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Concurrent Cetuximab, Cisplatin, and Concomitant Boost Radiotherapy for Locoregionally Advanced, Squamous Cell Head and Neck Cancer: A Pilot Phase II Study of a New Combined-Modality Paradigm

From the Memorial Sloan-Kettering Cancer Center, New York, NY; and ImClone Systems Incorporated, Branchburg, NJ

Address reprint requests to David G. Pfister, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: pfisterd{at}mskcc.org

	ABSTRACT

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

 
PURPOSE: Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor. Cetuximab has activity in squamous cell carcinoma and enhances both chemotherapy and radiotherapy. We conducted a pilot phase II study of a new combined-modality paradigm of targeted therapy (cetuximab) with chemoradiotherapy.

PATIENTS AND METHODS: Eligible patients had stage III or IV, M0, squamous cell head and neck cancer. Treatment included concomitant boost radiotherapy (1.8 Gy/d weeks 1 to 6; boost: 1.6 Gy 4 to 6 hours later weeks 5 to 6; 70 Gy total to gross disease), cisplatin (100 mg/m² intravenously weeks 1 and 4), and cetuximab (400 mg/m² intravenously week 1, followed by 250 mg/m² weeks 2 to 10).

RESULTS: Twenty-two patients were enrolled (median age, 57 years; range, 41 to 72 years; median Karnofsky status, 90%; range, 70% to 90%; oropharynx primary tumor, 59% of patients; T4, 36%; N2/3, 77%; stage IV disease, 86%). One patient did not receive study treatment because of an ineligible diagnosis. The severity of expected, acute toxicities was typical of concurrent cisplatin and radiotherapy alone. Grade 3 or 4 cetuximab-related toxicities included acne-like rash (10%) and hypersensitivity (5%). However, the study was closed for significant adverse events, including two deaths (one pneumonia and one unknown cause), one myocardial infarction, one bacteremia, and one atrial fibrillation. With a median follow-up of 52 months, the 3-year overall survival rate is 76%, the 3-year progression-free survival rate is 56%, and the 3-year locoregional control rate is 71%.

CONCLUSION: This regimen is not currently recommended outside of the clinical trial setting. Further investigation of its safety profile is needed. However, preliminary efficacy is encouraging, and further development of this targeted combined-modality paradigm is warranted.

	INTRODUCTION

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Concurrent chemoradiotherapy is a treatment program for locoregionally advanced squamous cell carcinomas of the head and neck (SCCHN), with established benefits in both organ preservation and survival.^1,2 Over the last decade, several approaches to improve chemoradiotherapy outcomes in this population have achieved some progress. These efforts have included modifying treatment sequencing; modifying chemotherapy dosing, content, and schedule; and modifying radiotherapy dosing and fractionation.^3-12 An emerging strategy to improve outcomes is to incorporate newer, biologically active, targeted therapies into established chemoradiotherapy programs.

One attractive target for such investigation is the epidermal growth factor receptor (EGFR), a transmembrane glycoprotein with tyrosine kinase activity that plays a critical role in the regulation of tumor cell growth and survival. EGFR ligand binding stimulates multiple cellular functions essential to tumor growth including invasiveness, cell damage repair, and angiogenesis.^13-15 EGFR is highly expressed by the majority of SCCHN cell lines and primary tumors,^16-18 and this expression is correlated in clinical models with poor prognosis including decreased survival and increased metastatic potential.^18-20

Cetuximab (Erbitux; ImClone Systems, Branchburg, NJ) is a chimerized immunoglobulin G1 monoclonal antibody that binds with high affinity to EGFR. By blocking interaction with transforming growth factor alpha and epidermal growth factor, cetuximab inhibits the tyrosine kinase activity of EGFR. Cetuximab binding also leads to EGFR internalization, preventing future receptor stimulation by these agonists.^21-25 In preclinical models, cetuximab is synergistic with both cisplatin alone²⁶ and radiotherapy alone.^27,28 Cetuximab has also been safely combined with cisplatin and radiotherapy in phase I clinical trials.^29-31

Given these data, this pilot phase II study was conducted to evaluate the preliminary efficacy and toxicity of a regimen combining a targeted therapy, cetuximab, with an established cisplatin-radiotherapy program for patients with locoregionally advanced SCCHN. The goal was for the pilot data generated to facilitate further development of this regimen and new treatment paradigm.

