Patient-reported Outcomes After External Beam Radiotherapy With Low Dose Rate Brachytherapy Boost vs Radical Prostatectomy for Localized Prostate Cancer: Five-year Results From a Prospective Comparative Effectiveness Study.

PURPOSE: Data comparing radical prostatectomy and external beam radiation therapy with low dose rate brachytherapy boost are lacking. To better guide shared decision making regarding treatment, we compared patient reported outcomes through 5 years following radical prostatectomy or external beam radiation therapy with low dose rate brachytherapy boost for localized prostate cancer. MATERIALS AND METHODS: From 2011-2012, men aged <80 years with localized prostate adenocarcinoma were enrolled and followed longitudinally. Patient reported outcomes included the Expanded Prostate Index Composite. Regression models adjusted for baseline scores and covariates were constructed. RESULTS: The study population included 112 men treated with external beam radiation therapy with low dose rate brachytherapy boost and 1,553 treated with radical prostatectomy. Compared to radical prostatectomy, external beam radiation therapy with low dose rate brachytherapy boost was associated with clinically meaningful worse urinary irritative/obstructive (adjusted mean score difference [95% confidence interval]: 5.0 [-8.7, -1.3]; P = .008 at 5 years) and better urinary incontinence function (13.3 [7.7, 18.9]; P < .001 at 5 years) through 5 years. Urinary function bother was similar between groups (P > .4 at all timepoints). Treatment with external beam radiation therapy with low dose rate brachytherapy boost was associated with worse bowel function (-4.0 [-6.9, -1.1]; P = .006 at 5 years) through 5 years compared to radical prostatectomy. Treatment with external beam radiation therapy with low dose rate brachytherapy boost was associated with better sexual function at 1 year (12.0 [6.5, 17.5]; P < .001 at 1 year) compared to radical prostatectomy, but there was insufficient evidence to reject the supposition that no difference was seen at 3 or 5 years. CONCLUSIONS: Compared to radical prostatectomy, external beam radiation therapy with low dose rate brachytherapy boost was associated with clinically meaningful worse urinary irritative/obstructive and bowel functions but better urinary incontinence function through 5 years after treatment. These patient-reported functional outcomes may clarify treatment expectations and help inform treatment choices for localized prostate cancer.

Five-year outcomes from a prospective comparative effectiveness study evaluating external-beam radiotherapy with or without low-dose-rate brachytherapy boost for localized prostate cancer.

BACKGROUND: To inform patients who are in the process of selecting prostate cancer treatment, the authors compared disease-specific function after external-beam radiotherapy (EBRT) alone versus EBRT plus a low-dose-rate (LDR) brachytherapy boost (EBRT-LDR). METHODS: For this prospective study, men who had localized prostate cancer in 2011 and 2012 were enrolled. Assessments at baseline, 0.5, 1, 3, and 5 years included the patient-reported Expanded Prostate Index Composite, the 36-item Medical Outcomes Study Short-Form Health Survey, and treatment-related regret. Regression models were adjusted for baseline function and for patient and treatment characteristics. The minimum clinically important difference in scores on the Expanded Prostate Index Composite 26-item instrument was from 5 to 7 for urinary irritation and from 4 to 6 for bowel function. RESULTS: Six-hundred ninety-five men met inclusion criteria and received either EBRT (n = 583) or EBRT-LDR (n = 112). Patients in the EBRT-LDR group were younger (median age, 66 years [interquartile range [IQR], 60-71 years] vs 69 years [IQR, 64-74 years]; P < .001), were less likely to receive pelvic radiotherapy (10% vs 18%; P = .040), and had higher baseline 36-item Medical Outcomes Study Short-Form Health Survey physical function scores (median score, 95 [IQR, 86-100] vs 90 [IQR, 70-100]; P < .001). Over a 3-year period, compared with EBRT, EBRT-LDR was associated with worse urinary irritative scores (adjusted mean difference at 3 years, -5.4; 95% CI, -9.3, -1.6) and bowel function scores (-4.1; 95% CI, -7.6, -0.5). The differences were no longer clinically meaningful at 5 years (difference in urinary irritative scores: -4.5; 95% CI, -8.4, -0.5; difference in bowel function scores: -2.1; 95% CI, -5.7, -1.4). However, men who received EBRT-LDR were more likely to report moderate or big problems with urinary function bother (adjusted odds ratio, 3.5; 95% CI, 1.5-8.2) and frequent urination (adjusted odds ratio, 2.6; 95% CI, 1.2-5.6) through 5 years. There were no differences in survival or treatment-related regret between treatment groups. CONCLUSIONS: Compared with EBRT alone, EBRT-LDR was associated with clinically meaningful worse urinary irritative and bowel function over 3 years after treatment and more urinary bother at 5 years. LAY SUMMARY: In men with prostate cancer who received external-beam radiation therapy (EBRT) with or without a brachytherapy boost (EBRT-LDR), EBRT-LDR was associated with clinically worse urinary irritation and bowel function through 3 years but resolved after 5 years. Men who received EBRT-LDR continued to report moderate-to-big problems with urinary function bother and frequent urination through 5 years. There was no difference in treatment-related regret or survival between patients who received EBRT and those who received EBRT-LDR. These intermediate-term estimates of function may facilitate counseling for men who are selecting treatment.

