Influence of Treatment Package Time on outcomes in High-Risk Oral Cavity Carcinoma in patients receiving Adjuvant Radiation and Concurrent Systemic Therapy: A Multi-Institutional Oral Cavity Collaborative study.

OBJECTIVES: To explore the influence of treatment package time(TPT) in high-risk oral cavity squamous cell carcinoma(OCSCC) receiving adjuvant radiotherapy with concurrent chemotherapy(CRT). MATERIALS AND METHODS: We queried our multi-institutional OCSCC collaborative database for cases diagnosed between 2005 and 2015 who underwent surgery followed by adjuvant CRT. All patients had high-risk features: extranodal extension(ENE) and/or positive surgical margin(PM). TPT was days between surgery to last radiotherapy fraction. Kaplan-Meier curves, log-rank p-values and multivariate analysis(MVA) were used to investigate the impact of TPT on overall(OS), disease-free(DFS), locoregional failure-free(LRFS) and distant metastases-free(DMFS) survival. RESULTS: We identified 187 cases: median age 58 (range, 24-87 years), males 66%, and ever smokers 69%. ENE and PM were detected in 85% and 32%, and oral tongue and floor of the mouth constituted 49% and 18%, respectively. Median radiotherapy and cisplatin doses received were 66 Gy and 200 mg/m2. Overall, median TPT was 98 (range, 63-162 days). OS was worse for TPT > 90-days (n = 134) than TPT ≤ 90 (n = 53) at two-(65% vs. 71%) and five-years (45% vs. 62%); p = 0.05, with similar results for DFS. No influence on LRFS or DMFS was noted. More lymph nodes(LN) dissected(P = 0.039), T3-4 disease(P = 0.017), and unplanned reoperations(P = 0.037) occurred with TPT > 90-days. On MVA, TPT in 10-day increments was independently detrimental for OS (Hazard Ratio: 1.14; 95 %Confidence Interval [1-1.28]; P = 0.043), perineural invasion, age and positive LN (p < 0.05 for all). CONCLUSION: In one of the largest multi-institutional cohorts, TPT > 90-days predicted worse OS for high-risk OCSCC receiving adjuvant CRT. All efforts are needed to optimize perioperative care and baseline conditions for favorable outcomes.

Stereotactic Radiotherapy and Short-course Pembrolizumab for Oligometastatic Renal Cell Carcinoma-The RAPPORT Trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is an option for oligometastatic clear cell renal cell carcinoma (ccRCC) but is limited by a lack of prospective clinical trial data. OBJECTIVE: The RAPPORT trial evaluated the safety and efficacy of total metastatic irradiation followed by short-course anti-programmed death receptor-1 immunotherapy in patients with oligometastatic ccRCC. DESIGN SETTING, AND PARTICIPANTS: RAPPORT was a single-arm multi-institutional phase I/II trial (NCT02855203). Patients with two or fewer lines of prior systemic therapy and one to five oligometastases from ccRCC were eligible. INTERVENTION: A single fraction of 20 Gy SABR (or if not feasible, ten fractions of 3 Gy) was given to all metastatic sites, followed by pembrolizumab 200 mg administered Q3W for eight cycles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The endpoints were adverse events (AEs), disease control rate (DCR) for at least 6 mo, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The Kaplan-Meier method was used for time-to-event endpoints. Freedom from local progression (FFLP) was assessed per lesion adding patient as a cluster effect. RESULTS AND LIMITATIONS: Thirty evaluable patients, with a median age of 62 yr, were enrolled. The median follow-up was 28 mo. There were 44% of patients with intermediate-risk and 56% with favorable-risk disease. Eighty-three oligometastases were irradiated (median three per patient): eight adrenal, 11 bone, 43 lung, 12 lymph node, and nine soft tissue. Four patients (13%) had grade 3 treatment-related AEs: pneumonitis (n = 2), dyspnea (n = 1), and elevated alkaline phosphatase/alanine transaminase (n = 1). There were no grade 4 or 5 AEs. FFLP at 2 yr was 92%. ORR was 63% and DCR was 83%. Estimated 1- and 2-yr OS was 90% and 74%, respectively, and PFS was 60% and 45%, respectively. Limitations include a single-arm design and selected patient population. CONCLUSIONS: SABR and short-course pembrolizumab in oligometastatic ccRCC is well tolerated, with excellent local control. Durable responses and encouraging PFS were observed, warranting further investigation. PATIENT SUMMARY: The RAPPORT trial investigated the combination of high-dose precision radiotherapy and a short course of immunotherapy in patients with low-volume metastatic kidney cancer. We found that this treatment regimen was well tolerated, with excellent cancer control in sites of known disease. A proportion of patients were free from cancer relapse in the longer term, and these encouraging findings warrant further investigation.

Stereotactic ablative radiotherapy for hepatocellular carcinoma: A systematic review and meta-analysis of local control, survival and toxicity outcomes.

