Erin F. Gillespie

MicroRNAs as Potential Agents to Alter Resistance to Cytotoxic Anticancer Therapy

Tumor cells use preexisting prosurvival signaling pathways to evade the damaging and cytotoxic effects of anticancer agents. Radiation therapy is a primary form of cytotoxic anticancer treatment, but agents that successfully modify the radiation response in vivo are lacking. MicroRNAs (miRNA) are global gene regulators that play critical roles in oncogenesis and have been found to regulate prosurvival pathways. However, there is little understanding of how cellular miRNA expression affects the response of a cancer to cytotoxic therapy and ultimately outcome. The let-7 family of miRNAs regulates expression of oncogenes, such as RAS, and is specifically down-regulated in many cancer subtypes. In fact, low levels of let-7 predict a poor outcome in lung cancer. Here, we report that the let-7 family of miRNAs is overrepresented in a class of miRNAs exhibiting altered expression in response to radiation. More strikingly, we also can create a radiosensitive state when the select let-7 family of miRNAs is overexpressed in vitro in lung cancer cells and in vivo in a Caenorhabditis elegans model of radiation-induced cell death, whereas decreasing their levels causes radioresistance. In C. elegans, we show that this is partly through control of the proto-oncogene homologue let-60/RAS and genes in the DNA damage response pathway. These findings are the first direct evidence that miRNAs can suppress resistance to anticancer cytotoxic therapy, a common feature of cancer cells, and suggest that miRNAs may be a viable tool to augment current cancer therapies.

Modern Radiation Therapy and Cardiac Outcomes in Breast Cancer

PURPOSE Adjuvant radiation therapy, which has proven benefit against breast cancer, has historically been associated with an increased incidence of ischemic heart disease. Modern techniques have reduced this risk, but a detailed evaluation has not recently been conducted. The present study evaluated the effect of current radiation practices on ischemia-related cardiac events and procedures in a population-based study of older women with nonmetastatic breast cancer. METHODS AND MATERIALS A total of 29,102 patients diagnosed from 2000 to 2009 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Medicare claims were used to identify the radiation therapy and cardiac outcomes. Competing risk models were used to assess the effect of radiation on these outcomes. RESULTS Patients with left-sided breast cancer had a small increase in their risk of percutaneous coronary intervention (PCI) after radiation therapy-the 10-year cumulative incidence for these patients was 5.5% (95% confidence interval [CI] 4.9%-6.2%) and 4.5% (95% CI 4.0%-5.0%) for right-sided patients. This risk was limited to women with previous cardiac disease. For patients who underwent PCI, those with left-sided breast cancer had a significantly increased risk of cardiac mortality with a subdistribution hazard ratio of 2.02 (95% CI 1.23-3.34). No other outcome, including cardiac mortality for the entire cohort, showed a significant relationship with tumor laterality. CONCLUSIONS For women with a history of cardiac disease, those with left-sided breast cancer who underwent radiation therapy had increased rates of PCI and a survival decrement if treated with PCI. The results of the present study could help cardiologists and radiation oncologists better stratify patients who need more aggressive cardioprotective techniques.

The Impact of Radiation Oncologists on the Early Adoption of Hypofractionated Radiation Therapy for Early-Stage Breast Cancer