Food and Drug Administration approvals in phase 3 Cancer clinical trials.

BACKGROUND: Phase 3 oncologic randomized clinical trials (RCTs) can lead to Food and Drug Administration (FDA) approvals. In this study, we aim to identify trial-related factors associated with trials leading to subsequent FDA drug approvals. METHODS: We performed a database query through the ClinicalTrials.gov registry to search for oncologic phase 3 RCTs on February 2020. We screened all trials for therapeutic, cancer-specific, phase 3, randomized, multi-arm trials. We then identified whether a trial was used for subsequent FDA drug approval through screening of FDA approval announcements. RESULTS: In total, 790 trials were included in our study, with 225 trials (28.4%) generating data that were subsequently used for FDA approvals. Of the 225 FDA approvals identified, 65 (28.9%) were based on trials assessing overall survival (OS) as a primary endpoint (PEP), two (0.9%) were based on trials with a quality of life (QoL) PEP, and 158 approvals (70.2%) were based on trials with other PEP (P = 0.01). FDA approvals were more common among industry funded-trials (219, 97.3%; P < 0.001), and less common among trials sponsored by national cooperative groups (21, 9.3%; P < 0.001). Finally, increased pre-hoc power and meeting patients' accrual target were associated with FDA approvals (P < 0.001). CONCLUSIONS: The majority of FDA approvals are based on data generated from trials analyzing surrogate primary endpoints and trials receiving industry funding. Additional studies are required to understand the complexity of FDA approvals.

Performance Status Restriction in Phase III Cancer Clinical Trials.

BACKGROUND: Patients with good performance status (PS) tend to be favored in randomized clinical trials (RCTs), possibly limiting the generalizability of trial findings. We aimed to characterize trial-related factors associated with the use of PS eligibility criteria and analyze patient accrual breakdown by PS. METHODS: Adult, therapeutic, multiarm phase III cancer-specific RCTs were identified through ClinicalTrials.gov. PS data were extracted from articles. Trials with a PS restriction ECOG score ≤1 were identified. Factors associated with PS restriction were determined, and the use of PS restrictions was analyzed over time. RESULTS: In total, 600 trials were included and 238,213 patients had PS data. Of those trials, 527 studies (87.8%) specified a PS restriction cutoff, with 237 (39.5%) having a strict inclusion criterion (ECOG PS ≤1). Enrollment criteria restrictions based on PS (ECOG PS ≤1) were more common among industry-supported trials (P<.001) and lung cancer trials (P<.001). Nearly half of trials that led to FDA approval included strict PS restrictions. Most patients enrolled across all trials had an ECOG PS of 0 to 1 (96.3%). Even among trials that allowed patients with ECOG PS ≥2, only 8.1% of those enrolled had a poor PS. Trials of lung, breast, gastrointestinal, and genitourinary cancers all included <5% of patients with poor PS. Finally, only 4.7% of patients enrolled in trials that led to subsequent FDA approval had poor PS. CONCLUSIONS: Use of PS restrictions in oncologic RCTs is pervasive, and exceedingly few patients with poor PS are enrolled. The selective accrual of healthier patients has the potential to severely limit and bias trial results. Future trials should consider a wider cancer population with close toxicity monitoring to ensure the generalizability of results while maintaining patient safety.

An analysis of reflective writing early in the medical curriculum: The relationship between reflective capacity and academic achievement.