	PATIENTS AND METHODS

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Patient Eligibility and Baseline Assessment
Enrolled patients were 18 years or older with histologically proven, stage III or IV, M0,³² new or recurrent SCCHN. Measurable or assessable disease was required. Additional inclusion criteria were as follows: Karnofsky performance status of 60%, adequate hematologic function (WBC count 3,000/µL, granulocytes 1,500/µL, hemoglobin 9 g/dL, and platelet count 100,000/µL), adequate liver function (total bilirubin 1.5x the upper limit of normal and alkaline phosphatase and AST 2.5x the upper limit of normal), adequate renal function (creatinine 1.5 mg/dL or calculated creatinine clearance 60 mL/min), and serum calcium 11.5 mg/dL. All patients provided written informed consent for this study, which was approved by the institutional review board of the Memorial Sloan-Kettering Cancer Center (New York, NY).

Exclusion criteria included the following: nasopharyngeal carcinoma; concurrent active malignancy other than localized, nonmelanoma skin cancer or carcinoma-in-situ of the cervix (unless definitive treatment was completed 3 years or more before study entry and the patient had remained disease free); prior radiotherapy to the head and neck; chemotherapy within the last 3 years; surgery for head and neck cancer within the last 60 days; prior immunotherapy or treatment with murine monoclonal antibodies or cetuximab; pregnant or breast-feeding patients; and no tumor tissue available for EGFR expression assessment.

Pretreatment evaluations performed to establish baseline values included a complete history and physical examination, including documentation of TNM disease stage³² and Karnofsky performance status; computed tomography or magnetic resonance imaging of the primary site and neck; dental evaluation; histologic confirmation of diagnosis; serum beta human chorionic gonadotropin for women of procreative potential; complete hematology, coagulation, and comprehensive chemistry profiles and urinalysis; ECG; assessment of cetuximab levels and anticetuximab antibodies; and quality-of-life assessment by the Functional Assessment of Cancer Therapy–Head and Neck (FACT-H&N; version 4.0) instrument.³³

Study Treatment
Radiotherapy was administered on a 6-week schedule using a delayed, accelerated (concomitant boost) fractionation scheme previously described by our group.³⁴ During weeks 1 to 6, patients received conventional radiotherapy at 1.8 Gy/fraction once daily both to areas of gross disease and sites at risk for subclinical disease. During weeks 5 to 6, patients received the concomitant boost as a second daily fraction of 1.6 Gy administered only to regions of gross disease with an interfraction interval of 4 to 6 hours after the morning treatment. The total dose delivered on this program was 70 Gy to sites of gross disease and 54 Gy to adjacent lymphatics at risk for subclinical metastasis. Spinal cord dose was limited to 45 Gy. There were no planned modifications of radiotherapy dose for toxicity, but treatment breaks were permitted at the discretion of the radiation oncologist for grade 3 to 4 mucositis, skin reactions, or leukopenia.

Cisplatin was administered at a dose of 100 mg/m². Two cycles were planned, administered once every 3 weeks, during weeks 1 and 4 of radiotherapy. Patients received standard hydration, mannitol infusion, and prophylactic antiemetic medications for high-dose cisplatin therapy.³⁵ Laboratory requirements before the first dose of cisplatin included granulocytes 1,500/µL, platelets 100,000/µL, and serum creatinine 1.5 mg/dL (or calculated creatinine clearance 60 mL/min). The second cycle of cisplatin was delayed 1 week for WBC count less than 3,000/µL or platelets less than 100,000/µL. Thereafter, cisplatin was administered at 100 mg/m² if the blood counts recovered; the dose was reduced to 50 mg/m² for persistent mild cytopenias (WBC = 2,000 to 2,900/µL or platelets = 75,000 to 99,000/µL) or held for lower blood counts. If the serum creatinine was more than 1.5 mg/dL, the second cycle was delayed by 24 hours to permit hydration. Creatinine was reassessed after hydration, and cisplatin was administered at 100 mg/m² if the creatinine was 1.5 mg/dL, reduced to 50 mg/m² if creatinine was 1.6 to 1.9 mg/dL and creatinine clearance was 35 mL/min, or held if creatinine levels were higher. Cisplatin was held for grade 3 to 4 neurologic or auditory toxicities.

Cetuximab was administered intravenously weekly for 10 weeks beginning on the first week of radiotherapy. The initial dose was 400 mg/m², followed by a weekly dose of 250 mg/m² (weeks 2 to 10). All patients received a 20-mg test dose 30 minutes before the initial dose. Premedication with diphenhydramine 50 mg was standard. H₂-antagonist premedication was optional at the discretion of the treating medical oncologist. Dose modification options for grade 3 skin toxicity included a 1-week delay, with dose reductions in increments of 50 mg/m² (minimum cetuximab dose, 150 mg/m²), or a 2-week delay without a dose reduction. Topical and oral antibiotics were permitted to facilitate recovery from cutaneous toxicity. Patients were removed from the study for any grade 4 toxicity that was felt to be principally attributable to cetuximab.

