Originally published as JCO Early Release 10.1200/JCO.2006.07.3569 on April 2 2007

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Induction Chemotherapy Followed by Chemoradiotherapy Compared With Chemoradiotherapy Alone for Regionally Advanced Unresectable Stage III Non–Small-Cell Lung Cancer: Cancer and Leukemia Group B

Everett E. Vokes, James E. Herndon, II, Michael J. Kelley, M. Giulia Cicchetti, Nithya Ramnath, Harvey Neill, James N. Atkins, Dorothy M. Watson, Wallace Akerley, Mark R. Green

From the University of Chicago, Chicago, IL; Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham; Wake Forest University School of Medicine, Winston-Salem, NC; Roswell Park Cancer Institute, Buffalo, NY; University of Tennessee at Memphis, Memphis, TN; University of Massachusetts Medical School, Worcester, MA; Rhode Island Hospital, Providence, RI; and the Medical University of South Carolina, Charleston, SC

Address reprint requests to Everett E. Vokes, MD, University of Chicago Hospitals, 5841 S Maryland Ave, MC 2115, Chicago, IL 60637-1470; e-mail: evokes{at}medicine.bsd.uchicago.edu

	ABSTRACT

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Purpose Standard therapy for unresectable stage III non–small-cell lung cancer includes concomitant chemoradiotherapy. In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival.

Patients and Methods Between July 1998 and May 2002, 366 patients were randomly assigned to arm A, which involved immediate concurrent chemoradiotherapy with carboplatin area under the concentration-time curve (AUC) of 2 and paclitaxel 50 mg/m² given weekly during 66 Gy of chest radiotherapy, or arm B, which involved two cycles of carboplatin AUC 6 and paclitaxel 200 mg/m² administered every 21 days followed by identical chemoradiotherapy. The accrual goal was 360 patients.

Results Thirty-four percent of patients were female, 66% were male, and the median age was 63 years. Grade 3 or 4 toxicities during induction chemotherapy on arm B consisted mainly of neutropenia (18% and 20%, respectively). During concurrent chemoradiotherapy, there was no difference in severity of in-field toxicities of esophagitis (grade 3 and 4 were, respectively, 30% and 2% for arm A v 28% and 8% for arm B) and dyspnea (grade 3 and 4 were, respectively, 11% and 3% for arm A v 15% and 4% for arm B). Survival differences were not statistically significant (P = .3), with a median survival on arm A of 12 months (95% CI, 10 to 16 months) versus 14 months (95% CI, 11 to 16 months) on arm B and a 2-year survival of 29% (95% CI, 22% to 35%) and 31% (95% CI, 25% to 38%). Age, weight loss before therapy, and performance status were statistically significant predictive factors.

Conclusion The addition of induction chemotherapy to concurrent chemoradiotherapy added toxicity and provided no survival benefit over concurrent chemoradiotherapy alone. The median survival achieved in each of the treatment groups is low, and the routine use of weekly carboplatin and paclitaxel with simultaneous radiotherapy should be re-examined.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Available therapies for unresectable stage III non–small-cell lung cancer (NSCLC) have advanced steadily during the last two decades.^1-6 Initially, studies demonstrated a prolongation of median survival times when adding two cycles of cisplatin-based induction chemotherapy to radiotherapy.^7-9 Similarly, concomitant chemoradiotherapy was shown to be superior to single modality radiotherapy.^10,11 More recently, induction chemotherapy and concomitant chemoradiotherapy have been directly compared, and the concomitant approach was shown to increase median survival to approximately 17 months.^12-17 Induction chemotherapy may improve systemic control, and concomitant chemoradiotherapy appears to increase locoregional control.

The Cancer and Leukemia Group B (CALGB) has conducted a series of phase II and III investigations in unresectable NSCLC. After establishing the positive impact of induction chemotherapy on survival, CALGB pursued the addition of weekly low doses of carboplatin as a radiation sensitizer,^7,18 with no further benefit, as recently confirmed by Gervais et al.¹⁹ CALGB 9431 explored the administration of more intensive doublet chemotherapy with cisplatin and either paclitaxel, vinorelbine, or gemcitabine administered as induction chemotherapy and during radiotherapy in a randomized phase II format.²⁰ The overall median survival ranged from 14.8 months on the paclitaxel arm to 18.3 months on the gemcitabine arm. In a parallel phase II investigation using the carboplatin-paclitaxel regimen, a median survival of 15.1 months was achieved.²¹ These studies demonstrated the feasibility of administering induction chemotherapy followed by cisplatin- or carboplatin-based concomitant chemoradiotherapy. Furthermore, the survival times were longer than previously achieved with induction chemotherapy alone. However, they were within a similar range of survival times reported from studies using concomitant chemoradiotherapy alone.

