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Phase II Trial of Chemoradiation for Organ Preservation in Resectable Stage III or IV Squamous Cell Carcinomas of the Larynx or Oropharynx: Results of Eastern Cooperative Oncology Group Study E2399

Anthony J. Cmelak, Sigui Li, Meredith A. Goldwasser, Barbara Murphy, Michael Cannon, Harlan Pinto, David I. Rosenthal, Maura Gillison, Arlene A. Forastiere

From the Vanderbilt University Medical Center, Nashville, TN; Dana Farber Cancer Institute, Boston, MA; Cancer Center of Kansas, Wichita, KS; University Medical Center, Stanford, CA; University of Pennsylvania, Philadelphia, PA; and Johns Hopkins University, Baltimore, MD

Address reprint requests to Anthony J. Cmelak, MD, B-902 TVC, 22nd Avenue at Pierce, Vanderbilt Medical Center, Nashville, TN 37232-5671; e-mail: Anthony.cmelak{at}vanderbilt.edu

	ABSTRACT

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Purpose Taxane-based concurrent chemoradiotherapy (CCR) for head and neck cancers has proven to have a favorable toxicity profile compared with cisplatin and radiation. This phase II multi-institutional trial evaluates taxane-based induction chemotherapy followed by CCR for organ preservation in resectable stage III/IVA and IVB larynx and oropharynx (OP) cancer patients.

Patients and Methods Eligibility required resectable stage T2N+, or T3-T4N0-3M0 biopsy-proven squamous carcinoma, age at least 18 years, PS 0 to 2, good organ function, and no prior chemotherapy or radiation. Treatment was induction paclitaxel 175 mg/m² and carboplatin area under the concentration-time curve (AUC) 6 for two cycles every 21 days followed by concurrent paclitaxel 30 mg/m² every 7 days with 70 Gy if no evidence of tumor progression. Weekly erythropoietin alpha 40 kU was used for suboptimal hemoglobin (< 14 gm/dL men, < 13 gm/dL women). The primary end point was organ preservation (freedom from primary site salvage surgery or primary tumor recurrence).

Results One hundred five of 111 patients (36 larynx, 69 OP) were eligible. Median follow-up was 36.7 months. Ninety-four percent received full-dose radiotherapy and 91% received at least five cycles of concurrent paclitaxel. No patient progressed while receiving chemotherapy. Organ preservation was 81% at 2 years after completion of therapy (larynx 74%, OP 84%). Thirteen patients required primary-site salvage surgery (seven larynx, six OP), and six of these have progressed and died (three larynx, three OP). Thirteen patients developed distant metastases (seven larynx, six OP; P = .02) and 10 of 36 larynx and 11 of 69 OP patients have died as a result of their disease. Two-year survival is 76% (63% larynx v 83% OP).

Conclusion A high organ preservation rate was obtained with this regimen for OP but not for larynx patients. Toxicity was low, and induction chemotherapy did not preclude delivery of concurrent chemoradiotherapy.

	INTRODUCTION

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The combination of cisplatin and fluorouracil for head and neck cancer (HNC) has been used extensively in both the induction and metastatic settings. Unfortunately, it is associated with significant toxicity. A phase II trial of a less toxic regimen was reported by Dang et al.¹ They tested three cycles of induction paclitaxel 175 mg/m² and carboplatin area under the concentration-time curve 6 to 7.5 for organ preservation in locally advanced patients. Toxicity was acceptable, and the response rate was impressive. Three of 23 patients developed grade 4 or worse toxicity (neutropenia). A 52% complete response rate and 43% partial response rate (95% overall response, 5% stable disease) were demonstrated. Cmelak et al² showed a platinum- and paclitaxel-based induction and concurrent regimen produced an 83% 2-year organ preservation rate with acceptable toxicity in larynx and OP patients. Others have reported similar results using taxane-based regimens.^3,4

Chemotherapy administered concomitantly with radiation provides a survival advantage as well as a significantly increased rate of organ preservation when compared with radiation alone.⁵ As local control rates improve, however, distant metastases are a relatively more common failure pattern. A number of controlled trials have shown that induction chemotherapy can decrease distant failure, leading to a resurgence of interest in induction followed by concurrent chemoradiotherapy.

