Vulvar cancer management and wrangling recurrent disease: A report from the society of gynecologic oncology journal club.

The Society of Gynecologic Oncology (SGO) Journal Club webinar series is an open forum that invites national experts to discuss the literature pertaining to important topics in the management of gynecologic cancers. On August 14th, 2023, SGO hosted a journal club focused on the management of upfront and recurrent vulvar cancer. Our discussants included Dr. Brian M Slomovitz from Mount Sinai Medical Center in Miami Beach, Dr. Emi Yoshida from the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and Dr. Lilian Gien from the University of Toronto Sunnybrook Odette Cancer Center. During the discussion,we reviewed the progression of vulvar cancer surgery from en bloc resection of the vulva and groins, to partial radical vulvectomy and sentinel lymph nodes. We also reviewed the management of node positive vulvar cancer including published and accruing Groningen International Study on Sentinel Nodes in Vulvar Cancer (GROINSS) trials and other sentinel trials from the Gynecologic Oncology Group (GOG). Here we will also review the literature on the management of recurrent vulvar cancer, highlighting current treatment options and ongoing clinical trials. The following is a report of the journal club presentation.

The role of adjuvant radiation therapy in older patients with node-positive vulvar cancer: A national cancer database analysis.

OBJECTIVE: We sought to evaluate whether the survival benefit of adjuvant radiotherapy in patients with node-positive vulvar cancer is maintained in older patients, who comprise a large subgroup of patients with vulvar cancer. METHODS: The National Cancer Database (NCDB) was queried for patients aged 65 years or older, who were diagnosed with vulvar squamous cell carcinoma from 2004 to 2017 and underwent surgery with confirmed node-positive disease. Statistical analysis was performed with propensity-score matching, chi-square test, log-rank test, Kaplan-Meier, and multivariable Cox proportional regression. RESULTS: A total of 2396 patients were analyzed, and 1517 (63.3%) received adjuvant radiotherapy. Median follow-up was 73 months. Median age at diagnosis was 77 years (range 65-90). In the propensity score-matched cohort, five-year overall survival (OS) was 29%. Five-year OS was 33% in patients who received surgery followed by adjuvant radiotherapy and 26% in patients who received surgery alone (p < 0.0001). Multivariable analysis continued to demonstrate a survival benefit associated with the addition of adjuvant radiotherapy (OR 0.77 [95% CI 0.69-00.87], p < 0.001). Adjuvant radiotherapy was associated with improved OS among patients aged 65-84 (5-year OS 35% vs 29%, p = 0.0004), but not in patients aged 85 years and older (5-year OS 20% vs 19%, p = 0.32). CONCLUSION: This NCDB study suggests that in older patients with node-positive vulvar cancer, radiotherapy continues to be a vital component of multimodality therapy. However, a comprehensive and geriatrics-specific approach is crucial for treating older adults with node-positive vulvar cancer, as the benefit of adjuvant radiotherapy may be compromised by treatment-related morbidity/toxicity.

Better late than never: Brachytherapy is more important than timing in treatment of locally advanced cervical cancer.

