Faculty Bibliography

BACKGROUND CONTEXT: Recent advances in image guidance and stereotactic body radiotherapy (SBRT) have resulted in unprecedented local control for spinal metastases of all histologies. However, little is known about early imaging biomarkers of local control. PURPOSE: To identify early MRI biomarkers to predict local control after SBRT for patients with sarcoma spine metastases. STUDY DESIGN/SETTING: Retrospective case series at a large tertiary cancer center. PATIENT SAMPLE: From 2011 to 2014, nine consecutive patients with 12 metastatic sarcoma lesions to the spine were treated with SBRT and underwent evaluation with DCE-MRI both pre- and post-SBRT. OUTCOME MEASURE: Changes in perfusion metrics, including the wash-in rate constant (Ktrans), plasma volume (Vp), composite multi-parametric MRI (mpMRI) score, bi-dimensional tumor size, and a graded response assessment were performed and correlated to local control. METHODS: All measurements were independent and blinded by two neuroradiologists. R2 statistics were performed to document correlation, and two-tailed t-tests were used to compare groups. P<0.05 was deemed statistically significant. RESULTS: The median time from SBRT until post-treatment MRI was 57 days. Local failure developed in one lesion (8.3%) 10 months after SBRT. Vp mean, Ktrans mean, Vp max, and Ktrans max were significantly decreased post-SBRT as compared to pre-SBRT (58.7%, 63.2%, 59.0%, and 55.2%; all p-values <0.05). Bi-dimensional tumor measurements demonstrated an average increase in size across the cohort, and 50%, 25%, and 25% of the treated lesions demonstrated features of "worsening," "no change," or "improvement," respectively, by both radiologists' graded impressions. There was good inter-reader reliability for both size and subjective disease response scores (R2 = 0.84). The mpMRI score had 100% accuracy in predicting local control at time of last follow-up. There was no apparent correlation with size changes compared to the mpMRI score change post-SBRT (R2 = 0.026). CONCLUSIONS: We report the first analysis on the utility of DCE-MRI for metastatic sarcoma spine metastases treated with SBRT. We demonstrate that early assessment at two months post-SBRT using size and subjective neuroradiology impressions is insufficient to judge ultimate disease progression, and that a combination of perfusion parameters provides excellent correlation to local control.

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is rare, comprising approximately 5% of all Hodgkin lymphoma (HL) cases. Patients with NLPHL tend to have better prognoses than those with classical HL (CHL). Our goal was to assess differences in survival between NLPHL and CHL patients, controlling for differences in patient and disease characteristics. METHODS AND MATERIALS: Using data from the population-based Surveillance, Epidemiology and End Results (SEER) cancer registry program, we identified patients diagnosed with pathologically confirmed HL between 1988 and 2010. RESULTS: We identified 1,162 patients with NLPHL and 29,083 patients with CHL. With a median follow-up of 7 years, 5- and 10-year overall survival (OS) rates were 91% and 83% for NLPHL, respectively, and 81% and 74% for CHL, respectively. After adjusting for all available characteristics, NLPHL (vs CHL) was associated with higher OS (hazard ratio [HR]: 0.62, P<.01) and disease-specific survival (DSS; HR: 0.48, P<.01). The male predominance of NLPHL, compared to CHL, as well as the more favorable prognostic features in NLPHL patients are most pronounced in NLPHL patients <20 years old. Among all NLPHL patients, younger patients were less likely to receive radiation, and radiation use has declined by 40% for all patients from 1988 to 2010. Receipt of radiation was associated with better OS (HR: 0.64, P=.03) and DSS (HR: 0.45, P=.01) in NLPHL patients after controlling for available baseline characteristics. Other factors associated with OS and DSS in NLPHL patients are younger age and early stage. CONCLUSIONS: Our results in a large population dataset demonstrated that NLPHL patients have improved prognosis compared to CHL patients, even after accounting for stage and baseline characteristics. Use of radiation is declining among NLPHL patients despite an association in this series between radiation and better DSS and OS. Unique treatment strategies for NLPHL are warranted in both early and advanced stage disease.

