Michael C. Repka

Nine-year Experience: Prophylactic Cranial Irradiation in Extensive Disease Small-cell Lung Cancer

Background In 2007, the European Organization for Research and Treatment of Cancer (EORTC) study (ClinicalTrials.gov identifier, NCT00016211) demonstrated a beneficial effect on overall survival (OS) with the use of prophylactic cranial irradiation (PCI) for extensive disease (ED) small‐cell lung cancer (SCLC). Nevertheless, debate is ongoing regarding the role of PCI, because the patients in that trial did not undergo magnetic resonance imaging (MRI) of the brain before treatment. Also, a recent Japanese randomized trial showed a detrimental effect of PCI on OS in patients with negative pretreatment brain MRI findings. Materials and Methods We examined the medical records of 136 patients with ED SCLC who had initially responded to chemotherapy and undergone PCI from 2007 to 2015. The outcomes, radiation toxicity, neurologic progression‐free survival, and OS after PCI were analyzed. Survival and correlations were calculated using log‐rank and univariate Cox proportional hazard ratio analyses. Results The median OS and the median neurologic progression‐free survival after PCI was 12 and 19 months, respectively. No significant survival difference was seen for patients who had undergone MRI before PCI compared with patients who had undergone contrast‐enhanced computed tomography (P = .20). Univariate analysis for OS did not show a statistically significant effect for known cofactors. Conclusion In the present cohort, PCI was associated with improved survival compared with the PCI arm of the EORTC trial, with a nearly doubled median OS period. Also, the median OS was prolonged by 2 months compared with the irradiation arm of the Japanese trial. Micro‐Abstract In 2007, a European Organization for Research and Treatment of Cancer (EORTC) study demonstrated a beneficial effect on overall survival (OS) with the use of prophylactic cranial irradiation (PCI) in extensive disease small‐cell lung cancer. Nevertheless, debate is ongoing regarding the role of PCI, because the patients in that trial did not undergo imaging of the brain before treatment. Also, a recent Japanese randomized trial showed a detrimental effect of PCI on OS in patients with negative pretreatment brain magnetic resonance imaging findings. Of our patients, 87% underwent brain imaging before PCI. In the present retrospective analysis, we found that PCI leads to a nearly doubled median OS compared with the irradiation arm of the EORTC trial, with a 2‐month prolonged median OS compared with the irradiation arm of the Japanese trial.

Metformin enhanced in vitro radiosensitivity associates with G2/M cell cycle arrest and elevated adenosine-5’-monophosphate-activated protein kinase levels in glioblastoma

Abstract Background It is hypothesized that metabolism plays a strong role in cancer cell regulation. We have recently demonstrated improved progression-free survival in patients with glioblastoma who received metformin as an antidiabetic substance during chemoradiation. Although metformin is well-established in clinical use the influence of metformin in glioblastoma is far from being understood especially in combination with other treatment modalities such as radiation and temozolomide. Materials and Methods In this study, we examined the influence of metformin in combinations with radiation and temozolomide on cell survival (clonogenic survival), cell cycle (routine flow cytometric analysis, FACScan), and phosphorylated Adenosine-5’-monophosphate-activated protein kinase (AMPK) (Phopho-AMPKalpha1 - ELISA) levels in glioblastoma cell lines LN18 and LN229. Results Metformin and temozolomide enhanced the effectiveness of photon irradiation in glioblastoma cells. Cell toxicity was more pronounced in O6-methylguanine DNA methyltransferase (MGMT) promoter non-methylated LN18 cells. Induction of a G2/M phase cell cycle block through metformin and combined treatments was observed up to 72 h. These findings were associated with elevated levels of activated AMPK levels in LN229 cells but not in LN18 cells after irradiation, metformin, and temozolomide treatment. Conclusions Radiosensitizing effects of metformin on glioblastoma cells treated with irradiation and temozolomide in vitro coincided with G2/M arrest and changes in pAMPK levels.