PURPOSE: To evaluate the utilization of brachytherapy and duration of treatment on overall survival for locally advanced cervical cancer. METHODS: The National Cancer Database (NCDB) was queried to identify stage II-IVA cervical cancer patients diagnosed in the United States between 2004 and 2015 who were treated with definitive chemoradiation therapy. We defined standard of care (SOC) treatment as receiving external beam radiation therapy (EBRT) and concurrent chemotherapy, brachytherapy (BT), and completing treatment within 8 weeks, and compared SOC treatment to non-SOC. The primary outcome was overall survival (OS). We also evaluated the effect of sociodemographic and clinical variables on receiving SOC. RESULTS: We identified 10,172 women with locally advanced cervical cancer primarily treated with chemotherapy and concurrent EBRT of which 6047 (59.4%) patients received brachytherapy, and only 2978 (29.3%) completed treatment within 8 weeks (SOC). Receipt of SOC was associated with significantly improved overall survival (median OS 131.0 mos vs 95.5 mos, 78.1 mos, 49.2 mos; p < 0.0001). Furthemore, in patients whose treatment extended beyond 8 weeks, brachytherapy was still associated with an improved survival (median OS 95.5 vs 49.2 mos, p < 0.0001). More advanced stage, Non-Hispanic Black race, lower income, lack of insurance or government insurance, less education, and rural residence were associated with decreased likelihood of receiving SOC. CONCLUSIONS: Completing standard of care concurrent chemoradiation therapy and brachytherapy in the recommended 8 weeks was associated with a superior overall survival. Patients who received brachytherapy boost show superior survival to patients receiving EBRT alone, regardless of treatment duration. Disparities in care for vulnerable populations highlight the challenges and importance of care coordination for patients with cervical cancer.

The incidence of discordant clinical and genomic risk in patients with invasive lobular or ductal carcinoma of the breast: a National Cancer Database Study.

When molecular testing classifies breast tumors as low risk but clinical risk is high, the optimal management strategy is unknown. One group of patients who may be more likely to have such discordant risk are those with invasive lobular carcinoma of the breast. We sought to examine whether patients with invasive lobular carcinoma are more likely to have clinical high/genomic low-risk tumors compared to those with invasive ductal carcinoma, and to evaluate the impact on receipt of chemotherapy and overall survival. We conducted a cohort study using the National Cancer Database from 2010-2016. Patients with hormone receptor positive, HER2 negative, stage I-III breast cancer who underwent 70-gene signature testing were included. We evaluated the proportion of patients with discordant clinical and genomic risk by histology using Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models with and without propensity score matching. A total of 7399 patients (1497 with invasive lobular carcinoma [20.2%]) were identified. Patients with invasive lobular carcinoma were significantly more likely to fall into a discordant risk category compared to those with invasive ductal carcinoma (46.8% versus 37.1%, p < 0.001), especially in the clinical high/genomic low risk subgroup (35.6% versus 19.2%, p < 0.001). In unadjusted analysis of the clinical high/genomic low-risk cohort who received chemotherapy, invasive ductal carcinoma patients had significantly improved overall survival compared to those with invasive lobular carcinoma (p = 0.02). These findings suggest that current tools for stratifying clinical and genomic risk could be improved for those with invasive lobular carcinoma to better tailor treatment selection.

Adjuvant radiation followed by chemotherapy is associated with improved overall survival in endometrial cancer.

OBJECTIVE: Although multimodality therapy has been shown to improve outcomes for patients with high-risk endometrial carcinoma, optimal type and timing of adjuvant therapies is unknown. METHODS: Patients with stage I-IVA endometrial carcinoma diagnosed from 2004 to 2015, and treated with surgery, chemotherapy, and radiation were identified in the National Cancer Database. Adjuvant treatment was categorized as sequential radiation followed by chemotherapy (RT-CT), concurrent chemoradiation (CCRT, RT and CT started within 7 days), or sequential chemotherapy followed by radiation (CT-RT). Analysis for propensity score matched (PSM) cohorts comparing RT-CT to CCRT and CT-RT groups was additionally performed. RESULTS: A total of 17,070 patients were identified, including 12,402 (72.7%) treated with RT-CT, 2,153 (12.6%) with CCRT, and 2,515 (14.7%) with CT-RT. Median follow-up was 44.3 months. Five-year overall-survival (OS) by adjuvant treatment regimen was 77.3% (95% CI 76.4%-78.2%), 74.3% (95% CI 72.0%-76.3%), and 74.4% (95% CI 72.5%-76.3%), respectively (p < .001). When unmatched cohorts were stratified by stage, adjuvant RT-CT was associated with improved OS in stage I and III patients. A similar survival advantage associated with RT-CT was observed in PSM cohorts comparing RT-CT group to CCRT/CT-RT group (5-year OS 77.4% vs 74.2%, p = .001). However, the difference in OS was significant only among stage III patients (RT-CT 73.9% compared to CCRT/CT-RT 69.7%, p =.002). CONCLUSION: Our findings suggest survival benefit with adjuvant RT-CT compared to CT-RT or CCRT in patients undergoing trimodality therapy for endometrial cancer. This survival benefit may be limited to stage III patients.