Based on this experience, we designed CALGB 39801 to test the value of induction chemotherapy administered in the context of standard concomitant chemoradiotherapy. Patients were randomly assigned to either receive concomitant chemoradiotherapy alone or two cycles of induction chemotherapy with the same chemotherapy agents followed by identical concomitant chemoradiotherapy. The choice of carboplatin and paclitaxel as a chemotherapy regimen was based on its widespread acceptance by oncologists and general good tolerance by patients.^16,21-25 Primary end points were the effect of induction chemotherapy on overall survival as well as toxicity and pattern of failure. We now report a mature analysis of this study.

	PATIENTS AND METHODS

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CALGB 39801 opened to accrual in July 1998 and was closed to accrual in May 2002. Eligible patients had histologic or cytologic documentation of NSCLC. Patients had previously untreated unresectable or inoperable stage III disease.¹ Patients with N3 disease were eligible if all gross disease could be encompassed in the radiation boost field, but patients with scalene, supraclavicular, or contralateral hilar lymph node involvement, direct invasion of the vertebral body, or with a pleural effusion were ineligible. All patients had measurable or assessable disease. Patients with resected tumors were ineligible. Additional eligibility criteria included CALGB performance status of 0 to 1, life expectancy exceeding 2 months, age of 18 years or older, and absence of pregnancy. A criterion of previous trials to exclude patients with a weight loss of 5% or more in the 3 months before diagnosis was abandoned because this parameter was felt to overlap with performance status. Standard initial laboratory tests were required. In addition, the forced expiratory volume in 1 second had to be more than 800 mL. Radiological studies included a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the chest and upper abdomen, including adrenals and liver, as well as a bone scan performed within 28 days of registration. Each participant signed an institutional review board–approved, protocol-specific informed consent in accordance with federal and institutional guidelines. Patient random assignment and data collection were managed by the CALGB Statistical Center. Data quality was ensured by careful review of data by CALGB Statistical Center staff and by the study chairperson following standard CALGB policies.

Treatment Plan
Following registration, patients were randomly assigned to one of two treatment arms (Fig 1). For arm A (concurrent chemoradiotherapy only), patients received weekly paclitaxel at 50 mg/m² intravenously (1 hour) for 7 consecutive weeks, with carboplatin administered at a formula time versus concentration curve (AUC) of two intravenously (30 minutes) following administration of paclitaxel. Concurrent radiotherapy to 66 Gy was administered at five fractions per week for 7 consecutive weeks at 2 Gy/fraction. Standard premedications consisted of dexamethasone, diphenhydramine, and cimetidine. The dose of carboplatin was calculated at 25 plus creatinine clearance x the desired AUC, according to the Calvert formula.²⁶ Creatinine clearance was determined as 140 – patient age x weight in kilograms ÷ by 72 x serum creatinine x (0.85 for female patients). For arm B, two cycles of induction chemotherapy consisted of paclitaxel administered at 200 mg/m² IV (3 hours) every 21 days, with carboplatin administered at an AUC of six intravenously (30 minutes) following paclitaxel. Following the completion of induction chemotherapy, concurrent chemoradiotherapy began on day 43 and continued as outlined for patients on arm A.

View larger version (37K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. CALGB 39801 study design. CT/X, concomitant chemoradiotherapy; AUC, area under the concentration-time curve; XRT, radiation therapy.

The target dose to the original volume was 44 Gy in 22 fractions of 2 Gy/fraction; the target dose to the boost volume was 22 Gy in 11 fractions. No corrections for lung or bone attenuation were made. The maximum dose allowed to any point in the spinal cord was 49 Gy.

A central review of the radiation therapy for each case, including review of diagnostic imaging, was performed at the Quality Assurance Review Center (QARC) by the radiation oncology co-chair, a chest CT radiologist, and QARC staff.

Chemotherapy Dose Modifications
For a platelet count of 50,000 to 74,999/µL or granulocyte count of 1,000 to 1,499/µL on the day of planned treatment, 50% of carboplatin and paclitaxel were administered. For a platelet count of less than 50,000/µL and for a granulocyte count of less than 1,000/µL, chemotherapy was held.

For neurotoxicity of grade 3 or more, chemotherapy was held until improvement to grade 1 or less and resumed at 75% or prior doses. For all other grade 3 toxicities—except alopecia, nausea, vomiting, fatigue, and anorexia—carboplatin and paclitaxel were reduced by 25%.

