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TARGIT-A was a pragmatic randomized noninferiority trial including women with early-stage breast cancer treated postlumpectomy with either external beam radiation therapy (EBRT) or 50 kV x-rays delivered intraoperatively with or without EBRT, as indicated. The long-term update of the pre-pathology cohort did not include a 10-year estimate of the primary endpoint of local failure (although tabular 5-year data was provided). Here, we used the data from the pre-pathology manuscript to estimate the cumulative incidence of local failure.Using digitizer software and the published survival curves, we extracted the Kaplan-Meier rate of local recurrence-free survival and overall survival. The extracted data were calibrated to the published point-estimates to within ±0.5%. The data were then fit to parametric survival models, and overall survival and local recurrence-free survival curves were subtracted to give the estimate of local failure in the presence of the competing risk of death. Bootstrap resampling was used to assess for parameter uncertainty in the modeling process.Our analysis estimated that the risk of local failure at 10 years in the TARGIT-A pre-pathology cohort is approximately 1.7% with EBRT (95% confidence interval [CI], 0%-4.3%) and 5.5% in the pragmatic risk-adapted TARGIT strategy (95% CI, 2.9%-8.0%). A weighted average estimate suggests that the risk of local failure in low-risk women treated with TARGIT alone is approximately 6.6% at 10 years (95% CI, 3.3%-10.0%), with an estimated difference of 4.9% (95% CI, 0.6%-9.2%) compared with EBRT.These data allow for contextualization and informed decisions when considering megavoltage EBRT, kilovoltage intraoperatively, or omission of radiation therapy entirely.

Retreatment of recurrent or second primary head and neck cancers occurring in a previously irradiated field is complex. Few guidelines exist to support practice. We performed an updated literature search of peer-reviewed journals in a systematic fashion. Search terms, key questions, and associated clinical case variants were formed by panel consensus. The literature search informed the committee during a blinded vote on the appropriateness of treatment options via the modified Delphi method. The final number of citations retained for review was 274. These informed 5 key questions, which focused on patient selection, adjuvant reirradiation, definitive reirradiation, stereotactic body radiation, and reirradiation to treat nonsquamous cancer. Results of the consensus voting are presented along with discussion of the most current evidence. This provides updated evidence-based recommendations and guidelines for the retreatment of recurrent or second primary cancer of the head and neck.

Purpose Volumetric modulated arc therapy (VMAT) craniospinal irradiation (CSI) has been shown to have significant dosimetric advantages compared to 3D-conformal therapy, but is a technically complex process. We sought to develop a guide for all aspects of the VMAT CSI process and report patient dosimetry results. Methods and materials We initiated VMAT CSI in 2017 and have regularly revised our standard operating procedure (SOP) for this process since then. Herein, we report a detailed template for the entire VMAT CSI process from initial patient setup and immobilization at time of CT simulation to contouring and treatment planning, quality assurance, and therapy delivery. The records of 12 patients who were treated with VMAT CSI were also retrospectively reviewed. Results Patient age ranged from 2 to 59 years with 5 pediatric patients (age 35 years). The majority of patients (67%) had medulloblastoma. CSI dose ranged from 21.6 Gy to 36 Gy, with a median of 36 Gy. The median CSI planning target volume (PTV) was 2383cc with a median V95% of 99.8% and median 0.03 cc hotspot of 112.5%. The average V107% was 7.4% and the average conformality index was 1.01. Conclusions VMAT CSI has potentially significant dosimetric and acute toxicity advantages compared to 3D-conformal. However, proper procedures need to be in place throughout the process in order to be able to realize these potential advantages. We herein describe our detailed SOP for VMAT CSI. Recognizing the scarcity of proton beam centers in many areas, VMAT CSI represents a feasible treatment with more widespread availability.

PURPOSE: Adjuvant therapy in patients with ductal carcinoma in situ who undergo partial mastectomy remains controversial, particularly for low-risk patients (60 years or older, estrogen-positive, tumor extent < 2.5 cm, grade 1 or 2, and margins ≥ 3 mm). We performed a cost-effectiveness analysis comparing three strategies: no adjuvant treatment after surgery, a five-fraction course of accelerated partial breast irradiation using intensity-modulated radiation therapy (accelerated partial breast irradiation [APBI]–alone), or APBI plus an aromatase inhibitor for 5 years. MATERIALS AND METHODS: Outcomes including local recurrence, distant metastases, and survival as well as toxicity data were modeled by a patient-level Markov microsimulation model, which were validated against trial data. Costs of treatment and possible adverse events were included from the societal perspective over a lifetime horizon, adjusted to 2019 US dollars and extracted from Medicare reimbursement data. Quality-adjusted life-years (QALYs) were calculated based on utilities extracted from the literature. RESULTS: No adjuvant therapy was the least costly approach ($5,744), followed by APBI-alone ($11,070); combined therapy was costliest ($16,052). Adjuvant therapy resulted in slightly higher QALYs (no adjuvant, 11.320; APBI-alone, 11.343; and combination, 11.381). In the base case, no treatment was the cost-effective strategy, with an incremental cost-effectiveness ratio of $239,109/QALY for APBI-alone and $171,718/QALY for combined therapy. The incremental cost-effectiveness ratio for combined therapy compared with APBI-alone was $131,949. Probabilistic sensitivity analyses found that no therapy was cost effective (defined as $100,000/QALY of lower) in 63% of trials, APBI-alone in 19%, and the combination in 18%. CONCLUSION: No adjuvant therapy represents the most cost-effective approach for postmenopausal women 60 years or older who receive partial mastectomy for low-risk ductal carcinoma in situ.

Survivorship care programs (SCPs) educate patients on post-treatment side-effects, which may lead to earlier identification and mitigation of their impact. This study assessed the impact of SCP on identification and management of post-treatment hypothyroidism in a head and neck cancer population and evaluated socio-demographic factors in the effectiveness of SCPs.A retrospective analysis was performed of sociodemographic and clinical characteristics of patients with head and neck cancer treated with radiation therapy between January 2011 and January 2019 at a large community cancer institution. Development of hypothyroidism was defined as elevated thyroid-stimulating hormone (TSH) or initiation of supplementation post-treatment. Cumulative incidence of hypothyroidism was analyzed with Gray's method.Of 608 patients, 483 (79%) had post-treatment TSH surveillance. A total of 203 (42%) of those patients developed hypothyroidism; 53 (11%) patients completed SCPs. The median follow-up was 1.4 (interquartile range=0.7-2.6) years with a median time until diagnosis of hypothyroidism of 1.2 (interquartile range=0.7-2.1) years. The median time to diagnosis was 12.0 months with SCP versus 14.2 months without. Race and insurance status were not associated with differences in thyroid surveillance. Patients with laryngeal cancer were at greatest risk of developing hypothyroidism (hazard ratio=1.92, confidence interval=1.44-2.56; p0.077). Cumulative incidence of post-treatment hypothyroidism was higher in patients managed with SCP, 65.4% at 4 years, compared to those without (49.0%). Receipt of SCP was independently associated with an increased incidence of hypothyroidism detection (hazard ratio=1.51, confidence interval=1.04-2.20; p=0.030).In our experience, SCP utilization was independently associated with a diagnosis of hypothyroidism. This study supports implementation of a survivorship program for identification and management of post-treatment sequelae.

