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Journal of Clinical Oncology, Vol 24, No 30 (October 20), 2006: pp. 4840-4847
© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.07.7016
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Randomized Phase II Trial of Pemetrexed Combined With Either Cisplatin or Carboplatin in Untreated Extensive-Stage Small-Cell Lung Cancer

Mark A. Socinski, Charles Weissman, Lowell L. Hart, J. Thaddeus Beck, Janak K. Choksi, John P. Hanson, Diane Prager, Matthew J. Monberg, Zhishen Ye, Coleman K. Obasaju

From the Lineberger Comprehensive Cancer Center, Multidisciplinary Thoracic Oncology Program, University of North Carolina at Chapel Hill, Chapel Hill; Alamance Regional Medical Center, Burlington, NC; US Oncology, Latham, NY; Florida Cancer Specialists, Fort Meyers, FL; Highlands Oncology Group, Fayetteville, AR; St Luke's Medical Center, Milwaukee, WI; University of California Los Angeles Medical Center, Los Angeles, CA; and Eli Lilly & Company, Indianapolis, IN

Address reprint requests to Mark A. Socinski, MD, Associate Professor of Medicine, Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, CB# 7305, University of North Carolina, Chapel Hill, NC 27599; e-mail: socinski{at}med.unc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
PURPOSE: Given the activity and tolerability of pemetrexed/platinum combinations in non–small-cell lung cancer, and the success of novel therapeutic strategies employed in recent extensive-stage small-cell lung cancer (ES-SCLC) trials, a randomized phase II trial was initiated to evaluate the use of cisplatin or carboplatin plus pemetrexed in previously untreated ES-SCLC.

PATIENTS AND METHODS: Patients were randomly assigned to receive pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or pemetrexed plus carboplatin area under the concentration curve 5. Treatment was administered once every 21 days for a maximum of six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis.

RESULTS: Between December 19, 2002, and May 17, 2004, 78 patients were enrolled onto this multicenter trial. Median age was 63 years (range, 46 to 82 years) for cisplatin/pemetrexed and 66 years (range, 47 to 75 years) for carboplatin/pemetrexed. Median survival time (MST) for cisplatin/pemetrexed was 7.6 months, with a 1-year survivorship of 33.4% and a response rate of 35% (95% CI, 20.6% to 51.7%). The MST for carboplatin/pemetrexed was 10.4 months, with a 1-year survivorship of 39.0% and a response rate of 39.5% (95% CI, 24.0 to 56.6). Median time to progression for cisplatin/pemetrexed was 4.9 months and for carboplatin/pemetrexed was 4.5 months. Median dose-intensity (actual/planned dose) was 98.94% for cisplatin and 99.95% for pemetrexed in the cisplatin/pemetrexed group and 93.21% for carboplatin and 98.50% for pemetrexed in the carboplatin/pemetrexed group. Grade 3/4 hematologic toxicities included neutropenia (15.8% v 20.0%) and thrombocytopenia (13.2% v 22.9%) in the cisplatin/pemetrexed and carboplatin/pemetrexed treatment groups, respectively.

CONCLUSION: Pemetrexed/platinum doublets had activity and appeared to be well-tolerated in first-line ES-SCLC.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Of the roughly 170,000 new cases of lung cancer diagnosed annually, small-cell lung cancer (SCLC) comprises approximately 13%, or an estimated 25,000 cases.1 Compared with other forms of lung cancer, SCLC is aggressive, with a high rate of metastases, but is sensitive to chemotherapy (objective response rates often exceed 50%).2 Historically, SCLC been divided into two stages, limited stage (LS) and extensive stage(ES), based on whether the disease can be encompassed within a reasonable radiation port.2,3 Patients with LS-SCLC are treated with combined-modality therapy with cure as the goal, but these patients represent the minority of cases.3-8 More commonly, ES-SCLC is diagnosed based on metastatic disease and treatment is undertaken with palliative intent.

