Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers.

Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.

Circulating cell-free methylated DNA reveals tissue-specific, cellular damage from radiation treatment.

Radiation therapy is an effective cancer treatment, although damage to healthy tissues is common. Here we analyzed cell-free, methylated DNA released from dying cells into the circulation to evaluate radiation-induced cellular damage in different tissues. To map the circulating DNA fragments to human and mouse tissues, we established sequencing-based, cell-type-specific reference DNA methylation atlases. We found that cell-type-specific DNA blocks were mostly hypomethylated and located within signature genes of cellular identity. Cell-free DNA fragments were captured from serum samples by hybridization to CpG-rich DNA panels and mapped to the DNA methylation atlases. In a mouse model, thoracic radiation-induced tissue damage was reflected by dose-dependent increases in lung endothelial and cardiomyocyte methylated DNA in serum. The analysis of serum samples from patients with breast cancer undergoing radiation treatment revealed distinct dose-dependent and tissue-specific epithelial and endothelial responses to radiation across multiple organs. Strikingly, patients treated for right-sided breast cancers also showed increased hepatocyte and liver endothelial DNA in the circulation, indicating the impact on liver tissues. Thus, changes in cell-free methylated DNA can uncover cell-type-specific effects of radiation and provide a readout of the biologically effective radiation dose received by healthy tissues.

Diastereo- and regioselective petasis aryl and allyl boration of ninhydrins towards synthesis of functionalized indene-diones and dihydrobenzoindeno-oxazin-ones.

Petasis aryl and allyl borations were accomplished using substituted ninhydrins, boronic acids or 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 1,2-aminophenols in Hexafluoroisopropanol (HFIP) without any catalysts to synthesize different aryl and allyl derivatives of ninhydrins. The nature of substitution in the boronic acids and 1,2-amino phenols was the key factor in determining the diastereo-regioselectivity and the type of product distributions. The products were isolated and characterized by HMBC, HSQC, 1H, 13C NMR experiments and X-ray single crystallographic analysis. A probable reaction pathway involves in situ formation of acyclic and cyclic ninhydrin-amino alcohol adducts, with the positioned hydroxyl group determining the stereo-regioselective outcome via tetracoordinated boron intermediates. A metal free diastereo- and regioselective Petasis aryl and allyl boration of ninhydrins.

Management of invasive ductal carcinoma in hypermobile Ehlers-Danlos syndrome: a case report.

Literature is sparse regarding the management and long-term outcomes of breast cancer in patients with Ehlers-Danlos syndrome (EDS). Of the EDS subtypes, hypermobile Ehlers-Danlos Syndrome (hEDS) is associated with cardiovascular dysautonomia which manifests as spontaneous episodes of tachycardia and hypotension. Given this clinical autonomic system impact, hEDS is known to have significant intraoperative risk and postoperative complications. However, outcomes of hEDS patients have not been specifically studied in the field of breast cancer surgery. Here we present a case of a 62-year-old female with hEDS and node-positive invasive ductal breast carcinoma. Given the patient's medical history of hEDS, close attention was given to the patient's intraoperative vital signs and predisposition for poor wound healing. The patient underwent left Goldilocks mastectomy with left axillary lymph node dissection. Due to cardiac comorbidities, she was not a candidate for neoadjuvant or adjuvant chemotherapy. The patient tolerated adjuvant radiation and endocrine therapy without side effects, and has remained free of local, regional, and distant cancer recurrence following treatment. This case report highlights a literature gap in the surgical and radiation therapy management of breast cancer in patients with hEDS. Although breast surgery and radiation therapy in patients with invasive breast cancer and hEDS can be a safe management option, we discuss how perioperative complications must be cautiously navigated and how treatment must be tailored to individuals' specific hEDS variant to ensure optimal patient safety and positive long-term outcomes.

Early Experience of the First Single-Room Gantry Mounted Active Scanning Proton Therapy System at an Integrated Cancer Center.