Background De-intensified treatment strategies for early human papillomavirus-positive (HPV+) oropharynx cancer (OPC) rely on selecting patients with an excellent prognosis. The criterion for enrollment in current de-intensification trials is ≤10 pack-years. More nuance to the pack-year criteria may expand enrollment, improve patient outcomes, and prevent overtreatment. It was hypothesized that patients with more than 10 pack-years may experience favorable outcomes if smoking cessation has been achieved. Methods From an institutional review board-approved database, patients with HPV+ oropharyngeal squamous carcinoma treated definitively with radiation with or without chemotherapy were retrospectively identified. Patients with a history of smoking who were eligible for national de-intensification trials were included (cT1-2N1-2b or T3N0-2b [American Joint Committee on Cancer, seventh edition]). Cox regression with penalized smoothing splines was used to evaluate nonlinear effects of cessation. Recursive partitioning analysis (RPA) was used to objectively search for relationships between the 2 colinear variables (pack-years and time since cessation). Results Among 330 patients meeting the inclusion criteria, 130 (40%) were never smokers, 139 (42%) were former smokers, and 61 (18%) were current smokers. With standard therapy, all former smokers achieved a progression-free survival (PFS) rate higher than 91%, regardless of pack-year exposure. Nonlinear Cox regression demonstrated that more recent cessation was associated with significantly worse PFS even among those with ≤20 pack-years. RPA demonstrated that only current smokers experienced a 2-year PFS rate lower than 91%; former smokers, regardless of pack-years, experienced a 2-year PFS rate higher than 91%. Conclusions The 10-pack-year rule may not apply to all early HPV+ OPCs, particularly for former smokers. Future randomized de-intensification trials should consider a broader and more nuanced approach until the predictive role of smoking status is established.

Introduction: It has been suggested that post-transoral robotic surgery (post-TORS) radiotherapy (RT) might reduce the dose to organs at risk (OARs) adjacent to the primary tumor bed; however, the evidence supporting this has yet to be sufficient. This study examined the radiation dose reduction to OARs by omitting the primary tumor bed through the use of an Auto-Planning (AP)-based workflow. Methods: Twelve patients were identified who underwent post-TORS RT to the primary tumor bed and the unilateral/bilateral neck lymph nodes. In each patient, two treatment plans were designed: a Comprehensive (Comp)-plan treating the original planning target volume (PTV) including both the primary tumor bed and the lymph nodes, and a Neck-plan treating only the lymph nodes and omitting the primary tumor bed. Both plans were optimized using AP to ensure plan quality consistency. We compared the doses received by 95% of the primary tumor beds and lymph nodes (D95%) and our institutional dose constraints for the OARs between the Comp- and Neck-plans. Statistical analysis was performed using R Statistical Software (R Foundation for Statistical Computing, Vienna, Austria) with a two-tailed paired Wilcoxon signed-rank test. Results: All plans met target dose coverage requirements with at least 95% of the PTVs covered with the corresponding prescription doses. The primary tumor bed in the Neck-plans was spared with a significantly lower mean D95% (25.9 Gy vs. 60.0 Gy; p < 0.01; Wilcoxon test). The mean dose to the oral cavity (20.9 Gy vs. 28.1 Gy; p < 0.01) and the supraglottis (36.9 Gy vs. 28.2 Gy; p < 0.01) was significantly lower in the Neck-plans. Conclusion: This study suggests that sparing the primary tumor bed during post-TORS RT offers dosimetric benefits to nearby OARs with significant dose reductions to the oral cavity and supraglottis. Further study of the clinical risks and benefits afforded by this strategy is needed.

PURPOSE: Patients with head and neck cancer are at risk of long-term dental complications. Proper dental assessment pre- and post-treatment can improve outcomes but is logistically challenging. We surveyed oncologists to better understand their perspectives surrounding dental care in this unique population. METHODS: We surveyed oncologists at institutions associated with an ongoing national study of oral health after treatment of head and neck cancer. Seventeen questions were used to assess provider characteristics, patterns of practice, patterns of referral, barriers to referral, and willingness to apply fluoride varnish in the oncology clinic. RESULTS: Ninety-seven oncologists were invited from six institutions, of whom 40 (41%) responded. Surgeons represented 45% of the sample, followed by radiation oncologists (40%) and medical oncologists (15%). Both generalists and subspecialists were included. All practiced in a metropolitan area with an academic dental practice, and many felt that this improved access to care. Despite this, most oncologists thought that financial factors were a significant barrier to obtaining timely dental care. Most oncologists performed a dental assessment during visits. Oncologists felt qualified to identify the most significant complications of treatment, such as exposed bone, but felt underqualified to identify early changes in need of intervention. When asked if the oncology clinic could apply fluoride varnish during follow-ups, most stated that this seemed feasible but would require education and financial support. CONCLUSION: Oncologists often perform limited dental evaluations during their routine visits. Given the challenges associated with access to proper dental care for this population, these oncology visits may provide a window for preventative intervention.

Background Adult intracranial ependymoma is rare, and the role for adjuvant radiotherapy (RT) is not well defined. Methods We used the National Cancer Database (NCDB) to select adults (age ≥ 22 years) with grade 2 to 3 intracranial ependymoma status postresection between 2004 and 2015 and treated with adjuvant RT vs observation. Four cohorts were generated: (1) all patients, (2) grade 2 only, (3) grade 2 status post–subtotal resection only, (4) and grade 3 only. The association between adjuvant RT use and overall survival (OS) was assessed using multivariate Cox and propensity score matched analyses. Results A total of 1787 patients were included in cohort 1, of which 856 patients (48%) received adjuvant RT and 931 (52%) were observed. Approximately two-thirds of tumors were supratentorial and 80% were grade 2. Cohorts 2, 3, and 4 included 1471, 345, and 316 patients, respectively. There was no significant association between adjuvant RT use and OS in multivariate or propensity score matched analysis in any of the cohorts. Older age, male sex, urban location, higher comorbidity score, earlier year of diagnosis, and grade 3 were associated with increased risk of death. Conclusions This large NCDB study did not demonstrate a significant association between adjuvant RT use and OS for adults with intracranial ependymoma, including for patients with grade 2 ependymoma status post–subtotal resection. The conflicting results regarding the efficacy of adjuvant RT in this patient population highlight the need for high-quality studies to guide therapy recommendations in adult ependymoma.

To investigate the association between tumor volume and locoregional failure (LRF) after concurrent chemoradiation (CCRT) for locally advanced larynx cancer (LC).This is a retrospective cohort study from 2009 to 2014 identified from an institutional review board-approved registry. Fifty-nine of 68 patients with locally advanced larynx cancer treated with definitive CCRT who had available imaging for review were identified. The main endpoint to be assessed was the association between gross tumor volumes (GTV; T = total, P = primary, N = nodal) and LRF. Receiver operative characteristic (ROC) curves were used to investigate diagnostic accuracy.Twenty LRFs were observed, resulting in a 2-year LRF rate of 39% (95% CI, 23-52%). On UVA, the GTV-T (P = .01), GTV-P (P = .05), and GTV-N (P = .04) were statistically significant predictors of LRF. Furthermore, age, smoking status, N-stage, larynx subsite, and tracheostomy/feeding tube dependence were potentially associated with LRF (P .3), whereas T-stage (T3-4 vs. T2) was not (HR 1.05, 95% CI, 0.38-2.91, P = .92). In the multivariable model, GTV-P (HR 1.022, 95% CI, 0.999-1.046, P = .07) and GTV-N (HR 1.053, 95% CI, 1.0004-1.108, P = .05) were the two most impactful covariates on the model's RGTV is associated with LRF after definitive CCRT for LC. Patients with bulky primary and/or nodal tumors may be better served with upfront surgical resection regardless of T-stage. Further investigation into the safety of larynx preservation for low-volume T4 tumors can be considered.4 Laryngoscope, 130:2372-2377, 2020.

BACKGROUND We investigated the impact of level I lymph node involvement (LNI) on survival for patients with oropharyngeal squamous cell carcinoma (OPSCC). METHODS We performed a cohort study of patients with OPSCC who underwent resection with known human papillomavirus (HPV) status in the National Cancer Database (2010-2014). RESULTS Among 5591 patients with OPSCC, 599 (10.7%) had level I LNI. Predictors of level I LNI included pT classification (pT3 vs pT1; odds ratio [OR], 1.95; P

Purpose Severe late toxicity is common after re-irradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck. However, many patients experience complications from tumor progression before manifesting late effects. We constructed a nomogram to examine this relationship between late toxicity and competing risks. Methods and materials Patients with RSP squamous carcinoma originating in a field previously irradiated to ≥40 Gy and treated with IMRT-based re-irradiation to ≥40 Gy were collected. Grade ≥3 late toxicity developing ≥90 days after re-irradiation was collected. A multivariable competing-risk model was fit to the actuarial risk of late toxicity with progression or death as the competing risk. The final bootstrap optimized model was converted into a nomogram. Results From 9 institutions, 505 patients were included. The 2-year incidence of grade ≥3 late toxicity was 16.7% (95% CI 13.2–20.2%) whereas progression or death was 64.2% (95% CI 59.7–68.8%). The median freedom from late toxicity, progression or death was 10.7, 5.5 and 3.2 months for RPA class I-III patients respectively, whereas the median OS was 44.9, 15.9 and 7.9 months, respectively. The final model included six clinical factors. Notably, dose, volume and fractionation did not significantly impact toxicity. Conclusions After re-irradiation, the risk of progression or death is approximately four times the risk of radiation-related severe late toxicity. The risk of late toxicity may be more dependent on patient and disease factors than modifiable treatment factors. This model is useful for patient selection, pre-treatment consent and post-treatment survivorship following re-irradiation.

The conformality of modern intensity modulated radiation therapy (IMRT) allows avoidance of the submandibular glands (SMG) in select patients, potentially improving late xerostomia. This study explores the safety and efficacy of this approach in select oropharyngeal carcinoma (OPC) patients.Patients with T1-2N+ human papillomavirus (HPV)-associated OPC treated with definitive IMRT at one institution from 2009 to 2014 were identified. Patients were divided into 3 groups: bilateral level IB targeted (A, n = 16), a single level IB targeted (B, n = 61), and bilateral IB spared (C, n = 9). Outcomes were reviewed to identify the rate of level IB regional recurrence. Odds ratios were calculated for xerostomia between groups.Level Ib was targeted in 93 instances (54.1%) and avoided in 79 instances (45.9%). Mean SMG doses were significantly lower when level IB was spared compared to when targeted (37.5 Gy vs 67.5 Gy; P 0.0001). Median doses to oral cavity decreased with increasing level Ib sparing (40.7 Gy [A] vs 35.4 Gy [B] vs 30.7 [C]; P = 0.002). The rate of late grade ≥2 xerostomia was significantly lower in patients with bilateral 1b sparing (53% in A vs 0% in C; P = 0.007). Sparing 1b unilaterally resulted in a non-significant decrease in late grade ≥2 xerostomia (P = 0.181). No regional failures were identified in levels IB (median follow up = 59.3 months).Sparing level IB is safe in T1-2N+ HPV+ OPC. Avoiding level Ib translates into significantly lower SMG and oral cavity doses. Larger studies are needed to validate these findings and the impact of this technique.

Municipal wastewater (MWW) effluent discharges can introduce contaminants to receiving waters which may have adverse impacts on local ecosystems and human health. Conservative chemical constituents specific to the MWW effluent stream can be used to quantify and trace wastewater effluent-sourced contaminant inputs. Gadolinium (Gd), a rare earth element used as a contrasting agent in medical magnetic resonance imaging, can be found in urban MWW streams. Dissolved anthropogenic Gd has been shown to be an indicator and potential conservative tracer for MWW effluent in receiving waters. Like other known MWW tracers, it can be difficult and expensive to measure. Dissolved rubidium (Rb) to strontium (Sr) ratio enrichment in biological materials such as blood and urine can lead to enriched Rb/Sr values in MWW effluent relative to natural waters. This ratio is relatively easy and inexpensive to measure and represents a promising additional indicator for MWW effluent in receiving waters in urbanized freshwater systems. In July 2015 and 2016 surface water samples were collected from sites in the tidal-fresh Potomac River in the vicinity of the Blue Plains Advanced Wastewater Treatment Plant (BPAWWTP) outfall near Washington, DC USA along with treated MWW effluent samples from the BPAWWTP. Dissolved Rb/Sr ratios were measured in these waters and compared to dissolved Gd concentrations in order to demonstrate the potential of the dissolved Rb/Sr ratio as a conservative indicator for MWW effluent. Results suggest the dissolved Rb/Sr ratio represents a simple and cost-effective indicator and conservative tracer for MWW effluent. It can be used with, or in place of, other proven tracers to investigate wastewater impacts in highly-urbanized, anthropogenically-impacted freshwater systems like the tidal fresh Potomac River and perhaps in a wider range of geologic settings than previously thought. A case study is presented as an example to demonstrate the potential of using dissolved Rb/Sr ratios to trace MWW-sourced nutrient inputs from a major WWTP like BPAWWTP to the receiving waters of tidal-fresh Potomac River.

PURPOSE/OBJECTIVE(S) The addition of cisplatin to radiation therapy (RT) results in improved outcomes in oropharyngeal head and neck cancer (OHNC) patients. This comes at the cost of increased toxicities over RT alone and often results in the inability to complete the initially prescribed chemotherapy regimen. In this study, potential predictors of chemotherapy completion and their effect on outcomes were investigated in OHNC patients treated at two different institutions. MATERIALS/METHODS We conducted a retrospective chart review of patients with OHNC at two different institutions. Patients were staged according to AJCC 8th Ed and separated into two groups: Completers (able to complete initially prescribed concurrent cisplatin regimen) and Non-Completers (unable to complete all prescribed cycles and/or required change to a different systemic therapy agent). Age, sex, race, ECOG, smoking status, HPV status, and stage were analyzed for ability to predict completion of chemotherapy regimen and for prognostic implication on outcomes. Overall survival (OS) and local control (LC) were calculated from start of RT. Chi-squared was used for associations, Kaplan-Meier estimates were compared using log-rank test, odds ratios (OR) and hazard ratios (HR) were generated from logistic and Cox regression analyses, respectively. RESULTS Between 2007 and 2019, 271 patients with OHNC were reviewed and included in the study. Most patients were Stage II (60%) and HPV positive (83%). More patients were Completers (61%) than Non-Completers (39%). Mean age was 56.6 years in Completers and 58.0 years in Non-Completers. Comparing Stage I to IV was the only significant predictor of chemotherapy completion (OR 6.139, 95% CI 1.43-26.35). HPV negative status trended towards significance for non-completion (OR 0.520 P = 0.061). Predictors of inferior OS were race (Non-White vs White) HR 2.520 P = 0.001; ECOG (2-3 vs 0-1) HR 2.324 P = 0.018; ever smoker (Yes vs No) HR 2.582 P = 0.001; HPV status (Negative vs Positive) HR 3.584 P < 0.001; and Stage (IV vs I) HR 5.983, 95% CI 1.38, 25.97. Inability to complete chemotherapy was not found to be a predictor of inferior survival (HR 0.737 P = 0.173). OS at 3 years was not statistically different between Completers (81%) and Non-Completers (77%), P = 0.404. LC at 3 years was not statistically different between Completers (93%) and Non-Completers (92%), P = 0.755. CONCLUSION In our study of OHNC patients who were mostly HPV positive and early stage, cancer stage was found to be the only significant predictor of chemotherapy completion. Chemotherapy completion was not found to be a predictor of outcome. Provided the Non-Completer group included those who had a change in systemic agent but may have completed the same total number of planned chemotherapy cycles, this study suggests the need for further multivariate analysis and potentially more upfront individualized chemotherapy regimens.

Purpose Previous trials have shown no benefit for radiation therapy (RT) dose escalation when RT is given as adjuvant monotherapy for infiltrative low-grade glioma (LGG). However, the current standard of care for high-risk LGG is RT with concurrent and/or adjuvant chemotherapy. The effect of RT dose escalation on overall survival (OS) in the setting of concurrent and/or adjuvant chemotherapy is not well established. Methods and Materials We used the National Cancer Database to select records for adult patients with intracranial grade 2 LGG diagnosed between 2004 and 2015. Patients must have received adjuvant external beam RT with concurrent and/or adjuvant chemotherapy. RT dose level was categorized as standard (45-54 Gy) or high (>54-65 Gy). Multivariable and propensity score matched analyses were used. Results The study cohort consisted of 1043 patients, of whom 644 (62%) received standard dose (median, 54 Gy) and 399 (38%) received high-dose RT (median, 60 Gy). RT dose level was not associated with OS (hazard ratio, 1.2; P = .1) in multivariable analysis. Propensity score matching yielded 380 matched pairs (n = 760). There was no difference in OS for high-dose versus standard-dose RT in the matched cohort (5-year OS 64% vs 69%; P = .14) or in the 2 prespecified subgroups of astrocytoma histology and 1p/19q noncodeleted. Conclusions Adjuvant RT dose escalation above 54 Gy in the setting of concurrent and/or adjuvant chemotherapy was not associated with improved OS for patients with infiltrative LGG in this National Cancer Database retrospective study. This was also true for the subgroups with less chemotherapy-sensitive disease, including astrocytoma histology and 1p/19q noncodeleted, although these analyses were limited by small size. Methods to improve OS other than RT dose escalation in the setting of concurrent and/or adjuvant chemotherapy should be considered for patients with poor-prognosis LGG.

Objectives Patients with human papillomavirus (HPV) associated squamous cell carcinoma of the oropharynx (SCC-OP) have improved overall survival (OS) after distant metastasis (DM) compared to HPV negative patients. These patients may be appropriate candidates for enrollment on clinical trials evaluating the efficacy of metastasis-directed therapy (MDT). This study seeks to identify prognostic factors associated with OS after DM, which could serve as enrollment criteria for such trials. Materials and methods From an IRB approved multi-institutional database, we retrospectively identified patients with HPV/p16 positive SCC-OP diagnosed between 2001 and 2018. Patterns of distant failure were assessed, including number of lesions at diagnosis and sites of involvement. The primary outcome was OS after DM. Prognostic factors for OS after DM were identified with Cox proportional hazards. Stepwise approach was used for multivariable analysis. Results We identified 621 patients with HPV-associated SCC-OP, of whom 82 (13.2%) were diagnosed with DM. Median OS after DM was 14.6 months. On multivariable analysis, smoking history and number of lesions were significantly associated with prolonged OS. Median OS after DM by smoking (never vs ever) was 37.6 vs 11.2 months (p = 0.006), and by lesion number (1 vs 2–4 vs 5 or more) was 41.2 vs 17.2 vs 10.8 months (p = 0.007). Conclusion Among patients with newly diagnosed metastatic HPV-associated SCC-OP, lesion number and smoking status were associated with significantly prolonged overall survival. These factors should be incorporated into the design of clinical trials investigating the utility of MDT, with or without systemic therapy, in this population.

We performed a cost-effectiveness analysis of three strategies for the adjuvant treatment of early breast cancer in women age 70 years or older: an aromatase inhibitor (AI-alone) for 5 years, a 5-fraction course of accelerated partial-breast irradiation using intensity-modulated radiation therapy (APBI-alone), or their combination. We constructed a patient-level Markov microsimulation from the societal perspective. Effectiveness data (local recurrence, distant metastases, survival), and toxicity data were obtained from randomized trials when possible. Costs of side effects were included. Costs were adjusted to 2019 US dollars and extracted from Medicare reimbursement data. Quality-adjusted life-years (QALY) were calculated using utilities extracted from the literature. The strategy of AI-alone ($12,637) was cheaper than both APBI-alone ($13,799) and combination therapy ($18,012) in the base case. All approaches resulted in similar QALY outcomes (AI-alone 7.775; APBI-alone 7.768; combination 7.807). In the base case, AI-alone was the cost-effective strategy and dominated APBI-alone, while combined therapy was not cost-effective when compared to AI-alone ($171,451/QALY) or APBI-alone ($107,932/QALY). In probabilistic sensitivity analyses, AI-alone was cost-effective at $100,000/QALY in 50% of trials, APBI-alone in 28% and the combination in 22%. Scenario analysis demonstrated that APBI-alone was more effective than AI-alone when AI compliance was lower than 26% at 5 years. Based on a Markov microsimulation analysis, both AI-alone and APBI-alone are appropriate options for patients 70 years or older with early breast cancer with small cost differences noted. A prospective trial comparing the approaches is warranted.

Following treatment of HPV-driven oropharynx cancer, surveillance nasopharyngoscopy and imaging are often performed but are expensive and frequently ineffective. A novel plasma circulating tumor-tissue modified viral HPV DNA (TTMV-HPV-DNA) assay accurately detects recurrences. We modeled the cost of the new assay.We designed and validated a partitioned survival model which replicated the results of the RTOG 1016 study and calculated cumulative surveillance costs from the payer's perspective. Two strategies were considered: a standard of routine endoscopy with imaging as needed and an alternative strategy which omitted scopes and imaging but obtained serial TTMV-HPV-DNA samples. No difference in effectiveness (QALY or LY) was assumed in the base case. A 5-year horizon was used, costs were reported in 2020 U.S. dollars discounted by 3%. Seven scenarios tested model assumptions and practice variation. Deterministic and probabilistic sensitivity analyses assessed parameter uncertainty.In the base case, at the list TTMV-HPV-DNA price, the cumulative cost of surveillance was $11,674 for the standard strategy and $20,756 for the TTMV-HPV-DNA strategy (+$9082 over 5 years). Probabilistic sensitivity analysis demonstrated the cost difference ranged from $4917-$12,047. The TTMV-HPV-DNA strategy was most likely to be either cost saving or cost-effective if future data demonstrate small improvements in quality or quantity of life (approximately 33 quality-adjusted life-days), if the assay reduces utilization of imaging, and if the periodicity of TTMV-HPV-DNA draws could be reduced from that on clinical trials.This data informs providers seeking to design more accurate, accessible, and economical post-treatment surveillance strategies.

PURPOSE: The therapeutic ratio of reirradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck may be improved in the intensity modulated radiation therapy (IMRT) era. However, patient selection for reirradiation remains challenging. We performed a multi-institution cohort study to investigate modern outcomes after IMRT-based reirradiation and to identify prognostic subgroups. PATIENTS AND METHODS: Patients with RSP squamous carcinoma originating in a previously irradiated field (≥40 Gy) who underwent reirradiation with IMRT (≥40 Gy re-IMRT) were included. Locoregional failure and late toxicity were calculated using the Gray competing risk method. Cox proportional hazards regression was used to identify factors associated with overall survival (OS). Factors associated with OS were entered into a recursive partitioning analysis (RPA) for OS. RESULTS: From 7 institutions, 412 patients were included. The median dose of re-IMRT was 60 Gy, and the median time between RT courses was 2.4 years. Chemotherapy was used in 76% of patients. The rates of grade ≥3, grade ≥4, and grade 5 acute toxicities were 19%, 4.4%, and 1.2%, respectively. The 2-year cumulative incidence of grade ≥3 late toxicity adjusted for the competing risks of recurrence or death was 14.2%. RPA identified 3 prognostic subgroups with distinct and homogenous OS (P2 years from their initial course of RT with resected tumors (2-year OS, 61.9%); class II included patients >2 years with unresected tumors or those ≤2 years and without feeding tube or tracheostomy dependence (2-year OS, 40.0%), and the remaining patients formed class III (2-year OS, 16.8%). Fifty-nine percent of class III patients underwent postoperative re-irradiation. CONCLUSIONS: This study informs outcomes and expectations with IMRT-based reirradiation. The RPA classification identifies 3 distinct subgroups, which can guide patient selection for therapy and clinical trial design. RPA class III patients are not ideal candidates for protracted chemoradiation regardless of resection status.

Purpose Limited data exist to guide the treatment technique for reirradiation of recurrent or second primary squamous carcinoma of the head and neck. We performed a multi-institution retrospective cohort study to investigate the effect of the elective treatment volume, dose, and fractionation on outcomes and toxicity. Methods and Materials Patients with recurrent or second primary squamous carcinoma originating in a previously irradiated field (≥40 Gy) who had undergone reirradiation with intensity modulated radiation therapy (IMRT); (≥40 Gy re-IMRT) were included. The effect of elective nodal treatment, dose, and fractionation on overall survival (OS), locoregional control, and acute and late toxicity were assessed. The Kaplan-Meier and Gray's competing risks methods were used for actuarial endpoints. Results From 8 institutions, 505 patients were included in the present updated analysis. The elective neck was not treated in 56.4% of patients. The median dose of re-IMRT was 60 Gy (range 39.6-79.2). Hyperfractionation was used in 20.2%. Systemic therapy was integrated for 77.4% of patients. Elective nodal radiation therapy did not appear to decrease the risk of locoregional failure (LRF) or improve the OS rate. Doses of ≥66 Gy were associated with improvements in both LRF and OS in the definitive re-IMRT setting. However, dose did not obviously affect LRF or OS in the postoperative re-IMRT setting. Hyperfractionation was not associated with improved LRF or OS. The rate of acute grade ≥3 toxicity was 22.1% overall. On multivariable logistic regression, elective neck irradiation was associated with increased acute toxicity in the postoperative setting. The rate of overall late grade ≥3 toxicity was 16.7%, with patients treated postoperatively with hyperfractionation experiencing the highest rates. Conclusions Doses of ≥66 Gy might be associated with improved outcomes in high-performance patients undergoing definitive re-IMRT. Postoperatively, doses of 50 to 66 Gy appear adequate after removal of gross disease. Hyperfractionation and elective neck irradiation were not associated with an obvious benefit and might increase toxicity.

BACKGROUND Time to treatment initiation (TTI) is increasing and is associated with worsening survival. In the current study, the authors sought to identify a mechanism for this relationship by assessing the effect of TTI on clinical-to-pathologic upstaging in patients with head and neck squamous cell carcinoma (HNSCC). METHODS Using the National Cancer Data Base, the authors analyzed patients receiving definitive surgery for SCC of the oral cavity, oropharynx, larynx, and hypopharynx from 2005 through 2014. The primary outcome was T, N, or stage group upstaging, defined as higher pathologic stage than clinical stage. TTI was defined as the time between diagnosis and surgery. Multivariable logistic and Cox proportional hazards regression modeled upstaging and survival, respectively. RESULTS Cohorts of 60,194 patients, 51,380 patients, and 52,980 patients, respectively, with complete T, N, and stage group data were included. N upstaging was most common (18.6%), followed by stage group (17.4%) and T (12.1%) upstaging; all types were predicted by TTI. Compared with a TTI of 1 to 6 days, TTIs as short as 7 to 13 days (odds ratio, 1.20; P = .038) or ≥ 70 days (odds ratio, 2.04; P

Purpose/Objective(s) Respiratory motion management with breath hold (BH) is one technique to limit normal lung and other organ dose during SBRT treatments of the lung. Surface guidance (SGRT) has been utilized for BH in larger targets such as breast cancer, but its reliability in BH treatments of small targets has not been investigated. We report the initial results of the reliability of utilizing SGRT alone as a technique for BH during a prospective study of treatment of primary and metastatic lung tumors. Materials/Methods An IRB approved prospective study was conducted in patients (pts) with primary NSCLC or lung metastasis undergoing SBRT. Eligible pts had at least 1 cm of respiratory associated motion on free breathing 4DCT. Pts underwent planning CT with BH either in end inspiration or expiration per investigator choice. The GTV was contoured on the BH planning CT and a 5mm margin added for PTV expansion. During each SBRT treatment, pts performed BH and were aligned within tolerance based on the reference BH surface capture created from the BH planning CT. Pts underwent short-arc CBCT during BH for volumetric match of the target. Before shifts were made for target match, pts performed a BH within tolerance, then shifts were made prior to a new reference surface capture being immediately obtained during the same BH. Pts were then treated in BH based on the new reference surface with a tolerance of 3mm translations and 2 degree rotations. Treatment was stopped if pts fell outside of the predefined tolerances. Midway through treatment, pts underwent a second short arc CBCT during BH to verify the reliability of target position during BH treatment utilizing SGRT. Any subsequent shifts on target volumetric match after the second CBCT were recorded. Linear mixed models for repeated measures were used to analyze rotational and translational shift measurements. Results 13 pts and 39 SBRT fractions were treated utilizing SGRT alone for BH. All pts were treated with 54 Gy in 3 fractions. Median free breathing range of motion (4D ROM) was 1.3 cm. Mean displacements after mid-treatment CBCT were minimal in all directions as shown in Table 1. Only one observed fraction had a displacement that exceeded the 5mm PTV expansion (longitudinal shift of 0.59 cm with resulting vector shift of 0.68cm). Factors evaluated for association with shift magnitude included age, BMI, gender, tumor location, 4D ROM, and GTV and PTV size. Higher 4D ROM was associated with increased longitudinal and vector shifts (P = 0.019 and 0.046). Conclusion SGRT provides a reliable technique for BH SBRT treatments of the lung. Minimal target displacements on mid treatment BH CBCT were observed. Higher 4D ROM on free breathing scans correlated with larger displacements in tumor position utilizing this technique.

Objective Nivolumab is the first drug to demonstrate a survival benefit for platinum-refractory recurrent or metastatic head and neck cancer. We performed a cost-utility analysis to assess the economic value of nivolumab as compared to alternative standard agents in this context. Materials and methods Using data from the CheckMate 141 trial, we constructed a Markov simulation model from the US payer’s perspective to evaluate the cost-effectiveness of nivolumab compared to physician choice of either cetuximab, methotrexate or docetaxel. Alternative strategies considered included: single-agent cetuximab, methotrexate or docetaxel, or first testing for PD-L1 to select for nivolumab. Costs were extracted from Medicare and utilities from the literature and CheckMate. Probabilistic sensitivity analysis (PSA) was used to evaluate parameter uncertainty. $100,000/QALY was the primary threshold for cost-effectiveness. Results When comparing nivolumab to the standard arm of CheckMate, nivolumab demonstrated an incremental cost-effectiveness ratio (ICER) of $140,672/QALY. When comparing standard therapies, methotrexate was the most cost-effective with similar results for docetaxel. Nivolumab was cost-effective compared to single-agent cetuximab (ICER $89,786/QALY). Treatment selection by PD-L1 immunohistochemistry did not markedly improve the cost-effectiveness of nivolumab. Factors likely to positively impact the cost-effectiveness of nivolumab include better baseline quality-of-life, poor tolerability of standard treatments and/or a lower cost of nivolumab. Conclusions Nivolumab is preferred to single-agent cetuximab but requires a willingness-to-pay of at least $150,000/QALY to be considered cost-effective when compared to docetaxel or methotrexate. Selection by PD-L1 does not markedly improve the cost-effectiveness of nivolumab. This informs patient selection and clinical care-path development.

Objectives/Hypothesis Patients with human papillomavirus (HPV)–induced cancer of unknown primary (CUP) are generally excluded from clinical trials, despite surgical series reporting detection rates of occult oropharynx primaries of >80%. We performed a matched-pair analysis to compare outcomes between T0N1-3M0 HPV+ CUP and T1-2N1-3M0 HPV+ oropharynx known primary (OPX). Study Design Retrospective cohort study at a single institution. Methods Patients with early T stage, node positive HPV+ OPX or CUP treated with curative intent between 1998 and 2016 were identified. For a subgroup of CUP patients with an unknown HPV status, we imputed HPV status and included patients with a >80% probability of being HPV+. Cohorts were matched based on patient demographics using a nearest neighbor propensity technique. After matching, patients were grouped according to either a favorable or unfavorable risk stratification designations per current NRG Oncology clinical trial enrollment criteria. Disease-free survival (DFS) and overall survival (OS) were calculated using Kaplan-Meier analysis. Results Of 298 patients with T1-2N1-3 OPX, 48 were matched to 48 HPV+ CUP patients (32 with confirmed and 16 imputed HPV status). Median follow-up for CUP (34.1 months) and OPX (27.8 months) patients were similar (P = .23).There were no significant differences between the CUP and OPX groups for 3-year DFS (89% vs. 85%, P = .44), and 3-year OS (91% vs. 91%, P = .11), respectively. Conclusions Patients with T0N+M0 HPV-induced CUP have similar survival outcomes to matched patients with T1-2N+M0 HPV+ OPX. These patients can reasonably be included in clinical trials investigating the role of treatment deintensification and risk stratified similar to patients with early-stage known primary OPX cancer. Level of Evidence 4. Laryngoscope, 2017

Objective/Hypothesis There are limited treatment options beyond surgical salvage for patients who fail nonoperative treatment for laryngeal squamous cell carcinoma. In this study, we examine the failure patterns after surgical salvage and the potential pathologic and clinical prognostic variables that might guide further postoperative intensification investigation. Study Design Retrospective analysis at a tertiary academic referral center. Methods From an institutional review board-approved institutional head and neck cancer registry, a consecutive series of 147 patients who underwent salvage laryngectomy for squamous cell cancer recurrence or persistence after radiotherapy with or without chemotherapy between May 1995 and May 2016 were identified. Variables potentially associated with oncologic outcome after surgical salvage were then collected and retrospectively evaluated. Results The projected 2-year locoregional failure rate was 21.8% (95% confidence interval [CI], 14.6%–29.0%]), and the overall survival 65% (95% CI, 57.5%–74.3%) for the entire cohort after salvage laryngectomy. On multivariable analysis, sarcomatoid/spindle cell pathology (hazard ratio [HR], 3.147; 95% CI, 1.181–8.386; P = 0.022), lymphovascular space invasion (LVSI) (positive vs. negative; HR, 2.31; 95% CI, 1.21–4.42; P = 0.011), and advanced initial American Joint Committee on Cancer 7th Edition grouped stage (stages III–IVB vs. stages I–II; HR, 1.64; 95% CI, 1.04–2.6; P = 0.035) were found to be independently associated with inferior disease-free survival. No other clinical or pathologic variables predicted failure. Conclusion Salvage laryngectomy after nonoperative treatment failure results in successful locoregional control rates and survival in the majority of patients failing initial therapy. This should temper enthusiasm for routine treatment intensification with postoperative re-irradiation and/or other systemic treatments for the vast majority of patients. Sarcomatoid pathology, LVSI, and an advanced initial stage are associated with inferior disease-free survival. The presence of these factors may warrant further investigational study of treatment intensification after salvage laryngectomy. Level of Evidence 4. Laryngoscope, 2017

Background Human papillomavirus (HPV)-positive oropharyngeal cancer is associated with favorable outcomes, prompting investigations into treatment deintensification. The purpose of this study was for us to present the predictors of distant metastases in patients with HPV-positive oropharyngeal cancer treated with cisplatin-based chemoradiotherapy (CRT) or cetuximab-based bioradiotherapy (bio-RT). Methods In patients with stage III to IVb HPV-positive oropharyngeal cancer, the Kaplan-Meier analysis was used to calculate distant metastases rates. Univariate analysis (UVA) and multivariate analysis (MVA) were used to identify factors associated with distant metastases. Results Increased distant metastases rates were noted in active smokers versus never/former smokers (22% vs 5%), T4 vs T1 to T3 (15% vs 6%), and cetuximab-based bio-RT versus CRT (23% vs 5%). All remained significant on MVA. Conclusion T4 tumors and active smokers have substantial rates of distant metastases, and trials investigating intensified systemic therapies may be considered. Higher rates of distant metastases observed with concurrent cetuximab are hypothesis generating, but further data are needed. © 2017 Wiley Periodicals, Inc. Head Neck 39: 940-946, 2017.

PURPOSE: To determine which factors influence cost in head and neck cancer (HNC) to inform the development of a bundled payment model (BPM). METHODS: Patients with stages 0 to IVB (by American Joint Commission on Cancer, 7th edition) HNC of various sites and histology treated definitively at a single tertiary care center during 2013 were included. Clinical variables and direct cost data were obtained, and their associations were investigated using χ2, t, Wilcoxon rank sum, and analysis of variance testing. Results were used to develop a BPM. RESULTS: One hundred fifty patients were included; 87% were white, 74% were men, 48% had oropharyngeal cancer, and 58% had stage IVA disease. Treatment consisted of surgery alone (17%), radiation alone (11%), surgery plus radiation (14%), chemoradiation (45%), and surgery plus chemoradiation (13%). On multivariable analysis, both increasing group stage and number of treatment modalities used were significantly associated with higher cost. Given that stage often dictates treatment, we developed three cost tiers that were based on overall treatment modality. Tier A, the least costly, consisted of single-modality therapy with either surgery alone or radiation alone (median cost divided by the median overall cost of treatment, 0.54; 25th to 75th percentile range, 0.29 to 1.02), followed by tier B, which consisted of bimodality therapy with either chemoradiation or surgery plus radiation (1.03; range, 0.81 to 1.35), followed by tier C, which consisted of trimodality therapy with surgery plus chemoradiation (1.43; range, 1.10 to 1.96). CONCLUSION: The number of treatment modalities required is the primary driver of cost in HNC. These data can simplify development of a comprehensive HNC BPM.

Purpose Hormone therapy without radiation therapy is considered appropriate for women age 70 or above with low-risk, hormone-positive breast cancer after partial mastectomy. However, some patients may prefer radiation without hormone therapy, for which there is minimal modern data. We modeled the comparative efficacy of aromatase inhibition alone without radiation versus radiation alone without hormone therapy. Methods and Materials We constructed a patient-level Markov model and compared 5 years of anastrozole to a 15-fraction course of radiation without boost or anastrozole. The relative effectiveness between treatments was based on the National Surgical Adjuvant Breast and Bowel Project B-21 trial, which was further adjusted such that the endocrine-alone arm matched the Cancer and Leukemia Group B 9343 and PRIME II trials. Common or severe side effects were considered. Eight survival metrics were assessed and validated against clinical trial data. The cost-efficacy of each strategy was considered using the quality-adjusted life year and incremental cost-effectiveness ratio (ICER). Results The model's predicted outcomes matched those demonstrated by modern trials. Aromatase inhibitors were superior in preventing contralateral cancers, with a small impact on the risk of distant metastatic disease. Radiation was superior in preventing ipsilateral breast tumor recurrence with a small impact on regional failure. No clinically significant differences were seen in the other 4 oncologic endpoints. Differences in quality-adjusted life years were small, but radiation therapy was $3809 more expensive over the average lifetime. The ICER suggested anastrozole was cost-effective in 62% of probabilistic simulations. However, the ICER was unstable owing to a denominator that approached zero. Conclusions Women age 70 or above with low-risk early breast cancer who are reluctant or unable to pursue adjuvant aromatase inhibition can safely pursue adjuvant radiation alone with limited differences in outcome and a modest increase in costs.

BACKGROUND The role of smoking among patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is unclear. METHODS A retrospective cohort study of patients with HPV(+) OPSCC from 2001 to 2015 at a tertiary-care institution was conducted. The primary outcome was overall survival (OS). RESULTS Among 484 included patients, 94 (19.4%) were active smokers, 226 (46.7%) were former smokers, and 164 (33.9%) never smoked. Among active smokers, 82 patients (87.2%) had a ≥10 pack-year and 69 (73.4%) had a ≥20 pack-year smoking history. After adjusting for covariates, active smoking was a significant predictor of inferior OS (HR 2.28, P

Purpose To characterize applicant interview experiences at radiation oncology residency programs during the 2016 match cycle and to assess applicant opinions regarding postinterview communication (PIC) after recent attention to gamesmanship noted in prior match cycles. Methods and Materials An anonymous, institutional review board–approved, 29-question survey was deployed following the rank order list deadline to all 2016 radiation oncology residency applicants applying to a single institution. Results Complete surveys were returned by 118 of 210 applicants, for a 56% response rate. Regarding possible match violation questions, 84% of respondents were asked at least once about where else they were interviewing (occurred at a median of 20% of program interviews); 51% were asked about marital status (6% of interviews); and 22% were asked about plans to have children (1% of interviews). Eighty-three percent of applicants wrote thank-you notes, with 55% reporting fear of being viewed unfavorably if such notes were not communicated. Sixty percent of applicants informed a program that they had ranked a program highly; 53% felt this PIC strategy would improve their standing on the rank order list, yet 46% reported feeling distressed by this obligation. A majority of applicants stated that they would feel relieved if programs explicitly discouraged PIC (89%) and that it would be preferable if programs prohibited applicants from notifying the program of their rank position (66%). Conclusions Potential match violations occur at a high rate but are experienced at a minority of interviews. Postinterview communication occurs frequently, with applicants reporting resultant distress. Respondents stated that active discouragement of both thank-you notes/e-mails and applicants' notification to programs of their ranking would be preferred.

Introduction Isolated nodal failure (INF) without synchronous local or distant failure is an uncommon occurrence after stereotactic body radiation therapy (SBRT) for lung cancer. Here we review the natural history and patterns of failure after post-SBRT INF with or without salvage mediastinal radiotherapy (SvRT). Methods Patients treated with SBRT for non–small cell lung cancer with definitive intent were identified. Patients who experienced hilar or mediastinal INF without synchronous distant, lobar, or local failure were included and grouped according to the use of SvRT. The rates of subsequent locoregional control, distant metastases, progression-free survival (PFS), and overall survival were assessed. Results Of 797 patients treated with definitive SBRT, 24 (3%) experienced INF and 15 (63%) received SvRT. The most common SvRT regimen (53%) was 45 Gy in 15 fractions. The median follow-up after INF was 11.3 months for survivors. There were no grade 3 or higher toxicities after SvRT. The 1-year Kaplan-Meier PFS and overall survival estimates were 33% and 56% for patients not receiving radiotherapy and 75% and 73% with SvRT. After SvRT, the rate of locoregional control at 1 year was 84.4%. Crude rates of distant failure were 20.0% with SvRT and 22.2% with no radiotherapy. Of the 13 deaths observed, five (38%) were related to distant progression of lung cancer, four (31%) to comorbidities, three (23%) to mediastinal progression, and one (8%) to an unknown cause. Conclusions INF is uncommon after SBRT. Despite the significant comorbidities of this population, intrathoracic progression remains a contributor to morbidity and mortality. SVRT for INF is well tolerated and may improve PFS.

BACKGROUND The purpose of this study was to investigate the use of systemic therapy along with definitive radiotherapy for elderly patients with head and neck cancer. METHODS Patients who were 71 years old or older with stage III to IVB squamous cell carcinoma of the nasopharynx, oropharynx, larynx, or hypopharynx treated with definitive radiotherapy with or without systemic therapy were identified from the National Cancer Data Base. Patterns of systemic therapy use before or during definitive radiotherapy were investigated. The association between systemic therapy use and overall survival was investigated with a multivariate, inverse probability–weighted propensity score–adjusted Cox proportional hazards model. RESULTS Elderly patients treated between 2004 and 2012 (n = 4165) were identified, and 80.4% received systemic therapy. The median follow-up was 26 months (range, 1.8-125 months), and the 3-year overall survival rate was 51.6% (95% confidence interval, 50.0%-53.2%). During the study period, there was an increase in the frequency of systemic therapy use from 64% in 2004 to 86% in 2012. The use of systemic therapy was associated with improved overall survival in the multivariate model (hazard ratio, 1.456; 95% confidence interval, 1.308-1.620; P