PURPOSE Despite multiple randomized trials showing the efficacy of hypofractionated radiation therapy in early-stage breast cancer, the United States has been slow to adopt this treatment. The goal of this study was to evaluate the impact of individual radiation oncologists on the early adoption of hypofractionated radiation therapy for early-stage breast cancer. METHODS We identified 22,233 Medicare beneficiaries with localized breast cancer that was diagnosed from 2004 to 2011 who underwent breast-conserving surgery with adjuvant radiation. Multilevel, multivariable logistic models clustered by radiation oncologist and geographic practice area were used to determine the impact of the provider and geographic region on the likelihood of receiving hypofractionated compared with standard fractionated radiation therapy while controlling for a patients clinical and demographic covariates. Odds ratios (OR) describe the impact of demographic or clinical covariates, and the median OR (MOR) describes the relative impact of the individual radiation oncologist and geographic region on the likelihood of undergoing hypofractionated radiation therapy. RESULTS Among the entire cohort, 2333 women (10.4%) were treated with hypofractionated radiation therapy, with unadjusted rates ranging from 0.0% in the bottom quintile of radiation oncologists to 30.4% in the top quintile. Multivariable analysis found that the individual radiation oncologist (MOR 3.08) had a greater impact on the use of hypofractionation than did geographic region (MOR 2.10) or clinical and demographic variables. The impact of the provider increased from the year 2004 to 2005 (MOR 2.82) to the year 2010 to 2011 (MOR 3.16) despite the publication of long-term randomized trial results in early 2010. Male physician and radiation oncologists treating the highest volume of breast cancer patients were less likely to perform hypofractionation (P<.05). CONCLUSIONS The individual radiation oncologist strongly influenced the likelihood of a patients receiving hypofractionated radiation therapy, and this trend increased despite the publication of long-term data showing equivalence to standard fractionation. Future research should focus on physician-related factors that influence this decision.

Lung stereotactic body radiotherapy (SBRT): a single institution's outcomes and methodology in the context of a literature review

Lung cancer is the leading cause of cancer death in the United States and worldwide, with the incidence of early stage lung cancer anticipated to rise with increasing use of screening CT. Improvements in systemic therapy have increased the need for durable local control both in primary lung cancer as well as oligometastatic disease to the lung. Since 2007, the University of California San Diego (UCSD) has employed SBRT in the treatment of early stage primary non-small cell histology (NSCLC), intrapulmonary oligometastases, and multiple primary lung cancers (MPLCs) with high efficacy and low toxicity using a frameless technique that involves non-invasive image guidance. We review our center’s general approach to management including our experience with clinical outcomes and toxicity in the context of a review of the literature, details of our preferred technique (including simulation and real-time tumor tracking), as well as our results and strategy for patient follow-up using PET to monitor tumor response in the post-SBRT setting.

An interactive contouring module improves engagement and interest in radiation oncology among preclinical medical students: Results of a randomized trial

PURPOSE Studies have shown significant gaps in knowledge of radiation therapy among medical students and primary care providers. The goal of this study was to evaluate the effect of an interactive contouring module on knowledge and interest in radiation oncology among preclinical medical students. METHODS AND MATERIALS Second-year medical students at the University of California, San Diego were randomized to participate in an interactive contouring exercise or watch a traditional didactic lecture on radiation oncology. Participants completed knowledge tests and surveys at baseline, immediately following the exercise, and 3 months later. Statistical analysis included Wilcoxon signed-rank test for pre- and posttest comparisons and Wilcoxon rank sum test for comparison between groups. RESULTS Forty-three medical students participated in the trial (21 in the didactic group; 22 in the contouring group). Students completing the contouring module demonstrated similar overall knowledge improvement compared with the traditional didactic group (+8.6% vs +6.6%, not significant) but endorsed greater engagement on a 5-point Likert-type scale (3.10 vs 3.76, P = .02). At 3-month follow-up, there was a nonsignificant trend toward improved overall knowledge in the contouring group (43% vs 51%, P = .10), with a significance difference in a subset of questions on knowledge of the process of radiation therapy as well as side effects (51% vs 75%, P = .002). Students in the contouring group demonstrated more interest in pursuing a clinical radiation oncology rotation (2.52 vs 3.27, P = .01). CONCLUSIONS Use of an interactive contouring module was an effective method to teach preclinical medical students about radiation oncology, with no significant difference in knowledge gained compared with a traditional didactic lecture; however, higher engagement among students completing the contouring module led to improved retention of knowledge of radiation side effects and greater interest in radiation oncology. These data suggest a potential benefit of integrating an interactive radiation oncology module into the preclinical medical school curriculum.

