Habitat escalated adaptive therapy (HEAT): a phase 2 trial utilizing radiomic habitat-directed and genomic-adjusted radiation dose (GARD) optimization for high-grade soft tissue sarcoma.

BACKGROUND: Soft tissue sarcomas (STS), have significant inter- and intra-tumoral heterogeneity, with poor response to standard neoadjuvant radiotherapy (RT). Achieving a favorable pathologic response (FPR ≥ 95%) from RT is associated with improved patient outcome. Genomic adjusted radiation dose (GARD), a radiation-specific metric that quantifies the expected RT treatment effect as a function of tumor dose and genomics, proposed that STS is significantly underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and targeting them with GARD-optimized doses, to improve FPR in high-grade STS. METHODS: Phase 2 non-randomized single-arm clinical trial includes non-metastatic, resectable high-grade STS patients. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that simultaneous integrated boost (SIB) doses of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50 Gy, would lead to a > 3 fold FPR increase to 24%. Pre-treatment CT guided biopsies of each habitat along with clip placement will be performed for pathologic evaluation, future genomic studies, and response assessment. An mpMRI taken between weeks two and three of treatment will be used for biological plan adaptation to account for tumor response, in addition to an mpMRI after the completion of radiotherapy in addition to pathologic response, toxicity, radiomic response, disease control, and survival will be evaluated as secondary endpoints. Furthermore, liquid biopsy will be performed with mpMRI for future ancillary studies. DISCUSSION: This is the first clinical trial to test a novel genomic-based RT dose optimization (GARD) and to utilize radiomic habitats to identify and target radioresistance regions, as a strategy to improve the outcome of RT-treated STS patients. Its success could usher in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and trial designs, and may reveal new radiomic and genomic biomarkers, refining personalized treatment strategies for STS. TRIAL REGISTRATION: NCT05301283. TRIAL STATUS: The trial started recruitment on March 17, 2022.

Novel Postoperative Hypofractionated Accelerated Radiation Dose-Painting Approach for Soft Tissue Sarcoma.

Purpose: Hypofractionated radiation therapy (RT) offers benefits in the treatment of soft tissue sarcomas (STS), including exploitation of the lower α/ß, patient convenience, and cost. This study evaluates the acute toxicity of a hypofractionated accelerated RT dose-painting (HARD) approach for postoperative treatment of STS. Methods and Materials: This is a retrospective review of 53 consecutive patients with STS who underwent resection followed by postoperative RT. Standard postoperative RT dosing for R0/R1/gross disease with sequential boost (50 Gy + 14/16/20 Gy in 32-35 fractions) were replaced with dose-painting, which adapts dose based on risk of disease burden, to 50.4 and 63, 64.4, 70 Gy in 28 fractions, respectively. The first 10 patients were replanned with a sequential boost RT approach and dosimetric indices were compared. Time-to-event outcomes, including local control, regional control, distant control, and overall survival, were estimated with Kaplan-Meier analysis. Results: Median follow-up was 25.2 months. Most patients had high-grade (59%) STS of the extremity (63%) who underwent resection with either R1 (40%) or close (36%) margins. Four patients experienced grade 3 acute dermatitis which resolved by the 3-month follow-up visit. The 2-year local control, regional control, distant control, and overall survival were 100%, 92%, 68%, and 86%, respectively. Compared with the sequential boost plan, HARD had a significantly lower field size (total V50 Gy; P = .002), bone V50 (P = .031), and maximum skin dose (P = .008). Overall treatment time was decreased by 4 to 7 fractions, which translated to a decrease in estimated average treatment cost of $3056 (range, $2651-$4335; P < .001). Conclusions: In addition to benefits in cost, convenience, and improved biologic effect in STS, HARD regimen offers a safe treatment approach with dosimetric advantages compared with conventional sequential boost, which may translate to improved long-term toxicity.

