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Background For patients with melanoma, gastrointestinal immune-related adverse events are common after receipt of anti-CTLA4 therapy. These present difficult decision points regarding whether to discontinue therapy. Detailing the situations in which colitis might predict for improved survival and how this is affected by discontinuation or resumption of therapy can help guide clinical decision-making. Materials and Methods Patients with stage IV melanoma receiving anti-CTLA4 therapy from 2008 to 2019 were analyzed. Immune-related colitis treated with ≥50 mg prednisone or equivalent daily or secondary immunosuppression was included. Moderate colitis was defined as receipt of oral glucocorticoids only; severe colitis was defined as requiring intravenous glucocorticoids or secondary immunosuppression. The primary outcome was overall survival (OS). Results In total, 171 patients received monotherapy, and 91 received dual checkpoint therapy. In the monotherapy group, 25 patients developed colitis and a nonsignificant trend toward improved OS was observed in this group. Notably, when colitis was categorized as none, moderate or severe, OS was significantly improved for moderate colitis only. This survival difference was not present after dual checkpoint therapy. There were no differences in known prognostic variables between groups, and on multivariable analysis neither completion of all ipilimumab cycles nor resumption of immunotherapy correlated with OS, while the development of moderate colitis did significantly affect OS. Conclusion This single-institution retrospective series suggests moderate colitis correlates with improved OS for patients with stage IV melanoma treated with single-agent anti-CTLA4, but not dual agent, and that this is true regardless of whether the immune-checkpoint blockade is permanently discontinued.

The recently identified bilateral macroscopic tubarial salivary glands present a potential opportunity for further toxicity mitigation for patients receiving head and neck radiotherapy. Here, we show superior dosimetric sparing of the tubarial salivary glands with proton radiation therapy (PRT) compared to intensity-modulated radiotherapy (IMRT) for patients treated postoperatively for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). This was a retrospective, single institutional study of all patients treated with adjuvant PRT for HPV-associated OPSCC from 2015 to 2019. Each patient had a treatment-approved, equivalent IMRT plan to serve as a reference. The main end point was dose delivered to the tubarial salivary glands by modality, assessed via a 2-tailed, paired t-test. We also report disease outcomes for the entire cohort, via the Kaplan-Meier method. Sixty-four patients were identified. The mean RT dose to the tubarial salivary glands was 23.6 Gy (95% confidence interval (CI) 21.7 to 25.5) and 30.4 Gy (28.6 to 32.2) for PRT and IMRT plans (p0.0001), respectively. With a median follow-up of 25.2 months, the two-year locoregional control, progression-free survival and overall survival were 97.8% (95% CI 85.6% to 99.7%), 94.1% (82.8% to 98.1%) and 98.1% (87.4% to 99.7%), respectively. Our study suggests that meaningful normal tissue sparing of the recently identified tubarial salivary glands is achievable with PRT. The apparent gains with PRT did not impact disease outcomes, with only 1 observed locoregional recurrence (0 local, 1 regional). Further studies are warranted to explore the impact of the improved dosimetric sparing of the tubarial salivary glands conveyed by PRT on patient toxicity and quality of life.

We evaluated if proton therapy is associated with decreased acute toxicities compared to intensity-modulated radiation therapy (IMRT) in patients receiving concurrent chemoradiotherapy for head and neck cancers.We analyzed 580 patients with nonmetastatic head and neck cancers. Primary endpoint was any 90-day grade ≥3 toxicity, prospectively collected and graded per CTCAEv4. Modified Poisson regression models were used.Ninety-five patients received proton and 485 IMRT. The proton group had more HPV-positive tumors (65.6 vs. 58.0%, p = 0.049), postoperative treatment (76.8 vs. 62.1%, p = 0.008), unilateral neck treatment (18.9 vs. 6.6%, p 0.001) and significantly lower doses to organs-at-risk compared to IMRT group. Adjusted for patient and treatment characteristics, the proton group had decreased grade 2 dysgeusia (RR0.67, 95%CI 0.53-0.84, p = 0.004) and a trend toward lower grade ≥3 toxicities (RR0.60, 95%CI 0.41-0.88, p = 0.06).Proton therapy was associated with significantly reduced grade 2 dysgeusia and nonstatistically significant decrease in acute grade ≥3 toxicities compared to IMRT.

