Raphael Yechieli

Delineation of Tumor Habitats based on Dynamic Contrast Enhanced MRI

Tumor heterogeneity can be elucidated by mapping subregions of the lesion with differential imaging characteristics, called habitats. Dynamic Contrast Enhanced (DCE-)MRI can depict the tumor microenvironments by identifying areas with variable perfusion and vascular permeability, since individual tumor habitats vary in the rate and magnitude of the contrast uptake and washout. Of particular interest is identifying areas of hypoxia, characterized by inadequate perfusion and hyper-permeable vasculature. An automatic procedure for delineation of tumor habitats from DCE-MRI was developed as a two-part process involving: (1) statistical testing in order to determine the number of the underlying habitats; and (2) an unsupervised pattern recognition technique to recover the temporal contrast patterns and locations of the associated habitats. The technique is examined on simulated data and DCE-MRI, obtained from prostate and brain pre-clinical cancer models, as well as clinical data from sarcoma and prostate cancer patients. The procedure successfully identified habitats previously associated with well-perfused, hypoxic and/or necrotic tumor compartments. Given the association of tumor hypoxia with more aggressive tumor phenotypes, the obtained in vivo information could impact management of cancer patients considerably.

Effect of a formal oncofertility program on fertility preservation rates—first year experience

Background A formal fertility preservation program was initiated at our institution in 2016 as part of a multi-disciplinary oncofertility initiative to improve the reproductive needs of oncologic patients. After 1 year of initial experience, we assessed sperm banking rates in men diagnosed with cancer, as well as examined the trends in the use of fertility preservation services. Methods We performed a chart review from 2011 to 2017 for men newly diagnosed with cancer, and for all men who underwent fertility preservation during that period of time at our institution. We assessed the rates of sperm banking among patients newly diagnosed with cancer, before and after the implementation of a standardized oncofertility program in 2016. The program includes nursing and physician education regarding indications of fertility preservation. Additionally, we evaluated the overall population undergoing sperm cryopreservation at our institution during the study period. Results From 2011 to 2016, 30 of 902 oncologic patients underwent sperm banking prior to their treatment (3.3% of total cancer patients). After the program was implemented, 42 of 218 patients underwent fertility preservation between June 2016 and August 2017 (19.3% of total cancer patients). In this group, patients’ mean age was 30.14 years old (range, 13–69 years old), with 6 pediatric patients; 36 of the samples (85.7%) were obtained from masturbation. When viable sperm could not be obtained from ejaculation, patients underwent either testicular or epididymal sperm extraction (6 cases). Overall, 98 men used the formal fertility preservation service. Of these, 42 were cancer patients and 56 were non-cancer patients. Of the non-cancer patients, 17 banked sperm after varicocelectomy, 6 prior to vasectomy and 6 because of hypogonadism. Conclusions Rate of sperm banking increased nearly six-fold after institution of a formal fertility preservation program, indicating the clinical need for such a program at academic institutions. Oncofertility is a relevant part of the care for oncologic patients, and should be considered as part of counseling before cancer treatment.

Local recurrence of soft-tissue sarcoma: issues in imaging surveillance strategy

Soft-tissue sarcomas pose diagnostic and therapeutic challenges to physicians, owing to the large number of subtypes, aggressive tumor biology, lack of consensus on management, and controversy surrounding interval and duration of surveillance scans. Advances in multidisciplinary management have improved the care of sarcoma patients, but controversy remains regarding strategies for surveillance following definitive local control. This review provides an updated, comprehensive overview of the current understanding of the risk of local recurrence of soft-tissue sarcoma, by examining the literature based on features such as histological type and grade, tumor size, and resection margin status, with the aim of helping clinicians, surgeons, and radiologists to develop a tailored approach to local imaging surveillance.

Automated inverse optimization facilitates lower doses to normal tissue in pancreatic stereotactic body radiotherapy

Purpose Inverse planning is trial-and-error iterative process. This work introduces a fully automated inverse optimization approach, where the treatment plan is closely tailored to the unique patient anatomy. The auto-optimization is applied to pancreatic stereotactic body radiotherapy (SBRT). Materials and methods The automation is based on stepwise reduction of dose-volume histograms (DVHs). Five uniformly spaced points, from 1% to 70% of the organ at risk (OAR) volumes, are used. Doses to those DVH points are iteratively decreased through multiple optimization runs. With each optimization run the doses to the OARs are decreased, while the dose homogeneity over the target is increased. The iterative process is terminated when a pre-specified dose heterogeneity over the target is reached. Twelve pancreatic cases were retrospectively studied. Doses to the target, maximum doses to duodenum, bowel, stomach, and spinal cord were evaluated. In addition, mean doses to liver and kidneys were tallied. The auto-optimized plans were compared to the actual treatment plans, which are based on national protocols. Results The prescription dose to 95% of the planning target volume (PTV) is the same for the treatment and the auto-optimized plans. The average difference for maximum doses to duodenum, bowel, stomach, and spinal cord are -4.6 Gy, -1.8 Gy, -1.6 Gy, and -2.4 Gy respectively. The negative sign indicates lower doses with the auto-optimization. The average differences in the mean doses to liver and kidneys are -0.6 Gy, and -1.1 Gy to -1.5 Gy respectively. Conclusions Automated inverse optimization holds great potential for personalization and tailoring of radiotherapy to particular patient anatomies. It can be utilized for normal tissue sparing or for an isotoxic dose escalation.