OBJECTIVE: To examine the relationship between reflection, gender, residency choice, word count, and academic achievement among medical students. METHODS: A modified version of the Reflection Evaluation for Learners' Enhanced Competencies Tool (REFLECT) was developed and used for this study (Cronbach's alpha of 0.86 with an intraclass correlation coefficient [ICC] of 0.68). This was applied to writing samples about professionalism in gross anatomy from first-year medical students between 2005 and 2011. Four analysts reviewed and scored written reflections independently. Composite reflection scores were compared with gender, residency choice, length of written reflection, NBME® Gross Anatomy and Embryology Subject Examination scores, and final gross anatomy course. RESULTS: Total of 319 written reflections were evaluated. Female students who pursued medicine specialties had the highest composite reflection scores (87 [27.2%]). Word count frequently correlated with reflection score (p < 0.0001). Students who performed well on the NBME® Gross Anatomy and Embryology Subject Examination tended to achieve high anatomy course grades (p < 0.0001). There was no statistically significant relationship between composite reflection scores and NBME® Gross Anatomy and Embryology Subject Examination scores (p = 0.16) or anatomy course grades (p = 0.90). CONCLUSIONS: This study suggests there are likely no correlations between reflective capacity and academic performance on tests of medical knowledge administered early in the medical curriculum.

The prevalence and contents of advance directives in patients with pacemakers.

BACKGROUND: Little is known about the use of advance directives (ADs) in patients who have implantable cardiac pacemakers (PMs). METHODS: We conducted a retrospective review of the medical records of residents of Olmsted County, Minnesota, who underwent implantation of a cardiac PM at Mayo Clinic (Rochester, Minnesota) during 2006 and 2007, and determined the prevalence and contents of ADs in these patients. RESULTS: During the study period, 205 residents of Olmsted County (men, 53%) underwent PM implantation (mean age [standard deviation] at implantation, 77 [15] years). Overall, 120 patients (59%) had ADs. Of these, 63 ADs (53%) were executed more than 12 months before and 33 (28%) were executed after PM implantation. Many patients specifically mentioned life-prolonging treatments in their ADs: cardiopulmonary resuscitation, 76 (63%); mechanical ventilation, 56 (47%); and hemodialysis, 31 (26%). Pain control was mentioned in 79 ADs (66%) and comfort measures were mentioned in 42 ADs (35%). Furthermore, the AD of many patients contained a general statement about end-of-life care (e.g., no "heroic measures"). However, only one AD (1%) specifically addressed the end-of-life management of the PM. CONCLUSIONS: More than half of the patients with PMs in our study had executed an AD, but only one patient specifically mentioned her PM in her AD. These results suggest that patients with PMs should be encouraged to execute ADs and specifically address end-of-life device management in their ADs. Doing so may prevent end-of-life ethical dilemmas related to PM management.

SABR for Sarcoma Lung Metastases: Indications for Treatment and Guidance for Patient Selection.

PURPOSE: The lungs are the most common site of metastasis for patients with soft tissue sarcoma. SABR is commonly employed to treat lung metastases among select patients with sarcoma with limited disease burden. We sought to evaluate outcomes and patterns of failure among patients with sarcoma treated with SABR for their lung metastases. METHODS AND MATERIALS: We performed a retrospective review of patients treated at a tertiary cancer center between 2006 and 2020. Patient disease status at the time of SABR was categorized as either oligorecurrent or oligoprogressive. The Kaplan-Meier method was used to estimate disease outcomes. Uni- and multivariable analyses were conducted using the Cox proportional hazards model. RESULTS: We identified 70 patients with soft tissue sarcoma treated with SABR to 98 metastatic lung lesions. Local recurrence-free survival after SABR treatment was 83% at 2 years. On univariable analysis, receipt of comprehensive SABR to all sites of pulmonary metastatic disease at the time of treatment was associated with improved progression-free survival (PFS; hazard ratio [HR], 0.51 [0.29-0.88]; P = .02). On multivariable analysis, only having systemic disease controlled at the time of SABR predicted improved PFS (median PFS, 14 vs 4 months; HR, 0.37 [0.20-0.69]; P = .002) and overall survival (median overall survival, 51 vs 14 months; HR, 0.17 [0.08-0.35]; P < .0001). CONCLUSIONS: SABR provides durable long-term local control for sarcoma lung metastases. The most important predictor for improved outcomes was systemic disease control. Careful consideration of these factors should help guide decisions in a multidisciplinary setting to appropriately select the optimal candidates for SABR.