Brain metastases (BM) frequently develop in patients with melanoma and are associated with a poor prognosis. Whole brain radiation therapy (WBRT) is a standard intervention for intracranial disease, particularly in patients with multiple BM. Ipilimumab improves survival in patients with advanced melanoma. The purpose of this study is to investigate the safety and efficacy of concurrent WBRT and ipilimumab. A retrospective analysis was conducted of 13 consecutive patients treated with WBRT within 30 days of ipilimumab administration. Radiographic response, as measured by serial magnetic resonance imaging scans post-treatment, was graded by modified World Health Organization (mWHO) and immune-related response criteria (irRC) in the 9 patients with follow-up imaging. Treatment-related toxicity was prospectively assessed during treatment. Four of nine patients (44 %) experienced partial response or stable central nervous system (CNS) disease as measured by mWHO criteria. This number increased to 5 patients (56 %) when irRC criteria were used. Rates of treatment-related neurologic toxicity were low with only one patient experiencing grade 3-4 neurologic toxicity. There was a high rate of intratumoral hemorrhage in this patient population, with 10 of 10 patients with post-treatment imaging demonstrating new or increased intratumoral bleeding after WBRT. This retrospective study demonstrates that the primary pattern of CNS response to WBRT and ipilimumab is stable disease and not regression of BM. Furthermore, while the combination of WBRT and ipilimumab may offer promising efficacy, prospective studies are needed to further assess efficacy and toxicity.

Whole-lung irradiation (WLI) is standard of care in the treatment of patients with rhabdomyosarcoma, Ewing sarcoma, and Wilms tumor and pulmonary metastases. However, it is not routinely utilized in the treatment of pulmonary metastases arising from other soft tissue sarcoma histologies. A patient presented with synovial sarcoma of his groin and punctate pulmonary metastases. After completion of multimodality treatment to his primary lesion, he received WLI. The patient is without evidence of disease at 3.8 years. This case demonstrates the need for further study of WLI in synovial sarcoma as it may improve outcomes in patients with this disease.

BACKGROUND: Glioblastoma (GBM) is a highly aggressive type of glioma with poor prognosis. However, a small number of patients live much longer than the median survival. A better understanding of these long-term survivors (LTSs) may provide important insight into the biology of GBM. METHODS: We identified 7 patients with GBM, treated at Memorial Sloan-Kettering Cancer Center (MSKCC), with survival >48 months. We characterized the transcriptome of each patient and determined rates of MGMT promoter methylation and IDH1 and IDH2 mutational status. We identified LTSs in 2 independent cohorts (The Cancer Genome Atlas [TCGA] and NCI Repository for Molecular Brain Neoplasia Data [REMBRANDT]) and analyzed the transcriptomal characteristics of these LTSs. RESULTS: The median overall survival of our cohort was 62.5 months. LTSs were distributed between the proneural (n = 2), neural (n = 2), classical (n = 2), and mesenchymal (n = 1) subtypes. Similarly, LTS in the TCGA and REMBRANDT cohorts demonstrated diverse transcriptomal subclassification identities. The majority of the MSKCC LTSs (71%) were found to have methylation of the MGMT promoter. None of the patients had an IDH1 or IDH2 mutation, and IDH mutation occurred in a minority of the TCGA LTSs as well. A set of 60 genes was found to be differentially expressed in the MSKCC and TCGA LTSs. CONCLUSIONS: While IDH mutant proneural tumors impart a better prognosis in the short-term, survival beyond 4 years does not require IDH mutation and is not dictated by a single transcriptional subclass. In contrast, MGMT methylation continues to have strong prognostic value for survival beyond 4 years. These findings have substantial impact for understanding GBM biology and progression.

PURPOSE: To evaluate feasibility and patterns of failure in adult patients with Ewing sarcoma (ES) treated with whole lung irradiation (WLI) for pulmonary metastases. METHODS AND MATERIALS: Retrospective review of all ES patients treated at age 18 or older with 12-15 Gy WLI for pulmonary metastases at a single institution between 1990 and 2014. Twenty-six patients met the study criteria. RESULTS: The median age at WLI was 23 years (range, 18-40). The median follow-up time of the surviving patients was 3.8 years (range, 1.0-9.6). The 3-year cumulative incidence of pulmonary relapse (PR) was 55%, with a 3-year cumulative incidence of PR as the site of first relapse of 42%. The 3-year event-free survival (EFS) and overall survival (OS) were 38 and 45%, respectively. Patients with exclusively pulmonary metastases had better outcomes than did those with extrapulmonary metastases: the 3-year PR was 45% in those with exclusively lung metastases versus 76% in those with extrapulmonary metastases (P=.01); the 3-year EFS was 49% versus 14% (P=.003); and the 3-year OS was 61% versus 13% (P=.009). Smoking status was a significant prognostic factor for EFS: the 3-year EFS was 61% in nonsmokers versus 11% in smokers (P=.04). Two patients experienced herpes zoster in the radiation field 6 and 12 weeks after radiation. No patients experienced pneumonitis or cardiac toxicity, and no significant acute or late sequelae were observed among the survivors. CONCLUSION: WLI in adult patients with ES and lung metastases is well tolerated and is associated with freedom from PR of 45% at 3 years. Given its acceptable toxicity and potential therapeutic effect, WLI for pulmonary metastases in ES should be considered for adults, as it is in pediatric patients. All patients should be advised to quit smoking before receiving WLI.