Introduction: Review the early experience with a single-room gantry mounted active scanning proton therapy system. Material and Methods: All patients treated with proton beam radiotherapy (PBT) were enrolled in an institutional review board-approved patient registry. Proton beam radiotherapy was delivered with a 250 MeV gantry mounted synchrocyclotron in a single-room integrated facility within the pre-existing cancer center. Demographic data, cancer diagnoses, treatment technique, and geographic patterns were obtained for all patients. Treatment plans were evaluated for mixed modality therapy. Insurance approval data was collected for all patients treated with PBT. Results: A total of 132 patients were treated with PBT between March 2018 and June 2019. The most common oncologic subsites treated included the central nervous system (22%), gastrointestinal tract (20%), and genitourinary tract (20%). The most common histologies treated included prostate adenocarcinoma (19%), non-small cell lung cancer (10%), primary CNS gliomas (8%), and esophageal cancer (8%). Rationale for PBT treatment included limitation of dose to adjacent critical organs at risk (67%), reirradiation (19%), and patient comorbidities (11%). Patients received at least one x-ray fraction delivered as prescribed (36%) or less commonly due to unplanned machine downtime (34%). Concurrent systemic therapy was administered to 57 patients (43%). Twenty-six patients (20%) were initially denied insurance coverage and required peer-to-peers (65%), written appeals (12%), secondary insurance approval (12%), and comparison x-ray to proton plans (8%) for subsequent approval. Proton beam radiotherapy approval required a median of 17 days from insurance submission. Discussion: Incorporation of PBT into our existing cancer center allowed for multidisciplinary oncologic treatment of a diverse population of patients. Insurance coverage for PBT presents as a significant hurdle and improvements are needed to provide more timely access to necessary oncologic care.

Time-driven activity-based costing of a novel form of CT-guided high-dose-rate brachytherapy intraoperative radiation therapy compared with conventional breast intraoperative radiation therapy for early stage breast cancer.

INTRODUCTION: Intraoperative radiation therapy is an emerging option for adjuvant therapy for early stage breast cancer, although it is not currently considered standard of care in the United States. We applied time-driven activity-based costing to compare two alternative methods of breast intraoperative radiation therapy, including treatment similar to the techniques employed in the TARGIT-A clinical trial and a novel version with CT-guidance and high-dose-rate (HRD) brachytherapy. METHODS AND MATERIALS: Process maps were created to describe the steps required to deliver intraoperative radiation therapy for early stage breast cancer at each institution. The components of intraoperative radiation therapy included personnel, equipment, and consumable supplies. The capacity cost rate was determined for each resource. Based on this, the delivery costs were calculated for each regimen. For comparison across centers, we did not account for indirect facilities costs and interinstitutional differences in personnel salaries. RESULTS: The CT-guided, HRD form of intraoperative radiation therapy costs more to deliver ($4,126.21) than the conventional method studied in the TARGIT-A trial ($1,070.45). The cost of the brachytherapy balloon applicator ($2,750) was the primary driver of the estimated differences in costs. Consumable supplies were the largest contributor to the brachytherapy-based approach, whereas personnel costs were the largest contributor to costs of the standard form of intraoperative radiation therapy. CONCLUSIONS: When compared with the more established method of intraoperative radiation therapy using a portable superficial photon unit, the delivery of treatment with CT guidance and HDR brachytherapy is associated with substantially higher costs. The excess costs are driven primarily by the cost of the disposable brachytherapy balloon applicator and, to a lesser extent, additional personnel costs. Future work should include evaluation of a less expensive brachytherapy applicator to increase the anticipated value of brachytherapy-based intraoperative radiation therapy.

Prostate Cancer Outcomes Following Solid-Organ Transplantation: A SEER-Medicare Analysis.

