Integrating Audiovisual Immersion Into Pediatric Radiation Therapy Across Multiple Centers: Methodology, Timeliness, and Cost of the Audiovisual-Assisted Therapeutic Ambience in Radiation Therapy Prospective Multi-Institutional Trial.

Purpose: The Audiovisual-Assisted Therapeutic Ambience in Radiotherapy (AVATAR) trial was a prospective multicenter study (NCT03991156) examining the combination of video immersion with radiation therapy and was successfully conducted through the collaboration of pediatric radiation oncology teams at 10 institutions independent of any pre-existing consortium. We sought to analyze and report the methodology of trial conception and development, process map, and cost. Methods and Materials: The study enrolled patients aged 3 to 10 years preparing to undergo radiation therapy, integrated the combination of AVATAR-based video immersion with radiation therapy at each institution, and offered AVATAR use as an alternative to anesthesia, with rates of anesthesia use and outcomes of serial standardized anxiety and quality-of-life assessments assessed among the 81 children enrolled. A process map was created based on the trial timeline with the following components: study development time (time from conception of the trial to the accrual of the first patient, including design phase, agreement and approval phase, and site preparation phase), and accrual duration time (time from the first to last accrual). Costs and institutional success rates were calculated. Results: Time from inception of study to last accrual was 3.6 years (1313 days). The study development time was 417 days (31.7%), and accrual duration time was 896 days (68.3%), with the final 50% of accrual occurring in <6 months. Equipment cost was approximately $550 per institution and was covered by funding from the lead study institution. All 10 centers were successful with AVATAR implementation, defined as ≥50% of patients able to avoid anesthesia with the use of AVATAR, including centers with both photon and proton therapy. Conclusions: This report elaborates on the methodology and timeline of trial conception and development using data from a previously published supportive care study combining video immersion with radiation therapy among 10 cooperating pediatric oncology institutions. It highlights the potential for multicenter collaborations on prospective trials integrating supportive care therapies with radiation therapy.

Redefining Candidates for Deintensification in Locoregionally Advanced P16+ Oropharyngeal Cancer Based on Relative Risk.

BACKGROUND: Randomized trials have found that patients with locoregionally advanced p16+ oropharyngeal squamous cell carcinoma (OPSCC) do not benefit from treatment deintensification, even among favorable risk groups. While various methods have been used to identify candidates for treatment deintensification, the optimal approach is unknown. METHODS: We conducted a multi-institutional cohort study of 444 patients with previously untreated p16+ OPSCC undergoing definitive radiotherapy with or without systemic therapy between 2009-2022. We compared two approaches for identifying candidates for deintensification: (1) favorable vs. unfavorable risk, using NRG-HN005 eligibility criteria, and (2) low vs. high relative risk for cancer events, using the HNCIG predictive classifier ("omega score"). We tested differences in outcomes and systemic therapy allocation by risk group using multivariable Cox models, competing event models, and logistic regression, and compared characteristics of hypothetical deintensification trials using the two approaches. PFS events were defined as cancer recurrence (locoregional or distant) or death from any cause. RESULTS: Median follow-up time was 52 months; 120 patients (27.0%) were favorable risk; a different 120 patients had low omega score; 28 patients (6.3%) met both criteria; 184 patients (41.4%) had discordant classification. On ordinal logistic regression, decreasing omega score was associated with a statistically significantly lower odds of receiving intensive therapy (normalized OR 0.37 per standard deviation; 95% CI: 0.24-0.57), with a greater magnitude than favorable risk group (OR 0.66; 95% CI: 0.44-0.99). Among patients receiving cisplatin and/or platinum-based induction (N=374), favorable risk was associated with significantly improved PFS (HR 0.59, 95% CI 0.36-0.99), whereas lower omega score was associated with a significantly decreased relative hazard for cancer events (RHR 0.18, 95% CI 0.070-0.46). In simulations, selecting patients with low omega scores increased the efficiency of hypothetical non-inferiority trials. CONCLUSIONS: Considering patients' relative risk for cancer events can help define optimal populations for treatment deintensification in p16+ OPSCC.

Target Delineation in Postoperative Radiation Therapy for Head and Neck Cancer After Flap Reconstruction.

