Clinical outcomes of melanoma brain metastases treated with nivolumab and ipilimumab alone versus nivolumab and ipilimumab with stereotactic radiosurgery.

PURPOSE: Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS. METHODS: 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan-Meier method. RESULTS: 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24 months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54% vs. 24%; p = 0.029). The SRS group received prior immunotherapy more often than the ICI alone group (54% vs. 8.0%; p < 0.001). There was no significant difference in 1-year OS (72% vs. 71%, p = 0.20) and DIC (63% v 51%, p = 0.26) between groups. The SRS group had higher 1-year LC (92% vs. 64%; p = 0.002). On multivariate analysis, LC was improved with combination therapy (AHR 0.38, p = 0.01). CONCLUSION: In our analysis, patients who received SRS with nivolumab and ipilimumab had superior LC without increased risk of toxicity or compromised immunotherapy treatment completion despite the SRS cohort having higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.

Current and future approaches in the surgical management of T3b/T4 primary and locoregionally advanced melanoma.

Currently accepted principles of surgical management-margin width, use of sentinel node biopsy, performance of radical node dissections for node-positive cases-and some aspects of postoperative management (use of radiation for desmoplastic melanoma primaries and for clinically node-positive disease) will change in the future with the potential widespread adoption of adjuvant and neoadjuvant therapies.

Adjuvant Radiation Therapy for Clinical Stage III Melanoma in the Modern Therapeutic Era.

BACKGROUND: Adjuvant radiation therapy (RT) can decrease lymph node basin (LNB) recurrences in patients with clinically evident melanoma lymph node (LN) metastases following lymphadenectomy, but its role in the era of modern systemic therapies (ST), immune checkpoint or BRAF/MEK inhibitors, is unclear. PATIENTS AND METHODS: Patients at four institutions who underwent lymphadenectomy (1/1/2010-12/31/2019) for clinically evident melanoma LN metastases and received neoadjuvant and/or adjuvant ST with RT, or ST alone, but met indications for RT, were identified. Comparisons were made between ST alone and ST/RT groups. The primary outcome was 3-year cumulative incidence (CI) of LNB recurrence. Secondary outcomes included 3-year incidences of in-transit/distant recurrence and survival estimates. RESULTS: Of 98 patients, 76 received ST alone and 22 received ST/RT. Median follow-up time for patients alive at last follow-up was 44.6 months. The ST/RT group had fewer inguinal node metastases (ST 36.8% versus ST/RT 9.1%; P = 0.04), and more extranodal extension (ST 50% versus ST/RT 77.3%; P = 0.02) and positive lymphadenectomy margins (ST 2.6% versus ST/RT 13.6%; P = 0.04). The 3-year CI of LNB recurrences was lower for the ST/RT group compared with the ST group (13.9% versus 25.2%), but this reduction was not statistically significant (P = 0.36). Groups did not differ significantly in in-transit/distant recurrences (P = 0.24), disease-free survival (P = 0.14), or melanoma-specific survival (P = 0.20). CONCLUSIONS: In the era of modern ST, RT may still have value in reducing LNB recurrences in melanoma with clinical LN metastases. Further research should focus on whether select patient populations derive benefit from combination therapy, and optimizing indications for RT following neoadjuvant ST.

Management of Sentinel Lymph Node Metastasis in Merkel Cell Carcinoma: Completion Lymphadenectomy, Radiation, or Both?