BACKGROUND: Immunosuppressive regimens associated with organ transplantation increase the risk of developing cancer. Transplant candidates and recipients with prostate cancer are often treated, even if low-risk features would ordinarily justify active surveillance. METHODS: Using SEER-Medicare, we identified 163 676 men aged 66 years and older diagnosed with nonmetastatic prostate cancer. History of solid organ transplant was identified using diagnosis or procedure codes. A propensity score-matched cohort was identified by matching transplanted men to nontransplanted controls by age, race, region, year, T-stage, grade, comorbidity, and cancer therapy. Fine-Gray competing risk models assessed associations between transplant status and prostate cancer-specific mortality (PCSM) and overall mortality (OM). RESULTS: We identified 620 men (0.4%) with transplant up to 10 years before (n = 320) or 5 years after (n = 300) prostate cancer diagnosis and matched them to 3100 men. At 10 years, OM was 55.7% and PCSM was 6.0% in the transplant cohort compared with 42.4% (P < .001) and 7.6% (P = .70) in the nontransplant cohort, respectively. Adjusted models showed no difference in PCSM for transplanted men (hazard ratio = 0.88, 95% confidence interval = 0.61 to 1.27, P = .70) or differences by prostate cancer therapy. Among 334 transplanted men with T1-2N0, well or moderately differentiated "low-risk" prostate cancer, PCSM was similar for treated and untreated men (hazard ratio = 0.92, 95% confidence interval = 0.47 to 1.81). CONCLUSIONS: Among men aged 66 years and older with prostate cancer, an organ transplant is associated with higher OM but no observable difference in PCSM. These findings suggest men with prostate cancer and previous or future organ transplantation should be managed per usual standards of care, including consideration of active surveillance for low-risk cancer characteristics.

Stereotactic Body Radiation Therapy: A Versatile, Well-Tolerated, and Effective Treatment Option for Extracranial Metastases From Primary Ovarian and Uterine Cancer.

PURPOSE: Single extracranial metastases from ovarian and uterine malignancies have historically been treated with surgery or conventional radiation. We report mature local control (LC), overall survival (OS), progression free survival (PFS), and toxicity for patients who completed 5-fraction stereotactic body radiation therapy (SBRT). METHODS: Patients with biopsy-proven, single extracranial metastases from primary ovarian and uterine malignancies treated with 5-fraction SBRT were included. Patients were stratified based on tumor volume (small < 50 cc or large ≥ 50 cc) and dose (low dose < 35 Gy or high ≥ 35 Gy). Kaplan-Meier method was used to estimate LC, OS, and PFS. RESULTS: Between July 2007 and July 2012, 20 patients underwent SBRT to a single extracranial metastasis. Primary site was divided evenly between ovarian and uterine (n = 10 each). Metastases involved the liver (30%), abdominal lymph nodes (25%), lung (20%), pelvic lymph nodes (10%), spine (10%), and extremity (5%). The median gross tumor volume (GTV) was 42.5 cc (range, 5-273 cc) and the median dose to the GTV was 35 Gy (range, 30-50 Gy). At a median follow-up of 56 months, the 5-year LC and OS estimates were 73 and 46%. When stratified by tumor volume, the 5-year LC and OS for small tumors were significantly better at 100% (p < 0.01) and 65% (p < 0.02). When stratified by dose, the 5-year LC was 87.5% with high dose and 53.6% with low dose (p = 0.035). The 5-year PFS for the entire cohort was 20%. Four patients with small metastases who had complete response remained disease free at study completion and were considered cured (median PFS > 10 years). Treatment was generally well tolerated, and only one patient experienced a late grade III musculoskeletal SBRT related toxicity. CONCLUSIONS: SBRT is a versatile, well-tolerated, and effective treatment option for single extracranial metastases from ovarian and uterine primary tumors. 35 Gy in five fractions appears to be a practical minimum effective dose. Four patients with small metastases were disease free at the study completion and considered cured. However, patients with larger metastases (≥50 cc) may require higher SBRT dosing or alternative treatments.

Pseudo five component reaction towards densely functionalized spiro[indole-3,2'-pyrrole] by picric acid, an efficient syn-diastereoselective catalyst: insight into the diastereoselection on C(sp3)-C(sp3) axial conformation.

