Why an Increasing Number of Unmatched Residency Positions in Radiation Oncology? A Survey of Fourth-Year Medical Students.

PURPOSE: The number of US fourth-year medical students applying to radiation oncology has decreased during the past few years. We conducted a survey of fourth-year medical students to examine factors that may be influencing the decision to pursue radiation oncology. METHODS AND MATERIALS: An anonymous online survey was sent to medical students at 9 participating US medical schools. RESULTS: A total of 232 medical students completed the survey. Of the 153 students who stated they were never interested in radiation oncology, 77 (50%) reported never having been exposed to the specialty as their reason for not pursuing radiation oncology. The job market was the most commonly cited factor among students who said they were once interested in but ultimately chose not to pursue radiation oncology. Conversely, the recent low pass rates for board examinations and a perception of a lack of diversity within radiation oncology had the least influence. CONCLUSIONS: Despite discussion of potential measures to address this disquieting trend, there have been minimal formal attempts to characterize and address potential causes of a decreasing interest in radiation oncology. This study's data are consistent with previous research regarding the trend of decreased medical student interest in radiation oncology and may be used as part of ongoing introspective assessment to inform future change within radiation oncology.

Pulmonary dose tolerance in hemithorax radiotherapy for Ewing sarcoma of the chest wall: Are we overestimating the risk of radiation pneumonitis?

BACKGROUND: Children with chest wall Ewing sarcoma with malignant pulmonary effusion or pleural stranding require hemithorax radiation, often with plans that exceed lung constraints. We investigated disease control and pneumonitis in children requiring hemithorax radiation. PROCEDURE: Eleven children (median age 13 years) received hemithorax radiotherapy. Symptomatic radiation pneumonitis was considered National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade 1+ with respiratory symptoms. Mean lung dose (MLD), volume of lung exposed to a dose ≥5 Gy (V5), ≥20 Gy (V20), and ≥35 Gy (V35) were recorded. Adult and pediatric lung constraints were obtained from Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines and Children's Oncology Group (COG) protocols, respectively. RESULTS: Median hemithorax dose was 15 Gy (1.5 Gy/fraction). Median total dose was 51 Gy (1.8 Gy/fraction). Most plans delivered both protons and photons. The ipsilateral MLD, V5, and V20 were 27.2 Gy, 100%, and 48.3%; the bilateral MLD, V20, and V35 were 14.1 Gy, 22.8%, and 14.3%, respectively. One hundred percent, 36%, and 91% of treatments exceeded recommended adult ipsilateral lung constraints of V5 <65%, V20 <52%, and MLD of 22 Gy; 64%, 45%, and 82% exceeded COG bilateral lung constraints of V20 <20%, MLD <15 Gy, and MLD <12 Gy, respectively; 82% of treatments exceeded the COG ipsilateral lung constraint of V20 <30%. At a median 36 months (range 12-129), the symptomatic radiation pneumonitis incidence was 0%. Two patients progressed with nonpulmonary metastatic disease and died at a median 12 months following radiotherapy. CONCLUSIONS: Existing guidelines may overestimate pneumonitis risk, even among young children receiving multiagent chemotherapy. For children with chest wall Ewing sarcoma and other thoracic malignancies, more data are needed to refine pediatric dose-effect models for pulmonary toxicity.

Neoadjuvant or Adjuvant Chemotherapy for Breast Cancer in Sub-Saharan Africa: A Retrospective Analysis of Recurrence and Survival in Women Treated for Breast Cancer at the Korle Bu Teaching Hospital in Ghana.

