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Phase II Study of Imatinib in Advanced Chordoma

  1. Paolo Giovanni Casali
  1. Silvia Stacchiotti, Elena Tamborini, Silvana Pilotti, Antonella Messina, Carlo Spreafico, Alessandro Gronchi, and Paolo Giovanni Casali, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Milan; Alessandra Longhi, Istituto Ortopedico Rizzoli, Bologna; Virginia Ferraresi, Istituti Fisioterapici Ospitalieri–Polo Oncologico Regina Elena, Rome; Giovanni Grignani, Istituto per la Ricerca e la Cura del Cancro, Candiolo; Alessandro Comandone, Presidio Sanitario Gradenigo, Turin; alexia Bertuzzi, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Clinico Humanitas, Rozzano; Paola Amore, Vincenza Vinaccia, Novartis Farma, Origgio, Italy; and Roger Stupp, University of Lausanne Hospitals, Lausanne, Switzerland.
  1. Corresponding author: Silvia Stacchiotti, MD, Sarcoma Unit, Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy; e-mail: silvia.stacchiotti{at}istitutotumori.mi.it.

  1. Presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL (abstract 10003).

 
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Abstract

Purpose To explore the antitumor activity of imatinib in patients with advanced platelet-derived growth factor β (PDGFB)/PDGF receptor β (PDGFRB)–positive chordomas.

Patients and Methods In a collaborative Italian-Swiss, prospective, phase II clinical study conducted from November 2004 through April 2006, 56 patients with advanced PDGFB and/or PDGFRB chordoma received 800 mg/d of imatinib until progression. The primary end point was the overall tumor response rate (ORR), defined by RECIST. Secondary, exploratory end points included tissue response (ie, changes in tumor density or signal intensity/contrast enhancement, and/or [18F]-fluorodeoxyglucose positron emission tomography [PET] uptake), overall survival, progression-free survival (PFS), and pain score.

Results Among 50 patients evaluable by RECIST, the best response was one partial response (PR) obtained at 6 months (ORR, 2%). There were 35 patients with stable disease (SD, 70%) and a 64% clinical benefit rate (ie, RECIST complete response + PR + SD ≥ 6 months). A minor dimensional response (< 20%) was detected in nine patients. A maximum standard uptake value decrease ≥ 25% was observed in 10 (39%) of 26 patients evaluable for PET response at 3 months. Changes in the Brief Pain Inventory score were consistent with the response assessment. Median PFS (intention-to-treat population, 56 patients) was 9 months. No unexpected toxicities were observed.

Conclusion This is the largest phase II study in chordoma to date. It confirms anecdotal evidence that imatinib has antitumor activity in this orphan disease, and therefore, it is worth further investigation.

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INTRODUCTION

Chordoma is a rare tumor.1 After surgery, local relapses occur in more than 50% of cases, with a minority of patients curable by further surgery.2–7 Metastases occur in at least 20% of patients.2,7–12 High-dose radiotherapy (RT) may be indicated for residual or recurrent disease.13–19 However, systemic therapy is needed in patients who are not amenable to surgery and/or RT.

Few prospective data are available. The only prospective phase II study evaluated the activity of 9-nitrocamptothecin,20 with a response rate of 1 of 15 patients. Anecdotal responses were reported to anthracyclines, cisplatin, alkylating agents,21–24, and, among targeted therapies, to cetuximab, gefitinib, erlotinib, sunitinib, and thalidomide.25–29

In 2002, we treated with imatinib a patient with advanced chordoma, as he was shown to have activated platelet-derived growth factor receptor β (PDGFRB).30 This patient demonstrated a response to therapy similar to that of patients with gastrointestinal stromal tumor (GIST) treated with the same agent.31 Afterward, an additional five patients received imatinib.32

This study was designed as an exploratory multicenter, nonrandomized, prospective, phase II study to assess hints of imatinib efficacy in patients with progressive PDGFRB/platelet-derived growth factor β (PDGFB) advanced chordoma.

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PATIENTS AND METHODS

Adults with progressive, locally advanced, or metastatic chordoma expressing PDGFRB and/or PDGFB were eligible for the study. Pathology and PDGFRB/PDGFB expression were centrally reviewed.

