Phase I Study of Lapatinib in Combination With Chemoradiation in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

  1. Jean Bourhis
  1. From the Head and Neck Unit, The Royal Marsden National Health Service Foundation Trust; The Institute of Cancer Research, London; Oncology Medicine Development Center, GlaxoSmithKline R&D, Stockley Park, United Kingdom; Department of Radiation Oncology, Institut Gustave-Roussy, Paris, France; and Biomedical Data Science, GlaxoSmithKline Pharmaceuticals Ltd, Bangalore, India.
  1. Corresponding author: Kevin J. Harrington, FRCP, Head and Neck Unit, The Royal Marsden National Health Service Foundation Trust, 203 Fulham Rd, London SW3 6JJ, United Kingdom; e-mail: Kevin.Harrington{at}icr.ac.uk.

  1. Presented in part at the 42nd Annual Meeting of the American Society for Clinical Oncology, June 2-6, 2006, Atlanta, Georgia; at the 31st European Society for Medical Oncology Congress, September 29-October 3, 2006, Istanbul, Turkey; and at the Joint International Meeting of the European Head and Neck Society and European Society for Therapeutic Radiation and Oncology, February 22-24, 2007, Barcelona, Spain.

  1. Both K.J.H. and I.A.E.-H. contributed equally to this work.

 
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Abstract

Purpose This study (EGF100262) sought to establish the recommended phase II dose of lapatinib with chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).

Patients and Methods Patients were enrolled onto cohorts of escalating lapatinib dose (500, 1,000, and 1,500 mg/d). Patients received 1 week of lapatinib alone followed by 6.5 to 7 weeks of the same dose of lapatinib plus radiotherapy 66 to 70 Gy and cisplatin 100 mg/m2 on days 1, 22, and 43 of radiotherapy. End points included safety/tolerability and clinical activity.

Results Thirty-one patients were enrolled (seven patients in each of the 500- and 1,000-mg cohorts and three in the 1,500-mg cohort; an additional 14 patients were enrolled at 1,500 mg in a safety cohort). Dose-limiting toxicities (DLTs) included perforated ulcer in one patient in the 500-mg cohort and transient elevation of liver enzymes in one patient in the 1,000-mg cohort. No DLTs were observed in the 1,500-mg cohort. Therefore, the recommended phase II dose was defined as lapatinib 1,500 mg/d with chemoradiotherapy. The most common grade 3 to 4 adverse events were radiation mucositis, radiation dermatitis, lymphopenia, and neutropenia. No patients experienced drug-related symptomatic cardiotoxicity, and no interstitial pneumonitis was reported. The overall response rate was 81% (65% at the recommended phase II dose).

Conclusion The recommended phase II dose is lapatinib 1,500 mg/d with chemoradiotherapy in patients with LA SCCHN; this regimen is associated with an acceptable tolerability profile. Given these findings, randomized phase II and III studies of lapatinib plus chemoradiotherapy have been initiated.

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INTRODUCTION

Improved survival outcomes are needed for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). However, new treatment regimens must not significantly increase the substantial toxicity caused by current standard surgery and/or chemoradiotherapy.1,2

The epidermal growth factor receptor (EGFR) tyrosine kinase family is involved in normal cell growth and differentiation.3,4 Abnormal expression or activity of these receptors is implicated in tumor growth and development.3,4 Overexpression of EGFR occurs in up to 90% of SCCHN3,5–7 and affects tumor development, growth, angiogenesis, and invasion.3,7,8 ErbB2 overexpression has been noted in SCCHN,7–9 and ErbB2 heterodimerization with EGFR may mediate disease progression.8,9 Because EGFR and ErbB2 have both been implicated in resistance to chemotherapy and radiation,3,5,9 their inhibition may increase the efficacy of chemoradiotherapy through enhanced radiosensitivity of tumor cells and reduced cellular proliferation during radiotherapy.10,11

Lapatinib is a novel, selective, and highly potent (9 to 10 nmol/L) dual inhibitor of both EGFR and ErbB2 tyrosine kinases, with antitumor activity in a range of solid tumors.12–14 This study evaluated the combination of lapatinib with chemoradiotherapy and determined the recommended phase II dose in patients with LA SCCHN.

