Multi-institutional Analysis of Prognostic Factors and Outcomes After Hypofractionated Stereotactic Radiotherapy to the Resection Cavity in Patients With Brain Metastases.

IMPORTANCE: For brain metastases, the combination of neurosurgical resection and postoperative hypofractionated stereotactic radiotherapy (HSRT) is an emerging therapeutic approach preferred to the prior practice of postoperative whole-brain radiotherapy. However, mature large-scale outcome data are lacking. OBJECTIVE: To evaluate outcomes and prognostic factors after HSRT to the resection cavity in patients with brain metastases. DESIGN, SETTING, AND PARTICIPANTS: An international, multi-institutional cohort study was performed in 558 patients with resected brain metastases and postoperative HSRT treated between December 1, 2003, and October 31, 2019, in 1 of 6 participating centers. Exclusion criteria were prior cranial radiotherapy (including whole-brain radiotherapy) and early termination of treatment. EXPOSURES: A median total dose of 30 Gy (range, 18-35 Gy) and a dose per fraction of 6 Gy (range, 5-10.7 Gy) were applied. MAIN OUTCOMES AND MEASURES: The primary end points were overall survival, local control (LC), and the analysis of prognostic factors associated with overall survival and LC. Secondary end points included distant intracranial failure, distant progression, and the incidence of neurologic toxicity. RESULTS: A total of 558 patients (mean [SD] age, 61 [0.50] years; 301 [53.9%] female) with 581 resected cavities were analyzed. The median follow-up was 12.3 months (interquartile range, 5.0-25.3 months). Overall survival was 65% at 1 year, 46% at 2 years, and 33% at 3 years, whereas LC was 84% at 1 year, 75% at 2 years, and 71% at 3 years. Radiation necrosis was present in 48 patients (8.6%) and leptomeningeal disease in 73 patients (13.1%). Neurologic toxic events according to the Common Terminology Criteria for Adverse Events grade 3 or higher occurred in 16 patients (2.8%) less than 6 months and 24 patients (4.1%) greater than 6 months after treatment. Multivariate analysis identified a Karnofsky Performance Status score of 80% or greater (hazard ratio [HR], 0.61; 95% CI, 0.46-0.82; P < .001), 22 to 33 days between resection and radiotherapy (HR, 1.50; 95% CI, 1.07-2.10; P = .02), and a controlled primary tumor (HR, 0.69; 95% CI, 0.52-0.90; P = .007) as prognostic factors associated with overall survival. For LC, a single brain metastasis (HR, 0.57; 95% CI, 0.35-0.93; P = .03) and a controlled primary tumor (HR, 0.59; 95% CI, 0.39-0.92; P = .02) were significant in the multivariate analysis. CONCLUSIONS AND RELEVANCE: To date, this cohort study includes one of the largest series of patients with brain metastases and postoperative HSRT and appears to confirm an excellent risk-benefit profile of local HSRT to the resection cavity. Additional studies will help determine radiation dose-volume parameters and provide a better understanding of synergistic effects with systemic and immunotherapies.

Perceptions of Barriers Towards Active Surveillance for Low-Risk Prostate Cancer: Results From a National Survey of Radiation Oncologists and Urologists.

PURPOSE: The reasons for low clinical adoption of active surveillance (AS) for low-risk prostate cancer (PCa) remain poorly understood. Thus, we conducted a national survey of radiation oncologists (ROs) and urologists (UROs) to elucidate perceived barriers to AS for low-risk PCa. METHODS: In 2017, we undertook a four-wave mail survey of 1855 ROs and UROs. The survey instrument assessed attitudes about possible barriers towards AS for low-risk PCa. We used Pearson Chi square and multivariable logistic regression analyses to identify physician characteristics associated with attitudes about AS. RESULTS: We received 691 completed surveys for an overall response rate of 37.3%. A majority of respondents indicated that they felt comfortable recommending AS (90.0%), agreed that high-level evidence supports it (82.3%), and considered AS equally effective for survival compared with surgery and radiation therapy (84.4%). UROs were less likely to agree that patients were not interested in AS for low-risk PCa compared with ROs (16.5 vs. 48.9%; adjusted odds ratio [OR] 0.18, p < 0.001). Similarly, UROs were less likely to concur patients avoid AS because of repeat prostate biopsies than ROs (36.3 vs. 55.4%; adjusted OR 0.41, p < 0.001). ROs and UROs were more likely to agree that patients preferred treatments delivered by the respondent's specialty. CONCLUSIONS: Physician perceptions of patient lack of interest in AS, need for repeat prostate biopsies, and biases of patient treatment preferences in favor of their own specialty treatments represent key barriers to AS. Shared decision making may be a meaningful approach to engaging patients in conversations about treatment decisions.