The association between facility volume and overall survival in patients with Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma is an uncommon malignancy often requiring multidisciplinary management. The purpose of this study was to determine whether high-volume facilities have improved outcomes in patients with Merkel cell carcinoma relative to lower-volume facilities. METHODS: A total of 5304 patients from the National Cancer Database with stage I-III Merkel cell carcinoma undergoing surgery were analyzed. High-volume facilities were the top 1% by case volume. Multivariable Cox regression and propensity score-matching were performed to account for imbalances between groups. RESULTS: Treatment at high-volume facilities (hazard ratio: 0.74; 95% confidence interval: 0.65-0.84, P < .001) was independently associated with improved overall survival (OS) in multivariable analyses. In propensity score-matched cohorts, 5-year OS was 62.3% at high-volume facilities vs 56.8% at lower-volume facilities (P < .001). Median OS was 111 months at high-volume facilities vs 79 months at lower-volume facilities. CONCLUSION: Treatment at high-volume facilities is associated with improved OS in Merkel cell carcinoma. Given the impracticality of referring all elderly patients with Merkel cell carcinoma to a small number of facilities, methods to mitigate this disparity should be explored.

Stage I HPV-positive oropharyngeal cancer: Should all patients receive similar treatments?

BACKGROUND: Patients with clinical stage I human papillomavirus (HPV)-positive oropharyngeal squamous cell cancer (OPSCC) according to the American Joint Committee on Cancer (AJCC) eighth edition classification comprise a heterogeneous group formerly classified as stage I to stage IVA according to the seventh edition of the AJCC classification. These patients historically were treated with disparate treatment regimens, particularly with respect to the use of concurrent chemotherapy. METHODS: The National Cancer Data Base was queried for patients with AJCC eighth edition clinical stage I HPV-positive OPSCC (AJCC seventh edition stage T1-2N0-2bM0) who were diagnosed from 2010 to 2014 and underwent definitive radiotherapy. Concurrent chemotherapy with definitive radiotherapy was defined as chemotherapy administered within 7 days of the initiation of radiotherapy. RESULTS: The current analysis included 4473 patients with HPV-positive stage I OPSCC with a median follow-up of 36.3 months. A total of 3127 patients (69.9%) received concurrent chemotherapy. Concurrent chemotherapy was found to be associated with improved overall survival on multivariable analyses (hazard ratio [HR], 0.782; 95% CI, 0.645-0.948 [P = .012]). The effect of chemotherapy on survival varied based on lymph node involvement (P for interaction = .001). Specifically, chemotherapy was associated with improved survival for patients with lymph node-positive stage I disease (stage III-IVA according to the AJCC seventh edition: HR, 0.682; 95% CI, 0.557-0.835 [P < .001]), but not for patients with N0 disease (stage I-II according to the AJCC seventh edition: HR, 1.646; 95% CI, 1.011-2.681 [P = .05]). Similar results were noted among propensity score-matched cohorts. CONCLUSIONS: Treatment with concurrent chemotherapy was associated with improved overall survival for patients with lymph node-positive, but not lymph node-negative, AJCC eighth edition stage I HPV-positive OPSCC undergoing definitive radiotherapy, thereby supporting different treatment paradigms for these patients.

Impact of insurance on survival in patients < 65 with head & neck cancer treated with radiotherapy.