Accurate, repeatable, and geometrically precise diffusion-weighted imaging on a 0.35 T magnetic resonance imaging-guided linear accelerator.

Background and purpose: Diffusion weighted imaging (DWI) allows for the interrogation of tissue cellularity, which is a surrogate for cellular proliferation. Previous attempts to incorporate DWI into the workflow of a 0.35 T MR-linac (MRL) have lacked quantitative accuracy. In this study, accuracy, repeatability, and geometric precision of apparent diffusion coefficient (ADC) maps produced using an echo planar imaging (EPI)-based DWI protocol on the MRL system is illustrated, and in vivo potential for longitudinal patient imaging is demonstrated. Materials and methods: Accuracy and repeatability were assessed by measuring ADC values in a diffusion phantom at three timepoints and comparing to reference ADC values. System-dependent geometric distortion was quantified by measuring the distance between 93 pairs of phantom features on ADC maps acquired on a 0.35 T MRL and a 3.0 T diagnostic scanner and comparing to spatially precise CT images. Additionally, for five sarcoma patients receiving radiotherapy on the MRL, same-day in vivo ADC maps were acquired on both systems, one of which at multiple timepoints. Results: Phantom ADC quantification was accurate on the 0.35 T MRL with significant discrepancies only seen at high ADC. Average geometric distortions were 0.35 (±0.02) mm and 0.85 (±0.02) mm in the central slice and 0.66 (±0.04) mm and 2.14 (±0.07) mm at 5.4 cm off-center for the MRL and diagnostic system, respectively. In the sarcoma patients, a mean pretreatment ADC of 910x10-6 (±100x10-6) mm2/s was measured on the MRL. Conclusions: The acquisition of accurate, repeatable, and geometrically precise ADC maps is possible at 0.35 T with an EPI approach.

Comparison of outcome after stereotactic ablative radiotherapy of patients with metachronous lung versus primary lung cancer.

BACKGROUND: Early-stage lung cancer, primarily treated with surgery, often occur in poor surgical candidates (impaired respiratory function, prior thoracic surgery, severe comorbidities). Stereotactic ablative radiotherapy (SABR) is a non-invasive alternative that provides comparable local control. This technique is particularly relevant for surgically resectable metachronous lung cancer, in patients unable to undergo surgery.. The objective of this study is to evaluate the clinical outcome of patients treated with SABR for stage I metachronous lung cancer (MLC) versus stage I primary lung cancer (PLC). PATIENTS AND METHODS: 137 patients treated with SABR for stage I non-small cell lung cancer were retrospectively reviewed, of which 28 (20.4%) were MLC and 109 (79.6%) were PLC. Cohorts were evaluated for differences in overall survival (OS), progression-free survival (PFS), metastasis-free survival, local control (LC), and toxicity. RESULTS: After SABR, patients treated for MLC have comparable median age (76.6 vs 78.6, p = 0.2), 3-year LC (83.6% vs. 72.6%, p = 0.2), PFS (68.7% vs. 50.9%, p = 0.9), and OS (78.6% vs. 52.1%, p = 0.9) as PLC, along with similar rates of total (54.1% vs. 42.9%, p = 0.6) and grade 3 + toxicity (3.7% vs. 3.6%, p = 0.9). Previous treatment of MLC patients was either surgery (21/28, 75%) or SABR (7/28, 25%). The median follow-up was 53 months. CONCLUSION: SABR is a safe and effective approach for localized metachronous lung cancer.

Neoadjuvant Simultaneous Integrated Boost Radiation Therapy Improves Clinical Outcomes for Retroperitoneal Sarcoma.

