient immunotherapy regimen, we did not show statistically significant differences in terms of overall survival, tumor response or duration of response. The duration of response was 90 days longer in the combination group than in the DTIC group, albeit this difference did not attain statistical significance. The results for other secondary endpoints were similar between groups.
The similarity in outcomes between the two treatment arms may be explained by their being equally ineffective against metastatic melanoma. However, a number of factors need to be considered before coming to this conclusion. The survival difference that this trial was powered to detect, at 50%, is very large. A more modest advantage in favor of immunotherapy may have been missed. At the time that this trial was conceived the sample size was on a par with many melanoma phase 3 trials. The drop-out rate by the end of cycle 1 matched the 20% we anticipated in the trial design. However, the lower percentage of patients in the immunotherapy arm able to go beyond the first cycle of treatment may also have contributed to an underestimate of its potential. In contrast, the treatment duration of the similar HDC/IL-2/IFN regimen used in the earlier single site phase II study was a median 5 months [14]. This was probably a reflection of the relative complexity of the regimen, and of physicians' unfamiliarity with it and the attendant side-effects.
The dose of IL-2 administered in this study, 144 MIU/m2 during a 12-week period, is lower than in the two randomized studies where the combination of HDC and IL-2 showed a survival benefit over IL-2 alone. In the previously mentioned study in melanoma [12] 224 MIU/m2 of IL-2 was given during a 12-week period. In a phase 2 study in renal cell carcinoma a flat dose of 540 MIU IL-2 was administered during a 10-week period [15].
The large intercountry differences in median survival observed for this relatively small cohort of 241 patients complicates interpretation of the trial. It is clear that, despite uniform entry criteria, patients in different countries were entered at different stages of their disease, as shown by the variations in proportions of patients with elevated LDH and/or M1c disease between countries. This may reflect differing care pathways, local predispositions towards particular types of therapy or competing studies available only in some countries. Whatever the reason, it highlights an important issue in the design of clinical trials in melanoma. The need for studies with several hundred patients means that international collaborations will be the norm for future studies, and careful attention will be required to ensure that baseline assumptions with respect to outcome apply across trials. For example, we assumed a 7-month median survival in our control arm, but in Germany DTIC-treated patient survival, at 17.7 months, was more than double that estimate.
This randomized, phase 3 study of combination immunotherapy with HDC/IL-2/IFN for AJCC stage IV malignant melanoma demonstrated similar efficacy with regards to overall survival, tumor response rates, duration of response and progression-free survival compared to DTIC. The lack of statistical difference between the treatment groups in overall survival may be explained by an insufficient biological activity of the combination treatment or, alternatively, by the study being insufficiently powered, intercountry differences with respect to survival, the lower percentage of patients in the HDC/IL-2/IFN group who completed more than one cycle of therapy and by the relatively low dosage of IL-2. Risk as measured by percentage of patients who died, had a severe AE or discontinued because of an AE was similar between the two groups. Immunotherapy regimens may yet provide treatment alternatives for patients with stage IV melanoma, but this immunotherapeutic regimen did not improve upon the response rate and overall survival seen with DTIC.
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Conflict of interest statement |
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TopAbstractintroductionpatients and methodsresultsdiscussionConflict of interest statementAcknowledgementsReferences |
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Dr A. Hauschild has served as consultant to Maxim Pharmaceuticals and Schering Plough (less than $10,000) and research funding from Schering Plough (less than $100,000). No stock ownership and others. Dr S. Burdette-Radoux had research funding from Maxim Pharmaceuticals (less than $100,000). Dr K. Gehlsen was Clinical Senior Officer of Maxim Pharmaceuticals at time of the study. Dr K. Hellstrand served as consultant to Maxim Pharmaceuticals (less than $100,000) and had research funding from Maxim Pharmaceuticals (more than $100,000). Dr P. Naredi served as consultant to Maxim Pharmaceuticals (less than $100,000) and had research funding from Maxim Pharmaceuticals (less than $100,000). Dr M. Middleton served as consultant to Maxim Pharmaceuticals (less than $10,000). Dr D. Thomson, none declared; Dr R. Andersson, none declared.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionConflict of interest statementAcknowledgementsReferences |
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We thank the other investigators participating in this study: M. Millward, P. Hersey, I. Davis, G. Toner, M. Byrne, I. Olver, J. Trotter, R. Kefford, D. Kotesak, D. Wyld, J. Mattsson, U. Stierner, C. Ingvar, A. Håkansson, J. Hansson, C. Lindholm, M. Randén, JH. Svensson, G. Wagenius, M. Breivald, T. Hamblin, P. Lorigan, C. Price, C. Garbe, EB Bröcker, H. Näher, R. Kaufmann, D. Schadendorf, C. Peschel, P. von den Driesch, W. Sterry, W. Tilgen, K. Belanger, Y. Drolet, F. Patenaude, R. Rajan, M. Smylie, T. Peretz, R. Weitzen and R. Isacson. We thank the people at Maxim Pharmaceuticals, Covance, CroMedica Global Inc. and Synteract who managed this clinical trial. Acknowledgment of research support: EpiCept Corporation (former Maxim Pharmaceuticals), San Diego, CA, USA.
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Footnotes |
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Now at Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford, UK 
Now at Vermont Cancer Center, University of Vermont, Burlington, VT, USA
Now at Research Corporation Technologies, Tucson, AZ, USA
Received for publication February 23, 2007. Revision received May 14, 2007. Accepted for publication May 20, 2007.
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References |
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