Delineation of the clinical target volume (CTV) after resection of head and neck cancer can be challenging, especially after flap reconstruction. The main area of contention is whether the entire flap should be included in the CTV. Several case series have reported marginal misses and intraflap failures when the entire flap was not routinely included in the CTV. On the other hand, available data have not convincingly demonstrated a detriment to long-term outcomes using intensity modulated radiotherapy after flap reconstruction. On the contrary, postoperative radiation can facilitate epilation and mucosalization of the flap tissue, reduce flap bulk, and improve long-term esthetic and functional outcomes. Therefore, our standard practice is to include the entire flap in the CTV. In certain scenarios, we may allow for a lower dose to part of flap distant from the resection bed than the flap-tumor bed junction, where recurrences are most likely. We provide three case vignettes describing such scenarios where sparing part of the flap, and more importantly, the nearby uninvolved native tissue, from high-dose radiation may be justified.

Retinopathy, Optic Neuropathy, and Cataract in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review.

PURPOSE: Few reports describe the risks of late ocular toxicities after radiation therapy (RT) for childhood cancers despite their effect on quality of life. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) ocular task force aims to quantify the radiation dose dependence of select late ocular adverse effects. Here, we report results concerning retinopathy, optic neuropathy, and cataract in childhood cancer survivors who received cranial RT. METHODS AND MATERIALS: A systematic literature search was performed using the PubMed, MEDLINE, and Cochrane Library databases for peer-reviewed studies published from 1980 to 2021 related to childhood cancer, RT, and ocular endpoints including dry eye, keratitis/corneal injury, conjunctival injury, cataract, retinopathy, and optic neuropathy. This initial search yielded abstracts for 2947 references, 269 of which were selected as potentially having useful outcomes and RT data. Data permitting, treatment and outcome data were used to generate normal tissue complication probability models. RESULTS: We identified sufficient RT data to generate normal tissue complication probability models for 3 endpoints: retinopathy, optic neuropathy, and cataract formation. Based on limited data, the model for development of retinopathy suggests 5% and 50% risk of toxicity at 42 and 62 Gy, respectively. The model for development of optic neuropathy suggests 5% and 50% risk of toxicity at 57 and 64 Gy, respectively. More extensive data were available to evaluate the risk of cataract, separated into self-reported versus ophthalmologist-diagnosed cataract. The models suggest 5% and 50% risk of self-reported cataract at 12 and >40 Gy, respectively, and 50% risk of ophthalmologist-diagnosed cataract at 9 Gy (>5% long-term risk at 0 Gy in patients treated with chemotherapy only). CONCLUSIONS: Radiation dose effects in the eye are inadequately studied in the pediatric population. Based on limited published data, this PENTEC comprehensive review establishes relationships between RT dose and subsequent risks of retinopathy, optic neuropathy, and cataract formation.

Feasibility of the Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) System for Anesthesia Avoidance in Pediatric Patients: A Multicenter Trial.

PURPOSE: The Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) system was the first published radiation therapy (RT)-compatible system to reduce the need for pediatric anesthesia through video-based distraction. We evaluated the feasibility of AVATAR implementation and effects on anesthesia use, quality of life, and anxiety in a multicenter pediatric trial. METHODS AND MATERIALS: Pediatric patients 3 to 10 years of age preparing to undergo RT at 10 institutions were prospectively enrolled. Children able to undergo at least 1 fraction of RT using AVATAR without anesthesia were considered successful (S). Patients requiring anesthesia for their entire treatment course were nonsuccessful (NS). The PedsQL3.0 Cancer Module (PedsQL) survey assessed quality of life and was administered to the patient and guardian at RT simulation, midway through RT, and at final treatment. The modified Yale Preoperative Anxiety Scale (mYPAS) assessed anxiety and was performed at the same 3 time points. Success was evaluated using the χ2 test. PedsQL and mYPAS scores were assessed using mixed effects models with time points evaluated as fixed effects and a random intercept on the subject. RESULTS: Eighty-one children were included; median age was 7 years. AVATAR was successful at all 10 institutions and with photon and proton RT. There were 63 (78%) S patients; anesthesia was avoided for a median of 20 fractions per patient. Success differed by age (P = .04) and private versus public insurance (P < .001). Both patient (P = .008) and parent (P = .006) PedsQL scores significantly improved over the course of RT for patients aged 5 to 7. Anxiety in the treatment room decreased for both S and NS patients over RT course (P < .001), by age (P < .001), and by S versus NS patients (P < .001). CONCLUSIONS: In this 10-center prospective trial, anesthesia avoidance with AVATAR was 78% in children aged 3 to 10 years, higher than among age-matched historical controls (49%; P < .001). AVATAR implementation is feasible across multiple institutions and should be further studied and made available to patients who may benefit from video-based distraction.