PURPOSE: Neoadjuvant radiation therapy (RT) with standard techniques (ST) offers a modest benefit in retroperitoneal sarcoma (RPS). As the high-risk region (HRR) at risk for a positive surgical margin and recurrence is posterior and away from radiosensitive organs at risk, using a simultaneous integrated boost (SIB) allows targeted dose escalation to the HRR while sparing these organs. We hypothesized that neoadjuvant SIB RT can improve disease control compared with ST, without increasing toxicity. METHODS AND MATERIALS: We retrospectively identified patients with resectable nonmetastatic RPS from 2000 to 2021 who received neoadjuvant RT of 180 to 200 cGy/fraction to standard volumes. SIB patients received 205 to 230 cGy/fraction to the appropriate HRR. Clinical endpoints included abdominopelvic control (APC), recurrence-free survival (RFS), overall survival (OS), and acute toxicity. RESULTS: With a median follow-up of 57 months (95% confidence interval [CI], 50-64), there were 103 patients with RPS who received either ST (n = 69) or SIB (n = 34) RT. Median standard volume dose was 5000 cGy (ST) and 4500 cGy (SIB), with a median HRR SIB dose of 5750 cGy. Liposarcomas (79% vs 53%; P = .004) and cT4 tumors (59% vs 19%; P < .001) were more common in the SIB cohort, without a significant difference in the rate of resection (82% vs 81%; P = .88) or R1 margin (53.5% vs 50%; P = .36); there were no R2 resections. SIB was associated with a significant improvement in 5-year APC (96% vs 70%; P = .046) and RFS (60.2% vs 36.3%; P = .036), with a nonsignificant OS difference (90.1% vs 67.5%; P = .164). On multivariable analysis, SIB remained a predictor for APC (hazard ratio, 0.07; 95% CI, 0.01-0.74; P = .027) and RFS (hazard ratio, 0.036; 95% CI, 0.13-0.98; P = .045). SIB showed no significant detriment in toxicity, albeit with a lower rate of overall grade 3 acute toxicity (3% vs 22%; P = .023) compared with ST. CONCLUSIONS: In RPS, dose escalation with neoadjuvant SIB RT may be independently associated with improved APC and RFS, without a detriment in toxicity, compared with ST. With the addition of standard RT having only a modest benefit compared with surgery alone, our study suggests that future prospective studies evaluating for the benefit of SIB RT should be considered.

Pathologic Complete Response and Clinical Outcomes in Patients With Localized Soft Tissue Sarcoma Treated With Neoadjuvant Chemoradiotherapy or Radiotherapy: The NRG/RTOG 9514 and 0630 Nonrandomized Clinical Trials.

Importance: Pathologic complete response (pCR) may be associated with prognosis in patients with soft tissue sarcoma (STS). Objective: We sought to determine the prognostic significance of pCR on survival outcomes in STS for patients receiving neoadjuvant chemoradiotherapy (CT-RT) (Radiation Therapy Oncology Group [RTOG] 9514) or preoperative image-guided radiotherapy alone (RT, RTOG 0630) and provide a long-term update of RTOG 0630. Design, Setting, and Participants: RTOG has completed 2 multi-institutional, nonrandomized phase 2 clinical trials for patients with localized STS. One hundred forty-three eligible patients from RTOG 0630 (n = 79) and RTOG 9514 (n = 64) were included in this ancillary analysis of pCR and 79 patients from RTOG 0630 were evaluated for long-term outcomes. Intervention: Patients in trial 9514 received CT interdigitated with RT, whereas those in trial 0630 received preoperative RT alone. Main Outcomes and Measures: Overall and disease-free survival (OS and DFS) rates were estimated by the Kaplan-Meier method. Hazard ratios (HRs) and P values were estimated by multivariable Cox model stratified by study, where possible; otherwise, P values were calculated by stratified log-rank test. Analysis took place between December 14, 2016, to April 13, 2017. Results: Overall there were 42 (53.2%) men; 68 (86.1%) were white; with a mean (SD) age of 59.6 (14.5) years. For RTOG 0630, at median follow-up of 6.0 years, there was 1 new in-field recurrence and 1 new distant failure since the initial report. From both studies, 123 patients were evaluable for pCR: 14 of 51 (27.5%) in trial 9514 and 14 of 72 (19.4%) in trial 0630 had pCR. Five-year OS was 100% for patients with pCR vs 76.5% (95% CI, 62.3%-90.8%) and 56.4% (95% CI, 43.3%-69.5%) for patients with less than pCR in trials 9514 and 0630, respectively. Overall, pCR was associated with improved OS (P = .01) and DFS (HR, 4.91; 95% CI, 1.51-15.93; P = .008) relative to less than pCR. Five-year local failure rate was 0% in patients with pCR vs 11.7% (95% CI, 3.6%-25.1%) and 9.1% (95% CI, 3.3%-18.5%) for patients with less than pCR in 9514 and 0630, respectively. Histologic types other than leiomyosarcoma, liposarcoma, and myxofibrosarcoma were associated with worse OS (HR, 2.24; 95% CI, 1.12-4.45). Conclusions and Relevance: This ancillary analysis of 2 nonrandomized clinical trials found that pCR was associated with improved survival in patients with STS and should be considered as a prognostic factor of clinical outcomes for future studies. Trial Registration: ClinicalTrials.gov Identifiers: RTOG 0630 (NCT00589121); RTOG 9514 (NCT00002791).