Although dose de-escalation is one proposed strategy to mitigate long-term toxicity in human papillomavirus associated oropharyngeal cancer, applying more stringent normal tissue constraints may be a complementary approach to further reduce toxicity. Our study demonstrates that in a postoperative setting, improving upon nationally accepted constraints is achievable and leads to reductions in normal tissue complication probabilities (NTCP) without compromising disease control.We identified 92 patients at our institution between 2015 and 2019 with p16+ oropharyngeal cancer who were treated with adjuvant volumetric modulated arc therapy. We included patients treated to postoperative doses and standard volumes (including bilateral neck). Doses delivered to organs at risk were compared with recommended dose constraints from a recent cooperative group head and neck cancer trial of radiation therapy to 60 Gy. We applied validated and published NTCP models for dysphagia, dysgeusia, esophagitis, oral mucositis, and xerostomia relevant to oropharyngeal cancer.Achievable and delivered mean doses to most normal head and neck tissues were well below national recommended constraints. This translates to notable absolute NTCP reductions for salivary flow (10% improvement in contralateral parotid, 35% improvement in submandibular gland), grade ≥ 2 esophagitis (23% improvement), grade ≥ 3 mucositis (17% improvement), dysgeusia (10% improvement), and dysphagia (8% improvement). Locoregional control at a median follow-up of 26.3 months was 96.7%, with only 3 patients experiencing locoregional recurrence (1 local, 2 regional).Modern radiation therapy planning techniques allow for improved normal tissue sparing compared with currently established dose constraints without compromising disease control. These improvements may lead to reduced toxicity in a patient population expected to have favorable long-term outcomes. Stricter constraints can be easily achieved and should be used in conjunction with other evolving efforts to mitigate toxicity.

PURPOSE: Physical activity is associated with decreased hospitalization during cancer treatment. We hypothesize that activity data can help identify and triage high-risk patients with GI cancer undergoing concurrent chemoradiation. MATERIALS AND METHODS: This prospective study randomly assigned patients to activity monitoring versus observation. In the intervention arm, a 20% decrease in daily steps or 20% increase in heart rate triggered triage visits to provide supportive care, medication changes, and escalation of care. In the observation group, activity data were recorded but not monitored. The primary objective was to show a 20% increase in triage visits in the intervention group. Secondary objectives were estimating the rates of emergency department (ED) visits and hospitalizations. Crude and adjusted odds ratios were computed using logistic regression modeling. RESULTS: There were 22 patients in the intervention and 18 in the observation group. Baseline patient and treatment characteristics were similar. The primary objective was met, with 3.4 more triage visits in the intervention group than in the observation group (95% CI, 2.10 to 5.50; P < .0001). Twenty-six (65.0%) patients required at least one triage visit, with a higher rate in the intervention arm compared with that in the observation arm (86.4% v 38.9%; odds ratio, 9.95; 95% CI, 2.13 to 46.56; P = .004). There was no statistically significant difference in ED visit (9.1% v 22.2%; P = .38) or hospitalization (4.5% v 16.7%; P = .31). CONCLUSION: It is feasible to use activity data to trigger triage visits for symptom management. Further studies are investigating whether automated activity monitoring can assist with early outpatient management to decrease ED visits and hospitalizations.

The coronavirus disease 2019 (COVID-19) pandemic resulted in severe interruptions to clinical research worldwide. This global public health crisis required investigators and researchers to rapidly develop and implement new strategies and solutions to mitigate its negative impact on the progress of clinical trials. In this paper, we describe the challenges, strategies, and lessons learned regarding the continuation of a supportive oncology clinical trial during the pandemic. We hope to provide insight into the implementation of clinical trials during a public health emergency to be better prepared for future instances.Trial registration: ClinicalTrials.gov, a service of the US National Institute of Health (NCT 03030859). Registered on 22 January 2017.