Main inclusion criteria were at least one measurable tumor lesion; adequate bone marrow, renal, hepatic, and cardiac function; and Eastern Cooperative Oncology Group performance status ≤ 4. All patients provided written informed consent. The study was registered with ClinicalTrials.gov and approved by the ethics committees of all centers.

Study Design and Statistical Analysis

This nonrandomized, open-label, multicenter, Italian-Swiss, phase II study was designed to prospectively confirm the antitumor activity of imatinib in a formal setting.32,33 The primary end point was overall response rate (ORR) according to RECIST.34

At the time of this study, preliminary data on imatinib showed that response could occur with a decrease in tumor density/contrast enhancement (CE) on computed tomography (CT)/magnetic resonance imaging (MRI) without tumor shrinkage.32

However, no validated criteria were available to assess nondimensional tissue response. Furthermore, the absence of prospective trials made it difficult to estimate tumor progression rates and time to treatment failure. Thus, in addition to RECIST rules34 and as an exploratory end point, we also investigated changes in enhancement on CT and MRI, defined as tissue responses. We also considered that chordoma is an “orphan” disease on which only one other trial had been conducted in 20 years.21 Moreover, the expected proportion of objective responses with standard chemotherapy in chordoma is close to zero. Therefore, this study was planned as being exploratory, to prospectively detect hints of antitumor activity, which could possibly justify a subsequent confirmatory trial. Therefore, we did not foresee any formal statistical hypothesis, through an exploratory, prospective study intended to accrue the foreseeable number of 50 patients in a reasonable time interval (2 years). The secondary end points were multifold, including overall survival (OS), progression-free survival (PFS), disease control rate at 6 months, and changes in pain score. PFS and OS were estimated using the Kaplan-Meier method.35 Approximate CIs were computed. Patients with no evidence of progression and withdrawing from the trial for any reason were censored at the last tumor assessment. death was considered an event regardless of the cause. Patients alive or lost to follow-up were censored at the last contact.

PDGFRB/PDGFB Assessment

PDGFRB was assessed by immunohistochemistry.30,36,37 PDGFRB expression/phosphorylation was analyzed by immunoprecipitation/Western blot analysis36 whenever fresh/frozen material was available. Alveolar soft part sarcoma was used as positive control.38,39 A pool of normal mesenchymal tissues was used as negative control to check PDGFRB basal expression.40 PDGFB cDNA expression was analyzed by reverse-transcriptase polymerase chain reaction (PCR)30,41 in all cases with adequate fixed material.

Treatment

Patients were to receive 400 mg of imatinib twice daily continuously for 24 months. Treatment was withheld for hematologic toxicity grade ≥ 3 and nonhematologic toxicity grade ≥ 2. Imatinib was resumed after recovery to hematologic toxicity grade ≤ 2 or nonhematologic toxicity grade ≤ 1. Dose reductions to 600 or 400 mg/d were allowed in case of toxicity. Patients who were still responsive after 24 months continued imatinib outside the study.

Patients had a regular physical examination and a complete blood count/serum chemistry evaluation. pain assessment was recorded according to the Brief Pain Inventory (BPI).42

Efficacy and Safety Evaluation

The intention-to-treat (ITT) population included all enrolled patients who received at least one dose of imatinib. In the ITT population, patients who went off study as a result of adverse events or toxicity before the key response evaluation were considered treatment failures. The efficacy analyzable population (EAP) comprised all eligible patients who completed the study treatment, withdrew from the study for progression or death related to cancer, or withdrew from the study for toxicity related to the study drug. These patients had at least one key response evaluation. The primary analysis was run primarily on the EAP and confirmed on the ITT population.

Response Assessment

Response was assessed every 3 months by CT and/or MRI, according to RECIST.34 [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) was recommended at baseline and until standardized uptake value (SUV) reduction. PET response was assessed according to the European Organization for Research and Treatment of Cancer 1999 criteria.43 Given the low FDG avidity of chordomas, 10% changes in mean/maximum SUV were also recorded.