A new series of highly-functionalized spiro compounds of pyrrole were synthesized by a one pot, step-economic condensation of isatin, arylamine and ß-keto ester catalyzed by wet picric acid. Initially, the reaction was proposed with an expectation of the formation of a multi-spiro heterocyclic framework of highly-substituted piperidine. However, the isomeric compound was characterized to be a five-membered pyrrole derivative with a diverse scope of variations having different types of substituents in the three components respectively. The possibility of formation of various diastereomers around the hindered single bond and the spiro carbon was limited, as only syn products syn-60 and syn-60' were isolated in all the reactions performed under the standard conditions. Probably the reactions were mediated by the si-facial formation of the bonds in a picric acid stabilized charge transfer complex transition state. Also, the manner a molecule achieves the most stabilized energy minimized arrangement with all its substituents in space was studied by DFT calculations where syn-60 was more stable than syn-60'. The studies on the formation of syn-60 and syn-60' were carried out by variation of electronic and steric factors in each of the components of the reactions.

A Prospective Analysis of Quality of Life and Toxicity Outcomes in Treating Early Breast Cancer With Breast Conservation Therapy and Intraoperative Radiation Therapy.

Introduction: Intraoperative radiation therapy (IORT) is a minimally invasive radiation option for select patients with early stage breast cancer. This prospective, single institution, pilot study summarizes patient-reported quality of life (QoL) outcomes and clinician-reported toxicity following IORT following breast conservation therapy. Methods: Forty-nine patients were enrolled in a prospective study from 2013 until 2015 to assess QoL and toxicity following breast conservation therapy and IORT. Nine patients did not meet criteria for IORT alone on final pathology and required whole breast irradiation afterwards. These patients were evaluated separately. Validated QoL questionnaires were provided to patients at 1-week, 1-month, and subsequent 6-month intervals for 2 years. Radiation-related toxicity symptoms were evaluated by clinicians at the same time intervals. Likert scale responses were converted to continuous variables to depict patient-reported and clinician-reported outcomes. Results: Outcomes were analyzed as weighted averages of the Likert scale for each symptom. Responses for negative QoL symptoms ranged largely from 0 (none) to 2 (moderate). Responses for positive QoL symptoms ranged largely from 3 (quite a bit) to 4 (very much). Seventy-five percent of patients developed a toxicity; however, 99% of the toxicities were grades 1 and 2. All toxicities demonstrated a downward trend over time, with the exception of breast fibrosis and nodularity, which increased over time. There were no local recurrences upon 2-year follow up. Conclusion: Early stage breast cancer treated with IORT yields favorable QoL outcomes and minimal toxicity profiles with adequate short-term local control.

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.

21-gene recurrence assay in patients receiving intraoperative radiotherapy: are "favorable" characteristics a surrogate for low recurrence?

BACKGROUND: Intraoperative radiotherapy (IORT) has gained momentum for early stage and favorable breast cancers (BC). The 21-gene recurrence assay guides treatment of hormone positive and node-negative BC. METHODS: Analysis of 82 invasive BC treated with breast conservation surgery (BCS) and IORT 2013-2015. Data collection included patient demographics, tumor characteristics, nodal status, recurrence test (RS) and adjuvant therapy. RESULTS: The mean age was 68 years. Tumors were stage Ia (86.6%), 3.6% Ib and 9.8% IIa. Of 50 patients (61.0%) with RS testing, 72% (n=36) were low risk (RS 0-17), with 28% (n=14) at intermediate risk (RS 18-30). The 39% (n=32) of patients without RS testing, were more likely to have smaller tumors (1.3 vs. 0.9 cm) and age >70 (P<0.05). CONCLUSIONS: Most patients selected for IORT based on clinical features were indeed low risk based on RS. Given the limited long-term clinical outcome and safety data of this technique, additional investigation is needed.

Stereotactic Accelerated Partial Breast Irradiation for Early-Stage Breast Cancer: Rationale, Feasibility, and Early Experience Using the CyberKnife Radiosurgery Delivery Platform.

