Abstract
Background
The objective was to study the results of induction chemotherapy followed by external beam radiation therapy with concurrent cetuximab in the treatment of locally advanced head and neck cancer.
Methods
Seventeen patients with stage III or IV squamous cell carcinomas of the head and neck who received docetaxel, cisplatinum, and 5-fluorouracil followed by radiation therapy with concurrent cetuximab were retrospectively analyzed. All radiation was delivered with image-guided intensity-modulated radiation treatments. Primary end points analyzed were local control and overall survival.
Results
With a median follow-up of 17 months, the approximate 2-year local control was 85%, with overall survival being 91%. At time of last follow-up, only 1 death was observed, with the cause of death unknown. Two local failures were observed, and the patients were under active management for their recurrences at time of last follow-up. No distant metastatic failures were noted among the patients.
Conclusions
Induction chemotherapy with docetaxel, cisplatinum, and 5-fluorouracil followed by concurrent radiation with cetuximab provides for excellent locoregional control of disease. Future prospective studies can better establish the efficacy of this treatment regimen to current favored protocols.
1
Introduction
Approximately 40 000 to 50 000 new head and neck cancers are diagnosed each year in the United States . Approximately 90% to 95% are squamous cell carcinomas of the head and neck (SCCHNs), and 60% present with stage III and IV disease . Many advances have been made in the multimodality treatment of SCCHN including the rise in the use of concurrent chemotherapy as well as advancements in radiation techniques such as the utilization of intensity-modulated radiation treatment (IMRT). These improvements have contributed in improving locoregional control and overall survival over the last 2 decades .
However, with distant metastatic disease still being a problem, induction chemotherapy has emerged as a focus of study. Other theoretical advantages to induction chemotherapy include high response rates and benefit with regard to organ preservation. The results of the EORTC 24971 (TAX 323) trial have shown benefit to an aggressive induction strategy . In this phase III trial comparing docetaxel, cisplatinum, and 5-fluorouracil (TPF) and PF induction chemotherapy followed by radiation therapy (RT) in patients with locally advanced unresectable SCCHN, patients in the TPF group had an improvement in median overall survival of 4.3 months and an absolute increase in 3-year survival of 10.9%.
In addition to these emerging data, a study demonstrated the effectiveness of the use of cetuximab (Erbitux, Imclone Systems, New York, NY, USA), an IgG monoclonal antibody that targets the epidermal growth factor receptor . That phase III study randomizing patients to high-dose RT or high-dose RT plus concomitant cetuximab showed improvement in locoregional control (median 24.4 vs 14.9 months, P = .005) and overall survival (median 49.0 vs 29.3 months, P = .03). Importantly, the addition of cetuximab did not increase the incidence of adverse events such as mucositis, xerostomia, dysphagia, pain, and weight loss. This is in contrast to the increase in adverse effects typically seen with traditional concurrent chemotherapy.
Thus far, however, no major trials have explored merging the 2 strategies. In theory, the toxicities incurred by an aggressive induction treatment may be offset with the concurrent use of cetuximab rather than platinum-containing regimens. In this study, we report a series of patients treated with induction chemotherapy with TPF followed by concurrent radiation with cetuximab to evaluate for clinical efficacy.
2
Materials and methods
Seventeen patients treated between 2006 and 2009 with SCCHN were retrospectively identified by chart review as having undergone induction chemotherapy with TPF followed by concurrent radiation with cetuximab. This treatment strategy was up to the sole discretion of the treating physicians involved, but all used the same chemotherapy regimen.
Induction chemotherapy consisted of 3 to 4 cycles every 3 weeks of docetaxel (day 1, 75 mg/m 2 ), cisplatin (day 1, 75 mg/m 2 ), and 5-FU (days 1–5, 750 mg/m 2 ). The patients received intravenous hydration, granulocyte colony-stimulating factor, and occasionally erythropoietin α at the discretion of the treating medical oncologist. Concomitant cetuximab was planned for 7 to 8 cycles. It was administered intravenously with infusion times designed to limit any hypersensitivity reaction (400 mg/m 2 over 2 hours, 1 week before the start of RT, then 250 mg/m 2 over 1 hour, once per week during the radiation period).