Radiation plus high-dose cisplatin every 3 weeks remains the most common regimen in US Cooperative Group clinical trials. However, this regimen is associated with substantial toxicity such that, at most, 70% of patients are able to receive all three planned cisplatin doses. Weekly chemotherapy has been of interest for its improved tolerability and a potential radiosensitizing benefit from more frequent dosing. Paclitaxel, a potent radiation sensitizer, can be administered weekly during radiation with a maximum tolerated dose of 30 to 40 mg/m².⁶

Retrospective studies confirm the predictive value of hemoglobin level on treatment outcome in HNC.⁷ Transfusions, and more recently erythropoietic agents, have proven effective at maintaining hemoglobin during chemotherapy and HNC radiation.⁸

This study evaluates a taxane/platinum induction regimen followed by paclitaxel concurrently with radiation in patients with locally advanced, surgically resectable American Joint Committee on Cancer (AJCC) stage III or IVA squamous cancers of the larynx and oropharynx. It is a phase II multi-institutional trial conducted within the Eastern Cooperative Oncology Group (E2399). Primary site preservation and toxicity are the primary end points. Secondary end points are assessments of speech and swallowing function, and quality of life.

	PATIENTS AND METHODS

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Design and Patients
Eligibility included biopsy-proven squamous cell carcinoma, age at least 18 years, performance status of 0 to 2, adequate organ function, no prior chemotherapy nor radiation above the clavicles, and resectable disease (T2N1-3, or T3-T4N0-3M0), defined as having a high chance of obtaining a clear surgical margin. Patients with tumor involving the cervical spine, pterygoids, anterior soft tissues of the neck, or fixation to carotid artery were ineligible. Institutional review board–approved informed consent was required. Baseline tumor measurements were required within 4 weeks before registration as measured by computed tomography (CT) and direct endoscopy. Exclusion criteria included evidence of other synchronous neoplasms, surgery other than biopsy or debulking, or evidence of distant metastatic disease.

Treatment
Induction chemotherapy. Induction chemotherapy consisted of two cycles of paclitaxel 175 mg/m² administered over 3 hours followed by carboplatin area under the concentration-time curve 6 administered over 30 to 60 minutes, repeated on day 22. If the absolute neutrophil count (ANC) was less than 1,200/mm³ or platelets were less than 100,000/mm³ on day 22, treatment was held until counts returned to this level. Dose reductions for cycle 2 were made for grade 3 and 4 toxicity. If the second cycle was held more than 3 weeks, patients proceeded to tumor response evaluation by repeat endoscopy. Erythropoietin alpha (40,000 units weekly) was instituted if hemoglobin level dropped to 15 gm/dL or lower for men or 14 gm/dL or lower for women.

Concurrent chemoradiotherapy. Patients with partial or complete response at the primary site after induction chemotherapy went on to concurrent chemoradiotherapy with paclitaxel 30 mg/m² intravenously (IV) administered over 60 minutes with radiation 70 Gy/35 fractions/7 weeks. Patients with progressive or stable disease at the primary site were referred for surgical resection. However, patients who refused surgery were allowed to proceed with concurrent chemoradiotherapy. Concurrent paclitaxel was withheld for ANC lower than 1,200 mm³, grade 4 mucositis, or grade 4 dermatitis.

Radiation was delivered using two- or three-dimensional technique. Treatment to the gross disease was administered at 2 Gy/fraction to 70 Gy, once each day, five days a week. The initial target volume included the primary tumor and involved nodes with a 3.0-cm margin to 50 Gy. Fields were then reduced to a 2.0-cm margin to 60 Gy, followed by a final field reduction using a 1-cm margin to 70 Gy. The maximal dose permitted to the spinal cord was 45 Gy.