The tissue response was assessed by describing radiologic changes of several parameters on MRI/CT/PET. Besides RECIST, at every MRI/CT/PET assessment, investigators had to record the following: tumor size; tumor density, or tumor signal intensity on turbo spin echo (TSE) T2-weighted and CE on TSE T1-weighted changes; tumor bleeding and necrosis; and FDG-PET mean/maximum SUV. On the basis of these parameters, a final clinical evaluation of tumor response was requested at every assessment, coding it as response, stable disease (SD), progressive disease (PD).

The central review board defined partial response (PR) as a ≥ 10% decrease in tumor size, a ≥ 15% decrease in tumor density (portal venous phase) on CT, and/or a ≥ 15% decrease in TSE T2-weighted signal intensity and TSE T1-weighted CE (late phase) at MRI compared with baseline, with muscle as reference tissue for normalization irrespective of any increase in tumor size, given the absence of new lesions. The response was classified as SD when criteria for PR or PD were not met. PD was defined by the presence of a ≥ 10% increase in tumor size and no criteria for PR or in case of a new lesion.

CT/MRI centralized review was planned for an exploratory analysis of tissue response assessment reproducibility. Two radiologists with more than 10 years of experience in sarcomas reviewed MRI/CT images retrospectively in a blinded fashion. Cases were eligible for the centralized review only when evaluated by using the same technique (MRI or CT) and whose images were available as Digital Imaging and Communications in Medicine files before/after contrast administration, in portal venous phase in case of CT and/or TSE T2-weighted/TSE T1-weighted CE (late phase) in case of MRI.

Toxic effects were graded according to the National Cancer Institute Common Toxicity Criteria version 2.0.

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RESULTS

Among 59 patients screened between November 2004 and April 2006, 56 patients were enrolled at 14 study centers (13 within the Italian Sarcoma Group, one in Switzerland). Figure 1 shows the CONSORT recruitment tracking flowchart. The analysis presented here includes data from all 56 patients on an ITT basis. The EAP data analysis on 37 patients is superimposable on the ITT population results (Appendix Table A1, online only). Table 1 summarizes patient characteristics.

View this table:
Table 1.

Baseline Demographics and Clinical Characteristics of the Study Population

Fig 1.
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Fig 1.

CONSORT diagram. Patients not experiencing disease progression at the end of 24 months of treatment were allowed to continue therapy with imatinib outside the study. AE, adverse event; EAP, efficacy analyzable population; ITT, intention to treat; PD, progressive disease; PS, performance status.

All patients screened for PDGFRB/PDGFB were positive at least on one technique. PDGFRB expression was assessed by immunohistochemistry in all 56 cases, detecting it in all but one case, which was positive by reverse-transcriptase PCR. PDGFRB activation was detected in seven of seven cases analyzed by immunoprecipitation/Western blot analysis and in 39 of 40 cases evaluated by reverse-transcriptase PCR (Appendix Fig A1, online only).

Median treatment duration was 9.1 months (range, 0.03 to 28.2 months). Eight patients were treated for ≥ 24 months. Three patients continued imatinib after the end of the study (one for 39 months, two for 35 months). Median follow-up for OS was 26.4 months (interquartile range, 24.1 to 57.8 months). Reasons for discontinuation were PD (28 patients, 58%), death (six patients, 12.5%), adverse event (nine patients, 18.8%), and various unrelated reasons (five patients, 10.4%: one protocol violation, two consent withdrawal, one lost to follow-up, and one other). Major protocol violations included nonmeasurable disease (n = 1), another cancer treatment less than 28 days before study drug (n = 1), and severe/uncontrolled medical disease (n = 2).

Antitumor Activity

Table 2 summarizes data on tumor response.

View this table:
Table 2.

Efficacy Data in ITT Population

RECIST Assessment

Fifty patients were evaluable for RECIST (six patients had no postbaseline tumor assessment). Best responses were complete response (CR), PR, SD, and PD in 0, one (2%), 35 (70%), and 14 patients (28%), respectively. The ORR, which was the primary study end point, was 2% (95% CI, 0% to 5.3%). The response rate at 3 months was 0%, because the only PR was achieved after 6 months of treatment; this patient experienced PD at 12 months. Among 36 patients (72%) with RECIST SD at 3 months, 28 (56%) showed no progression at 6 months. A minor response (< 20% decrease in maximum diameter) was detected in nine cases (Fig 2), for an overall 20% dimensional response rate. Figure 3 shows the plot of best radiologic outcome by RECIST. Clinical benefit (ie, RECIST CR + PR + SD ≥ 6 months), evaluated as exploratory unplanned analysis, was 64.1% (95% CI, 49.2% to 75.7%) for the ITT population. No relationship were observed between disease status and response.