OBJECTIVES: The United States has a heterogenous health insurance landscape for patients <65 years. We sought to characterise the impact of primary payer on overall survival (OS) in insured patients younger than 65 with head and neck squamous cell carcinoma (HNSCC) treated with definitive radiotherapy. DESIGN/STUDY/PARTICIPANTS: The National Cancer Database was queried for patients <65 years old diagnosed from 2004 to 2014 undergoing definitive radiotherapy ± chemotherapy for cancers of the nasopharynx, oropharynx, hypopharynx and larynx. Uninsured patients and oropharyngeal cancers without known HPV status were excluded. MAIN OUTCOME: Overall survival. RESULTS: Overall, 27 292 insured patients were identified, including 17 060 (62.5%) with private insurance. Median follow-up was 52.1 months. In multivariable models, patients receiving Medicaid (HR = 1.66, 95% CI 1.57-1.75, P < .001), Medicare (HR = 1.64, 95% CI 1.55-1.73, P < .001) and other government insurance (HR = 1.44, 95% CI 1.29-1., P < .001) had independently increased mortality in comparison to those with private insurance. In propensity score-matched cohorts, 5-year OS was 65.5% vs 50.6% for privately vs government-insured patients, respectively (P < .001). In multivariable subgroup analysis, private insurance was associated with improved survival in all subgroups. However, the magnitude of this effect was most pronounced in patients with HPV-positive oropharyngeal cancer vs non-HPV-related cancer (interaction P < .001), younger patients (interaction P = .001), and those without comorbidity (interaction P < .001). CONCLUSIONS: Patients <65 with HNSCC undergoing definitive radiation with private health insurance have markedly longer survival relative to patients with government-sponsored insurance. This illustrates that increasing access to care may be necessary, but is not sufficient, to mitigate the significant disparities in the US healthcare system.

The relationship between ventricular volume and whole-brain irradiation dose in central nervous system germ cell tumors.

BACKGROUND: Advanced irradiation techniques, including intensity-modulated radiation therapy (IMRT), aim to limit irradiation to adjoining tissues by conforming beams to a well-defined volume. In intracranial germinomas, whole-ventricular IMRT decreases the volume of irradiation to surrounding parenchyma. This study examined the relationship between ventricular volume and radiation dose to surrounding tissue. PROCEDURE: We retrospectively reviewed age, sex, ventricular and brain volume, ventricular dose, and volume of brain that received 12 Gy (V12) for patients diagnosed with germ cell tumors at our institution treated with whole-ventricular IMRT between 2002 and 2016. Variables were assessed for correlation and statistical significance. RESULTS: Forty-seven patients were analyzed. The median whole-ventricular irradiation dose was 24 Gy with a median boost dose of 30 Gy. The median ventricular volume was 234.3 cm3 , and median brain volume was 1408 cm3 . There was no significant difference between mean ventricular volume of suprasellar versus pineal tumors (P = .95). The median V12 of the brain, including the ventricles, was 58.9%. The strongest correlation was between ventricular volume and V12, with an r2 (coefficient of determination) of .47 (P < .001). Multiple regression analysis indicated that total boost dose and boost planning target volume significantly predicted V12 (P < .001). CONCLUSIONS: Although whole-ventricular IMRT limited irradiation to surrounding tissue in our cohort, a significant percentage of the brain received at least 12 Gy. This study suggests that there is a positive correlation between ventricular volume and the volume of brain parenchyma receiving at least 12 Gy with an important contribution from the boost phase of treatment.

Survival Impact of Adjuvant Therapy in Salivary Gland Cancers following Resection and Neck Dissection.