PURPOSE: It is established that addition of systemic therapy to locoregional treatment for breast cancer improves survival. However, reliable data are lacking about the outcomes of such treatment in women with breast cancer in low middle-income countries. We compared the outcomes of treatment in patients who had received neoadjuvant chemotherapy (NACT) or adjuvant chemotherapy and examined the factors associated with breast cancer recurrence and survival at the National Radiotherapy Oncology and Nuclear Medicine Centre, Korle Bu Teaching Hospital, Ghana. METHODS: This was a retrospective cohort study. The medical charts of women with breast cancer managed at the National Radiotherapy Oncology and Nuclear Medicine Centre from 2005 to 2014 were reviewed. A total of 388 patients with a median follow-up of 48 months were included in the study. Logistic regression was used to estimate the risk of recurrence. Survival was estimated using cox proportional hazards model. All models were adjusted with clinicopathologic variables. A P value of < .05 was considered statistically significant. RESULTS: Fifty-nine percent received adjuvant chemotherapy. In an adjusted logistic model, no difference was observed in locoregional recurrence between patients receiving NACT compared with those receiving adjuvant chemotherapy (odds ratio = 1.05; 95% CI, 0.44 to 2.47). However, NACT recipients had a higher likelihood of distant recurrence (odds ratio = 1.97; 95% CI, 1.24 to 3.15). In a multivariable analysis, no differences were observed in overall survival between the two chemotherapy groups (hazard ratio = 1.43; 95% CI, 0.91 to 2.26). CONCLUSION: NACT yields similar outcomes compared with adjuvant chemotherapy; however, recipients of NACT with advanced disease may have more distant failures. Early detection in a resource-limited setting is therefore crucial to optimal outcomes, significantly limiting recurrence and improving survival.

Proton radiotherapy for infant rhabdomyosarcoma: Rethinking young age as an adverse prognostic factor.

BACKGROUND & PURPOSE: In infants with rhabdomyosarcoma, young age is considered an adverse prognostic factor and treatment is often attenuated to reduce side effects. Proton therapy may improve the therapeutic ratio in these patients. We report outcomes in infants with rhabdomyosarcoma treated with proton therapy. MATERIALS & METHODS: Between 2009 and 2019, 37 infants <24 months old with non-metastatic rhabdomyosarcoma received proton therapy. Local control (LC), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier product limit. The log-rank test assessed significance between selected prognostic factors. Toxicity was graded per CTCAEv5.0. RESULTS: Median follow-up was 5.1 years. Overall, 76% of patients had an unfavorable primary site. Median dose was 50.4GyRBE. At 5 years, LC, PFS, and OS rates were 83%, 78%, and 83%. On univariate analysis, 5-year LC and OS were inferior for favorable versus unfavorable disease sites (67% vs 89%, 67% vs 89%, respectively; p < .05) and 5-year OS was superior in stage 3 versus stage 1-2 disease (91% vs 69%; p = .05), owing to inclusion of nasal ala patients among stage 1. Of 9 recurrences, 7 were in-field, 4 occurring in infants with nasal ala primaries. Recategorizing nasal ala as an unfavorable site resulted in 100% 5-year LC and OS for favorable sites. Six infants experienced late grade 3 toxicity. None developed grade 4 or 5 late toxicity. CONCLUSIONS: Young age alone may not be an adverse prognostic factor provided infants receive local therapy similar to older children. Consideration should be given to classifying nasal ala primaries as an unfavorable site.

Geographic Distribution of Radiation Oncologists in the United States.

PURPOSE: The geographic distribution of radiation oncologists determines access to care for patients and job opportunities for practicing physicians, yet available data on practicing radiation oncologists are outdated or use large geographic unit definitions precluding granular analysis. We present an updated county-level analysis of the American radiation oncology workforce. METHODS AND MATERIALS: We used the Area Health Resource File published by the Health Resources and Services Administration of the U.S. Department of Health and Human Services to determine the number of radiation oncologists per 100,000 people in every or equivalent area in the United States as of 2017 (the most recently published data). We then analyzed geographic distribution per U.S. Census Bureau-defined regions, subregions, and combined statistical areas. RESULTS: The Area Health Resource File reports 5338 practicing radiation oncologists for an estimated American population of 326.1 million people as of 2017, resulting in a nationwide average of 1.64 radiation oncologists per 100,000 people. Counties located outside of a metropolitan area had a lower density of radiation oncologists than those within a metropolitan area. Among combined statistical areas (representing most large cities) the variations in density of radiation oncologists are small, with the highest-density areas located in smaller communities with academic medical centers. There was no relationship between population of combined statistical areas and density of radiation oncologists. CONCLUSIONS: The geographic distribution of American radiation oncologists varies widely; the primary variation exists along the urban/rural continuum, with rural areas having fewer practitioners than urban areas. This analysis informs future work in understanding how to optimize the delivery of radiation oncology services throughout the United States.

Nonclinical Time in U.S. Radiation Oncology Residency Programs: Number of Months and Resident Opinion of Value.

