Prognostic impact of mismatch repair deficiency in high- and low-intermediate-risk, early-stage endometrial cancer following vaginal brachytherapy.

OBJECTIVES: To examine the impact of mismatch repair (MMR) status on prognosis among patients with high- and low-intermediate-risk endometrioid endometrial cancer (EEC) treated with vaginal brachytherapy (VBT). MATERIALS/METHODS: 198 stage I-II EEC patients with known MMR status treated with adjuvant VBT were identified. Both low-intermediate (LIR) and high-intermediate-risk (HIR) patients were included. Clinical characteristics were compared between patients with proficient and deficient mismatch repair (pMMR and dMMR) using Fisher's exact tests for categorical variables and t-tests for continuous variables. Recurrence-free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards regression. RESULTS: Patients with dMMR compared to pMMR were more likely to have grade 2-3 tumors (75% vs. 57%, p = 0.006), lympho-vascular invasion (40% vs. 25%, p = 0.034), and HIR classification (65% vs. 49%, p = 0.011). Three-year RFS was inferior for dMMR compared to pMMR patients (75% vs. 96%, p = 0.001). dMMR patients compared to pMMR had similarly reduced 3-year RFS within the LIR (74% vs. 100%, p = 0.026) and HIR (75% vs. 91%, p = 0.038) subgroups. Three-year OS was not different between dMMR/pMMR patients (98% vs. 97%, p = 0.653) or HIR/LIR patients (97% vs. 97%, p = 0.999). On multivariable Cox regression, dMMR status was a significant prognostic variable for RFS (HR 3.774, CI 1.495-9.526, p = 0.005), though it was not significant for OS. CONCLUSION: Following VBT, patients with dMMR have poorer RFS compared to pMMR patients regardless of HIR/LIR risk classification. The prognosis of intermediate-risk EEC patients may lie more on a continuum dependent on molecular features rather than distinct clinicopathologic risk categories.

Association between prolonged metastatic free interval and recurrent metastatic breast cancer survival: findings from the SEER database.

PURPOSE: The prevalence of patients living with prolonged interval between initial breast cancer diagnosis and development of subsequent metastatic disease may be increasing with improved treatment. In order to counsel these patients as to their prognosis, we investigated the association between metastatic free interval (MFI) and subsequent survival from newly diagnosed metastatic breast cancer (MBC) in a population-level U.S. cohort. METHODS: The Surveillance, Epidemiology and End Results database was used to identify patients with both an initial stage 1-3 breast cancer diagnosis and subsequent MBC diagnosis recorded from 1988 to 2014. Patients were stratified by MFI (< 5 years, 5-10 years, > 10 years). The association between MFI and metastatic breast cancer-specific mortality (MBCSM) was analyzed with Fine-Gray competing risks regression. RESULTS: Five-year recurrent metastatic breast cancer-specific survival rate was 23%, 26%, and 35% for patients with MFI < 5, 5-10, and > 10 years, respectively. Patients with > 10 year MFI were less likely to die of breast cancer when compared with a referent group with < 5 years MFI (standard hazard ratio (SHR) 0.77 [95% CI 0.65-0.90] P < 0.001). There was no significant difference for patients with MFI of 5-10 years (SHR 0.92 [95% CI 0.81-1.04, P 0.191]) compared to < 5 years. Other prognostic factors like White race, lower tumor grade, and ER/PR-positive receptors were also associated with improved cancer-specific survival after diagnosis of MBC. CONCLUSION: Prolonged MFI greater than 10 years between initial breast cancer diagnosis and subsequent metastatic disease was found to be associated with improved recurrent MBC 5-year survival and decreased risk of breast cancer-specific mortality. This has potential implications for counseling patients as to prognosis, choice of treatment, as well as the stratification of patients considered for MBC clinical trials.

Adjuvant Therapy Use and Survival in Stage II Endometrial Cancer.