PURPOSE/OBJECTIVE(S) To identify the patient characteristics, treatment indications, and toxicities among patients receiving proton beam therapy (PBT) in the final year of life at a tertiary academic medical center. MATERIALS/METHODS A retrospective review of patients who received PBT within the final 12 months of life was performed. Electronic medical records were reviewed for patient and treatment details from 2010-2019. Follow-up was calculated from start of PBT until death or last follow-up. Treatment intent was retrospectively defined as curative treatment for localized disease, for isolated local recurrence, oligometastatic disease, durable local control, or palliation of symptoms. Durable local control was defined as treatment for durable control of otherwise incurable disease whereas palliation was defined as treatment for symptom palliation only. Acute ( 3 months) toxicities were graded using the CTCAE v5.0. Chi-square test was performed to evaluate factors associated with palliative treatment. Simple logistic regression was used to evaluate factors associated with any acute toxicity. RESULTS During the study period, 299 patients were treated at the end of life (EOL) out of 5802 total patients treated with PBT (5.2%). Mean age was 66 years (19-94 years), with 58% male. The most common cancers were non-small cell lung cancer (27%), hepatocellular carcinoma (13%), and small cell lung cancer (6%). Eleven percent of patients were treated for symptom palliation; the remainder were treated for durable local control (57%), definitively (16%), for an isolated local recurrence (14%), or oligometastatic disease (2%). Forty-five percent received PBT for re-irradiation. Concurrent systemic therapy was delivered to 47%. Median prescribed dose was 50 Gy (15-80 Gy). Mean treatment time was 34 days (1-189 days). Seven patients received split-course proton therapy for hepatocellular carcinoma. Median time from final fraction to death was 139 days (1-363 days). On average, patients spent 24% of the remaining days of life receiving PBT. Acute toxicity of any grade was noted in 85% of patients (31% G1, 53% G2, 15% G3). Fifty-two patients (17%) experienced chronic toxicity, the most severe of which was a tracheo-esophageal fistula (G4). In the chi-square test, breast and hematologic malignancy were associated with palliative intent (χ2 (1, N = 14) = 15.9, P < 0.001; (χ2 (1, N = 14) = 15.9, P < 0.001). In the simple logistic regression model, concurrent systemic therapy was positively associated with any acute toxicity (OR: 2.0, P = 0.05). CONCLUSION The number of patients treated with PBT at the EOL was low compared to all-comers. Many of these patients received treatment with definitive doses and concurrent systemic therapy. Nearly half received re-irradiation. Grade 3 or higher acute toxicity was moderate, and some patients spent a large portion of their remaining days on treatment. Thus, the incorporation of a prognostic indicator in clinical practice may further optimize use of PBT.

PURPOSE/OBJECTIVE(S) Toxicity mitigation is a salient focus in the treatment of HPV-associated oropharyngeal cancer. As the standard of care evolves, toxicity mitigation can be facilitated by adopting more stringent normal tissue constraints. We hypothesize that further reduction in currently accepted constraints leads to reductions in normal tissue complication probabilities (NTCP) without compromising disease outcomes. MATERIALS/METHODS This was a retrospective, single-institution study of patients with oropharynx cancer treated with adjuvant volumetric modulated arc therapy to standard doses (60-66 Gy) and volumes (i.e., bilateral neck) from 2015-2018. Doses delivered to organs at risk were compared to recommended dose acceptance criteria from a recent, cooperative trial of RT to 60 Gy (NRG HN002). We applied validated, published NTCP models for xerostomia, dysphagia, dysgeusia, oral mucositis and esophagitis relevant to oropharyngeal cancer. RESULTS 92 patients were identified. Median follow-up was 2.2 years. The doses achieved and corresponding estimates of NTCP are shown in Table 1, as compared to a nationally recognized standard (NRG HN002). Notable NTCP reductions were observed for salivary flow, dysphagia, dysgeusia, mucositis, and esophagitis. The use of more stringent constraints did not impact disease outcome, with only a total of 3 patients having experienced locoregional recurrence (1 local, 2 regional), for an overall locoregional control of 96.7%. CONCLUSION Improved normal tissue sparing compared to current dose constraint standards is achievable with contemporary RT planning techniques. These improved constraints may lead to decreased toxicity, while preserving excellent disease outcomes. Our constraints can easily be adopted as standard of care and used in conjunction with other efforts to mitigate toxicity.