BACKGROUND: Approximately 30% of patients with clinically localized Merkel cell carcinoma (MCC) show nodal involvement on sentinel lymph node biopsy (SLNB). Optimal management of SLNB-positive disease has not been defined. This study compared outcomes after completion lymphadenectomy (CLND), radiation, and combined CLND plus radiation after a positive SLNB. METHODS: All patients treated at a single institution for SLNB-positive MCC (1998-2015) were retrospectively evaluated, with examination of patient demographics, clinicopathologic characteristics, outcomes, and regional toxicity. RESULTS: The study identified 71 evaluable patients with SLNB-positive disease. The median age of these patients was 76 years, and 76.1% were men. Of the 71 patients, 11 (15.5%) underwent CLND, 40 (56.3%) received radiation, and 20 (28.2%) underwent CLND plus postoperative radiation. Lymphovascular invasion was significantly more common in the radiation-alone cohort (p = 0.04). For the three cohorts, the median percentages of nodal involvement were respectively 2, 10, and 30% (p = 0.06). After a median follow-up period of 22.3 months, four patients had recurrence in their regional nodal basin (3 radiation-alone patients and 1 CLND + radiation patient). The three cohorts did not differ significantly in the development of distant metastases (p = 0.68) or overall survival (p = 0.72). Six patients experienced surgical-site infections (2 CLND and 4 CLND + radiation patients), and three patients experienced symptomatic lymphedema (1 CLND patient and 2 CLND + radiation patients). CONCLUSIONS: Regional failure was infrequent (≤ 10%) regardless of treatment, and morbidity appeared to be low with all approaches. Given that multiple treatment approaches can be successful in treating micrometastatic MCC, future efforts should be directed at refining criteria for allocating patients to a specific method, or possibly no further nodal basin treatment, in an effort to maximize regional control at the lowest cost and morbidity.

Resection Margins in Merkel Cell Carcinoma: Is a 1-cm Margin Wide Enough?

BACKGROUND: Guidelines regarding specific resection margins for primary Merkel cell carcinoma (MCC) are not well established. The current National Comprehensive Cancer Network (NCCN) guidelines recommend 1- to 2-cm resection margins. This study aimed to determine the impact of margin width on local recurrence (LR), disease-specific survival (DSS), overall survival (OS), and type of wound closure. METHODS: All patients who underwent resection of primary MCC at a single institution from 2000 to 2015 were reviewed. Patient demographics, clinicopathologic characteristics, treatments, and outcomes were reviewed. RESULTS: A total of 240 patients underwent resection of primary MCC with resection margin width identified in the operative report. The median age was 76 years, and 65.8% of the patients were men. Of the 240 patients, 85 (35.4%) had head and neck primaries, 140 (58.3%) had extremity primaries, and 15 (6.3%) had trunk primaries. In terms of margins, 69 patients (28.8%) had a margin of 1 cm, 36 patients (15%) had a margin of 1.1-1.9 cm, and 135 patients (56.2%) had a margin of 2 cm or more. The median follow-up period was 21 months. The LR rate was 2.9% for a margin of 1 cm, 2.8% for a margin of 1.1-1.9 cm, and 5.2% for a margin of 2 cm or more (p = 0.80). The 5-year OS was 63.6% for a margin of 1 cm, 59.7% for a margin of 1.1-1.9, and 70.7% for a margin of 2 cm or more (p = 0.66). The 5-year DSS was 80.3% for a margin of 1 cm, 66.2% for a margin of 1.1-1.9 cm, and 91.8% for a margin of 2 cm or more (p = 0.28). For wound closure, 43.5, 50, and 65.9% of the patients respectively required a flap or graft with a margin of 1, 1.1-1.9, and 2 cm or more (p = 0.006). CONCLUSIONS: A 1-cm resection margins did not increase the risk of LR. Margin width did not make a significant difference in DSS or OS. Larger resection margins increase the need for a graft or flap closure.

Clinical feasibility of 90Y digital PET/CT for imaging microsphere biodistribution following radioembolization.