OBJECTIVE: Radiotherapy (RT) is an established adjuvant treatment for stage II endometrioid endometrial carcinoma (EEC). The role of chemotherapy (CT) in stage II EEC is less proven. We used the National Cancer Data Base to identify factors associated with adjuvant CT in stage II EEC and to explore whether receipt of CT was associated with improved overall survival (OS). METHODS/MATERIALS: Women diagnosed in 2010 to 2013 with International Federation of Obstetrics and Gynecology stage II EEC (grades 1-3) after hysterectomy and bilateral salpingo-oophorectomy were identified in the National Cancer Data Base. Multivariable logistic regression was used to identify covariates associated with receipt of CT. Overall survival among patients receiving RT, CT, or chemoradiotherapy (CRT) after surgery was compared using Kaplan-Meier estimates, the log-rank test, Cox proportional hazards regression, and propensity score matching. RESULTS: We identified 6102 stage II EEC patients. There were 358 patients (6%) who received adjuvant CT alone and 525 (9%) who received CRT; the remainder received RT alone (n = 1906; 31%) or no adjuvant treatment (n = 3313; 54%). The presence of lymphovascular invasion (odds ratio, 3.58; P < 0.001) and grade 3 disease (odds ratio, 3.40; P < 0.001) was strongly associated with receipt of CT or CRT. The OS at 3 years for the entire cohort was 89%. On multivariable analysis, CT versus RT was associated with worse OS (hazard ratio [HR], 2.12 [95% confidence interval, 1.46-3.06]; P < 0.001), whereas CRT versus RT was not associated with improved OS (HR, 1.07 [95% confidence interval, 0.71-1.62]; P = 0.781). After propensity score matching, there remained no difference in OS between RT and CRT (HR, 1.14; P = 0.614). CONCLUSIONS: Patients with stage II EEC have an excellent prognosis, and most undergo observation or receive adjuvant RT in the United States. Receipt of CT (alone or with RT) was not associated with an OS advantage compared with RT alone in this observational cohort. Randomized trials will help clarify the role of CT in stage II patients.

Who benefits from chemoradiation in stage III-IVA endometrial cancer? An analysis of the National Cancer Data Base.

OBJECTIVE: Adjuvant therapy for advanced endometrial cancer (AEC) is not standardized. We investigated whether regional radiotherapy with chemotherapy (CRT) compared to chemotherapy alone (CT) was associated with improved overall survival (OS) in an AEC cohort and among subgroups by stage and histologic grade. METHODS: Women who received CT or CRT after hysterectomy and bilateral salpingo-oophorectomy for FIGO stage III-IVA AEC diagnosed in 2004-2012 were identified in the National Cancer Data Base. Multilevel modeling was used to identify covariates associated with treatment selection. OS was compared using Kaplan-Meier estimates, the log-rank test, Cox proportional hazards regression, and propensity score matching. RESULTS: We identified 9837 patients, of whom 6358 (65%) received CT and 3479 (35%) received CRT. Median follow-up was 59.6months. OS was higher in patients receiving CRT compared to CT (70% v 55% at 5years, log-rank P<0.001). Controlling for stage, histologic grade, tumor size, age, comorbidity and race, CRT remained independently associated with improved OS (HR 0.63, 95% CI 0.57-0.70, P<0.001). When stratified by stage and histologic grade, there was a significant OS benefit for stage IIIA, IIIB, IIIC, grade 2, and grade 3 (all P<0.001), a trend for stage IVA (P=0.06), but no benefit for grade 1 (P=0.91). On multivariable subgroup analyses, these findings persisted, including lack of benefit in grade 1 patients (HR 0.72, P=0.14). These results were further confirmed after propensity score matching. CONCLUSIONS: Adjuvant CRT for AEC was associated with improved OS, except for patients with well-differentiated disease, who fared equally well with CT alone.

Combinations of immunotherapy and radiation therapy in head and neck squamous cell carcinoma: a narrative review.