Development of a new photonumeric scale for acute radiation dermatitis in patients with breast cancer.

86 Background: The Common Terminology Criteria for Adverse Events (CTCAE) is frequently used to grade the severity of acute radiation dermatitis (ARD), but has not been validated despite decades of clinical use. We sought to develop a photonumeric scale to consistently describe ARD in breast cancer patients undergoing radiation (RT). METHODS Patients enrolled on a prospective study that included photographs and quantitative measurements of erythema and hyperpigmentation using colorimetry. 209 photographs from 35 patients with white skin and 369 photographs from 50 patients with skin of color were used to develop two photonumeric scales. Predominant erythema (in white skin) OR hyperpigmentation (in skin of color) were rated on a 4 point scale, with grading of desquamation on a separate 3 point scale. Four raters used both CTCAE and photonumeric scales to independently score all photographs. Intra- and inter-rater agreements were assessed using weighted kappa scores. RESULTS Using the CTCAE, 95% of photos were rated as grade 1 or 2. There was a trend toward higher grade in patients with skin of color, with grade 2 toxicity in 43% vs. 24%. Intra-rater agreement for CTCAE ratings was 65-87% (kappa 0.34-0.67), with a wide range of inter-rater agreement (56-81% agreement fraction, kappa 0.04-0.58). Using the photonumeric scale, intra-rater agreement was high for erythema/hyperpigmentation in patients with white skin (74-82%, kappa 0.49-0.70) and skin of color (69-86%, kappa 0.55-0.79), along with desquamation (78-87%, kappa 0.52-0.66). There was moderate inter-rater agreement for erythema/hyperpigmentation (51-82%, kappa 0.15-0.71) and desquamation (63-88%, kappa 0.36-0.58). Colorimetric measurements correlated strongly with photonumeric grade. CONCLUSIONS We report a new photonumeric scale for ARD in breast cancer patients with satisfactory reliability across the spectrum of skin pigmentation. Intra-physician ratings were consistent, with moderate inter-physician agreement. The CTCAE functions as a binary scale, with 95% of ARD rated as grade 1 or 2 toxicity. Future work includes correlation with patient-reported outcomes and physician ratings at the point-of-care. Funded by a Munn Idea Grant (G011480).

The impact of daily bladder filling on small bowel dose for intensity modulated radiation therapy for cervical cancer

Research demonstrates that instructing patients to have a full bladder for pelvic radiotherapy results in highly variable bladder volumes at daily treatment. We aimed to determine bladder volume variation in patients with intact cervical cancer treated with intensity-modulated radiotherapy (IMRT) on an empty bladder and estimate the difference in radiation dose to the small bowel compared to treating on a full bladder. We identified 29 patients treated with IMRT from 2010 to 2013 who underwent 2 planning computed tomography (CT) scans, 1 with a full bladder followed by 1 with an empty bladder. Interfractional variation in bladder volume was measured using 782 daily cone beam computed tomography (CBCT) scans. To estimate dose to small bowel, radiation plans were created on both empty and full bladder CT scans using an automated knowledge-based planning modeling program. Mean bladder volume with empty bladder instructions was 67 ± 26 cc compared to 91 ± 43 cc for no bladder instructions and 154 ± 54 cc for full bladder instructions (p < 0.001). There was a significant reduction in the absolute bladder volume variation in patients given empty bladder instructions compared to full bladder instructions (p < 0.05) The intraclass correlation coefficient showed low reliability of bladder filling across all groups (p = 0.6). The average bowel V45 for the empty bladder plans was 188 cc, compared to 139 cc for the full bladder plans (p < 0.05). More plans created on an empty bladder exceeded Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) guidelines but this was not significant (31% vs 14%, p = 0.12). Reliability of bladder volume at the time of radiation treatment is low, regardless of bladder filling instructions, although an empty bladder reduces absolute variation in bladder volume. Radiation planning on an empty bladder predicts a larger volume of small bowel receiving 45 Gy compared to a full bladder, although bowel dose on average is still within QUANTEC guidelines (V45 < 195 cc).