The standard of care for ES-SCLC has been the combination of cisplatin or carboplatin plus etoposide.2 Although this combination has produced objective response rates as high as 80%, median survival times range from 9 to 11 months, with a 2-year survival rate of less than 10%. Several novel strategies failed to improve patient outcomes, including the addition of paclitaxel to cisplatin/etoposide9 and sequential or maintenance therapy with topotecan in patients whose disease did not progress, after four cycles of cisplatin/etoposide.10 More recently, a phase III trial performed by Noda et al11 and the Japanese Clinical Oncology Group (JCOG 9511) produced superior survival outcomes by replacing etoposide with irinotecan in combination with cisplatin. However, two large phase III trials evaluating the use of topoisomerase-I inhibitors (irinotecan12 or topotecan13) in combination with cisplatin produced similar survival outcomes compared with etoposide plus cisplatin. These observations provided a rationale for novel platinum-based doublets in ES-SCLC with the intent of either increased efficacy or the retention of a similar efficacy profile but with less toxicity and perhaps more convenient schedules.

Pemetrexed (ALIMTA; Eli Lilly and Company, Indianapolis, IN) is a structurally novel, multitargeted antifolate that inhibits several enzymes involved in purine and pyrimidine synthesis,14,15 including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase.16,17 Pemetrexed has broad cytotoxic activity, as demonstrated by single agent and combination studies in lung cancer,18-25 as well as investigational studies of colorectal, pancreatic, breast, and bladder tumor types.26-31 Pemetrexed was initially approved in combination with cisplatin for the treatment of malignant pleural mesothelioma, on the basis of a phase III trial showing superiority to cisplatin alone,24 and later attained regulatory approval as a single agent in previously treated advanced non–small-cell lung cancer (NSCLC) on the basis of a phase III trial showing the agent to have equivalent activity but diminished toxicity compared with docetaxel.32 The principal toxicities of pemetrexed are neutropenia, diarrhea, nausea/vomiting, mucositis, and skin rash. Niyikiza et al33 reported that the severity of these toxicities correlate with markers of folate and vitamin B12 deficiency (mainly, elevated homocysteine and methylmalonic acid levels). The coadministration of folic acid, vitamin B12, and dexamethasone has improved the tolerability of pemetrexed.24

Pemetrexed had not been previously evaluated in SCLC but comes from a class of agents, antifolates, which have been used in combination chemotherapy regimens. Given the activity and tolerability of single-agent pemetrexed and pemetrexed/platinum combinations in NSCLC, as well as the success of novel therapeutic strategies employed in recent ES-SCLC trials, a randomized phase II trial was initiated to evaluate the use of cisplatin plus pemetrexed and carboplatin plus pemetrexed in previously untreated ES-SCLC patients.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Patient Selection
Patients with histologic or cytologic evidence of ES-SCLC, including malignant pleural effusion, were enrolled onto this randomized multicenter phase II trial. Patients had not received prior systemic chemotherapy, immunotherapy, biologic therapy, or radiation therapy. Other inclusion criteria included measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) criteria,34 patient age ≥ 18 years, an Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 2, a life expectancy of at least 12 weeks, and adequate end-organ function and bone marrow reserve (defined as absolute neutrophil count ≥ 1.5 x 109/L; platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL; bilirubin ≤ 1.5x the institutional upper normal limit; ALP, AST, and ALT ≤ 3x institutional upper normal limit; and calculated creatinine clearance ≥ 45 mL/min using the Cockroft and Gault formula35). Patients were required to use an appropriate contraceptive method.

Patients who had received treatment with any investigational drug within 30 days of study entry were excluded. Additional exclusion criteria included serious concomitant systemic disorders (eg, infection), pregnancy or breastfeeding, prior malignancy within the last 5 years (excluding in situ cancers or nonmelanomatous cancers of the skin), inability to interrupt nonsteroidal anti-inflammatory agents, symptomatic brain metastases, presence of uncontrollable third-space fluid collections (eg, ascites or pleural effusions), and an inability or unwillingness to take folate, vitamin B12, or dexamethasone.

This study was performed in accordance with principles of good clinical practice, applicable laws and regulations, and the Declaration of Helsinki. Before initiation of the study, investigators were responsible for obtaining written consent from participating patients and approval from study sites' ethical review boards.

Treatment Schedule
Study design for this trial is summarized in Figure A1 (online only). Patients with ES-SCLC were randomly assigned to receive pemetrexed 500 mg/m2 in combination with either cisplatin 75 mg/m2 or carboplatin at an area under the concentration curve of 5. All treatment was administered on day 1 of treatment cycles that repeated every 21 days. Six cycles of therapy were planned on both arms. Pemetrexed infusion duration occurred over a period of approximately 10 minutes and was followed by cisplatin or carboplatin, which was administered over a period of approximately 30 to 60 minutes.