There is a growing body of literature supporting the use of stereotactic ablative body radiotherapy (SABR) in the management of primary hepatocellular carcinoma (HCC). This systematic review and meta-analysis of the current published evidence for SABR for HCC assessed the impact of treatment dose, fractionation and tumour size on the outcomes of local control (LC), overall survival (OS) and toxicity. A systematic search was independently performed by two authors for articles published in peer-reviewed journals between January 2005 and December 2019. A DerSimonian and Laird random effects model was used to assess pooled results. A multivariate meta-regression analysis incorporated the effect of explanatory variables (radiation dose in EQD2[10], fractionation and tumour size) on outcomes of OS, LC and toxicity. Forty-nine cohorts involving 2846 HCC patients with 3088 lesions treated with SABR were included. Pooled 1-, 2- and 3-year LC rates were 91.1% (95% confidence interval [CI] 88.3-93.2), 86.7% (95% CI 82.7-89.8) and 84.2% (95% CI 77.9-88.9) respectively. Pooled 1-, 2- and 3-year OS rates were 78.4% (95% CI 73.4-82.6), 61.3% (55.2-66.9) and 48.3% (95% CI 39.0-57). Population-weighted median grade 3 toxicity rates were 6.5% (IQR 3.2-16) and mean grade 4/5 rates were 1.4% (IQR 0-2.1). Within EQD2[10] ranges of 40 to 83.33 Gy corresponding to common dose-fractionation regimens of 30-50 Gy in 5 fractions, there was a multivariate association between superior LC and OS with increasing EQD2[10] , with a proportionately smaller increase in grade 3 toxicity and no association with grade 4/5 toxicity. Stereotactic ablative body radiotherapy is a viable treatment option for HCC with high LC rates and low rates of reported grade 3/4 toxicity. Increasing EQD2[10] was associated with improvements in LC and OS with a comparatively smaller increase in toxicity. Prospective randomised trials are warranted to define optimal patient selection and dose-fractionation regimens.

Outcomes of Post-Operative Treatment with Concurrent Chemoradiotherapy (CRT) in High-Risk Resected Oral Cavity Squamous Cell Carcinoma (OCSCC): A Multi-Institutional Collaboration.

Adjuvant chemoradiation (CRT), with high-dose cisplatin remains standard treatment for oral cavity squamous cell carcinoma (OCSCC) with high-risk pathologic features. We evaluated outcomes associated with different cisplatin dosing and schedules, concurrent with radiation (RT), and the effect of cumulative dosing of cisplatin. An IRB-approved collaborative database of patients (pts) with primary OCSCC (Stage I-IVB AJCC 7th edition) treated with primary surgical resection between January 2005 and January 2015, with or without adjuvant therapy, was established from six academic institutions. Patients were categorized by cisplatin dose and schedule, and resultant groups compared for demographic data, pathologic features, and outcomes by statistical analysis to determine disease free survival (DFS) and freedom from metastatic disease (DM). From a total sample size of 1282 pts, 196 pts were identified with high-risk features who were treated with adjuvant CRT. Administration schedule of cisplatin was not significantly associated with DFS. On multivariate (MVA), DFS was significantly better in patients without perineural invasion (PNI) and in those receiving ≥200 mg/m2 cisplatin dose (p < 0.001 and 0.007). Median DFS, by cisplatin dose, was 10.5 (<200 mg/m2) vs. 20.8 months (≥200 mg/m2). Our analysis demonstrated cumulative cisplatin dose ≥200 mg/m2 was associated with improved DFS in high-risk resected OCSCC pts.

Indications and limits of postoperative radiotherapy for skin malignancies.

PURPOSE OF REVIEW: To provide a summary of the current evidence, with a focus on recent publications, pertaining to indications for postoperative radiation therapy for cutaneous squamous-cell carcinoma (cSCC), basal-cell carcinoma, Merkel-cell carcinoma and melanoma of the head and neck. RECENT FINDINGS: Meta-analyses in cSCC and Merkel-cell carcinoma have shown an association between postoperative radiation therapy and overall survival. Prospective phase III data in head and neck cSCC has shown excellent locoregional control following surgery and postoperative radiation therapy. The addition of concurrent cytotoxic chemotherapy to postoperative radiation therapy has not improved outcomes in either of these two entities. Postoperative immune checkpoint inhibition or combined BRAF and MEK blockade in stage-III melanoma improves progression-free survival whereas postoperative radiation therapy does not. SUMMARY: Further improvement in outcomes with high-risk cSCC and Merkel-cell carcinoma might be achieved with concurrent or sequential immune checkpoint inhibition and postoperative radiation therapy. Postoperative radiation therapy for cutaneous melanoma should be reserved for patients in whom novel systemic therapies are not a treatment option.

Stereotactic radiotherapy for hepatocellular carcinoma: Expanding the multidisciplinary armamentarium.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third most common cause of cancer-related death. Long-term prognosis remains poor with treatment options frequently limited by advanced tumor stage, tumor location, or underlying liver dysfunction. Stereotactic ablative body radiotherapy (SABR) utilizes technological advances to deliver highly precise, tumoricidal doses of radiation. There is an emerging body of literature on SABR in HCC demonstrating high rates of local control in the order of 80-90% at 3 years. SABR is associated with a low risk of radiation-induced liver disease or decompensation in appropriately selected HCC patients with compensated liver function and is now being incorporated into guidelines as an additional treatment option. This review outlines the emerging role of SABR in the multidisciplinary management of HCC and summarizes the current evidence for its use as an alternative ablative option for early-stage disease, as a bridge to transplant, and as palliation for advanced-stage disease. We outline specific considerations regarding patient selection, toxicities, and response assessment. Finally, we compare current international guidelines and recommendations for the use of SABR and summarize ongoing studies.