Quality Assurance for Stereotactic Body Radiation Therapy for Gynecologic Malignancies.

The use of stereotactic body radiation therapy (SBRT) is not well studied or reported in the treatment of gynecologic malignancies, despite its success in the definitive management of other cancer sites. This report describes a rigorous quality assurance process for patients to undergo dose escalation to the pelvis via stereotactic photon beam irradiation. Patients who receive SBRT must be ineligible for conventional brachytherapy boost and undergo comprehensive informed consent. Fiducial placement, bowel prep, Foley catheter placement with standardized bladder filling, computerized tomography (CT) simulation with whole-body immobilization, magnetic resonance imaging (MRI)-assisted target delineation, planning aims based on the established brachytherapy literature, and physics consultation for SBRT plan optimization are necessary. Prior to each fraction, the simulation position is reproduced and verified with on-table cone beam CT, and the position is maintained with whole-body immobilization. Following treatment, the treating physician is active in survivorship and toxicity management. Gynecologic SBRT is an ongoing area of study, and preliminary successes in delivering high-quality stereotactic dose escalation suggest prospective investigation is warranted. By adhering to strict quality control measures and following a pre-defined best standard of practice, patients with gynecologic malignancies who are ineligible for traditional brachytherapy procedures can be safely treated with SBRT.

Apparent diffusion coefficient values predict response to brachytherapy in bulky cervical cancer.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (DWI) provides a measurement of tumor cellularity. We evaluated the potential of apparent diffusion coefficient (ADC) values obtained from post-external beam radiation therapy (EBRT) DWI and prior to brachytherapy (BT) to predict for complete metabolic response (CMR) in bulky cervical cancer. METHODS: Clinical and DWI (b value = 500 s/mm2) data were obtained from patients undergoing interstitial BT with high-risk clinical target volumes (HR-CTVs) > 30 cc. Volumes were contoured on co-registered T2 weighted images and 90th percentile ADC values were calculated. Patients were stratified by CMR (defined by PET-CT at three months post-BT). Relation of CMR with 90th percentile ADC values and other clinical factors (International Federation of Gynecology and Obstetrics (FIGO) stage, histology, tumor and HR-CTV size, pre-treatment hemoglobin, and age) was assessed both in univariate and multivariate logistic regression analyses. Youden's J statistic was used to identify a threshold value. RESULTS: Among 45 patients, twenty-eight (62%) achieved a CMR. On univariate analysis for CMR, only 90th percentile ADC value was significant (p = 0.029) while other imaging and clinical factors were not. Borderline significant factors were HR-CTV size (p = 0.054) and number of chemotherapy cycles (p = 0.078). On multivariate analysis 90th percentile ADC (p < 0.0001) and HR-CTV size (p < 0.003) were highly significant. Patients with 90th percentile ADC values above 2.10 × 10- 3 mm2/s were 5.33 (95% CI, 1.35-24.4) times more likely to achieve CMR. CONCLUSIONS: Clinical DWI may serve to risk-stratify patients undergoing interstitial BT for bulky cervical cancer.

Effect of Quality of Life on Radiation Adherence for Patients With Cervical Cancer in an Urban Safety Net Health System.

PURPOSE: Outcomes for patients undergoing chemoradiation for cervical cancer are dependent on adherence to radiation therapy (RT). In other diseases, quality of life (QoL) is associated with treatment adherence, but the association between QoL and RT adherence for patients with cervical cancer remains unclear. METHODS AND MATERIALS: This prospective study included patients undergoing RT for cervical cancer from 2017 to 2021 at an urban safety net hospital. The Functional Assessment of Cancer Therapy-Cervical Cancer Version 4 was used to assess QoL based on 5 subscales (physical, functional, social and emotional, and cervical-cancer specific). The survey was administered at radiation consult, then weekly during RT and at follow-up. Patient information was abstracted from the medical record. Radiation nonadherence was defined as missing ≥2 days of external beam RT. The Functional Assessment of Cancer Therapy-Cervical Cancer Version 4 total and subscale scores were compared between adherent and nonadherent patients. Multivariable logistic regression was performed to control for confounding variables. RESULTS: Ninety-three patients were enrolled, completing 522 surveys. Median age at diagnosis was 46 years (interquartile range, 40-51); 76% of patients were Hispanic, and 12% were Black. Only 30% of patients were nonadherent with RT. A psychiatric comorbidity (P = .012) and symptomatic presentation (P = .027) were associated with decreased adherence. Baseline total QoL was higher in treatment-adherent than in nonadherent patients (median, 124.86; range, 48-160; 108.9, 46-150; P = .01). Higher baseline functional and physical subscale scores were associated with adherence (P < .05). Change from baseline to lowest score during treatment in the emotional subscale was also associated with patient adherence (P < .05). In multivariable analysis, higher baseline physical score, baseline total score, and change in emotional subscale score were associated with adherence (P < .05). CONCLUSIONS: Poor QoL during chemoradiation for cervical cancer is associated with missed treatments. Physician assessment of a patient's well-being while they are undergoing RT is of utmost importance to improve adherence to treatment.