Eli Lilly and Company (Indianapolis, IN) provided lyophilized powder forms of pemetrexed in 100- or 500-mg vials. Vial contents were reconstituted using sodium chloride, producing a clear solution for intravenous infusion. Commercially available forms of cisplatin or carboplatin were used.

On the day immediately preceding, the day of, and the day immediately following pemetrexed administration, prophylactic dexamethasone (4 mg or its equivalent twice daily) was administered to prevent rash. Additionally, folic acid (300 to 650 µg or its equivalent daily) and vitamin B12 (1,000 µg, once every 9 weeks) supplementation were administered.

Dose adjustments at the start of a subsequent cycle of therapy were based on platelet and neutrophil nadir (lowest value) counts from the preceding cycle of therapy. Before the start of any cycle, absolute neutrophil count had to be ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L. Treatment was delayed to allow sufficient time for recovery. When treatment was resumed, if the ANC from the previous cycle was less than 0.5 x 109/L, the patient received 75% of the planned dose. If the platelet count nadir was less than 50 x 109/L, and the absolute neutrophil count nadir was low, the patient received 50% of the planned dose. In the event of grade 3 or 4 thrombocytopenia or neutropenia after two dose reductions, the patient was removed from the study. Following any grade 3 or 4 nonhematologic toxicity, the subsequent dose was reduced 50%. Recurrence of any grade 3 or 4 nonhematologic toxicity after two dose reductions resulted in withdrawal of the patient from the study.

Any patient who required a dose reduction continued to receive a reduced dose for the remainder of the study. Any patient with two prior dose reductions who experienced a toxicity that would cause a third dose reduction was to be withdrawn from study therapy.

Treatment could be delayed for up to 42 days from day 1 of the current cycle to allow a patient sufficient time to recover from study drug–related toxicity. A patient who could not receive the study drug for 42 days from the time of last treatment was withdrawn from the study unless continuation was approved by the study sponsor.

Study End Points
The primary end point of this trial was tumor response rate, defined as the best response for patients every two cycles while on therapy and during follow-up visits, as reported by the investigator. Complete response (CR) was defined as the disappearance of all known disease (target and nontarget lesions). A partial response (PR) was defined as a 30% reduction from baseline in the sum of the longest diameter (LD) of the target lesions taking as reference the baseline LD sum and a lack of disease progression in nontarget lesions. Progressive disease (PD) was defined as the development of any new lesions or an increase of 20% in the LD sum of target lesions, taking as reference the smallest sum LD recorded since the treatment started. Patients with stable disease (SD) did not meet the criteria for PR or PD.

Disease progression was defined as the time from the date of randomization to the first date of documented progression or death from any cause. Time to disease progression (TTP) was censored at the date of the last follow-up visit for patients who were still alive and whose disease had not progressed. Overall survival time was defined as the time from the date of randomization to the date of patient death from any cause. Overall survival time was censored at the date of the last follow-up visit for patients who were still alive.

Statistical Methods
As noted above, the primary end point of the trial was tumor response rate. The response rate of interest for either arm was 60% and a two-stage design was used to calculate patient accrual numbers. Based on this assumption, the planned enrollment for this open-label phase II trial was 72 patients (36 patients per study arm). Study enrollment was to occur in two stages. In the first stage, 17 qualified patients were to be enrolled onto each arm with the possibility of stopping the study early for either lack of efficacy (nine or fewer responses) or unacceptable toxicity. Following the enrollment of 17 patients onto each arm, the activity of the treatment was also assessed in the context of tumor-specific clinical considerations including the overall response rate and the rate of early progression, stable disease rate, and progression-free survival. In addition, toxicity profiles of the two study arms were observed and considered. If the treatment arms were considered worthy of further analysis, enrollment continued until at least 36 qualified patients were enrolled onto each arm.

As this study was not statistically powered to show differences between treatment groups, the two treatment arms were analyzed separately. Overall survival time and TTP were estimated using the Kaplan and Meier method.36 For response, progression, and survival data, two-sided 95% CIs were calculated based on an exact binomial probability at an alpha level of .05. Drug toxicity was measured according to Medical Dictionary for Regulatory Activities (MedRA) version 8.0 (MedDRA MSSO, Northrop Grumman, Reston, VA). Dose-intensity for pemetrexed, cisplatin, and carboplatin was measured as the amount of actual drug administered as a percentage of planned doses for all cycles.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Between December 19, 2002, and May 17, 2004, 78 patients were enrolled onto this randomized multicenter trial. Patient disposition is summarized in Figure 1. Baseline characteristics were collected for patients who were randomly assigned (40 patients in the cisplatin/pemetrexed arm and 38 in the carboplatin/pemetrexed arm), who comprised the intent-to-treat (ITT) populations. At least one dose of study drug was administered to 38 patients in the cisplatin/pemetrexed arm and 35 patients in the cisplatin/pemetrexed arm (safety populations). Patients in the safety populations were assessed for drug safety.


