Phase II randomized trial of radiation therapy, cetuximab, and pemetrexed with or without bevacizumab in patients with locally advanced head and neck cancer.

BACKGROUND: We previously reported the safety of concurrent cetuximab, an antibody against epidermal growth factor receptor (EGFR), pemetrexed, and radiation therapy (RT) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In this non-comparative phase II randomized trial, we evaluated this non-platinum combination with or without bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF). PATIENTS AND METHODS: Patients with previously untreated stage III-IVB SCCHN were randomized to receive: conventionally fractionated radiation (70 Gy), concurrent cetuximab, and concurrent pemetrexed (arm A); or the identical regimen plus concurrent bevacizumab followed by bevacizumab maintenance for 24 weeks (arm B). The primary end point was 2-year progression-free survival (PFS), with each arm compared with historical control. Exploratory analyses included the relationship of established prognostic factors to PFS and quality of life (QoL). RESULTS: Seventy-eight patients were randomized: 66 oropharynx (42 HPV-positive, 15 HPV-negative, 9 unknown) and 12 larynx; 38 (49%) had heavy tobacco exposure. Two-year PFS was 79% [90% confidence interval (CI) 0.69-0.92; P < 0.0001] for arm A and 75% (90% CI 0.64-0.88; P < 0.0001) for arm B, both higher than historical control. No differences in PFS were observed for stage, tobacco history, HPV status, or type of center (community versus academic). A significantly increased rate of hemorrhage occurred in arm B. SCCHN-specific QoL declined acutely, with marked improvement but residual symptom burden 1 year post-treatment. CONCLUSIONS: RT with a concurrent non-platinum regimen of cetuximab and pemetrexed is feasible in academic and community settings, demonstrating expected toxicities and promising efficacy. Adding bevacizumab increased toxicity without apparent improvement in efficacy, countering the hypothesis that dual EGFR-VEGF targeting would overcome radiation resistance, and enhance clinical benefit. Further development of cetuximab, pemetrexed, and RT will require additional prospective study in defined, high-risk populations where treatment intensification is justified.

Negative predictive value of surveillance PET/CT in head and neck squamous cell cancer.

BACKGROUND AND PURPOSE: Optimizing the utilization of surveillance PET/CT in treated HNSCC is an area of ongoing research. Our aim was to determine the negative predictive value of PET/CT in patients with treated head and neck squamous cell cancer and to determine whether negative PET/CT reduces the need for further imaging surveillance. MATERIALS AND METHODS: We evaluated patients with treated HNSCC who underwent posttreatment surveillance PET/CT. During routine clinical readouts, scans were categorized as having negative, probably negative, probably malignant, or malignant findings. We followed patients clinically and radiographically for at least 12 months from their last PET/CT (mean, 26 months; median, 28 months; range, 12-89 months) to determine recurrence rates. All suspected recurrences underwent biopsy for confirmation. RESULTS: Five hundred twelve patients (1553 scans) were included in the study. Two hundred fourteen patients had at least 1 PET/CT with negative findings. Of the 214 patients with a scan with negative findings, 19 (9%) eventually experienced recurrence, resulting in a NPV of 91%. In addition, a subgroup of 114 patients with 2 consecutive PET/CT examinations with negative findings within a 6-month period was identified. Only 2 recurrences were found in this group, giving a NPV of 98%. CONCLUSIONS: In patients treated for HNSCC, a single PET/CT with negative findings carries a NPV of 91%, which is not adequate to defer further radiologic surveillance. Two consecutive PET/CT examinations with negative findings within a 6-month period, however, resulted in a NPV of 98%, which could obviate further radiologic imaging in the absence of clinical signs of recurrence.

Radioassays and experimental evaluation of dose calibrator settings for 18F.

The positron emitter 18F continues to be one of the most important imaging radionuclides in diagnostic nuclear medicine. Assays of radiopharmaceuticals containing this nuclide are often performed in the clinic using commercial reentrant ionization chambers, or "dose calibrators". Meaningful quantitative clinical studies require accurate knowledge of the injected activity which requires proper calibration of these instruments. Radioassays were performed at the National Institute of Standards and Technology (NIST) on a solution of 18F produced at the National Institutes of Health (NIH) using 4pibeta liquid scintillation (fS) counting with 3H-standard efficiency tracing. Cocktails containing water fractions of approximately 0.9 and 9% (both as saline) were used. The massic activity values were measured to be 2.52+/-0.06 and 2.50+/-0.03 MBq g(-1), respectively, for the 0.9 and 9% water cocktails as of the reference time. The uncertainties on the activity measurements are expanded (k = 2) uncertainties. The largest uncertainty component was found to be the repeatability on a single LS source, with the cocktails containing 0.9% water fraction exhibiting a larger variability by nearly a factor of two. Reproducibility between LS cocktails with the same water fraction was also found to be a large uncertainty component, but with a value less than half that due to measurement repeatability. Radionuclidic impurities consisted of 48V and 46Sc, at levels of 0.11+/-0.08% (expanded uncertainties) and approximately 2 x 10(-3)% (upper limit) relative to the activity of the 18F, as of the reference time. Dose calibrator dial settings for measuring solutions of 18F were experimentally determined for Capintec CRC-12 and CRC-35R dose calibrators in three measurement geometries: a 5-ml standard NIST ampoule (two ampoules measured), a 12-ml plastic syringe containing 9 ml of solution and a 10-ml Mallinckrodt molded dose vial filled with 5 ml of solution. The experimental dial settings (and the corresponding expanded uncertainties) for these geometries were found to be 477+/-7, 474+/-6, 482+/-6 and 463+/-7 for the two ampoules, the syringe and the dose vial, respectively, in the CRC-12. The dial settings determined for the CRC-35R were 472+/-7, 470+/-7, 464+/-6 and 456+/-6 for the two ampoules, the syringe, and the dose vial, respectively. The uncertainties in the dial settings are expanded uncertainties. Comparisons between the empirically determined dial settings and the manufacturer's recommended setting of "439" indicate that use of the manufacturer's setting overestimates the activity by between 3 and 6%, depending upon the geometry used.