Proton Accelerated Partial Breast Irradiation: Clinical Outcomes at a Planned Interim Analysis of a Prospective Phase 2 Trial.

PURPOSE: To perform a planned interim analysis of acute (within 12 months) and late (after 12 months) toxicities and cosmetic outcomes after proton accelerated partial breast irradiation (APBI). METHODS AND MATERIALS: A total of 100 patients with pTis or pT1-2 N0 (≤3cm) breast cancer status after segmental mastectomy were enrolled in a single-arm phase 2 study from 2010 to 2019. The clinically determined postlumpectomy target volume, including tumor bed surgical clips and operative-cavity soft-tissue changes seen on imaging plus a radial clinical expansion, was irradiated with passively scattered proton APBI (34 Gy in 10 fractions delivered twice daily with a minimum 6-hour interfraction interval). Patients were evaluated at protocol-specific time intervals for recurrence, physician reports of cosmetic outcomes and toxicities, and patient reports of cosmetic outcomes and satisfaction with the treatment or experience. RESULTS: Median follow-up was 24 months (interquartile range [IQR], 12-43 months). Local control and overall survival were 100% at 12 and 24 months. There were no acute or late toxicities of grade 3 or higher; no patients experienced fat necrosis, fibrosis, infection, or breast shrinkage. Excellent or good cosmesis at 12 months was reported by 91% of patients and 94% of physicians; at the most recent follow-up, these were 94% and 87%, respectively. The most commonly reported late cosmetic effect was telangiectasis (17%). The total patient satisfaction rate for treatment and results at 12 and 24 months was 96% and 100%, respectively. Patients' mean time away from work was 5 days (IQR, 2-5 days), and the median out-of-pocket cost was $700 (IQR, $100-$1600). The mean left-sided heart dose was 2 cGy (range, 0.2-75 cGy), and the mean ipsilateral lung dose was 19 cGy (range, 0.2-164 cGy). CONCLUSIONS: Proton APBI is a maturing treatment option with high local control, favorable intermediate-term cosmesis, high treatment satisfaction, low treatment burden, and exceptional heart and lung sparing.

Proton Beam Therapy for Head and Neck Carcinoma of Unknown Primary: Toxicity and Quality of Life.

PURPOSE: Proton radiation therapy (PRT) may offer dosimetric and clinical benefit in the treatment of head and neck carcinoma of unknown primary (HNCUP). We sought to describe toxicity and quality of life (QOL) in patients with HNCUP treated with PRT. PATIENTS AND METHODS: Toxicity and QOL were prospectively tracked in patients with HNCUP from 2011 to 2019 after institutional review board approval. Patients received PRT to the mucosa of the nasopharynx, oropharynx, and bilateral cervical lymph nodes with sparing of the larynx and hypopharynx. Patient-reported outcomes were tracked with the MD Anderson Symptom Inventory-Head and Neck Module, the Functional Assessment of Cancer Therapy-Head and Neck, the MD Anderson Dysphagia Inventory, and the Xerostomia-Related QOL Scale. Primary study endpoints were the incidence of grade ≥ 3 (G3) toxicity and QOL patterns. RESULTS: Fourteen patients (median follow-up, 2 years) were evaluated. Most patients presented with human papillomavirus-positive disease (n = 12, 86%). Rates of G3 oral mucositis, xerostomia, and dermatitis were 7% (n = 1), 21% (n = 3), and 36% (n = 5), respectively. None required a gastrostomy. During PRT, QOL was reduced relative to baseline and recovered shortly after PRT. At 2 years after PRT, the local regional control, disease-free survival, and overall survival were 100% (among 7 patients at risk), 79% (among 6 patients at risk), and 90% (among 7 patients at risk), respectively. CONCLUSION: Therefore, PRT for HNCUP was associated with highly favorable dosimetric and clinical outcomes, including minimal oral mucositis, xerostomia, and dysphagia. Toxicity and QOL may be superior with PRT compared with conventional radiation therapy and PRT maintains equivalent oncologic control. Further prospective studies are needed to evaluate late effects and cost-effectiveness.

Activity-Based Costing of Intensity-Modulated Proton versus Photon Therapy for Oropharyngeal Cancer.

