Distant Failure Rates Research Articles

Ten-Year Experience in Implementing Single-Fraction Lung SBRT for Medically Inoperable Early-Stage Lung Cancer.

To review 10 years of using single-fraction lung stereotactic body radiation therapy (SF-SBRT) for medically inoperable peripheral early-stage lung cancer. An institutional review board-approved prospective lung SBRT data registry was surveyed until the end of December 2019 for all patients receiving SF-SBRT with minimum 6-month follow-up. Doses used were either 34 Gy or 30 Gy. Outcomes of interest included rates of local failure and overall survival (OS), as well as treatment-related toxicity graded per Common Terminology Criteria for Adverse Events version 3.0. A total of 229 patients met the study criteria. Patient characteristics included female sex (55%); median age, 74.6 years (range, 47-94); and median Karnofsky Performance Status 80 (range, 50-100). Tumor characteristics included median diameter, 1.6 cm (range, 0.7-4.1); median positron emission tomography standardized uptake value maximum 6.1 (range, 0.8-24.3); and 63.6% of patients biopsied. SF-SBRT dose was 34 Gy in 72.1% cases and 30 Gy in 27.9%, with patient and tumor characteristics balanced between cohorts. Overall median follow-up times for 30 Gy and 34 Gy were 36.7 and 17.2 months, respectively (P < .0001). At analysis, 55.9% patients were alive. Two (0.9%) patients developed grade 3 toxicities, and none had grade 4/5 toxicities. Grades 1 to 2 pneumonitis and chest wall toxicity were seen in 7% and 12.7% patients, respectively. Median overall survival was 44.1 months. Rates of 2-year local, nodal, and distant failure were 7.3%, 9.4%, and 12.2%, respectively. There were no significant differences in outcomes by dose. This is the largest institutional series to date reporting on SF-SBRT outcomes for medically inoperable peripheral early-stage lung cancer and the first to report on a decade's experience in implementing this schedule. Outcomes from this analysis are comparable to published results from 2 randomized trials and validate the use of this schedule in routine practice. In the absence of phase 3 trials, this study should encourage increased use of SF-SBRT for inoperable tumors.

P05.02 Does Non-Small Cell Lung Cancer Histologic Type Influence Outcomes with Single-Fraction Stereotactic Body Radiotherapy?

For early stage medically inoperable Non-Small Cell Lung Cancer (NSCLC) treated with fractionated stereotactic body radiotherapy (SBRT), when compared by biologically equivalent dose (BED) higher rates of local failure have been associated with squamous (SqC) histology compared to adenocarcinoma (AC) for equivalent BEDs. We sought to determine if histology outcomes differed when using single-fraction schedules (SF-SBRT). An IRB-approved prospective lung SBRT data registry was surveyed from 12/2009 till 12/2019 for all patients (pts) receiving SF-SBRT with minimum 6-month follow up with biopsy-proven AC or SqC excluding bronchoalveolar and “NSCLC not-otherwise specified” cases. Doses employed were either 34 Gy, planned per RTOG 0915, or 30 Gy, planned per RPCI-124407. Outcomes of interest included cumulative incidence rates of local (LF), nodal (NF), and distant (DF) failure and overall survival (OS), as well as treatment-related toxicity graded per CTCAE version 3.0. 229 SF-SBRT pts treated over 10 years had a 2-year LF rate of 7.28%. For this analysis 113 (49.3%) met study’s pathology criteria and had a 2-year LF rate of 8.41%. No association was seen between histology type and the SF-SBRT dose given: 65 pts (57.5%) had AC, of these 19 (29.2%) and 46 (70.8%) received 30 Gy and 34 Gy, respectively. Of 48 SqC pts (42.5%), 17 (35.4%) and 31 (64.6%) received 30 Gy and 34 Gy, respectively. Median follow up was 22.9 months. Patient characteristics were balanced between histologies. Median tumor size was 1.9 cm and 2.05 cm for AC and SqC, respectively. When comparing tumor features for each histology or by dose group, there were no significant (NS) differences including specifically tumor distance from the chest wall. Comparing total Ac vs. SqC cohorts, 2-year LF rates in % were 7.32 vs. 9.64, respectively (p=0.9805). In %, 2-year LF, NF, DF and OS rates for AC for 30 Gy and 34 Gy, respectively, were 10.84 vs. 6.41; 10.53 vs. 16.24; 15.79 vs. 13.04; 77.9 vs.71.2 (all NS). In %, 2-year LF, NF, DF, and OS rates for SqC for 30 Gy and 34 Gy, respectively, were 11.76 vs. 8.08; 5.88 vs. 17.94; 23.53 vs. 9.68; 70.6 vs. 77.1 (all NS). There were no grade 4/5 toxicities and NS differences in any other toxicity rate by histology or dose. For AC pts, pneumonitis rates were: 4 pts (6.2%) with grades 1-2; chest wall toxicity rates were: 7pts (10.8%) with grade 1-2 and 1 (1.5%) with grade 3. For SqC, pneumonitis rates were: 4 pts (8.3%) with grade 1-2 rates pneumonitis; chest wall toxicity rates were: 10 (20.8%) with grade 1-2 only. SqC LF rates are similar to AC’s with either SF-SBRT schedule and no significant differences were seen for other outcomes or for toxicity profiles by histology and dose. This suggests equivalent efficacy for SF-SBRT doses independent of NSCLC histology