Radiation therapy for hepatobiliary malignancies

Hepatobiliary malignancies represent a heterogeneous group of diseases, which often arise in a background of underlying hepatic dysfunction complicating their local management. Surgical resection continues to be the standard of care for hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC); unfortunately the majority of patients are inoperable at presentation. The aggressiveness of these lesions makes locoregional control of particular importance. Historical experience with less sophisticated radiotherapy resulted in underwhelming efficacy and oftentimes prohibitive liver toxicity. However, with the advent of extremely conformal and precise radiotherapy delivery, dose escalation to the tumor with sparing of surrounding normal tissue has yielded notable improvements in efficacy for this modality of treatment. Dose escalation has come in a variety of forms most notably as stereotactic body radiation therapy (SBRT) and hypofractionated proton therapy. As radiation techniques continue to improve, their proper incorporation into the local management of hepatobiliary malignancies will be paramount in improving the prognosis of what is a grave diagnosis.

Predictors of acute urinary symptom flare following stereotactic body radiation therapy (SBRT) in the definitive treatment of localized prostate cancer

Michael C. Repka, Thomas P. Kole, Jacqueline Lee, Binbin Wu, Siyuan Lei, Thomas Yung, Brian T. Collins, Simeng Suy, Anatoly Dritschilo, John H. Lynch and Sean P. Collins Department of Radiation Medicine, Georgetown University Hospital, Washington, DC, USA; Department of Radiation Oncology, The Valley Health Hospital, Ridgewood, NJ, USA; Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Urology, Georgetown University Hospital, Washington, DC, USA

From Röntgen Rays to Carbon Ion Therapy: The Evolution of Modern Radiation Oncology in Germany.

Beginning with the discovery of X-rays in 1895, German scientists and clinicians were instrumental in establishing the fields of diagnostic and therapeutic radiology, creating the first radiotherapy peer-reviewed journal, and holding the first international oncologic conference. These landmark achievements profoundly influenced the nascent field of radiation oncology. However, the rapid early scientific progress was first halted by World War I, derailed during World War II, and was slowly reestablished amid the divisions of the Cold War. Figure 1 chronicles many radiotherapy milestones during these distinct periods. Today, Germany has reemerged as a scientific leader in the field of radiotherapy, and a pioneer in basic radiobiology research and clinical implementation of particle therapy. Here we explore the technical advances as well as the clinical evolution of radiotherapy in Germany from the groundbreaking establishment of Bismarck’s healthcare system to a modern view of radiotherapy practice.

Overview of Toxicity Outcomes with Prostate SBRT and Comparison to Other Treatment Interventions (Urinary, Rectal and Sexual Outcomes)

Prostate cancer is the most common cancer diagnosis amongst adult males in the United States, with approximately 160,000 new diagnoses per year in the United States. Treatment of this disease may be associated with genitourinary, gastrointestinal, and sexual adverse effects. Stereotactic body radiation therapy (SBRT) has recently gained acceptance as an effective treatment modality, although concerns have been voiced over a potentially increased risk of toxicity given the high dose-per-fraction regimens employed. Fortunately, a wealth patient-reported outcome (PRO) data, in addition to standard physician-scored toxicity, is available from single and multi-institutional reports. This chapter will review the adverse effects that have been reported following SBRT, provide guidelines for prevention and management of symptoms, and compare these outcomes with those achieved by other treatment methods.

First Annual Report of the Resident Committee of the American College of Radiation Oncology

The American College of Radiation Oncology (ACRO) Resident Committee (RC) was established to provide meaningful educational content, professional development, and opportunities for service within the United States radiation oncology resident community. The goals of the RCmirror those of the ACROmission at large to Bpromote success in the practice of radiation oncology through education, responsible socioeconomic advocacy, and integration of science and technology into clinical practice.^ The ACRO Board of Chancellors has given marked independence to the ACRO RC to explore and implement a resident-focused agenda, which has allowed great ideas to flourish into full-fledged national programs. The RC has worked diligently to improve resident quality of life and education through the creation and implementation of distinct subcommittees within the RC, which include the following: membership, mentorship, research, scholarship, and scientific. Over the past year, the ACRO RC has developed and implemented a variety of projects; here, we report the results of the 2016–2017 academic year.