PURPOSE: The purpose of this study was to evaluate the clinical feasibility of next generation solid-state digital photon counting PET/CT (dPET/CT) technology and imaging findings in patients following 90Y microsphere radioembolization in comparison with standard of care (SOC) bremsstrahlung SPECT/CT (bSPECT/CT). METHODS: Five patients underwent SOC 90Y bremsstrahlung imaging immediately following routine radioembolization with 3.5 ± 1.7 GBq of 90Y-labeled glass microspheres. All patients also underwent dPET/CT imaging at 29 ± 11 h following radioembolization. Matched pairs comparison was used to compare image quality, image contrast and 90Y biodistribution between dPET/CT and bSPECT/CT images. Volumetric assessments of 90Y activity using different isocontour thresholds on dPET/CT and bSPECT/CT images were also compared. RESULTS: Digital PET/CT consistently provided better visual image quality and 90Y-to-background image contrast while depicting 90Y biodistribution than bSPECT/CT. Isocontour volumetric assessment using a 1% threshold precisely outlined 90Y activity and the treatment volume on dPET/CT images, whereas a more restrictive 20% threshold on bSPECT/CT images was needed to obtain comparable treatment volumes. The use of a less restrictive 10% threshold isocontour on bSPECT/CT images grossly overestimated the treatment volume when compared with the 1% threshold on dPET/CT images. CONCLUSIONS: Digital PET/CT is clinically feasible for the assessment of 90Y microsphere biodistribution following radioembolization, and provides better visual image quality and image contrast than routine bSPECT/CT with comparable acquisition times. With further optimization and clinical validation, dPET technology may allow faster and more accurate imaging-based assessment of 90Y microsphere biodistribution.

Durability of response to immune checkpoint blockade following treatment discontinuation and efficacy of rechallenge in advanced Merkel cell carcinoma.

BACKGROUND: Advanced Merkel cell carcinoma (MCC) has a high response rate to immune checkpoint blockade (ICB) therapy, but the durability of responses once treatment is discontinued remains unclear. We therefore reviewed the long-term outcomes of advanced patients with MCC who discontinued ICB treatment after achieving favorable initial response. METHODS: We performed a retrospective review of advanced patients with MCC treated at a single high-volume referral center, including all patients who received at least one dose of anti-programmed death receptor 1 (ligand) monotherapy for unresectable or metastatic disease, achieved stable disease (SD) or better, and discontinued treatment for a reason other than disease progression. RESULTS: Of 195 advanced patients with MCC treated with ICB, we identified 45 who met the study criteria. Of these, 21 (46.6%) had a complete response (CR) to initial ICB treatment, 23 (51.1%) a partial response and 1 (2.2%) SD. 25 (55.6%) patients discontinued ICB electively and 20 (44.4%) discontinued due to toxicity. In total, 21 of the 45 patients (46.6%) experienced disease progression at a median of 11.3 months (range 2.1-22.7 months) from ICB cessation. There was a lower rate of progression in patients who achieved CR versus non-CR (23.8% vs 66.7%, p=0.006) and a trend towards a lower rate in those who discontinued electively versus due to toxicity (36.0% vs 60.0%, p=0.14). There was a higher risk for progression in patients with viral positive MCC compared with viral negative MCC (75.0 vs 30.8%, p=0.02). 16 of the 21 patients who experienced progression were retreated subsequently with ICB therapy, including both single-agent rechallenge (12) and escalation to combination ICB (4). 11 of 15 evaluable ICB-retreated patients (73.3%) achieved an objective response. CONCLUSIONS: Patients with advanced MCC have a substantial risk of disease progression following treatment discontinuation despite initial favorable ICB response, particularly in those that achieve less than a CR. Most of these patients maintain sensitivity to retreatment with the same drug class. Virus-positive MCC may be a risk factor for post-discontinuation relapse, which should be validated in future studies.

Adjuvant Radiation Does Not Affect Locoregional Control Following Resection of Melanoma Satellitosis or In-Transit Disease.

BACKGROUND: This study evaluates the association of adjuvant radiation therapy (RT) with improved locoregional (LR) recurrence for resected melanoma satellitosis and in-transit disease (ITD). MATERIALS AND METHODS: Data were collected retrospectively for resected melanoma satellitosis/ITD from 1996 to 2017. RESULTS: 99 patients were identified. 20 patients (20.2%) received adjuvant RT while 79 (79.8%) did not. Mean follow-up in the RT group was 4.3 years and 4.7 years in the non-RT group. 80% of patients who underwent RT suffered a complication, most commonly dermatitis. Locoregional recurrence occurred in 9 patients (45%) treated with adjuvant RT and 30 patients (38%) in the non-RT group (P = 0.805). Median LR-DFS was 5.8 years in the RT group and 9.5 years in the non-RT group (P = 0.604). On multivariable analysis, having a close or positive margin was the only independent predictor of LR-DFS (HR 3.8 95% CI 1.7-8.7). In-transit disease was associated with improved overall survival when compared to satellitosis (HR 0.260, 95% CI 0.08-0.82). DISCUSSION: The use of adjuvant RT is not associated with improved locoregional control in resected melanoma satellitosis or ITD. Close or positive margin was the only treatment-related factor associated with decreased LR-DFS after surgical resection of satellitosis/ITD.