The Evolving Role of Radiotherapy for Pediatric Cancers With Advancements in Molecular Tumor Characterization and Targeted Therapies.

Ongoing rapid advances in molecular diagnostics, precision imaging, and development of targeted therapies have resulted in a constantly evolving landscape for treatment of pediatric cancers. Radiotherapy remains a critical element of the therapeutic toolbox, and its role in the era of precision medicine continues to adapt and undergo re-evaluation. Here, we review emerging strategies for combining radiotherapy with novel targeted systemic therapies (for example, for pediatric gliomas or soft tissue sarcomas), modifying use or intensity of radiotherapy when appropriate via molecular diagnostics that allow better characterization and individualization of each patient's treatments (for example, de-intensification of radiotherapy in WNT subgroup medulloblastoma), as well as exploring more effective targeted systemic therapies that may allow omission or delay of radiotherapy. Many of these strategies are still under investigation but highlight the importance of continued pre-clinical and clinical studies evaluating the role of radiotherapy in this era of precision oncology.

Prognostic and Predictive Clinical and Biological Factors in HPV Malignancies.

Human papillomavirus (HPV) causes the majority of oropharyngeal, cervical, and anal cancers, among others. These HPV-associated cancers cause substantial morbidity and mortality despite ongoing vaccination efforts. Aside from the earliest stage tumors, chemoradiation is used to treat most HPV-associated cancers across disease sites. Response rates are variable, and opportunities to improve oncologic control and reduce toxicity remain. HPV malignancies share multiple commonalities in oncogenesis and tumor biology that may inform personalized methods of screening, diagnosis, treatment and surveillance. In this review we discuss the current literature and identify promising molecular targets, prognostic and predictive clinical factors and biomarkers in HPV-associated oropharyngeal, cervical and anal cancer.

Phase 1 trial of adavosertib (AZD1775) in combination with concurrent radiation and cisplatin for intermediate-risk and high-risk head and neck squamous cell carcinoma.

BACKGROUND: Adavosertib (AZD1775) is an inhibitor of the Wee1 kinase. The authors conducted a phase 1b trial to evaluate the safety of adavosertib in combination with definitive chemoradiotherapy for patients with newly diagnosed, intermediate-risk/high-risk, locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Twelve patients with intermediate-risk/high-risk HNSCC were enrolled, including those with p16-negative tumors of the oropharynx, p16-positive tumors of the oropharynx with ≥10 tobacco pack-years, and tumors of the larynx/hypopharynx regardless of p16 status. All patients were treated with an 8-week course of concurrent intensity-modulated radiotherapy at 70 grays (Gy) (2 Gy daily in weeks 1-7), cisplatin 30 mg/m2 weekly (in weeks 1-7), and adavosertib (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8). The primary objective was to determine the maximum tolerated dose and the recommended phase 2 dose of adavosertib given concurrently with radiation and cisplatin. Secondary objectives were to determine the 12-week objective response rate and progression-free and overall survival. RESULTS: Three patients (25%) experienced a dose-limiting toxicity, including febrile neutropenia (n = 2) and grade 4 thromboembolism (n = 1). Two dose-limiting toxicities occurred with adavosertib at 150 mg. The median follow-up was 14.7 months. The 12-week posttreatment objective response rate determined by positron emission tomography/computed tomography was 100%. The 1-year progression-free and overall survival rates were both 90%. The maximum tolerated dose of adavosertib was 100 mg. CONCLUSIONS: Adavosertib 100 mg (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8), in combination with 70 Gy of intensity-modulated radiotherapy and cisplatin 30 mg/m2 , is the recommended phase 2 dose for patients with HNSCC.

Radiation therapy for infants with cancer.

The clinical outcomes for infants with malignant tumors are often worse than older children due to a combination of more biologically aggressive disease in some cases, and increased toxicity-or deintensification of therapies due to concern for toxicity-in others. Especially in infants and very young children, finding the appropriate balance between maximizing treatment efficacy while minimizing toxicity-in particular late side effects-is crucial. We review here the management of malignant tumors in infants and very young children, focusing on central nervous system (CNS) malignancies and rhabdomyosarcoma.

NTCP modeling and dose-volume correlations for acute xerostomia and dry eye after whole brain radiation.

BACKGROUND: Whole brain radiation (WBRT) may lead to acute xerostomia and dry eye from incidental parotid and lacrimal exposure, respectively. We performed a prospective observational study to assess the incidence/severity of this toxicity. We herein perform a secondary analysis relating parotid and lacrimal dosimetric parameters to normal tissue complication probability (NTCP) rates and associated models. METHODS: Patients received WBRT to 25-40 Gy in 10-20 fractions using 3D-conformal radiation therapy without prospective delineation of the parotids or lacrimals. Patients completed questionnaires at baseline and 1 month post-WBRT. Xerostomia was assessed using the University of Michigan xerostomia score (scored 0-100, toxicity defined as ≥ 20 pt increase) and xerostomia bother score (scored from 0 to 3, toxicity defined as ≥ 2 pt increase). Dry eye was assessed using the Subjective Evaluation of Symptom of Dryness (SESoD, scored from 0 to 4, toxicity defined as ≥ 2 pt increase). The clinical data were fitted by the Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP models. RESULTS: Of 55 evaluable patients, 19 (35%) had ≥ 20 point increase in xerostomia score, 11 (20%) had ≥ 2 point increase in xerostomia bother score, and 13 (24%) had ≥ 2 point increase in SESoD score. For xerostomia, parotid V10Gy-V20Gy correlated best with toxicity, with AUC 0.68 for xerostomia score and 0.69-0.71 for bother score. The values for the D50, m and n parameters of the LKB model were 22.3 Gy, 0.84 and 1.0 for xerostomia score and 28.4 Gy, 0.55 and 1.0 for bother score, respectively. The corresponding values for the D50, γ and s parameters of the RS model were 23.5 Gy, 0.28 and 0.0001 for xerostomia score and 32.0 Gy, 0.45 and 0.0001 for bother score, respectively. For dry eye, lacrimal V10Gy-V15Gy were found to correlate best with toxicity, with AUC values from 0.67 to 0.68. The parameter values of the LKB model were 53.5 Gy, 0.74 and 1.0, whereas of the RS model were 54.0 Gy, 0.37 and 0.0001, respectively. CONCLUSIONS: Xerostomia was most associated with parotid V10Gy-V20Gy, and dry eye with lacrimal V10Gy-V15Gy. NTCP models were successfully created for both toxicities and may help clinicians refine dosimetric goals and assess levels of risk in patients receiving palliative WBRT.

Consolidative or palliative whole brain radiation for secondary CNS diffuse large B-Cell lymphoma.

We analyzed 25 patients receiving whole brain radiation (WBRT) for secondary CNS lymphoma (SCNSL), grouped by consolidative intent (after complete/partial response, n = 13) vs. palliative intent (initial CNS treatment, primary refractory disease, or CNS progression, n = 12). Median WBRT dose for the consolidative and palliative cohorts were 24 Gy and 30 Gy, respectively. For 13 patients receiving consolidative WBRT, median OS was 24 months from WBRT and 2-year OS was 64%. Three patients had CNS relapse at 2, 9, and 24 months after consolidative WBRT. For 12 patients receiving palliative WBRT, median OS was 3 months from WBRT and two-year OS was 8%. All 10 patients with neurologic symptoms had documented improvement. In conclusion, consolidative WBRT after chemotherapy response led to reasonable long-term survival and may be an effective strategy for SCNSL, especially transplant-ineligible patients and/or isolated CNS recurrence. Palliative WBRT effectively improved neurologic symptoms, but survival was usually only months.

Common Error Pathways in CyberKnife™ Radiation Therapy.

Purpose/Objectives: Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) may be considered "high risk" due to the high doses per fraction. We analyzed CyberKnife™ (CK) SRS and SBRT-related incidents that were prospectively reported to our in-house incident learning system (ILS) in order to identify severity, contributing factors, and common error pathways. Material and Methods: From 2012 to 2019, 221 reported incidents related to the 4,569 CK fractions delivered (5.8%) were prospectively analyzed by our multi-professional Quality and Safety Committee with regard to severity, contributing factors, as well as the location where the incident occurred (tripped), where it was discovered (caught), and the safety barriers that were traversed (crossed) on the CK process map. Based on the particular step in the process map that incidents tripped, we categorized incidents into general error pathways. Results: There were 205 severity grade 1-2 (did not reach patient or no clinical impact), 11 grade 3 (clinical impact unlikely), 5 grade 4 (altered the intended treatment), and 0 grade 5-6 (life-threatening or death) incidents, with human performance being the most common contributing factor (79% of incidents). Incidents most commonly tripped near the time when the practitioner requested CK simulation (e.g., pre-CK simulation fiducial marker placement) and most commonly caught during the physics pre-treatment checklist. The four general error pathways included pre-authorization, billing, and scheduling issues (n= 119); plan quality (n= 30); administration of IV contrast during simulation or pre-medications during treatment (n= 22); and image guidance (n= 12). Conclusion: Most CK incidents led to little or no patient harm and most were related to billing and scheduling issues. Suboptimal human performance appeared to be the most common contributing factor to CK incidents. Additional study is warranted to develop and share best practices to reduce incidents to further improve patient safety.

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication.

PURPOSE: Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes tumor-directed immune stimulation, which may potentiate anti-PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC. PATIENTS AND METHODS: This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin-ineligible patients. Patients received radiotherapy concurrently with three cycles of pembrolizumab 200 mg every 3 weeks followed by three adjuvant cycles. The primary endpoint was a progression-free survival (PFS) of ≥16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling. RESULTS: Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated 24-month PFS and overall survival rates were 71% (95% confidence interval, 49%-84%) and 75% (51%-88%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however, high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased, while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells. CONCLUSIONS: Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets.

Novel Strategies to Effectively De-escalate Curative-Intent Therapy for Patients With HPV-Associated Oropharyngeal Cancer: Current and Future Directions.

The treatment of patients with HPV-associated oropharyngeal cancer (HPV-OPC) is rapidly evolving and challenging the standard of care of definitive radiotherapy with concurrent cisplatin. There are numerous promising de-escalation strategies under investigation, including deintensified definitive chemoradiotherapy, transoral surgery followed by de-escalated adjuvant therapy, and induction chemotherapy followed by de-escalated locoregional therapy. Definitive radiotherapy alone or with cetuximab is not recommended for curative-intent treatment of patients with locally advanced HPV-OPC. The results of ongoing phase III studies are awaited to help answer key questions and address ongoing controversies to transform the treatment of patients with HPV-OPC. Strategies for de-escalation under investigation include the incorporation of immunotherapy and the use of novel biomarkers for patient selection for de-escalation.

Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen in a micrometastatic model of prostate cancer.

Auger radiopharmaceutical therapy is a promising strategy for micrometastatic disease given high linear energy transfer and short range in tissues, potentially limiting normal tissue toxicities. We previously demonstrated anti-tumor efficacy of a small-molecule Auger electron emitter targeting the prostate-specific membrane antigen (PSMA), 2-[3-[1-carboxy-5-(4-[125I]iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid), or 125I-DCIBzL, in a mouse xenograft model. Here, we investigated the therapeutic efficacy, long-term toxicity, and biodistribution of 125I-DCIBzL in a micrometastatic model of prostate cancer (PC). Methods: To test the therapeutic efficacy of 125I-DCIBzL in micrometastatic PC, we used a murine model of human metastatic PC in which PSMA+ PC3-ML cells expressing firefly luciferase were injected intravenously in NSG mice to form micrometastatic deposits. One week later, 0, 0.37, 1.85, 3.7, 18.5, 37, or 111 MBq of 125I-DCIBzL was administered (intravenously). Metastatic tumor burden was assessed using bioluminescence imaging (BLI). Long-term toxicity was evaluated via serial weights and urinalysis of non-tumor-bearing mice over a 12-month period, as well as final necropsy. Results: In the micrometastatic PC model, activities of 18.5 MBq 125I-DCIBzL and above significantly delayed development of detectable metastatic disease by BLI and prolonged survival in mice. Gross metastases were detectable in control mice and those treated with 0.37-3.7 MBq 125I-DCIBzL at a median of 2 weeks post-treatment, versus 4 weeks for those treated with 18.5-111 MBq 125I-DCIBzL (P<0.0001 by log-rank test). Similarly, treatment with ≥18.5 MBq 125I-DCIBzL yielded a median survival of 11 weeks, compared with 6 weeks for control mice (P<0.0001). At 12 months, there was no appreciable toxicity via weight, urinalysis, or necropsy evaluation in mice treated with any activity of 125I-DCIBzL, which represents markedly less toxicity than the analogous PSMA-targeted α-particle emitter. Macro-to-microscale dosimetry modeling demonstrated lower absorbed dose in renal cell nuclei versus tumor cell nuclei due to lower levels of drug uptake and cellular internalization in combination with the short range of Auger emissions. Conclusion: PSMA-targeted radiopharmaceutical therapy with the Auger emitter 125I-DCIBzL significantly delayed development of detectable metastatic disease and improved survival in a micrometastatic model of PC, with no long-term toxicities noted at 12 months, suggesting a favorable therapeutic ratio for treatment of micrometastatic PC.

PIK3CA Mutation in HPV-Associated OPSCC Patients Receiving Deintensified Chemoradiation.

PIK3CA is the most frequently mutated gene in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Prognostic implications of such mutations remain unknown. We sought to elucidate the clinical significance of PIK3CA mutations in HPV-associated OPSCC patients treated with definitive chemoradiation (CRT). Seventy-seven patients with HPV-associated OPSCC were enrolled on two phase II clinical trials of deintensified CRT (60 Gy intensity-modulated radiotherapy with concurrent weekly cisplatin). Targeted next-generation sequencing was performed. Of the 77 patients, nine had disease recurrence (two regional, four distant, three regional and distant). Thirty-four patients had mutation(s) identified; 16 had PIK3CA mutations. Patients with wild-type-PIK3CA had statistically significantly higher 3-year disease-free survival than PIK3CA-mutant patients (93.4%, 95% confidence interval [CI] = 85.0% to 99.9% vs 68.8%, 95% CI = 26.7% to 89.8%; P = .004). On multivariate analysis, PIK3CA mutation was the only variable statistically significantly associated with disease recurrence (hazard ratio = 5.71, 95% CI = 1.53 to 21.3; P = .01). PIK3CA mutation is associated with worse disease-free survival in a prospective cohort of newly diagnosed HPV-associated OPSCC patients treated with deintensified CRT.

Updated risk models demonstrate low risk of symptomatic radionecrosis following stereotactic radiosurgery for brain metastases.

BACKGROUND: Improvements in systemic therapy continue to increase survival for patients with brain metastases. Updated dosimetric models are required to optimize long-term safety of stereotactic radiosurgery (SRS) for this indication. METHODS: Patients at a single institution receiving SRS from December 2011 to December 2014 were retrospectively reviewed. Patients with radiographic progression of at least one lesion, and with at least 6 months of follow-up from the start of SRS were included. Grade 3 necrosis was defined as requiring surgical intervention. This data were combined with two additional published datasets to construct logistic models describing necrosis risk as a function of dose and volume. RESULTS: From our institution, 294 brain metastases across 57 patients in 139 treatment plans met inclusion criteria. Primary histologies included non-small cell lung cancer (n = 19), melanoma (n = 13), breast carcinoma (n = 9), renal cell carcinoma (n = 7), and other (n = 9). Median follow-up from SRS of first cranial metastasis was 21.7 months (range: 6.3-56.6) and median overall survival was 25.6 months (range: 6.5-56.6). There were eight cases of Grade 1-2 and two cases of Grade 3 necrosis. As a useful clinical reference point, 20 cc of total brain receiving a single-fraction equivalent dose ≥14 Gy corresponded to 12.1% risk for Grade 1-3 (P < 0.003) and 3.4% risk for Grade 3 necrosis (P < 0.001). CONCLUSIONS: These results compare favorably with the QUANTEC brain tolerance estimates for radiosurgery, providing optimism for lower toxicity in the modern era. Additional studies are needed to determine dose tolerance parameters across a broad spectrum of patients.

Prospective Assessment of Patient-Reported Dry Eye Syndrome After Whole Brain Radiation.

PURPOSE: Dry eye is not typically considered a toxicity of whole brain radiation therapy (WBRT). We analyzed dry eye syndrome as part of a prospective study of patient-reported outcomes after WBRT. METHODS AND MATERIALS: Patients receiving WBRT to 25 to 40 Gy were enrolled on a study with dry mouth as the primary endpoint and dry eye syndrome as a secondary endpoint. Patients received 3-dimensional WBRT using opposed lateral fields. Per standard practice, lacrimal glands were not prospectively delineated. Patients completed the Subjective Evaluation of Symptom of Dryness (SESoD, scored 0-4, with higher scores representing worse dry eye symptoms) at baseline, immediately after WBRT (EndRT), and at 1 month (1M), 3 months, and 6 months. Patients with baseline SESoD ≥3 (moderate dry eye) were excluded. The endpoints analyzed were ≥1-point and ≥2-point increase in SESoD score at 1M. Lacrimal glands were retrospectively delineated with fused magnetic resonance imaging scans. RESULTS: One hundred patients were enrolled, 70 were eligible for analysis, and 54 were evaluable at 1M. Median bilateral lacrimal V20Gy was 79%. At 1M, 17 patients (32%) had a ≥1-point increase in SESoD score, and 13 (24%) a ≥2-point increase. Lacrimal doses appeared to be associated with an increase in SESoD score of both ≥1 point (V10Gy: P = .042, odds ratio [OR] 1.09/%; V20Gy: P = .071, OR 1.03/%) and ≥2 points (V10Gy: P = .038, OR 1.15/%; V20Gy: P = .063, OR 1.04/%). The proportion with increase in dry eye symptoms at 1M for lacrimal V20Gy ≥79% versus <79% was 46% versus 15%, respectively, for ≥1 point SESoD increase (P = .02) and 36% versus 12%, respectively, for ≥2 point SESoD increase (P = .056). CONCLUSIONS: Dry eye appears to be a relatively common, dose/volume-dependent acute toxicity of WBRT. Minimization of lacrimal gland dose may reduce this toxicity, and patients should be counseled regarding the existence of this potential side effect and treatments for dry eye.

Assessing the Effectiveness of Systemic Therapy after Stereotactic Radiosurgery on Cancer Recurrence and All-Cause Mortality.

BACKGROUND: Patients with cancer often present with brain metastases in the setting of controlled extracranial disease, for which they receive stereotactic radiosurgery (SRS) and surgical resection. The role of systemic therapy after SRS is unclear. Brain metastasis indicates active cancer dissemination, and microscopic systemic disease may be present despite absence of gross disease as assessed by conventional imaging modalities. OBJECTIVE: The aim was to determine if post-SRS systemic therapy reduces the risk of brain relapse, systemic relapse, and death in patients with brain metastases and controlled extracranial disease. METHODS: We retrospectively reviewed the medical records of 67 patients with controlled extracranial disease who received SRS for brain metastases. Kaplan-Meier analysis and Cox proportional hazards regression were used to assess how post-SRS systemic therapy affected the risk of brain relapse, systemic relapse, and all-cause mortality. RESULTS: In our sample, 31% of patients received systemic therapy after SRS. Post-SRS systemic therapy did not affect median time to brain relapse (P = 0.43), systemic relapse (P = 0.16), or death (P = 0.33) by univariate analysis. After accounting for confounding factors such as cancer histology and age, post-SRS systemic therapy significantly reduced the risk of brain relapse (hazard ratio [HR], 0.22; P = 0.002) but not systemic relapse (HR, 0.38; P = 0.09) or all-cause mortality (HR, 2.16; P = 0.09). CONCLUSIONS: Only a minority of patients with brain metastases and controlled extracranial disease receive adjuvant systemic therapy after SRS, but those that do have a reduced risk of brain relapse. Post-SRS systemic therapy may act prophylactically to reduce the risk of intracranial cancer recurrence.

Shoulder symptoms and quality of life impact of limited neck dissection after de-intensified chemoradiotherapy: Secondary analysis of two prospective trials.

BACKGROUND: We investigated the quality of life (QOL) impact of post-radiation therapy (RT) superselective/selective neck dissection after de-intensified chemoradiation for human papillomavirus-associated oropharynx cancer. METHODS: A total of 147 patients received 60 Gy and weekly low-dose cisplatin on two phase 2 trials with planned post-RT neck dissection or surveillance positron emission tomography with neck dissection reserved for salvage. UW-QOL Shoulder Score, EORTC H&N-35, and EAT-10 were assessed. RESULTS: In all, 48 of 147 patients had post-RT neck dissection. At 2 years, 37% and 13% of patients receiving post-RT neck dissection had Shoulder Score ≥ 1 (any shoulder symptoms) and ≥ 2 (symptoms affecting work/hobbies), respectively, versus only 16% and 3% of patients not receiving post-RT neck dissection. Post-RT neck dissection was associated with Shoulder Score ≥ 1 (P = 0.005) and Shoulder Score ≥ 2 (P = 0.03) at 2 years, but not H&N-35 or EAT-10 scores. CONCLUSIONS: Post-RT superselective/selective neck dissection was associated with modest but persistent shoulder symptoms. These toxicities should be weighed against the probability of persistent disease when evaluating patients for post-RT neck dissection.