PURPOSE/OBJECTIVE(S) Patients undergoing concurrent chemoradiotherapy (CRT) for head and neck cancer often experience significant toxicities. Proton therapy permits decreased dose delivery to non-target structures and the potential for superior organs-at-risk sparing. The aim of this study was to evaluate if proton therapy is associated with decreased acute grade ≥3 toxicities compared to photon therapy in the setting of concurrent CRT for head and neck cancers. MATERIALS/METHODS This study included 654 adult patients with nonmetastatic, locally advanced head and neck cancer treated with definitive concurrent CRT from January 1, 2011 to April 30, 2019 at one institution. 90-day toxicity data were prospectively collected as defined by Common Terminology Criteria for Adverse Events, version 4. Acute toxicities were grouped into five categories for analysis: mucosal (mucosal infection, mucositis), oral cavity (dry mouth, dysgeusia), swallow (aspiration, dysphagia), constitutional (fatigue, anorexia, dehydration), and skin (dermatitis, edema, superficial soft tissue necrosis, alopecia) toxicities. Modified Poisson regression models with covariate adjustment were used to model toxicity risk following multiple imputation for missing covariate values. Ten hypotheses were tested. Thus, the Bonferroni multiple testing correction was applied and statistical significance was assessed at the 0.005 level. RESULTS One hundred and six patients received proton therapy and 548 received photon therapy. Patients receiving proton therapy were older (mean age [SD] 61.2 [12.2] vs 58.9 [9.30], P = 0.029) and were more likely to be HPV-positive (67.0% vs 57.0%, P = 0.036). Proton therapy patients had lower dose to the parotid glands (right mean [SD], 21.8 Gy [12.9] vs 27.9 [11.3], P < 0.001; left 23.1 Gy [12.7] vs 27.2 [11.0], P = 0.001), oral cavity (13.7 Gy [9.88] vs 28.8 [10.8], P < 0.001) and constrictor muscle (35.6 Gy [10.37] vs 43.7 [9.24], P < 0.001) compared to photon therapy patients. Charlson-Deyo comorbidity scores were similar for both groups (mean [SD] 6.18 [1.74] vs 6.40 [2.57], P = 0.39), as were the distributions for sex (P = 0.118), race (P = 0.16), cancer stage (P = 0.163), and baseline ECOG (P = 0.57). In covariate-adjusted analyses, proton therapy was associated with a significantly lower relative risk of any 90-day grade ≥3 toxicity (0.57, 95% CI 0.40-0.83, P = 0.003). For acute grade 2 toxicity proton therapy was associated with significantly reduced relative risk of oral cavity toxicity (0.74, 95% CI 0.61-0.90, P = 0.002) but higher skin toxicity (1.35, 95% CI 1.14-1.59, P = 0.0004). CONCLUSION Concurrent chemoradiotherapy with proton therapy for head and neck cancers was associated with lower dose to nontarget structures and significantly reduced acute grade ≥3 toxicity and acute grade 2 oral cavity toxicity compared to photon therapy. Grade 2 skin toxicity favored photon therapy.

OBJECTIVES: Increasing use of transoral robotic surgery (TORS) is likely to impact outcomes for HPV+ oropharyngeal squamous cell carcinomas (OPSCCs). We aimed to describe oncologic outcomes for a large HPV+ OPSCC cohort after TORS and develop a risk prediction model for recurrence under this treatment paradigm. MATERIALS AND METHODS: 634 HPV+ OPSCC patients receiving TORS-based therapy at a single institution were reviewed retrospectively to describe survival across the entire cohort and for patients suffering recurrence. Risks for distant metastatic recurrence (DMR) and locoregional recurrence (LRR) were modeled using multivariate logistic regression analyses of case-control sub-cohorts. RESULTS: 5-year overall and recurrence-free survival were 91.2% and 86.1%, respectively. 5-year overall survival was 52.5% following DMR and 83.3% after isolated LRR (P=.01). In case-control analyses, positive surgical margins were associated with DMR (adjusted OR 5.8, CI 2.1–16.0, P=.001), but not isolated LRR, and increased DMR risk 4.2 fold in patients with early clinical stage disease. By contrast, LRR was associated with not receiving recommended adjuvant therapy (OR 13.4, CI 6.3–28.5, P