Patients without residual disease after completing study therapy were observed. Patients with N2-3 disease at study entry were considered for prophylactic neck dissection. Patients with residual cancer or progression after completing study therapy were recommended to receive additional treatment, including salvage surgery for patients with potentially resectable disease.

Evaluation During Study and Response Assessment
During study treatment, patients underwent weekly evaluations that included history, physical examination, and CBCs. Comprehensive chemistry profiles were performed at 14-day intervals. For patients with measurable disease, repeat imaging of the head and neck was planned at 4 to 6 weeks after therapy and again at 12 to 16 weeks after therapy to assess response status. Subsequent clinical evaluations with repeat imaging as necessary were planned at 3-month intervals for the first 2 years after completion of therapy or until disease progression. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0), except for mucous membrane toxicity, which was graded according to the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria.

Specimens for pharmacokinetic studies were collected before cetuximab infusion at weeks 1, 4, 8, and 10 and during follow-up at 4 to 6 weeks and 12 to 16 weeks after completion of therapy. Detection and quantification of cetuximab was performed with an instrument-based Biacore assay (Biacore, Uppsala, Sweden) with a detection range of 0.04 to 10 nmol/L and a lower limit of quantification of 1.25 nmol/L. Assessments of quality of life using the FACT-H&N (version 4.0) instrument³³ were performed at week 6 and during follow-up at 4 to 6 weeks and 12 to 16 weeks after therapy.

Measurable disease was assessed by comparing bidimensional tumor measurements on pre- and post-treatment imaging studies. Complete response (CR) was defined as complete resolution of all radiographic evidence of tumor. Partial response (PR) was a 50% reduction in the sum of the products bidimensional tumor measurements. Minor response was a 25% to 50% reduction. Stable disease was a less than 25% reduction or increase. New lesions or a 25% increase from nadir size constituted progression of disease. Clinical response was based on the status of assessable disease when bidimensional tumor measurements could not be made. In these cases, CR was defined as the resolution of all clinical evidence of tumor. Improving disease was a 50% or greater shrinkage of the tumor bulk without worsening signs and symptoms of disease. Patients had stable disease if there was a less than 50% reduction in the bulk of assessable lesions. Progressive disease was defined as the unequivocal increase in the size of assessable tumors or the development of new lesions. For patients with measurable and assessable disease, responses were considered confirmed if they were evaluated at 4 to 6 weeks and 12 to 16 weeks after therapy.

Statistical Considerations
This was a single-institution, open-label, single-arm pilot phase II study that was conducted to generate pilot data regarding preliminary efficacy and toxicity of cetuximab in combination with concurrent cisplatin and radiotherapy. All treated patients received the investigational therapy. Planned accrual was 25 assessable patients. Given the preliminary/pilot nature of the study, no early stopping rule was prospectively planned outside of observed toxicity.

The primary end point was response rate (CR or PR), as previously defined. Secondary end points were to assess feasibility/toxicity and to evaluate overall survival, progression-free survival, and quality-of-life outcomes on a preliminary basis.

Survival and response analysis was performed on all treated patients. Survival was estimated by the Kaplan-Meier method,³⁶ with time measured from the first day of treatment. Overall survival was defined as the time from day 1 of treatment to death from any cause. Progression-free survival was defined as the time from day 1 of treatment to either disease progression or death from any cause. Locoregional control was defined as the time from day 1 of treatment to either disease recurrence in the head and neck region or death from any cause other than distant metastasis. Living patients without known disease were censored at last follow-up. Summary statistics for pharmacokinetic and quality-of-life data were determined for each time point of collection and included arithmetic mean, median, standard deviation, minimum, maximum, and percent coefficient of variation.

	RESULTS

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Patient Characteristics
A total of 22 patients were enrolled onto the study from February to November 2000. Table 1 lists the patient characteristics. The median age was 57 years (range, 41 to 72 years). The majority of patients were male (91%), had oropharynx primary tumors (59%), regionally advanced tumors (N2-3, 77%), and stage IV disease (86%). One patient was found to have an ineligible diagnosis (poorly differentiated [undifferentiated] carcinoma) on pretreatment histologic confirmation and was removed from study without receiving protocol therapy. No patients had prior exposure to EGFR-targeted agents.