Effect of Favorable Pathologic Response After Neoadjuvant Radiation Therapy Alone in Soft-tissue Sarcoma.

Purpose: Whether the therapeutic response of soft-tissue sarcoma to neoadjuvant treatment is predictive for clinical outcomes is unclear. Given the rarity of this disease and the confounding effects of chemotherapy, this study analyzes whether a favorable pathologic response (fPR) after neoadjuvant radiation therapy (RT) alone is associated with clinical benefits. Methods and Materials: An institutional review board-approved retrospective review was conducted on a database of patients with primary soft-tissue sarcoma treated at our institution between 1987 and 2015 with neoadjuvant RT alone followed by surgical resection. Time-to-event outcomes estimated with a Kaplan-Meier analysis included overall survival, progression-free survival (PFS), locoregional control, and distant control (DC). Cox regression analyses were performed to determine prognostic variables associated with clinical outcomes. Results: Of the overall cohort of 315 patients, 181 patients (57%) were included in the primary analysis with documented pathologic necrosis (PN) rates (mean: 59%) and a median follow up from diagnosis of 48 months (range, 4-170 months). The median neoadjuvant RT dose was 50 Gy (range, 40-60 Gy), and the majority of patients had negative surgical margins (79%). Only 35 patients (19%) achieved a fPR (PN ≥95%), which was associated with a higher R0 resection rate (94% vs. 75%; P = .013), a significant 5-year PFS benefit (74% vs. 43%; P = .014), and a nonsignificant 5-year DC benefit (76% vs. 62%; P = .12) compared with PN <95%. On multivariable analysis, fPR was an independent predictor for PFS (hazard ratio: 0.47; 95% confidence interval, 0.25-0.90; P = .022). Conclusions: Achieving fPR with neoadjuvant RT alone is associated with a higher R0 resection rate and possible DC benefit, translating into a significant improvement in PFS. Further studies to improve pathologic response rates and prospectively validate this endpoint are warranted.

Identifying and overcoming barriers to participation of minority populations in clinical trials: Lessons learned from the VanDAAM study.

Participation in cancer research trials by minority populations is imperative in reducing disparities in clinical outcomes. Even with increased awareness of the importance of minority patient inclusion in clinical research to improve cancer care and survival, significant barriers persist in accruing and retaining minority patients into clinical trials. This study sought to identify and address barriers to minority accrual to a minimal risk clinical research study in real-time.

Updates in the use of radiotherapy in the management of primary and locally-advanced penile cancer.