Figure 1
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  		Fig 1. Summary of patient disposition. ITT, intent-to-treat.

 
Patient characteristics for the ITT population are listed in Table 1. Median age was 63 years (range, 46 to 82 years) for the cisplatin/pemetrexed group and 66 years (range, 47 to 75 years) for the carboplatin/pemetrexed group. The carboplatin/pemetrexed group had a greater percentage of patients who were older than 65 years (50% v 35%). The ratio of performance status of 0:1:2:unknown was 35%:45%:13%:7% for the cisplatin/pemetrexed group and 24%:55%:13%:8% for the carboplatin/pemetrexed group, respectively. The histologic:cytologic diagnosis ratio was 72%:28% for the cisplatin/pemetrexed group and 66%:34% for the carboplatin/pemetrexed group. There were no patient entry or protocol violations in the cisplatin/pemetrexed group, compared with one patient entry violation (2.6%) and one protocol violation (2.6%) in the carboplatin/pemetrexed group.


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  		Table 1. Baseline Characteristics for Intent-to-Treat Population

 
Dose administration is listed in Table A1 (online-only appendix). A total of 158 cycles (median, 4.0) were administered to the cisplatin/pemetrexed group and 153 cycles (median, 4.0) were administered to the carboplatin/pemetrexed group. Dose adjustments occurred in 39.5% of patients in the cisplatin/pemetrexed group and 51.4% of patients in the carboplatin/pemetrexed group. Median dose intensity (actual dose/planned dose) was 98.94% for cisplatin and 99.95% for pemetrexed in the cisplatin/pemetrexed group and 93.21% for carboplatin and 98.50% for pemetrexed in the carboplatin/pemetrexed group.

Confirmed response rates for the ITT population of both treatment groups are listed in Table 2. In the cisplatin/pemetrexed group, there were 0 patients with CRs, 14 patients with PRs (35.0%), 14 patients with SD (35.0%), four patients with PD (10.0%), and eight patients with unknown responses (20.0%). The overall response rate for the cisplatin/pemetrexed group was 35.0%. In the carboplatin/pemetrexed group, there were 0 patients with CRs, 15 patients with PRs (39.5%), 10 patients with SD (26.3%), seven patients with PD (18.4%), and six patients with unknown responses (15.8%). The overall response rate for the carboplatin/pemetrexed group was 39.5%. Unknown response included patients who did not receive treatment and patients who were not assessable. Excluding these patients, response would be 43.8% for cisplatin/pemetrexed and 46.9% for carboplatin/pemetrexed. Median duration of response (CR or PR) was 4.3 months for cisplatin/pemetrexed and 4.4 months for carboplatin/pemetrexed.


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  		Table 2. Summary of Confirmed Responses

 
Overall survival for the cisplatin/pemetrexed and carboplatin/pemetrexed groups is summarized in Figures 2A and 2B, respectively. Median survival for the cisplatin/pemetrexed group was 7.6 months (95% CI, 4.9 to 10.3), with a censorship rate of 15.0%. At 1 year, 33.4% of patients in the cisplatin/pemetrexed group had survived. Median survival for the carboplatin/pemetrexed group was 10.4 months (95% CI, 7.4 to 12.0), with a censorship rate of 18.4%. At 1 year, 39.0% of carboplatin/pemetrexed patients had survived.


Figure 2
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  		Fig 2. (A) Overall survival for cisplatin/pemetrexed; (B) overall survival for carboplatin/pemetrexed.

 
TTP for the cisplatin/pemetrexed and carboplatin/pemetrexed groups is summarized in Figure A2 (online-only appendix; parts A and B), respectively. Median TTP for the cisplatin/pemetrexed group was 4.9 months (95% CI, 4.2 to 5.9), and none of the patients in the cisplatin/pemetrexed group were progression free at 1 year. Median TTP for the carboplatin/pemetrexed group was 4.5 months (95% CI, 3.2 to 5.9), and 24.5% of carboplatin/pemetrexed patients were progression free at 1 year.

