Adjuvant Chemotherapy With or Without Radiotherapy for Resected Pancreatic Cancer After Multiagent Neoadjuvant Chemotherapy.

BACKGROUND: Adjuvant therapy is associated with improved pancreatic cancer survival after neoadjuvant chemotherapy and surgery. However, whether adjuvant treatment should include radiotherapy is unclear in this setting. METHODS: This study queried the National Cancer Database for pancreatic adenocarcinoma patients who underwent curative resection after multiagent neoadjuvant chemotherapy between 2010 and 2019 and received adjuvant treatment. Adjuvant chemotherapy plus radiotherapy (external beam, 45-50.4 gray) was compared with adjuvant chemotherapy alone. Uni- and multivariable Cox regression was used to assess survival associations. Analyses were repeated in a propensity score-matched subgroup. RESULTS: Of 1983 patients who received adjuvant treatment after multiagent neoadjuvant chemotherapy and resection, 1502 (75.7%) received adjuvant chemotherapy alone and 481 (24.3%) received concomitant adjuvant radiotherapy (chemoradiotherapy). The patients treated with adjuvant chemoradiotherapy were younger, were treated at non-academic facilities more often, and had higher rates of lymph node metastasis (ypN1-2), positive resection margins (R1), and lymphovascular invasion (LVI+). The median survival was shorter for the chemoradiotherapy-treated patients according to the unadjusted analysis (26.8 vs 33.2 months; p = 0.0017). After adjustment for confounders, chemoradiotherapy was associated with better outcomes in the multivariable model (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.61-0.93; p = 0.008). The association between chemoradiotherapy and improved outcomes was stronger for the patients with grade III tumors (HR, 0.53; 95% CI, 0.37-0.74) or LVI+ tumors (HR, 0.58; 95% CI, 0.44-0.75). In a subgroup of 396 propensity-matched patients, chemoradiotherapy was associated with a survival benefit only for the patients with LVI+ or grade III tumors. CONCLUSION: After multiagent neoadjuvant chemotherapy and resection for pancreatic cancer, additional adjuvant chemoradiotherapy versus adjuvant chemotherapy alone is associated with improved survival for patients with LVI+ or grade III tumors.

PPARα Agonism Enhances Immune Response to Radiotherapy While Dietary Oleic Acid Results in Counteraction.

PURPOSE: Head and neck cancer (HNC) improvements are stagnant, even with advances in immunotherapy. Our previous clinical trial data show that altered fatty acid (FA) metabolism correlates with outcome. We hypothesized that pharmacologic and dietary modulation of FA catabolism will affect therapeutic efficacy. EXPERIMENTAL DESIGN: We performed in vivo and in vitro experiments using PPARα agonism with fenofibrate (FF) or high oleic acid diets (OAD) with radiotherapy, generating metabolomic, proteomic, stable isotope tracing, extracellular flux analysis, and flow-cytometric data to investigate these alterations. RESULTS: FF improved antitumor efficacy of high dose per fraction radiotherapy in HNC murine models, whereas the OAD reversed this effect. FF-treated mice on the control diet had evidence of increased FA catabolism. Stable isotope tracing showed less glycolytic utilization by ex vivo CD8+ T cells. Improved efficacy correlated with intratumoral alterations in eicosanoid metabolism and downregulated mTOR and CD36. CONCLUSIONS: Metabolic intervention with increased FA catabolism improves the efficacy of HNC therapy and enhances antitumoral immune response.

Simultaneous targeting of PD-1 and IL-2Rßγ with radiation therapy inhibits pancreatic cancer growth and metastasis.

In pancreatic ductal adenocarcinoma (PDAC) patients, we show that response to radiation therapy (RT) is characterized by increased IL-2Rß and IL-2Rγ along with decreased IL-2Rα expression. The bispecific PD1-IL2v is a PD-1-targeted IL-2 variant (IL-2v) immunocytokine with engineered IL-2 cis targeted to PD-1 and abolished IL-2Rα binding, which enhances tumor-antigen-specific T cell activation while reducing regulatory T cell (Treg) suppression. Using PD1-IL2v in orthotopic PDAC KPC-driven tumor models, we show marked improvement in local and metastatic survival, along with a profound increase in tumor-infiltrating CD8+ T cell subsets with a transcriptionally and metabolically active phenotype and preferential activation of antigen-specific CD8+ T cells. In combination with single-dose RT, PD1-IL2v treatment results in a robust, durable expansion of polyfunctional CD8+ T cells, T cell stemness, tumor-specific memory immune response, natural killer (NK) cell activation, and decreased Tregs. These data show that PD1-IL2v leads to profound local and distant response in PDAC.

Vasculitis, CA19-9, and Perineural Invasion Differentially Predict Response and Surgical Outcome in Pancreatic Ductal Adenocarcinoma.