Radiation therapy and systemic therapy are the primary non-surgical treatment modalities for head and neck squamous cell carcinoma (HNSCC). Despite advances in our biologic understanding of this disease and the development of novel therapeutics, treatment resistance remains a significant problem. It has become increasingly evident that the innate and adaptive immune systems play a significant role in the modulation of anti-tumor responses to traditional cancer-directed therapies. By inducing DNA damage and cell death, radiation therapy appears to activate both innate and adaptive immune responses. Immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) also have yielded promising results, particularly in the recurrent/metastatic setting. In this review, we will discuss the rationale for combining radiotherapy with immunotherapy to harness the immunomodulatory effects of radiation therapy on HNSCC, as well as biomarkers for immune response. We will also review recent preclinical and clinical data exploring these combinations in various contexts, including recurrent/metastatic and locally advanced disease. Among those with locally advanced HNSCC, we will discuss clinical trials employing immunotherapy either concurrently with radiation therapy or as maintenance following chemoradiation in both the definitive and postoperative settings, with or without the use of cisplatin-based or non-cisplatin-based chemotherapy.

Revisiting the Radiation Therapy Oncology Group 1221 Hypothesis: Treatment for Stage III/IV HPV-Negative Oropharyngeal Cancer.

OBJECTIVE: In 2014, the Radiation Therapy Oncology Group 1221 trial was initiated to analyze whether surgery with risk-based radiation therapy or chemoradiation therapy was superior to chemoradiation therapy alone in patients with clinically staged T1-2N1-2bM0 HPV-negative oropharyngeal squamous cell carcinoma. However, the study was prematurely terminated. Given the lack of a randomized controlled trial, we retrospectively approached the same question using large national cancer databases. STUDY DESIGN: Retrospective cohort study. SETTING: The National Cancer Database and Surveillance, Epidemiology, and End Results (SEER) program from 2010 to 2016. METHODS: We identified 3004 patients in the National Cancer Database and 670 patients in the SEER database. Statistical techniques included Kaplan-Meier survival analysis, binary and multinomial logistic regressions, Cox proportional hazard regressions, and inverse propensity score weighting. RESULTS: On weighted multivariable Cox regression, patients recommended to receive frontline surgery had improved overall survival as compared with those recommended to receive chemoradiation therapy alone (hazard ratio [HR], 0.77; 95% CI, 0.68-0.86). On post hoc multivariable analysis based on therapy actually received, frontline surgery with adjuvant chemoradiation therapy was associated with improved overall survival (HR, 0.59; 95% CI, 0.50-0.71) as compared with chemoradiation therapy without surgery. Analysis of the SEER cohort revealed improved overall survival (HR, 0.69; 95% CI, 0.54-0.87) and head and neck cancer-specific survival (HR, 0.59; 95% CI, 0.41-0.84) in patients recommended to receive frontline surgery over chemoradiation therapy alone. CONCLUSION: Our findings support the use of surgery with risk-based addition of adjuvant therapy in patients with cT1-2N1-2bM0 HPV-negative oropharyngeal cancer.

Benefits of a Multidisciplinary Women's Sexual Health Clinic in the Management of Sexual and Menopausal Symptoms After Pelvic Radiotherapy.

