Clinical Investigation
Long-Term Outcomes and Toxicity of Concurrent Paclitaxel and Radiotherapy for Locally Advanced Head-and-Neck Cancer

https://doi.org/10.1016/j.ijrobp.2008.09.053Get rights and content

Purpose

To report the long-term outcomes and toxicity of a regimen of infusion paclitaxel delivered concurrently with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck.

Patients and Methods

Between 1995 and 1999, 35 patients with nonmetastatic, Stage III or IV squamous cell carcinoma of the head and neck were treated with three cycles of paclitaxel as a 120-h continuous infusion beginning on Days 1, 21, and 42, concurrent with radiotherapy. The initial 16 patients received 105 mg/m2/cycle, and the subsequent 19 patients received 120 mg/m2/cycle. External beam radiotherapy was delivered to a dose of 70.2–72 Gy at five fractions weekly. Patients were followed to evaluate the disease outcomes and late toxicity of this regimen.

Results

The median follow-up for all patients was 56.5 months. The median survival was 56.5 months, and the median time to local recurrence was not reached. Of the 35 patients, 15 (43%) developed hypothyroidism. Of the 33 patients who underwent percutaneous endoscopic gastrostomy tube placement, 11 were percutaneous endoscopic gastrostomy tube dependent until death or their last follow-up visit. Also, 5 patients (14%) required a tracheostomy until death, and 3 (9%) developed a severe esophageal stricture. All evaluated long-term survivors exhibited salivary hypofunction. Fibrosis in the radiation field occurred in 24 patients (69%).

Conclusion

The results of our study have shown that concurrent chemoradiotherapy with a 120-h infusion of paclitaxel provides long-term local control and survival in patients with squamous cell carcinoma of the head and neck. Xerostomia, hypothyroidism, esophageal and pharyngeal complications, and subcutaneous fibrosis were common long-term toxicities; however, the vast majority of toxicities were grade 1 or 2.

Introduction

Therapy for locally advanced squamous cell carcinoma of the head and neck (SCCHN) has the major goals of eradicating locoregional disease, treating distant micrometastases, preserving organ function, and minimizing toxicities. Because of the aggressive nature of SCCHN, and the consequences of local failure, intensive treatment regimens have become standard. Prospective trials evaluating concurrent platinum-based chemoradiotherapy regimens have demonstrated improved disease control rates compared with those obtained using radiotherapy (RT) alone, with the cost of increased high-grade mucositis, weight loss, and hematologic toxicity 1, 2, 3.

In an attempt to improve the outcomes and identify agents lacking the renal toxicity of cisplatin, a variety of radiosensitizing chemotherapy regimens have been delivered concurrently with RT in patients with SCCHN. Paclitaxel was shown to be a radiosensitizer for human squamous cell cancer in preclinical studies. This led to the evaluation of concurrent RT and paclitaxel, either alone or with other chemotherapeutic agents, for the treatment of SCCHN 4, 5, 6, 7, 8, 9, 10, 11, 12. Although the acute toxicities of these regimens are well-described, the long-term disease outcomes and late toxicities have often not been reported owing to the challenges of patient attrition and long-term data collection.

Combined modality regimens are now the standard of care for cancers at a number of anatomic sites, and it remains critically important to evaluate and report the long-term outcomes. Late toxicity from chemoradiotherapy can take months to years to develop, requiring long-term follow-up to adequately describe the late toxicities in survivors. As regimens become increasingly efficacious, the number of patients surviving with toxicities will increase.

In 1995, a prospective study of concurrent infusion paclitaxel and RT for SCCHN was initiated at the intramural program of the National Cancer Institute. The objectives of this study were to assess the feasibility of concurrent treatment with RT and a 120-h infusion of paclitaxel; to assess patients' speech and swallowing after treatment; and to evaluate the pretreatment predictors of outcome. The response rates, local control rates, and pharmacokinetic data obtained in this trial have been previously reported (13). In the present study, we report on the long-term disease control rates and late toxicity associated with this regimen.

Section snippets

Patient eligibility

All patients were enrolled in an institutional review board–approved protocol at the National Cancer Institute and provided informed consent. Eligible patients had biopsy-proven Stage III or IV SCCHN without distant metastasis (American Joint Committee on Cancer, 4th edition staging system) and were either ineligible for curative resection or had refused surgery. Additional eligibility criteria included Eastern Cooperative Oncology Group performance status of ≤2, age of ≥18 years, absolute

Patient characteristics and treatment

A full description of the adherence to the protocol therapy and the toxicity of the regimen were reported at a point at which 2 of the 35 patients had yet to reach an evaluable point of follow-up (13). For this reason, they were not included in the original report but were included in the present analysis. The characteristics of the study population are summarized in Table 1. The median age of the enrolled patients was 55 years (range, 25–78). Most patients were male, with a history of smoking

Discussion

Long-term follow-up of the survivors of chemoradiotherapy regimens has revealed the effect of toxicity on patient's quality of life 19, 20 and function 21, 22. We studied a regimen of infusion paclitaxel combined with conventionally fractionated RT to test the hypothesis that this combination could provide a mechanism for improving the disease outcomes. Paclitaxel has now been delivered concurrently with RT for patients with head-and-neck cancer in a variety of schedules alone and combined with

Conclusion

The results of this study have shown that concurrent RT and paclitaxel delivered as a 120-h infusion provides durable local control and survival at rates similar to those of platinum-containing regimens. The late toxicities from this regimen were typical for those seen in the head-and-neck cancer population undergoing chemoradiotherapy and included xerostomia, hypothyroidism, and swallowing dysfunction. Late skin effects and subcutaneous fibrosis were pronounced with this regimen.

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    Supported by the Intramural Research Program of the National Institutes of Health, Bethesda, MD.

    Presented in part at the American Society for Therapeutic Radiology and Oncology 2007 Meeting.

    Conflict of interest: none.

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