PURPOSE: In value-based health care delivery, radiation oncologists need to compare empiric costs of care delivery with advanced technologies, such as intensity-modulated proton therapy (IMPT) and intensity-modulated radiation therapy (IMRT). We used time-driven activity-based costing (TDABC) to compare the costs of delivering IMPT and IMRT in a case-matched pilot study of patients with newly diagnosed oropharyngeal (OPC) cancer. MATERIALS AND METHODS: We used clinicopathologic factors to match 25 patients with OPC who received IMPT in 2011-12 with 25 patients with OPC treated with IMRT in 2000-09. Process maps were created for each multidisciplinary clinical activity (including chemotherapy and ancillary services) from initial consultation through 1 month of follow-up. Resource costs and times were determined for each activity. Each patient-specific activity was linked with a process map and TDABC over the full cycle of care. All calculated costs were normalized to the lowest-cost IMRT patient. RESULTS: TDABC costs for IMRT were 1.00 to 3.33 times that of the lowest-cost IMRT patient (mean ± SD: 1.65 ± 0.56), while costs for IMPT were 1.88 to 4.32 times that of the lowest-cost IMRT patient (2.58 ± 0.39) (P < .05). Although single-fraction costs were 2.79 times higher for IMPT than for IMRT (owing to higher equipment costs), average full cycle cost of IMPT was 1.53 times higher than IMRT, suggesting that the initial cost increase is partly mitigated by reductions in costs for other, non-RT supportive health care services. CONCLUSIONS: In this matched sample, although IMPT was on average more costly than IMRT primarily owing to higher equipment costs, a subset of IMRT patients had similar costs to IMPT patients, owing to greater use of supportive care resources. Multidimensional patient outcomes and TDABC provide vital methodology for defining the value of radiation therapy modalities.

Detecting the Dark Matter of Unpublished Clinical Cancer Studies: An Analysis of Phase 3 Randomized Controlled Trials.

Unpublished randomized controlled trial (RCT) frequency, correlates, and financial impact are not well understood. We sought to characterize the nonpublication of peer-reviewed manuscripts among interventional, therapeutic, multi-arm, phase 3 oncology RCTs. Trials were identified by searching ClinicalTrials.gov, while publications and abstracts were identified through PubMed and Google Scholar. Trial data were extracted from ClinicalTrials.gov and individual publications. Publication was defined as a peer-reviewed manuscript addressing the primary endpoint. Patient accrual cost was extrapolated from experimental data; investigators/sponsors were contacted to determine nonpublication reasons. Six hundred eighty-four completed RCTs met inclusion criteria, which accrued 434,610 patients from 1994 to 2015; 638 were published (93.3%) and 46 were unpublished (6.7%). Among the unpublished trials, the time difference from primary endpoint maturity to data abstraction was a median of 6 years (interquartile range, 4 to 8 years). On multiple binary logistic regression analysis, factors associated with unpublished trials included lack of cooperative group sponsorship (odds ratio, 5.91, 95% CI, 1.35 to 25.97; P=.019) and supportive care investigation (odds ratio, 2.90; 95% CI, 1.13 to 7.41; P=.027). The estimated inflation-adjusted average cost of patient accrual for all unpublished trials was $113,937,849 (range, $41,136,883 to $320,201,063). Direct contact with sponsors/investigators led to a 50.0% response rate (n=23 of 46); manuscript in preparation and/or in submission (n=10 of 23) was the most commonly cited reason for nonpublication. In conclusion, approximately 1 in 15 clinical oncology RCTs are unpublished and this has a profound impact on the research enterprise. The cooperative group infrastructure may serve as a blueprint to reduce nonpublication.

The impact of cell-of-origin, MYC/Bcl-2 dual expression and MYC rearrangement on disease relapse among early stage diffuse large B-cell lymphoma patients treated with combined modality therapy.

We addressed the prognostic impact of cell-of-origin (COO), MYC and Bcl-2 overexpression as well as isolated MYC rearrangement among 111 patients with limited stage diffuse large B-cell lymphoma (DLBCL) treated with consolidative radiation therapy (RT) after a metabolic complete response to immunochemotherapy. With a median follow-up of 31.1 months (95% CI 27.4 - 34.8), 4 relapses occurred. The 3-year progression free survival (PFS), overall survival (OS), and loco-regional relapse free survival (LRFS) for the cohort were 95%, 96%, and 100%, respectively. There were no differences in OS, PFS, or LRFS based on COO or MYC/Bcl-2 dual expression (DE). Similarly, patients with MYC translocations without BCL2 or BCL6 rearrangements did not have worse outcomes. Consolidative RT produced excellent local control, regardless of DLBCL biology, with one late in-field failure.