Purpose/Objective(s) Patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) generally have a good prognosis, though those with locally advanced (LA) disease are at increased risk of locoregional failure (LRF) and distant metastases (DM). A recent SEER study suggested improvement in overall survival and cancer-specific mortality with trimodality therapy compared to definitive chemoradiation (dCRT) for LA HPV+ OPSCC, but is prone to confounding and lacks pattern of failure data. We therefore performed this retrospective analysis of oncologic outcomes for patients with T3/T4 HPV+ OPSCC treated at a high-volume TORS center with surgery +/- adjuvant therapy compared to dCRT alone. Materials/Methods Included were patients with cT3/T4 HPV+ OPSCC treated with dCRT or upfront TORS +/- adjuvant therapy from 2010-2019 with ≥1 year of follow-up. Patients with DM at diagnosis were excluded. Primary outcomes were freedom from LRF (FF-LRF) and LRF leading to death, defined as LRF directly resulting in death or occurring at the same time or before DM resulting in death. Secondary outcomes were freedom from DM (FF-DM) and cancer-specific survival (CSS). Patients were risk stratified based on criteria in the secondary analysis of RTOG 0129 by Ang et al (NEJM 2010): Low-risk: ≤10 pack-year (py) smoking, or > 10 py and N0–N2a disease (AJCC 7th ed.); Intermediate-risk: > 10 py and N2b-N3 disease. Fisher's exact test was used to compare demographics and Kaplan-Meier estimates to compare endpoints. Results 78 patients were treated with dCRT and 44 with upfront TORS. Significantly more dCRT patients were Intermediate-risk (per RTOG 0129 criteria) compared to TORS patients (35.9% vs 6.8%, P Conclusion This large, single-institution series of patients with T3/T4 HPV+ OPSCC treated with either dCRT or upfront TORS +/- adjuvant therapy shows high FF-LRF and low rates of LRF leading to death regardless of treatment. Even in patients with advanced T stage, dCRT was able to obtain excellent disease outcomes. Future prospective studies are warranted to determine which combinations of multimodality therapy are optimal for LA HPV+ OPSCC, incorporating both oncologic and functional outcome endpoints.