Toxicity profiles are listed in Tables 3 and 4. Grade 3/4 hematologic toxicities included anemia (10.5% v 5.7%), neutropenia (15.8% v 20.0%), and thrombocytopenia (13.2% v 22.9%) in the cisplatin/pemetrexed and carboplatin/pemetrexed treatment groups, respectively. Only one patient (cisplatin/pemetrexed treatment group) experienced febrile neutropenia (grade 3).


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  		Table 3. Toxicity Summary for Cisplatin/Pemetrexed

 

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  		Table 4. Toxicity Summary for Carboplatin/Pemetrexed

 
Grade 3/4 nonhematologic toxicities occurring in the cisplatin/pemetrexed and the carboplatin/pemetrexed arms included dyspnea (5.3% v 20.0%), nausea (15.8% v 14.3%), vomiting (7.9% v 14.3%), nervous system toxicity (15.8% v 2.9%), diarrhea (2.6% v 2.9%), fatigue (10.5% v 0%), elevation in AST (2.6% v 0%) and/or ALT (5.3% v 0%), and elevation in serum creatinine (0% v 2.9%), respectively. Grade 2 mucositis and skin rash were rare, occurring in less than 10% of patients.

Table A2 (online-only appendix) lists transfusions for both arms. There were five patients (13.2%) in the cisplatin/pemetrexed arm and seven patients (20.0%) in the carboplatin/pemetrexed arm who received one or more blood transfusions of any type.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
This randomized phase II trial established that platinum/pemetrexed doublets have activity in the first-line treatment of ES-SCLC. Differences between treatment groups were not statistically compared, given the randomized phase II nature of this trial. Nonetheless, it is notable that while both arms produced similar response rates (35.0% to 39.5%) and TTP rates (4.9 to 4.5 months), the carboplatin/pemetrexed arm produced a median survival of 10.4 months (1-year survival = 39.0%), compared with 7.6 months (1-year survival = 33.4%) associated with the cisplatin/pemetrexed arm. While the objective response rates were not as great as those observed in previous trials in ES-SCLC, cisplatin/pemetrexed and carboplatin/pemetrexed were associated with disease progression rates (as best response) of only 10.0% and 18.4%, respectively. A previous study in ES-SCLC has indicated that stable disease may be as important in contributing to survival outcomes as actual tumor response.4

The utility of platinum/pemetrexed combinations in ES-SCLC may be enhanced by the high-dose intensity of drug delivered and the low rate of toxicity observed in a relatively toxicity-sensitive group of patients. Nearly 100% of the planned dose of pemetrexed was administered in this trial, and dose intensities for cisplatin and carboplatin were both greater than 90%. Neutropenia and thrombocytopenia each occurred in less than one quarter of patients in each treatment group (and febrile neutropenia was notably uncommon). Anemia occurred in approximately 10% or fewer of the patients in each treatment group. Nonhematologic toxicities, including nausea and vomiting, occurred with similar frequency, although the rate of nervous-system toxicity (15.8% v 2.9%) was more frequent on the cisplatin/pemetrexed arm. Alopecia was rare in the study, only occurring in one patient (in the carboplatin/pemetrexed arm).

A summary of recent platinum-based studies in ES-SCLC is listed in Table 5. One must interpret comparisons cautiously across trials particularly between phase II and III trials. However, the median survival for the carboplatin/pemetrexed arm of the current study is in the high range of other regimens that have been reported, including cisplatin/etoposide, cisplatin/topotecan, and carboplatin/etoposide. Studies reporting median survival times exceeding 10 months, however, have typically been associated with more than 80% of grade 3/4 neutropenia.13,37,38 Compared with these studies, platinum/pemetrexed doublets appear to be associated with a favorable toxicity profile, especially with respect to neutropenia, anemia, febrile neutropenia, and alopecia.


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  		Table 5. Platinum-Containing Regimens in ES-SCLC

 
Although the therapeutic index of platinum/pemetrexed doublets appears to be favorable in ES-SCLC, future confirmatory phase II trials of these regimens are warranted. Based on the survival data reported in this trial, a future trial comparing carboplatin/pemetrexed with a standard combination of platinum plus a topoisomerase-I inhibitor would be justified. In addition, single-agent pemetrexed may have a role in salvage therapy, given the limited options available to patients with relapsed disease. A phase II trial in which pemetrexed is being evaluated in both sensitive and refractory-relapsed patients is currently ongoing.39 Lastly, preliminary data from Vokes et al40 suggest that it is possible to administer thoracic radiotherapy with systemically active doses of carboplatin (at area under the curve 6) with pemetrexed (500 mg/m2), both administered every 3 weeks. Given the favorable activity of carboplatin/pemetrexed in our trial, these data may form the basis of future clinical trials in LS-SCLC in combination with thoracic radiation therapy.