Assessment of Oropharyngeal and Laryngeal Cancer Treatment Delay in a Private and Safety Net Hospital System

Objective To examine the impact of treatment setting and demographic factors on oropharyngeal and laryngeal cancer time to treatment initiation (TTI). Study Design Retrospective case series. Setting Safety net hospital and adjacent private academic hospital. Subjects and Methods Demographic, staging, and treatment details were retrospectively collected for 239 patients treated from January 1, 2014, to June 30, 2016. TTI was defined as days between diagnostic biopsy and initiation of curative treatment (defined as first day of radiotherapy [RT], surgery, or chemotherapy). Results On multivariable analysis, safety net hospital treatment (vs private academic hospital treatment), initial diagnosis at outside hospital, and oropharyngeal cancer (vs laryngeal cancer) were all associated with increased TTI. Surgical treatment, severe comorbidity, and both N1 and N2 status were associated with decreased TTI. Conclusion Safety net hospital treatment was associated with increased TTI. No differences in TTI were found when language spoken and socioeconomic status were examined in the overall cohort.

Delays in definitive cervical cancer treatment: An analysis of disparities and overall survival impact

OBJECTIVE Delays in time to treatment initiation (TTI) with definitive radiation therapy (RT) or chemotherapy and RT (CRT) for cervical cancer could lead to poorer outcomes. This study investigates disparities in TTI and the impact of TTI on overall survival (OS). METHODS Adult women with non-metastatic cervical squamous cell carcinoma diagnosed between 2004 and 2014, treated with definitive RT or CRT, and reported to the National Cancer Database were included. TTI was defined as days from diagnosis to start of RT or CRT. The impact of TTI on OS in patients treated with concurrent CRT which included brachytherapy was then assessed. RESULTS Overall, 14,924 patients were included (84.7% CRT, 15.3% RT). TTI was significantly longer for Non-Hispanic Black (NHB) (RR, 1.14; 95% CI, 1.11 to 1.18) and Hispanic women (RR, 1.19; 95% CI, 1.15 to 1.24) compared to Non-Hispanic White (NHW) women. Expected TTI (eTTI) for NHW, NHB, and Hispanic women were 38.1, 45.2, and 49.4days. eTTI rose from 36.2days in 2004 to 44.3days by 2014. Intensity-modulated radiation therapy (IMRT) was associated with increased eTTI of 46.5days versus 40.0days for non-IMRT. Longer TTI was not associated with inferior OS in patients treated with concurrent CRT. CONCLUSIONS Delays in starting RT/CRT for cervical cancer increased from 2004 to 2014. Delays disproportionately affect NHB and Hispanic women. However, increased TTI was not associated with increased mortality for women receiving CRT. Further study of TTIs impact on other endpoints is warranted to determine if TTI represents an important quality indicator.

Limb-sparing surgery plus radiotherapy results in superior survival: an analysis of patients with high-grade, extremity soft-tissue sarcoma from the NCDB and SEER

Small randomized trials have not shown an overall survival (OS) difference among local treatment modalities for patients with extremity soft‐tissue sarcomas (E‐STS) but were underpowered for OS. We examine the impact of local treatment modalities on OS and sarcoma mortality (SM) using two national registries. The National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program were analyzed separately to identify patients with stage II‐III, high‐grade E‐STS diagnosed between 2004 and 2013 and treated with (1) amputation alone, (2) limb‐sparing surgery (LSS) alone, (3) preoperative radiation therapy (RT) and LSS, or (4) LSS and postoperative RT. Multivariable analyses (MVAs) and 1:1 matched pair analyses (MPAs) examined treatment impacts on OS (both databases) and SM (SEER only). From the NCDB and SEER, 7828 and 2937 patients were included. On MVAs, amputation was associated with inferior OS and SM. Relative to LSS alone, both preoperative RT and LSS (HR, 0.70; 95% CI: 0.62‐0.78) and LSS and postoperative RT (HR, 0.69; 95% CI: 0.63‐0.75) improved OS in NCDB analyses with confirmation by SEER. Estimated median survivals from MPA utilizing NCDB data were 7.2 years with LSS alone (95% CI: 6.5‐8.9 years) vs 9.8 years (95% CI: 9.0‐11.2 years) with LSS and postoperative RT. A MPA comparing preoperative RT and LSS to LSS alone found median survivals of 8.9 years (95% CI: 7.9‐not estimable) and 6.6 years (95% CI: 5.4‐7.8 years). Optimal high‐grade E‐STS management includes LSS with preoperative or postoperative RT as evidenced by superior OS and SM.

