IMPORTANCE Delay in time to treatment initiation (TTI) can alter survival and oncologic outcomes. There is a need to characterize these consequences and identify risk factors and reasons for treatment delay, particularly in underserved urban populations.OBJECTIVES To investigate the association of delayed treatment initiation with outcomes of overall survival and recurrence among patients with head and neck squamous cell carcinoma (HNSCC), to analyze factors that are predictive of delayed treatment initiation, and to identify specific reasons for delayed treatment initiation. DESIGN, SETTING, AND PARTICIPANTSRetrospective cohort study at an urban community-based academic center. Participants were 956 patients with primary HNSCC treated between February 8, 2005, and July 17, 2017, identified through the Montefiore Medical Center Cancer Registry.EXPOSURES The primary exposure was TTI, defined as the duration between histopathological diagnosis and initial treatment. The threshold for delayed treatment initiation was determined by recursive partitioning analysis. MAIN OUTCOMES AND MEASURESOverall survival, recurrence, and reasons for treatment delay.RESULTS Among 956 patients with HNSCC (mean [SD] age, 60.8 [18.2] years; 72.6% male), the median TTI was 40 days (interquartile range, 28-56 days). The optimal TTI threshold to differentiate overall survival was greater than 60 days (20.8% [199 of 956] of patients in our cohort). Independent of other relevant factors, patients with HNSCC with TTI exceeding 60 days had poorer survival (hazard ratio, 1.69; 95% CI, 1.32-2.18). Similarly, TTI exceeding 60 days was associated with greater risk of recurrence (odds ratio, 1.77; 95% CI, 1.07-2.93). Predictors of delayed TTI included African American race/ethnicity, Medicaid insurance, body mass index less than 18.5, and initial diagnosis at a different institution. Commonly identified individual reasons for treatment delay were missed appointments (21.2% [14 of 66]), extensive pretreatment evaluation (21.2% [14 of 66]), and treatment refusal (13.6% [9 of 66]). CONCLUSIONS AND RELEVANCEDelaying TTI beyond 60 days was associated with decreased overall survival and increased HNSCC recurrence. Identification of predictive factors and reasons for treatment delay will help target at-risk patients and facilitate intervention in hospitals with underserved urban populations.
Background Body mass index (BMI), sarcopenia, and obesity‐related comorbidities have been associated with head and neck squamous cell carcinoma (HNSCC) progression. Methods We conducted a retrospective analysis of 441 normal‐weight, overweight, and obese HNSCC patients treated at Montefiore Medical Center (New York). Patients were grouped by BMI prior to treatment and assessed for differences in survival adjusting for comorbid conditions (cardiovascular disease and diabetes). Evidence of sarcopenia was also assessed using pretreatment abdominal CT scans in a subset of 113 patients. Results Prior to treatment, 55% of HNSCC patients were overweight or obese. Overweight/obese patients had significantly better overall survival (hazard ratio [HR] = 0.4, 95% CI: 0.3‐0.6) compared to normal‐weight patients, independent of comorbid conditions. Patients with sarcopenia had significantly poorer survival (HR = 2.1, 95% CI: 1.1‐3.9) compared to non‐sarcopenic patients, with the strongest association seen among overweight/obese patients. Conclusion Our data support the importance of sarcopenia assessment, in addition to BMI, among patients with HNSCC.
Mechanisms of treatment resistance in head and neck squamous cell carcinoma (HNSCC) are not well characterized. In this study, HNSCC tumors from a cohort of prospectively enrolled subjects on an ongoing tissue banking study were divided into those that persisted or recurred locoregionally (n=23) and those that responded without recurrence (n=35). Gene expression was evaluated using llumina HumanHT-12-v3 Expression BeadChip microarrays. Sparse Partial Least Squares – Discriminant Analysis (sPLS-DA) identified 135 genes discriminating treatment-resistant from treatment-sensitive tumors. BCL-xL was identified among 23% of canonical pathways derived from this set of genes using Ingenuity Pathway analysis. The BCL-xL protein was expressed in 8 HNSCC cell lines examined. Cells were treated with the BCL-xL inhibitor, ABT-263 (navitoclax): the average half maximal inhibitory concentration (IC50) was 8.9μM (range 6.6μM – 13.9μM). Combining ABT-263 did not significantly increase responses to 2 Gy radiation or cisplatin in the majority of cell lines. MCL-1, a potential mediator of resistance to ABT-263, was expressed in all cell lines and HNSCC patient tumors, in addition to BCL-xL. Treatment with the MCL-1 inhibitor, A-1210477, in HNSCC cell lines showed an average IC50 of 10.7μM (range, 8.8μM to 12.7μM). Adding A-1210477 to ABT-263 (navitoclax) treatment resulted in an average 7-fold reduction in the required lethal dose of ABT-263 (navitoclax) when measured across all 8 cell lines. Synergistic activity was confirmed in PCI15B, Detroit 562, MDA686LN, and HN30 based on Bliss Independence analysis. This study demonstrates that targeting both BCL-xL and MCL-1 is required to optimally inhibit BCL-family pro-survival molecules in HNSCC, and co-inhibition is synergistic in HNSCC cancer cells.
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