A Phase 1b trial of prexasertib in combination with chemoradiation in patients with locally advanced head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: This study explored the feasibility of safely combining prexasertib, with cisplatin-radiotherapy (Part A) or cetuximab-radiotherapy (Part B) in patients with previously untreated, locoregionally advanced head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Escalating doses of prexasertib were administered in each combination using a modified Time-to-Event Continual Reassessment Method. Pharmacokinetic (PK) analysis was performed using standard non-compartmental methods of analysis. Antitumor activity was evaluated using RECIST version 1.1. RESULTS: In Part A, 7 patients received 20 mg/m2 prexasertib and cisplatin-radiotherapy. This dose exceeded the maximum tolerated dose (MTD); no other prexasertib dose was assessed. In Part B, 18 patients received prexasertib (20-40 mg/m2) and cetuximab-radiotherapy. The 30 mg/m2 dose of prexasertib was determined as the MTD. Febrile neutropenia was the dose-limiting toxicity in each arm. Most common treatment-emergent adverse events with both combinations were neutropenia, thrombocytopenia, dysphagia, stomatitis, dry mouth, anemia, radiation skin injury [reported term radiation dermatitis], and nausea. PK of prexasertib was consistent with previously published data following prexasertib monotherapy. Overall response rate in Parts A and B was 71.4% and 83.3%, respectively. The small number of patients and follow-up limits the interpretation of efficacy data. CONCLUSION: This study did not establish a safe dose of cisplatin-radiotherapy. However, it demonstrates the proof-of-principle that prexasertib could be safely combined with cetuximab-radiotherapy. These data will provide the basis to leverage the potential radio-sensitization properties of a CHK1 inhibitor in combination with radiation or other targeted agents in a variety of therapeutic settings.

A dynamic supraclavicular field-matching technique for head-and-neck cancer patients treated with IMRT.

PURPOSE: The conventional single-isocenter and half-beam (SIHB) technique for matching supraclavicular fields with head-and-neck (HN) intensity-modulated radiotherapy (IMRT) fields is subject to substantial dose inhomogeneities from imperfect accelerator jaw/MLC calibration. It also limits the isocenter location and restricts the useful field size for IMRT. We propose a dynamic field-matching technique to overcome these limitations. METHODS AND MATERIALS: The proposed dynamic field-matching technique makes use of wedge junctions for the abutment of supraclavicular and HN IMRT fields. The supraclavicular field was shaped with a multileaf collimator (MLC), which was orientated such that the leaves traveled along the superoinferior direction. The leaves that defined the superior field border moved continuously during treatment from 1.5 cm below to 1.5 cm above the conventional match line to generate a 3-cm-wide wedge-shaped junction. The HN IMRT fields were optimized by taking into account the dose contribution from the supraclavicular field to the junction area, which generates a complementary wedge to produce a smooth junction in the abutment region. This technique was evaluated on a polystyrene phantom and 10 HN cancer patients. Treatment plans were generated for the phantom and the 10 patients. Dose profiles across the abutment region were measured in the phantom on films. For patient plans, dose profiles that passed through the center of the neck lymph nodes were calculated using the proposed technique and the SIHB technique, and dose uniformity in the abutment region was compared. Field mismatches of +/- 1 mm and +/- 2 mm because of imperfect jaw/MLC calibration were simulated, and the resulting dose inhomogeneities were studied for the two techniques with film measurements and patient plans. Three-dimensional volumetric doses were analyzed, and equivalent uniform doses (EUD) were computed. The effect of field mismatches on EUD was compared for the two match techniques. RESULTS: For a perfect jaw/MLC calibration, dose profiles for the 10 patients in the 3-cm match zone had an average inhomogeneity range of -1.6% to +1.6% using the dynamic-matching technique and -3.7% to +3.8% according to the SIHB technique. Measurements showed that dose inhomogeneities that resulted from 1-mm and 2-mm jaw/MLC calibration errors were reduced from as large as 27% and 45% with the SIHB technique to less than 2% and 5.7% with the dynamic technique, respectively. For -1-mm, -2-mm, +1-mm, and +2-mm jaw/MLC calibration errors, respectively, treatment plans for the 10 patients yielded average dose inhomogeneities of -5.9%, -3.0%, +2.7%, and +5.8% with the dynamic technique as compared to -22.8%, -11.1%, +9.8%, and +22.1% with the SIHB technique. Calculation based on a dose-volume histogram (DVH) showed that the SIHB technique resulted in larger changes in EUD of the PTV in the junction area than did the dynamic technique. CONCLUSION: Compared with the conventional SIHB technique, the dynamic field-matching technique provides superior dose homogeneity in the abutment region between the supraclavicular and HN IMRT fields. The dynamic feathering mechanism substantially reduces dose inhomogeneities that result from imperfect jaw/MLC calibration. In addition, isocenter location in the dynamic field-matching technique can be chosen for reproducible patient setup and for adequate IMRT field size rather than being dictated by the match position. It also allows angling of the supraclavicular field to reduce the volume of healthy lung irradiated, which is impractical with the SIHB technique. In principle, this technique should be applicable to any treatment site that requires the abutment of static and intensity-modulated fields.