Magnetic Resonance-Guided Stereotactic Body Radiation Therapy/Hypofractionated Radiation therapy for Metastatic and Primary Central and Ultracentral Lung Lesions.

Introduction: The recent results from the Nordic-HILUS study indicate stereotactic body radiation therapy (SBRT) is associated with high-grade toxicity for ultracentral (UC) tumors. We hypothesized that magnetic resonance-guided SBRT (MRgSBRT) or hypofractionated radiation therapy (MRgHRT) enables the safe delivery of high-dose radiation to central and UC lung lesions. Methods: Patients with UC or central lesions were treated with MRgSBRT/MRgHRT with real-time gating or adaptation. Central lesions were defined as per the Radiation Therapy Oncology Group and UC as per the HILUS study definitions: (1) group A or tumors less than 1 cm from the trachea and/or mainstem bronchi; or (2) group B or tumors less than 1 cm from the lobar bronchi. The Kaplan-Meier estimate and log-rank test were used to estimate survival. Associations between toxicities and other patient factors were tested using the Mann-Whitney U test and Fisher's exact test. Results: A total of 47 patients were included with a median follow-up of 22.9 months (95% confidence interval: 16.4-29.4). Most (53%) had metastatic disease. All patients had central lesions and 55.3% (n = 26) had UC group A. The median distance from the proximal bronchial tree was 6.0 mm (range: 0.0-19.0 mm). The median biologically equivalent dose (α/ß = 10) was 105 Gy (range: 75-151.2). The most common radiation schedule was 60 Gy in eight fractions (40.4%). Most (55%) had previous systemic therapy, 32% had immunotherapy and 23.4% had previous thoracic radiation therapy. There were 16 patients who underwent daily adaptation. The 1-year overall survival was 82% (median = not reached), local control 87% (median = not reached), and progression-free survival 54% (median = 15.1 mo, 95% confidence interval: 5.1-25.1). Acute toxicity included grade 1 (26%) and grade 2 (21%) with only two patients experiencing grade 3 (4.3%) in the long term. No grade 4 or 5 toxicities were seen. Conclusions: Previous studies noted high rates of toxicity after SBRT to central and UC lung lesions, with reports of grade 5 toxicities. In our cohort, the use of MRgSBRT/MRgHRT with high biologically effective doses was well tolerated, with two grade 3 toxicities and no grade 4/5.

Stereotactic radiosurgery and anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitors, or conventional chemotherapy for the management of melanoma brain metastases.

BACKGROUND: Immunotherapy and targeted BRAF/MEK inhibitors (i) have revolutionised the systemic management of advanced melanoma. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and various systemic therapies. METHODS: Patients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1+CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy. Comparisons between groups were made for overall survival (OS), distant MBM control, local MBM, systemic progression-free survival (sPFS), and neurotoxicity. RESULTS: In total, 257 patients with 1048 MBM treated over 368 SRS sessions between 2011 and 2020 were identified. On MVA, treatment with anti-PD1+anti-CTLA-4, anti-PD-1, and BRAF/MEK-i improved distant intracranial control over conventional chemotherapy. No significant differences were noted in local control (LC) between groups (p = 0.78). Kaplan-Meier OS at 12 months for anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, and conventional chemotherapy was 68%, 59%, 45%, 62%, 21%, and 15%, respectively (p = <0.0001). The sPFS rates at 12 months were 57%, 53%, 42%, 45%, 14%, and 6% (p = <0.0001). No significant differences were noted in rates of radiation necrosis (p = 0.93). CONCLUSIONS: This is among the largest series evaluating MBM treated with SRS and various systemic therapy regimens. Our analysis noted significant differences in OS, distant MBM control, and sPFS by systemic therapy. No differences in LC or radiation necrosis risk were noted.