Comparison of Clinical Efficacy of Neoadjuvant Chemoradiation Therapy Between Lower and Higher Radiation Doses for Carcinoma of the Esophagus and Gastroesophageal Junction: A Systematic Review

<h3>Purpose</h3> Neoadjuvant concurrent chemoradiation therapy (nCRT) plus surgery has been a standard treatment for locoregionally advanced esophageal cancer and carcinoma of the gastroesophageal junction (EC/GEJ), but the optimal preoperative radiation dose is still unclear. We performed this systematic review to explore the treatment efficacy and toxicity of different radiation dose levels and find an optimal dose‐fractionation strategy in EC/GEJ patients receiving nCRT. <h3>Methods and Materials</h3> Embase and Ovid Medline were searched for articles involving cases of operable squamous and adenocarcinoma of the esophagus and GEJ in which patients received nCRT up to a dose of 50.4 Gy in 28 fractions that were published until July 2019, when the search was performed. Physical dose distributions were converted to biologically equivalent doses (BEDs), which were described in units of gray (alpha/beta). Pooled rates of overall survival (OS), progression-free survival (PFS), failure patterns, and toxicities were compared between lower-dose radiation therapy (LDRT; BED ≤48.85 Gy₁₀) and higher-dose radiation therapy (HDRT; BED >48.85 Gy₁₀) for patients treated with nCRT. <h3>Results</h3> A total of 110 studies with 7577 EC/GEJ patients receiving nCRT were included in this pooled analysis. Both the PFS and OS rates of patients receiving LDRT were significantly higher than those of patients receiving HDRT. Patients receiving LDRT had improved safety regarding treatment-related adverse events and lower distant failure rates than patients receiving HDRT. Utilization of modern radiation therapy (RT) techniques, including 3-dimensional conformal RT and intensity modulated RT, was associated with improved oncologic outcomes compared with 2-dimensional methods. Subgroup analysis showed that EC/GEJ patients receiving conventionally fractionated radiation to a dose of 40.0 to 41.4 Gy in 20-23 fractions showed improved OS compared with those receiving radiation above this dose. <h3>Conclusions</h3> Based on the limited data, nCRT using BED ≤48.85 Gy₁₀ was suitable for locoregionally advanced, resectable EC/GEJ. A total dose of 40.0 to 41.4 Gy in 20 to 23 fractions using modern RT techniques might provide the optimal therapeutic ratio.

AGITG MASTERPLAN: a randomised phase II study of modified FOLFIRINOX alone or in combination with stereotactic body radiotherapy for patients with high-risk and locally advanced pancreatic cancer

BackgroundAmong patients with non-metastatic pancreatic cancer, 80% have high-risk, borderline resectable or locally advanced cancer, with a 5-year overall survival of 12%. MASTERPLAN evaluates the safety and activity of stereotactic body radiotherapy (SBRT) in addition to chemotherapy in these patients.Methods and designMASTERPLAN is a multi-centre randomised phase II trial of 120 patients with histologically confirmed potentially operable pancreatic cancer (POPC) or inoperable pancreatic cancer (IPC). POPC includes patients with borderline resectable or high-risk tumours; IPC is defined as locally advanced or medically inoperable pancreatic cancer. Randomisation is 2:1 to chemotherapy + SBRT (investigational arm) or chemotherapy alone (control arm) by minimisation and stratified by patient cohort (POPC v IPC), planned induction chemotherapy and institution. Chemotherapy can have been commenced ≤28 days prior to randomisation. Both arms receive 6 × 2 weekly cycles of modified FOLFIRINOX (oxaliplatin (85 mg/m2 IV), irinotecan (150 mg/m2), 5-fluorouracil (2400 mg/m2 CIV), leucovorin (50 mg IV bolus)) plus SBRT in the investigational arm. Gemcitabine+nab-paclitaxel is permitted for patients unsuitable for mFOLFIRINOX. SBRT is 40Gy in five fractions with planning quality assurance to occur in real time. Following initial chemotherapy ± SBRT, resectability will be evaluated. For resected patients, adjuvant chemotherapy is six cycles of mFOLFIRINOX. Where gemcitabine+nab-paclitaxel was used initially, the adjuvant treatment is 12 weeks of gemcitabine and capecitabine or mFOLFIRINOX. Unresectable or medically inoperable patients with stable/responding disease will continue with a further six cycles of mFOLFIRINOX or three cycles of gemcitabine+nab-paclitaxel, whatever was used initially. The primary endpoint is 12-month locoregional control. Secondary endpoints are safety, surgical morbidity and mortality, radiological response rates, progression-free survival, pathological response rates, surgical resection rates, R0 resection rate, quality of life, deterioration-free survival and overall survival. Tertiary/correlative objectives are radiological measures of nutrition and sarcopenia, and serial tissue, blood and microbiome samples to be assessed for associations between clinical endpoints and potential predictive/prognostic biomarkers. Interim analysis will review rates of locoregional recurrence, distant failure and death after 40 patients complete 12 months follow-up. Fifteen Australian and New Zealand sites will recruit over a 4-year period, with minimum follow-up period of 12 months.DiscussionMASTERPLAN evaluates SBRT in both resectable and unresectable patients with pancreatic ductal adenocarcinoma.Trial registrationAustralia New Zealand Clinical Trials Registry ACTRN12619000409178, 13/03/2019.Protocol version: 2.0, 19 May 2019

English

BACKGROUND Concurrent chemotherapy is a well-established treatment modality for locally advanced head and neck cancer. The concept of concurrent chemotherapy and radiation was introduced in an attempt to improve the local control and possibly influence the survival because of the high rate of local and distant failures observed with the combination of surgery and postoperative radiation. The relevance of this study was to assess the efficacy of our treatment and patience compliance and also study the effect in patients treated with cisplatin based concurrent chemo radiotherapy in advanced head and neck cancer. METHODS The prospective study was conducted in the Department of Radiotherapy, Government Medical college, Thrissur, Kerala comprising the newly diagnosed patients with locally advanced head &amp; neck cancers over one year. Conventional radiotherapy with a dose of 66 Gy in 33 fractions over 6.5 weeks was given concurrently with Inj cisplatin 100 mg / 2 IV every 3 weeks and periodically followed up for one year. RESULTS This study revealed that complete response rate was higher in 61 – 70 year age group compared to lower age groups. Complete response cases were slightly higher in T1 disease compared to higher stages. Regarding nodal status, complete response and DFS were more in N0 tumours and worst in N3 tumours. It was found that complete response rates were slightly higher in stage III than stage IV. Comparing the grade of the tumour, complete response cases were slightly higher in WD and MD compared to PD. Complete response rate and disease free survival (DFS) were slightly higher in cases who had more than two chemotherapy cycles compared to one cycle. CONCLUSIONS Concurrent chemo radiation was not well tolerated in our study group. Only 23.5 % patients were able to complete the planned treatment. The positive side was that complete response was found in about 79.4 % of study patients &amp; DFS at one year was 80 %. KEY WORDS Concurrent Chemo Radiation, Head and Neck Cancer, Cisplatin

Clinical Course of Breast Cancer Patients with Local-Regional Progression During Neoadjuvant Systemic Therapy.

Neoadjuvant systemic therapy (NST) is standard for locally advanced breast cancer and is now frequently considered for those with early-stage and node-positive disease. We aimed to evaluate the treatment course and outcomes in patients with disease progression during NST. Patients diagnosed with unilateral stage I-III breast cancer between 2005 and 2015 with documented local-regional progression while receiving NST, by clinical examination and/or imaging after two or more cycles of chemotherapy, were identified from a prospective database, stratified by receipt of surgery and outcomes analyzed. Of 6362 patients treated with NST during the study period, 124 (1.9%) developed disease progression. At a median live follow-up of 71 months, 23.4% were alive without disease and 70.2% had died from breast cancer. Median overall survival (OS) time for patients with progression was 26 months and median distant disease-free survival (DFS) was 14 months. Triple-negative breast cancer was associated with a higher likelihood of death (p<0.001) and development of distant metastasis (p=0.002). Among patients who had surgery (104, 89.3%), 40 (38.5%) developed local-regional recurrence, 67 (64.4%) developed distant metastasis, and 69 (66.3%) died from breast cancer. Median OS and median distant DFS in this subgroup was 31 and 16 months, respectively. High rates of local-regional and distant failure were seen following disease progression while receiving NST. This suggests aggressive tumor biology and the need to study novel systemic therapies. Poor survival outcomes despite surgical management highlight the importance of careful patient selection when considering operative intervention after progression while receiving NST.

Intensified Induction Chemotherapy in Locally Advanced Squamous Cell Carcinoma of the Anus-A Population-Based Experience from the Danish Anal Cancer Group.

Simple SummaryThe primary treatment modality for anal cancer is chemoradiotherapy, but patients with locally advanced disease (i.e., large tumors and/or involvement of regional lymph nodes) have a high risk of treatment failure. The use of chemotherapy prior to radiotherapy (induction chemotherapy) can potentially shrink the tumor and/or eradicate small cancer cells with metastatic potential, with a chance of a better outcome. With this paper, the authors present 20 years of nationwide experience with intensified induction chemotherapy in the treatment of locally advanced anal cancer, which indicates a role for further investigation in the most advanced cases.Locally advanced squamous cell carcinoma of the anus (LASCCA) has a poor prognosis with a high risk of treatment failure calling for intensified therapy. We present the long-term follow-up of a nationwide cohort of LASCCA treated with intensified induction chemotherapy (ICT). The study included patients with LASCCA (T3-4N0 or T1-4N+) treated with at least one cycle of ICT (cisplatin, ifosfamide, leucoverin, and 5-flourouracil) between 1998–2018. Data were retrospectively collected from medical records, and statistics were performed in STATA 16.1. In total, 166 patients with LASCCA were identified. Following ICT, 157 patients (95%) received primary curative treatment with either radiotherapy (70%), chemoradiotherapy (27%), or abdominal perineal resection (3%). The overall local tumor response rate after ICT was 76% with 20 (13%) achieving complete local tumor response. After the primary treatment, 123 patients (79%) obtained complete response, and 27 underwent salvage surgery due to persistent disease. The median follow-up time was 6 years, local and distant failure rates 22% and 13%, respectively. The 3- and 5-year disease-free survival rates were 70% and 67%, and the 3- and 5-year overall survival rates were 76% and 70%, respectively. Intensified ICT regimen could be a supplementary treatment option in the most advanced cases of LASCCA. Prospective randomized trials are needed to investigate this approach further.

Stereotactic radiosurgery for brain metastases from small cell lung cancer without prior whole-brain radiotherapy: A meta-analysis

ObjectivesAssess upfront Stereotactic radiosurgery (SRS) effectiveness for small cell lung cancer (SCLC) brain metastases (BM). Where possible, a comparison with whole-brain radiotherapy (WBRT) was performed. MethodsFollowing PRISMA and MOOSE guidelines, eligible studies were identified on Medline, Embase, Cochrane Library, and proceedings of annual meetings between inception and July 01, 2020. ResultsNine observational studies with 1638 patients were included. The median overall survival (OS) was 8.3 months (95% CI 7.1–9.5 months, I2 = 0%). OS rate at 12 months was 39% (95% CI 31–44%, I2 = 0%). The relative risk between SRS and WBRT for the OS at 12 months was 1.33 (95% CI 1.13–1.51, P = 0.0001). The projected OS for 6, 12, 18- and 24-months comparing SRS with WBRT was 67% vs. 57%, 39% vs. 29%, 22% vs. 15% and 15% vs 9%, favoring SRS (P < 0.001). The LC rate at 12 months was 93% (95% CI 91–94%, I2 = 0%). The distant brain failure rate (DBFR) at 12 months was 41% (95% CI 33–48%, I2 = 52%, P = 0.08). The SRS or WBRT as salvage treatment after upfront SRS was 32% and 19%, respectively. The freedom from neurologic death at 12 months was 87% (95% CI 84–89%). ConclusionBased on the pooling of a large sample of retrospective studies our meta-analysis suggests that for high selected SCLC patients with limited BM upfront SRS produces favorable lesion control and survival outcomes. These findings support the design of randomized clinical trial to confirm the role of SRS in this clinical scenario.

Single Fraction Frameless Stereotactic Radiosurgery on the Gamma Knife Icon for Patients With Brain Metastases: Time to Abandon the Frame?

PurposeThe latest version of the Gamma Knife, the Icon, allows for immobilization with a mask in lieu of the traditional frame during stereotactic radiosurgery. There have been some concerns regarding extent of immobilization during single fraction frameless treatment and potential effect on outcomes. As such, we reviewed outcomes in patients with brain metastases treated in a single fraction using either a frame or mask on the Gamma Knife Icon at our institution. Methods and MaterialsWe reviewed the records of 95 patients with a total of 374 metastases treated between May 2019 and January 2021. Thirty-nine patients (41%) were treated using the Leksell frame with the remainder being immobilized with a mask. The median number of metastatic lesions was 2 (1–20). The median prescription dose was 20 Gy (11.5–24 Gy). Odds ratios were generated to identify predictors of mask use. Kaplan-Meier analysis was used to calculate survival, local failure, and distant failure rates. Cox regression was used to identify predictors of survival. Propensity matching was used to account for indication bias. ResultsOf the 95 patients treated, 88 (93%) had follow-up with a median duration of 5 months (1–18). Frame utilization was more likely with 6 to 10 brain metastases. Median overall survival was not reached and was 70% and 60% at 6 and 12 months for the entire cohort, respectively. There was no significant difference in survival by immobilization method (P = .12). Six patients had local failure in 10 total lesions (3 patients in each group). After propensity matching the 12 month tumor local control was 96% and 85% for framed and frameless cases, respectively (P = .07). ConclusionsFrameless mask-based stereotactic radiosurgery using the Gamma Knife Icon is feasible and maintains the excellent local control seen with the use of the headframe.

Stereotactic ablative radiotherapy in operable stage I NSCLC patients: Long-term results of the expanded STARS clinical trial.

8506 Background: We published a pooled analysis of 2 randomized trials (STARS/ROSEL) that compared lobectomy with mediastinal lymph node dissection (L-MLND) vs stereotactic ablative radiotherapy (SABR) in operable stage I NSCLC. There were no significant differences in disease progression but significantly higher 3-year overall survival (OS) in the SABR arm (95% vs 79%). Owing to concerns regarding the small sample size (n = 58), short follow-up (3 years), and non-uniform use of video-assisted thoracoscopic surgery (VATS), we expanded the STARS protocol to a single-arm SABR trial with a protocol-specified comparison to a published, longitudinally-followed institutional cohort of stage IA NSCLC status post VATS L-MLND (n = 229). Methods: Inclusion criteria were stage IA NSCLC (≤3 cm, N0M0 and staged by PET/CT with EBUS) with Zubrod performance status (PS) 0-2, baseline FEV1 &gt; 40% and DLCO &gt; 40% and deemed operable by a multidisciplinary team. SABR utilized 4-dimensional CT simulation and volumetric image guidance; 54 Gy in 3 fractions were delivered to planning target volumes (PTVs) located peripherally, or 50 Gy in 4 fractions to more central PTVs. All patients were followed by chest CT every three months for the first two years, every 6 months for another three years, and then annually. Non-inferiority of SABR could be claimed if the 3-year OS was not lower than the historical VATS L-MLND cohort by more than 12%. We conducted a risk-factor matched comparison study of the primary outcome between the SABR and the historical VATS L-MLND. Results: The median follow-up among the 80 SABR patients was 61 months (range, 34-79 months). The OS and progression-free survival (PFS) were 91% (95% CI: 85̃98%) and 80% (95% CI: 72̃89%) at 3 years, and 87% (95% CI: 79̃95%) and 77% (95% CI: 68̃87%) at 5 years, respectively. The 5-year cumulative incidence rate counting death as competing risk was 6.3% (95% CI: 2.3̃13.2%) local, 12.5% (95% CI: 6.4̃20.8%) regional, and 8.8% (95% CI: 3.8̃16.2%) distant (any recurrence 17.6% (95% CI: 10.1̃26.7%)). The 5 year cumulative incidence rate of second lung primary was 6.9% (95% CI: 2.5̃14.6%). There were 1.3% grade 3 and no grade 4-5 toxicities. The propensity score matched (age, gender, tumor size, histology, PS) comparison of SABR vs VATS L-MLND revealed no significant differences in PFS (p = 0.063), lung cancer-specific survival (p = 0.075), or cumulative incidence rates of local (p = 0.54), regional (p = 0.97), or distant failures (p = 0.33). The SABR arm was associated with significantly higher OS (91% vs 82% at 3 years and 87% vs 72% at 5 years; p = 0.012 from log-rank test). The hazard ratio was 0.411 (95% CI: 0.193̃0.875; p = 0.021). Conclusions: The long-term OS and PFS of SABR is not inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains a promising approach for this population, but multidisciplinary management is strongly recommended. Clinical trial information: NCT02357992.

Does adjuvant chemoradiation benefit patients with lymph node-positive biliary tract cancer? A secondary analysis of SWOG S0809.

4104 Background: Biliary tract cancers are rare tumors with a median overall survival (OS) of 16 months for node-positive (N+) and 37 months for node-negative (N0) disease despite resection. Lymph node status is a known strong prognostic factor for local recurrence with an average estimated 2-year disease-free survival (DFS): 65.5% for N0 and 29.7% for N+ tumors. The Phase II Intergroup Trial S0809 showed that adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine improved OS in patients with extrahepatic cholangiocarcinoma (EHCC) and gallbladder cancer (GBC) compared to historical controls. We hypothesized that nodal status is a prognostic factor for local recurrence in this patient population who received adjuvant therapy. Methods: This analysis included patients with stage pT2-4, N+ or positive margin EHCC or GBC. Treatment included four cycles of gemcitabine (1,000 mg/m2 intravenously on days 1 and 8) and capecitabine (1,500 mg/m2 per day on days 1 to 14) every 21 days followed by concurrent capecitabine (1,330 mg/m2 per day) and radiotherapy (45 Gy to regional lymphatics; 52.5 to 59.4 Gy to tumor bed). S0809 patients who did not receive radiotherapy were excluded from analysis. Correlations between nodal status, resection margin, and other clinicopathological factors, patterns of recurrence and survival were analyzed, and Cox regression models were used to estimate the prognostic significance of nodal status. A Z-test was used to compare DFS rates between these patients and historical data. Results: A total of 69 patients [EHCC n = 46 (66%); GBCA n = 23 (33%)] were evaluated with a median age of 61.7 (26.1-80.6). The majority of N0 patients were female (17/24, 70.8%), whereas most N+ patients were male (25/45, 55.6%; p &lt; 0.04). Distribution of R0 (66.7%) and R1 (33.3%) resections was similar in the N0 and N+ groups. Thirty-four patients with EHCC had N+ disease (73.9%) compared with 11 patients with GBCA (47.8%, p = 0.03). Nodal status did not significantly impact OS (HR = 2.03, 95% CI 0.92-4.49, p = 0.08) or DFS (HR = 1.75, 95% CI 0.85-3.59, p = 0.13). Two-year OS was 70.6% for N0 and 60.9% for N+ disease (p = 0.11). Nodal status was not significantly associated with 2-year DFS: 62.5% for N0 and 49.8% for N+ (p = 0.20). N+ vs N0 tumors showed higher rates of distant failure (51.1% vs 25.0%, p &lt; 0.04), but similar local recurrence (17.8% vs 12.5%, p = 0.88). The observed 2-year DFS in patients with N+ tumors was significantly longer compared to the historical rate of 29.7% (p = 0.004). Conclusions: This combination adjuvant treatment regimen following curative resection for EHCC and GBCA provides favorable outcomes regardless of nodal status. These data suggest that adjuvant chemoradiation may positively impact local control in N+ patients. These findings need to be validated in future clinical trials. Clinical trial information: NCT00789958.

Improved Survival Outcomes in Medically Fit Patients With Early-Stage Non–Small-Cell Lung Cancer Undergoing Stereotactic Body Radiotherapy

IntroductionStereotactic body radiotherapy (SBRT) has been shown to result in excellent disease control rates for early-stage non–small-cell lung cancer (NSCLC). It remains unknown which patients would most benefit from SBRT in treating NSCLC. Patients and MethodsWe conducted a retrospective analysis of 346 patients treated with SBRT for early-stage NSCLC at 2 institutions (86 patients from City of Hope National Medical Center and 260 patients from The Newport Beach Radiosurgery Center/Hoag Hospital) from February 2010 to July 2019. The primary endpoint was overall survival (OS). The omnibus test of model coefficients was performed to study the associations between clinical factors and OS. Survival analyses were performed by the log-rank test and Cox proportional hazards regression. ResultsUnder the univariate analysis, variables associated with a decreased likelihood of death included age < 65 years (P = .040) and being a surgical candidate (P = .010). Multivariate analysis found that surgical candidates still had a significantly decreased likelihood of death compared to nonsurgical candidates (Hazard ratio 0.360, 95% confidence interval 0.153-0.848, P = .019). Median OS was significantly increased for surgical candidates versus nonsurgical candidates (83 vs 53 months, P = .017). The local failure rate was 9.1%, the locoregional failure rate was 12.7%, and the distant failure rate was 10.7%. ConclusionPatients who are deemed to be candidates for surgery have improved OS compared to those who are not when treated with SBRT. This raises the question of selection bias in trials comparing surgery with SBRT in NSCLC, as patients who are deemed to be surgical candidates and then go on to undergo surgery may have an inherent OS benefit.

Preoperative radiotherapy and total neoadjuvant therapy in locally advanced rectal cancer management: So far, so good

The treatment outcomes of locally advanced rectal cancer (LARC) have significantly improved in the last few decades due to the continuous evolution of multimodality management. However, the distant failure remains a concern leading to more cancer-related deaths. Conventionally, preoperative chemoradiotherapy followed by total mesolectal excision and adjuvant chemotherapy is the standard of care for LARC patients. However, noncompliance to adjuvant chemotherapy due to various factors leads to more distant failure rates. As an alternative to this, multiple approaches of total neoadjuvant therapy (TNT) were investigated over time, and multiple reports have shown promising results. This review highlights the evolution of the multimodality management approach to LARC patients, emphasising preoperative radiotherapy and TNT.

Substantial lymph-vascular space invasion (LVSI) as predictor of distant relapse and poor prognosis in low-risk early-stage endometrial cancer.

ObjectiveThe aim of this study is to analyze the prognostic role of lymph-vascular space invasion (LVSI), evaluated in a semi-quantitative fashion on prognosis of early stage, low risk endometrial cancer (EC).MethodsWe enrolled patients who underwent surgery for endometrial cancer between 2003 and 2018 in two referral cancer center. All patients had endometrioid EC, G1–G2, with myometrial invasion <50%, and no lymph-node involvement. LVSI was analyzed in a semi-quantitative way, according to a 3-tiered scoring system in absent, focal and substantial.ResultsAmong 524 patients, any positive LVSI was found in 57 patients (10.9%) with focal LVSI (n=35, 6.7%) and substantial LVSI (n=22, 4.2%). Substantial LVSI was associated to higher rate of G2 (p<0.001), myometrial infiltration (p=0.002) and greater tumor dimensions (p=0.014). Patients with substantial LVSI were more likely to receive adjuvant treatment (6.6% vs. 52.6%, p<0.001). The 5-year OS was 99.5% in patients with absent LVSI and 70.6% in those with substantial LVSI (p<0.001). The 5-year disease free survival (DFS) was 93.6% in patients with absent LVSI and 56.5% in those with substantial LVSI (p<0.001). The rate of distant failures increased from 1.8% for absent LVSI to 22.7% for substantial LVSI (p=0.002). In univariate analysis substantial LVSI was the strongest predictor of poor overall survival (hazard ratio [HR]=11.9, p=0.001). Multivariate analysis showed that substantial LVSI was an independent predictive factor of both recurrence (HR=5.88, p=0.001) and distant failure (HR=10.6, p=0.006).ConclusionsSubstantial LVSI represents the strongest independent risk factor for decreased survival and distant relapse, indicating a role for potential hematogenous dissemination.

Comparative Analysis of 5-Year Clinical Outcomes and Patterns of Failure of Proton Beam Therapy Versus Intensity Modulated Radiation therapy for Prostate Cancer in the Postoperative Setting

PurposeAlthough proton beam therapy (PBT) is a rapidly expanding modality to treat prostate cancer compared with intensity modulated radiation therapy (IMRT), data comparing disease control outcomes and patterns of failure in the postprostatectomy setting remain substantially limited. Methods and MaterialsAll patients who underwent postoperative IMRT or PBT to the prostate bed only at a single institution were included (2009-2017). Endpoints included biochemical failure (BF; using institutional and recent cooperative group trial definitions), local failure (LF), regional failure (RF), distant failure (DF), and all-cause mortality. A case-matched cohort analysis was performed using 3-to-1 nearest-neighbor matching; multivariable Cox proportional hazards modeling (MVA) estimated hazard ratios for disease-related outcomes by treatment modality. ResultsOf 295 men, 260 were matched (n = 65 PBT, 195 IMRT); after matching, only age at diagnosis (P < .01) significantly differed between cohorts. At a median follow-up of 59 months, BF (institution-defined), LF, RF, DF, and mortality rates were 45% (n = 29), 2% (n = 1), 9% (n = 6), 9% (n = 6), and 2% (n = 1) for PBT, and 41% (n = 80), 3% (n = 5), 7% (n = 13), 9% (n = 18), and 5% (n = 9) for IMRT (all P > .05). RT modality was not significantly associated with BF on MVA using institutional or cooperative group definitions (all P > .05), nor with LF (P = .82), RF (P = .11), DF (P = .36), or all-cause mortality (P = .69). Patterns of failure were qualitatively similar between cohorts (DF: bone, retroperitoneal nodes, lung). ConclusionsIn this single institution, case-matched analysis, PBT yielded similar long-term disease-related outcomes and patterns of failure to IMRT in the postprostatectomy setting.

Long-Term Results of NRG Oncology/RTOG 0321: A Phase II Trial of Combined High Dose Rate Brachytherapy and External Beam Radiation Therapy for Adenocarcinoma of the Prostate

To report the long-term outcome of patients with prostate cancer treated with external beam radiation therapy and high dose rate (HDR) brachytherapy from a prospective multi-institutional trial conducted by NRG Oncology/RTOG. Patients with clinically localized (T1c-T3b) prostate cancer without prior history of transurethral resection of prostate or hip prosthesis were eligible for this study. All patients were treated with a combination of 45 Gy in 25 fractions from external beam radiation therapy and one HDR implant delivering 19 Gy in 2 fractions. Adverse events (AE) were collected using Common Toxicity Criteria for Adverse Events, version 3. Cumulative incidence was used to estimate time to severe late gastrointestinal (GI)/genitourinary (GU) toxicity, biochemical failure, disease-specific mortality, local failure, and distant failure. Overall survival was estimated using the Kaplan-Meier method. One hundred and twenty-nine patients were enrolled from July 2004 to May 2006. AE data was available for 115 patients. Patients were National Comprehensive Cancer Network (NCCN) intermediate to very high risk. The median age was 68, T1c-T2c 91%, T3a-T3b 9%, PSA ≤10 70%, PSA >10 to ≤20 30%, GS 6 10%, GS 7 72%, and GS 8 to 10 18%. Forty-three percent of patients received hormonal therapy. At a median follow-up time of 10 years, there were 6 (5%) patients with grade 3 GI and GU treatment-related AEs, and no late grade 4 to 5 GI and GU AEs. At 5 and 10 years, the rate of late grade 3gastrointestinal and genitourinary AEs was 4% and 5%, respectively. Five- and 10-year overall survival rates were 95% and 76%. Biochemical failure rates per Phoenix definition at 5 and 10 years were 14% and 23%. The 10-year rate of disease-specific mortality was 6%. At 5 and 10 years, the rates of distant failure were 4% and 8%, respectively. The rates of local failure at 5 and 10 years were 2% at both time points. Combined modality treatment using HDR prostate brachytherapy leads to excellent long-term clinical outcomes in this prospective multi-institutional trial.

Gene Expression Signature for Distant Metastasis in Loco-regionally Advanced Head and Neck Squamous Cell Carcinoma

Nearly two-thirds of head and neck squamous cell cancer (HNSCC) present with loco-regionally advanced disease. Despite improved local tumor control from advances in surgery, chemotherapy, and radiotherapy, the rate of distant failure has remained relatively unchanged. Distant metastasis is known to be driven by a series of biological processes that occur in a subset of malignant tumors. We hypothesized that a gene expression signature measured from primary HNSCC tumors could identify patients at highest risk of developing distant metastasis (DM). Patients with Stage III or IV HNSCC in The Cancer Genome Atlas (TCGA) HNSCC dataset with new tumor events of distant metastasis on follow-up were matched with non-metastatic controls in a 1:2 ratio. Differential gene expression, pathway analysis, and bulk tissue cell-type deconvolution were applied to characterize alterations in regulatory programs within the tumor microenvironment. Adaptive LASSO-penalized regression, a form of supervised machine-learning, was used to develop a transcriptional risk score (RS) for distant metastasis. Area under the ROC curve (AUC) assessed performance of the model with ten-fold internal cross-validation. The RS was applied to a separate validation cohort from our institution, with distant metastasis free survival (DMFS) and overall survival as primary endpoints. A subgroup analysis was performed based on HPV status. Twenty-four HNSCC cases with distant metastases and forty-eight matched non-metastatic controls were identified in TCGA dataset. 1100 genes were differentially expressed, composed largely of genes involved in epithelial-stromal remodeling, and cytokine-immune interactions, annotated based on pathway analysis. Single-cell deconvolution revealed a significant increase in fibroblasts and T-cell dysregulation within the tumor microenvironment among DM cases. A 28-gene risk score was developed with an AUC of 0.938. In the validation cohort of 122 patients, high-RS patients had significantly shorter DMFS (hazard-ratio [HR] 9.0; 95% CI, 2.6-31.7, P<0.0001). Overall survival was inversely associated with metastatic cases; however, this did not achieve significance (HR 1.5; 95% CI, 0.9-2.3, P = 0.10). RS was superior to T- and N- stage for DM prognostication, and remained statistically significant after multivariable adjustment. RS had improved predictive value for DMFS in the HPV-negative subgroup (HR 20.8; 95% CI, 2.6-166, P = 0.004). We have identified and validated a group of genes that predict distant metastasis among loco-regionally advanced HNSCC tumors. This score offers a prognostic tool for detecting a group of HNSCC patients at high risk for DM who may benefit from intensified monitoring and/or treatment.

Ten-Year Experience in Implementing Single-Fraction Lung SBRT for Medically Inoperable Early Stage Lung Cancer

