Assessment of Patients With Prostate Cancer and Their Understanding of the International Prostate Symptom Score Questionnaire.

Purpose: The International Prostate Symptom Score (IPSS) is a widely used tool for evaluating patient-reported lower urinary tract symptoms. In this study, we assessed patients with prostate cancer and their understanding of IPSS questions. Methods and Materials: Consecutive patients with prostate cancer (N = 144) self-completed an online IPSS questionnaire within 1 week before their visit at our radiation oncology clinic. At the visit, a nurse reviewed each IPSS question to ensure the patient understood it and then verified the patient's answer. Preverified and nurse-verified scores were recorded and analyzed for discrepancies. Results: Complete concordance between preverified and nurse-verified responses to individual IPSS questions existed for 70 men (49%). In terms of overall IPSS score, 61 men (42%) had a lower or improved IPSS after nurse verification, and 9 men (6%) had a higher or worse IPSS. Before verification, patients overstated their symptoms of frequency, intermittency, and incomplete emptying. As a result of the nurse verification, 4 of 7 patients with IPSS in the severe range (20-35) were recategorized to the moderate range (8-19). Sixteen percent of patients whose preverified IPSS were in the moderate range were recategorized after nurse verification to the mild range (0-7). Treatment option eligibility changed for 10% of patients after nurse verification. Conclusions: Patients frequently misunderstand the IPSS questionnaire, leading them to respond in ways that do not accurately reflect their symptoms. Clinicians should verify patient understanding of the IPSS questions, particularly when using the score to determine eligibility for treatments.

Proton Radiotherapy to Preserve Fertility and Endocrine Function: A Translational Investigation.

PURPOSE: Photon radiation therapy (x-ray radiation therapy [XRT] and gamma-ray radiation therapy [GRT]) of tumors close to ovaries causes reproductive and endocrine sequelae due to ovarian primordial follicle depletion. Given its finite range, proton radiation therapy (PRT) can preserve ovarian function when ovaries are positioned distal to the spread-out Bragg peak (SOBP) in tumors of the abdominopelvic region. This study compared anti-Müllerian hormone (AMH) levels (a biomarker of ovarian function) and primordial follicle survival after in vivo mouse pelvic GRT versus PRT. METHODS AND MATERIALS: One hundred twenty-four female prepubertal mice received sham, GRT, or PRT with ovaries positioned at various depth with respect to the proton SOBP, with single doses of 1.8 or 0.2 Gy. AMH was measured at baseline, 1, 3, and 8 weeks after treatment, and the total number of surviving primordial follicles was counted. Multivariable linear mixed-effects modeling was used to assess the relationship between radiation therapy modality and dose on AMH and primordial follicle survival. RESULTS: For ovaries beyond the SOBP, ovarian function (P = .5) and ovarian primordial follicle (OPF; P = 1.0) were spared relative to sham controls. For ovaries in the SOBP plateau, ovarian function and primordial follicle reserve 8 weeks after treatment were reduced for all groups: 1.8 Gy GRT (ßAMH = -4.9 ng/mL; ßOPF = -728.2/animal), 1.8 Gy (relative biological effectiveness [RBE] = 1.1) PRT (ßAMH = -5.1 ng/mL; ßOPF = -728.2/animal), 0.2 Gy GRT (ßAMH = -2.5 ng/mL; ßOPF = -595.1/animal), and 0.2 Gy (RBE = 1.1) PRT (ßAMH = -3.0 ng/mL; ßOPF = -555.4/animal) relative to sham controls (all differences P < .001). CONCLUSIONS: This study uses an animal model to demonstrate the safety of proton therapy in sparing fertility. Ovaries positioned beyond the SOBP during PRT maintain ovarian reserve, suggesting that a proton beam has no energy and exit dose beyond SOBP. This study proposes that proton therapy is much safer than photon radiation therapy to protect ovarian follicles with the same dose, and it supports further testing of proton therapy for abdominopelvic tumors in young women.

Medical oncologist perspectives on palliative care reveal physician-centered barriers to early integration.