Factors associated with long-term dysphagia after definitive radiotherapy for locally advanced head-and-neck cancer.

PURPOSE: The use of altered fractionation radiotherapy (RT) regimens, as well as concomitant chemotherapy and RT, to intensify therapy for locally advanced head-and-neck cancer can lead to increased rates of long-term dysphagia. METHODS AND MATERIALS: We identified 122 patients who had undergone definitive RT for locally advanced head-and-neck cancer, after excluding those who had been treated for a second or recurrent head-and-neck primary, had Stage I-II disease, developed locoregional recurrence, had <12 months of follow-up, or had undergone postoperative RT. The patient, tumor, and treatment factors were correlated with a composite of 3 objective endpoints as a surrogate for severe long-term dysphagia: percutaneous endoscopic gastrostomy tube dependence at the last follow-up visit; aspiration on a modified barium swallow study or a clinical diagnosis of aspiration pneumonia; or the presence of a pharyngoesophageal stricture. RESULTS: A composite dysphagia outcome occurred in 38.5% of patients. On univariate analysis, the primary site (p = 0.01), use of concurrent chemotherapy (p = 0.01), RT schedule (p = 0.02), and increasing age (p = 0.04) were significantly associated with development of composite long-term dysphagia. The use of concurrent chemotherapy (p = 0.01), primary site (p = 0.02), and increasing age (p = 0.02) remained significant on multivariate analysis. CONCLUSION: The addition of concurrent chemotherapy to RT for locally advanced head-and-neck cancer resulted in increased long-term dysphagia. Early intervention using swallowing exercises, avoidance of nothing-by-mouth periods, and the use of intensity-modulated RT to reduce the dose to the uninvolved swallowing structures should be explored further in populations at greater risk of long-term dysphagia.

Final report of RTOG 9610, a multi-institutional trial of reirradiation and chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck.

BACKGROUND: Our objectives were to determine the incidence of acute and late toxicities and to estimate the 2-year overall survival for patients treated with reirradiation and chemotherapy for unresectable squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients with recurrent squamous cell carcinoma or a second primary arising in a previously irradiated field were eligible. Four weekly cycles of 5-fluorouracil 300 mg/m2 IV bolus and hydroxyurea 1.5 g by mouth were used with 60 Gy at 1.5 Gy twice-daily fractions. Toxicity was scored according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria. RESULTS: Seventy-nine of the 86 patients enrolled were analyzable. The worst acute toxicity was grade 4 in 17.7% and grade 5 in 7.6%. Grade 3 and 4 late toxicities were found in 19.4% and 3.0%, respectively. The estimated cumulative incidence of grade 3 to 4 late effects occurring at >1 year was 9.4% (95% confidence interval [CI]: 0, 19.7) at 2 and 5 years. The 2- and 5-year cumulative incidence for grade 4 toxicity was 3.1% (95% CI: 0, 9.3). The estimated 2- and 5-year survival rates were 15.2% (95% CI: 7.3, 23.1) and 3.8% (95% CI: 0.8, 8.0), respectively. Patients who entered the study at >1 year from initial radiotherapy (RT) had better survival than did those who were <1 year from prior RT (median survival, 9.8 months vs 5.8 months; p = .036). No correlation was detected between dose received and overall survival. Three patients were alive at 5 years. CONCLUSION: This is the first prospective multi-institutional trial testing reirradiation plus chemotherapy for recurrent or second SCCHN. The approach is feasible with acceptable acute and late effects. The results serve as a benchmark for ongoing RTOG trials.