Objective: Penile cancer is a rare malignancy in most developed countries, but may represent a significant oncologic challenge in certain African, Asian, and South American regions. Various treatment approaches have been described in penile cancer, including radiotherapy. This review aimed to provide a synopsis of radiotherapy use in penile cancer management and the associated toxicities. In addition, we aimed to discuss palliative radiation for metastases to the penis and provide a brief overview of how tumor biology may assist with treatment decision-making. Methods: Peer-reviewed manuscripts related to the treatment of penile cancer with radiotherapy were evaluated by a PubMed search (1960-2021) in order to assess its role in the definitive and adjuvant settings. Selected manuscripts were also evaluated for descriptions of radiation-related toxicity. Results: Though surgical resection of the primary is an excellent option for tumor control, select patients may be treated with organ-sparing radiotherapy by either external beam radiation or brachytherapy. Data from randomized controlled trials comparing radiotherapy and surgery are lacking, and thus management is frequently determined by institutional practice patterns and available expertise. Similarly, this lack of clinical trial data leads to divergence in opinion regarding lymph node management. This is further complicated in that many cited studies evaluating lymph node radiotherapy used non-modern radiotherapy delivery techniques. Groin toxicity from either surgery or radiotherapy remains a challenging problem and further risk assessment is needed to guide intensification with multi-modal therapy. Intrinsic differences in tumor biology, based on human papillomavirus infection, may help aid future prognostic and predictive models in patient risk stratification or treatment approach. Conclusion: Penile cancer is a rare disease with limited clinical trial data driving the majority of treatment decisions. As a result, the goal of management is to effectively treat the disease while balancing the importance of quality of life through integrated multidisciplinary discussions. More international collaborations and interrogations of penile cancer biology are needed to better understand this disease and improve patient outcomes.

Genomic Testing in Localized Prostate Cancer Can Identify Subsets of African Americans With Aggressive Disease.

BACKGROUND: Personalized genomic classifiers have transformed the management of prostate cancer (PCa) by identifying the most aggressive subsets of PCa. Nevertheless, the performance of genomic classifiers to risk classify African American men is thus far lacking in a prospective setting. METHODS: This is a prospective study of the Decipher genomic classifier for National Comprehensive Cancer Network low- and intermediate-risk PCa. Study-eligible non-African American men were matched to African American men. Diagnostic biopsy specimens were processed to estimate Decipher scores. Samples accrued in NCT02723734, a prospective study, were interrogated to determine the genomic risk of reclassification (GrR) between conventional clinical risk classifiers and the Decipher score. RESULTS: The final analysis included a clinically balanced cohort of 226 patients with complete genomic information (113 African American men and 113 non-African American men). A higher proportion of African American men with National Comprehensive Cancer Network-classified low-risk (18.2%) and favorable intermediate-risk (37.8%) PCa had a higher Decipher score than non-African American men. Self-identified African American men were twice more likely than non-African American men to experience GrR (relative risk [RR] = 2.23, 95% confidence interval [CI] = 1.02 to 4.90; P = .04). In an ancestry-determined race model, we consistently validated a higher risk of reclassification in African American men (RR = 5.26, 95% CI = 1.66 to 16.63; P = .004). Race-stratified analysis of GrR vs non-GrR tumors also revealed molecular differences in these tumor subtypes. CONCLUSIONS: Integration of genomic classifiers with clinically based risk classification can help identify the subset of African American men with localized PCa who harbor high genomic risk of early metastatic disease. It is vital to identify and appropriately risk stratify the subset of African American men with aggressive disease who may benefit from more targeted interventions.

Novel portable apparatus for outpatient high-dose-rate (HDR) brachytherapy in penile cancer.