BACKGROUND: Early palliative care referral for patients with advanced cancer has demonstrable benefits but is underutilized. We sought to characterize medical oncologists' perceptions about palliative care referral in their clinical practices. METHODS: We conducted 4 focus groups with a national sample of medical oncologists to elicit perspectives about the optimal timing of and barriers to palliative care referral for patients with cancer. We used qualitative content analysis to uncover themes related to early integration of palliative care into standard oncologic practice. RESULTS: Study participants readily acknowledged the evidence supporting early palliative care referral. However, medical oncologists identified patient-centered and physician-centered barriers to widespread adoption of early palliative care. Patient-centered barriers included patients' and families' perceptions or misperceptions of the role of palliative care. Additionally, physicians themselves described acting as a barrier to palliative care referral because they were concerned that palliative care physicians may interfere with the plan of care, or offer options that were not endorsed by the medical oncologist. Medical oncologists depicted themselves having authority over the timing of palliative care referral, and as granting limited autonomy to other clinical team members in counseling patients about advanced care planning. CONCLUSIONS: Medical oncologists are hesitant to adopt the practice of early palliative care referral because they are concerned that other physicians may disrupt a patient's treatment plan. Physician-centered barriers may delay integration of palliative care, and future efforts to promote a collaborative approach to advanced care planning may improve patient-centered outcomes through access to early palliative care.

Radiation Oncologists' Role in End-of-Life Care: A Perspective From Medical Oncologists.

PURPOSE: Multidisciplinary communication and collaboration are key to planning and delivering end-of-life care for patients with advanced and metastatic cancer. We sought to characterize medical oncologists' perspectives on the role of radiation oncologists in end-of-life care. MATERIALS AND METHODS: A sample of US medical oncologists was recruited using snowball sampling methods. Audio recordings of 4 professionally moderated focus groups were transcribed. Investigators from diverse backgrounds (medical oncology, radiation oncology, critical care medicine, palliative care, and public health) independently reviewed each transcript. Qualitative content analysis was used to create consensus codes that were applied to subsequent focus group transcripts in an iterative process. RESULTS: Medical oncologists expressed complex views regarding the role of radiation oncologists in end-of-life care. Identified themes included the limited role of radiation oncologists, territorial concerns, capability, and desire of radiation oncologists in this realm, and the need for communication between providers. Radiation oncologists were compared with surgeons, whose interaction with patients ceased after their service had been performed. In this regard, control of palliative care referral or end-of-life care discussions was thought to be in the territory of medical oncologists who had longitudinal relationships with patients from diagnosis. Medical oncologists were concerned about the capability of radiation oncologists to accurately prognosticate, and stated radiation oncologists lacked knowledge of subsequent lines of systemic therapy available to patients. Radiation oncologists' fear of upsetting medical oncologists was thought to be justified if they engaged in end-of-life care planning without direct permission from the referring medical oncologist. CONCLUSIONS: Participation of radiation oncologists in end-of-life care planning was viewed with skepticism by medical oncologists. Radiation oncologists should focus on increasing open communication and teamwork with medical oncologists and demonstrate their ability to prognosticate and counsel patients regarding end-of-life care decisions.

Development and Validation of a Nomogram to Predict Lymphedema After Axillary Surgery and Radiation Therapy in Women With Breast Cancer From the NCIC CTG MA.20 Randomized Trial.

PURPOSE: Regional nodal irradiation for women with breast cancer is known to be an important risk factor for the development of upper extremity lymphedema, but tools to accurately predict lymphedema risks for individual patients are lacking. This study sought to develop and validate a nomogram to predict lymphedema risk after axillary surgery and radiation therapy in women with breast cancer. METHODS AND MATERIALS: Data from 1832 women accrued on the MA.20 trial between March 2000 and February 2007 were used to create a prognostic model with National Cancer Institute Common Toxicity Criteria Version 2.0 grade 2 or higher lymphedema as the primary endpoint. Multivariable logistic regression estimated model performance. External validation was performed on data from a single large academic cancer center (N = 785). RESULTS: In the MA.20 trial cohort, 3 risk factors were predictive of lymphedema risk: body mass index (adjusted odds ratio, 1.05 per unit body mass index; 95% confidence interval [CI], 1.03-1.08, P < .001), extent of axillary surgery (adjusted odds radio for 8-11 lymph nodes removed, 3.28 [95% CI, 1.53-7.89] P = .004; 12-15 lymph nodes, 4.04 [95% CI, 1.76-10.26] P = .002; ≥16 nodes, 5.08 [95% CI, 2.26-12.70] P < .001), and extent of nodal irradiation (adjusted odds radio for limited, 1.66 [95% CI, 1.08-2.56] P = .02; for extensive, 2.31 [95% CI, 1.28-4.10] P = .004). A nomogram was created from these data that predicted lymphedema risk with reasonable accuracy confirmed by both internal (concordance index, 0.69; 95% CI, 0.64-0.74) and external validation (concordance index, 0.71; 95% CI, 0.66-0.76). CONCLUSIONS: The nomogram created from the MA.20 randomized trial data using clinical information may be useful for lymphedema screening and risk stratification for therapeutic intervention trials.