Toxicities
All 21 patients who received study therapy were assessable for toxicity. All grade 3 or 4 toxicities are listed in Table 2. In general, toxicities were typical of those expected with definitive concurrent cisplatin and delayed, accelerated radiotherapy for head and neck cancer. Common toxicities occurring at least once with grade 3 or 4 severity included mucous membrane toxicity, skin toxicity, nausea/vomiting, metabolic abnormalities, fever, dehydration, and constipation. Excluding the two patients who died during treatment, median percent weight loss during treatment was 7.8% (range, 1.3% to 18.2%). A percutaneous endoscopic gastrostomy tube was placed in 17 (81%) of 21 patients before or during treatment. Of the patients who were alive and disease free at last follow-up, none were percutaneous endoscopic gastrostomy dependent. Overall, 95% of patients experienced at least grade 1 skin toxicity. Although attribution of lower grade skin toxicity within the radiation portal was often unclear because of the concurrent nature of the protocol therapy and the potential for corticosteroids administered for control of emesis to lead to acne, acne-like rash attributed to cetuximab occurred in 12 patients (57%), including two patients (10%) with grade 3 severity. One episode of grade 4 hypersensitivity reaction (5%) was observed.

The investigators, sponsor, and institutional review board carefully reviewed these two grade 5 events and considered both their potential relationship to the investigational regimen and the uncertainty of toxicity attribution as a result of the common medical comorbidity seen with advanced SCCHN. The decision was made to continue study accrual with particular vigilance for further significant toxicity. Ultimately, a series of three nonfatal but significant adverse events occurred in short succession, prompting study closure as a result of patient safety concerns.

Patient 19, a 69-year-old man with diabetes, hypertension, and history of heavy tobacco smoking, had a nonfatal myocardial infarction 1 week after his fifth dose of cetuximab. He recovered uneventfully. Patient 20, a 66-year-old man, was hospitalized after the first week of therapy with cisplatin and cetuximab for Staphylococcus aureus bacteremia related to an implanted central venous access device. He was not neutropenic at the time of the infection and recovered uneventfully after line removal and antibiotic therapy. Finally, patient 21, a 61-year-old man, was hospitalized 3 days after his second dose of cetuximab for fever and rash. During his hospitalization, he developed hypotension as a result of new-onset atrial fibrillation, requiring electrocardioversion. He recovered uneventfully.

Response
Of the 21 patients treated, five patients were not assessable for response. These five patients included the two patients who died during study treatment and the patient with S aureus bacteremia after 1 week of therapy. Two additional patients withdrew consent after one cycle of therapy. The first patient withdrew as a result of concern for back pain, despite a low suspicion of drug-related adverse event by the treating physician. The second patient, who was one of the last patients to be treated, withdrew consent secondary to grade 1 skin rash and fever in the context of prior informed consent regarding deaths on study.

Of the 16 patients assessable for response, 15 had a major response (two CRs and 13 PRs), and one patient had progression of disease, yielding a response rate of 94% (95% CI, 70% to 100%). In five of 13 patients, the PR was considered unconfirmed because only one radiographic evaluation, either at 4 to 6 or 12 to 16 weeks after therapy, was available for response assessment. Of these five patients, three have been continuously disease free from their SCCHN, with follow-up times ranging from 49 to 59 months; one patient died with distant metastases only at 37 months; and one patient died with disease status unknown at 39 months.

Survival
Median follow-up time is 52 months, with all living patients observed for a minimum of 32 months. Of the original 21 patients, 13 were alive with no evidence of disease at last follow-up; one died of unknown cause after having been disease free; and five died after relapse (two locoregional, one distant, and two both). The two remaining patients died on study as previously described.

The 3-year overall survival rate (Fig 1) was 76% (95% CI, 58% to 94%). Median overall survival has not yet been reached. The 3-year progression-free survival rate (Fig 2) and 3-year locoregional control rate (Fig 3) are 56% (95% CI, 35% to 78%) and 71% (95% CI, 52% to 91%), respectively.

View larger version (8K): [in this window] [in a new window]   Fig 1. Overall survival (n = 21).

View larger version (8K): [in this window] [in a new window]   Fig 2. Progression-free survival (n = 21).

View larger version (7K): [in this window] [in a new window]   Fig 3. Locoregional control (n = 21).

View larger version (10K): [in this window] [in a new window]   Fig 4. Cetuximab pharmacokinetics. Tx, therapy.

