David M. Routman

Prognostic factors for melanoma brain metastases treated with stereotactic radiosurgery.

OBJECTIVE Stereotactic radiosurgery (SRS) is routinely used to treat brain metastases from melanoma due to their radioresistant nature. The median survival for these patients is 4-6 months, according to earlier studies. The aim of this study was to evaluate prognostic factors that influence survival in patients with metastatic melanoma to the brain treated with SRS. METHODS This retrospective analysis included all patients with melanoma brain metastases treated with SRS at the University of Southern California between 1994 and 2015. For the entire cohort, the authors performed a multivariable Cox regression analysis with an end point of survival. Covariates included number of lesions, total intracranial tumor volume, age, sex, and treatment date prior to 2005 or 2005 onward. In the subset of patients with > 1 lesion, additional multivariable Cox regression was performed, with covariates of Karnofsky Performance Scale, Graded Prognostic Assessment, Recursive Partitioning Analysis, timing of metastases (synchronous/metachronous), change in lesion number, and previous whole-brain radiation therapy or resection in addition to the previously mentioned covariates. Overall survival (OS) was calculated from the day SRS was performed to the date of last follow-up or date of death. RESULTS A total of 401 patients were available for analysis. The median follow-up was 35.1 months for patients alive at the time of analysis, and the median OS was 7.7 months for the entire cohort (95% CI 6.7-8.3 months). In the entire cohort, greater number of brain lesions, higher total intracranial tumor volume, age > 50 years, treatment prior to 2005, and male sex were found to be statistically significant factors associated with worse survival. The strongest risk factors for decreased OS were tumor volume > 10 cm3 and ≥ 5 lesions, with hazard ratios for risk of death of 1.7 and 2.2, respectively. In the subset of patients with > 1 lesion, tumor volume > 10 cm3 and no resection were the only factors significantly associated with decreased OS, with hazard ratios of 1.9 and 2.0 (hazard ratio of 0.49 for resection), respectively. CONCLUSIONS This study suggests that greater lesion number, higher intracranial tumor volume, older age, treatment prior to 2005, and male sex have prognostic significance for decreased OS in patients with melanoma brain metastases treated with SRS. Additionally, in the subset of patients with > 1 lesion, only higher total tumor volume and no resection were associated with worse survival.

Combination ipilimumab and radiosurgery for brain metastases: tumor, edema, and adverse radiation effects

OBJECTIVETumor and edema volume changes of brain metastases after stereotactic radiosurgery (SRS) and ipilimumab are not well described, and there is concern regarding the safety of combination treatment. The authors evaluated tumor, edema, and adverse radiation-induced changes after SRS with and without ipilimumab and identified associated risk factors.METHODSThis single-institution retrospective study included 72 patients with melanoma brain metastases treated consecutively with upfront SRS from 2006 to 2015. Concurrent ipilimumab was defined as ipilimumab treatment within 4 weeks of SRS. At baseline and during each follow-up, tumor and edema were measured in 3 orthogonal planes. The (length × width × height/2) formula was used to estimate tumor and edema volumes and was validated in the present study for estimation of edema volume. Tumor and edema volume changes from baseline were compared using the Kruskal-Wallis test. Local failure, lesion hemorrhage, and treatment-related imaging changes (TRICs) were analyzed with the Cox proportional hazards model.RESULTSOf 310 analyzed lesions, 91 were not treated with ipilimumab, 59 were treated with concurrent ipilimumab, and 160 were treated with nonconcurrent ipilimumab. Of 106 randomly selected lesions with measurable peritumoral edema, the mean edema volume by manual contouring was 7.45 cm3 and the mean volume by (length × width × height)/2 formula estimation was 7.79 cm3 with R2 = 0.99 and slope of 1.08 on line of best fit. At 6 months after SRS, the ipilimumab groups had greater tumor (p = 0.001) and edema (p = 0.005) volume reduction than the control group. The concurrent ipilimumab group had the highest rate of lesion response and lowest rate of lesion progression (p = 0.002). Within the concurrent ipilimumab group, SRS dose ≥ 20 Gy was associated with significantly greater median tumor volume reduction at 3 months (p = 0.01) and 6 months (p = 0.02). The concurrent ipilimumab group also had the highest rate of lesion hemorrhage (p = 0.01). Any ipilimumab was associated with higher incidence of symptomatic TRICs (p = 0.005). The overall incidence of pathologically confirmed radiation necrosis (RN) was 2%. In multivariate analysis, tumor and edema response at 3 months were the strongest predictors of local failure (HR 0.131 and HR 0.125) and lesion hemorrhage (HR 0.225 and HR 0.262). Tumor and edema response at 1.5 months were the strongest predictors of TRICs (HR 0.144 and HR 0.297).CONCLUSIONSThe addition of ipilimumab improved tumor and edema volume reduction but was associated with a higher incidence of lesion hemorrhage and symptomatic TRICs. There may be a radiation dose-response relationship between SRS and ipilimumab when administered concurrently. Early tumor and edema response were excellent predictors of subsequent local failure, lesion hemorrhage, and TRICs. The incidence of pathologically proven RN was low, supporting the relative safety of ipilimumab in radiosurgery treatment.