BACKGROUND: Penile squamous cell carcinoma (PSC) is traditionally treated with surgical resection with significant morbidity. Penile sparing approaches, such as brachytherapy, require expertise, prolonged inpatient stays, poor patient convenience, and heterogenous plans with variable long-term toxicity. In this study, we describe the protocol for novel portable apparatus created for PSC, allowing outpatient hybrid interstitial/surface brachytherapy, improving homogeneity and patient convenience. METHODS: A portable brachytherapy apparatus was developed utilizing a foley catheter, prostate template, 6F interstitial catheters, 5 mm bolus, and a jock strap. The apparatus allowed for internal and external catheter placement housed in a jock strap to allow mobility and defecation without affecting the implant. High-dose-rate brachytherapy was performed as an outpatient. RESULTS: The apparatus was then used on a 62-year-old male with cT2pN0M0 (stage IIA) PSC with bilateral glans and urethral meatus involvement, who elected for definitive brachytherapy (4000cGy in 10 fractions over 5-days). Given external dwell positions, heterogeneity correction of the template was calculated (AAPM TG186) with <2% variation. Patient had minimal impact on his active lifestyle during treatment and had complete clinical response at 3-months. Grade 2 skin desquamation resolved at 2-months, with no necrosis. At 6-months, he was able to resume sexual intercourse, and at 12-months, he remained disease-free with sexual and urinary function intact. CONCLUSIONS: Novel portable implant allows for improved patient convenience, reduced inpatient stay, capable of optimizing dosimetry with hybrid brachytherapy. This outpatient treatment allows the opportunity to increase fractionation, offering high local-control and lower toxicity. Future studies utilizing this apparatus for more fractionated regimens with further lower dose-per-fraction (∼3 Gy/fraction) is recommended.

American Brachytherapy Society radiation oncology alternative payment model task force: Quality measures and metrics for brachytherapy.

PURPOSE: Brachytherapy is an essential technique to deliver radiation therapy and is involved in the treatment of multiple disease sites as monotherapy or as an adjunct to external beam radiation therapy. With a growing focus on the cost and value of cancer treatments as well as new payment models, it is essential that standardized quality measures and metrics exist to allow for straightforward assessment of brachytherapy quality and for the development of clinically significant and relevant clinical data elements. We present the American Brachytherapy Society consensus statement on quality measures and metrics for brachytherapy as well as suggested clinical data elements. METHODS AND MATERIALS: Members of the American Brachytherapy Society with expertise in disease site specific brachytherapy created a consensus statement based on a literature review and clinical experience. RESULTS: Key quality measures (ex. workup, clinical indications), dosimetric metrics, and clinical data elements for brachytherapy were evaluated for each modality including breast cancer, cervical cancer, endometrial cancer, prostate cancer, keratinocyte carcinoma, soft tissue sarcoma, and uveal melanoma. CONCLUSIONS: This consensus statement provides standardized quality measures and dosimetric quality metrics as well as clinical data elements for each disease site to allow for standardized assessments of brachytherapy quality. Moving forward, a similar paradigm can be considered for external beam radiation therapy as well, providing comprehensive radiation therapy quality measures, metrics, and clinical data elements that can be incorporated into new payment models.

Genomic identification of sarcoma radiosensitivity and the clinical implications for radiation dose personalization.

BACKGROUND: Soft-tissue sarcomas (STS) are heterogeneous with variable response to radiation therapy (RT). Utilizing the radiosensitivity index (RSI) we estimated the radiobiologic ratio of lethal to sublethal damage (α/ß), genomic-adjusted radiation dose(GARD), and in-turn a biological effective radiation dose (BED). METHODS: Two independent cohorts of patients with soft-tissue sarcoma were identified. The first cohort included 217 genomically-profiled samples from our institutional prospective tissue collection protocol; RSI was calculated for these samples, which were then used to dichotomize the population as either highly radioresistant (HRR) or conventionally radioresistant (CRR). In addition, RSI was used to calculate α/ß ratio and GARD, providing ideal dosing based on sarcoma genomic radiosensitivity. A second cohort comprising 399 non-metastatic-STS patients treated with neoadjuvant RT and surgery was used to validate our findings. RESULTS: Based on the RSI of the sample cohort, 84% would historically be considered radioresistant. We identified a HRR subset that had a significant difference in the RSI, and clinically a lower tumor response to radiation (2.4% vs. 19.4%), 5-year locoregional-control (76.5% vs. 90.8%), and lower estimated α/ß (3.29 vs. 5.98), when compared to CRR sarcoma. Using GARD, the dose required to optimize outcome in the HRR subset is a BEDα/ß=3.29 of 97 Gy. CONCLUSIONS: We demonstrate that on a genomic scale, that although STS is radioresistant overall, they are heterogeneous in terms of radiosensitivity. We validated this clinically and estimated an α/ß ratio and dosing that would optimize outcome, personalizing dose.

