Clinical Investigation
Phase 2 Study of Docetaxel, Cisplatin, and Concurrent Radiation for Technically Resectable Stage III-IV Squamous Cell Carcinoma of the Head and Neck

https://doi.org/10.1016/j.ijrobp.2014.12.032Get rights and content

Purpose

We investigated the efficacy and safety of weekly low-dose docetaxel and cisplatin therapy concurrent with conventionally fractionated radiation in patients with technically resectable stage III-IV squamous cell carcinoma of the head and neck.

Methods and Materials

Between March 2004 and October 2011, we enrolled 117 patients, of whom 116 were analyzable (43 had oropharyngeal cancer, 54 had hypopharyngeal cancer, and 19 had laryngeal cancer), and 85 (73%) had stage IV disease. Radiation consisted of 66 Gy in 33 fractions. Docetaxel, 10 mg/m2, followed by cisplatin, 20 mg/m2, administered on the same day were given once a week for 6 cycles. The primary endpoint was overall complete response (CR) rate after chemoradiation therapy. Human papillomavirus (HPV) DNA in oropharyngeal cancer was examined by PCR.

Results

Of 116 patients, 82 (71%) completed treatment per protocol; 102 (88%) received the full radiation therapy dose; and 90 (78%) and 12 (10%) patients received 6 and 5 chemotherapy cycles, respectively. Overall CR rate was 71%. After median follow-up of 50.9 months (range: 15.6-113.9 months for surviving patients), 2-year and 4-year overall survival rates were 82% and 68%, respectively. Cumulative 2-year and 4-year local failure rates were 27% and 28%, respectively, whereas distant metastasis rates were 15% and 22%, respectively. HPV status in oropharyngeal cancer was not associated with treatment efficacy. Acute toxicity included grade 3 and 4 in-field mucositis in 73% and 5% of patients, respectively, whereas myelosuppression and renal injury were minimal. No patients died of toxicity. Feeding tube dependence in 8% and tracheostomy in 1% of patients were evident at 2 years postchemoradiation therapy in patients who survived without local treatment failure.

Conclusions

Local control and survival with this regimen were satisfactory. Although acute toxicity, such as mucositis, was common, late toxicity, such as laryngoesophageal dysfunction, was minimal. Therapy using weekly low-dose docetaxel and cisplatin concurrent with radiation warrants further evaluation.

Introduction

The contemporary organ-preserving treatment for locally advanced head and neck squamous cell carcinoma (HNSCC) is concurrent chemoradiation therapy (CRT) (1), with high-dose cisplatin (CDDP) and radiation as the standard regimen (2). Adding concurrent high-dose CDDP to radiation improves overall survival (OS) over radiation therapy alone, whereas this regimen increases both acute toxicity, including myelosuppression, renal injury, and vomiting, and severe late toxicity such as dysphagia (3), which compromise patients' quality of life. An optimal concurrent regimen with lower mortality and morbidity than high-dose CDDP is needed.

As docetaxel (DTX) serves as a radiosensitizer (4) and enhances cytotoxicity of CDDP by modifying intracellular platinum metabolism (5), DTX and CDDP in combination (DTX/CDDP) would be expected to synergistically affect concurrent radiation therapy. We conducted a phase 1 study of weekly administration of low-dose DTX/CDDP concurrent with conventionally fractionated radiation therapy (6). Hematologic toxicity, except for lymphocytopenia, renal injury, and vomiting, was minimal, but in-field mucositis was common and dose-limiting. We established 10 mg/m2 as the recommended dose for DTX and 20 mg/m2 for CDDP and proceeded to phase 2 study. Here, we report long-term results of this phase 2 study.

Section snippets

Patients

We recruited patients with previously untreated, measureable, nonmetastatic, histologically proven, technically resectable stage III or IV HNSCC, 20 to 75 years of age, with Eastern Cooperative Oncology Group performance status 0 to 1 and adequate bone marrow, liver, and renal function. We excluded those patients with T1N1 disease, previous radiation therapy above the clavicles, cancer diagnoses within the previous 2 years, excluding superficial disease, or another active cancer. The initial

Patient characteristics and treatment adherence

We enrolled 117 patients from March 29, 2004, to October 19, 2011, 116 of whom were analyzable (43 with oropharyngeal cancer, 54 with hypopharyngeal cancer, and 19 with laryngeal cancer) and 85 (73%) of whom had stage IV disease. One patient was excluded from analysis owing to protocol violation. Patient characteristics are shown in Table 1, and tumor-versus-node stage is shown in supplemental Table E1; available online at www.redjournal.com.

Of 116 patients, 82 (71%) completed treatment per

Discussion

The primary objective of this phase 2 trial was to determine whether overall CR rate would exceed 65%. We obtained an overall CR rate of 71%, with acceptable toxicity, and 2- and 4-year OS rates of 82% and 68%, respectively. Another series of phase 2 trials addressed the efficacy of taxane plus platin-based concurrent CRT. Tsao et al (12) used DTX, 15 mg/m2, and CDDP, 20 mg/m2 weekly, during weeks 1 to 4 with concomitant boost radiation of 72 Gy, which yielded 53% overall CR and 65% 2-year OS

Conclusions

In conclusion, weekly low-dose DTX/CDDP concurrent with standard fractionation radiation therapy for technically resectable stage III-IV HNSCC led to high local control and survival. Acute toxicity, such as mucositis, was common, but late toxicity, such as dysphagia, was uncommon. This regimen might be superior to high-dose CDDP regimen in terms of efficacy and/or toxicity. A randomized phase 3 study to address this issue is currently under consideration.

References (20)

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Conflict of interest: none.

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