OBJECTIVE: To evaluate the impact of postoperative radiotherapy (PORT) and chemotherapy on survival in salivary gland cancer (SGC) treated with curative-intent local resection and neck dissection. STUDY DESIGN: Retrospective population-based cohort study. SETTING: National Cancer Database. SUBJECTS AND METHODS: Patients with SGC who were undergoing surgery were identified from the National Cancer Database between 2004 and 2013. Neck dissection removing a minimum of 10 lymph nodes was required. Because PORT violated the proportional hazards assumption, this variable was treated as a time-dependent covariate. RESULTS: Overall, 4145 cases met inclusion criteria (median follow-up, 54 months). PORT was associated with improved overall survival in multivariable analysis, both ≤9 months from diagnosis (hazard ratio [HR], 0.26; 95% CI, 0.20-0.34; P < .001) and >9 months (HR, 0.75; 95% CI, 0.66-0.86; P < .001). In propensity score-matched cohorts, 5-year overall survival was 67.1% and 60.6% with PORT and observation, respectively ( P < .001). Similar results were observed in landmark analysis of patients surviving at least 6 months following diagnosis. Adjuvant chemotherapy was not associated with improved survival (HR, 1.15; 95% CI, 0.99-1.34; P = .06). CONCLUSION: PORT, but not chemotherapy, is associated with improved survival among patients with SGC for whom neck dissection was deemed necessary. These results are not applicable to low-risk SGCs not requiring neck dissection.

Demographic and facility volume related outcomes in radiofrequency ablation for early-stage hepatocellular carcinoma.

BACKGROUND: To evaluate outcomes related to disparities in facility volume and patient demographics in patients with early-stage hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA). METHODS: This is a retrospective study of patients with stage I/II HCC treated with RFA in the National Cancer Database. Independent contributors to overall survival were determined with Cox regression analysis. The Kaplan-Meier method and log-rank analyses were used to estimate overall survival and compare survival curves. A propensity score matched cohort analysis was performed. P-values < 0.05 were considered statistically significant. RESULTS: In total, 2911 patients were included. Stage II disease (p-value = 0.006), increasing alpha fetoprotein (p-value = 0.007), and increasing bilirubin (p-value < 0.001) were associated with worse survival. Improved survival was seen in patients treated at high-volume centers (p-value = 0.004), which persisted following propensity score adjustment (p-value = 0.003). Asian race was associated with significantly improved survival (p-value < 0.001), while governmental insurance was associated with a significant decrease in survival (p-value < 0.001). CONCLUSION: Treatment at a high-volume center and Asian race were significantly associated with improved survival following RFA for early-stage HCC. Governmental insurance, increasing alpha fetoprotein, increasing bilirubin, and higher disease stage were significantly associated with worse survival.

Patient and Facility Demographics Related Outcomes in Early-Stage Non-Small Cell Lung Cancer Treated with Radiofrequency Ablation: A National Cancer Database Analysis.

PURPOSE: To determine facility and patient demographics associated with survival in early-stage non-small cell lung cancer (NSCLC) treated with radiofrequency (RF) ablation. MATERIALS AND METHODS: The National Cancer Database was queried for cases of stage 1a NSCLC treated with RF ablation without chemotherapy or radiotherapy from 2004 to 2014. High-volume centers (HVCs) were defined as the top 95th percentile of facilities by number of procedures performed. Overall survival (OS) was estimated with the Kaplan-Meier method, and comparisons between survival curves were performed with the log-rank test. Propensity score-matched cohort analysis was performed. P values less than .05 were considered statistically significant. RESULTS: In the final cohort, 967 cases were included. Estimated median survival and follow-up were 33.1 and 62.5 months, respectively. Of 305 facilities, 15 were determined to be HVCs, treating 13 or more patients from 2004 to 2014. A total of 335 cases (34.6%) were treated at HVCs. On multivariate Cox regression analysis, treatment at an HVC was independently associated with improved OS (hazard ratio [HR] = 0.766; P = .006). After propensity score adjustment, 1-, 3-, and 5-year OS was 89.8%, 51.2%, and 27.7%, respectively, for patients treated at HVCs, compared to 85.2%, 41.5%, and 19.6%, respectively, for patients treated at non-HVCs (P = .015). Increasing age (HR = 1.012; P = .013) and higher T-classification (HR = 1.392; P < .001) were independently associated with worse OS. CONCLUSION: Patients with early-stage NSCLC treated with RF ablation at HVCs experienced a significant increase in OS, suggesting regionalization of lung cancer management as a means of improving outcomes.