OBJECTIVE: The objective of this study was to examine patterns of care and outcomes of female cancer patients treated for sexual and menopausal symptoms following pelvic radiotherapy (PRT) at our institution's multidisciplinary Sexuality, Intimacy, and Menopause (SIMS) Program. MATERIALS AND METHODS: We performed a retrospective review of 69 female patients who received PRT for gynecologic or gastrointestinal malignancies and were referred for SIMS Program intervention. Indications for referral and treatment patterns were summarized. Preintervention and postintervention, patients were screened at follow-up visits, and symptoms were recorded. Statistics were performed using Stata 13.1. RESULTS: Cancer types included cervical (53.6%), endometrial (31.9%), anorectal (5.8%), and vulvar/vaginal (8.7%). The median age was 48 years (interquartile range: 38 to 58 y). Patients were educated on vaginal lubricants, moisturizers, and dilator therapy both before and after PRT. Reasons for SIMS referral included persistent menopausal symptoms (50.7%), dyspareunia (40.6%), vaginal dryness (37.7%), decreased libido (17.4%), intimacy concerns (17.4%), and/or physical examination alterations (27.5%). SIMS interventions included vaginal estrogen (77.3%), nonhormonal climacteric interventions (53%), systemic hormone therapy (31.8%), dehydroepiandrosterone (4.6%), testosterone cream (4.6%), and/or psychological pharmacotherapy or counseling (13.6%). With a median follow-up of 36 months (interquartile range: 18 to 58 mo), sexual symptoms improved or were stable in 83.6%, while menopausal symptoms improved or were stable in 80.5%. CONCLUSIONS: This study highlights the importance of multidisciplinary care in improving the sexual and menopausal symptoms of women after PRT. Future work examining the impact of intervention timing with respect to PRT and measures of patient satisfaction is warranted.

Stage III uterine serous carcinoma: modern trends in multimodality treatment.

OBJECTIVE: To examine outcomes in a modern treatment era for stage III uterine serous carcinoma (USC). METHODS: Fifty women were retrospectively identified as 2009 International Federation of Gynecology and Obstetrics stage III USC patients who received radiotherapy (RT) at our institution between 1/2003-5/2018. The patients were divided into 2 cohorts: 20 in the early era (2003-2010) and 30 in the modern era (2011-2018). Patient characteristics were compared using χ² tests for categorical variables and t-tests for continuous variables. Recurrence free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards. RESULTS: The modern era differed from the early era in the increased use of volume-directed external beam RT (EBRT) as opposed to vaginal brachytherapy (VB) alone (33.3% vs 5.0%, p=0.048), minimally invasive surgery (56.7% vs. 25%, p=0.027), sentinel node sampling (26.7% vs. 0%, p=0.012), computed tomography imaging in the perioperative period (63.3% vs. 30%, p=0.044), and human epidermal growth factor receptor 2/neu testing (96.7% vs. 55%, p=0.001). Median follow-up for early and modern eras was 37.27 and 33.23 months, respectively. The early vs. modern 3-year RFS was 33% and 64% (p=0.039), respectively, while the 3-year OS was 55% and 90% (p=0.034). Regional nodal recurrence more common among the patients who received VB only (p=0.048). CONCLUSION: Modern era treatment was associated with improved RFS and OS in patients with stage III USC. Regional nodal recurrences were significantly reduced in patients who received EBRT.

Standard Tangential Radiation Fields Do Not Provide Incidental Coverage to the Internal Mammary Nodes.

PURPOSE: The purpose of the study was to evaluate the incidental dose delivered to the internal mammary nodes (IMNs) in patients treated with tangential 3-dimensional conformal radiation therapy and to identify potential parameters that may affect the IMN mean dose. METHODS AND MATERIALS: The study cohort consisted of 362 consecutively treated patients with breast cancer in our center between January 2015 and July 2017 who had received adjuvant whole-breast radiation therapy or postmastectomy radiation with or without a supraclavicular ± axillary field and without intentional inclusion of the IMN chain. The clinical target volume (CTV) for the IMNs was contoured per the Radiation Therapy Oncology Group 3509/3510 protocol and was then divided into 3 subregions: upper, mid, and lower thirds. The planning target volume for the IMNs was generated by adding 5 mm to the CTV. The primary endpoint was to assess the V40 (volume receiving 40 Gy) to the IMN planning target volume and its potential influencing parameters using a linear regression model. RESULTS: The mean (±standard deviation) dose to the CTV IMN chain was 36% ± 28.7%. The Kruskal-Wallis test demonstrated significant differences in the median dose delivered to each level: upper third (7.2%), mid third (21.5%), and lower third (41.7%) (P < .001). The mean V40 IMN planning target volume was 14.2% (standard deviation, 18.7%). Presternal fat thickness (regression coefficient [RC] = -16.4; P < .001), postmastectomy radiation (RC = 24; P < .001), reconstruction after mastectomy (RC = -22.4; P < .001), and the addition of a supraclavicular field (RC = 8.8; P = .03) were all significantly associated with IMN mean dose. CONCLUSIONS: For patients receiving standard breast/chest wall tangential radiation fields, the IMN chain is not incidentally covered with therapeutic doses in the vast majority of cases. Therefore, if regional nodal radiation is intended to include the IMNs, contouring and careful plan review are necessary to ensure adequate therapeutic coverage.

