External Beam Radiation Therapy With or Without Brachytherapy Boost in Men With Very-High-Risk Prostate Cancer: A Large Multicenter International Consortium Analysis.

PURPOSE: Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear. METHODS AND MATERIALS: This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression. RESULTS: Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P = .42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P = .42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P = .38). CONCLUSIONS: In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

IMPORTANCE: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain. OBJECTIVE: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). DESIGN, SETTINGS, AND PARTICIPANTS: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021. EXPOSURES: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs). MAIN OUTCOMES AND MEASURES: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months). RESULTS: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01). CONCLUSIONS AND RELEVANCE: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.

Performance of a Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Derived Risk-Stratification Tool for High-risk and Very High-risk Prostate Cancer.

Importance: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect low-volume, nonlocalized (ie, regional or metastatic) prostate cancer that was occult on conventional imaging. However, the long-term clinical implications of PSMA PET/CT upstaging remain unclear. Objectives: To evaluate the prognostic significance of a nomogram that models an individual's risk of nonlocalized upstaging on PSMA PET/CT and to compare its performance with existing risk-stratification tools. Design, Setting, and Participants: This cohort study included patients diagnosed with high-risk or very high-risk prostate cancer (ie, prostate-specific antigen [PSA] level >20 ng/mL, Gleason score 8-10, and/or clinical stage T3-T4, without evidence of nodal or metastatic disease by conventional workup) from April 1995 to August 2018. This multinational study was conducted at 15 centers. Data were analyzed from December 2020 to March 2021. Exposures: Curative-intent radical prostatectomy (RP), external beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT), with or without androgen deprivation therapy. Main Outcomes and Measures: PSMA upstage probability was calculated from a nomogram using the biopsy Gleason score, percentage positive systematic biopsy cores, clinical T category, and PSA level. Biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) were analyzed using Fine-Gray and Cox regressions. Model performance was quantified with the concordance (C) index. Results: Of 5275 patients, the median (IQR) age was 66 (60-72) years; 2883 (55%) were treated with RP, 1669 (32%) with EBRT, and 723 (14%) with EBRT plus BT; median (IQR) PSA level was 10.5 (5.9-23.2) ng/mL; 3987 (76%) had Gleason grade 8 to 10 disease; and 750 (14%) had stage T3 to T4 disease. Median (IQR) follow-up was 5.1 (3.1-7.9) years; 1221 (23%) were followed up for at least 8 years. Overall, 1895 (36%) had BCR, 851 (16%) developed DM, and 242 (5%) died of prostate cancer. PSMA upstage probability was significantly prognostic of all clinical end points, with 8-year C indices of 0.63 (95% CI, 0.61-0.65) for BCR, 0.69 (95% CI, 0.66-0.71) for DM, 0.71 (95% CI, 0.67-0.75) for PCSM, and 0.60 (95% CI, 0.57-0.62) for PCSM (P < .001). The PSMA nomogram outperformed existing risk-stratification tools, except for similar performance to Staging Collaboration for Cancer of the Prostate (STAR-CAP) for PCSM (eg, DM: PSMA, 0.69 [95% CI, 0.66-0.71] vs STAR-CAP, 0.65 [95% CI, 0.62-0.68]; P < .001; Memorial Sloan Kettering Cancer Center nomogram, 0.57 [95% CI, 0.54-0.60]; P < .001; Cancer of the Prostate Risk Assessment groups, 0.53 [95% CI, 0.51-0.56]; P < .001). Results were validated in secondary cohorts from the Surveillance, Epidemiology, and End Results database and the National Cancer Database. Conclusions and Relevance: These findings suggest that PSMA upstage probability is associated with long-term, clinically meaningful end points. Furthermore, PSMA upstaging had superior risk discrimination compared with existing tools. Formerly occult, PSMA PET/CT-detectable nonlocalized disease may be the main driver of outcomes in high-risk patients.

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown. Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment. Design, Setting, and Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT). Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models. Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001). Conclusions and Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.

Single Application Multifractionated Image Guided Adaptive High-Dose-Rate Brachytherapy for Cervical Cancer: Dosimetric and Clinical Outcomes.

PURPOSE: A prospective phase 2 study was conducted to evaluate the feasibility and safety of single-application multifractionated (SA-MF), high-dose-rate (HDR), image guided adaptive brachytherapy (IGABT) for cervical cancer. METHODS AND MATERIALS: Patients (N = 41) with International Federation of Gynaecology and Obstetrics 2009 stage IIB-IVA disease recruited between 2017 and 2019 underwent SA-MF. After completion of external beam radiation therapy of 50 Gy in 25 fractions, patients received magnetic resonance IGABT. The IGABT protocol consisted of a single brachytherapy (BT) application and treatment with 3 fractions of HDR (9 Gy on day 1; 2 fractions of 7 Gy with a minimum 6-hour gap on day 2) after achieving planning aims of the high-risk clinical target volume (HRCTV) receiving >84 Gy EQD2 and 2 cm3 of the bladder and rectum/sigmoid receiving ≤85 Gy and <71 Gy, respectively. Interfraction variation was addressed by performing computed tomography planning and coregistration using a mutual information-based coordinate system on day 2 before the second fraction. Organ at risk contouring was done on computed tomography, and doses were re-evaluated and reoptimized if required. RESULTS: Thirty-eight patients were treated as per the protocol. All patients underwent Intracavitary + Interstitial BT with needles (median, 4; range, 3-11). The mean ± standard deviation HRCTV volume was 41 ± 21 cm3 and HRCTV D90 dose was 87.2 ± 3.6Gy. The 0.1 cm3 and 2 cm3 to bladder, rectum, and sigmoid were -103.2 ± 10.6 Gy and -84.6 ± 6.8 Gy, 82.2 ± 9.5 Gy and -68.3 ± 5.7 Gy, and 83.5 ± 9.8 Gy and -69.5 ± 5.9 Gy, respectively. Six patients required reoptimization before the second fraction to meet planning aims. Mean overall treatment time was 47 ± 6 days. With a median follow up of 22 months (range, 2-37), 2-year local control and disease-free and overall survival were 90.1%, 85%, and 94.5%, respectively. So far 1 patient with grade II and 2 patients with grade III rectal toxicities have been reported. CONCLUSION: Magnetic resonance IGABT with SA-MF BT was feasible in 95% of patients. The dosimetric parameters and clinical results achieved so far look promising.

Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer.

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa. PATIENT SUMMARY: High-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.

Prognostic value of clinical and radiologic extranodal extension and their role in the 8th edition TNM cN classification for HPV-negative oropharyngeal carcinoma.

BACKGROUND/OBJECTIVES: We evaluate the performance between the TNM-8 versus TNM-7 cN-classification and explore the relative prognostic contribution of radiologic extranodal extension (rENE) for HPV-negative oropharyngeal cancer (HPV-OPC). MATERIALS/METHODS: All HPV- OPC treated with IMRT between 2005 and 2016 were included. cENE was defined as unambiguous "fixation" of a neck mass or "skin involvement" on clinical examination. rENE was recorded by re-reviewing pre-treatment CT/MR. Disease-free survival (DFS) stratified by cENE or rENE were compared. Multivariable analyses (MVA) calculated the adjusted hazard ratio (aHR) for the separate cENE and rENE attributes and their combination. A refined cN-category incorporating both cENE and rENE parameters was proposed. The performance of the revision was compared to TNM-8 and TNM-7. RESULTS: Of 361 HPV- OPC, 97 were cN0 and 264 were cN+ with 48 cENE+ and 72 rENE+ respectively. Median follow-up was 5.4 years. The 3-year DFS was lower in cENE+ vs cENE-negative (cENE-) (23% vs 45%; aHR = 1.68, p = 0.008) and rENE+ vs rENE-negative (rENE-) patients (29% vs 45%; aHR = 1.44, p = 0.037). The cENE+/rENE+ subset had the worse DFS vs cENE-/rENE+ or cENE-/rENE- (24%/37%/46%, p = 0.005). We propose a refined cN-category wherein any cENE-/rENE+ case is reclassified one N-stratum higher while any cENE+ case remains cN3b. The stage schema with the refined N-categorization outperformed TNM-8, and both outperformed TNM-7. CONCLUSIONS: cENE and rENE are both prognostic but the cENE+/rENE+ subset has the worst outcome. The TNM-8 cN-categories improves outcome prediction compared to the TNM-7. Incorporation of rENE into TNM-8 cN-categories may further augment performance.

