Mitchell Machtay

TPS6097 Background: Nivolumab (Nivo), a monoclonal antibody to the programmed death-1 (PD-1) immune checkpoint receptor, improved overall survival (OS) for patients (pts) with platinum-refractory, recurrent/metastatic HNSCC compared with standard therapy. A placebo controlled phase IIR trial was designed to investigate the hypothesis that Nivo added to platinum-based CRT will improve progression free survival (PFS) for pts with newly diagnosed IR/HR HNSCC. Methods: Eligibility includes IR HNSCC (p16+, oropharynx T1-2N2b-N3/T3-4N0-3, > 10 pack-years (pys) or T4N0-N3, T1-3N3 ≤ 10 pys) and HR HNSCC (oral cavity, larynx, hypopharynx, or p16(-) oropharynx, stage T1-2N2a-N3 or T3-4N0-3). After safety evaluation in 8 evaluable pts, 176 pts will be randomized (1:1) to cisplatin (40 mg/m²/week X 7) with radiation (IMRT, 70 Gy in 7 weeks) +/- Nivo/placebo (240 mgs q14 days X 5, then 480 mgs q28 X3). Primary endpoint is PFS. Secondary endpoints include OS, acute and chronic toxicity, quality of life and biomarkers (tumor PD-L1 expression; E6/7 seroreactivity and frequency of functional circulating and intraumoral T cells). Parallel with Phase IIR are sequential safety evaluations (see Table) in platinum eligible and ineligible ( > 70 years; ≥3 grade neuropathy; ≥2 hearing loss; or CrCl < 60 ml/min) cohorts (N = 10-20) of Nivo +/- Liri (anti-KIR) or Ipi (anti-CTLA4) concomitant with RT alone, cisplatin-RT or cetuximab-RT platforms followed by 3 months of adjuvant immunotherapy. The primary endpoint is safety and feasibility. With 8 evaluable pts, the probability of treatment assessed as toxic is > 78% when the true toxicity rate is > 45% and treatment assessed tolerable is > 80% if the true toxicity rate is < 20%. Clinical trial information: NCT02764593. [Table: see text]

Stereotactic body radiotherapy (SBRT) has become a standard treatment option for early stage, node negative non-small cell lung cancer (NSCLC) in patients who are either medically inoperable or refuse surgical resection. SBRT has high local control rates and a favorable toxicity profile relative to other surgical and non-surgical approaches. Given the excellent tumor control rates and increasing utilization of SBRT, recent efforts have focused on limiting toxicity while expanding treatment to increasingly complex patients. We review toxicities from SBRT for lung cancer, including central airway, esophageal, vascular (e.g., aorta), lung parenchyma (e.g., radiation pneumonitis), and chest wall toxicities, as well as radiation-induced neuropathies (e.g., brachial plexus, vagus nerve and recurrent laryngeal nerve). We summarize patient-related, tumor-related, dosimetric characteristics of these toxicities, review published dose constraints, and propose strategies to reduce such complications.

Purpose: In this prospective National Cancer Institute–funded American College of Radiology Imaging Network/Radiation Therapy Oncology Group cooperative group trial, we hypothesized that standardized uptake value (SUV) on post-treatment [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET) correlates with survival in stage III non–small-cell lung cancer (NSCLC). Patients and Methods: Patients received conventional concurrent platinum-based chemoradiotherapy without surgery; postradiotherapy consolidation chemotherapy was allowed. Post-treatment FDG-PET was performed at approximately 14 weeks after radiotherapy. SUVs were analyzed both as peak SUV (SUV_peak) and maximum SUV (SUV_max; both institutional and central review readings), with institutional SUV_peak as the primary end point. Relationships between the continuous and categorical (cutoff) SUVs and survival were analyzed using Cox proportional hazards multivariate models. Results: Of 250 enrolled patients (226 were evaluable for pretreatment SUV), 173 patients were evaluable for post-treatment SUV analyses. The 2-year survival rate for the entire population was 42.5%. Pretreatment SUV_peak and SUV_max (mean, 10.3 and 13.1, respectively) were not associated with survival. Mean post-treatment SUV_peak and SUV_max were 3.2 and 4.0, respectively. Post-treatment SUV_peak was associated with survival in a continuous variable model (hazard ratio, 1.087; 95% CI, 1.014 to 1.166; P = .020). When analyzed as a prespecified binary value (≤ v > 3.5), there was no association with survival. However, in exploratory analyses, significant results for survival were found using an SUV_peak cutoff of 5.0 (P = .041) or 7.0 (P < .001). All results were similar when SUV_max was used in univariate and multivariate models in place of SUV_peak. Conclusion: Higher post-treatment tumor SUV (SUV_peak or SUV_max) is associated with worse survival in stage III NSCLC, although a clear cutoff value for routine clinical use as a prognostic factor is uncertain at this time.

The management of pancreatic cancer continues to be challenging. Despite surgical, genetic and molecular advances, its overall prognosis remains poor. Surgical resection is the only modality that offers a chance for a cure, with an overall survival rate of 10-20% at 5 years. However, only 20% of the patients are surgical candidates because of locally advanced disease or systemic stage at presentation. Conventional radiotherapy, with or without chemotherapy, has been used to treat patients with advanced-stage pancreatic cancer, an approach with high rates of local recurrence. Stereotactic body radiation therapy, also known as stereotactic ablative radiotherapy has emerged as a treatment modality that allows the precise delivery of a large ablative radiation dose to a tumor volume while sparing surrounding organs and tissues. Phase I and II studies have shown good rates of local control of the disease but rates of distant metastasis remain significant. Strategies to combine novel systemic therapy and stereotactic body radiation therapy are to be explored.

Skull base meningiomas commonly present with cranial neuropathies. Fractionated stereotactic radiation therapy (FSRT) has been used to treat these tumors with excellent local control, but rates of improvement in cranial neuropathies have not been well defined. We review the experience at Thomas Jefferson University using FSRT in the management of these patients with a focus on symptom outcomes.