	DISCUSSION

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Five significant adverse events of unclear attribution in this trial led to early study closure. However, these events have no clearly shared pathophysiology that convincingly implicates the addition of cetuximab as the cause. Because the two deaths were acute and two of the grade 4 events were cardiac (nonfatal myocardial infarction and atrial fibrillation), a review of the cetuximab clinical trial database was conducted to better evaluate the potential for cardiotoxicity as a result of cetuximab. Of the 2,174 patients in this database known to have received cetuximab, only 2.6% experienced a related grade 3 to 4 cardiovascular event, including the patients who experienced events in this study. Moreover, considering the known significant medical comorbidity of the SCCHN population, these adverse events are not clearly attributable to the investigational therapy. Despite this, the uncertain attribution and timing of these significant adverse events early in the trial mandated the early closure of this study for patient safety concerns in the absence of more information. Phase I evaluation of this program was not conducted before the current trial was undertaken, given the established safety of both cetuximab plus cisplatin and cetuximab plus radiotherapy combinations reported in prior phase I clinical trials.^29-31 How to optimally and efficiently develop combinations of new targeted agents and chemoradiotherapy using phase I, early stopping rules or other trial methodologies requires further investigation.

Despite the adverse events observed on this study, the preliminary survival data are encouraging in this predominantly stage IV population, although CIs are wide as a result of the preliminary nature of the study. With a median follow-up time of 52 months, the 3-year overall survival rate was 76%, which is superior to the historical experience at our institution for a predominantly stage IV population receiving cisplatin concurrent with delayed, accelerated radiotherapy for SCCHN.³⁸ Progression-free survival and locoregional control rates were similarly encouraging. These survival data also compare favorably with those reported in the major published randomized trials supporting concurrent chemoradiotherapy.^7-12

Another compelling finding of this investigation is that, although CR is infrequent in this setting when strict radiographic criteria are applied, many patients with PR prove to be disease free in the long term. Thirteen of 16 assessable patients in this study had a radiographic PR, having residual abnormalities on post-treatment scans. Despite this, eight of these 13 patients were alive with no evidence of disease at last follow-up, and only three of these 13 patients have had locoregional failure. These data highlight that progression-free survival and locoregional control rate are preferable end points to response rate in this setting.

For the present, this regimen is not recommended outside the clinical trial setting. Further clarification of its safety profile is needed. In light of the medically comorbid nature of the SCCHN population, however, attributing cause to the pathophysiologically variable constellation of serious adverse events observed is particularly difficult. Better quantification of its efficacy relative to cisplatin and concurrent radiotherapy alone is also needed. However, the preliminary overall survival, progression-free survival, and locoregional control data are promising in this predominantly stage IV population. Furthermore, recent phase III data are consistent with clinical benefit for cetuximab when combined with cisplatin in recurrent/metastatic SCCHN, as well as with radiotherapy in locoregionally advanced disease, supporting the further development of cetuximab as part of this new combined-modality paradigm.^39,40

	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.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other David G. Pfister ImClone (C) Michael N. Needle ImClone (N/R) ImClone (C) ImClone (C) ImClone (N/R) Michael J. Zelefsky InClone (C)

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

	Author Contributions

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Conception and design: David G. Pfister, Dennis H. Kraus, Suzanne L. Wolden, Eric Lis, Ashok R. Shaha, Jatin P. Shah, Michael J. Zelefsky Financial support: Michael N. Needle Administrative support: David G. Pfister, Simone Lake, Michael N. Needle, Michael J. Zelefsky Provision of study materials or patients: David G. Pfister, Dennis H. Kraus, Suzanne L. Wolden, Ashok R. Shaha, Jatin P. Shah, Michael J. Zelefsky Collection and assembly of data: David G. Pfister, Yungpo Bernard Su, Eric Lis, Timothy B. Aliff, Andrew J. Zahalsky, Simone Lake, Michael N. Needle, Michael J. Zelefsky Data analysis and interpretation: David G. Pfister, Yungpo Bernard Su, Eric Lis, Timothy B. Aliff, Andrew J. Zahalsky, Michael J. Zelefsky Manuscript writing: David G. Pfister, Yungpo Bernard Su, Timothy B. Aliff, Michael J. Zelefsky Final approval of manuscript: David G. Pfister, Yungpo Bernard Su, Dennis H. Kraus, Suzanne L. Wolden, Eric Lis, Timothy B. Aliff, Andrew J. Zahalsky, Simone Lake, Michael N. Needle, Ashok R. Shaha, Jatin P. Shah, Michael J. Zelefsky

 

	NOTES

 
Supported by ImClone Systems Incorporated, Branchburg, NJ.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003; and 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.

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Submitted September 30, 2004; accepted November 22, 2005.

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