PURPOSE: Data regarding the amount and use of nonclinical time (NCT) in radiation oncology residency programs are scarce. We surveyed every U.S. radiation oncology residency program to obtain benchmark data to inform decisions about optimal program structure. METHODS AND MATERIALS: An anonymous, web-based survey was distributed to postgraduate year 5 residents at Accreditation Council for Graduate Medical Education-accredited radiation oncology training programs. The survey included 33 yes/no, Likert-scale, and free-response questions. Program data were analyzed for all programs, including those considered "top 10" per Doximity and those "not top 10." Likert-scale responses were dichotomized as "not as satisfied" (1, 2, 3) or "very satisfied" (4, 5). RESULTS: One hundred twenty-six residents (69%) completed the survey. Program-specific data were obtained for 100% of programs (n = 82). Almost all training programs (98%) provide residents with protected NCT. Including programs with no NCT, the median NCT is 10 months in all programs. The median NCT is 12 months in "top 10" programs and 9 months in "not top 10" programs (P < .01). Most programs (68%) reported >6 months of NCT. The proportion of residents wanting more NCT decreased as the amount of NCT increased (73%, 52%, and 19% for 4-6, 7-9, and 10-12 months, respectively; P < .01). The proportion of residents who were very satisfied with NCT flexibility increased with more NCT (64%, 79%, and 94% for 4-6, 7-9, and 10-12 months, respectively; P < .01), as did the proportion of residents who were very satisfied with accomplishments during NCT (35%, 53%, and 72% for 4-6, 7-9, and 10-12 months, respectively; P < .01). When asked whether residents would theoretically give up some NCT to shorten residency, the proportion of residents willing to shorten their residencies decreased as the amount of NCT increased (65%, 47%, and 33% for 4-6, 7-9, and 10-12 months respectively; P = .04). CONCLUSIONS: Programs should maintain an emphasis on NCT and implement measures to ensure meaningful resident experiences.

STING Promotes Homeostasis via Regulation of Cell Proliferation and Chromosomal Stability.

Given the integral role of stimulator of interferon genes (STING, TMEM173) in the innate immune response, its loss or impairment in cancer is thought to primarily affect antitumor immunity. Here we demonstrate a role for STING in the maintenance of cellular homeostasis through regulation of the cell cycle. Depletion of STING in human and murine cancer cells and tumors resulted in increased proliferation compared with wild-type controls. Microarray analysis revealed genes involved in cell-cycle regulation are differentially expressed in STINGko compared with WT MEFs. STING-mediated regulation of the cell cycle converged on NFκB- and p53-driven activation of p21. The absence of STING led to premature activation of cyclin-dependent kinase 1 (CDK1), early onset to S-phase and mitosis, and increased chromosome instability, which was enhanced by ionizing radiation. These results suggest a pivotal role for STING in maintaining cellular homeostasis and response to genotoxic stress. SIGNIFICANCE: These findings provide clear mechanistic understanding of the role of STING in cell-cycle regulation, which may be exploited in cancer therapy because most normal cells express STING, while many tumor cells do not.See related commentary by Gius and Zhu, p. 1295.

Late toxicity after post-prostatectomy intensity modulated radiation therapy: Evaluating normal-tissue sparing guidelines.

PURPOSE: Dose-volume histogram (DVH) toxicity relationships are poorly defined in men who receive radiation after radical prostatectomy (RP). We evaluated Radiation Therapy Oncology Group (RTOG) study 0534 and institutional intact normal-tissue sparing guidelines, as well as dose to bladder trigone, for ability to minimize late toxicity. METHODS AND MATERIALS: 164 men received intensity modulated radiation therapy (RT) to a median prostate bed dose of 66.6 Gy at a median of 22 months after RP. 46% of men were prescribed androgen deprivation therapy and pelvic lymph node irradiation to a median dose of 50.4 Gy. DVH relationships for the rectum, bladder, trigone, and bladder excluding the clinical target volume (bladder-CTV) were analyzed against the Common Terminology Criteria for Adverse Events late grade 2 + (G2+) gastrointestinal (GI) and genitourinary (GU) toxicity by log-rank test. RTOG 0534 (rectum V65, 40 Gy ≤35, 55%, and bladder-CTV V65, 40 ≤50, 70%) and intact prostate RT institutional guidelines (rectum V70, 65, 40 ≤20, 40, 80% and bladder V70, 65, 40 ≤30, 60, 80%, respectively) guidelines were evaluated. RESULTS: With a median follow-up time of of 33 months, the 4-year freedom from G2 + GI and GU toxicity were both 91%. G2 + GI (n = 12) and GU (n = 15) toxicity included 4% diarrhea (n = 6), 4% hemorrhage (n = 6), 1% proctitis (n = 1), and 4% urinary frequency (n = 7), 1% obstructive (n = 2), 2% cystitis (n = 3), and 3% incontinence (n = 5), respectively. RTOG 0534 rectum and bladder goals were not achieved in 65% and 41% of cases, while the institutional intact prostate goals were not achieved in 21% and 25% of cases, respectively. Neither dose to the bladder trigone nor any of the proposed normal tissue goals were associated with late toxicity (P > .1). In the univariate analysis, age, pelvic RT, RT dose, anticoagulation use, androgen deprivation therapy, time from RP to RT, and tobacco history were not associated with toxicity. CONCLUSIONS: More than 90% of men were free from late G2 + toxicity 4 years after post-RP intensity modulated RT. No tested parameters were associated with late toxicity. In the absence of established normal-tissue DVH guidelines in the postoperative setting, the use of intact guidelines is reasonable.