Postoperative hypofractionated stereotactic brain radiation (HSRT) for resected brain metastases: improved local control with higher BED10.

INTRODUCTION: HSRT directed to large surgical beds in patients with resected brain metastases improves local control while sparing patients the toxicity associated with whole brain radiation. We review our institutional series to determine factors predictive of local failure. METHODS: In a total of 39 consecutive patients with brain metastases treated from August 2011 to August 2016, 43 surgical beds were treated with HSRT in three or five fractions. All treatments were completed on a robotic radiosurgery platform using the 6D Skull tracking system. Volumetric MRIs from before and after surgery were used for radiation planning. A 2-mm PTV margin was used around the contoured surgical bed and resection margins; these were reviewed by the radiation oncologist and neurosurgeon. Lower total doses were prescribed based on proximity to critical structures or if prior radiation treatments were given. Local control in this study is defined as no volumetric MRI evidence of recurrence of tumor within the high dose radiation volume. Statistics were calculated using JMP Pro v13. RESULTS: Of the 43 surgical beds analyzed, 23 were from NSCLC, 5 were from breast, 4 from melanoma, 5 from esophagus, and 1 each from SCLC, sarcoma, colon, renal, rectal, and unknown primary. Ten were treated with three fractions with median dose 24 Gy and 33 were treated with five fractions with median dose 27.5 Gy using an every other day fractionation. There were no reported grade 3 or higher toxicities. Median follow up was 212 days after completion of radiation. 10 (23%) surgical beds developed local failure with a median time to failure of 148 days. All but three patients developed new brain metastases outside of the treated field and were treated with stereotactic radiosurgery, whole brain radiation and/or chemotherapy. Five patients (13%) developed leptomeningeal disease. With a median follow up of 226 days, 30 Gy/5 fx was associated with the best local control (93%) with only 1 local failure. A lower total dose in five fractions (ie 27.5 or 25 Gy) had a local control rate of 70%. For three fraction SBRT, local control was 100% using a dose of 27 Gy in three fractions (follow up was > 600 days) and 71% if 24 Gy in three fractions was used. A higher total biologically equivalent dose (BED10) was statistically significant for improved local control (p = 0.04) with a threshold BED10 ≥ 48 associated with better local control. CONCLUSIONS: HSRT after surgical resection for brain metastasis is well tolerated and has improved local control with BED10 ≥ 48 (30 Gy/5 fx and 27 Gy/3 fx). Additional study is warranted.

Influence of radiation treatment technique on outcome and toxicity in anal cancer.

OBJECTIVE: Intensity-modulated radiation therapy (IMRT) has largely supplanted three-dimensional conformal radiation (3D-CRT) for definitive anal cancer treatment due to decreased toxicity and potentially improved outcomes. Convincing data demonstrating its advantages, however, remain limited. We compared outcomes and toxicity with concurrent chemotherapy and IMRT vs 3D-CRT for anal cancer. METHODS: We performed a single-institution retrospective review of patients treated with IMRT or 3D-CRT as part of definitive mitomycin-C/5-fluorouricil-based chemoradiation for anal cancer from January 2003 to December 2012. RESULTS: One hundred sixty-five patients were included, with 61 and 104 receiving IMRT and 3D-CRT, respectively. Overall, 92.7% had squamous cell carcinoma. The mean initial pelvic dose was 48.3 and 44 Gy for IMRT and 3D-CRT, respectively. Complete response, partial response, and disease progression rates were similar (IMRT 83.6, 8.2, 8.2%; 3D-CRT 85.6, 6.7, 7.7%; p = 0.608, p = 0.728, p = 0.729). There was no significant difference in overall survival (p = 0.971), event-free survival (p = 0.900), or local or distant recurrence rates (p = 0.118, p = 0.373). IMRT caused significantly less acute grade 1-2 incontinence (p = 0.035), grade 3-4 pain (p = 0.033), and fatigue (p = 0.030). IMRT patients had significantly fewer chronic post-treatment toxicities (p = 0.008), outperforming 3D-CRT in six of eight toxicities reviewed. Though total treatment length was comparable (43.6 and 44.5 days), IMRT recipients had fewer (27.9 vs 41.3% of patients, p = 0.89), shorter treatment breaks (mean 2.9 vs 4.1 days, p = 0.229). CONCLUSION: This report represents the largest series directly comparing concurrent chemotherapy with IMRT vs 3D-CRT for definitive treatment of anal cancer. IMRT significantly reduced acute and post-treatment toxicities and allowed for safe and effective pelvic dose escalation.