Predictors of follow-up non-compliance after definitive radiotherapy for locally advanced cervical cancer at a community cancer center.

Introduction: Non-compliance to post-treatment cancer surveillance can lead to late detection of recurrence. This study aims to identify patients at high risk for loss of follow-up after radiotherapy for locally advanced cervical cancer. Methods: Consecutive patients with locally advanced cervical cancer treated with definitive chemoradiotherapy (2013-2020) at a community cancer center were retrospectively reviewed. The main outcome was overall follow-up compliance rate over time. Additionally, specialist-specific follow-up times, reasons for discontinuation and predictors of loss of follow-up events were evaluated. Results: The median age of the 154 patients included was 46.5 years (range: 26-84). The 6-month, 1-, 3-, and 5-year overall loss of follow-up rates were: 5.3%, 15.3%, 33.6%, and 48.2%, respectively. After a median overall follow-up time of 21.0 months, the median specialist-specific surveillance times were 17 months and 6 months with gynecologic and radiation oncologists, respectively (p < 0.01). Overall, the most common reasons for loss of follow-up were financial (21.7%) and relocation to another city (28.3%). By specialty, the most common reasons were relocation of care (56.5%, gynecologic oncologist) and disease progression (31.3%, radiation oncologist). In the multivariable analysis, older age (continuous, OR: 0.96; p < 0.01) and Hispanic ethnicity (OR: 0.39; p < 0.01) were protective against loss of follow-up, while increased number of gestations (continuous, OR: 1.23, p = 0.01) and living farther from the cancer center (continuous, OR: 1.002; p = 0.03) increased the chance of loss of follow-up. Conclusion: Younger, non-Hispanic, multiparous women that live far from the community cancer center have an increased chance of follow-up discontinuity, which are attributed to financial reasons in more than 20% of the cases.

Family Planning, Fertility, and Career Decisions Among Female Oncologists.

Importance: Female oncologists often spend their childbearing years in training and establishing careers, with many later experiencing fertility issues when starting a family. Physician fertility and family planning are rarely discussed during training. Attitudes among female oncologists regarding family planning are unknown. Objectives: To understand barriers to family planning as well as the association of fertility treatment with career decisions and to assess experiences of pregnancy-based discrimination among female oncologists. Design, Setting, and Participants: In this survey study, a novel 39-item questionnaire was distributed to US female oncologists from May 7 to June 30, 2020, via email and social media channels. Questions regarding factors associated with family planning, maternity leave, and discrimination were included. Main Outcomes and Measures: The distribution of survey responses was compared by oncology subspecialty. Multivariable logistic regression was performed to determine independent variables for discrimination experienced during maternity leave. Results: Responses were collected from 1004 female oncologists. Most respondents (847 [84.4%]) were married, and 713 (71.0%) were currently working full-time. A total of 351 oncologists (35.0%) worked in radiation oncology, 344 (34.3%) in medical oncology, 186 (18.4%) in surgical oncology, and 91 (9.1%) in pediatric oncology. A total of 768 respondents (76.5%) had children, and of these, 415 (41.3%) first gave birth during postgraduate training, and 275 (27.4%) gave birth in years 1 to 5 as an attending physician. Almost all respondents (951 [94.7%]) stated that their career plans were at least somewhat associated with the timing of when to start a family. Having a supportive partner was the most commonly cited positive association with family planning (802 [79.9%]), while long work hours and heavy workload (669 [66.6%]) were the most common negative factors. One-third (318 [31.7%]) had miscarried, and 315 (31.4%) reported difficulty with infertility that required fertility counseling and/or treatment; 660 (65.7%) thought fertility preservation should be discussed with women during medical school and/or residency. One-third (312 [31.1%]) reported experiencing discrimination during pregnancy, and 332 (33.1%) stated they experienced discrimination for taking maternity leave. On multivariable logistic regression, having more than 1 child was associated with increased likelihood of experiencing discrimination during maternity leave (2 children: odds ratio, 1.62 [95% CI, 1.10-2.39]; P = .02; ≥3 children: odds ratio, 1.84 [95% CI, 1.14-2.95; P = .01). Conclusions and Relevance: In this survey study of female oncologists, 1 in 3 reported experiencing infertility and 1 in 3 stated they experienced discrimination during pregnancy and/or for taking maternity leave. Systemic changes are necessary to ensure women are supported and able to advance equitably in the field.

Analyzing factors associated with clinical trial publication in radiation oncology.

Clinical trials are considered the gold standard of clinical research and are sought in the medical literature for the goal of providing quality care. To identify factors associated with successful or unsuccessful publication of clinical trials in radiation oncology, data on trial characteristics were collected from the National Institutes of Health database on clinicaltrials.gov. To assess studies that had adequate time to accrue, trials between 2000 and 2005 were extracted by filtering for "radiation oncology". Studies were excluded if they were incomplete, observational, Phase 4, or lacked sufficient method descriptions. Included studies underwent independent samples t-tests and Pearson Chi-Square bivariate analyses. 538 studies were candidates for analysis of clinical trial characteristics. United States (US) origin, multi-center sites, government funding, Phase III status, and randomized allocation were factors associated with increased publication rate. The number of study arms, study length, and number of participants were significantly greater in published trials. The review's results demonstrate potential barriers or facilitators to publication, and they suggest that publication status may be influenced by geographic, financial, and temporal characteristics of clinical trials. Understanding trial background factors that may impact publication improve data visibility and clinical advancements for all.

Endoscopic assessment of radiological stage IVA cervical cancer: A bivariate meta-analysis supporting an evidence-based staging algorithm proposal.

OBJECTIVE: To optimize the use of confirmatory endoscopic exams (cystoscopy/proctoscopy) in the staging of locally advanced cervical cancer (LACC), the present study evaluates the predictive value of radiological exams (CT and MRI) to detect bladder/rectum invasion. METHODS: A systematic search of databases (PubMed and EMBASE) was performed (CRD42021270329). The inclusion criteria were: a) cervix cancer diagnosis; b) staging CT and/or MRI (index test); c) staging cystoscopy and/or proctoscopy (standard test); and d) numbers of true positives (TP), true negatives (TN), false positives (FP), and false negatives (FN) provided. A random-effects bivariate meta-analysis of positive predictive value (PPV) and negative predictive value (NPV) was performed with moderator analyses by imaging modality (CT and MRI) and prevalence. RESULTS: Nineteen studies met the inclusion criteria, totaling 3480 and 1641 patients for bladder and rectum analyses, respectively. For bladder invasion (prevalence ranged from 0.9% to 34.5%), the overall PPV was 45% (95% confidence interval, 33%-57%, based on 19 studies). Per subgroup, the PPV was 31% for MRI/prevalence ≤6%, 33% for CT/prevalence ≤6%, and 69% for CT/prevalence >6%. For rectal invasion (prevalence ranged from 0.4% to 20.0%), the overall PPV was 30% (95% confidence interval, 17%-47%, based on 8 studies). Per subgroup, the PPV was 36% for MRI/prevalence ≤1%, 17% for MRI/prevalence >1%, and 38% for CT/prevalence >1%. The overall NPV for bladder invasion and rectal invasion were 98% (95% confidence interval, 97%-99%) and 100% (95% confidence interval, 99%-100%), respectively. Considering prevalence and radiological modality, the point estimate of NPV varied from 95% to 100% for bladder invasion and from 99% to 100% for rectum invasion. CONCLUSIONS: Due to low PPV (<50%) of radiological staging, endoscopic exams may be necessary to correctly assess radiological stage IVA LACC. However, they are not necessary after negative radiological exam (NPV ≥95%).