A National Cancer Database Analysis of Radiofrequency Ablation versus Stereotactic Body Radiotherapy in Early-Stage Non-Small Cell Lung Cancer.

PURPOSE: To compare overall survival (OS) after radiofrequency (RF) ablation and stereotactic body radiotherapy (SBRT) at high-volume centers in patients with early-stage non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Cases in the National Cancer Database of stage 1a and 1b NSCLC treated with primary RF ablation or SBRT from 2004 to 2014 were included. Patients treated at low-volume centers, defined as facilities below the 95th percentile in volume of cases performed, were excluded. Outcomes measured include OS and rate of 30-day readmission. The Kaplan-Meier method was used to estimate OS. The log-rank test was used to compare survival curves. Propensity score matched cohort analysis was performed. P < .05 was considered statistically significant. RESULTS: The final cohort comprised 4,454 cases of SBRT and 335 cases of RF ablation. Estimated median survival and follow-up were 38.8 months and 42.0 months, respectively. Patients treated with RF ablation had significantly more comorbidities (P < .001) and higher risk for an unplanned readmission within 30 days (hazard ratio = 11.536; P < .001). No difference in OS for the unmatched groups was found on multivariate Cox regression analysis (P = .285). No difference was found in the matched groups with 1-, 3-, and 5-year OS of 85.5%, 54.3%, and 31.9% in the SBRT group vs 89.3%, 52.7%, and 27.1% in the RF ablation group (P = .835). CONCLUSIONS: No significant difference in OS was seen between patients with early-stage NSCLC treated with RF ablation and SBRT.

Development of a novel salivary gland cancer lymph node staging system.

BACKGROUND: Current lymph node (LN) staging for salivary gland cancer (SGC) is extrapolated from mucosal head and neck squamous cell carcinoma. However, given its unique biology and clinical behavior, it is possible that a SGC-specific LN staging system would be more accurate. METHODS: Patients from the National Cancer Data Base with nonmetastatic SGC of the head and neck who were diagnosed from 2004 through 2013 and underwent surgical resection and neck dissection removing at least 10 LNs were included. Multivariable models were constructed to assess the association between survival and LN factors, including number of metastatic LNs, extranodal extension, LN size, and lower LN involvement. RESULTS: Overall, 4520 patients met the inclusion criteria. An increasing number of metastatic LNs was found to be strongly associated with worse survival without plateau. The risk of death increased more rapidly up to 4 LNs (hazard ratio, 1.34; 95% confidence interval, 1.27-1.41 [P < .001]), and was more gradual for additional LNs >4 (hazard ratio, 1.02; 95% confidence interval, 1.01-1.03 [P < .001]). LN size, extranodal extension, and lower LN involvement appeared to have no impact on survival when accounting for the number of metastatic LNs. Recursive partitioning analysis was used to create a novel SGC LN staging system in which N0 indicates 0 positive LNs, N1 indicates 1 to 2 positive LNs, N2 indicates 3 to 21 positive LNs, and N3 indicates ≥ 22 positive LNs. This system exhibited greater concordance than the current American Joint Committee on Cancer (eighth edition) system. CONCLUSIONS: Quantitative LN burden is an important determinant of survival in patients with SGC. Use of this variable may improve SGC staging. Cancer 2018. © 2018 American Cancer Society.

Postoperative chemoradiotherapy in patients with head and neck cancer aged 70 or older with positive margins or extranodal extension and the influence of nodal classification.