Neoadjuvant chemoradiation for non-metastatic pancreatic cancer increases margin-negative and node-negative rates at resection.

OBJECTIVE: To compare neoadjuvant to adjuvant chemoradiation in non-metastatic pancreatic cancer patients. METHODS: Single-institution data were obtained for patients with non-metastatic pancreatic cancer treated with concurrent chemoradiation from 2011 to 2014. Univariate analyses were performed to evaluate clinical and pathological outcomes. RESULTS: Fifty-two well-matched patients were enrolled (21 underwent neoadjuvant chemoradiation, 11 with adjuvant chemoradiation and 20 in the definitive group). Median tumor size was 2.6 cm pretreatment and 2.5 cm after neoadjuvant chemoradiation but 3.2 cm on pathology, with a treatment effect in 95.2% of specimens. Clinical node positivity at diagnosis for neoadjuvant and adjuvant chemoradiation groups was similar (28.6% vs 27.3%, P = 0.12). Of the 36 neoadjuvant patients, 21 (58.3%) underwent complete resection. In the neoadjuvant vs adjuvant chemoradiation groups, positive margins were decreased (4.8% vs 63.6%, P < 0.001), as was pathological nodal positivity (23.8% vs 90.9%, P < 0.001). After a median follow-up of 13.3 months, locoregional control for neoadjuvant and adjuvant chemoradiation was 7.7 and 7.2 months, respectively (P = 0.12) and the definitive group was 1.2 months (P = 0.014 compared with the surgical cohort). One-year overall survival was better with neoadjuvant than with adjuvant chemoradiation but this was not significant (94% vs 82%, P = 0.20); 1-year survival for the definitive group was 59% (P = 0.03 compared with the surgical cohort). CONCLUSIONS: Neoadjuvant chemoradiation remains a promising approach for non-metastatic pancreatic cancer for improving resectability and pathological and clinical findings. Computed tomography may not fully demonstrate the effectiveness of neoadjuvant treatment.

Safety and efficacy of salvage low-dose-rate brachytherapy for prostate bed recurrences following radical prostatectomy.

PURPOSE: To report efficacy in our series of nodular recurrences in the post-surgical bed that underwent salvage low-dose-rate (LDR) brachytherapy. MATERIAL AND METHODS: Patients with radical prostatectomy (RP) who had biochemical failure with nodular recurrence detected by DRE, ultrasound, and pelvic CT and then salvaged with LDR (125)I brachytherapy were included. Nodular recurrences were biopsy confirmed adenocarcinoma, and patients had no evidence of nodal or distant metastasis on imaging including bone scan. Follow up was at least every 6 months with a serial prostate specific antigen (PSA). RESULTS: Twelve patients had salvage LDR brachytherapy with median age 69 years (range 59-86) and median pre-salvage PSA of 4.22 ng/ml. Nodule biopsy Gleason score was 7, 8, or undifferentiated. Median rectal V100 was 0.00 cc. Compared to pre-salvage, patients reported no additional genitourinary (GU) toxicity. After a median 35 months post-salvage follow up (range 10-81 months), patients had a median PSA nadir of 0.72 ng/ml (range 0.01-22.4). At 6 months post salvage, 90% of patients had a PSA below pre-salvage levels. At last follow up, 4 patients had PSA control. CONCLUSIONS: There was a trend to improved biochemical relapse free survival for lower Gleason score and pre-salvage PSA, which may be indicative of the lack of or only low volume metastatic disease. LDR brachytherapy is an effective salvage technique and can be considered in well selected patients allowing for dose escalation to the nodular recurrence.

Radiation therapy in patients with inflammatory bowel disease and colorectal cancer: risks and benefits.