Simulation as More Than a Treatment-Planning Tool: A Systematic Review of the Literature on Radiation Oncology Simulation-Based Medical Education

PURPOSE Simulation-based medical education (SBME) is gaining prominence as a tool to meet Accreditation Council for Graduate Medical Education-mandated competency-based assessment educational goals. SBME is used in radiation oncology, although the type and extent are not clear. This study reports a systematic literature review designed to clarify the type and extent of radiation oncology SBME. METHODS AND MATERIALS The systematic review focused on radiation oncology SBME literature. The methods followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The inclusion criteria were identified according to the PICOS (population, intervention, comparison, outcome, and setting) framework. The population included undergraduate, graduate, and continuing medical education learners. Studies were limited to English-language studies published on or after January 1, 1990, in peer-reviewed journals. PubMed, MedEdPORTAL, and in-press articles were searched. The PubMed search was conducted using predefined search terms. References and similar articles were examined. Medical Subject Headings terms in selected articles were reviewed to ensure relevant terms were included. RESULTS Fifty-four SBME publications met the inclusion criteria. Only 9 of 54 studies (17%) self-identified as SBME. SBME types included screen-based simulators (56%), simulated environments (13%), virtual reality and haptic systems (13%), simulated patients (11%), part-task trainers (6%), and computer-based systems with mannequins (2%). A variety of radiation oncology skill sets were addressed, including contouring (54%), treatment planning (20%), clinical decision making (17%), anatomy and/or radiology (13%), radiation biology and/or physics (13%), communication skills and/or patient education (13%), brachytherapy (13%), and immobilization (11%). A target learning population was defined in 47 studies, including residents (53%), attending physicians (36%), medical students (21%), medical physicists (11%), radiation therapists (9%), nurses (6%), administrative staff (4%), and dosimetrists (4%). Learner feedback was reported in 32 studies. CONCLUSIONS Overall, this systematic literature review provides context and guidance for future radiation oncology SBME development. Appropriately framing SBME reports in the radiation oncology literature will facilitate development, implementation, and evaluation of SBME interventions. SBME resources should be centralized to facilitate dissemination and share resources.

Abstract P1-15-12: Development of a photonumeric scale for acute radiation dermatitis in breast cancer patients

Purpose Scales for rating acute radiation dermatitis (ARD) are inconsistent and have not been validated despite decades of clinical use, making ARD difficult to report reliably. We sought to design a photonumeric scale to consistently describe ARD in breast cancer patients undergoing radiation (RT). Methods Patients undergoing RT for breast cancer were enrolled on a prospective study that included photographs and reporting of physician-rated erythema, hyperpigmentation, and CTCAE toxicity score at baseline and 2, 4, and 6 weeks after initiating RT. Erythema and hyperpigmentation were also quantified using a hand-held colorimetric device. Photographs were taken using a standardized protocol that included 3 views to fully assess the breast/chest wall, axilla, and inframammary fold. 209 photographs from 35 patients with white skin (Fitzpatrick skin types I-IV) and 369 photographs from 50 patients with skin of color (Fitzpatrick skin types V-VI) were clustered according to the apparent severity of ARD. Due to the prevalence of hyperpigmentation that obscured erythema in patients with skin of color, separate images were used to illustrate ARD in this population. Two photonumeric scales (for white skin and skin of color) were developed via an iterative process until group consensus was achieved. Four raters with experience in the evaluation of ARD in breast cancer patients used the photonumeric scale to independently score the entire collection of photographs, sequenced in random order. Intra- and inter-rater agreements were assessed using weighted kappa scores. Results Of the 35 patients with white skin, 20% experienced severe erythema, and 40% experienced dry or moist desquamation. Of the 50 patients with skin of color, 34% experience severe hyperpigmentation, and 48% experienced dry or moist desquamation. Using the photonumeric scales, we observed high intra-rater agreement for independent ratings of erythema or hyperpigmentation (70 to 89% agreement fraction, kappa 0.55 to 0.81) and desquamation (79 to 87% agreement fraction, kappa 0.52 to 0.64). Similarly, we observed moderate to high inter-rater agreement for independent ratings of erythema or hyperpigmentation (61 to 76% agreement fraction, kappa 0.40 to 0.62) and desquamation (69 to 84% agreement fraction, kappa 0.36 to 0.58). Quantitative measurements of erythema in white patients using colorimetry correlated strongly with photonumeric grade (correlation coefficient 0.76, p Conclusions We report a new photonumeric scale with high intra- and inter-rater reliability for acute radiation dermatitis in breast cancer patients. To our knowledge, this is the first rigorously evaluated scale that is applicable to patients across the spectrum of skin pigmentation, including white skin and skin of color. The photonumeric scale will facilitate consistent reporting of acute radiation dermatitis in research and clinical settings using a simple, standardized instrument. Future work will include prospective real-time clinical validation with multiple raters and correlation with patient-reported outcomes. Funded by a Munn Idea Grant (G011480). Citation Format: Dean Shumway, Eleanor M Walker, Nirav Kapadia, Thy Thy Do, Kent Griffith, Mary Feng, Bonnie DePalma, Reshma Jagsi, Yolanda Helfrich, Erin Gillespie, Alexandria Miller, Adam Liss, Lori J Pierce. Development of a photonumeric scale for acute radiation dermatitis in breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-12.