Outcomes and Toxicities of Proton and Photon Radiation Therapy for Testicular Seminoma.

PURPOSE: To determine the clinical outcomes and toxicities of proton beam therapy (PBT) versus 3D-conformal photon radiation therapy (XRT) in patients with testicular seminoma. MATERIALS AND METHODS: This observational study evaluated consecutive patients with testicular seminoma who were treated with inguinal orchiectomy and radiation therapy at a single, tertiary, high-volume center in 2008-19. Acute toxicity was scored with the Common Terminology Criteria for Adverse Events V 4.0. Organs at risk were contoured retrospectively by 2 investigators. Recurrences and secondary malignancies were based on routine follow-up imaging, either computed tomography or magnetic resonance imaging. RESULTS: Fifty-five patients were treated with radiation therapy, 11 in the PBT-arm and 44 in the XRT-arm, with a median follow-up interval of 61 months (interquartile range [IQR]: 32-79 months). Acute treatment-related diarrhea, grade 1 to 2, was more common among XRT-treated patients (0% vs 29.5%, P = .039), and dermatitis, grade 1, was more likely among PBT-treated patients (27.3% vs 2.3%, P = .004). Dosimetrically, PBT-treated patients, relative to XRT-treated patients, had lower dose to organs at risk including the kidney, bladder, femoral head, spinal cord, bowel, pancreas, and stomach. The 5-year overall survival rate was 100% and disease-free survival rate was 96.4% for all patients. Two patients, all in the XRT-arm, had disease recurrence: 1 in the pelvis and 1 in the lung. Three patients, all in the XRT-arm, were diagnosed with a secondary malignancy: 1 in-field pancreaticoblastoma, 1 in-field colon adenocarcinoma, and a stage IV T-cell lymphoma. CONCLUSION: Proton beam therapy for testicular seminoma resulted in excellent clinical outcomes and was associated with lower rates of acute diarrhea but higher rates of acute dermatitis. Proton beam therapy resulted in no in-field secondary malignancies and a more favorable dosimetric profile for organs at risk relative to XRT. Reduced dose to organs at risk, such as the kidneys, may result in long-term improvement in function.

Trial Sponsorship and Time to Reporting for Phase 3 Randomized Cancer Clinical Trials.

The pace of clinical trial data generation and publication is an area of interest within clinical oncology; however, little is known about the dynamics and covariates of time to reporting (TTR) of trial results. To assess these, ClinicalTrials.gov was queried for phase three clinical trials for patients with metastatic solid tumors, and the factors associated with TTR from enrollment completion to publication were analyzed. Based on the 319 included trials, cooperative-group-sponsored trials were reported at a slower rate than non-cooperative-group trials (median 37.5 vs. 31.0 months; p < 0.001), while industry-funded studies were reported at a faster rate than non-industry-supported trials (31.0 vs. 40.0 months; p = 0.005). Furthermore, successful trials (those meeting their primary endpoint) were reported at a faster rate than unsuccessful studies (27.5 vs. 36.0 months; p < 0.001). Multivariable analysis confirmed that industry funding was independently associated with a shorter TTR (p = 0.006), while cooperative group sponsorship was not associated with a statistically significant difference in TTR (p = 0.18). These data underscore an opportunity to improve cooperative group trial efficiency by reducing TTR.

Estimating PTV Margins in Head and Neck Stereotactic Ablative Radiation Therapy (SABR) Through Target Site Analysis of Positioning and Intrafractional Accuracy.