Delivery of Online Adaptive MRI-Guided Radiation Therapy for a Deaf Patient.

MRI-guided radiation therapy (MRgRT) enables real-time imaging during treatment and daily online adaptive planning. It is particularly useful for areas of treatment that have been previously excluded or restricted from ablative doses due to potential damage to adjacent normal tissue. In certain cases, ablative doses to metastatic lesions may be justified and treated with MRgRT using video-assisted gated breath-hold adjustments throughout delivery. The workflow relies on patient biofeedback and auditory cues. A 74-year-old deaf male with a history of prostate cancer status post prostatectomy was found to have an enlarged cervical lymph node, which was excised with histopathology demonstrating Merkel cell carcinoma. Approximately one year after treatment with two cycles of pembrolizumab, which was subsequently discontinued due to toxicity, surveillance imaging demonstrated an enlarging left adrenal nodule. It was initially stable for an additional seven months with pembrolizumab rechallenge but was again found enlarged on subsequent imaging. The patient underwent MRg stereotactic body radiation therapy (MRgSBRT) to a total dose of 60 Gy in five fractions to this isolated site of progression. The patient was equipped with mirrored glasses to view the tracking structure with respect to gating the boundary structure, and the traditional reliance on verbal cues for coaching was reimagined to rely on visual cues instead. Follow-up positron emission tomography/CT (PET/CT) two weeks after treatment demonstrated interval resolution of the left adrenal metastatic nodule and a return to symmetric bilateral adrenal gland metabolic activity. The necessary MRgSBRT treatment for single metastatic lesions near normal tissue structures relies on verbal cues and coaching. However, deaf patients are unable to receive this treatment according to the traditional workflow model. Unique opportunities exist for the implementation of culturally competent care for the Deaf community, relying more heavily on visual cues, in radiation oncology practice.

A phase 1b trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies.

BACKGROUND: In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies. METHODS: Eligible patients had CNS malignancies that required a (minimum) 2-week course of RT. Sunitinib (37.5 mg) was administered daily for the duration of RT with optional treatment extension of 1 month. Urine was collected at 3 time points for correlative biomarker studies. The primary endpoint was acute toxicity defined according to Common Toxicity Criteria version 3. RESULTS: Fifteen patients were enrolled (12 with CNS metastasis and 3 with primary tumors). RT doses ranged from 14 Gray (Gy) to 70 Gy (1.8-3.5 Gy per fraction). Acute toxicities included hematologic, nausea, hyperglycemia, fatigue, hypocalcemia, and diarrhea. Six patients (40%) developed grade ≤ 2 toxicities. Grade 3 toxicities occurred in 7 patients (47%) and included hematologic toxicity, fatigue, deep vein thrombosis, dysphasia, hyperglycemia, and hyponatremia. No grade 3 through 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events attributed to disease progression occurred. The median follow-up was 34.2 months. Two patients (13%) achieved a partial response, 9 patients (60%) had stable disease, and 2 patients (13%) patients had progressive disease. The 6-month progression-free survival rate for patients who had brain metastasis was 58%. Grade 3 hematologic toxicity was correlated with greater changes in vascular endothelial growth factor levels changes between baseline and the completion of RT. CONCLUSIONS: Continuous 37.5-mg sunitinib combined with RT in patients who had CNS malignancies yielded acceptable toxicities and adverse events. The current results indicated that changes in urine vascular endothelial growth factor levels are associated with hematologic toxicity, and this association should be analyzed in a larger cohort. The feasibility, safety, and early response results warrant a phase 2 trial.

Perineural invasion predicts for locoregional failure in patients with oesophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy.

AIM: The prognostic significance of perineural invasion (PNI) in oesophageal adenocarcinoma (EAC) is unclear. We examined the association of PNI with clinical outcomes in patients treated with neoadjuvant chemoradiotherapy (nCRT) and surgery. METHODS: We performed a single institutional retrospective study. We evaluated the association of PNI with locoregional recurrence-free survival (LRFS), distant metastasis-free survival, disease-free survival (DFS) and overall survival using log-rank and Cox proportional hazard modelling. RESULTS: 29 out of 73 patients (40%) had PNI at the time of surgery. The median follow-up was 20.1 months. The median DFS was 18.4 months for patients with PNI vs 41.3 months for patients without PNI (p<0.05). The median LRFS was 23.3 months for patients with PNI and median not reached for patients without PNI (p<0.01). In a multivariate model including age and pathological variables, PNI remained a significant independent predictor of LRFS (HR 0.20, 95% CI 0.07 to 0.60; p=0.004). CONCLUSIONS: For patients with EAC treated with nCRT, PNI found at the time of surgery is significantly associated with worse LRFS. Our data support attempts to validate this finding and perhaps testing the role of adjuvant therapy in patients with PNI.

MR-guided stereotactic body radiation therapy for intracardiac and pericardial metastases.

AIMS: To assess the safety and efficacy of MR-guided stereotactic body radiation therapy (MRgSBRT) for cardiac metastases. MATERIALS/METHODS: This single institution retrospective analysis evaluated our experience with MRgSBRT for cardiac metastases. Response rate was compared between pre-RT and post-RT imaging. Symptomatic changes were also tracked and documented. RESULTS: Between 4/2019 and 3/2020, five patients with cardiac metastases (4 intracardiac and 1 pericardial) were treated with MRgSBRT. Median age at treatment was 73 years (range 64-80) and two patients had pre-existing cardiac disease. Histologies included melanoma and breast adenocarcinoma. Median lesion diameter was 2 cm (range 1.96-5.8 cm). Three patients were symptomatic, one of whom had pulmonary hypertension and RV enlargement. Another patient had an asymptomatic arrythmia. Median PTV prescribed dose was 40 Gy (range 40-50 Gy) and delivered in five fractions on nonconsecutive days. Median PTV volume was 53.4 cc (range 8.7-116.6 cc) and median coverage was 95% (range 84.1-100%). A uniform 3 mm margin was used for real-time gating, allowing a median 7% (range 5-10%) pixel excursion tolerance. Median follow-up was 4.7 months (range 0.9-12.3). Two patients exhibited stable disease, two had a partial response and one exhibited a complete response. All symptomatic patients experienced some relief. There were no acute adverse events, however, one patient without prior cardiac disease developed atrial fibrillation 6 months after treatment. Two patients died of causes unrelated to cardiac MRgSBRT. CONCLUSION: In this largest known series of cardiac metastasis MRgSBRT, real-time image guidance enables safe treatment resulting in good response with improving presenting symptoms without acute adverse events.

Do Not Forget About the Importance of Loco-Regional Therapy in Melanoma Management.

Immunotherapy agents have significantly changed the landscape of melanoma treatment over the past decade. Paradigm shifts in treatment require reanalysis of the treatment algorithms in melanoma. Despite surgical excision, certain high risk patients with desmoplastic melanoma remain at high risk for local recurrence and retrospective data suggests improvement in local control with adjuvant radiation therapy. Likewise, despite surgical excision and effective systemic therapy agents, patients with extracapsular extension and other high risk features are at substantial risk of nodal basin (regional) recurrence. Adjuvant radiation therapy has been demonstrated to reduce the local recurrence risk. Despite these benefits, adjuvant radiation therapy in melanoma remains controversial in part because its use has not been definitively demonstrated to improve overall or disease-free survival in a randomized prospective study.

Novel Genomic-Based Strategies to Personalize Lymph Node Radiation Therapy.