PURPOSE: The effects of radiotherapy are debated in inflammatory bowel disease (IBD). We examined IBD patients with colorectal cancer (CRC) and compared those who underwent external beam radiation therapy (EBRT) to those who did not. We then compared those same patients treated with EBRT to similarly treated non-IBD patients to ascertain differences in toxicity and perioperative outcomes. METHODS: Fifty-seven IBD patients with CRC received EBRT, of which 23 had perioperative follow-up and 15 had complete records. The 23 patients were compared to 229 IBD patients with CRC who did not receive EBRT. The 15 patients were matched, 1:2, to similarly treated non-IBD patients with CRC based on age (±5 years), treatment year (±1 year), BMI (±10 kg/m2), and clinical stage. RESULTS: There was significantly more postoperative bleeding (5.3 % vs. 0 %, p < 0.01), wound dehiscence (3.5 % vs. 0 %, p < 0.01), and perineal infection (8.8 % vs. 1.3 %, p < 0.01) in IBD patients with EBRT compared to those without EBRT. IBD patients were significantly more likely to have grade 3 or higher lower GI toxicity (40 % vs. 7 %, p = 0.02) and wound dehiscence (36 % vs. 7 %, p = 0.02) than non-IBD patients, however without significant difference in bleeding, infection, ileus, or survival. CONCLUSION: IBD patients with CRC who received EBRT were more likely than similar patients without EBRT to experience perioperative complications. These patients also experienced more lower GI toxicity than similarly treated non-IBD patients with CRC. The expected decrease in survival in IBD-associated CRC was not observed. Thus, EBRT may contribute to a survival benefit in this group.

Synchronous non small cell lung cancer nodules treated with stereotactic body radiation therapy (SBRT).

BACKGROUND AND PURPOSE: We compare our institutional outcomes of synchronous primary (SP) lung lesion patients with non-SP patients.Materials and Methods: From an IRB approved prospective registry of 445 NSCLC patients treated with SBRT (8/2005 8/2012), 26 (5.8%) had SPs by biopsy or PET/CT. SBRT was delivered on a Novalis/BrainLAB platform with daily Exactrac set-up. RESULTS: There were no significant differences comparing SP vs non-SP groups for age, Charlson score, smoking pack years, and PET SUV (p=ns). 18 (69%) SP patients had at least one lesion biopsied. Ipsilateral and bilateral SPs were seen in 10 (38.4%) and 16 (61.6%) respectively. 77% received 50 Gy / 5 fx. SP vs non-SP median follow up was 12 (range 1.5-49.8) vs 15.2 months. Median survival for SP vs non-SP groups was 20.7 vs 28.4 months (p=0.3). In SP vs non-SP groups, local failure was 4% vs 7.6% (p=ns) and nodal/distant failure was 23% vs 24.6% (p=ns). Patients with ipsilateral and bilateral SPs had a 50% vs 14% distant failure respectively (p=0.037). CONCLUSIONS: After SBRT, there were no differences in survival and patterns of failure for SP vs non-SP patients. Ipsilateral SPs had significantly worse distant failure compared to bilateral SPs.

Effect of monomer structure and solvent on the growth of supramolecular nanoassemblies on a graphite surface.

The self-assembly of high aspect ratio hierarchical surface assemblies, as observed by fluid tapping mode AFM, can be achieved through careful design of the supramolecular interactions between low-molecular-weight adsorbates. Needlelike assemblies of monotopic guanine end-capped alkanes grow on a graphite surface when deposited from a water/DMSO solution. The growth of these assemblies can be monitored by AFM in real time, and the growth rate along the two different axes can be understood (through molecular modeling) in terms of the specific adsorbate-adsorbate interactions along those axes. Additionally, through judicious solvent selection (e.g., use of non-H-bonding solvents such as o-dichlorobenzene), which allows the formation of hydrogen-bonding aggregates in solution and influences the surface-adsorbate interactions, dramatically different surface assemblies of these guanine derivatives are obtained.

Molecular engineering of supramolecular scaffold coatings that can reduce static platelet adhesion.

Novel supramolecular coatings that make use of low-molecular weight ditopic monomers with guanine end groups are studied using fluid tapping AFM. These molecules assemble on highly oriented pyrolytic graphite (HOPG) from aqueous solutions to form nanosized banding structures whose sizes can be systematically tuned at the nanoscale by tailoring the molecular structure of the monomers. The nature of the self-assembly in these systems has been studied through a combination of the self-assembly of structural derivatives and molecular modeling. Furthermore, we introduce the concept of using these molecular assemblies as scaffolds to organize functional groups on the surface. As a first demonstration of this concept, scaffold monomers that contain a monomethyl triethyleneglycol branch were used to organize these "functional" units on a HOPG surface. These supramolecular grafted assemblies have been shown to be stable at biologically relevant temperatures and even have the ability to significantly reduce static platelet adhesion.