Total dose of radiation was targeted to be at least 7000 to 7020 cGy, in 180- to 200-cGy fractions, to all areas of initial gross disease before induction chemotherapy. The dose administered to uninvolved lymph nodes was at least 5000 cGy. Doses were reduced in some patients during treatment at the discretion of the attending radiation oncologist. All patients received a noncontrast computed tomographic (CT) scan for treatment planning. Contouring was performed by the radiation oncologists using fusion studies as deemed to be necessary by the physician. For IMRT planning, all patients were treated with image-guided helical tomotherapy (TomoTherapy, Inc, Madison, WI, USA). For treatment delivery, all patients received a megavoltage CT before each treatment fraction. Image fusion, where the daily megavoltage CT is fused to the original kilovoltage treatment planning CT, was performed by the treating therapists under the guidance of the treating physician.
Complete response (CR) after induction chemotherapy was defined as no disease detected on physical examination and magnetic resonance imaging or CT–positron emission tomography (PET) scan imaging. Anything less than a CR on imaging or physical examination was defined as a partial response (PR). Locoregional control was defined as no evidence of disease on imaging (magnetic resonance imaging or CT/PET scan) and physical examination. Time was measured from the completion of radiation treatment rather than initiation of treatment. Rates of locoregional control and overall survival were estimated according to Kaplan-Meier method.
2
Materials and methods
Seventeen patients treated between 2006 and 2009 with SCCHN were retrospectively identified by chart review as having undergone induction chemotherapy with TPF followed by concurrent radiation with cetuximab. This treatment strategy was up to the sole discretion of the treating physicians involved, but all used the same chemotherapy regimen.
Induction chemotherapy consisted of 3 to 4 cycles every 3 weeks of docetaxel (day 1, 75 mg/m 2 ), cisplatin (day 1, 75 mg/m 2 ), and 5-FU (days 1–5, 750 mg/m 2 ). The patients received intravenous hydration, granulocyte colony-stimulating factor, and occasionally erythropoietin α at the discretion of the treating medical oncologist. Concomitant cetuximab was planned for 7 to 8 cycles. It was administered intravenously with infusion times designed to limit any hypersensitivity reaction (400 mg/m 2 over 2 hours, 1 week before the start of RT, then 250 mg/m 2 over 1 hour, once per week during the radiation period).
Total dose of radiation was targeted to be at least 7000 to 7020 cGy, in 180- to 200-cGy fractions, to all areas of initial gross disease before induction chemotherapy. The dose administered to uninvolved lymph nodes was at least 5000 cGy. Doses were reduced in some patients during treatment at the discretion of the attending radiation oncologist. All patients received a noncontrast computed tomographic (CT) scan for treatment planning. Contouring was performed by the radiation oncologists using fusion studies as deemed to be necessary by the physician. For IMRT planning, all patients were treated with image-guided helical tomotherapy (TomoTherapy, Inc, Madison, WI, USA). For treatment delivery, all patients received a megavoltage CT before each treatment fraction. Image fusion, where the daily megavoltage CT is fused to the original kilovoltage treatment planning CT, was performed by the treating therapists under the guidance of the treating physician.
Complete response (CR) after induction chemotherapy was defined as no disease detected on physical examination and magnetic resonance imaging or CT–positron emission tomography (PET) scan imaging. Anything less than a CR on imaging or physical examination was defined as a partial response (PR). Locoregional control was defined as no evidence of disease on imaging (magnetic resonance imaging or CT/PET scan) and physical examination. Time was measured from the completion of radiation treatment rather than initiation of treatment. Rates of locoregional control and overall survival were estimated according to Kaplan-Meier method.
3
Results
Median age at diagnosis was 65 years (15 male and 2 female subjects), with all patients presenting with either stage III or IV disease (4 patients with stage III and 13 patients with stage IV disease). The majority of cases had the primary site of disease in the oropharynx (14 out the 17 patients). Location of disease along with the patient characteristics is listed in Table 1 .