Determining the Organ at Risk for Lymphedema After Regional Nodal Irradiation in Breast Cancer.

PURPOSE: Lymphedema after regional nodal irradiation is a severe complication that could be minimized without significantly compromising nodal coverage if the anatomic region(s) associated with lymphedema were better defined. This study sought to correlate dose-volume relationships within subregions of the axilla with lymphedema outcomes to generate treatment planning guidelines for reducing lymphedema risk. METHODS AND MATERIALS: Women with stage II-III breast cancer who underwent breast surgery with axillary assessment and regional nodal irradiation were identified. Nodal targets were prospectively contoured per Radiation Therapy Oncology Group guidelines for field design. The axilla was divided into 8 distinct subregions that were retrospectively contoured. Lymphedema outcomes were assessed by arm circumferences. Multivariate Cox proportional hazards regression assessed patient, surgical, and dosimetric predictors of lymphedema outcomes. RESULTS: Treatment planning computed tomography scans for 265 women treated between 2013 and 2017 were identified. Median post-radiation therapy follow-up was 3 years (interquartile range [IQR], 1.9-3.6). Dose to the axillary-lateral thoracic vessel juncture (ALTJ; superior to level I) was most associated with lymphedema risk (maximally selected rank statistic = 6.3, P < .001). The optimal metric was ALTJ minimum dose (Dmin) <38.6 Gy (3-year lymphedema rate 5.7% vs 37.4%, P <.001), although multiple parameters relating to sparing of the ALTJ were highly correlated. Multivariate analysis confirmed ALTJ Dmin <38.6 Gy (hazard ratio [HR], 0.13; P < .001), body mass index (HR, 1.06/unit; P = .002), and number of lymph nodes removed (HR, 1.08/node; P < .001) as significant predictors. Women with ALTJ Dmin <38.6 Gy maintained median V45Gy of 99% in the supraclavicular (IQR, 94-100%), 100% in level III (IQR, 97%-100%), 98% in level II (IQR, 86%-100%), and 91% in level I (IQR, 75%-98%) nodal basins. CONCLUSIONS: Anatomic studies suggest the ALTJ region is typically traversed by arm lymphatics and appears to be an organ at risk in breast radiation therapy. Ideally, avoidance of the ALTJ may be feasible while simultaneously encompassing breast-draining nodal basins. Confirmation of this finding in future prospective studies is needed.

Improved neuropsychological outcomes following proton therapy relative to X-ray therapy for pediatric brain tumor patients.

BACKGROUND: Survivors of pediatric brain tumors are at risk for impaired development in multiple neuropsychological domains. The purpose of this study was to compare neuropsychological outcomes of pediatric brain tumor patients who underwent X-ray radiotherapy (XRT) versus proton radiotherapy (PRT). METHODS: Pediatric patients who underwent either XRT or PRT and received posttreatment age-appropriate neuropsychological evaluation-including measures of intelligence (IQ), attention, memory, visuographic skills, academic skills, and parent-reported adaptive functioning-were identified. Multivariate analyses were performed to assess differences in neuropsychological outcomes and included tests for interaction between treatment cohort and follow-up time. RESULTS: Between 1998 and 2017, 125 patients with tumors located in the supratentorial (17.6%), midline (28.8%), or posterior fossa (53.6%) compartments received radiation and had posttreatment neuropsychological evaluation. Median age at treatment was 7.4 years. The PRT patient cohort had higher estimated SES and shorter median time from radiotherapy completion to last neuropsychological evaluation (6.7 vs 2.6 y, P < 0.001). On multivariable analysis, PRT was associated with higher full-scale IQ (ß = 10.6, P = 0.048) and processing speed (ß = 14.4, P = 0.007) relative to XRT, with trend toward higher verbal IQ (ß = 9.9, P = 0.06) and general adaptive functioning (ß = 11.4, P = 0.07). Planned sensitivity analyses truncating follow-up interval in the XRT cohort re-demonstrated higher verbal IQ (P = 0.01) and IQ (P = 0.04) following PRT, with trend toward improved processing speed (P = 0.09). CONCLUSIONS: PRT is associated with favorable outcomes for intelligence and processing speed. Combined with other strategies for treatment de-intensification, PRT may further reduce neuropsychological morbidity of brain tumor treatment.

Radiation Therapy Field Design and Lymphedema Risk After Regional Nodal Irradiation for Breast Cancer.

PURPOSE: The occurrence of upper extremity lymphedema after regional nodal irradiation (RNI) for breast cancer treatment varies significantly based on patient and treatment factors. The relationship between the radiation therapy (RT) field design and lymphedema risk is not well-characterized. The present study sought to correlate the variations in RT field design with lymphedema outcomes. METHODS AND MATERIALS: Women with stage II-IV breast cancer receiving RNI after breast surgery that included sentinel lymph node biopsy or axillary dissection were identified. Their arm circumference was measured before RT and at each follow-up visit to assess for lymphedema. Nodal RT fields were defined using a trifurcated system. Group 1 excluded the upper level I and II axilla, defined by the lateral border of the nodal field encompassing less than one-third of the humeral head. Group 2 included the upper level I and II axilla, defined by the lateral border of the nodal field encompassing more than one-third of the humoral head treated with an anterior oblique beam. Group 3 included the upper level I and II axilla the same as for group 2 but with parallel-opposed beams delivering a significant dose to the musculature posterior to the axilla. RESULTS: From 1999 to 2013, 526 women received RNI. The median post-RT follow-up was 5.5 years. For the 492 women meeting the inclusion criteria, the cumulative incidence of lymphedema was 23.5% at 2 years and 31.8% at 5 years. On univariate analysis, the patients in group 1 had a lower 5-year lymphedema rate (7.7%) than those in group 2 (37.1%) and group 3 (36.7%; P < .0001). On multivariate analysis, inclusion of the upper level I and II axilla (groups 2 and 3) remained significantly associated with increased lymphedema risk. CONCLUSIONS: Variations in the RT field design significantly affect the development of lymphedema after RNI. In particular, the upper level I and II axilla appear to be important regions for lymphedema risk after axillary dissection.

c-Met Overexpression in Cervical Cancer, a Prognostic Factor and a Potential Molecular Therapeutic Target.

PURPOSE: This study aimed to assess the association between pretreatment c-Met overexpression in local-regional advanced cervical cancer patients treated definitively with concurrent chemoradiation therapy (CRT) and treatment outcomes including overall survival (OS), progression-free survival (PFS), distant metastases (DM) control, and local-regional control (LC). PATIENTS AND METHODS: This Institutional Review Board-approved study included cervical cancer patients treated definitively and consecutively with CRT. Evaluation of cytoplasmic immunoreactivity for c-Met was performed and scored semiquantitatively by 3 pathologists, blinded to the treatment outcomes, and incorporated both the intensity and percentage of immunoreactivity in invasive carcinoma (H score). Treatment outcomes were reviewed and reported. Outcomes were stratified by c-Met overexpression and tumor characteristics. OS, PFS, LC, and DC rates were obtained via the Kaplan-Meier method and differences between groups were evaluated by the log-rank test. Hazard ratios were obtained via Cox regression for both univariate and multivariate analyses. RESULTS: The 5-year OS, PFS, LC, and DC were 57.18%, 48.07%, 72.11%, and 62.85%, respectively. Ten (35.7%) and 18 patients (64.3%) had c-Met H index >30 and<30, respectively. c-Met overexpression was significantly associated with worse 3- and 5-year OS (P=0.003), PFS (P=0.002), LC (P=0.01), and DC (P=0.0003). Patients with c-Met overexpression had a hazard ratio of 6.297, 5.782, 6.28, and 18.173 for the risks of death, disease progression, local recurrence, and DM, respectively. CONCLUSION: c-Met overexpression could be a potential predictive marker and therapeutic target for local-regional advanced cervical cancer patients treated definitively with CRT.

Perspective: after a century of criticizing premedical education, are we missing the point?

Ever since Abraham Flexner formalized the idea of premedical education in 1910, medical educators have argued about how best to prepare students for medical school. This back-and-forth about the premedical years has focused almost exclusively on the range and content of the required course work; noticeably absent from the debate is consideration of the ways in which the experience of the premedical years-including the curricular and noncurricular demands placed on students-shape the moral education of the next generation of physicians. The authors review the century-long conversation about premedical education, highlighting the themes of that discussion and the important aspects of being a "premed" that have not been a part of the conversation. From their systematic review of college and university Web sites designed for premedical students and from comments collected from a symposium on the premedical years, the authors describe how life as a premedical student, and not just curricular content, teaches important lessons about what it means to be a professional. The authors also report important disparities in attitudes about premedical education; for example, premedical advisors regard the "sifting process" of premedical education as a "journey of discovery," whereas students describe their premedical years as a competition. The authors' work suggests a new approach to premedical education, an approach that combines the coursework needed to succeed in medical school with formal opportunities to reflect on both the positive and pernicious effects of the premedical years.