PURPOSE: Recurrent or previously irradiated head and neck cancers (HNC) are therapeutically challenging and may benefit from high-dose, highly accurate radiation techniques, such as stereotactic ablative radiation therapy (SABR). Here, we compare set-up and positioning accuracy across HNC subsites to further optimize the treatment process and planning target volume (PTV) margin recommendations for head and neck SABR. METHODS AND MATERIALS: We prospectively collected data on 405 treatment fractions across 79 patients treated with SABR for recurrent/previously irradiated HNC. First, interfractional error was determined by comparing ExacTrac x-ray to the treatment plan. Patients were then shifted and residual error was measured with repeat x-ray. Next, cone beam computed tomography (CBCT) was compared with ExacTrac for positioning agreement, and final shifts were applied. Lastly, intrafractional error was measured with x-ray before each arc. Results were stratified by treatment site into skull base, neck/parotid, and mucosal. RESULTS: Most patients (66.7%) were treated to 45 Gy in 5 fractions (range, 21-47.5 Gy in 3-5 fractions). The initial mean ± standard deviation interfractional errors were -0.2 ± 1.4 mm (anteroposterior), 0.2 ± 1.8 mm (craniocaudal), and -0.1 ± 1.7 mm (left-right). Interfractional 3-dimensional vector error was 2.48 ± 1.44, with skull base significantly lower than other sites (2.22 vs 2.77; P = .0016). All interfractional errors were corrected to within 1.3 mm and 1.8°. CBCT agreed with ExacTrac to within 3.6 mm and 3.4°. CBCT disagreements and intrafractional errors of >1 mm or >1° occurred at significantly lower rates in skull base sites (CBCT: 16.4% vs 50.0% neck, 52.0% mucosal, P < .0001; intrafractional: 22.0% vs 48.7% all others, P < .0001). Final PTVs were 1.5 mm (skull base), 2.0 mm (neck/parotid), and 1.8 mm (mucosal). CONCLUSIONS: Head and neck SABR PTV margins should be optimized by target site. PTV margins of 1.5 to 2 mm may be sufficient in the skull base, whereas 2 to 2.5 mm may be necessary for neck and mucosal targets. When using ExacTrac, skull base sites show significantly fewer uncertainties throughout the treatment process, but neck/mucosal targets may require the addition of CBCT to account for positioning errors and internal organ motion.

Progression-free survival is a suboptimal predictor for overall survival among metastatic solid tumour clinical trials.

BACKGROUND: The use of overall survival (OS) as the gold standard primary end-point (PEP) in metastatic oncologic randomised controlled trials (RCTs) has declined in favour of progression-free survival (PFS) without a complete understanding of the degree to which PFS reliably predicts for OS. METHODS: Using ClinicalTrials.gov, we identified 1239 phase III oncologic RCTs, 260 of which were metastatic solid tumour trials with a superiority-design investigating a therapeutic intervention by using either a PFS or OS PEP. Each individual trial was reviewed to quantify RCT design factors and disease-related outcomes. RESULTS: A total of 172,133 patients were enrolled from the year 1999 to 2015 in RCTs that used PFS (56.2%, 146/260) or OS (43.8%, 114/260) as the PEP. PFS trials were more likely to restrict patient eligibility by using molecular criteria (15.1% versus 4.4%, p = 0.005) use targeted therapy (80.1% versus 67.5%, p = 0.048), accrue fewer patients (median 495 versus 619, p = 0.03), and successfully meet the trial PEP (66.9% versus 33.3%, p < 0.0001). On multiple binary logistic regression analysis, factors that predicted for PFS or OS PEP trial success included choice of PFS PEP (p < 0.0001), molecular profile restriction (p = 0.02) and single agent therapy (p = 0.02). Notably, there was only a 38% (31/82) conversion rate of positive PFS-to-OS benefit; lack of industry sponsorship predicted for PFS-to-OS signal conversion (80.0% without industry sponsorship versus 35.1% with industry sponsorship, p = 0.045). CONCLUSIONS: A PFS PEP has suboptimal positive predictive value for OS among phase III metastatic solid tumour RCTs. Regulatory agency decisions should be judicious in using PFS results as the primary basis for approval.

Predictors of urinary toxicity with MRI-assisted radiosurgery for low-dose-rate prostate brachytherapy.