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PATIENTS AND METHODS

Study Design

This open-label, dose-escalation study was conducted in two centers in France and the United Kingdom. The primary objective was to determine the recommended phase II dose of lapatinib with chemoradiotherapy. Other objectives were safety and tolerability and clinical activity. The study was approved by each center's independent ethics committees and was performed in accordance with the Declaration of Helsinki and Good Clinical Practice.

Key Eligibility Criteria

Patients with histologically confirmed stage III, IVA, or IVB SCCHN who were suitable for definitive chemoradiotherapy were eligible. Patients with high-risk features eligible for postoperative chemoradiotherapy were also permitted, as were patients who had received prior adjuvant or neoadjuvant chemotherapy. Patients were required to be at least 18 years old, with an Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate renal, hepatic, and bone marrow function. Patients had to have normal left ventricular ejection fraction (LVEF) assessed by echocardiogram or multigated acquisition scan. All patients gave written informed consent. Patients with distant metastasis or peripheral neuropathy ≥ grade 2 were excluded. Patients who had received prior systemic chemotherapy with curative intent or who required concomitant use of CYP3A4 inducers or inhibitors were ineligible.

Study Assessments

Patient demographics and medical history were recorded at baseline. Adverse events (AEs), physical examination, vital signs, and performance status were assessed at baseline, weekly during treatment, and then monthly for 3 months. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Multigated acquisition or echocardiogram scans were performed at baseline and then after 4 and 8 weeks of lapatinib. Neurologic assessment at baseline was repeated as clinically indicated. Hematology, clinical chemistry, and creatinine clearance were measured at baseline and weekly during treatment. All patients had baseline panendoscopy. Radiologic studies (computed tomography/magnetic resonance imaging scans and chest x-ray) were performed at baseline and 8 weeks after treatment. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors; complete responses (CRs) and partial responses (PRs) were confirmed 4 weeks later.

Study Treatment and Dose Escalation

The following three dose cohorts of lapatinib were investigated: 500, 1,000, and 1,500 mg orally once daily. Lapatinib alone was administered for 1 week before starting chemoradiotherapy (Fig 1). Radiotherapy was administered in 2-Gy fractions, 5 days a week, to a total dose of 66 to 70 Gy. As a phase I study, radiotherapy planning and delivery were supervised by the two investigational sites. No external quality assurance was used. No patient received intensity-modulated radiotherapy. Instead, patients received radiotherapy based on two-dimensional or three-dimensional conformal planning according to standard departmental protocols. Cisplatin was administered at 100 mg/m2 on days 1, 22, and 43 of radiotherapy. Lapatinib and cisplatin dose reductions or delays were based on predefined toxicity criteria.

Fig 1.
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Fig 1.

Illustration of study design. SCCHN, squamous cell carcinoma of the head and neck. (*) Cisplatin was administered intravenously on days 1, 22, and 43 of radiotherapy (approximately on study days 8, 29, and 50).

Each cohort comprised three patients, with expansion to six patients if one of the three initial patients experienced dose-limiting toxicity (DLT). The definition of DLT followed the generally accepted parameters in published phase I trials and aimed to identify any amplification of the expected toxicities of standard chemoradiotherapy by addition of lapatinib. Therefore, DLT was defined as grade 4 thrombocytopenia (or grade 3 with hemorrhage); grade 4 neutropenia lasting more than 7 days (or grade 3 with fever); grade 4 anemia; grade 4 mucositis (or grade 3 with confluent lesions lasting > 6 weeks); ≥ grade 3 left ventricular cardiac dysfunction or a more than 20% relative decrease in LVEF from baseline that was also less than the institution's lower limit of normal; more than 2 weeks of toxicity-related treatment delay; or any other ≥ grade 3 nonhematologic toxicity (except nausea and vomiting) that in the opinion of the investigator was considered dose limiting.

Doses were escalated after all patients in the preceding cohort had completed treatment. No intrapatient dose escalation was allowed. The recommended phase II dose was defined as the dose of lapatinib with chemoradiotherapy at which no more than one of six patients experienced DLT. Once the recommended phase II dose was determined, this cohort was expanded with 14 additional patients to further define the safety profile.