Relapse Rates With Surgery Alone in Human Papillomavirus–Related Intermediate- and High-Risk Group Oropharynx Squamous Cell Cancer: A Multi-Institutional Review

PURPOSEnToxa0evaluate whether historic risk categories and indications for adjuvant therapy in the pre-human papillomavirus (HPV) and pre-transoral surgery (TOS) era were associated with clinically significant relapse rates in HPV+xa0oropharyngeal squamous cell cancer patients undergoing TOS.nnnMETHODS AND MATERIALSnA multi-institutional retrospective review of intermediate- and high-risk HPV+xa0oropharyngeal squamous cell cancer patients not receiving adjuvant therapy after TOS was performed. Perineural invasion, lymphovascular invasion, T3-T4, orxa0≥N2 disease were considered to be intermediate-risk factors, and extracapsular extension or positive margins were considered to be high-risk features, according to established risk categories.nnnRESULTSnMedian follow-up was 42.9xa0months. Among all 53 patients, the 3-year cumulative incidence of relapse was 26.0%. The 3-year cumulative incidence was 11.8% in the 37 intermediate-risk patients and 52.4% in the 16 high-risk patients. On univariate analysis only high-risk status was significantly associated with an increased risk of relapse (hazard ratio 3.9; P=.018). The salvage rate for relapse was 77%, with 10 of 13 patients undergoing salvage therapy.nnnCONCLUSIONSnRisk category was associated with clinically significant relapse ratesxa0after TOS alone in HPV+xa0oropharyngeal cancer, comparable to historical dataxa0andxa0traditional indications for adjuvant therapy for all oropharyngeal cancer.

Low-Grade Glioma

Approximately 3000 new cases of low-grade glioma (LGG) will be diagnosed annually in the United States. LGG includes grade I and grade II glioma and represents a heterogeneous group of tumors. The pathologic criteria for diagnosis of LGG have been updated per the World Health Organization 2016 classification system. Pilocytic grade I astrocytoma is the most common grade I lesion, and grade II lesions are mainly diffuse astrocytoma and oligodendroglioma, which comprise the majority of adult LGG and are the focus of this chapter.

Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity

IntroductionThere is evidence that the combination of ipilimumab and stereotactic radiosurgery (SRS) for brain metastases improves outcomes. We investigated clinical outcomes, radiation toxicity, and impact of ipilimumab timing in patients treated with SRS for melanoma brain metastases.MethodsWe retrospectively identified 91 patients treated with SRS at our institution for melanoma brain metastases from 2006 to 2015. Concurrent ipilimumab administration was defined as within ±u20094xa0weeks of SRS procedure. Acute and late toxicities were graded with CTCAE v4.03. Overall survival (OS), local failure, distant brain failure, and failure-free survival were analyzed with the Kaplan–Meier method. OS was analyzed with Cox regression.ResultsTwenty-three patients received ipilimumab concurrent with SRS, 28 patients non-concurrently, and 40 patients did not receive ipilimumab. The median age was 62xa0years and 91% had KPSu2009≥u200980. The median follow-up time was 7.4xa0months. Patients who received ipilimumab had a median OS of 15.1xa0months compared to 7.8xa0months in patients who did not (pu2009=u20090.02). In multivariate analysis, ipilimumab (pu2009=u20090.02) and diagnosis-specific graded prognostic assessment (pu2009=u20090.02) were associated with OS. There were no differences in intracranial control by ipilimumab administration or timing. The incidence of radiation necrosis was 5%, with most events occurring in patients who received ipilimumab.ConclusionsPatients who received ipilimumab had improved OS even after adjusting for prognostic factors. Ipilimumab did not appear to increase risk for acute toxicity. The majority of radiation necrosis events, however, occurred in patients who received ipilimumab. Our results support the continued use of SRS and ipilimumab as clinically appropriate.

The growing importance of lesion volume as a prognostic factor in patients with multiple brain metastases treated with stereotactic radiosurgery