American Brachytherapy Society (ABS) consensus statement for soft-tissue sarcoma brachytherapy.

PURPOSE: Growing data supports the role of radiation therapy in the treatment of soft tissue sarcoma (STS). Brachytherapy has been used for decades in the management of STS and can be utilized as monotherapy or as a boost to external beam radiation. We present updated guidelines from the American Brachytherapy Society regarding the utilization of brachytherapy in the management of STS. METHODS AND MATERIALS: Members of the American Brachytherapy Society with expertise in STS and STS brachytherapy created an updated clinical practice guideline including step-by-step details for performing STS brachytherapy based on a literature review and clinical experience. RESULTS: Brachytherapy monotherapy should be considered for lower-recurrence risk patients or after a local recurrence following previous external beam radiation; a brachytherapy boost can be considered in higher-risk patents meeting implant criteria. Multiple dose/fractionation regimens are available, with determination based on tumor location and treatment intent. Techniques to limit wound complications are based on the type of wound closure; wound complication can be mitigated with a delay in the start of brachytherapy with immediate wound closure or by utilizing a staged reconstruction technique, which allows an earlier treatment start with a delayed wound closure. CONCLUSIONS: These updated guidelines provide clinicians with data on indications for STS brachytherapy as well as guidelines on how to perform and deliver high quality STS brachytherapy safely with minimal toxicity.

Proof-of-principle Phase I results of combining nivolumab with brachytherapy and external beam radiation therapy for Grade Group 5 prostate cancer: safety, feasibility, and exploratory analysis.

BACKGROUND: To determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa. METHODS: Eligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with ClinicalTrials.gov (NCT03543189). RESULTS: Between September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post-HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders. CONCLUSION: Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.

TMPRSS2-ERG fusion impacts anterior tumor location in men with prostate cancer.

BACKGROUND: In prostate cancer (PCa), lack of androgen receptor (AR) regulated TMPRSS2-ETS-related gene (ERG) gene fusion (ERGnegative ) status has been associated with African American race; however, the implications of ERG status for the location of dominant tumors within the prostate remains understudied. METHODS: An African American-enriched multiinstitutional cohort of 726 PCa patients consisting of both African American men (AAM; n = 254) and European American men (EAM; n = 472) was used in the analyses. Methods of categorical analysis were used. Messenger RNA (mRNA) expression differences between anterior and posterior tumor lesions were analyzed using Wilcoxon rank-sum tests with multiple comparison corrections. RESULTS: Anti-ERG immunohistochemistry staining showed that the association between ERG status and anterior tumors is independent of race and is consistently robust for both AAM (ERGnegative 81.4% vs. ERGpositive 18.6%; p = .005) and EAM (ERGnegative 60.4% vs. ERGpositive 39.6%; p < .001). In a multivariable model, anterior tumors were more likely to be IHC-ERGnegative (odds ratio [OR]: 3.20; 95% confidence interval [CI]: 2.14-4.78; p < .001). IHC-ERGnegative were also more likely to have high-grade tumors (OR: 1.73; 95% CI: 1.06-2.82; p = .02). In the exploratory genomic analysis, mRNA expression of location-dependent genes is highly influenced by ERG status and African American race. However, tumor location did not impact the expression of AR or the major canonical AR-target genes (KLK3, AMACR, and MYC). CONCLUSIONS: ERGnegative tumor status is the strongest predictor of anterior prostate tumors, regardless of race. Furthermore, AR expression and canonical AR signaling do not impact tumor location.