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RESULTS

Patient Characteristics

Overall, 31 patients were enrolled; seven, seven, and 17 patients were included in the 500-, 1,000-, and 1,500-mg cohorts, respectively. Baseline characteristics are listed in Table 1. For transparency, all 31 patients were included in the analyses, regardless of eligibility or treatment duration, on an intent-to-treat basis. However, there were two patients whose data were compromised, both of whom were treated on the expanded 1,500-mg cohort. The first patient withdrew consent for chemotherapy after 3 days of lapatinib treatment and no cisplatin and continued to receive radiotherapy alone. The second patient was found to be ineligible after registration onto the study by virtue of insufficient renal and cardiac function and recent history of another malignancy.

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Table 1.

Patient Characteristics at Baseline

Study Treatment

Five patients discontinued lapatinib before completing 40 days of treatment. One patient from the 500-mg cohort discontinued treatment as a result of the serious AE (SAE) of duodenal ulcer perforation; one patient from the 1,000-mg cohort discontinued as a result of noncompliance; and three patients from the 1,500-mg cohort discontinued as a result of consent withdrawal, protocol violation (insufficient renal function), and death from neutropenic sepsis.

Twenty-five patients (81%) received the full 70-Gy dose of radiation. The only postoperative patient received the full target dose of 66 Gy. Of the remaining five patients, the two patients who died during treatment received 58 and 26 Gy. The patient who experienced duodenal ulcer perforation received 65 Gy, as did the patient who withdrew consent. The patient withdrawn as a result of a protocol violation (insufficient renal function) received only 10 Gy. Median duration of radiation was 50 days (range, 48 to 53 days), 50 days (range, 47 to 52 days), and 49 days (range, 5 to 53 days) in the 500-, 1,000-, and 1,500-mg cohorts, respectively.

Twenty-two patients (71%) received all three doses of cisplatin. Four patients (13%), all on the 1,500-mg cohort, received only two cisplatin doses as a result of lymphopenia and thrombocytopenia in one patient, neutropenia in one patient, neutropenic sepsis in one patient, and death from pulmonary embolism and venous thrombosis in one patient. Three patients (10%) received only one dose of cisplatin as a result of perforated ulcer (500-mg cohort), low creatinine clearance (500-mg cohort), and death from sepsis (1,500-mg cohort). Two patients (6%), both on the 1,500-mg cohort, received no cisplatin as a result of withdrawal of consent and low creatinine clearance. Sixteen patients had dose reductions or delays (two, four, and 10 patients in the 500-, 1,000-, and 1,500-mg cohorts, respectively) or switched to carboplatin (one patient in the 500-mg cohort).

Recommended Phase II Dose

At the 500-mg dose, one patient experienced a DLT (perforated ulcer). This event was probably a result of administration of corticosteroid antiemetic medication during self-medication with nonsteroidal anti-inflammatory drugs. After this event, the protocol was amended to allow proton pump inhibitor prophylaxis during corticosteroid use. This cohort was expanded to seven patients because two patients were registered simultaneously at separate sites. No further DLT was observed in this cohort, so the dose was escalated.

In cohort 2 (1,000 mg), one patient experienced a DLT of transient elevation of ALT and AST levels that decreased markedly over a 4-week period from 437 to 185 U/L and 193 to 77 U/L, respectively, despite continued lapatinib treatment. The cohort was expanded to seven patients because one patient was replaced as a result of noncompliance. No further DLT was observed; therefore, the dose was escalated to 1,500 mg.

None of the three patients in the final 1,500-mg cohort experienced a DLT. Therefore, the recommended phase II dose was determined to be lapatinib 1,500 mg/d combined with radiotherapy 66 to 70 Gy (5 days a week in 2-Gy fractions for 6.5 to 7 weeks) and cisplatin 100 mg/m2 (on days 1, 22, and 43 of radiotherapy).

The recommended phase II dose level cohort was expanded with 14 additional patients to further define the safety profile. Of these 14 patients, four experienced toxicities that would have been considered dose limiting in the dose-escalation phase; one patient experienced grade 4 hypokalemia; one patient experienced grade 3 pyelonephritis, grade 4 pulmonary edema, and grade 3 left ventricular systolic dysfunction; one patient died as a result of pulmonary embolism; and one patient died of neutropenic sepsis. It should be noted that the patient with multiple toxicities was ineligible, as mentioned earlier. However, even including these observed toxicities, the standard criteria for maximum-tolerated dose (≥ two of six patients, or 33%) have not been met, and therefore, these toxicities did not affect the conclusion that the recommended phase II dose of lapatinib should be 1,500 mg/d.