Gender disparities in head and neck cancer chemotherapy clinical trials participation and treatment.

OBJECTIVES: To characterize the representation of women in clinical trials directing the National Comprehensive Cancer Network (NCCN) guidelines for chemotherapy use in head and neck squamous cell carcinoma (HNSCC), as well as the relationship between gender and chemotherapy administration in the definitive treatment of HNSCC in the United States. METHODS: A review of all HNSCC chemotherapy clinical trials cited by the 2018 NCCN guidelines was performed. Sex-based proportions were compared with the corresponding proportions in the general U.S. population of patients with HNSCC between 1985 and 2015, derived from the Surveillance, Epidemiology, and End Results (SEER) program. A second analysis using the National Cancer Database (NCDB), identified 63,544 adult patients diagnosed with stages III-IVB HNSCC between 2004 and 2014 and treated with definitive radiotherapy or chemoradiotherapy. Univariable and multivariable logistic regression analyses were used to identify predictors of chemotherapy administration. RESULTS: While women comprised 26.2% of U.S. patients with HNSCC between 1985 and 2015, they comprised only 17.0% of patients analyzed in U.S. NCCN-cited chemotherapy clinical trials between 1985 and 2017. On multivariable analysis, women had decreased odds of receiving chemotherapy (Odds Ratio [OR]: 0.875; 95% Confidence Interval [CI]: 0.821-0.931; p < 0.001). CONCLUSION: Women are underrepresented in HNSCC chemotherapy clinical trials cited by the national guidelines. Additionally, women are less likely than men to receive definitive chemoradiotherapy as oppose to definitive radiotherapy. Reasons for these disparities warrant further investigation as well as re-evaluation of eligibility criteria and enrollment strategies, in order to improve relevance of clinical trials to women with HNSCC.

Cost-effectiveness of adjuvant intravaginal brachytherapy in high-intermediate risk endometrial carcinoma.

PURPOSE: We assessed the cost-effectiveness of adjuvant intravaginal brachytherapy (IVBT) vs. observation after total hysterectomy and bilateral salpingo-oophorectomy (TH/BSO) for high-intermediate risk (HIR) endometrial carcinoma. METHODS AND MATERIALS: A Markov model was used to assess the cost-effectiveness of IVBT by comparing average cumulative costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) between patients allocated to (1) 'observation' or (2) 'IVBT' after TH/BSO. We used a prototype Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-defined HIR patient in the base case analysis. We calibrated the model to match the outcomes reported in the PORTEC-1 and PORTEC-2 trials. Utilities were obtained from published estimates, and costs were calculated based on Medicare reimbursement ($5445 for IVBT). The societal willingness-to-pay threshold was set at $100,000 per QALY. The time horizon was 5 years. RESULTS: IVBT was associated with a net increase of 0.094 QALYs (4.512 vs. 4.418) as well as an increase in mean cost ($17,453 vs. $15,620) relative to observation. The ICER for IVBT was $19,500 per QALY. On one-way sensitivity analysis, IVBT remained cost-effective when its cost was less than $12,937. If the probability of vaginal recurrence in the observation arm was increased or decreased by 25%, the ICER became $1335 per QALY and $87,925 per QALY, respectively. Probabilistic sensitivity analysis revealed that IVBT was the preferred management option in 86% of simulations. CONCLUSIONS: IVBT is cost-effective compared with observation after TH/BSO for HIR endometrial carcinoma by commonly accepted willingness-to-pay thresholds.