Coronavirus Disease 2019's (COVID-19's) Silver Lining-Through the Eyes of Radiation Oncology Fellows.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has propelled health care workers to the front lines against the pandemic. In addition to anxiety related to infection risks, trainees have the additional burden of learning and career planning while providing care in an uncertain and rapidly changing environment. We conducted a survey to evaluate the practical and psychosocial impact on radiation oncology fellows during the first month of the pandemic. METHODS AND MATERIALS: A 4-part survey was designed and distributed to the fellows in our program. The survey was designed to evaluate the impact of the pandemic on scope of activity and well-being ("Impact on You") and to identify key lessons learned and social factors ("About You") using Likert scales and open-ended response options. The survey included items from the Oldenburg Burnout questionnaire. RESULTS: A total of 17 participants (71%) responded to the survey. Although there was a significant reduction in the mean time spent on in-person clinics (13.5 h/wk [pre-COVID] vs 9.3 h/wk [3 weeks into the COVID emergency response]; P = .002), this was replaced by virtual consults and other COVID-related activities. The proportion of respondents demonstrating features of burnout in the domains of "disengagement" and "exhaustion" was 71% and 64%, respectively. However, there was also evidence of resilience, with 47% respondents "feeling energized." Top "concerns" and "negative changes" identified related to learning, infection risk and safety, patient care, coping, and concerns about their home country. Top "positive changes" highlighted include work culture, appreciation for leadership caring for the team, the insistence on evidence to guide change, and the implementation of virtual health care. CONCLUSIONS: Negative impact needs to be anticipated, acknowledged, and managed. We anticipate understanding the positives that have emerged under these extraordinary circumstances is the "silver lining" of the pandemic, giving us tools and the best leverage to plan for the future.

Clinical outcomes for nasopharyngeal cancer with intracranial extension after taxane-based induction chemotherapy and concurrent chemo-radiotherapy in the modern era.

OBJECTIVE: To evaluate the survival outcomes for a cohort of nasopharyngeal cancer with intracranial extension (ICE) treated with induction chemotherapy (ICT) followed by chemo-intensity-modulated radiotherapy (CTRT) at a tertiary cancer center. METHODS: We retrospectively analyzed 45 patients with histologically proven, non-metastatic NPC with ICE treated at our institute between October 2008 and October 2016. Patients were classified as minor ICE or major ICE, based on the extent of ICE. All the patients received 2-3 cycles of a taxane-based ICT regimen followed by CTRT. Radiotherapy was delivered with "risk-adapted" intensity-modulated radiotherapy (IMRT) technique in all patients. RESULTS: After a median follow up of 45 months (range: 8-113 months), the estimated 5-year DFS, LRFS, DMFS, and OS of the entire cohort was 58%, 82%, 67% and 74% respectively. On multivariate analysis, histological subtype was an independent predictor of LRFS, and age was an independent predictor of DFS. The extent of ICE showed only a trend towards worse DFS (P = 0.06). None of the factors significantly predicted for DMFS or OS. Gender, N-stage, and response to ICT did not significantly affect any of the outcomes. Grade 2 or worse subcutaneous fibrosis was seen in 22% of patients and grade 2 or worse xerostomia was seen in 24% of patients at last follow up. Thirty-three percent of the patients developed clinical hypothyroidism at last follow up. None of the patients experienced any neurological or vascular complications. CONCLUSIONS: Taxane-based induction chemotherapy followed by chemo-intensity modulated radiotherapy resulted in excellent locoregional control and survival with acceptable toxicities in patients of nasopharyngeal cancer with intracranial extension. Distant metastasis continues to be the predominant problem in these patients.