Definitive hypofractionated radiation therapy for early stage breast cancer: Dosimetric feasibility of stereotactic ablative radiotherapy and proton beam therapy for intact breast tumors

Purpose Few definitive treatment options exist for elderly patients diagnosed with early stage breast cancer who are medically inoperable or refuse surgery. Historical data suggest very poor local control with hormone therapy alone. We examined the dosimetric feasibility of hypofractionated radiation therapy using stereotactic ablative radiotherapy (SABR) and proton beam therapy (PBT) as a means of definitive treatment for early stage breast cancer. Methods and Materials Fifteen patients with biopsy-proven early stage breast cancer with a clinically visible tumor on preoperative computed tomography scans were identified. Gross tumor volumes were contoured and correlated with known biopsy-proven malignancy on prior imaging. Treatment margins were created on the basis of set-up uncertainty and image guidance capabilities of the three radiation modalities analyzed (3-dimensional conformal radiation therapy [3D-CRT], SABR, and PBT) to deliver a total dose of 50 Gy in 5 fractions. Dose volume histograms were analyzed and compared between treatment techniques. Results The median planning target volume (PTV) for SABR, PBT, and 3-dimensional CRT was 11.91, 21.03, and 45.08 cm3, respectively, and were significantly different (P < .0001) between treatment modalities. Overall target coverage of gross tumor and clinical target volumes was excellent with all three modalities. Both SABR and PBT demonstrated significant dosimetric improvements, each in its own unique manner, relative to 3D-CRT. Dose constraints to normal structures including ipsilateral/contralateral breast, bilateral lungs, and heart were all consistently achieved using SABR and PBT. However, skin or chest wall dose constraints were exceeded in some cases for both SABR and PBT plans and was dictated by the anatomic location of the tumor. Conclusions Definitive hypofractionated radiation therapy using SABR and PBT appears to be dosimetrically feasible for the treatment of early stage breast cancer. The anatomical location of the tumor relative to the skin and chest wall appears to be the primary limiting dosimetric factor.

Social determinants of stage IV anal cancer and the impact of pelvic radiotherapy in the metastatic setting

Anal cancer is a relatively rare malignancy, and a minority of patients present with metastatic disease in the United States. The National Cancer Database (NCDB) was used to identify factors associated with metastatic disease at presentation and evaluate the role of pelvic radiotherapy in these patients. The NCDB was queried for patients with squamous cell cancer of the anus diagnosed between 2004 and 2013. Patients were stratified by clinical stage at diagnosis, and a binary logistic regression model was created to identify factors associated with metastatic disease at diagnosis. A secondary metastatic cohort was generated and a multivariable Cox proportional hazards model was created to identify factors associated with improved survival. To validate findings, propensity‐score matching was performed to generate a 1:1 paired dataset stratified by receipt of pelvic radiotherapy. The primary analysis cohort consisted of 28,500 patients. Facility location, male gender, and lack of insurance were confirmed as independent risk factors for metastatic disease. The metastatic cohort consisted of 1264 patients. Multivariable analysis confirmed female sex, possession of a private or Medicare insurance plan, pelvic radiotherapy, and chemotherapy as independent predictors of improved survival. A propensity‐score matched cohort of 730 patients was generated. The median survival was 17.6 months in patients who received radiotherapy versus 14.5 months in those who did not (P < 0.01). In this cohort, male gender and lack of insurance were associated with metastatic disease at presentation. Furthermore, a significant benefit was associated with the use of pelvic radiotherapy. Future prospective research is warranted to confirm these findings.