Concurrent Chemo-radiation As a Means of Achieving Pathologic Complete Response in Triple Negative Breast Cancer.

Management of triple negative breast cancer (TNBC) that is resistant to chemotherapy remains a challenge. Many studies have investigated the unconventional approach of concurrent chemotherapy with radiation in management of TNBC that is resistant to neoadjuvant anthracycline and taxane containing chemotherapy. Various chemotherapies have been used as radiosensitizers. In this report we summarize the published literature and highlight clinical trials that pertain to management of TNBC.

Impact of hematologic toxicities during concurrent chemoradiation for cervical cancer.

OBJECTIVE: To evaluate the prognostic significance of hematological toxicities during cervical cancer treatment. METHODS: Patients treated for cervical carcinoma with definitive chemoradiation were identified. Toxicities were assessed during weeks 1 to 6 of concurrent external beam radiation and chemotherapy. Outcomes were analyzed using Cox regression analysis. RESULTS: One hundred twenty-one patients with Federation of Gynecology and Obstetrics stage I-III disease were eligible for analysis. Median age at diagnosis was 45 years (interquartile range, 40-52) with median follow-up time of 34 months (95% confidence interval, 30.8-37.2). All patients experienced some grade of hematologic toxicity. The most common grade 3+ toxicities were low absolute lymphocyte count (n=115, 95%), low white blood cell count (n=21, 17%), and anemia (n=11, 9%). The most common grade 4 toxicity was lymphopenia, experienced by 36% of patients (n=44). Grade 4 lymphopenia was associated with reduced overall survival (hazard ratio [HR], 4.5; P=0.005), progression-free survival (HR, 3.4; P=0.001), and local control (HR, 4.1; P=0.047). Anemia grade 3, 4 was also associated with reduced overall survival (HR, 4.1; P=0.014). After controlling for disease and treatment variables, grade 4 lymphopenia remained significantly associated with reduced overall survival (HR, 9.85; P=0.007). The association with grade 4 lymphopenia only remained significant in women of Hispanic ethnicity. CONCLUSION: Severe lymphopenia was associated with reduced overall survival and progression-free survival in Hispanic women undergoing definitive chemoradiation for cervical cancer, but not associated with outcomes in non-Hispanic women.

Esomeprazole enhances the effect of ionizing radiation to improve tumor control.

The resistance of cancer cells to radiation-based treatment is a major clinical challenge confounding standard of care in cancer. This problem is particularly notable in many solid tumors where cancer cells are only partially responsive to radiation therapy. Combination of radiation with radiosensitizers is able to enhance tumor cell killing. However, currently available radiosensitizers are associated with significant normal tissue toxicity. Accordingly, there is an unmet need to develop safer and more effective radiosensitizers to improve tumor control. Here, we evaluated the radiosensitizing effect of the FDA-approved drug esomeprazole in normal and radioresistant human head and neck squamous cell carcinoma (HNSCC) cells in vitro, and in a mouse model of HNSCC. For the in vitro studies, we used cancer cell colony formation (clonogenicity) assay to compare cancer cell growth in the absence or presence of esomeprazole. To determine mechanism(s) of action, we assessed cell proliferation and profiled cell cycle regulatory proteins. In addition, we performed reverse phase protein array (RPPA) study to understand the global effect of esomeprazole on over 200 cancer-related proteins. For the in vivo study, we engrafted HNSCC in a mouse model and compared tumor growth in animals treated with radiation, esomeprazole, and combination of radiation with esomeprazole. We found that esomeprazole inhibits tumor growth and dose-dependently enhances the cell killing effect of ionizing radiation in wildtype and p53-mutant radioresistant cancer cells. Mechanistic studies demonstrate that esomeprazole arrests cancer cells in the G1 phase of the cell cycle through upregulation of p21 protein and inhibition of cyclin-dependent kinases (Cdks) type 1 (Cdk1) and type 2 (Cdk2). In vivo data showed greater tumor control in animals treated with combination of radiation and esomeprazole compared to either treatment alone, and that this was associated with inhibition of cell proliferation in vivo. In addition, combination of esomeprazole with radiation significantly impaired repair following radiation-induced DNA damage. Our studies indicate that esomeprazole sensitizes cancer cells to ionizing radiation, and is associated with upregulation of p21 to arrest cells in the G1 phase of the cell cycle. Our findings have significant therapeutic implications for the repurposing of esomeprazole as a radiosensitizer in HNSCC and other solid tumors.