Impact of vaginal cylinder diameter on outcomes following brachytherapy for early stage endometrial cancer.

OBJECTIVE: To examine the outcomes (tolerability, toxicity, and recurrence) of vaginal brachytherapy (VBT) among endometrial cancer (EC) patients treated with small cylinder size. METHODS: Patients with EC who received adjuvant VBT between September 2011 and December 2015 were reviewed. Patients were fitted with the largest vaginal cylinder they could comfortably accommodate, from 2.0-3.0 cm diameter. Small cylinders were defined as size 2.3 cm or less. Patient, tumor, or treatment characteristics were correlated with need for small cylinders. Treatment tolerability, measures of gastrointestinal (GI), genitourinary (GU), and vaginal toxicity, and rates of recurrence were analyzed. RESULTS: Three hundred four patients were included. Small cylinders were used in 51 patients (17%). Normal body mass index (BMI; p<0.001), nulligravidity (p<0.001), and shorter vaginal length (p<0.001) were associated with small cylinder size. There was no acute or late grade 3 toxicity. Rates of acute (grade 1-2) GI, GU, or vaginal symptoms were low (10%, 11%, and 19%, respectively). Small cylinder size was associated with increased likelihood of reporting acute GI (p<0.05) but not GU or vaginal symptoms. Small cylinder size was associated with higher risk of grade 1-2 vaginal stenosis (odds ratio [OR]=4.7; 95% confidence interval [CI]=1.5-14.7; p=0.007). There was no association between cylinder size and recurrence rate (p=0.55). CONCLUSION: VBT is generally very well tolerated, however, patients fitted with smaller cylinders (commonly nulligravid and low BMI) may have increased side effects. Further study to improve the dosimetry of VBT for patients requiring small cylinders may be worthwhile.

Optimizing a lupus autoantibody for targeted cancer therapy.

The specificity of binding by antibodies to target antigens is a compelling advantage to antibody-based cancer therapy, but most antibodies cannot penetrate cells to affect intracellular processes. Select lupus autoantibodies penetrate into cell nuclei, and the potential for application of these antibodies in cancer therapy is an emerging concept. Here, we show that a divalent lupus anti-DNA autoantibody fragment with enhancing mutations that increase its ability to penetrate cell nuclei and bind DNA causes accumulation of DNA double-strand breaks in and is highly and selectively toxic to cancer cells and tumors with defective homology-directed repair of DNA double-strand breaks. These findings provide proof of principle for the use of optimized lupus autoantibodies in targeted cancer therapy.

A nucleolytic lupus autoantibody is toxic to BRCA2-deficient cancer cells.

Cancer cells with defects in DNA repair are highly susceptible to DNA-damaging agents, but delivery of therapeutic agents into cell nuclei can be challenging. A subset of lupus autoantibodies is associated with nucleolytic activity, and some of these antibodies are capable of nuclear penetration. We hypothesized that such antibodies might have potential as therapeutic agents targeted towards DNA repair-deficient malignancies. We identified the lupus autoantibody 5C6 as a cell-penetrating nucleolytic antibody and found that 5C6 has a differential effect on a matched pair of BRCA2-proficient and deficient DLD1 colon cancer cells. 5C6 selectively induced γH2AX in, and suppressed the growth of, the BRCA2-deficient cells. These findings demonstrate the potential utility of 5C6 in targeted therapy for DNA repair-deficient malignancies and strengthen the rationale for studies of additional lupus autoantibodies in order to identify the best candidates for development as therapeutic agents. In addition, the toxic effect of 5C6 on BRCA2-deficient cells provides further support for the hypothesis that some lupus autoantibodies contribute to the lower risk of specific cancers associated with systemic lupus erythematosus.