Stereotactic body radiation therapy for medically inoperable early-stage lung cancer: Tata Memorial Hospital perspective and practice recommendations.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is now considered the standard treatment for medically inoperable early-stage non-small lung cell cancer (ES-NSCLC). PURPOSE: There is a paucity of data related to outcomes with SBRT in ES-NSCLC from the developing countries. We report the early outcomes of ES-NSCLC patients treated with SBRT at our institute. MATERIALS AND METHODS: Between 2007 and 2015, 40 consecutive patients with histologically proven ES-NSCLC were treated with SBRT. Median age was 71 years (range: 46-88 years) and median Charlson comorbidity index (CCI) was 3. The majority had stage I (70%) and 45% of the tumors were centrally located. The median tumor diameter was 3.8 cm (range: 2-7.6 cm). The mean gross tumor volume was 41 cc (range: 4-139 cc) and the mean planning target volume (PTV) was 141 cc (range: 27-251 cc). Varying dose and fraction (fr) sizes were used depending on tumor location, tumor size, and treatment period. The median biologically effective dose (BED) was 77 Gy10 (range: 77-105 Gy10) for the initial cohort (2007-2012) and 105 Gy10 (range: 77-132 Gy10) for the subsequent cohort (2013-2015). RESULTS: After a median follow-up of 16 months (range: 3-99 months), the 2-year local control (LC), overall survival, and cancer-specific survival (CSS) rates were 94%, 41%, and 62%, respectively. The univariate and multivariate analysis determined CCI >3 and PTV >80.6 cc as significant predictors of worse OS and CSS (P< 0.01). The clinical stage, tumor location, BED, and treatment period (2007-2012 vs. 2013-2015) did not significantly predict any of the outcomes. The most common acute toxicities were skin erythema (10%), grade 1 esophagitis (8%), and exacerbation of previous chronic obstructive pulmonary disease (10%). Grade ≥2 late radiation pneumonitis was seen in 17.5%. One patient developed a rib fracture. No neurological or vascular complications were seen. CONCLUSIONS: SBRT results in excellent local control (LC) and acceptable survival in medically inoperable ES-NSCLC with minimal adverse effects. Charlson comorbidity index and target volume are important prognostic factors and may aid in patient selection.

Extranodal extension in resected oral cavity squamous cell carcinoma: more to it than meets the eye.

OBJECTIVE/HYPOTHESIS: Extranodal extension (ENE) is an independent prognosticator in head-neck Squamous cell carcinoma (SCC). All patients with ENE, however, do not behave the same, and there is a need for further risk stratification. This study evaluates the prognostic significance of various grades of ENE and the number of nodes with ENE on overall survival (OS) in oral cavity SCC (OCSCC). STUDY DESIGN: Retrospective cohort study. METHODS: Ninety-four patients with node-positive OCSCC treated with primary surgery and appropriate adjuvant therapy during the year 2011 were evaluated. Surgical histopathology slides of all patients were reviewed, and ENE was graded according to the grading system proposed by Lewis Jr et al. RESULTS: On univariate analysis, lymph node density (LND) greater than or equal to 0.12 (P = 0.013), the presence of ENE in more than two nodes (P = 0.006), and ENE grade 3 through 4 (P = 0.035) were associated with worse (OS). Conventional prognostic factors such as tumor (T) stage, nodal (N) stage, stage grouping, depth of invasion, and pattern of invasion did not have a significant impact on OS. On multivariate analysis, the presence of ENE in more than two nodes (P = 0.018) independently predicted a worse OS. Extranodal extension grade 3 through 4 showed a trend toward significance (P = 0.08). A combination of LND greater than or equal to 0.12, ENE grade 3 through 4, and ENE in more than two lymph nodes conferred the poorest prognosis (3-year OS: 18%; P = 0.000). CONCLUSION: In patients with ENE and advanced nodal disease, T stage, N stage, stage group, depth, and pattern of invasion lose their impact on OS. In patients with ENE, nodal characteristics such as LND, the number of nodes with ENE, and grade of ENE serve as important prognosticators and aid in further risk stratification. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1130-1136, 2019.

Interstitial brachytherapy for pediatric soft tissue sarcoma: Evolving practice over three decades and long-term outcomes.