BACKGROUND: Postoperative concomitant chemoradiotherapy (CRT) improves outcomes for younger adults with head and neck squamous cell carcinoma (HNSCC) and positive margins or extranodal extension (ENE), but its benefit for older adults is not well established. METHODS: Patients from the National Cancer Data Base (NCDB) with HNSCC undergoing curative-intent resection, neck dissection, and postoperative radiation with positive margins or ENE were identified. RESULTS: This analysis included 1199 patients aged ≥ 70 years with median follow-up of 42.6 months. Postoperative concurrent CRT was associated with improved overall survival (OS; hazard ratio [HR] 0.752; 95% confidence interval [CI] 0.638-0.886) compared to radiation alone in multivariable analysis. Three-year OS was 52.4% with CRT versus 43.4% with radiation (P = .012) in propensity-score matched cohorts. The survival impact of CRT varied by N classification (P = .002 for interaction), with benefit seen only in those with N2 to N3 disease. CONCLUSION: Postoperative concurrent CRT may benefit older patients with HNSCC with positive margins or ENE, particularly those with higher nodal burden.

Facility Volume and Survival in Nasopharyngeal Carcinoma.

INTRODUCTION: Definitive treatment of nasopharyngeal carcinoma (NPC) is challenging owing to its rarity, complicated regional anatomy, and the intensity of therapy. In contrast to other head and neck cancers, the effect of facility volume has not been well described for NPC. METHODS AND MATERIALS: The National Cancer Database was queried for patients with stage II-IVB NPC diagnosed from 2004 to 2014 and treated with definitive radiation. Patients with incomplete staging, unknown receipt or timing of treatment, unknown follow-up duration, incomplete socioeconomic information, or treatment outside the reporting facility were excluded. High-volume facilities (HVFs) were defined as the top 5% of facilities according to the annual facility volume. RESULTS: The present analysis included 3941 NPC patients treated at 804 facilities with a median follow-up duration of 59.4 months, including 1025 patients (26.0%) treated at HVFs. Treatment at HVFs was associated with significantly improved overall survival (OS) on multivariable analysis (hazard ratio 0.79, 95% confidence interval 0.69-0.90; P=.001). In propensity score-matched cohorts, 5-year OS was 69.1% versus 63.3% at HVFs versus lower volume facilities (LVFs), respectively (P=.003). Similar results were seen when facility volume was analyzed as a continuous variable. The effect of facility volume on survival varied by academic status (P=.002 for interaction). At academic centers, the propensity score-matched cohorts had 5-year OS of 71.4% compared with 62.4% (P<.001) at HVFs and LVFs, respectively. In contrast, the 5-year OS was 63.5% versus 67.9% (P=.68) in propensity score-matched patients at nonacademic HVFs and LVFs. CONCLUSIONS: Treatment at HVFs was associated with improved OS for patients with NPC, with the effect exclusively seen at academic centers.

Data integration from pathology slides for quantitative imaging of multiple cell types within the tumor immune cell infiltrate.

BACKGROUND: Immune cell infiltrates (ICI) of tumors are scored by pathologists around tumor glands. To obtain a better understanding of the immune infiltrate, individual immune cell types, their activation states and location relative to tumor cells need to be determined. This process requires precise identification of the tumor area and enumeration of immune cell subtypes separately in the stroma and inside tumor nests. Such measurements can be accomplished by a multiplex format using immunohistochemistry (IHC). METHOD: We developed a pipeline that combines immunohistochemistry (IHC) and digital image analysis. One slide was stained with pan-cytokeratin and CD45 and the other slide with CD8, CD4 and CD68. The tumor mask generated through pan-cytokeratin staining was transferred from one slide to the other using affine image co-registration. Bland-Altman plots and Pearson correlation were used to investigate differences between densities and counts of immune cell underneath the transferred versus manually annotated tumor masks. One-way ANOVA was used to compare the mask transfer error for tissues with solid and glandular tumor architecture. RESULTS: The overlap between manual and transferred tumor masks ranged from 20%-90% across all cases. The error of transferring the mask was 2- to 4-fold greater in tumor regions with glandular compared to solid growth pattern (p < 10-6). Analyzing data from a single slide, the Pearson correlation coefficients of cell type densities outside and inside tumor regions were highest for CD4 + T-cells (r = 0.8), CD8 + T-cells (r = 0.68) or CD68+ macrophages (r = 0.79). The correlation coefficient for CD45+ T- and B-cells was only 0.45. The transfer of the mask generated an error in the measurement of intra- and extra- tumoral CD68+, CD8+ or CD4+ counts (p < 10-10). CONCLUSIONS: In summary, we developed a general method to integrate data from IHC stained slides into a single dataset. Because of the transfer error between slides, we recommend applying the antibody for demarcation of the tumor on the same slide as the ICI antibodies.