JAK2 Inhibitor SAR302503 Abrogates PD-L1 Expression and Targets Therapy-Resistant Non-small Cell Lung Cancers.

Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 85% of all lung cancers are non-small cell histology [non-small cell lung cancer (NSCLC)]. Modern treatment strategies for NSCLC target driver oncogenes and immune checkpoints. However, less than 15% of patients survive beyond 5 years. Here, we investigated the effects of SAR302503 (SAR), a selective JAK2 inhibitor, on NSCLC cell lines and tumors. We show that SAR is cytotoxic to NSCLC cells, which exhibit resistance to genotoxic therapies, such as ionizing radiation, cisplatin, and etoposide. We demonstrate that constitutive IFN-stimulated gene expression, including an IFN-related DNA damage resistance signature, predicts for sensitivity to SAR. Importantly, tumor cell-intrinsic expression of PD-L1 is IFN-inducible and abrogated by SAR. Taken together, these findings suggest potential dual roles for JAK2 inhibitors, both as a novel monotherapy in NSCLCs resistant to genotoxic therapies, and in tandem with immune checkpoint inhibition. Mol Cancer Ther; 17(4); 732-9. ©2018 AACR.

Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs.

Emerging evidence indicates that ionizing radiation (IR) and chemotherapy activate Type I interferon (IFN) signaling in tumor and host cells. However, the mechanism of induction is poorly understood. We identified a novel radioprotective role for the DEXH box RNA helicase LGP2 (DHX58) through its suppression of IR-induced cytotoxic IFN-beta [1]. LGP2 inhibits activation of the RIG-I-like receptor (RLR) pathway upon binding of viral RNA to the cytoplasmic sensors RIG-I (DDX58) and MDA5 (IFIH1) and subsequent IFN signaling via the mitochondrial adaptor protein MAVS (IPS1). Here we show that MAVS is necessary for IFN-beta induction and interferon-stimulated gene expression in the response to IR. Suppression of MAVS conferred radioresistance in normal and cancer cells. Germline deletion of RIG-I, but not MDA5, protected mice from death following total body irradiation, while deletion of LGP2 accelerated the death of irradiated animals. In human tumors depletion of RIG-I conferred resistance to IR and different classes of chemotherapy drugs. Mechanistically, IR stimulated the binding of cytoplasmic RIG-I with small endogenous non-coding RNAs (sncRNAs), which triggered IFN-beta activity. We demonstrate that the small nuclear RNAs U1 and U2 translocate to the cytoplasm after IR treatment, thus stimulating the formation of RIG-I: RNA complexes and initiating downstream signaling events. Taken together, these findings suggest that the physiologic responses to radio-/chemo-therapy converge on an antiviral program in recruitment of the RLR pathway by a sncRNA-dependent activation of RIG-I which commences cytotoxic IFN signaling. Importantly, activation of interferon genes by radiation or chemotherapy is associated with a favorable outcome in patients undergoing treatment for cancer. To our knowledge, this is the first demonstration of a cell-intrinsic response to clinically relevant genotoxic treatments mediated by an RNA-dependent mechanism.

RIG-I-like receptor LGP2 protects tumor cells from ionizing radiation.

An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNß. Specifically (i) suppression of LGP2 leads to enhanced IFNß, (ii) cytotoxic effects following IR correlated with expression of IFNß inasmuch as inhibition of IFNß by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNß and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNß.