Freedom From Local Recurrence Research Articles

High dose proton and photon-based radiation therapy for 213 liver lesions: a multi-institutional dosimetric comparison with a clinical perspective

BackgroundStereotactic radiotherapy (SRT) and Proton therapy (PT) are both options in the management of liver lesions. Limited clinical-dosimetric comparison are available. Moreover, dose-constraint routinely used in liver PT and SRT considers only the liver spared, while optimization strategies to limit the liver damaged are poorly reported.MethodsPrimary endpoint was to assess and compare liver sparing of four contemporary RT techniques. Secondary endpoints were freedom from local recurrence (FFLR), overall survival (OS), acute and late toxicity. We hypothesize that Focal Liver Reaction (FLR) is determined by a similar biologic dose. FLR was delineated on follow-up MRI. Mean C.I. was computed for all the schedules used. A so-called Fall-off Volume (FOV) was defined as the area of healthy liver (liver-PTV) receiving more than the isotoxic dose. Fall-off Volume Ratio (FOVR) was defined as ratio between FOV and PTV.Results213 lesions were identified. Mean best fitting isodose (isotoxic doses) for FLR were 18Gy, 21.5 Gy and 28.5 Gy for 3, 5 and 15 fractions. Among photons, an advantage in terms of healthy liver sparing was found for Vmat FFF with 5mm jaws (p = 0.013) and Cyberknife (p = 0.03). FOV and FOVR resulted lower for PT (p < 0.001). Three years FFLR resulted 83%. Classic Radiation induced liver disease (RILD, any grade) affected 2 patients.ConclusionsCyberknife and V-MAT FFF with 5mm jaws spare more liver than V-MAT FF with 10 mm jaws. PT spare more liver compared to photons. FOV and FOVR allows a quantitative analysis of healthy tissue sparing performance showing also the quality of plan in terms of dose fall-off.

Definitive radiotherapy in patients with clinical T1N0M0 esophageal squamous cell carcinoma: A multicenter retrospective study (KROG 21–10)

PurposeTo assess the failure pattern and analyze the treatment scheme of definitive radiation therapy (RT) for T1N0M0 esophageal squamous cell carcinoma (ESCC). MethodsWe performed a multi-institutional retrospective analysis in T1N0M0 ESCC patients who underwent definitive RT from 2010 to 2019. Patterns of failure were demonstrated as in-, and out-field locoregional, and distant metastasis. In the analysis, freedom-from locoregional recurrence (FFLRR) and their association with clinicopathologic factors were evaluated. Propensity score matching in cT1b patients was done. Results168 patients were included with a median follow-up of 34.0 months, and 26 cT1a, 116 cT1b disease. The rates of 3-year all and locoregional recurrence for cT1a were 30.5% and 24.1% and those for cT1b were 27.1% and 25.9%, respectively. Among 116 cT1b patients, 69 patients received elective nodal irradiation (ENI) and 47 received involved field irradiation (IFI). After propensity score matching, the 3-year FFLRR rate was 84.5%. There was no difference between ENI and IFI in FFLRR (P = 0.831) and OS (P = 0.525). The 3-year FFLRR was 83.8% (95% Confidence interval (CI), 61.8–93.8%) in IFI group and 85.3% (95% CI, 65.1–94.3%) in ENI group. In multivariate analysis, concurrent chemotherapy use was marginally associated with FFLRR (Hazard ratio, 0.16; P = 0.064). ConclusioncT1a patients who cannot receive endoscopic resection showed similar failure rates as cT1b patients, questioning the staging accuracy and raised the need for thorough treatment like chemoradiotherapy. In cT1b patients, IFI with 50 to 60 Gy and concurrent chemotherapy could be reasonable.

Anal squamous cell carcinoma: Impact of radiochemotherapy evolution over years and an explorative analysis of MRI prediction of tumor response in a mono-institutional series of 131 patients.

Radiochemotherapy (RCHT) for the treatment of anal squamous cell carcinoma (ASCC) has evolved dramatically, also thanks to intensity-modulated RT (IMRT) and 3D image guidance (3D IGRT). Despite most patients presenting fair outcomes, unmet needs still exist. Predictors of poor tumor response are lacking; acute toxicity remains challenging; and local relapse remains the main pattern of failure. Between 2010 and 2020, ASCC stages I-III treated with 3D conformal radiotherapy or IMRT and CDDP-5FU or Mytomicine-5FU CHT were identified. Image guidance accepted included 2D IGRT or 3D IGRT. The study endpoints included freedom from locoregional recurrence (FFLR), colostomy free survival (CFS), freedom from distant metastasis (FFDM), overall survival (OS), and acute and late toxicity as measured by common terminology criteria for adverse events (CTCAE) version 5.0. An exploratory analysis was performed to identify possible radiomic predictors of tumor response. Feature extraction and data analysis were performed in Python™, while other statistics were performed using SPSS® v.26.0 software (IBM®). A total of 131 patients were identified. After a median FU of 52 months, 83 patients (63.4%) were alive. A total of 35 patients (26.7%) experienced locoregional failure, while 31 patients (23.7%) relapsed with distant metastasis. Five year FFLR, CFS, DMFS and PS resulted 72.3%, 80.1%, 74.5% and 64.6%. In multivariate analysis, 2D IGRT was associated with poorer FFLR, OS, and CFS (HR 4.5, 4.1, and 5.6, respectively); 3DcRT was associated with poorer OS and CFS (HR 3.1 and 6.6, respectively). IMRT reduced severe acute gastro-intestinal (GI) and severe skin acute toxicity in comparison with 3DcRT. In the exploratory analysis, the risk of relapse depended on a combination of three parameters: Total Energy, Gray Level Size Zone Matrix's Large Area High Gray Level Emphasis (GLSZM's LAHGLE), and GTV volume. Advances in radiotherapy have independently improved the prognosis of ASCC patients over years while decreasing acute GI and skin toxicity. IMRT and daily 3D image guidance may be considered standard of care in the management of ASCC. A combination of three pre-treatment MRI parameters such as low signal intensity (SI), high GLSZM's LAHGLE, and GTV volume could be integrated in risk stratification to identify candidates for RT dose-escalation to be enrolled in clinical trials.

Positive margins matter regardless of subsequent resection findings

ObjectivesIn the resection of oral cavity squamous cell carcinoma (OCSCC), an intraoperative positive surgical margin (SM) communicated to the head and neck surgeon necessitates further resection of the area of identified involvement to achieve a final negative SM. The prognostic implication of initial positive SM when the final SM is negative is understudied. Materials and MethodsWe retrospectively reviewed 249 patients with non-metastatic (stage I–IVB) OCSCC who underwent a resection from 2010 to 2019 to assess the prognostic impact of an initial positive SM. Chi-squared analysis was used to evaluate the association between an initial positive SM and clinicopathologic parameters. A Kaplan–Meier analysis was performed to estimate patient outcomes with Cox regression analysis used to determine absolute hazards. ResultsAt a median follow-up of 28.4 months, the 2-year freedom from local recurrence (FFLR), disease-free survival (DFS), and overall survival (OS) rates were 82.1%, 63.5%, and 78.5%, respectively. Fifty patients (20.1%) had an initial positive SM which was revised to a negative SM on frozen and permanent sections by resecting further tissue while 12 patients (4.8%) had a final positive SM. An initial positive SM was independently associated with a worse FFLR (HR: 2.696, p = 0.004), DFS (HR: 1.57, p = 0.044), and OS (HR: 1.72, p = 0.029). ConclusionAn initial positive SM is independently associated with worse disease control and patient survival. A positive SM may be a surrogate for diffusely infiltrative disease as further malignancy identified on the re-resection specimen was associated with worse outcomes.

Impact of lymph node ratio on survival and recurrence outcomes in oral squamous cell carcinoma

Growing evidence supports the lymph node ratio (LNR) as a prognostic factor for survival in patients with oral squamous cell carcinoma (OSCC). However, there is a lack of data regarding its association with recurrence outcomes. Data on 163 patients with OSCC who underwent primary surgical treatment at a tertiary centre between January 2009 and December 2015 were collected retrospectively and analysed. Receiver operating characteristic curve analysis was performed to determine optimal cut-off values for the survival analyses. Survival endpoints were disease progression/relapse for disease-free time (DFT), freedom from loco-regional recurrence (FLR), and freedom from distant metastasis (FDM), and as death from any cause for overall survival (OS). Patients with a lower LNR were found to have significantly superior DFT (LNR < 14%, P < 0.001), FLR (LNR <14%, P < 0.001), FDM (LNR <16%, P = 0.004), and OS (LNR <7%, P = 0.004) in comparison to patients with a higher LNR. LNR is a good predictor of survival and recurrence outcomes in OSCC.

Salvage brachytherapy for multiply recurrent metastatic brain tumors: A matched case analysis.

BackgroundPatients with recurrent brain metastases who have exhausted external radiation options pose a treatment challenge in the setting of advances in systemic disease control which have improved quality of life and survival. Brachytherapy holds promise as salvage therapy given its ability to enforce surgical cytoreduction and minimize regional toxicity. This study investigates the role of salvage brachytherapy in maintaining local control for recurrent metastatic lesions.MethodsWe retrospectively reviewed our institution’s experience with brachytherapy in patients with multiply recurrent cerebral metastases who have exhausted external radiation treatment options (14 cases). The primary outcome of the study was freedom from local recurrence (FFLR). To capture the nuances of tumor biology, we compared FFLR achieved by brachytherapy to the preceding treatment for each patient. We further compared the response to brachytherapy in patients with lung cancer (8 cases) against a matched cohort of maximally radiated lung brain metastases (10 cases).ResultsBrachytherapy treatment conferred significantly longer FFLR compared to prior treatments (median 7.39 vs 5.51 months, P = .011) for multiply recurrent brain metastases. Compared to an independent matched cohort, brachytherapy demonstrated superior FFLR (median 8.49 vs 1.61 months, P = .004) and longer median overall survival (11.07 vs 5.93 months, P = .055), with comparable side effects.ConclusionBrachytherapy used as salvage treatment for select patients with a multiply recurrent oligometastatic brain metastasis in the setting of well-controlled systemic disease holds promise for improving local control in this challenging patient population.

Risk groups of laryngeal cancer treated with chemoradiation according to nomogram scores – A pooled analysis of RTOG 0129 and 0522

ObjectivesTo develop nomograms predicting overall survival (OS), freedom from locoregional recurrence (FFLR), and freedom from distant metastasis (FFDM) for patients receiving chemoradiation for laryngeal squamous cell carcinoma (LSCC). Material and methodsClinical and treatment data for patients with LSCC enrolled on NRG Oncology/RTOG 0129 and 0522 were extracted from the RTOG database. The dataset was partitioned into 70% training and 30% independent validation datasets. Significant predictors of OS, FFLR, and FFDM were obtained using univariate analysis on the training dataset. Nomograms were built using multivariate analysis with four a priori variables (age, gender, T-stage, and N-stage) and significant predictors from the univariate analyses. These nomograms were internally and externally validated using c-statistics (c) on the training and validation datasets, respectively. ResultsThe OS nomogram included age, gender, T stage, N stage, and number of cisplatin cycles. The FFLR nomogram included age, gender, T-stage, N-stage, and time-equivalent biologically effective dose. The FFDM nomogram included age, gender, N-stage, and number of cisplatin cycles. Internal validation of the OS nomogram, FFLR nomogram, and FFDM nomogram yielded c = 0.66, c = 0.66 and c = 0.73, respectively. External validation of these nomograms yielded c = 0.59, c = 0.70, and c = 0.73, respectively. Using nomogram score cutoffs, three risk groups were separated for each outcome. ConclusionsWe have developed and validated easy-to-use nomograms for LSCC outcomes using prospective cooperative group trial data.

Systemic inflammation is associated with inferior disease control and survival in stage III non-small cell lung cancer

BackgroundThe systemic immune-inflammation index (SII) correlates with patient survival in various types of solid malignancies, including non-small cell lung cancer (NSCLC). However, limited information is available on the prognostic implication and disease-specific survival of SII in patients undergoing definitive chemoradiation therapy (CRT) for stage III NSCLC.MethodsWe retrospectively reviewed 125 patients who underwent curative intent CRT for stage III NSCLC with sufficient laboratory assessment from 2010–2019. SII was calculated at the time of diagnosis as platelet count × neutrophil count/lymphocyte count. Chi-squared analysis was used to compare categorical variables. A Kaplan-Meier analysis was performed to estimate progression-free survival (PFS), disease specific survival (DSS), and overall survival (OS) rates, with Cox regression used to determine absolute hazards.ResultsAt a median follow-up of 19.7 months, 5-year OS, DSS, and PFS rates were 22.6%, 30.9%, and 13.4%, respectively. A low SII (<1,266) at diagnosis was independently associated with an improved OS (HR: 0.399, 95%, CI: 0.247–0.644, P<0.001), DSS (HR: 0.383, 95%, CI: 0.228–0.645, P<0.001), and PFS (HR: 0.616, 95%, CI: 0.407–0.932, P=0.022). We did not detect an association between SII and freedom from recurrence (FFR), freedom from locoregional recurrence (FFLRR), or freedom from distant recurrence (FFDR). NSAID (1,483.4 vs. 2,302.9, P=0.038) and statin usage (1,443.9 vs. 2,201.7, P=0.046) were associated with a lower SII while COPD exacerbations (2,699.7 vs. 1,573.7, P=0.032) and antibiotic prescriptions (2,384.6 vs. 1,347.9, P=0.009) were associated with an elevated SII. These factors were not independently associated with improved survival outcomes.ConclusionsLow SII scores were independently associated with improved OS, DSS, and PFS rates in patients with stage III NSCLC undergoing definitive CRT. NSAIDs and statin usage may be associated with lower SII at diagnosis of NSCLC. This study suggests that SII may be an effective prognostic indicator of patient mortality. Further investigation of the therapeutic potential of these agents in patients with an elevated SII in this setting may be warranted.

Tumor volume: a new prognostic factor of oncological outcome of localized clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (ccRCC) is one of the most frequent malignancies; however, the present prognostic factors was deficient. This study aims to explore whether there is a relationship between tumor volume (TV) and oncological outcomes for localized ccRCC.MethodsSeven hundred forty-nine localized ccRCC patients underwent surgery in our hospital. TV was outlined and calculated using a three-dimensional conformal radiotherapy planning system. We used receiver operating characteristic (ROC) curves to identified optimal cut-off value. Univariable and multivariable Cox regression models were performed to explore the association between TV and oncological outcomes. Kaplan-Meier method and log-rank test were used to estimate survival probabilities and determine the significance, respectively. Time-dependent ROC curve was utilized to assess the prognostic effect.ResultsLog rank test showed that higher Fuhrman grade, advanced pT classification and higher TV were associated with shortened OS, cancer-specific survival (CSS), freedom from metastasis (FFM) and freedom from local recurrence (FFLR). multivariable analysis showed higher Fuhrman grade and higher TV were predictors of adverse OS and CSS. The AUC of TV for FFLR was 0.822. The AUC of TV (0.864) for FFM was higher than that of pT classification (0.818) and Fuhrman grade (0.803). For OS and CSS, the AUC of TV was higher than that of Fuhrman grade (0.832 vs. 0.799; 0.829 vs 0.790).ConclusionsHigh TV was an independent predictor of poor CSS, OS, FFLR and FFM of localized ccRCC. Compared with pT classification and Fuhrman grade, TV could be a new and better prognostic factor of oncological outcome of localized ccRCC, which might contribute to tailored follow-up or management strategies.

Prognostic significance of lymph node ratio after neoadjuvant chemoradiation therapy for esophageal squamous cell carcinoma

PurposeWe retrospectively evaluated the prognostic significance of lymph node ratio (LNR) in patients with esophageal squamous cell carcinoma who underwent neoadjuvant concurrent chemoradiation therapy (NCRT) followed by surgery.Materials and MethodsIn total, 270 patients who underwent NCRT followed by surgery between August 2005 and December 2015 were included. They were divided into three groups: LNR 0 (n = 196), LNR low (0 < LNR ≤ 0.1; n = 63), and LNR high (>0.1; n = 11). The primary endpoint was overall survival (OS), and the secondary endpoints were freedom from local recurrence (FFLR), distant metastasis-free survival (DMFS), and disease-free survival (DFS). ResultsThe median number of retrieved lymph nodes per patient was 33. Pathologically, 74 patients had positive lymph nodes. The median follow-up duration was 36.1 months, and the median survival period was 68.4 months. There was a significant correlation between LNR and the number of positive lymph nodes (correlation coefficient = 0.763, p < 0.001). There was a substantial difference in the OS among the LNR groups, with 2-year survival rates of 79.0%, 54.0%, and 9.1% in the LNR 0, LNR low, and LNR high groups, respectively (p < 0.001). A marked decrease in FFLP, DMFS, and DFS was observed with the increasing LNR. In subgroup analysis, the survival results of patients with clinically positive lymph node were similar from those of entire cohort.ConclusionLNR is a significant prognostic factor in patients with esophageal squamous cell carcinoma who underwent NCRT followed by surgery. Additional treatment and closer follow-up would be necessary for patients with a high LNR.

Association of Interim FDG-PET During Chemoradiation for Anal Squamous Cell Carcinoma with Recurrence: An Updated Analysis

Concurrent chemoradiation (CRT) is standard of care for anal squamous cell carcinoma (SCC), and there is ongoing interest in identifying prognostic markers to better stratify patients. Imaging metrics derived from 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) before and after CRT correlate with clinical outcomes in anal SCC. Intra-treatment PET has been shown to have predictive value in numerous other disease sites. However, no studies have evaluated interim PET as a potential prognostic tool for anal SCC. This prospective, hypothesis-generating pilot study investigates the relationship between interim PET during CRT for anal SCC and clinical outcomes. This analysis updates previously published results after additional patient accrual and follow-up. From June 2012 to January 2020, 40 patients with anal cancer were enrolled. Patients underwent PET/CT at simulation and during CRT after ∼30 Gy (range 28.8-41.4 Gy). Previously described PET parameters were calculated including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for the primary site. MTV and TLG were calculated based on 40% SUVmax (MTV40, TLG40) and SUV2.5 (MTV2.5, TLG2.5) thresholds. For each parameter, the pretreatment, interim, and relative change were analyzed. Freedom from locoregional recurrence (FFLR) was estimated using the Kaplan-Meier method. Association of PET parameters with FFLR was analyzed using single-predictor Cox regression models. Of 40 patients enrolled, 31 were eligible for analysis. Patients were excluded with non-squamous cell histology (adenocarcinoma, melanoma) (3 patients), recurrent anal cancer (1 patient), no gross primary disease at time of simulation (1 patient), and studies not performed due to treatment toxicity or patient choice (4 patients). Median age was 58.2 years (range 42.8-92.3). Twenty-five patients (80.6%) were female. Clinical stage was T3-4 in 15 patients (48.4%), and 15 patients (48.4%) were node-positive. Twenty patients (64.5%) received both planned doses of mitomycin C. Median follow-up was 3.9 years. There were 4 locoregional recurrences, 6 distant failures, and 6 deaths. Interim SUVmax (HR 4.6 [95% CI 1.03-20.96]), MTV2.5 (1.3 [1.02-1.61]), TLG2.5 (1.1 [1.01-1.14]), and TLG40 (1.2 [1.01-1.40]) were statistically associated with FFLR. There were no correlations detected between pretreatment PET parameters or change in PET parameters from pretreatment to interim PET and FFLR. In this prospective pilot study, metrics from FDG-PET acquired during CRT for anal SCC were significantly associated with FFLR. Interim PET may be a useful imaging biomarker to identify treatment responders and non-responders in an effort to personalize therapy. Additional patient accrual and analyses for this study are ongoing.

Factors Impacting Differential Outcomes in the Definitive Radiation Treatment of Anal Cancer Between HIV-Positive and HIV-Negative Patients.

Anal squamous cell carcinoma (ASCC) is uncommon, yet seen more frequently in the setting of the human immunodeficiency virus (HIV). Chemoradiotherapy is the definitive modality of treatment for patients with ASCC; this study examines factors impacting clinical outcomes in a large cohort of HIV-positive and HIV-negative patients. A retrospective review was conducted of patients treated for nonmetastatic ASCC at a single institution between 2005 and 2018. Freedom from local recurrence (FFLR), freedom from distant metastasis, and overall survival (OS) were calculated using the Kaplan-Meier method, and univariate and multivariate analysis were performed using the Cox proportional hazards model. During the study period, 111 patients initiated definitive treatment for ASCC. Median age of the entire cohort was 56.7 years (interquartile range, 51.5-63.5), with 52 patients (46.8%) being HIV-positive. At median follow-up of 28.0 months, the 2- and 5-year FFLR were 78.2% (95% confidence interval [CI], 70.4-87.0) and 74.6% (95% CI, 65.8-84.5), respectively. Multivariate analysis revealed time from diagnosis to treatment initiation (median, 8 weeks; hazard ratio, 1.06; 95% CI, 1.03-1.10) to be significantly associated with worse FFLR and OS. HIV-positive patients had a trend toward worse FFLR (log-ranked p = .06). For HIV-positive patients with post-treatment CD4 less than 150 cells per mm3 , there was significantly worse OS (log-ranked p = .015). A trend toward worse FFLR was seen in HIV-positive patients, despite similar baseline disease characteristics as HIV-negative patients. Worse FFLR and OS was significantly associated with increased time from diagnosis to treatment initiation. Poorer OS was seen in HIV-positive patients with a post-treatment CD4 count less than 150 cells per mm3 . Human immunodeficiency virus (HIV)-positive patients with anal squamous cell carcinoma can represent a difficult clinical scenario. Definitive radiation with concurrent chemotherapy is highly effective but can result in significant toxicity and a decrease in CD4 count that could predispose to HIV-related complications. As HIV-positive patients have largely been excluded from prospective clinical trials, this study seeks to provide greater understanding of their outcomes with radiation therapy, potential predictors of worse local control and overall survival, and those most at risk after completion of treatment.

Improved Tumor Control Related to Radiotherapy Technological Development for Hypopharyngeal Cancer.

Squamous cell carcinoma of the hypopharynx (SCCHP) is associated with worse survival compared to other head and neck subsites. This report quantifies the impact of technological improvements in radiotherapy (RT) on outcomes over 6 decades. Patients with SCCHP receiving curative-intent treatment between 1962 and 2015 were retrospectively reviewed. Kaplan-Meier analyses of freedom from local recurrence (FFLR), progression-free survival (PFS), and overall survival (OS) were compared across treatment eras and radiation techniques. Multivariable Cox proportional hazards modeling was performed to specify the effect of RT technique. One hundred thirty-four patients had a median follow-up of 17 months (IQR = 9-38). There were no differences in staging or use of surgery over time, but use of chemotherapy concurrent with RT increased (P < .001) beginning in the 2000s. The 24-month FFLR using two-dimensional RT (2D-RT), three-dimensional conformal RT (3D-CRT), and intensity-modulated RT (IMRT) was 52%, 55%, and 80%, respectively; 24-month PFS was 39%, 46%, and 73%, respectively; and 24-month OS was 27%, 40%, and 68%, respectively. OS (P = .01), PFS (P = .03), and FFLR (P = 0.02) were improved with IMRT over 2D-RT, and FFLR appeared to be improved over 3D-CRT (P = .06). Controlling for chemotherapy use and other major variables, IMRT produced a strong influence over FFLR (adjusted hazard ratio [HR] = 0.2, 95% confidence interval [CI]: 0.0-1.2, P = .08) and a benefit in OS (adjusted HR = 0.1, 95% CI: 0.0-0.4, P = .005). Across 6 decades, patient and tumor characteristics remained similar whereas use of chemoradiation increased and IMRT was adopted. The introduction of IMRT was associated with improved FFLR, PFS, and OS, and a reduction in acute toxicity as compared to earlier radiation technologies. 4 Laryngoscope, 131:E452-E458, 2021.

Understanding the Utility of PET-Volume Metrics in Prognostication of Local Recurrence and Treatment Response in Anal Squamous Cell Carcinoma

Anal squamous cell carcinoma is an uncommon malignancy primarily treated with radiation therapy and concurrent chemotherapy. The use of pre-treatment PET/CT has become common for target delineation and assessment of disease extent, with traditional PET metrics, such as SUVmax, being prognostic of progression free survival (PFS) and overall survival (OS). This study sought to understand the significance of quantitative PET metrics for pre and post-treatment prognostication of treatment response in anal cancer. Databases of a single institution were retrospectively reviewed for patients treated definitively for anal squamous cell carcinoma between 2005 and 2017. Patients were required to have a pre-treatment PET/CT, and a subset of patient had a post-treatment PET/CT within 2-6 months of completion of treatment. Relevant clinical data was extracted for evaluation of baseline patient characteristics, treatment parameters, freedom from local recurrence (FFLR), and OS. PET data was analyzed for metabolic tumor volume (MTV2.5), defined as the extent of tumor with SUV > 2.5, and total lesion glycolysis (TLG2.5), defined as the MTV multiplied by the SUVmean. Both the absolute and relative change in quantitative PET parameters were assessed for association with FFLR, PFS, and OS using univariate and multivariate Cox regression models. With a median follow up of 25 months, 75 patients had a pre-treatment PET/CT, and 59 patients underwent a 2 to 6-month post-treatment PET/CT. The cohort consisted of 49 males and 26 females, 37 were HIV positive and 38 HIV negative, with a median age of 57.4 years (IQR: 50.4-65.5). The 24-month freedom from LR, PFS, and OS were 79.8% (95% CI: 70.9-89.9), 75.4% (95% CI: 65.8-86.4), and 84.2% (95% CI: 75.5-93.8) respectively. On univariate analysis of pre-treatment PET metrics both MTV2.5 and TLG2.5 were significant for FFLR, and PFS. On multivariate analysis only MTV2.5 remained significant for FFLR and PFS with HR 1.017 (95% CI: 1.002-1.033) and 1.018 (95% CI: 1.004-1.032) respectively. On univariate and multivariate analysis of post-treatment PET/CT, MTV2.5 was the most significant metric for FFLR and PFS with HR 1.115 (95% CI: 1.030-1.208) p=0.007, and HR 1.086 (95% CI: 1.012-1.166) p=0.021 respectively. There was no significant association between the relative changes of the quantitative PET metrics and FFLR or PFS. No significant association between these metrics was established for OS. Quantitative PET metrics for anal cancer can be useful for pre-treatment prognostication and post-treatment assessment of disease response. MTV2.5 demonstrated itself to be the most robust metric assessed in this study. Use of these measurements prior to treatment could allow for personalized planning based on patient risks, and in the post treatment setting could stratified patients to intensified surveillance regimens or adjuvant immunotherapy to improve disease outcomes.

Risk of Vertebral Fracture and Local Recurrence after Palliative Spine Stereotactic Body Radiotherapy (SBRT)

Bony metastases to the spinal column are a common manifestation of cancer that can lead to significant morbidity. Although stereotactic body radiotherapy (SBRT) has been increasingly employed as an effective treatment for spinal column metastases, the optimal dosimetric parameters to maximize disease control and minimize toxicity remain unclear. Thus, we sought to understand the dosimetric factors associated with pain palliation, local control, and toxicity with spinal column SBRT for bone metastases. Patients from a single institution treated with spine SBRT between 2010 and 2017 for metastatic disease had electronic records retrospectively reviewed. Baseline patient characteristics, treatment parameters including spinal cord dose, and follow-up data were collected. Treatment-related outcomes including freedom from fracture rate (FFFR), myelitis, and freedom from local recurrence (FFLR) were assessed. Statistical analysis of categorical variables was done with Fischer’s exact test and continuous variables with Wilcoxon rank sum, with the threshold for significance of all tests at a p-value <0.05. During the study period 96 patients were treated with SBRT to 137 sites in the cervical, thoracic, and lumbar spine, with a median clinical follow up of 15 months per lesion (IQR: 4-33). There were 79, 19, and 39 treatments with 1, 3, and 5 fractions, with dose ranges of 14-20 Gy, 24-27 Gy, and 30-40 Gy, respectively. Eight lesions were treated post-operatively, 19 lesions were treated with SBRT as re-irradiation, with the rest of the lesions undergoing SBRT as the first treatment of choice. Pain was a presenting symptom at 104 of treated sites, and the median pain score was 3/10 (IQR: 1-7). On post treatment clinical follow up approximately 2-4 weeks after treatment, 89% of patients noted improved pain, with a median decrease in score of 3 points. FFFR at 12 and 24 months was 91% (CI: 86-97) and 86% (CI: 78-94) respectively without significant association with fractionation, dose, SINS score, or pre-existing compression fracture. The median D0.035cc of the true spinal cord for 1, 3, and 5 fraction treatments were 12.9 Gy (IQR:10.4-14.4), 18.5 Gy (IQR: 17.2-20.8), and 25.2 Gy (IQR: 21.8-28.4), with only one case of asymptomatic radiographic myelitis noted. FFLR at 12 and 24 months was 84% (CI: 77-92) and 78% (CI: 69-87) respectively, with no significant association between histology, dose, or fractionation and local recurrence. Spine SBRT demonstrated high rates of pain relief with acceptable toxicity profile over a range of relatively conservative dose-fractionation schema. Treatments typically exceeded TG101 guideline spinal cord “threshold doses,” while respecting maximum point doses, for the spinal cord without evidence of symptomatic myelitis. These results show superior FFFR and FFLR than prior reported studies and supports increasing use of SBRT in a wide range of patients.

A Multi-Institutional Experience of Proton Beam Therapy for Sinonasal Tumors

PurposeTo report the outcomes of sinonasal tumors treated with proton beam therapy (PBT) on the Proton Collaborative Group registry study. Methods and MaterialsSixty-nine patients with sinonasal tumors underwent curative intent PBT between 2010 and 2016. Patients who received de novo irradiation (42 patients) were analyzed separately from those who received reirradiation (27 patients) (re-RT). Median age was 53.1 years (range, 15.7-82.1; de novo) and 57.4 years (range, 31.3-88.0; re-RT). The most common histology was squamous cell carcinoma in both groups. Median PBT dose was 58.5 Gy (RBE) (range, 12-78.3; de novo) and 60.0 Gy (RBE) (range 18.2-72.3; re-RT), and median dose per fraction was 2.0 Gy (RBE) for both cohorts. Survival estimates for patients who received de novo irradiation and those who received re-RT were calculated using the Kaplan-Meier method. ResultsMedian follow-up for surviving patients was 26.4 months (range, 3.5-220.5). The 3-year overall survival (OS), freedom from distant metastasis, freedom from disease progression, and freedom from locoregional recurrence (FFLR) for de novo irradiation were 100%, 84.0%, 77.3%, and 92.9%, respectively. With re-RT, the 3-year OS, freedom from distant metastasis, FFDP, and FFLR were 76.2%, 47.4%, 32.1%, and 33.8%, respectively. In addition, 12 patients (17.4%) experienced recurrent disease. Re-RT was associated with inferior FFLR (P = .04). On univariate analysis, squamous cell carcinoma was associated with inferior OS (P < .01) for patients receiving re-RT. There were 11 patients with acute grade 3 toxicities. Late toxicities occurred in 15% of patients, with no grade ≥3 toxicities. No patients developed vision loss or symptomatic brain necrosis. ConclusionsAs one of the largest studies of sinonasal tumors treated with PBT, our findings suggest that PBT may be a safe and efficacious treatment option for patients with sinonasal tumors.