Stereotactic Radiosurgery (SRS) is considered standard of care for patients with 1–3 brain metastases (BM). Recent observational studies have shown equivalent OS in patients with 5+ BM compared to those with 2–4, suggesting SRS alone may be appropriate in these patients. We aim to review outcomes of patients treated with SRS with 2–4 versus 5+ BM. This analysis included consecutive patients from 1994 to 2015 treated with SRS. Of 1017 patients, we excluded patients with a single BM and patients without adequate survival data, resulting in 391 patients. All risk factors were entered into univariate analysis using Cox proportional hazards model, and significant factors were entered into multivariate analysis (MVA). We additionally analyzed outcomes after excluding patients with prior surgery or whole‐brain radiotherapy (WBRT). Median follow‐up was 7.1 months. Median KPS was 90, mean age was 59, and most common histologies were melanoma and lung. Median tumor volume was 3.41 cc. Patients with 2–4 BM had a median OS of 8.1 months compared to 6.2 months for those with 5+ BM (P = 0.0136). On MVA, tumor volume, KPS, and histology remained significant for OS, whereas lesion number did not. Similar results were found when excluding patients with prior surgery or WBRT. Rather than lesion number, the strongest prognostic factors for patients undergoing SRS were tumor volume >10 cc, KPS, and histology. BM number may therefore not be the most important criterion for candidacy for SRS. Patients with 5 or more BM should be considered for SRS.

Patient-reported outcomes of catheter-based accelerated partial breast brachytherapy and whole breast irradiation, a single institution experience

PurposeAccelerated partial breast irradiation (APBI) and whole breast irradiation (WBI) are treatment options for early-stage breast cancer. The purpose of this study was to compare patient-reported-outcomes (PRO) between patients receiving multi-channel intra-cavitary brachytherapy APBI or WBI.MethodsBetween 2012 and 2015, 131 patients with ductal carcinoma in situ (DCIS) or early stage invasive breast cancer were treated with adjuvant APBI (64) or WBI (67) and participated in a PRO questionnaire. The linear analog scale assessment (LASA), harvard breast cosmesis scale (HBCS), PRO-common terminology criteria for adverse events- PRO (PRO-CTCAE), and breast cancer treatment outcome scale (BCTOS) were used to assess quality of life (QoL), pain, fatigue, aesthetic and functional status, and breast cosmesis. Comparisons of PROs were performed using t-tests, Wilcoxon rank-sum, Chi square, Fisher exact test, and regression methods.ResultsMedian follow-up from completion of radiotherapy and questionnaire completion was 13.3xa0months. There was no significant difference in QoL, pain, or fatigue severity, as assessed by the LASA, between treatment groups (pxa0>xa00.05). No factors were found to be predictive of overall QoL on regression analysis. BCTOS health-related QoL scores were similar between treatment groups (pxa0=xa00.52).The majority of APBI and WBI patients reported excellent/good breast cosmesis, 88.5% versus 93.7% (pxa0=xa00.37). Skin color change (pxa0=xa00.011) and breast elevation (pxa0=xa00.01) relative to baseline were more common in the group receiving WBI.ConclusionsAPBI and WBI were both associated with favorable patient-reported outcomes in early follow-up. APBI resulted in a lesser degree of patient-reported skin color change and breast elevation relative to baseline.

Increased utilization of external beam radiotherapy relative to cystectomy for localized, muscle-invasive bladder cancer: a SEER analysis

OBJECTIVE To assess recent utilization patterns of radiotherapy (RT) relative to cystectomy for muscle-invasive bladder cancer (MIBC) and evaluate survival trends over time in patients receiving RT. MATERIALS AND METHODS The surveillance, epidemiology, and end results program (SEER) was used to identify patients diagnosed between 1992 and 2013 with localized MIBC. Patients with a prior history of non-bladder malignancy, who received no treatment, or did not have available treatment information, were excluded. Treatment utilization patterns were assessed using Cochran-Armitage tests for trend, and patient characteristics were compared using chi-square tests. Overall survival (OS) and cause-specific survival (CSS) were estimated using the Kaplan-Meier method. All-cause (ACM) and cause-specific mortality (CSM) were evaluated with multivariable Cox proportional hazards regression. RESULTS Of 16175 patients analyzed, 11917 (74%) underwent cystectomy, and 4258 (26%) were treated with RT. Patients who received RT were older (median age 79 vs. 68, P < 0.01). Over time, the proportion of patients receiving RT relative to cystectomy increased (24% 1992–2002 vs. 28% 2003–2013, P < 0.01), despite median patient age throughout the study period remaining unchanged (71 for each 1992–2002 and 2003–2013, P = 0.41). For RT, compared with patients diagnosed earlier, those diagnosed from 2010–2013 showed improved OS (64% vs. 60% at 1 year, P < 0.01; 38% vs. 29% at 3 years, P < 0.01) and CSS (71% vs. 67% at 1 year, P = 0.01; 51% vs. 40% at 3 years, P < 0.01). On multivariable analysis, diagnosis from 2010–2013 was associated with a lower estimated risk of ACM (hazard ratio 0.77; 95% confidence interval 0.66–0.89, P < 0.001) and CSM (hazard ratio 0.81; 95% confidence interval 0.67–0.97, P = 0.02). CONCLUSION Utilization of RT for localized MIBC increased relative to cystectomy from 1992 to 2013, despite the median age of treated patients remaining unchanged. More recent survival outcomes for patients receiving RT were improved, supporting continued use of bladder preservation strategies utilizing RT.