PURPOSE: The efficacy of accelerated partial breast irradiation (APBI) utilizing brachytherapy or conventional external beam radiation has been studied in early-stage breast cancer treated with breast-conserving surgery. Data regarding stereotactic treatment approaches are emerging. The CyberKnife linear accelerator enables excellent dose conformality to target structures while adjusting for target and patient motion. We report our institutional experience on the technical feasibility and rationale for stereotactic accelerated partial breast irradiation (SAPBI) delivery using the CyberKnife radiosurgery system. METHODS: Ten patients completed CyberKnife SAPBI (CK-SAPBI) in 2013 at Georgetown University Hospital. Four gold fiducials were implanted around the lumpectomy cavity prior to treatment under ultrasound guidance. The synchrony system tracked intrafraction motion of the fiducials. The clinical target volume was defined on contrast enhanced CT scans using surgical clips and post-operative changes. A 5 mm expansion was added to create the planning treatment volume (PTV). A total dose of 30 Gy was delivered to the PTV in five consecutive fractions. Target and critical structure doses were assessed as per the National Surgical Adjuvant Breast and Bowel Project B-39 study. RESULTS: At least three fiducials were tracked in 100% of cases. The Mean treated PTV was 70 cm(3) and the mean prescription isodose line was 80%. Mean dose to target volumes and constraints are as follows: 100% of the PTV received the prescription dose (PTV30). The volume of the ipsilateral breast receiving 30 Gy (V30) and above 15 Gy (V > 15) was 14 and 31%, respectively. The ipsilateral lung volume receiving 9 Gy (V9) was 3%, and the contralateral lung volume receiving 1.5 Gy (V1.5) was 8%. For left-sided breast cancers, the volume of heart receiving 1.5 Gy (V1.5) was 31%. Maximum skin dose was 36 Gy. At a median follow-up of 1.3 years, all patients have experienced excellent/good breast cosmesis outcomes, and no breast events have been recorded. CONCLUSION: CyberKnife stereotactic accelerated partial breast irradiation is an appealing technique for partial breast irradiation offering improvements over existing APBI techniques. Our early findings indicate that CK-SAPBI delivered in five daily fractions is feasible, well tolerated, and is a reliable platform for delivering APBI.

Five-fraction stereotactic radiosurgery (SRS) for single inoperable high-risk non-small cell lung cancer (NSCLC) brain metastases.

BACKGROUND: Achieving durable local control while limiting normal tissue toxicity with definitive radiation therapy in the management of high-risk brain metastases remains a radiobiological challenge. The objective of this study was to examine the local control and toxicity of a 5-fraction stereotactic radiosurgical approach for treatment of patients with inoperable single high-risk NSCLC brain metastases. METHODS: This retrospective analysis examines 20 patients who were deemed to have "high-risk" brain metastases. High-risk tumors were defined as those with a maximum diameter greater than 2 cm and/or those located within an eloquent cortex. Patients were evaluated by a neurosurgeon prior to treatment and determined to be inoperable due to tumor or patient characteristics. Patients were treated using the CyberKnife® SRS system in 5 fractions to a total dose of 30 Gy, 35 Gy, or 40 Gy. RESULTS: Twenty patients with a median age of 65.5 years were treated from April 2010 to August 2014 in 5 fractions to a median total dose of 35 Gy. At a median follow up of 11.3 months local tumor control was observed in 18 of 20 metastases (90 %). Both local failures were observed in patients receiving a lower dose of 30 Gy. Median pre-treatment dexamethasone dose was 10 mg/day and median post-treatment nadir dose was 0 mg/day. Salvage intracranial therapy was required in 45 % of patients. Symptomatic radionecrosis was observed in 4 of 20 patients (20 %), two of which were treated to 40 Gy and the remainder to 35 Gy. Kaplan-Meier 1-year, 2-year, and median survival were calculated to be 45 %, 20 %, and 13.2 months, respectively. CONCLUSIONS: Five-fraction SRS to a total dose of 35 Gy appears to be a safe and effective management strategy for single high-risk NSCLC brain metastases, while a total dose of 40 Gy leads to an excess risk of neurotoxicity.

Effect of RTOG breast/chest wall guidelines on dose-volume histogram parameters.