Factors affecting differential outcomes in the definitive treatment of anal cancer between HIV+ and HIV- patients.

3572 Background: Anal cancer is an uncommon malignancy with numerous factors that influence treatment outcomes. Historically, HIV+ patients were restricted from entering clinical trials, limiting data on their outcomes to small retrospective reports. This study seeks to understand the factors related to anal cancer outcomes, specifically the differences between HIV+ and HIV- patients. Methods: Inclusion criteria was non-metastatic anal squamous cell carcinoma treated with a definitive course of chemotherapy and radiation between 2005 and 2018 at a single institution. Clinical data related to baseline characteristics, treatment parameters, and post-treatment follow-up were extracted for calculation of freedom from local recurrence (FFLR) and overall survival (OS). Univariate analysis (UVA) and multivariate analysis (MVA) were done using cox proportional hazard model, and FFLR and OS were calculated using the Kaplan-Meier method. Results: During the study period, 111 patient initiated definitive treatment for anal cancer. Median age was 56.7 years (IQR: 51.4-63.5), and 47% (N = 52) were HIV+. At median follow-up of 28 months, 12 and 24-month FFLR was 84.1% and 78.2% respectively, with 24-month OS of 87.3%. MVA demonstrated significant association between FFLR and T-stage HR 4.02 (95% CI: 2.14-7.55) p &lt; 0.001, elapsed treatment time (median of 50 days) 1.08 (95% CI: 1.04-1.12) p &lt; 0.001, and diagnosis to treatment start (median time of 15 weeks) 1.05 (95% CI: 1.01-1.08) p = 0.005. Additional analysis with log-rank test for FFLR demonstrated significant difference between patients taking &lt; 50 days to complete treatment (p = 0.03), and &lt; 15 weeks from diagnosis to treatment completion (p = 0.006). In HIV+ patients, post-treatment CD4 &lt; 150 was significantly associated with worse OS on log-rank test (p = 0.016), with pretreatment CD4 values being non-significant. Conclusions: This study represents the largest single institution report of HIV positive patients treated for anal cancer. No difference in local recurrence or overall survival between HIV+ and HIV- patients was elucidated; however, HIV+ patients with lower post-treatment CD4 counts had worse OS. The most significant predictors of local recurrence were advanced T-stage, increased time from diagnosis to treatment initiation, and prolonged treatment time.

Stereotactic radiosurgery to surgical cavity post resection of brain metastases: Local recurrence and overall survival rates. A single-centre experience.

We reviewed local control (LC) and overall survival (OS) post intracranial SRS to cavity post resection of brain metastases at one institution, and factors affecting LC. A retrospective review was conducted of adjuvant SRS at one institution from 2013 to 2016. Patient records, treatment plans and diagnostic images were reviewed. Local failure was MRI defined. Categorical variables were analysed using chi-square and Fisher's exact tests. Continuous variables were analysed using Mann-Whitney tests. The Kaplan-Meier method was used to estimate survival times and the log-rank test was used to compare differences in survival. Forty-seven patients with 48 cavities were treated with SRS post operatively. LC rate was 69%, and the distant intracranial failure rate was 47% for entirety of the follow-up period. The 12-month freedom from local recurrence (FFLR) was 77% (63-91%). Median OS (95% CI) was 22.7 (14.6-30.8) months. Patients with a single metastasis had longer FFLR (30.1 vs 14.4months; P=0.014). Median interval from surgery to SRS was 6.3weeks. Patients with interval >7weeks had increased local recurrence (LR) (62%) than <7weeks (37%), P=0.025. Patients with a margin < 2mm were more likely to experience LR (48%) than those with margin equal to 2mm (20%); this approached statistical significance (P=0.063). The median follow-up for all patients was 15.4months (2-41). We determined LC and OS post adjuvant SRS at our institution. Based on the findings of this retrospective review SRS should be given promptly post operatively with a 2mm PTV margin.

Cardiac dose is associated with immunosuppression and poor survival in locally advanced non-small cell lung cancer

PurposeStudies have associated increased radiation therapy (RT) heart dose with cardiac toxicity. Others have correlated RT-related immunosuppression with worsened survival. Given the large vascular volumes irradiated during locally advanced non-small cell lung cancer (LA-NSCLC) treatment, we hypothesized an association between increased heart dose and immunosuppression. MethodsWe identified 400 LA-NSCLC patients treated with definitive RT ± chemotherapy between 2001 and 2016. Absolute lymphocyte counts (ALC), absolute neutrophil counts (ANC), and neutrophil-to-lymphocyte ratio (NLR = ANC/ALC) were analyzed pre-RT, during RT, and post-RT. Multivariable analysis (MVA) was performed to correlate Clinical factors with both hematologic toxicity and overall survival. An upper tertile threshold to increase specificity of NLR was chosen to dichotomize continuous hematologic variables. ResultsMedian follow up was 17 months (range 0.2–174 months) in all patients and 46 months (range 0.2–161 months) in survivors. A total of 94% of patients had stage III disease and 77% received concurrent chemo radiation. Two-year overall survival (OS), freedom from local recurrence (FFLR), and freedom from distant metastases (FFDM) was 42%, 60% and 45%, respectively. Median survival was 18 months. On MVA for OS (n = 207), male gender (Hazard Ratio [HR] 1.7; 95% CI 1.2–2.3), RT alone (HR 2.1; 95% CI 1.9–4.0), the percentage of heart receiving ≥50 Gy (V50) (HR 1.02; 95% CI 1.01–1.03), and higher NLR at 4 months (HR 1.02, 95% CI 1.01–1.03) were associated with reduced OS. ALC nadir was not associated with treatment outcomes. NLR >10.5 was associated with decreased OS (p < 0.001) and decreased FFDM (p = 0.04). On MVA evaluating factors associated with hematological toxicity (n = 247), adjuvant chemotherapy (HR 2.6; 95% CI 1.3–5.0; p = 0.006), RT alone (HR 3.6; 95% CI 1.1–12; p = 0.04), and heart V50 >25% (HR 2.0; 95% CI 1.1–3.5; p = 0.02) were associated with a NLR >10.5 4 months post-RT. ConclusionRT related immunosuppression is associated with worse patient outcomes, and may represent a source of increased mortality beyond cardiac toxicity alone.

(P37) Radiation-Induced Immunosuppression in Locally Advanced Non-Small Cell Lung Cancer: Another Cardiac Toxicity?

Recent reports have associated increased radiation therapy (RT) dose to the heart with higher rates of cardiac toxicity. Other reports have correlated RT-related immunosuppression with worsened survival in patients with solid malignancies. Given the large vascularized volumes exposed to RT during locally advanced non-small cell lung cancer (LA-NSCLC) treatment, we hypothesized that there is an association between increased heart dose and immunosuppression. A total of 400 LA-NSCLC patients with follow up laboratory values treated at a single institution with definitive intent RT +/- chemotherapy between 2001-2016 were identified. Organs at risk were reviewed and re-contoured according to the RTOG 0617 cardiac secondary analysis atlas. Absolute lymphocyte counts (ALC), absolute neutrophil counts (ANC), and neutrophil to lymphocyte ratio (NLR = ANC/ALC) were analyzed pre-RT, during RT, and at 2 and 4 months post-RT start. Patient, tumor, treatment, and dosimetric factors were correlated with hematologic toxicity and treatment outcomes. An upper tertile threshold to increase specificity of NLR was chosen to dichotomize continuous hematologic variables and identify cutpoints for hematologic values as a predictor of mortality. The median follow up was 17 (range 0.2-174) months in all patients and 46 (range 0.2-161) months in survivors. Patients received a median dose of 66 Gy (range 50-75.25 Gy) in median 2 Gy (range 1.8-2.5 Gy) fractions delivered with IMRT in 41% of patients. The estimated median overall survival (OS) was 17.9 months and progression free survival (PFS) 12.8 months. The estimated 5 year freedom from local recurrence (FFLR) and freedom from distant metastasis (FFDM) were 49% and 34%, respectively. There were 331/363 (91%) cases of ≥ grade 3 lymphopenia and 129/362 (36%) ≥ grade 4 lymphopenia at the nadir. At 4 months after RT start (290 patients), the median ALC, ANC, and NLR were 600 cells/mm3 (range: 100-4600), 4700 cells/mm3 (range: 300-113,600), and 7.2 (range: 0.60-259), respectively. On multivariable analysis, male gender (Hazard Ration [HR] 1.66; 95% CI 1.20-2.29; p=0.02), RT alone (HR 2.08; 95% CI 1.9-3.96; p=0.026), heart V50 (HR 1.02; 95% CI 1.01-1.03; p<0.001), and higher NLR at 4 months (HR 1.015, 95% CI 1.005-1.025; p=0.002) were significantly associated with worse OS. An upper tertile cutpoint of NLR > 10.5 at 4 months post RT, was associated with decreased OS (p<0.001) and decreased FFDM (p=0.04). The median OS stratified by NLR > 10.5 and NLR ≤ 10.5 was 11 months and 24 months, respectively (p < 0.001). NLR > 10.5 was associated with worse FFDM (p=0.04) and was borderline for PFS (p=0.08). On multivariable analysis, CRT with adjuvant chemotherapy (HR 2.55; 95% CI 1.30-4.98; p=0.006), RT alone (HR 3.56; 95% CI 1.07-11.88; P=0.039), and heart V50 > 25% (HR 1.98; 95% CI 1.11-3.54; p=0.021) were associated with an NLR>10.5 at 4 months post-RT. Higher RT dose to the heart is associated with increased immunosuppression and worse tumor control, and may represent an additional actionable cause of increased mortality beyond cardiac toxicity alone.