Resident satisfaction with radiation oncology training

Purpose Residency training environments can differ significantly; therefore, resident satisfaction may vary widely among programs. Here, we sought to examine several variables in program satisfaction through a survey of radiation oncology (RO) trainees in the United States. Methods and materials An anonymous, institutional review board-approved, internet-based survey was developed and distributed to U.S. residents in RO in September 2016. This email-based survey assessed program-specific factors with regard to workload, work-life balance, and education as well as resident-specific factors such as marital status and postgraduate year. Binomial multivariable regression assessed the correlations between these factors and the endpoint of resident-reported likelihood of selecting an alternative RO residency program if given the choice again. Results A total of 215 residents completed the required survey sections, representing 29.3% of U.S. RO residents. When asked whether residency allowed for an adequate balance between work and personal life, the majority of residents (75.6%) agreed or strongly agreed, but a minority (9.3%) did not feel that residency allowed for sufficient time for personal life. The majority of residents (69.7%) indicated that they would choose the same residency program again, but 12.2% would have made a different choice. Almost three-fourths of residents (73.0%) felt that faculty and staff cared about the educational success of residents, but 9.27% did not. Binomial multivariable regression revealed that senior residents (odds ratio: 6.70; 95% confidence interval, 2.20-22.4) were more likely to desire a different residency program. In contrast, residents who reported constructive feedback use by the residency program (odds ratio:0.22; 95% confidence interval, 0.06-0.91) were more satisfied with their program choice. Conclusions Most RO residents reported satisfaction with their choice of residency program, but seniors had higher rates of dissatisfaction. Possible interventions to improve professional satisfaction include incorporating constructive resident feedback to enhance the program. The potential impact of job market pressures on seniors should be further explored.

Impact of Performance Status and Comorbidity on Palliative Radiation Treatment Tolerance and End-Of-Life Decision-Making

Purpose Previous studies have indicated a relationship between functional status and comorbidity on overall survival when treating patients with bone and brain metastases. However, the degree to which these findings have been integrated into modern-day practice remains unknown. This study examines the impact of performance measures, including Karnofsky Performance Status (KPS) and comorbidity, on palliative radiation therapy treatment tolerance and fractionation schedule. The relationship between a shorter fractionation schedule (SFx) and pending mortality is examined. Methods and materials This study included patients who were treated with palliative intent to the brain or bone between January 1, 2016 and June 30, 2016. Demographic and medical characteristics collected included KPS score (stratified as good [90-100], fair [70-80], and poor (≤60]), socioeconomic status, comorbidity (binary measure using the Adult Comorbidity Evaluation-27 scale), site of metastatic disease, and treatment facility. Univariable analyses were performed using the Cox proportional hazards regression model to assess the impact of the variables on the prescribed number of fractions (binary measure, ≥10 [long fractionation schedule], and <10 [SFx]), and major treatment interruptions (MTIs; defined as missing ≥3 radiation therapy treatment days or ending treatment prematurely). Results A total of 145 patients were eligible for study inclusion, including 95 patients who were treated for bony metastatic disease and 50 patients for brain metastases. High comorbidity (P = .029) and both fair (P = .051) and poor (P = .065) functional status were associated with more frequent MTIs. However, high comorbidity and low KPS score were not associated with shorter treatment plans. In addition, patients with an earlier time to death were not more likely to receive an SFx (P = .871). Conclusions Low KPS and elevated comorbidity scores predict for a poorer prognosis and more frequent MTIs; however, there was no indication that physicians incorporated this information in the fractionation scheduling.

Oncofertility in sarcoma patients

Treatment for sarcoma can significantly decrease fertility, both due to the irradiation of gonads, and the impact of chemotherapy on gametogenesis. Infertility in cancer survivors causes significant regret and decreased quality of life in their adulthood. As this cancer mainly affects children and young adults, fertility preservation is an essential part of survivorship care, however it remains one of the least implemented services in adolescent and young adult cancer patients. Success of fertility preservation is highly dependent on the referral prior to oncologic treatment. Early patient counseling with possible consult with oncofertility specialists should be offered to every oncologic patient in reproductive age or younger. There are several options available and in continuous evolution for fertility preservation. Cryopreservation of sperm and oocytes constitutes nowadays the standard of care, and should be offered to all patients. Other methods currently under development will potentially bring in the future reliable options for fertility preservation in a wider range of patients, such as those in pre-pubertal age at the time of diagnosis, or with an insufficient sperm count for semen banking. These include testicular sperm extraction (TESE), autologous ovarian tissue transplant, and in vitro maturation of gametes. Novel therapies such as molecular-targeted agents offer a safer toxicity profile regarding fertility, but further research is required to evaluate their impact on the long term, both alone and in combination therapies. Difficulties to access fertility preservation and its costs remain a significant impediment for many patients in need. Warranting access to all sarcoma patients should be a priority in all healthcare professionals involved in their care.