Treatment planning for breast cancer has been traditionally based on clinical landmarks. The Radiation Therapy Oncology Group (RTOG) published consensus guidelines on contouring target volumes (TV) for the breast/chest wall and draining lymphatics. The effect of these guidelines on dosimetric parameters in surrounding organs at risk (OAR) and TVs is unknown. Fourteen patients treated with clinically derived plans from 2007-2011 (Group I) and fourteen patients treated with target volume-based plans from 2011-2012 were selected for comparison (Group II). Treatment plans were constructed based on clinical landmarks (Group I) or TVs (Group II) to a median dose of 50.4 Gy to the breast/chest wall, axilla (Ax), supraclavicular (SCV), and internal mammary (IMN) lymph nodes. The RTOG TVs were then contoured in Group I patients by a single investigator blinded to the dose distributions. Dose-volume histograms (DVH) were computed for the RTOG TVs and OARs in both groups, and DVH parameters were compared. In Group II, coverage improved for the SCV (V90 = 78.0% versus 93.6%, p = 0.02) and intact breast (V95 = 95.6% versus 99.3%, p = 0.007). The dose to the cord, the lung (V20Gy and V30Gy), and contralateral breast (V5Gy) were the same. Finally, the low dose to the heart and lung was decreased in Group II (heart V5Gy= 48.7% versus 27.3%, p= 0.02, heart V10Gy = 33.5% vs. 17.5%, p = 0.01, and ipsilateral lung V5Gy = 84.5% vs. 69.3%, p = 0.001). Overall, our study supports that treatment planning using the RTOG consensus guidelines can improve coverage to certain target volumes compared to treatments based solely on clinical landmarks. Additionally, treatment planning using these target volumes does not increase dose to the contralateral breast, cord, heart, or lungs. Longer follow-up is needed to determine if using these target volumes will affect clinical outcomes.

Lymph node density--prognostic value in head and neck cancer.

BACKGROUND: The purpose of this study was to determine the prognostic value of lymph node density in head and neck cancer. METHODS: We utilized a prospective, multicenter database of 223 patients with head and neck cancer to identify patients who underwent lymph node dissection before chemoradiation to assess the prognostic significance of lymph node density. RESULTS: In 38 patients who met study criteria, lymph node density ≤0.20 predicted for improved overall survival (OS; 79% vs 50%; p = .04). Lymph node density was also associated with a trend toward improved 3-year locoregional control (96% vs 79%; p = .14) and distant metastasis-free survival (93% vs 78%; p = .13). In the patients with treatment failure distantly or locoregionally, that failure was earlier in patients with lymph node density >0.20 than in patients with lymph node density ≤0.20 (median, 12.7 months vs 5.2 months; p = .004). CONCLUSION: Our data suggest that lymph node density predicts for OS in patients with head and neck cancer and that the difference in OS may be because of differences in time to failure.

Radiation oncology medical student clerkship: implementation and evaluation of a bi-institutional pilot curriculum.

PURPOSE: To develop and evaluate a structured didactic curriculum to complement clinical experiences during radiation oncology clerkships at 2 academic medical centers. METHODS AND MATERIALS: A structured didactic curriculum was developed to teach fundamentals of radiation oncology and improve confidence in clinical competence. Curriculum lectures included: (1) an overview of radiation oncology (history, types of treatments, and basic clinic flow); (2) fundamentals of radiation biology and physics; and (3) practical aspects of radiation treatment simulation and planning. In addition, a hands-on dosimetry session taught students fundamentals of treatment planning. The curriculum was implemented at 2 academic departments in 2012. Students completed anonymous evaluations using a Likert scale to rate the usefulness of curriculum components (1=not at all, 5=extremely). Likert scores are reported as (median [interquartile range]). RESULTS: Eighteen students completed the curriculum during their 4-week rotation (University of Chicago n=13, Harvard Longwood Campus n=5). All curriculum components were rated as extremely useful: introduction to radiation oncology (5 [4-5]); radiation biology and physics (5 [5-5]); practical aspects of radiation oncology (5 [4-5]); and the treatment planning session (5 [5-5]). Students rated the curriculum as "quite useful" to "extremely useful" (1) to help students understand radiation oncology as a specialty; (2) to increase student comfort with their specialty decision; and (3) to help students with their future transition to a radiation oncology residency. CONCLUSIONS: A standardized curriculum for medical students completing a 4-week radiation oncology clerkship was successfully implemented at 2 institutions. The curriculum was favorably reviewed. As a result of completing the curriculum, medical students felt more comfortable with their specialty decision and better prepared to begin radiation oncology residency.