Surgery
Surgical salvage at the primary site was required for all patients experiencing tumor progression at any time. All patients with initial N3 disease required a postradiation neck dissection, as did any patients with N1 or N2 disease not obtaining a complete tumor response by 2 to 3 months after treatment.

Correlative Studies
Patient-reported outcomes. The quality of life and symptoms were evaluated at baseline, after induction chemotherapy, and at 3, 12, and 24 months post-treatment using the Functional Assessment of Cancer Therapy (FACT)-G (version 4) with HN subscale and the PSS-HN.^9-11 Objective speech and swallowing assessments were obtained at the same time points using a modified barium swallow, scored using the Dysphagia Outcome Severity Scale (DOSS)¹² and the Functional Communication Measure (FCM).¹³ Speech function was evaluated by the Voice Handicap Index,¹⁴ which is a 30-question patient self-assessment instrument of global speech function, evaluating the patient's physical, emotional, and functional perceptions of voice. Objective measure of voice utility was reported by the treating physician using the Voice Desirability Index,¹⁵ using a linear scale from 0 ("aphonic") to 50 ("perfect voice").

Human papillomavirus. Correlation of treatment response and outcome with presence of human papillomavirus (HPV) was evaluated. Method and results will be presented separately by Fakhry et al.

Statistical Design and Analysis
The organ preservation rate is defined as freedom from either local recurrence or need for salvage surgery at the primary site. With 50 eligible patients from larynx and OP subsites having a projected 75% organ preservation rate, the 90% CI would be 64.02% to 85.53%. For any calculated preservation rate, the maximum CI width would be 0.248. Achieving 75% organ preservation would have allowed consideration for further testing of the regimen in a phase III setting. A total of 110 patients total were needed to account for an expected 10% ineligibility rate. Local, regional, and distant failure rates were assessed using a cumulative incidence estimation method accounting for competing risks.¹⁶ Overall survival (OS) was defined as the time from the date of registration to date of death, censored at the date last known alive. Progression-free survival (PFS) is defined as time from registration to tumor recurrence or salvage surgery for recurrent or persistent disease at any site; patients who died without documented recurrence were excluded at the date of death. Toxicity was graded using National Cancer Institute Common Toxicity Criteria version 2.0. Clinically significant toxicity was defined as any grade 3 or 4 toxicity probably or definitely attributable to therapy.

	RESULTS

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Patient Characteristics
One hundred eleven patients were accrued between March 16, 2001, and May 11, 2004. One hundred five patients were eligible for inclusion in the toxicity and treatment analysis, including 36 larynx patients and 69 OP patients from 16 institutions. Ineligible patients included two with synchronous cancers, one with lab abnormalities, one improperly registered, one missing baseline tumor measurement, and one nasopharynx primary. Patient characteristics are shown in Table 1. Median follow-up is 36.7 months (range, 11.8 to 47.4 months for surviving patients).

Tumor Control and Patterns of Failure
To date, 27 patients have progressed including 15 (22%) of 69 OP patients: six patients at the primary site, three in regional nodes, four with distant metastases, one at both the primary site and regional nodes, and one at primary site, regional nodes, and distant sites. Twelve (33%) of 36 larynx patients have progressed: one at the primary site, one in regional nodes, seven with distant metastases, two at both the primary site and regional nodes, and one with primary site, regional nodes, and distant metastases.

The 2-year organ preservation rate for all patients is 81%. The local failure rate at 2 years was 25% for larynx and 16% for OP. There was no statistical difference between larynx and OP patients in time to local failure (P = .30; Fig 1A) and no difference in local failure or survival whether or not patients received erythropoietin (P = .82). For all patients, the 2-year distant failure rate was 9.6% (20% larynx, 4% OP; P = .02; Fig 1B).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Time to (A) local and (B) distant failure by primary site.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Progression-free and (B) overall survival by primary site.