For esophagitis, mucositis, stomatitis, and dermatitis of grade 3, during radiotherapy, paclitaxel was held and carboplatin was continued. Paclitaxel was resumed at a 50% dose once toxicity had resolved to grade 2. For grade 4 toxicities, all protocol therapy was held and resumed following resolution of toxicity to grade 2. For patients with a decline in performance status to 3 or more, radiotherapy was completed without further chemotherapy.

Statistical Considerations
CALGB 39801 was designed to have 80% power to detect a 40% increase in median survival, from approximately 13 months to 18.2 months, with the addition of induction chemotherapy using a one-tailed log-rank test conducted at the 0.025 level of significance. The accrual of 360 patients during a 3-year period followed by 1.5 to 2 years of follow-up was required to observe 290 deaths. The status and progress of CALGB 39801 was reviewed semiannually by the CALGB Data and Safety Monitoring Board. Interim monitoring of the study was conducted to allow for early stopping with rejection of the null and alternative hypothesis. Boundaries analogous to those proposed by O'Brien and Fleming truncated at the nominal level of 0.001 were used. Methodology of Lan and DeMets and Pampallona et al allowed the type I and II error to be used as a function of the accumulating information to maintain overall type I and II errors of 0.025 and 0.2, respectively.

Overall and failure-free survival curves were calculated using the Kaplan-Meier life-table methods. Failure-free survival was defined as the time between random assignment and disease relapse or death. Survival time was defined as the time between random assignment and death. Comparisons of survival were performed using the log-rank test.

Fisher's exact test was used to compare treatment groups with respect to overall response rates, as well as toxicity rates.

	RESULTS

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A total of 366 patients were registered. Twenty-four registrations were cancelled before initiation of therapy, including 17 on arm A and seven on arm B, as allowed by CALGB policy at the time. Eleven patients were ineligible on study review—four patients on arm A, and seven patients on arm B (low performance status in one patient and incorrect stage in 10 patients; higher stage in eight and lower stage in two patients). Intent-to-treat analysis included all 366 patients. Additional survival analyses were performed to exclude cancelled and ineligible patients (analysis of 161 patients on arm A and 170 on arm B) and to exclude cancelled and ineligible patients and those having weight loss of more than 5% (analysis of 244 patients).

Patient characteristics for all patients are summarized in Table 1. Overall, 66% of patients were male. The median age was 63 years, with 25% of patients older than 70 years and 2% 80 years or older. Performance status was 0 or 1 in 45% and 54% of patients, respectively. Pretreatment weight loss was less than 5% in 67% of patients, and it was known to exceed 5% in 26%. There was an imbalance with respect to the extent of prior weight loss between the two study arms, with 30% of patients on arm A having weight loss of 5% or more versus 22% on arm B.

The overall best response to treatment in eligible and noncancelled patients (Table A1, online only) was 67% and 61%, respectively, for arms A and B.

Toxicity
Adverse events to treatment during induction chemotherapy on arm B included grade 3 or 4 granulocytopenia in 18% and 20% of patients, respectively (Table 2). Maximum toxicity was grade 3 in 31% and grade 4 in 23% of patients. Toxicities observed during concomitant chemoradiotherapy are shown in Table 3. Neutropenia was significantly increased on arm B, reflecting the effects of induction chemotherapy. However, radiation-related toxicity of dysphagia, dyspnea, and pneumonitis were not statistically different between arm A and arm B. Grade 3 dysphagia was observed in 30% and 28% of patients, respectively, and dyspnea in 11% and 15% of patients, respectively. One patient on arm B developed fatal pneumonitis. Overall maximum toxicity (combining toxicities of induction and concomitant chemoradiotherapy) was more severe on arm B, with 40% of patients reporting a grade 4 event on arm B versus 26% on arm A.

Survival
At a median follow-up time of 38 months, treatment differences in survival were not statistically significant (P = .3). Median survival times were 12 and 14 months for arms A and B, respectively (Fig 2). Two-year survival estimates were 29% and 31%, and 3-year estimates were 19% and 23%. Similarly, failure-free survival was not significantly different with 7 and 8 months median, respectively (P = .2; Fig A1, online only).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Survival intent to treat.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Survival of eligible patients with a weight loss of less than 5% who started therapy.

A variety of additional factors were analyzed for possible predictive value (Table 4). Of these, age, performance status, and weight loss were statistically significant.^7,17

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
This is the first phase III trial to address the role of induction chemotherapy in the context of concomitant chemoradiotherapy for stage III NSCLC. It demonstrates that the addition of induction chemotherapy does not provide a survival benefit over concurrent therapy alone. Although there is a numerical trend in median survival time favoring patients receiving induction chemotherapy, this trend disappears when adjusted for weight loss exceeding 5%, an eligibility criteria of prior CALGB trials. Therefore, CALGB 39801 reaffirms the status of early concomitant chemoradiotherapy as current standard therapy for patients with unresectable stage IIIB NSCLC. Furthermore, our data demonstrate that the addition of induction chemotherapy increases neutropenia and overall maximal toxicity, although severe radiotherapy-related toxicities of esophagitis or pneumonitis are not affected.