Multidisciplinary care of the patient with head and neck cancer.

Head and neck cancer is a heterogeneous group of cancers, which require a multidisciplinary approach to achieve excellent treatment results. This article focuses on current treatment guidelines and controversies in the management of head and neck cancer. It also provides insight into future directions and newest advances in the treatment of head and neck cancer.

Stereotactic body radiation therapy for curative treatment of adrenal metastases.

The detection of oligometastatic adrenal metastases is increasing and there are limited data supporting the use of curative intent stereotactic body radiation therapy (SBRT) to treat patients with limited metastatic disease with adrenal involvement. Therefore, we utilized a prospectively maintained database of consecutive patients treated with SBRT for limited metastatic disease (≤5 sites) to identify patients with adrenal metastases. Patients were either treated on a three-fraction dose escalation protocol or a ten fraction off-protocol regimen. Outcomes including treated-metastasis control (TMC), distant control (DC), and overall survival (OS) were calculated by the Kaplan-Meier method. Ten patients with 13 adrenal metastases were identified for this case series. The median follow-up was 14.9 months. No patient experienced grade 3 toxicity. The most common grade 1-2 acute toxicities were fatigue (80%) and GI toxicity (40%). One patient experienced late grade 2 adrenal insufficiency. Overall, the 1-year TMC rate was 73%, DC was 30%, and OS was 90%. Three treated adrenal metastases progressed, all receiving the lowest BED10 (43.2 Gy), corresponding to 24 Gy in 3 fractions. After treatment of adrenal metastases with SBRT, the median time to salvage chemotherapy was 5.3 months (range 1.0-38.8 months) and 1-year freedom from salvage chemotherapy was 44%. These results suggest that SBRT to adrenal metastases was tolerated with low toxicity in limited metastatic patients and control rates are promising. This study supports the growing body of literature treating patients with adrenal metastases with SBRT.

The effect of treatment time in locally advanced cervical cancer in the era of concurrent chemoradiotherapy.

BACKGROUND: This study sought to determine if treatment time impacts pelvic failure (PF), distant failure (DF), or disease-specific mortality (DSM) in patients undergoing concurrent chemoradiotherapy (CCRT). METHODS: A retrospective review was performed of 113 consecutive eligible patients with stage IB2 to IIIB cervical cancer. All patients received whole-pelvis radiation with concurrent chemotherapy and consolidative intracavitary brachytherapy (BT) to the cervix, followed by an external beam parametrial boost when appropriate. The effect of treatment time on PF, DF, and DSM was examined with univariate and multivariate analyses. Characteristics of patients with and without treatment prolongation were compared to explore reasons for treatment prolongation. RESULTS: The median time to completion of BT was 60 days, and the median time to complete all RT was 68 days. The 3-year cumulative incidence of PF, DF, and DSM were 18%, 23%, and 26%, respectively. On multivariate analysis, time to completion of BT >56 days was associated with increased PF (hazard ratio, 3.8; 95% confidence interval, 1.2-16; P = .02). The 3-year PF for >56 days versus ≤56 days was 26% versus 9% (P = .04). Treatment time was not associated with DF or DSM. Treatment prolongation was found to be associated with delay in starting BT and higher incidence of acute grade 3/4 toxicities. CONCLUSIONS: In the setting of CCRT, treatment time >56 days is detrimental to pelvic control but is not associated with an increase in DF or DSM. To maximize pelvic control, we recommend completing BT in 8 weeks or less.