Purpose/Objective(s) This study sought to measure circulating plasma tumor-tissue modified human papilloma virus DNA (TTMV-HPV DNA) and kinetics following trans-oral robotic surgery (TORS), neck dissection, and adjuvant (chemo)radiation for p16+ oropharyngeal squamous cell carcinoma (OPSCC). Materials/Methods Patients with p16+ OPSCC currently enrolled on an ongoing phase II clinical trial investigating radiation dose de-intensification following TORS and neck dissection (TORS version 2.0, NCT03729518) with available post-operative plasma samples were included. Plasma was collected following TORS procedure (∼6 weeks post-operatively), during adjuvant (chemo)radiation, and at treatment completion. Plasma samples were analyzed for TTMV-HPV DNA using a liquid biopsy assay. Multivariate robust linear regression analysis was used to identify clinicopathologic features associated with detectable post-operative TTMV-HPV DNA levels. Results Thirty-four patients were included (median age 59 years, IQR 55-62 years; 94% male). The majority of patients had pT1-2 (n = 32, 94%; 1 pT0,1 pT3) and pN1 (n = 32, 94%; 2 pN0) disease. Other pathologic features included LVI (n = 5, 15%), PNI (n = 2, 6%), close or positive margin (n = 9, 26%), number of positive nodes (median 1.5, IQR 1-2), largest node size (median 3.7 cm, IQR 3.0-4.4 cm), and ENE (n = 8, 24%; 4 macroscopic). The majority of patients had undetectable TTMV-HPV DNA following TORS (n = 31, 91%). Three patients (9%) had detectable TTMV-HPV DNA post-operatively with 2 having very low detectable levels (≤ 10 copies/mL) and 1 having a high detectable level (4421 copies/mL). Largest node size (P = 0.0083) and ENE (P = 0.041) were significantly associated with detectable post-operative TTMV-HPV DNA levels. Of those with initially undetectable TTMV-HPV DNA, levels remained undetectable during and after adjuvant (chemo)radiation with 1 patient developing a very low detectable level (7 copies/mL) following treatment. The 2 patients with low detectable TTMV-HPV DNA levels post-operatively (≤ 10 copies/mL) had complete clearance following adjuvant therapy. There were no locoregional recurrences (median follow-up 15 months, IQR 12-21 months) including the patient who developed a low detectable level (7 copies/mL) following treatment (currently 24 months post-TORS). The patient with the high detectable level post-operatively (4421 copies/mL) developed osseous metastatic disease 5 months post-TORS. Conclusion Tumor-tissue modified HPV DNA can be detected with high sensitivity following definitive surgery for p16+ OPSCC. Further prospective studies are warranted to determine if the observed range of post-operative values allows for stratification of patients into those with distant metastatic disease, persistent locoregional disease that warrants adjuvant therapy, versus active surveillance.

PURPOSE/OBJECTIVE(S) Recent landmark trials have suggested a survival benefit to definitive tumor directed therapies (DTDT) for selected patients with metastatic disease for various malignancies. We sought 1) to confirm the prognostic significance of metachronous oligometastatic burden for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) and 2) to evaluate disease outcomes for oligometastatic HPV-associated OPSCC after upfront DTDT versus upfront systemic therapy. MATERIALS/METHODS This was a single institution retrospective observational cohort study of patients with HPV-associated OPSCC who developed metachronous metastases ≥3 months after primary treatment with trans-oral robotic surgery (TORS) from 2008-2017. At metastatic presentation, patients were classified as oligometastatic (≤5 metastases) or polymetastatic (> 5 metastases). Treatment was classified as DTDT (all metastases initially treated with surgery/radiotherapy) or as upfront systemic therapy. Overall survival (OS) was compared using log-rank tests at a significance of P < 0.05. Univariable and multivariable (MV) Cox proportional hazard models were used to assess the association of patient, disease, and treatment characteristics with survival. Variables with P < 0.15 on univariable analysis (initial metastatic treatment, metastatic site, and number of metastases) were included in the multivariable model. RESULTS Of 676 patients undergoing primary surgical management for HPV-associated OPSCC, 36 patients subsequently developed metachronous metastases. For those 36 patients, the median follow-up time after surgery was 27.5 months (range 4.5-127.0), and the median OS was 42.8 months. The median age at distant metastasis was 62 (range 32-86), and most patients were male (86.1%) and Caucasian (97.2%). Overall, 27 patients presented with oligometastasis and 9 with polymetastasis. Oligometastatic patients had improved median OS compared to polymetastatic patients (47.9 vs. 22.7 months, P = 0.020). For the 27 oligometastatic patients, 12 were initially treated with DTDT while 15 received systemic therapy. DTDT was associated with an improved median OS when compared to systemic therapy (median OS not reached for DTDT vs 40.7 months, P = 0.021), with 3 year OS of 90.0% and 55.0% respectively. DTDT was also associated with improved OS on MV Cox regression (hazard ratio = 0.06, 95% CI 0.004-0.73, P = 0.027) compared to systemic therapy when controlling for number of metastases and metastatic site. CONCLUSION Our study findings suggest that the extent of metastatic disease at metastatic presentation is related to prognosis, with oligometastasis associated with improved overall survival compared to polymetastasis. Among patients with oligometastatic disease, initial DTDT is associated with superior overall survival when compared to upfront systemic therapy.