Overall, the survival times of patients with stage III NSCLC in this study are disappointing and similar to those achieved in trials using induction chemotherapy followed by radiotherapy alone or with low-dose weekly concomitant carboplatin.^7-9,18,19 Even for the weight loss–adjusted cohort, the survival times are at the lower range of reported values for patients with stage III disease treated with concomitant chemoradiotherapy in recent trials.^10-16,25,27

Some of the more encouraging data from concurrent chemoradiotherapy trials in NSCLC have been obtained with regimens that allow for administration of full-dose chemotherapy during radiation.^12,13,27-30 Combinations of cisplatin and etoposide or cisplatin and vinblastine allow for early systemic exposure of potential micrometastatic disease to chemotherapy. In contrast, regimens combining carboplatin with a taxane or gemcitabine or vinorelbine typically involve a significant attenuation of dose during radiation. Thus, a patient's exposure to systemic chemotherapy may be insufficient to optimize outcome.

There are several other possible explanations for the low median survival times reported here. First, CALGB 39801 allowed entry of patients with weight loss in excess of 5%. Our data suggest that significant pretreatment weight loss is a poor prognostic factor in itself that needs to be considered independent of performance status. It is of interest that in patients with higher weight loss the initial use of induction chemotherapy resulted in a numerically superior survival. For this group of patients, future studies investigating initial induction chemotherapy remain of interest. An alternative explanation for the low survival times on both study arms is that the widespread acceptance of concomitant chemoradiotherapy and the general good tolerance of the carboplatin-paclitaxel regimen have led to the inclusion of broader patient groups into concomitant chemoradiotherapy studies representing a form of stage migration that is not well quantified at present. Finally, a significant proportion of patients failed to receive radiotherapy as intended in this trial. However, when eliminating these patients from the analysis, survival times are not improved (median survival time was 11 and 14 months, respectively), suggesting that this patient group did not adversely affect overall survival outcomes for the two study arms.

To improve the outcome in future studies, several approaches might be investigated. First, while induction chemotherapy seems to add little benefit, it is possible there is a role for consolidation chemotherapy.^27,30 A phase III evaluation of that concept is currently in progress. The identification of novel regimens that allow for administration of systemic doses of chemotherapy during radiotherapy may be feasible using novel cytotoxic agents.³¹ Similarly, the addition of targeted agents to radiotherapy is well supported by preclinical data and may not be compromised by enhanced in-field toxicity.^32-36 Administration of cetuximab with concomitant radiotherapy has proved successful for patients with head and neck cancer and is currently undergoing evaluation in NSCLC.³⁶

CALGB 39801 has reaffirmed the early use of concomitant chemoradiotherapy as current standard therapy for the majority of patients with stage III NSCLC. It similarly points out the need to identify more active chemoradiotherapy regimens. The most promising focus appears to be on novel chemoradiotherapy regimens that allow for administration of systemic doses of chemotherapy during radiotherapy and the integration of novel therapies.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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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: Everett E. Vokes, AstraZeneca, Bristol-Meyers Squibb Co, Eli Lilly, Genentech, ImClone Systems Inc, OSI Pharmaceuticals, Pfizer Inc, Sanofi-aventis Stock: N/A Honoraria: Everett E. Vokes, AstraZeneca, Bristol-Meyers Squibb, Eli Lilly, Genentech, ImClone Systems Inc, OSI Pharmaceuticals, Sanofi-aventis Research Funds: Nithya Ramnath, Roche, Genentech, Sanofi-aventis Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Everett E. Vokes, James E. Herndon II, Wallace Akerley, Mark R. Green

Provision of study materials or patients: M. Giulia Cicchetti, Nithya Ramnath, James N. Atkins

Collection and assembly of data: Harvey Neill, Wallace Akerley

Data analysis and interpretation: Everett E. Vokes, James E. Herndon II, Michael J. Kelley, James N. Atkins, Dorothy M. Watson, Wallace Akerley, Mark R. Green

Manuscript writing: Everett E. Vokes, James E. Herndon II, James N. Atkins, Wallace Akerley, Mark R. Green

Final approval of manuscript: Everett E. Vokes, James E. Herndon II, Michael J. Kelley, Wallace Akerley, Mark R. Green

Other: M. Giulia Cicchetti [Radiation therapy principal investigator; review at QARC of all the patients’ diagnostic and radiation therapy images and radiation treatment design]

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Failure-free survival intent-to-treat analysis.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Survival of eligible patients who started therapy.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A3. Survival of eligible patients who started therapy with a weight loss of 5% or more.