Surgical Salvage
Surgical salvage rates, including neck dissections and salvage surgery at the primary site, are included in Table 4. Thirteen patients (14%) required surgical salvage at the primary tumor site (seven larynx, 19%; six OP, 9%). Neck dissections were performed in 30 patients (29%), including five larynx and six OP patients who had them performed simultaneously with salvage resections of the primary tumor. The need for neck dissection after chemoradiotherapy, therefore, was low if the primary tumor was controlled (two larynx, 5%; three OP, 4%).

Tissue Procurement and Correlative Studies
The presence of HPV status was determined on a subset (96 of 105 patients) of the study population. HPV presence correlated with improved response and survival (P = .005). Detailed information on this is presented in an article by Fakhry et al (submitted for publication).

Speech and Swallowing Function
The number of assessable DOSS and FCM swallowing assessments at each time point included 45 of 84 patients at baseline, 14 of 60 at 3 months, four of 34 at 12 months, and one of 22 at 24 months. As measured by both the DOSS and FCM, the majority of patients had normal or minimal swallow deficits at baseline. At 3 months after chemoradiotherapy, swallowing was markedly impaired in 21% of larynx and 17% of OP patients, or moderately impaired in 16% of larynx and 32% of OP patients. By 12 months, swallowing had improved for most patients, with severe swallowing abnormalities found in less than 10% of patients at 12 and 24 months. Patient-perceived swallowing correlated well with objective swallowing measures. Three percent of patients continued to require PEG after 12 months. The quality-of-life and speech and swallowing results will be reported in detail at a later date.

	DISCUSSION

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We conclude that this regimen is feasible to deliver with acceptable acute toxicity, and that this taxane based induction chemotherapy regimen does not preclude administration of subsequent chemoradiotherapy. This corroborates single-institution reports from which this trial was based.^2-4 Dose delivery of both chemotherapy and radiation was very good, and 2-year organ preservation rate was 81%. Long-term PEG dependence was 3%. The 2-year survival for patients with OP tumors was in line with other recent phase II trials sequencing induction chemotherapy and chemoradiotherapy.¹⁷ Treatment outcomes for larynx patients, however, were disappointing; they had a trend toward higher distant metastatic failure (20%), lower major response to induction chemotherapy (50%), and lower 2-year PFS (50%) for unclear reasons. Toxicity rates between larynx and OP patients were comparable. The larynx preservation rate is difficult to compare to the 88% reported in the Intergroup R9111 trial for patients receiving concurrent high-dose cisplatin during radiation, which defined larynx preservation as only those patients who had undergone laryngectomy (not all local failures). The 20% distant failure rate in our larynx patients at 2 years also suggests that only two cycles of induction paclitaxel and carboplatin was insufficient to significantly influence this failure pattern. Indirect comparisons of our 81% organ preservation rate and 9.6% distant failure rate with Radiation Therapy Oncology Group (RTOG) trial 9914 results using concomitant-boost radiation with cisplatin suggest comparable or improved efficacy compared with its reported 3-year locoregional control of 61%, distant failure of 23%, and 2-year survival of 72%. We noted fever toxicities in comparison, particularly grade 5 (4%), long-term grade 3 or higher adverse effects (51%), and PEG dependency at 1 year (33%) seen in RTOG 9914.¹⁸ There are currently no plans, however, to compare these two regimens in a randomized setting.

Many questions remain for future head and neck clinical trials. Does induction response provide useful information about inherent tumor radiosensitivity in an era when chemotherapy is now administered concurrently with radiation? Can survival be improved by combining induction chemotherapy to reduce distant failure with concurrent chemoradiotherapy, which has shown to substantially improve locoregional control and organ preservation rates? Will an aggressive induction chemotherapy regimen preclude administration of full doses of concurrent chemotherapy or limit radiation tolerability? Studies show differing results.^19,20 Three or four cycles of induction chemotherapy appear optimal for maximizing the tumor response rate, but toxicity is cumulative. Randomized studies now show that adding a taxane to a cisplatin/fluorouracil induction regimen can improve both response rate and overall survival in patients with advanced disease when compared with the standard cisplatin/fluorouracil induction regimen.^21-24 However, we do not know the relative contribution of the induction triplet to concurrent chemoradiotherapy. Randomized trials attempt to answer this question, but typically utilize less aggressive chemotherapy during radiation. Lastly, the appropriate patient population to administer these aggressive induction regimens has yet to be well characterized.