Predictors of survival in head and neck mucosal melanoma.

OBJECTIVES: To evaluate hospital-based data of head and neck mucosal melanoma patients in order to identify predictors of survival. MATERIALS AND METHODS: The National Cancer Data Base was used to identify 1368 patients with head and neck mucosal melanoma diagnosed between the years of 2004 and 2012. The Kaplan-Meier method was utilized to estimate overall survival, and multivariate Cox regression analyses were performed to assess the impact of covariates on survival after adjusting for confounding variables. RESULTS: Median follow-up was 55.2months. Median survival of all patients was 29.3months, and the 5-year survival was 27.4%. After adjusting for other prognostic factors in multivariate analysis, paranasal sinus location [hazard ratio (HR)=1.54, 95% Confidence Interval (CI)=1.30-1.82, P<0.001)] and the use of radiotherapy alone for definitive local treatment (HR=2.27, 95% CI=1.72-2.98, P<0.001) were associated with worse survival. Similar results were seen in the subgroup of patients with complete clinical staging information. In terms of patterns of care, the use of combined surgery and radiotherapy as the primary local treatment modality has significant increased from 2004 and 2012 (P=0.03). CONCLUSION: Outcomes in mucosal melanoma of the head and neck remain suboptimal, despite increased use of multimodality local therapy, likely due to the high risk of distant metastases. Mucosal melanomas arising from the paranasal sinuses have particularly poor prognosis. Novel therapeutic paradigms for head and neck mucosal melanoma, incorporating systemic therapies to decrease the risk of distant relapse, should be pursued in clinical trials.

Combined high-intensity local treatment and systemic therapy in metastatic head and neck squamous cell carcinoma: An analysis of the National Cancer Data Base.

BACKGROUND: There is increasing evidence that primary tumor ablation can improve survival for some cancer patients with distant metastases. This may be particularly applicable to head and neck squamous cell carcinoma (HNSCC) because of its tropism for locoregional progression. METHODS: This study included patients with metastatic HNSCC undergoing systemic therapy identified in the National Cancer Data Base. High-intensity local treatment was defined as radiation doses ≥ 60 Gy or oncologic resection of the primary tumor. Multivariate Cox regression, propensity score matching, landmark analysis, and subgroup analysis were performed to account for imbalances in covariates, including adjustments for the number and location of metastatic sites in the subset of patients with this information available. RESULTS: In all, 3269 patients were included (median follow-up, 51.5 months). Patients undergoing systemic therapy with local treatment had improved survival in comparison with patients receiving systemic therapy alone in propensity score-matched cohorts (2-year overall survival, 34.2% vs 20.6%; P < .001). Improved survival was associated only with patients receiving high-intensity local treatment, whereas those receiving lower-intensity local treatment had survival similar to that of patients receiving systemic therapy without local treatment. The impact of high-intensity local therapy was time-dependent, with a stronger impact within the first 6 months after the diagnosis (adjusted hazard ratio [AHR], 0.255; 95% confidence interval [CI], 0.210-0.309; P < .001) in comparison with more than 6 months after the diagnosis (AHR, 0.622; 95% CI, 0.561-0.689; P < .001) in the multivariate analysis. A benefit was seen in all subgroups, in landmark analyses of 1-, 2-, and 3-year survivors, and when adjusting for the number and location of metastatic sites. CONCLUSIONS: Aggressive local treatment warrants prospective evaluation for select patients with metastatic HNSCC. Cancer 2017;123:4583-4593. © 2017 American Cancer Society.