Multi-Institutional Study Validates Safety of Intraoperative Cesium-131 Brachytherapy for Treatment of Recurrent Head and Neck Cancer

Salvage surgery is widely viewed as a "double-edged sword." It is the best option for many patients with recurrent cancer of the upper aerodigestive tract, especially when original therapy included irradiation, yet it may provide only modest benefit at high personal cost to the patient. The stakes are high because alternatives are of limited value. The primary objective of this study was to fully assess the value of salvage surgical procedures in the treatment of local and regional recurrence. The following hypotheses were developed to focus the study design and data analysis. 1) The efficacy of salvage surgery correlates recurrent stage, recurrent site, and time to presalvage recurrence. 2) The economic and noneconomic costs of salvage surgery increase with higher recurrent stage. 3) Information relating the value of salvage surgery to recurrent stage and recurrent site will be useful to these patients and the physicians who treat them. Two complimentary methods of investigation were used: a meta-analysis of the published literature and a prospective observational study of patients undergoing salvage surgery for recurrent cancer of the upper aerodigestive tract. The meta-analysis combined 32 published reports to obtain an estimate of average treatment effect for salvage surgery with regard to survival, disease-free survival, surgical complications, and operative mortality. The prospective observational study included detailed data in 109 patients who underwent salvage surgery. In addition to parameters studied in the meta-analysis, we obtained baseline and interval quality of life data (Functional Living Index for Cancer [FLIC] scores), baseline and interval performance status evaluations (Performance Status Scale for Head and Neck Cancer Patients [PSS head and neck scores]), length of hospital stay, and hospital and physician charges, and related this data primarily to recurrent stage, recurrent site, and time to presalvage recurrence. The weighted average of 5-year survival in the meta-analysis was 39% in 1,080 patients from 28 different institutions. In the prospective study, median disease-free survival was 17.9 months in 109 patients, and this correlated strongly with recurrent stage, weakly with recurrent site, and not at all with time to presalvage recurrence. Noneconomic costs for patients and economic costs correlated with recurrent stage, but not with site. Baseline FLIC and PSS head and neck scores correlated with recurrent stage, but not with site. After salvage surgery the percentage of patients reaching or exceeding baseline was 51% for FLIC scores, and this differed significantly with recurrent stage. Postoperative interval "success" in PSS head and neck subscale scores for diet and eating in public also correlated with recurrent stage. Overall, the expected efficacy for salvage surgery in patients with recurrent head and neck cancer was surprisingly good, but success was limited and costs were great in stage III and, especially, in stage IV recurrences. A strong correlation of efficacy and noneconomic costs with recurrent stage allowed the creation of expectation profiles that may be useful to patients. Additional systematic clinical research is needed to improve results. In the end, the decision to undergo salvage surgery should be a personal choice made by the patient after honest and compassionate discussion with his or her surgeon.

Pembrolizumab improved survival in recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC) patients. The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC. Neoadjuvant pembrolizumab (200 mg) was administered and followed 2–3 weeks later by surgical tumor ablation. Post-operative (chemo) radiation was planned. High-risk pathology patients (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10–49%), and pTR-2 (≥50%). Co-primary endpoints were pTR-2 among all patients and one-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 and T-cell infiltration with pTR were assessed. Tumor clonal dynamics were evaluated ( ClinicalTrials.gov NCT02296684 ). Thirty-six patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3–4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). One-year relapse rate among eighteen patients with high-risk pathology was 16.7% (95%CI: 3.6–41.4%). pTR ≥10% correlated with baseline tumor PD-L1, immune infiltrate, and IFN-γ activity. Matched samples showed upregulation of inhibitory checkpoints in patients with pTR-0, and confirmed clonal loss in some patients. Among patients with locally advanced, HPV-unrelated HNSCC, pembrolizumab was safe, and any pathologic response was observed in 44% of patients with 0% pathologic complete responses. The one-year relapse rate in patients with high-risk-pathology was lower than historical.

A common problem encountered in many medical applications is the comparison of survival curves. Often, rather than comparison of the entire survival curves, interest is focused on the comparison at a fixed point in time. In most cases, the naive test based on a difference in the estimates of survival is used for this comparison. In this note, we examine the performance of alternatives to the naive test. These include tests based on a number of transformations of the survival function and a test based on a generalized linear model for pseudo-observations. The type I errors and power of these tests for a variety of sample sizes are compared by a Monte Carlo study. We also discuss how these tests may be extended to situations where the data are stratified. The pseudo-value approach is also applicable in more detailed regression analysis of the survival probability at a fixed point in time. The methods are illustrated on a study comparing survival for autologous and allogeneic bone marrow transplants. Copyright (c) 2007 John Wiley & Sons, Ltd.