Chemotherapy improves distant control in localized high-grade soft tissue sarcoma of the extremity/trunk.

BACKGROUND: Soft tissue sarcomas (STS) are rare and heterogeneous tumors making chemotherapy use controversial. Our goal was to identify a subset of patients with primary STS that benefit with the addition of chemotherapy. METHODS: A retrospective chart review included intermediate to high-grade localized primary STS of the extremity/trunk, and tumor size > 5 cm. The effect of chemotherapy was evaluated for local control (LC), distant control (DC), progression free survival (PFS), and overall survival (OS). RESULTS: In this cohort (n = 273), patients were treated with surgery (98%), radiation (81%), and chemotherapy (24.5%). With a median follow-up of 51 months, the entire cohort's 5-year LC, DC, PFS, and OS are 79.1%, 59.9%, 43.8%, and 68.7%, respectively. The addition of chemotherapy did not provide a DC benefit (p = 0.238) for the entire cohort. High-grade disease (n = 210) experienced a 5-year benefit in DC (68% vs. 54.4%, p = 0.04), which was more pronounced with MAI (Mesna, Adriamycin, Ifosfamide) based regimens (74.2%, p = 0.016), and a 5-year PFS (50.8% vs 45%, p = 0.025) and OS benefit (76.2% vs 70%, p = 0.067) vs. no chemotherapy. On multivariate analysis of the high-grade subset, chemotherapy independently predicted for a DC benefit (HR 0.48 95% CI 0.26-89, p = 0.019). The benefit of chemotherapy was more pronounced with MAI, showing a significant benefit in DC (HR 0.333 95% CI 0.145-0.767, p = 0.01) and PFS (HR 0.52 95% CI 0.28-0.99, p = 0.047). CONCLUSION: In patients with localized STS > 5 cm, the high-grade subset had a distant control benefit with the addition of chemotherapy, leading to improved progression free survival. This is more pronounced with the use of MAI and should be considered in patients eligible for this regimen.

Using the revised Edmonton symptom assessment scale during neoadjuvant radiotherapy for retroperitoneal sarcoma.

BACKGROUND AND PURPOSE: Retroperitoneal sarcoma (RPS) is a rare, complex disease requiring multidisciplinary management. We have previously reported that use of the Revised Edmonton Symptom Assessment Scale (ESAS-r-CSS) allows for proactive symptom management, and we sought to report the results of ESAS-r-CSS screening during pre-operative radiotherapy (RT) for a cadre of patients with RPS. MATERIALS AND METHODS: We reviewed records of 47 patients with RPS evaluated at our institution between 2015 and 2018. Of this group, 29 non-metastatic patients were treated with definitive intent neoadjuvant RT with at least 2 weekly ESAS-r-CSS reports. A generalized estimating equation model was used to compare 13 symptoms during weekly on-treatment visits compared to baseline scores at week 1 of RT. Additionally, covariate effects of age, gender, dose, tumor size and location were assessed. RESULTS: The population was predominantly male (66%) with median age of 65 years, KPS of 90, and tumor size of 12.8 cm. ESAS scores significantly decreased for anxiety at week 3 (P = 0.01), and pain at week 5 (P = 0.01). Worse constipation was reported at week 2 (P = 0.02). In an exploratory covariate analysis, female gender, age, high dose, and larger tumor size were associated with worse ESAS scores across all time points. CONCLUSION: Patient reporting of symptoms during radiotherapy through weekly ESAS-r-CSS facilitates timely management in patients with this unique tumor type. Expectant care during RT offers the opportunity to minimize symptom progression or treatment interruptions in a population that generally has worsening side effects.