PURPOSE: Curative intent treatment of pancreatic adenocarcinoma (PDAC) relies on surgical resection. Modern treatment protocols focus on optimizing neoadjuvant therapy to increase resectability and improve oncologic outcomes. To elucidate differences in outcomes, we investigated the relationship between neoadjuvant chemotherapy (NAC), either with or without stereotactic body radiation therapy (SBRT), and vascular inflammation, surgical outcomes, and the resultant transcriptomic changes. METHODS AND MATERIALS: Clinical data were collected from patients with borderline resectable PDAC (clinical T3-T4N0-1) who underwent NAC or NAC-SBRT followed by curative intent resection between 2014 and 2019. Vascular structures on surgical specimens were histologically evaluated for vasculitis. RNA sequencing was used to evaluate differential gene expression and to generate enrichment maps. Multivariate analysis was used to analyze the relationship between patient characteristics and oncological outcome. RESULTS: In total, 46 patients met inclusion criteria (n = 12 NAC, n = 34 NAC-SBRT) with a median follow-up of 20.1 months. All patients underwent curative resection, with 91.3% achieving R0. There was no significant difference in patterns of failure, overall survival, or progression-free survival between NAC and NAC-SBRT groups. Patients with vasculitis had a lower median overall survival compared with those without (14.5 vs 28.3 months; hazard ratio, 12.96; 95% confidence interval, 3.55-47.28; P < .001). There was no significant correlation between inflammation and surgical complications or pathologic response. Neoadjuvant therapy did not have a significant effect on development of vasculitis (odds radio, 1.64 for NAC-SBRT; 95% confidence interval, 0.40-8.43; P = .52). Predictors of poor survival included perineural invasion and high baseline carbohydrate antigen 19-9 (CA19-9) (>191 U/mL). Patients with robust CA19-9 (>20% decrease) responses to neoadjuvant therapy had enrichment in immune response, chemotaxis, and cytotoxic T-cell and natural killer-cell proliferation. CONCLUSIONS: Vasculitis predicts for poor survival outcomes in patients with PDAC; NAC-SBRT did not increase the rate of vasculitis compared with NAC. Perineural invasion and CA19-9 remain strong prognosticators. Understanding and optimizing immune interactions remain a crucial hurdle in achieving response in pancreatic cancer.

A matched comparison of human papillomavirus-induced squamous cancer of unknown primary with early oropharynx cancer.

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, 128:1379-1385, 2018.

Modern Image-Guided Intensity-Modulated Radiotherapy for Oropharynx Cancer and Severe Late Toxic Effects: Implications for Clinical Trial Design.

Importance: Late toxic effects are common after definitive radiotherapy and chemoradiotherapy for oropharynx cancer and are considered a significant contributor to decreased quality of life for survivors. The incidence of severe late toxic effects may be reduced by modern narrow-margin image-guided intensity-modulated radiotherapy (IG-IMRT), current supportive care improvements, and the changing epidemiology of oropharynx cancer. Objective: Assess the incidence of severe late toxic effects after modern definitive non-operative treatment for oropharynx cancer. Design, Setting, and Participants: For this single-institution retrospective review, 156 patients with stage I-IVB squamous cell carcinoma of the oropharynx treated between April 2009 and February 2015 at a tertiary-referral academic multidisciplinary head and neck practice were recruited. Interventions: Definitive narrow-margin IG-IMRT to a dose of 66 Gy (to convert milligray to rad, multiply by 0.1) or higher with or without concurrent cisplatin. Main Outcomes and Measures: The primary outcome was the prospectively collected 2-year cumulative incidence of severe late toxic effects (Common Terminology Criteria for Adverse Events grade 3 or higher) occurring 3 months or more after radiotherapy. Toxic effect end points investigated included esophageal stricture requiring dilation, aspiration pneumonia hospitalization, vocal dysfunction, delayed feeding tube insertions, and osteoradionecrosis. Feeding tube dependence at 1 year was also considered a severe late toxic effect. Secondary outcomes collected include physician-reported grade 2 or higher neck fibrosis and xerostomia. The competing risks of recurrence and death were accounted for using the Gray method. Results: One-hundred fifty-six patients (median [range] age, 58 [37-96] years) were identified; 130 patients (83%) were HPV positive. Concurrent cisplatin was delivered in 131 patients (84%) and 5 patients (3%) underwent an adjuvant neck dissection. The median (range) follow-up for survivors was 22 (4-73) months from diagnosis. The projected 2-year locoregional control was 93% (95% CI, 88.4%-97.6%) and overall survival was 88% (95% CI, 82.2%-94.0%). Thirty-eight patients (23%) required a feeding tube during treatment. The cumulative incidence of severe late toxic effects adjusted for competing risks at 2-year posttreatment was 2.3% (95% CI, 0%-5.6%). One patient required free-flap reconstruction for grade 3 osteoradionecrosis at 47 months. At 1 year, 2 patients (1%) experienced grade 2 neck fibrosis and 38 patients (23%) experienced grade 2 xerostomia. Conclusions and Relevance: These results suggest that severe late toxic effects after modern definitive IG-IMRT, with or without cisplatin, for oropharynx cancer is likely uncommon. The importance of late toxic effect reduction in current and future investigational strategies, including clinical trials, should be considered.