PURPOSE: Evaluate long-term clinical outcomes, adverse effects, and evolving practice of interstitial brachytherapy (BT) for pediatric soft tissue sarcomas (STS). METHODS: From September 1984 to December 2014, 105 children (median age 10 years) were included. There were 60 males and 45 females. The majority (74%) had primary lesions. Synovial sarcoma (22%) was the most frequent histology. Treatment included wide local excision and BT with or without external beam radiotherapy (EBRT). Eighty-five (81%) received BT alone. RESULTS: After a median follow-up of 65 months, local control (LC), disease-free survival (DFS), and overall survival (OS) at 10 years were 83, 66, and 73%, respectively. On univariate analysis, LC was superior with tumors <5 cm versus >5 cm (93% vs. 75%, P = 0.10), Grade I/II versus Grade III tumors (97% vs. 73%, P = 0.01), nonround cell versus round cell histology (89% vs. 72%, P = 0.03), and trunk/extremity versus head and neck/genitourinary sites (87% vs. 57%, P = 0.0001). On multivariate analysis tumor size (P = 0.03) and location (P = 0.002) retained significance. Children receiving BT alone had comparable LC to those receiving BT and EBRT (84% vs. 80%, P = 0.43). There was no difference in LC between LDR versus HDR BT (86% vs. 83%, P = 0.30). Wound complications were seen in 6%. Subcutaneous fibrosis (25%), limb edema (6%), skeletal abnormalities (3%), and neuropathy (1%) were the late complications. One child (0.9%) developed a second malignancy after 7 years. CONCLUSION: Interstitial BT with or without EBRT results in excellent outcomes. Radical BT alone, when used judiciously, results in excellent local control and function with minimal treatment-related morbidity.

Interstitial brachytherapy for orbital soft tissue sarcoma: an innovative technique.

PURPOSE: To report an innovative technique of interstitial brachytherapy developed for treatment of orbital soft tissue tumors. MATERIAL AND METHODS: A 4-month-old child diagnosed with rhabdomyosarcoma of orbit was treated with multiagent chemotherapy (CTh) and brachytherapy. Pre-planning computed tomography (CT) images were obtained and clinical target volume (CTV) was defined using the pre-treatment magnetic resonance imaging (MRI). Brachytherapy plan was generated for deciding optimal catheter placement. With the child under general anesthesia, catheter entry points were extrapolated and marked on the skin as determined from the pre-planning CT scan. Implantation of catheters was performed as per pre-determined catheter position and depths. Brachytherapy plan was generated and evaluated using dose volume histograms (DVH). A comparative external beam radiotherapy (EBRT) plan using RapidArc was also generated for the CTV with a 3 mm margin as the planning target volume (PTV). RESULTS: The mean CTV dose with brachytherapy was 158% compared to 101% with RapidArc. The CTV V100 was 90% for brachytherapy vs. 95% for RapidArc. The mean dose to Lt Lens were 51% and 60%, respectively for brachytherapy and RapidArc, while the corresponding mean doses to the bony orbit were 39% and 68%, respectively. Follow-up MRI at 3 months showed complete response of the tumor. CONCLUSIONS: Interstitial brachytherapy for orbit using this innovative technique is a safe and effective modality of local treatment for appropriately selected orbital soft tissue tumors. Brachytherapy resulted in excellent disease control with significant reduction of dose to surrounding ocular structures compared to EBRT.

Intraoperative radiotherapy: review of techniques and results.

Intraoperative radiotherapy (IORT) is a technique that involves precise delivery of a large dose of ionising radiation to the tumour or tumour bed during surgery. Direct visualisation of the tumour bed and ability to space out the normal tissues from the tumour bed allows maximisation of the dose to the tumour while minimising the dose to normal tissues. This results in an improved therapeutic ratio with IORT. Although it was introduced in the 1960s, it has seen a resurgence of popularity with the introduction of self-shielding mobile linear accelerators and low-kV IORT devices, which by eliminating the logistical issues of transport of the patient during surgery for radiotherapy or building a shielded operating room, has enabled its wider use in the community. Electrons, low-kV X-rays and HDR brachytherapy are all different methods of IORT in current clinical use. Each method has its own unique set of advantages and disadvantages, its own set of indications where one may be better suited than the other, and each requires a specific kind of expertise. IORT has demonstrated its efficacy in a wide variety of intra-abdominal tumours, recurrent colorectal cancers, recurrent gynaecological cancers, and soft-tissue tumours. Recently, it has emerged as an attractive treatment option for selected, early-stage breast cancer, owing to the ability to complete the entire course of radiotherapy during surgery. IORT has been used in a multitude of roles across these sites, for dose escalation (retroperitoneal sarcoma), EBRT dose de-escalation (paediatric tumours), as sole radiation modality (early breast cancers) and as a re-irradiation modality (recurrent rectal and gynaecological cancers). This article aims to provide a review of the rationale, techniques, and outcomes for IORT across different sites relevant to current clinical practice.