Toxicity

The most common toxicities reported during study treatment regardless of causality are listed in Table 2. The majority of AEs were grade 1 and 2.

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Table 2.

Adverse Events of Any Grade Reported in ≥ 10% of Patients During Study Treatment Regardless of Causality

The most commonly reported AEs were radiation mucositis (27 patients; 87%) and radiation dermatitis (25 patients; 81%). No grade 4 radiation mucositis or radiation dermatitis was reported; however, 11 patients (35%) had grade 3 radiation mucositis, and six patients (19%) had radiation dermatitis. Only four patients experienced radiation mucositis events, which were considered serious; no radiation dermatitis events were considered serious. No apparent dose-related trends were observed with lapatinib for either of these toxicities.

Nineteen patients (61%) and 16 patients (52%) had nausea and vomiting, respectively, and three patients (10%) and five patients (16%), respectively, experienced these as an SAE, although all events were mild to moderate in severity. The incidence of vomiting (500 mg = 14%; 1,000 mg = 57%; and 1,500 mg = 65%) and, to some extent, nausea (500 mg = 29%; 1,000 mg = 86%; and 1,500 mg = 65%) increased with increasing lapatinib dose.

The most common hematologic toxicities considered by the investigator to be clinically significant were neutropenia and anemia, occurring in seven patients (23%) each. Of these, only two patients (6%) in the 1,500-mg cohort had grade 3 neutropenia.

Rash was reported in one patient (14%), one patient (14%), and four patients (24%) in the lapatinib 500-, 1,000-, and 1,500-mg cohorts, respectively. All instances of rash were grade 1.

Nine patients (29%) had grade 1 (n = 8) or grade 2 (n = 1) diarrhea. No patient experienced diarrhea as an SAE.

Only one patient (1,500-mg cohort) had a more than 20% (asymptomatic) decrease in LVEF that was also below the institution's lower limit of normal. One patient (1,500-mg cohort) experienced atrial fibrillation, which resolved after 3 days and was not deemed to be related to study treatment. No patients experienced interstitial pneumonitis.

Table 3 lists the most common grade 3 to 4 AEs, regardless of causality. Few grade 4 toxicities were reported in any cohort; lymphopenia was the only grade 4 toxicity reported by more than one patient. The cumulative grade 3 to 4 toxicities for the 500-, 1,000-, and 1,500-mg cohorts were 71% (five patients), 57% (four patients), and 82% (14 patients), respectively.

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Table 3.

Incidence of CTCAE Grade 3 and 4 On-Treatment Adverse Events Occurring in ≥ Two Patients Regardless of Causality

On-treatment SAEs that occurred in 5% or more of all patients are listed in Table 4. All patients in 1,000-mg cohort experienced at least one SAE compared with four patients (57%) in the 500-mg cohort and 11 patients (65%) in 1,500-mg cohort. The most common SAE overall was vomiting in five patients (16%). Two patients (both in the 1,500-mg cohort) died from SAEs; one patient died of deep vein thrombosis and pulmonary embolism, and one patient died of neutropenic sepsis. In the investigators' opinion, neither event was related to lapatinib.

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Table 4.

Patients With On-Treatment Serious Adverse Events (≥ 5% of all patients)

Tumor Response

The objective response rate (ORR) was 81% (16 CRs and nine PRs); in the 17 patients receiving the recommended phase II dose, the ORR was 65% (five CRs and six PRs; Table 5). All patients in 500- and 1,000-mg cohorts achieved either CR or PR. In the 1,500-mg group, the ORR was 64%, two patients (12%) had progressive disease, and four patients (24%) were considered nonassessable as a result of consent withdrawal (n = 1), death (n = 2), and protocol violation (n = 1).

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Table 5.