In conclusion, platinum/pemetrexed doublets have activity in ES-SCLC in the first-line setting, and both regimens (pemetrexed plus carboplatin or cisplatin) appeared to be well-tolerated in this patient population. The ease of administration and convenient schedule make pemetrexed/platinum doublets attractive in this disease setting as they may retain comparable efficacy with less toxicity. Future clinical trials should also elucidate the role of pemetrexed in treating first-line LS-SCLC and relapsed disease.


   Appendix
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Go


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  		Table A1. Dose Administration (safety population)

 
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  		Table A2. Summary of Blood Transfusions

 
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Figure 3
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  		Fig A1. Study design of two pemetrexed/platinum combinations in extensive-stage small-cell lung cancer (ES-SCLC). Routine vitamin (folic acid and vitamin B12) supplementation and prophylactic dexamethasone were coadministered. PS, performance status; AUC, area under the concentration time curve; IV, intravenous.

 
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Figure 4
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  		Fig A2. (A) Time to disease progression for cisplatin/pemetrexed; (B) time to disease progression (TTP) for carboplatin/pemetrexed.

 

   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
Author Contributions
 REFERENCES
 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.


Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other
Mark A. Socinski Amgen (A); Bristol-Myers Squibb (A); Genentech (A); Eli Lilly & Company (A); Sanofi-Aventis (A) Eli Lilly & Company (A); AstraZeneca (A); Sanofi-Aventis (A); Pfizer (A); Bristol-Myers Squibb (A); Amgen (A); Genentech (A)
Thaddeus Beck Eli Lilly & Company (A)
Janak K. Choksi Genentech (A) Amgen (A); Genentech (A)
Diane Prager Eli Lilly & Company (A) Eli Lilly & Company (A)
Matthew J. Monberg Eli Lilly & Company (N/R) Eli Lilly & Company (A)
Zhishen Ye Eli Lilly & Company (N/R) Eli Lilly & Company (A)
Coleman K. Obasaju Eli Lilly & Company (N/R) Eli Lilly & Company (A)

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


   Author Contributions
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
REFERENCES
 

Conception and design: Mark A. Socinski, Charles Weissman, Lowell L. Hart, J. Thaddeus Beck, Janak K. Choksi, John P. Hanson, Diane Prager, Zhishen Ye, Coleman K. Obasaju

Administrative support: Mark A. Socinski, Matthew J. Monberg, Coleman K. Obasaju

Provision of study materials or patients: Mark A. Socinski, Charles Weissman, Lowell L. Hart, J. Thaddeus Beck, Janak K. Choksi, John P. Hanson, Diane Prager, Zhishen Ye, Coleman K. Obasaju

Collection and assembly of data: Mark A. Socinski, Charles Weissman, Lowell L. Hart, J. Thaddeus Beck, Janak K. Choksi, John P. Hanson, Diane Prager, Zhishen Ye, Coleman K. Obasaju

Data analysis and interpretation: Mark A. Socinski, Charles Weissman, Lowell L. Hart, J. Thaddeus Beck, Janak K. Choksi, John P. Hanson, Diane Prager, Matthew J. Monberg, Zhishen Ye, Coleman K. Obasaju

Manuscript writing: Mark A. Socinski, Charles Weissman, Lowell L. Hart, J. Thaddeus Beck, Janak K. Choksi, John P. Hanson, Diane Prager, Matthew J. Monberg, Zhishen Ye, Coleman K. Obasaju

Final approval of manuscript: Mark A. Socinski, Charles Weissman, Lowell L. Hart, J. Thaddeus Beck, Janak K. Choksi, John P. Hanson, Diane Prager, Matthew J. Monberg, Zhishen Ye, Coleman K. Obasaju

 


   ACKNOWLEDGMENTS
 
We thank all of the investigators who contributed to study development and patient enrollment.


   NOTES
 
Supported by Eli Lilly & Company.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

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


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
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Submitted May 31, 2006; accepted August 9, 2006.




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