PURPOSE To review ten years of employing single-fraction lung SBRT (SF-SBRT) for medically inoperable peripheral early stage lung cancer. METHODS An IRB-approved prospective lung SBRT data registry was surveyed until the end of December 2019 for all patients receiving SF-SBRT with minimum 6-month follow up. Doses employed were either 34 Gy or 30 Gy. Outcomes of interest included rates of local failure (LF) and overall survival (OS), as well as treatment-related toxicity graded per CTCAE version 3.0. RESULTS 229 patients met study criteria. Patient characteristics included: female (55%); median age 74.6 years (range 47-94); median KPS 80 (range 50-100). Tumor characteristics included: median diameter 1.6 cm (range 0.7-4.1); median PET SUVmax 6.1 (range 0.8-24.3); 63.6% of patients biopsied. SF-SBRT dose was 34 Gy in 72.1% cases and 30 Gy in 27.9%, with patient and tumor characteristics balanced between cohorts. Overall median follow up times for 30 Gy and 34 Gy were 36.7 and 17.2 months, respectively (p <0.0001). At analysis, 55.9% patients were alive. Two (0.9%) patients developed grade 3 toxicities and none grade 4/5 toxicities. Grades 1-2 pneumonitis and chest wall toxicity were seen in 7% and 12.7% patients, respectively. Median overall survival was 44.1 months. Rates (in %) of 2-year local, nodal and distant failure were 7.3, 9.4 and 12.2, respectively. There were no significant differences in outcomes by dose. CONCLUSIONS This is the largest institutional series to date reporting on SF-SBRT outcomes for medically inoperable peripheral early stage lung cancer and the first to report on a decade's experience in implementing this schedule. Outcomes from this analysis are comparable to published results from two randomized trials and validate the utilization of this schedule in routine practice. In the absence of phase III trials, this study should encourage increased utilization of SF-SBRT for inoperable tumors.

Long Term Outcomes And Patterns Of Failure After Single Fraction Preoperative Radiosurgery For Brain Metastases

Postoperative (post-op) radiosurgery (SRS) after resection of brain metastases (BM) is associated with up to 30% risk of leptomeningeal disease (LMD). Approximately 60-70% of LMD is nodular pattern in this setting, which is thought to be associated with surgical tumor spillage. We have previously demonstrated that preoperative (pre-op) SRS is a feasible alternative to post-op SRS. Herein we report patterns of failure and long terms outcomes for patients (pts) treated with pre-op SRS. The records for pts with BM treated with pre-op SRS and planned surgical resection were reviewed. Pts with classically radiosensitive tumors, prior or planned adjuvant whole brain radiotherapy (WBRT), or no cranial imaging ≥ 1 month after surgery were excluded. Pre-op SRS dose was based on lesion size and was reduced approximately 10-20% from standard. No gross tumor volume (GTV) margin expansion was used. Surgery generally followed within 48 hours. Overall survival (OS) was estimated using the Kaplan-Meier method. Intracranial event rates were estimated using cumulative incidence with competing risk of death. Radiographic pattern of LMD was classified as classical “sugarcoating” (cLMD) vs. nodular (nLMD). The study cohort consisted of 141 pts with 150 lesions treated with single fraction pre-op SRS followed by planned surgery between 2005 – 2018. Most pts had a single BM (67%), underwent gross total resection (GTR, 96%), and had non-small cell lung cancer (41%). Median interval between pre-op SRS and surgery was 2 days, median SRS dose was 15 Gy, and median GTV volume was 8.4 cc (approximately equivalent to 2.5 cm diameter lesion). The 2-year cavity local recurrence (LR) rate was 23% overall and 20% in pts status post GTR. Five of 6 pts status post subtotal resection experienced LR. Multivariate analysis demonstrated GTR and renal cell histology as significantly associated with reduced risk of LR. SRS dose, lesion volume, and time between pre-op SRS and surgery were not significant. The 2-year LMD rate was 5%. Two of the 9 patients with LMD (22%) had nLMD while 78% had cLMD. The 2-year radiation necrosis (RN), symptomatic RN, and non-LMD distant brain failure rate was 7%, 4%, and 58%, respectively. Median OS was 19 months. Thirty-seven pts with 40 lesions had long term (≥2 years of cranial imaging) follow-up. In this subset, the 5-year cavity LR, symptomatic RN, and LMD rate was 25%, 8%, and 12%, respectively. Single fraction pre-op SRS is an effective treatment for surgically resected BM with low rates of cavity LR, RN, and LMD. LMD after pre-op SRS seems to be distinct from post-op SRS with a lower overall rate and lower proportion of nLMD pattern, which supports pre-op SRS sterilization of surgical tumor spillage. Outcomes in pts with long term imaging follow-up are consistent with the overall cohort. These data support further studies of pre-op SRS, including a randomized trial of pre-op vs. post-op SRS.

Gammaknife Radiosurgery for Small Cell Lung Cancer

Small cell lung cancer (SCLC) has traditionally been treated with whole brain radiation (WBRT) secondary to concerns about high rates of CNS failure. For other histologies, including non-small cell lung cancer, stereotactic radiosurgery (SRS) has been shown to have less toxicity and no detriment to overall survival. Evaluation of SCLC patients treated with SRS on a prospective SRS database. A total of 70 patients were evaluated. Forty-five had received previous WBRT and 25 were treated with SRS alone and had not had any previous WBRT. The median number of treated CNS mets was 4 (range 1 to 29). Median follow-up for all patients was 116 days. Median survival was 149 days. For patients that had not had previous WBRT, the one-year distant failure rate was 52% with 7 distant CNS failures, median time to distant failure was 467 days. For all patients there were 2 local failures. There were no differences in survival between patients treated with SRS alone versus having previous WBRT. Number of treated CNS mets was associated with different CNS control rates with a one-year control rate of 40% for 1-2 mets, 30% for 3-5 mets and no patients without CNS failure with more than 5 treated CNS mets at one year. Systemic disease control was not associated with difference in CNS control. SCLC has a higher likelihood of CNS recurrence when treated with SRS alone but still appears to be an effective option, especially for patients with < 5 CNS mets.