PURPOSE: MRI-assisted radiosurgery (MARS) is a modern technique for prostate brachytherapy that provides superior soft tissue contrast. The purpose of this analysis was to evaluate treatment planning factors associated with urinary toxicity, particularly damage to the membranous urethra (MUL) and external urethral sphincter (EUS), after MARS. MATERIAL AND METHODS: We retrospectively reviewed 227 patients treated with MARS. Comparisons were made between several factors including preimplantation length of the MUL and EUS dosimetric characteristics after implantation with longitudinal changes in American Urological Association (AUA) urinary symptom score. RESULTS: Rates of grade 3 urinary incontinence and obstructive urinary symptoms were 4% and 2%. A piecewise mixed univariate model revealed that MUL and V200, V150, V125, and D5 to the EUS were all associated with increased rates of urinary toxicity over time. On univariate logistic regression, MUL >14.2 mm (odds ratio [OR] 2.03 per cm3, 95% confidence interval [CI] 1.10-3.77, p = 0.025), V125 to the EUS (OR 3.21 cm3, 95% CI 1.18-8.71, p = 0.022), and use of the I-125 isotope (OR 3.45, 95% CI 1.55-7.70, p = 0.001) were associated with subacute urinary toxicity (i.e., that occurring at 4-8 months). Optimal dose-constraint limits to the EUS were determined to be V200 < 0.04 cm3 (p = 0.002), V150 < 0.12 cm3 (p = 0.041), V125 < 0.45 cm3 (p = 0.033), D30 < 160 Gy (p = 0.004), and D5 < 218 Gy (p = 0.016). CONCLUSIONS: MARS brachytherapy provides detailed anatomic information for treatment planning, implantation, and quality assurance. Overall rates of urinary toxicity are low; however, several dosimetric variables associated with the EUS were found to correlate with urinary toxicity.

Patient-reported outcomes, physician-reported toxicities, and treatment outcomes in a modern cohort of patients with sinonasal cancer treated using proton beam therapy.

BACKGROUND AND PURPOSE: To report physician-assessed toxicities (PATs) and patient-reported outcomes (PROs) in a prospective cohort of patients treated using proton beam therapy (PBT). METHODS AND MATERIALS: From 2011 to 2019, PBT-treated patients with a sinonasal malignancy were enrolled with a primary endpoint of toxicity assessment. PATs and PROs were assessed at baseline, acute (during PBT), subacute (within 90 days after PBT), and chronic time points. PATs were graded with the Common Terminology Criteria for Adverse Events V4.0. PROs were assessed with the Xerostomia-Related Quality-of-Life Scale (XeQoLS), MD Anderson Dysphagia Inventory (MDADI), and Functional Assessment of Cancer Therapy (FACT). PRO changes from baseline to follow-up were defined as significantly different based on a paired t-test plus a minimal clinically important difference. RESULTS: Sixty-four patients had a median follow-up time of 33 months (interquartile range: 10-52 months). The most common histology was olfactory neuroblastoma (28%) and most patients had T4 disease (46%). One acute G3 neurologic PAT (blurred vision) resolved, and no late G3-4 neurologic PATs were observed. Feeding tube placement occurred in 6% of patients. No significant changes were noted in PROs from baseline to the chronic period. Significant worsening from baseline was noted in the XeQoLS acute-subacute physical functioning, pain, personal/psychological distress, and social function; acute-subacute MDADI physical function; and acute-subacute FACT head/neck subscale. The 3-year local control, disease-free survival, and overall survival rates were 88%, 76%, and 82%, respectively. CONCLUSIONS: We demonstrate low grade ≥3 toxicity and encouraging disease outcomes with PBT. PROs suggest significant changes in the acute-subacute period but no chronic sequelae.

Outcomes and toxicities following stereotactic ablative radiotherapy for pulmonary metastases in patients with primary head and neck cancer.

BACKGROUND: Metastatic head and neck cancers (HNCs) predominantly affect the lungs and have a two-year overall survival (OS) of 15% to 50%, if amenable for pulmonary metastasectomy. METHODS: Retrospective review of the two-year local control (LC), local-regional control (LRC) within the same lobe, OS, and toxicity rates in consecutive patients with metastatic pulmonary HNC who underwent stereotactic ablative radiotherapy (SABR) January 2007 to May 2018. RESULTS: Evaluated 82 patients with 107 lung lesions, most commonly squamous cell carcinoma (SCC; 64%). Median follow-up was 20 months (range: 9.0-97.6). Systemic therapy administered in 34%. LC, LRC, and OS rates were 94%, 90%, and 62%. Patients with oligometastatic disease had a higher OS than polymetastatic disease, 72% vs 44% (HR = 0.30, 95% CI: 0.14-0.64; P = .008). OS in oligometastatic non-SCC and SCC were 100% and 66% (P = .03). There were no grade ≥3 toxicities. CONCLUSIONS: Metastatic pulmonary HNCs after SABR have a two-year OS rate comparable to pulmonary metastasectomy.