Like cisplatin, carboplatin is active in squamous cell carcinomas of the head and neck region^25-27 and has radiation-sensitizing properties.²⁸ We chose to utilize carboplatin in the induction regimen because of its ease of administration, improved toxicity profile, high rates of dose delivery, and prior results showing excellent response rates with paclitaxel for three cycles every 21 days in the induction setting.² We also chose to use induction chemotherapy as a predictor of response to subsequent chemoradiotherapy, rather than as a means to significantly reduce distant metastases or improve survival. Therefore, we used only two cycles of induction chemotherapy before response evaluation, as had been done in previous organ preservation trials.^15,16 Our results with OP patients appear comparable to if not better than previous studies using concurrent cisplatin-based regimens. Currently, we do not advocate the use of concurrent erythropoietin in patients outside accepted practice guidelines for anemic patients. The role of growth factors to maintain hemoglobin levels within normal range is under debate. Retrospective studies indicated that hemoglobin level was correlated with improved tumor control and survival.²⁹ At the time of designing our study, it was observed that the utilization of erythropoietin alpha could help prevent the need for transfusions because of combined-modality therapy.³⁰ In addition, maintaining adequate tumor oxygenation during radiation is required for optimal local control.³¹ Erythropoietin has been shown to provide radiosensitivity independent of its effect of hemoglobin.³² We did not observe a significant number of thrombovascular events, and whether our use of erythropoietin provided tumor protection in our larynx patients is unknown. There was no difference in outcome between patients who did or did not received erythropoietin, but the theoretical concern about tumor protection using this cytokine is justified.³³ Henke et al³⁴ review patients treated with erythropoietin during radiation and found a significantly lower tumor control rate if a patient's tumor expressed erythropoietin receptors.

An encouraging result of the study was the ability to perform standard speech and swallowing assessments via formal instruments in a multi-institutional setting as an adjunct to standard quality-of-life questionnaires. Patient-reported outcome instruments correlated well with modified barium swallow measurements; therefore, it is reasonable to consider excluding more costly and time-consuming instruments in future clinical trials.

	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: N/A Stock: N/A Honoraria: Anthony J. Cmelak, Bristol-Myers-Squibb, Ortho Biotech Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Anthony J. Cmelak, Sigui Li, Meredith A. Goldwasser, Barbara Murphy, Harlan Pinto, David I. Rosenthal, Maura Gillison, Arlene A. Forastiere

Administrative support: Sigui Li, Meredith A. Goldwasser, Barbara Murphy, Maura Gillison, Arlene A. Forastiere

Provision of study materials or patients: Anthony J. Cmelak, Meredith A. Goldwasser, Barbara Murphy, Michael Cannon, Harlan Pinto, David I. Rosenthal, Maura Gillison

Collection and assembly of data: Anthony J. Cmelak, Sigui Li, Meredith A. Goldwasser, Barbara Murphy

Data analysis and interpretation: Anthony J. Cmelak, Sigui Li, Meredith A. Goldwasser, Barbara Murphy, David I. Rosenthal, Arlene A. Forastiere

Manuscript writing: Anthony J. Cmelak, Sigui Li, Meredith A. Goldwasser, Barbara Murphy, Harlan Pinto, David I. Rosenthal, Maura Gillison, Arlene A. Forastiere

Final approval of manuscript: Anthony J. Cmelak, Sigui Li, Meredith A. Goldwasser, Barbara Murphy, Michael Cannon, Harlan Pinto, David I. Rosenthal, Maura Gillison, Arlene A. Forastiere

	ACKNOWLEDGMENTS

	NOTES

 
Supported in part by a research grant from Bristol-Myers-Squibb.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

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

	REFERENCES

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Submitted January 24, 2007; accepted May 9, 2007.

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