Current standard radiotherapy doses have been derived from empiric methods rather than a scientific framework. Subclinical nodal dosing remains relatively uniform across most disease sites, despite heterogeneity in patient and tumor biology. It is now clear that there are subsets of patients who will benefit from genomically-informed radiotherapy planning, and there are increasing efforts toward prescribing radiation dose to match the radiosensitivity of the tumor. By using novel genomic biomarkers to personalize delivery of radiotherapy, there is an opportunity to improve loco-regional control and cure rates. We survey the current landscape of personalized radiation oncology across commonly treated disease sites.

Yttrium-90 microsphere selective internal radiation therapy for liver metastases following systemic chemotherapy and surgical resection for metastatic adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy with generally poor outcomes and limited treatment options. While surgical resection can be curative for early local disease, most patients present with advanced ACC owing to nonspecific symptoms. For those patients, treatment options include systemic chemotherapy and locoregional therapies including radiofrequency ablation and transarterial chemoembolization. We present the first reported case of utilizing yttrium-90 microsphere selective internal radiation therapy (SIRT) in combination with first line EDP-M (Etoposide, Doxorubicin, Cisplatin, Mitotane) chemotherapy and debulking surgical primary tumor resection for treatment of metastatic ACC. Stable complete radiologic response has been maintained after twelve months with resolution of clinical symptoms. These findings prompt the need for further consideration and studies to elucidate the role of SIRT in combination with systemic and surgical treatment for metastatic ACC.

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases.

PURPOSE: We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. METHODS AND MATERIALS: Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507. RESULTS: The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60 years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5 months and 8 months and in arm B was 2.1 months and not reached, respectively. CONCLUSIONS: Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.

90Y Digital PET/CT Imaging Following Radioembolization.

Imaging of Y internal pair production with conventional photomultiplier detector PET technology has been previously reported for patients with malignant/metastatic liver lesions treated with Y radioembolization (RE). We present a 54-year-old man with unresectable liver metastases from rectal carcinoma (involving the right and left lobes) who was referred for Y RE and subsequently imaged using new solid-state digital photon counting technology (Vereos 64 Time-of-Flight PET/CT; Philips, Cleveland, OH). Despite imaging at 26 hours following RE, digital PET/CT provides improved image quality and Y-to-background contrast as well as accurate visualization of Y biodistribution when compared with Bremsstrahlung SPECT/CT.

Institutional clinical trial accrual volume and survival of patients with head and neck cancer.

PURPOSE: National Comprehensive Cancer Network guidelines recommend patients with head and neck cancer (HNC) receive treatment at centers with expertise, but whether provider experience affects survival is unknown. PATIENTS AND METHODS: The effect of institutional experience on overall survival (OS) in patients with stage III or IV HNC was investigated within a randomized trial of the Radiation Therapy Oncology Group (RTOG 0129), which compared cisplatin concurrent with standard versus accelerated fractionation radiotherapy. As a surrogate for experience, institutions were classified as historically low- (HLACs) or high-accruing centers (HHACs) based on accrual to 21 RTOG HNC trials (1997 to 2002). The effect of accrual volume on OS was estimated by Cox proportional hazards models. RESULTS: Median RTOG accrual (1997 to 2002) at HLACs was four versus 65 patients at HHACs. Analysis included 471 patients in RTOG 0129 (2002 to 2005) with known human papillomavirus and smoking status. Patients at HLACs versus HHACs had better performance status (0: 62% v 52%; P = .04) and lower T stage (T4: 26.5% v 35.3%; P = .002) but were otherwise similar. Radiotherapy protocol deviations were higher at HLACs versus HHACs (18% v 6%; P < .001). When compared with HHACs, patients at HLACs had worse OS (5 years: 51.0% v 69.1%; P = .002). Treatment at HLACs was associated with increased death risk of 91% (hazard ratio [HR], 1.91; 95% CI, 1.37 to 2.65) after adjustment for prognostic factors and 72% (HR, 1.72; 95% CI, 1.23 to 2.40) after radiotherapy compliance adjustment. CONCLUSION: OS is worse for patients with HNC treated at HLACs versus HHACs to cooperative group trials after accounting for radiotherapy protocol deviations. Institutional experience substantially influences survival in locally advanced HNC.