Pathologic response after neoadjuvant chemotherapy predicts locoregional control in patients with triple negative breast cancer

Purpose Our goal was to determine the impact of pathologic response after neoadjuvant chemotherapy in triple negative breast cancer (TNBC) on the subsequent risk of locoregional recurrence (LRR) and disease-free survival (DFS) in the setting of adjuvant radiation therapy. Methods and materials This was an institutional review board–approved retrospective chart review of patients with clinical stage I-III breast cancer treated with neoadjuvant chemotherapy, local surgery (breast conservation or mastectomy), and adjuvant radiation therapy between 1997 and 2015. Medical records were reviewed for clinical stage, tumor grade and subtype, neoadjuvant chemotherapy regimen, type of surgery, pathologic stage, use of radiation therapy, date and location of recurrence, and date of death. Molecular subtypes were defined using immunohistochemistry and histologic grade. ypT0 and ypN0 were defined as no residual invasive disease in breast or nodes, respectively. LRR was defined as any failure within the breast, chest wall, or regional lymph nodes. Statistical analysis was performed; LRR and DFS rates over 30 months were determined from Kaplan-Meier plots. Results Ninety-four patients with TNBC were analyzed, of whom 72 received radiation therapy. This subgroup was isolated for further investigation. Median follow-up was 32.5 months in this group. The pathologic complete response (pCR) rate was 36%, and presence or absence of disease in breast and/or nodes was significantly predictive of LRR. In TNBC patients who received radiation therapy, 30-month LRR was 22% in 41 patients with ypT+ versus 0% in 31 patients with ypT0 (P = .003), 23% in 31 patients with ypN+ versus 5% in 41 patients with ypN0 (P = .016), and 20% in 46 patients with residual disease in breast or nodes versus 0% in 26 patients with pCR (P = .015). The difference in the rate of LRR between those who underwent lumpectomy versus mastectomy did not reach significance (8% vs 17%, respectively). Furthermore, patients with residual disease had a higher rate of DFS events (hazard ratio, 3.58; 95% confidence interval, 1.37-9.41; P = .006). The difference in DFS was not significantly associated with the type of surgery received. Conclusions Patients with TNBC treated with neoadjuvant chemotherapy who have residual disease in the breast or lymph nodes at the time of surgery have significantly higher rates of locoregional failure and lower DFS compared with those with a pCR despite the use of adjuvant radiation therapy. Strategies to intensify therapy for patients with residual disease warrant further investigation.