Fig 2.
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Fig 2.

Tissue response in patient with relapsed sacral chordoma treated with imatinib. (A) Baseline; (B) more than 6 months; (C) standardized uptake value (SUV) maximum, 5.43; mean, 3.52; (D) SUV maximum, 3.83; mean, 2.68.

Fig 3.
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Fig 3.

Plot of best radiologic outcome by RECIST by patient. Asterisk indicates patients with new lesions (ie, RECIST progressive disease), despite a less than 20% change in the target lesions.

FDG-PET Assessment

PET evaluation was available for 30, 26, and 17 patients at baseline, 3 months, and 6 months, respectively. Applying a threshold of 10% and 25% decrease in maximum SUV at 3 months, a PET response was observed in 13 and in 10 patients, respectively (Fig 2). PET responses corresponded to RECIST PR/SD in all patients but one, who experienced PD at 3 months.

Tissue Response Assessment

The best responses for the 50 patients were coded as response, SD, and PD in seven (14%), 33 (66%), and 10 patients (20%), respectively. Among 39 patients (78%) with response/SD at 3 months, 33 (66%) were still responsive or SD at 6 months. Appendix Figure A2 (online only) shows a graph correlating tissue response with OS.

Centralized Radiologic Review

Thirty-two patients were eligible for the centralized review. Thirty-one of them were evaluable for RECIST and 30 for tissue response. PET images could not be properly collected, and therefore they were not centrally reviewed. By RECIST, best responses at 6 months for the 31 patients were PR, SD, and PD in one (3%), 21 (68%), and nine patients (29%), respectively. A tissue response was detected in 11 (37%) of 30 cases (Fig 2), whereas nine (30%) and 10 (33%) had SD and PD, respectively.

The agreement between central review and local investigator evaluation results was analyzed by Cohen's κ statistic. With respect to RECIST, the κ statistic was 0.77 (ie, substantial strength of agreement). Conversely, with respect to tissue response evaluation, κ test was 0.40 (ie, fair strength of agreement).44

PFS and OS

Figure 4 shows OS and PFS per RECIST. Median OS was 34.9 months. The estimated survival rate for all patients was 79% (95% CI, 64.9% to 87.7%) and 72.3% (95% CI, 57.6% to 82.6%), respectively. Median PFS was 9.2 months. Median PFS for patients who were not experiencing PD at 6 months was 18.5 months (95% CI, 12.1 months to not determined).

Fig 4.
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Fig 4.

Overall survival and progression-free survival (PFS) according to RECIST in intention-to-treat population.

pain assessment

At 0, 3, and 6 months, BPI was assessed in 53, 31, and 28 patients, respectively. Those requiring analgesic treatment were 35, 23, and 18 patients (67%, 74%, and 64%), respectively. Overall, a trend in mean pain intensity was consistent with radiologic response evaluation (Fig 5). Among 22 patients symptomatic at baseline and not experiencing PD at 6 months, an improvement in pain was reported at 3 months in 9 (50%) of 18 and 6 (33%) of 18 patients, respectively, for medium- and maximum-intensity pain; no change was reported in five (28%) of 18 and seven (39%) of 18 patients, and worsening pain was reported in four (22%) of 18 and five (28%) of 18 patients. At 6 months (20 patients), pain improvement was reported in eight patients (40%), no change was reported in five patients (25%), and worsening pain was reported in seven patients (35%) for both medium- and maximum-intensity pain. Overall, pain had not worsened at 6 months in 65% of symptomatic patients.

Fig 5.
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Fig 5.

(A) Mean maximum intensity pain score variations as recorded by the Brief Pain Inventory (BPI). (B) Mean medium (Mid) intensity pain score variations as recorded by the BPI. ITT, intention-to-treat; PD, progressive disease; SD, stable disease.

Drug Delivery and Toxicity

All patients started imatinib at 800 mg/d. The actually administered mean dosage was 694 mg/d (median, 734 mg/d), for a median exposure duration of 9.1 months (range, 0.03 to 28.2 months). Most patients experienced some mild or moderate adverse event. Thirty-nine patients (70%) had at least one dose interruption owing to toxicity, 15 patients (27%) had more than three dose interruptions, and 27 patients (48%) had at least one dose reduction. The imatinib dose was permanently reduced to 600 or 400 mg/d in 26 patients (46%).

Overall, a grade ≥ 3 toxicity was reported in 37 patients (72%). Major toxicities included chronic anemia (grade ≥ 2, 21%), fatigue (grade ≥ 2, 13%), and fluid retention (grade 2 and 3, 25% and 29%, respectively).

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DISCUSSION

Fifty-six patients with advanced chordoma were treated with imatinib. The RECIST objective ORR (ie, the study primary end point) was 2%, with one patient achieving a RECIST PR. Nine additional patients achieved a minor response. Confirmed disease stabilization (RECIST PR + SD) was observed as best response in 72% of cases, with a median PFS of 9 months and a 64% clinical benefit rate, defined as RECIST CR + PR + SD ≥ 6 months. Ten of 26 patients (39%) who had a PET at baseline and after 3 months achieved a ≥ 25% decrease in maximum SUV. Changes in the formally assessed intensity of pain were consistent with the response evaluation.

Treatment of chordoma is challenging. Chordomas still represent an unmet medical need, as confirmed by the fact that, despite the rarity of the disease, more than 50 patients could be enrolled in this study in 18 months. In addition, only one phase II, negative study has ever been published, and no standard medical therapy is available.20

Since we learned from the first anecdotal cases that tumor responses could have been nondimensional,32,33 we conceived this trial as a prospective, exploratory study aimed at describing our clinical observations in patients with chordoma homogeneously treated with a targeted therapy to highlight any possible hints of antitumor activity, as well as the impact in terms of conventional RECIST responses. Thus this study is negative with regard to its primary end point, which was formulated in terms of RECIST. However, we observed one RECIST objective response after 6 months and nine minor dimensional responses. We also observed tissue responses and a decrease in maximum SUV on PET in more than one third of the evaluable patients. Intensity of pain was assessed through the BPI, and results were consistent with tumor response assessment through nondimensional and PET criteria. We observed a clinical benefit rate exceeding 60%. These were secondary end points. In addition, the study was powered on the basis of the potential of accrual rather than on a formal statistical hypothesis. Therefore, these results should be viewed as hints of antitumor activity, rather than a formal demonstration of efficacy.

Regarding future studies, one should take into account the nondimensional pattern of tumor responses of chordoma to targeted therapies. In this regard, Choi criteria31 validated for GIST evaluated by CT after imatinib had not yet been described when we drafted this protocol. The tissue response criteria used by investigators in this study were mostly descriptive and subject to a degree of interobserver variability. Conversely, the central review we did took into account Choi criteria, which were published in the meantime, in an effort to give a more quantitative evaluation. However, going retrospectively, we faced a technical limitation, because CTs were not always performed according to the protocol requested by Choi. Moreover, our study largely used MRI.

An apparently noteworthy proportion of patients with SD were seen. However, this was not a randomized trial, and a tumor growth modulation assessment was not foreseen in the protocol. This is a major limitation of this study, because it may be argued that a RECIST SD at 6 months is not necessarily proof of antitumor activity in a potentially indolent disease such as chordoma. Indeed, the only prospective clinical study published on a medical treatment in chordoma (a series of 15 patients who received 9-nitro-camptothecine) reported one objective response and 33% median 6-month PFS.21 Furthermore, 42% of patients included in this study had metastasis, a stage of disease marked by increased aggressiveness and a growth rate higher than usual, with a published expected survival between less than 1 and 3 years.2,7–12

We chose the dosage of 800 mg/d to improve the likelihood of response in the absence of PDGFRB-activating mutations. In fact, a dose-dependent response was also seen in GISTs with selected mutational profiles.45 However, in chordoma the best dose remains to be defined, considering the risk/benefit ratio.

Toxicity was consistent with that seen in other published series.46 Some adverse effects seemed more severe. In particular, edema affected 25% of patients. A possible explanation for this is that patients with advanced chordoma may have motion impairment, often need corticosteroids, and often underwent pelvic surgery and/or RT. A prompt managing of fluid retention is needed to avoid treatment interruption.

All patients treated in this study had some evidence of PDGFRB involvement, even those who did not benefit from the treatment. This study was not designed to investigate the mechanism of action of imatinib in chordoma. However, recent data suggest that other receptor tyrosine kinases besides PDGFRB, such as epidermal growth factor receptor,37,47 or effectors, as well as mammalian target of rapamycin, are involved in chordoma pathogenesis.37,48 These factors may account for a nonresponse to therapy. Moreover, the expression or activation of different targets may differ among cases.37 In fact, the activity of epidermal growth factor receptor inhibitors, sunitinib and imatinib, plus mTOR inhibitors was reported preliminarily in imatinib-resistant cases.26–28,49 Phase II studies of these drugs in chordoma are currently ongoing.

In conclusion, this prospective study, carried out in a collaborative setting, confirms that imatinib has some antitumor activity in chordoma. This is a new achievement in an orphan disease devoid of any standard medical therapy. The lack of RECIST responses and the potentially slow natural course of the disease on one hand and the largely exploratory intent of this study on the other hand do not allow us to affirm that this treatment is effective. However, it is worth further investigating imatinib, either alone or in combination.

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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: Paola Amore, Novartis (C); Vincenza Vinaccia, Novartis (C) Consultant or Advisory Role: Alessandro Gronchi, Novartis (C); Paolo Giovanni Casali, Novartis (C) Stock Ownership: Paola Amore, Novartis Honoraria: Giovanni Grignani, Novartis; Alessandro Gronchi, Novartis; Paolo Giovanni Casali, Novartis Research Funding: Silvia Stacchiotti, Novartis; Alessandro Gronchi, Novartis; Paolo Giovanni Casali, Novartis Expert Testimony: None Other Remuneration: Silvia Stacchiotti, Novartis: travel coverage; Alessandro Gronchi, Novartis: travel coverage; Paolo Giovanni Casali, Novartis: travel coverage

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Acknowledgment

We thank the investigators Gaetano Apice, Tommaso M. De Pas, Francesco Di Costanzo, Sergio Frustaci, Antonio Jirillo, Pietro Mortini, and Antonella Romanini for their contributions to this study; Chiara Gnocchi and Francesca Rancati for study coordination; and the patients and their families for their contribution.

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Appendix

View this table:
Table A1.

Efficacy Data in EAP

Fig A1.
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Fig A1.

(A) Platelet-derived growth factor receptor β (PDGFRB) immunohistochemical analysis. Left panel, positive control: alveolar soft part sarcoma (ASPS) revealing an intense staining for PDGFRB. Middle panel, chordoma. Right panel, negative control: follicular lymphoma. (B) Immunoprecipitation/Western blot experiments revealed PDGFRB activation (lane a-pTYR) and PDGFRB expression (lane a-PDGFRB). Total proteins were extracted from the corresponding cryopreserved materials of both ASPS and chordoma. As positive control (C+), a cell line, 2N5A, expressing an activated PDGFRB, was used. As negative control, a pool of normal mesenchymal tissues was immunoprecipitated.38 (C) Reverse transcriptase polymerase chain reaction for platelet-derived growth factor β (PDGFB) ligand indicating its expression in chordoma and its absence in follicular lymphoma.

Fig A2.
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Fig A2.

Graph correlating tissue response (according to investigators) with overall survival. PD, progressive disease; PR, partial response; SD, stable disease.

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Footnotes

  • See accompanying editorial on page 896

  • Supported by Novartis Farma, Origgio, Italy.

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

  • Clinical trial information can be found for the following: NCT00150072.

  • Received February 14, 2011.
  • Accepted December 5, 2011.
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  1. Published online before print February 13, 2012, doi: 10.1200/JCO.2011.35.3656 JCO vol. 30 no. 9 914-920
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