Association Between Metabolic Syndrome and Endometrial Cancer Survival in a SEER-Medicare Linked Database.

BACKGROUND: Metabolic syndrome has previously been linked to increased risk of endometrial cancer. This study examines the association between metabolic syndrome and cancer-specific survival (CSS) in early stage and locoregionally advanced endometrial cancer. METHODS: The SEER-Medicare linked database was used to identify a cohort of patients with endometrial cancer between 1992 and 2011 who underwent hysterectomy. Patients with incomplete stage or grade information were excluded. Patients were stratified into early stage (stage I to II) or locoregionally advanced (stage III to IVa) disease. Metabolic syndrome status was determined through Medicare claims 1 year before diagnosis. The relationship between metabolic syndrome and CSS was evaluated using univariable and multivariable Cox proportional hazards regression analyses. RESULTS: A total of 10,090 patients with endometrial cancer were identified. The mean age was 75 and the majority (91.5%) were white. At diagnosis, 86.6% of patients were early stage and 13.4% were locoregionally advanced. Sixteen percent of patients had metabolic syndrome. On stage stratified multivariable analysis, race, income quartile, year of diagnosis, histopathology, and adjuvant treatment were associated with CSS in early stage disease. Presence of metabolic syndrome was associated with worse CSS in early stage disease (hazard ratio=1.28, 95% confidence interval: 1.09-1.53); this difference did not exist for locoregionally advanced disease (hazard ratio=1.18, 95% confidence interval: 0.93-1.49). CONCLUSIONS: In elderly early stage endometrial cancer patients, metabolic syndrome is associated with worse CSS. Control of metabolic syndrome through lifestyle and pharmacologic therapies may improve cancer prognosis in this population.

Risk of thyroid cancer after therapeutic irradiation in adult patients: An Age-Based surveillance, epidemiology, and end results analysis.

OBJECTIVES/HYPOTHESIS: One risk of radiation therapy exposure (XRTe) is second primary thyroid cancer (SPTC). Previous reports examined this in children, but no population-based studies have explored XRTe and SPTC across all ages or stratified by histological subtypes. STUDY DESIGN: Database study. METHODS: We report patient characteristics of a Surveillance, Epidemiology, and End Results (SEER) dataset of SPTC (n = 4,669) using χ2 and t tests. Odds ratio (OR) for SPTC was determined based on age, histology, and XRTe compared to expected values in the SEER database. Kaplan-Meier survival and Cox proportional hazard ratios were reported to determine factors influencing latent survival (LS; time from initial diagnosis to SPTC) and overall survival in univariate and multivariate models. RESULTS: Extrathyroid extension and node status based on XRTe were similar (P = .684 and P = .776, respectively). XRTe patients were more likely to have smaller tumors (17.6 vs. 19.3 mm, P = .007). XRTe patients were diagnosed with SPTC at younger ages (59.8 vs. 62.7 years, P < .001) without a difference in LS (7.45 vs. 7.50 years, P = .426). Patients aged 1 to 14 years and 15 to 29 years at diagnosis of first cancer are at higher risk of SPTC after XRTe (OR = 1.89, P = .005 and OR = 2.35, P = .001, respectively), unlike patients age 30 to 44 years and 45+ years (OR = 1.03, P = .823 and OR = 0.97, P = .624, respectively). This difference is not present for follicular and medullary SPTC. CONCLUSIONS: Patients aged 30+ years receiving radiation therapy (XRT) do not have an increased risk of SPTC. Deliberation is necessary in recommending, planning, and delivering XRT to minimize risk of subsequent malignancy in younger patients. LEVEL OF EVIDENCE: NA Laryngoscope, 130: 2081-2086, 2020.

Topical Esomeprazole Mitigates Radiation-Induced Dermal Inflammation and Fibrosis.

