Dose Dense Weekly Carboplatin-Paclitaxel Prior to Concurrent Chemoradiotherapy for Locally Advanced Head and Neck Cancer

Abstract & Commentary

By William B. Ershler, MD

Synopsis: With more effective local therapy achieved by concurrent chemoradiotherapy for patients with advanced squamous cell carcinoma of the head and neck, the occurrence of distant relapse is becoming increasingly observed. In a Phase 2 study, six weekly doses of carboplatin and paclitaxel prior to concurrent chemoradiotherapy resulted in comparable local control and fewer distant relapses when compared to prior studies from this group. The role for induction chemotherapy and the agents selected remains to be established.

Source: Ready NE, et al. Weekly paclitaxel and carboplatin induction chemotherapy followed by concurrent chemotherapy in locally advanced squamous cell carcinoma of the head and neck. Am J Clin Oncol 2012;35:6-12.

Concurrent radiation with platinum-based chemotherapy as initial therapy for locally advanced squamous cell cancer of the head and neck region has resulted in improved local control and overall survival when compared to radiation therapy alone.1,2 Approximately 20% of patients treated in this manner recur with metastases at distant sites.3 The current trial was designed to test the hypothesis that a short course of systemic chemotherapy prior to combined chemoradiotherapy (CRT) would result in a lower incidence of distant metastatic disease. The study (HN-79) was conducted at multiple participating centers coordinated by the Brown University Oncology Group (BrUOG).

Thirty-five patients received six weekly doses of carboplatin (area under the curve = 2) and paclitaxel (135mg/m2) followed 2 weeks thereafter by concurrent weekly paclitaxel (40 mg/m2) and carboplatin (area under the curve = 1) and daily radiation (66-72 Gy). The initial treatment volume included the gross disease with a margin of 2 cm and potential sites of tumor extension and regional lymph nodes to a dose of 4500 cGy at 180 cGy fractions with parallel opposed lateral fields. The boost volume included tumor plus 2 cm margin or the anatomic compartment (e.g., larynx, nasopharynx, etc.) as necessary. A second cone down or boost was recommended when possible after tumor dose of 5940 cGy to allow normal tissue sparing. A single anterior neck field was used to treat the supraclavicular lymph nodes to a depth of 3 cm. Electron beam was used to treat neck nodes when deemed appropriate. Maximal dose to the spinal cord at any given point was 4500 cGy.

During the initial induction chemotherapy, the most common grade 3 or 4 toxicities were neutropenia without fever (26%), mucositis (17%), dysphagia (17%), dermatologic (9%), and neuropathy (6%). The dysphagia usually was present at diagnosis and tumor related. During combined chemoradiotherapy (CRT), the most common grade 3 or 4 toxicities were mucositis (50%), dysphagia (32%), dermatologic (18%), neutropenia without fever (12%), and dehydration (6%). One patient died from neutropenic sepsis and a second experienced sudden death during CRT without any hematologic or other toxicities > grade 2. This 50-year-old patient had comorbid illnesses that included diabetes, sleep apnea, and significant obesity.

The overall response rate with induction was 79%. With more than 40 months of follow-up, the 36-month overall survival was 67% and loss of life for causes directly related to squamous cell carcinoma of the head and neck was 16% (i.e., head/ neck cancer-specific survival was 84%). The locoregional relapse rate was 40% at 36 months and distant relapse rate was 8% at 28 months.

Commentary

With more effective local treatment, it comes as no surprise that distant relapses are increasingly observed. Thus, developing comprehensive treatment strategies not unlike the application of neoadjuvant chemotherapy for patients with breast and colorectal cancer is a worthy consideration. For patients with locally advanced head and neck cancer, there is this sense of urgency about achieving local control and the "dose dense" induction chemotherapy, such as this developed by the BrUOG, seems to be a reasonable and effective approach. Reasonable in that CRT was only delayed 8 weeks and effective in that distant relapses were detected in only 8% at 28 months. This rate of distant recurrence is comparably less than both their own and other trials, in which CRT was initial therapy and distant metastases developed in 20% or more. Of course, to be sure, a randomized, controlled clinical trial would be needed to answer the question. To this end, ongoing Phase 3 trials in which induction chemotherapy (with docetaxel, cipslatin, and 5-fluorouracil [TPF] followed by CRT vs CRT alone) are underway, and others recently have been published in which various induction chemotherapies are being tested.4,5

The current study included patients enrolled more than a decade ago and although the chemotherapy used and "dose dense" scheduling remain appropriate, the use of more modern intensity-modulated radiotherapy may influence clinical outcomes in a more favorable way and the role for molecular targeting agents, such as cetuximab, needs to be established in the context of both induction and concurrent therapy.

References

1. Adelstein DJ, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92-98.

2. Brizel DM, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998;338:1798-1804.

3. Garden AS, et al. Preliminary results of Radiation Therapy Oncology Group 97-03: A randomized Phase 2 trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck. J Clin Oncol 2004;22:2856-2864.

4. Lorch JH, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: Long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011;12:153-159.

5. Posner MR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-1715.