View larger version (22K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A4. Sites of relapse.

	ACKNOWLEDGMENTS

The following institutions participated in this study: Baptist Cancer Institute CCOP, Memphis, TN, Lee S. Schwartzberg, MD, supported by CA71323; CALGB Statistical Center, Durham, NC, Stephen George, PhD, supported by CA33601; Cancer Centers of the Carolinas, Greenville, SC, Jeffrey K. Giguere, MD, supported by CA29165; Community Hospital-Syracuse CCOP, Syracuse, NY, Jeffrey Kirshner, MD, supported by CA45389; Dana-Farber Partners, Boston, MA, George P. Canellos, MD, supported by CA32291; Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, NH, Marc S. Ernstoff, MD, supported by CA04326; Duke University Medical Center, Durham, NC, Jeffrey Crawford, MD, supported by CA47577; Georgetown University Medical Center, Washington, DC, Edward Gelmann, MD, supported by CA77597; Long Island Jewish Medical Center, Lake Success, NY, Marc Citron, MD, supported by CA11028; Massachusetts General Hospital, Boston, MA, Michael L. Grossbard, MD, supported by CA12449; Medical University of South Carolina, Charleston, SC, Mark Green, MD, supported by CA03927; Mount Sinai Medical Center, Miami, FL, Rogerio Lilenbaum, MD, supported by CA45564; Mount Sinai School of Medicine, New York, NY, Lewis R. Silverman, MD, supported by CA04457; Northern Indiana Cancer Research Consortium CCOP, South Bend, IN, Rafat Ansari, MD, supported by CA86726; Rhode Island Hospital, Providence, RI, William Sikov, MD, supported by CA08025; Roswell Park Cancer Institute, Buffalo, NY, Ellis Levine, MD, supported by CA02599; Southeast Cancer Control Consortium Inc CCOP, Goldsboro, NC, James N. Atkins, MD, supported by CA45808; Southern Nevada Cancer Research Foundation CCOP, Las Vegas, NV, John Ellerton, MD, supported by CA35421; State University of New York Upstate Medical University, Syracuse, NY, Stephen L. Graziano, MD, supported by CA21060; Syracuse Hematology-Oncology Associates CCOP, Syracuse, NY, Jeffrey Kirshner, MD, supported by CA45389; The Ohio State University Medical Center, Columbus, OH, Clara D. Bloomfield, MD, supported by CA77658; University of California at San Diego, San Diego, CA, Joanne Mortimer, MD, supported by CA11789; University of Chicago, Chicago, IL, Gini Fleming, MD, supported by CA41287; University of Illinois MBCCOP, Chicago, IL, Lawrence E. Feldman, MD, supported by CA74811; University of Iowa, Iowa City, IA, Gerald Clamon, MD, supported by CA47642; University of Maryland Greenebaum Cancer Center, Baltimore, MD, Martin Edelman, MD, supported by CA31983; University of Massachusetts Medical School, Worcester, MA, William V. Walsh, MD, supported by CA37135; University of Minnesota, Minneapolis, MN, Bruce A. Peterson, MD, supported by CA16450; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO, Michael C. Perry, MD, supported by CA12046; University of Nebraska Medical Center, Omaha, NE, Anne Kessinger, MD, supported by CA77298; University of North Carolina at Chapel Hill, Chapel Hill, NC, Thomas C. Shea, MD, supported by CA47559; University of Tennessee Memphis, Memphis, TN, Harvey B. Niell, MD, supported by CA47555; University of Texas Southwestern Medical Center, Dallas, TX, Debasish Tripathy, MD; Wake Forest University School of Medicine, Winston-Salem, NC, David D. Hurd, MD, supported by CA03927; Walter Reed Army Medical Center, Washington, DC, Thomas Reid, MD, supported by CA26806; Washington University School of Medicine, St Louis, MO, Nancy Bartlett, MD, supported by CA77440; Weill Medical College of Cornell University, New York, NY, Scott Wadler, MD, supported by CA07968.

	NOTES

 
published online ahead of print at www.jco.org on April 2, 2007.

Supported in part by Grants no. CA41287, CA33601, CA47577, CA02599, CA47555, CA03927, CA37135, CA08025, and CA03927.

The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

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

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Submitted May 23, 2006; accepted November 21, 2006.

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