Investigator-Evaluated Assessment of Best Overall Response 12 Weeks After the End of Treatment

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DISCUSSION

This study showed that lapatinib 1,500 mg/d given with chemoradiotherapy was well tolerated in patients with LA SCCHN. Both the 500- and 1,000-mg cohorts had one DLT. There were no DLTs in the 1,500-mg dose-escalation cohort, and therefore, this dose was selected as the recommended phase II dose. The low incidence of toxicities in the safety cohort verified the phase II dose selection. After this phase I dose-finding study, several other phase II and III studies have been initiated using the 1,500-mg daily lapatinib dose. An independent data monitoring committee (IDMC), consisting of renowned SCCHN researchers and independent specialists (statistician, cardiologist, and safety physician) has been assembled to protect the ethical and safety interests of patients recruited onto these studies, while protecting, as far as possible, the scientific validity of the data. The IDMC meets twice a year to evaluate safety and, as appropriate, efficacy data to identify potential treatment harm and all-cause mortality/morbidity and to identify potential treatment benefit. The IDMC has met on two occasions and has found no safety concerns and has recommended that all studies continue without modification.

The majority of patients (81%) received the planned radiotherapy dose. Similarly, 71% of patients completed three cisplatin cycles, which was similar to that seen in other studies investigating similar chemoradiotherapy regimens.15,16 Only two patients received neoadjuvant/induction chemotherapy before starting protocol treatment. From a toxicity perspective, one patient was not affected, whereas the second patient had multiple toxicities and subsequent discontinuation of cisplatin after the first concurrent cycle with radiation. Therefore, it is difficult to conclude whether prior neoadjuvant treatment influenced the pattern of toxicity and the administration of subsequent therapy. Only one patient received protocol treatment in the adjuvant setting after tonsillectomy.

The toxicity profile of lapatinib combined with chemoradiotherapy is consistent with toxicity profiles for chemoradiotherapy alone in several randomized trials.15–17 Many of the most frequent grade 3 to 4 AEs are commonly associated with radiotherapy (mucositis and dermatitis) or with cisplatin (lymphopenia and neutropenia). Importantly, lapatinib did not enhance radiation mucositis, with ≥ grade 3 seen in 35% of patients compared with 43% to 77% in the literature.18,19

Adding lapatinib to cisplatin-based chemoradiotherapy does not seem to exacerbate cisplatin-induced nausea or vomiting, which occurred in 50% to 60% of the patients and were ≤ grade 2. In contrast, severe (≥ grade 3) nausea and vomiting have been reported in 11% to 40% of patients receiving cisplatin-based chemoradiotherapy for SCCHN.15–17

In this study, the incidence of rash was 19% overall in this study (24% in the 1,500-mg treatment group) compared with 27% to 74% in other lapatinib studies.12,20 This study's slightly lower than expected incidence of rash may be a result of rash reporting being confounded by radiation dermatitis, making identification of lapatinib-related rash difficult. It has been suggested that rash may be a surrogate marker of EGFR inhibitor activity,21 with some studies reporting incidences of rash as high as 87%;22 however, correlation between antitumor activity and rash has yet to be proven for all EGFR inhibitors. A recent study of lapatinib treatment for advanced solid tumors showed no correlation between rash and dose or serum concentration or clinical response.23 Furthermore, the number of responders without rash was larger than those with rash, demonstrating that rash is not an indicator of clinical response to lapatinib. This may be related to the unique 4-anilinoquinazoline structure of lapatinib in contrast to either gefitinib or erlotinib, which are quinazolines.

Diarrhea (29%) was mild to moderate and occurred at only a slightly higher incidence than seen recently with the monoclonal EGFR antibody cetuximab (20%) combined with radiotherapy (but no other cytotoxic agent) for SCCHN.22 In all ongoing lapatinib studies, it is recommended that diarrhea events be managed using American Society of Clinical Oncology guidelines for cancer therapy–induced diarrhea.24

Left ventricular dysfunction and, occasionally, advanced congestive heart failure have been observed with the ErbB2 monoclonal antibody trastuzumab.25,26 However, in general, cardiac events occur infrequently with lapatinib;12,23 in this study, only one patient had an asymptomatic more than 20% relative decrease in LVEF. The single case of atrial fibrillation resolved after 3 days and was considered unrelated to lapatinib.