Radiation therapy is a mainstream strategy in the treatment of several cancer types that are surgically unresectable. Unfortunately, cancer patients often suffer from unintended consequences of radiotherapy, including the development of skin inflammation (dermatitis), which may progress to fibrosis. These morbid complications often require interruption of radiotherapy and threaten the relapse of underlying cancer. Current treatment options for radiation dermatitis are suboptimal and compel the need to develop safer, more effective therapies. In this study, we assessed the biophysical properties of topically-formulated esomeprazole (here referred to as dermaprazole) and performed proof-of-concept studies to evaluate its efficacy in vitro and in vivo. We found that dermaprazole induced nuclear translocation of erythroid 2-related factor 2 (Nrf2) and significantly upregulated heme oxygenase 1 (HO1) gene and protein expression in a 3D human skin model. Our animal study demonstrated that dermaprazole improved macroscopic appearance of the irradiated skin and accelerated healing of the wounds. Histopathology data corroborated the photographic evidence and confirmed that both prophylactically and therapeutically administered dermaprazole conferred potent anti-inflammatory and antifibrotic effects. Gene expression data showed that dermaprazole downregulated several pro-oxidant, pro-inflammatory and profibrotic genes. In conclusion, topical formulation of the FDA-approved drug esomeprazole is highly effective in attenuating dermal inflammation and fibrosis.

Evaluating Treatment Patterns for Small Cell Carcinoma of the Colon Using the National Cancer Database (NCDB).

OBJECTIVE(S): The objective of this study was to characterize the clinicopathological prognostic factors and treatment patterns for small cell carcinoma (SCC) of the colon, a rare disease without standard treatment guidelines. METHODS: We analyzed clinicopathological and treatment variables for 503 cases of histologically proven SCC colon entered into the National Cancer Database (NCDB) between 2004 and 2013. Survival curves were generated using Kaplan-Meier and compared by the log-rank test. Cox proportional hazard regression was used to control for covariates and evaluate the effect of different treatment modalities on overall survival. RESULTS: Four hundred seventy-two (93.8%) patients had complete clinical staging information and were therefore included in our analysis. Of these patients, 149 (31.5%) had limited stage disease (LD) and 323 (68.4%) had extensive stage disease (ED) at presentation. Median overall survival (OS) for patients with ED was significantly lower than for those with LD (4.04 months vs. 21.82 months; p < 0.001). Multivariate Cox regression analysis showed administration of chemotherapy was associated with improved survival in patients with LD and ED (p = 0.026, p < 0.001) while surgery was not associated with improved survival in patients with LD or ED (p = 0.943, p = 0.630). Radiation therapy was associated with improved survival in patients with ED (p = 0.044). CONCLUSIONS: SCC of the colon carries a poor prognosis, especially in patients presenting with metastatic disease. Surgery and chemotherapy are administered more frequently than radiation, and chemotherapy is associated with improved survival, unlike surgery.

Genetic characterization of medullary thyroid cancer in childhood survivors of the Chernobyl accident.

BACKGROUND: Radiation-associated fusion oncogenes play a direct role in papillary thyroid cancer development and pathogenic fusions have recently been reported in medullary thyroid cancer. To date, no studies have evaluated oncogenic events in medullary thyroid cancer in a radiation-exposed population. METHODS: Somatic and germline alterations, including RET fusions, were evaluated in paired medullary thyroid cancer tumor and normal samples from the Chernobyl Tissue Bank, a heavily screened population affected by the Chernobyl disaster. RESULTS: Tissue was available for 49 individuals. The median age of diagnosis was 26 years (range 9 to 43 years); 16 were radiation-exposed at a median age of 6 (range 2 days to 17 years). A total of 21 patients harbored germline RET mutations (codons 634[13], 918[5], 790[1], 609[1], and 620[1]); 4 had family history. Sporadic medullary thyroid cancer was identified in 27 patients (RET[18], KRAS[1], RET+KRAS[1], TP53[1], wild type [6]), with 1 RET fusion (1/49;2%). The age at operation for patients with hereditary medullary thyroid cancer was not different than sporadic medullary thyroid cancer (23.5 vs 28 years, P = .063). In sporadic medullary thyroid cancer, radiation was not associated with a difference in age at operation, tumor size, or tumor stage (P > .05). CONCLUSION: In a heavily screened cohort, genetic analysis revealed germline RET mutations in previously unrecognized probands and a remarkable number of sporadic medullary thyroid cancer cases with a young age at presentation.