In a study by Abidoye et al,27 lapatinib as a single agent in recurrent or metastatic SCCHN did not show any objective responses. However, the newly diagnosed locally advanced setting differs from the recurrent setting with respect to the natural course of the disease and the biologic and phenotypic characteristics. More importantly, the current study tests the feasibility of combining lapatinib and chemoradiotherapy, whereas other ongoing phase II and III studies test the added benefit of lapatinib as a radiotherapy sensitizer.

Few published studies have combined EGFR inhibition with a similar schedule of chemoradiotherapy. However, the results obtained here are comparable with those obtained by Herchenhorn et al,28 who found that the combination of erlotinib with a virtually identical cisplatin/radiation regimen was safe and that the toxicity profile was similar to that expected for standard chemoradiotherapy. Recent results from an Eastern Cooperative Oncology Group study showed that cetuximab with radiotherapy and cisplatin (albeit a slightly lower dose of 75 mg/m2) was feasible in fit patients.29

This study has established the recommended phase II dose of lapatinib as 1,500 mg/d when combined with chemoradiotherapy in patients with LA SCCHN. Furthermore, this dose is associated with an acceptable tolerability profile, similar to that observed with chemoradiotherapy alone. Given these findings, randomized phase II and III studies of lapatinib plus chemoradiotherapy have been initiated in LA SCCHN.

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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. 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 or Leadership Position: Iman A. El-Hariry, GlaxoSmithKline (C); Clare S. Holford, GlaxoSmithKline (C), GlaxoSmithKline (C); Simon J. Turner, GlaxoSmithKline (C); Jagannatha S. Pandeshwara, GlaxoSmithKline (C) Consultant or Advisory Role: Jean Bourhis, Sanofi-Aventis (C), GlaxoSmithKline (C), Merck Serono (C) Stock Ownership: Iman A. El-Hariry, GlaxoSmithKline; Clare S. Holford, GlaxoSmithKline; Simon J. Turner, GlaxoSmithKline; Jagannatha S. Pandeshwara, GlaxoSmithKline Honoraria: Kevin J. Harrington, GlaxoSmithKline Research Funding: Jean Bourhis, Sanofi-Aventis, GlaxoSmithKline Expert Testimony: None Other Remuneration: None

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AUTHOR CONTRIBUTIONS

Conception and design: Kevin J. Harrington, Iman A. El-Hariry, Antoine Lusinchi, Christopher M. Nutting, Dominique Rosine, Eric Deutsch, Jean Bourhis

Administrative support: Iman A. El-Hariry, Mary Tanay, Jennifer Matthews

Provision of study materials or patients: Kevin J. Harrington, Antoine Lusinchi, Christopher M. Nutting, Dominique Rosine, Eric Deutsch, Consuelo D'Ambrosio, Jean Bourhis

Collection and assembly of data: Kevin J. Harrington, Antoine Lusinchi, Christopher M. Nutting, Dominique Rosine, Mary Tanay, Eric Deutsch, Jennifer Matthews, Consuelo D'Ambrosio, Jean Bourhis

Data analysis and interpretation: Kevin J. Harrington, Iman A. El-Hariry, Clare S. Holford, Antoine Lusinchi, Christopher M. Nutting, Dominique Rosine, Eric Deutsch, Simon J. Turner, Jagannatha S. Pandeshwara, Jean Bourhis

Manuscript writing: Kevin J. Harrington, Iman A. El-Hariry, Clare S. Holford, Antoine Lusinchi, Christopher M. Nutting, Dominique Rosine, Eric Deutsch, Simon J. Turner, Jagannatha S. Pandeshwara, Jean Bourhis

Final approval of manuscript: Kevin J. Harrington, Iman A. El-Hariry, Clare S. Holford, Antoine Lusinchi, Christopher M. Nutting, Dominique Rosine, Eric Deutsch, Consuelo D'Ambrosio, Simon J. Turner, Jagannatha S. Pandeshwara, Jean Bourhis

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Acknowledgment

We thank the patients and their families; Shirley Young and John Farrell of GlaxoSmithKline (study management); and Complete Medical Communications.

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Footnotes

  • Supported by an unrestricted grant from GlaxoSmithKline (medical writing support also funded by GlaxoSmithKline).

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

  • Received April 4, 2008.
  • Accepted September 22, 2008.
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  1. Published online before print January 26, 2009, doi: 10.1200/JCO.2008.17.5349 JCO vol. 27 no. 7 1100-1107
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