PURPOSE: To determine a relationship between sexual functioning and health state among survivors of stage I endometrial cancer, and to examine whether adjuvant intravaginal radiotherapy (IVRT) affects these measures compared to hysterectomy alone. METHODS: Two hundred five survivors (>1 year from surgery) completed questionnaires containing the EuroQol (EQ5D) and the Female Sexual Function Index (FSFI). A total of 136 (66.3 %) underwent surgery alone, and 69 (33.7 %) received IVRT. Pearson correlation was used to correlate FSFI and EQ5D-Health State scores. Multivariable regression was performed to measure the impact of IVRT on sexual functioning and health state. RESULTS: A majority of patients (80 %) met criteria for sexual dysfunction by FSFI < 26.5. A significant correlation was detected between FSFI and EQ5D scores (Pearson correlation = 0.21, p = 0.003). Compared to the IVRT group, the surgery group was younger (p = 0.001) and trended toward more frequent use of minimally invasive surgery versus laparotomy (p = 0.08). Otherwise, the two groups were well balanced with respect to demographics, comorbidities, and baseline sexual activity. Controlling for age and surgery type, IVRT was not associated with poorer health state or sexual function. Receipt of laparotomy was associated with both poorer health state and sexual function (p = 0.0156 and p = 0.0247, respectively). CONCLUSIONS: Sexual functioning was generally poor among endometrial cancer survivors; however, those with improved FSFI scores tended to have superior health states. IVRT was not a significant risk factor; however, receipt of laparotomy appeared to be associated with poorer sexual functioning and health state.

PURPOSE/OBJECTIVES: Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system, it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. METHODS AND MATERIALS: Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. RESULTS: 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole brain RT (WBRT), and 15 with stereotactic radiosurgery (SRS). The median overall survival (OS) for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median, 35 vs 26 months; P=.62), whereas patients treated with SRS had a longer OS than did those in the erlotinib group (median, 64 months; P=.004). The median time to intracranial progression was 17 months. There was a longer time to intracranial progression in patients who received WBRT than in those who received erlotinib upfront (median, 24 vs 16 months, P=.04). Patients in the erlotinib or SRS group were more likely to experience intracranial failure as a component of first failure, whereas WBRT patients were more likely to experience failure outside the brain (P=.004). CONCLUSIONS: The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison with a targeted biologic agent with known central nervous system activity.

The inhibition of the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway through the suppression of mutated Ras or MAPK/extracellular signal-regulated kinase 1/2 (MEK1/2) has been shown to sensitize tumor cells to ionizing radiation (IR). The molecular mechanisms of this sensitization however, are not yet fully understood. In this study, we investigated the role of transforming growth factor-alpha (TGF-alpha) in the radiosensitizing effects of selumetinib, a selective inhibitor of MEK1/2. The expression of epidermal growth factor receptor (EGFR) ligands was assessed by ELISA in both Ras wild-type and Ras mutant cells that were exposed to radiation with or without selumetinib. The effects of selumetinib on the TGF-alpha/EGFR signaling cascade in response to radiation were examined by western blot analysis, clonogenic assay and by determing the yield of mitotic catastrophe. The treatment of cells with selumetinib reduced the basal and IR-induced secretion of TGF-alpha in both Ras wild-type and Ras mutant cell lines in vitro and in vivo. The reduction of TGF-alpha secretion was accompanied with a reduction in phosphorylated tumor necrosis factor-alpha converting enzyme (TACE) in the cells treated with selumetinib with or without IR. The treatment of cells with selumetinib with or without IR inhibited the phosphorylation of EGFR and checkpoint kinase 2 (Chk2), and reduced the expression of survivin. Supplementation with exogenous TGF-alpha partially rescued the selumetinib-treated cells from IR-induced cell death, restored EGFR and Chk2 phosphorylation and increased survivin expression. These data suggest that the inhibition of MEK1/2 with selumetinib may provide a mechanism to sensitize tumor cells to IR in a fashion that prevents the activation of the TGF-alpha autocrine loop following IR.

PURPOSE: Rhabdomyosarcoma (RMS) is a pediatric sarcoma rarely occurring in adults. For unknown reasons, adults with RMS have worse outcomes than do children. METHODS AND MATERIALS: We analyzed data from all patients who presented to Memorial Sloan-Kettering Cancer Center between 1990 and 2011 with RMS diagnosed at age 16 or older. One hundred forty-eight patients met the study criteria. Ten were excluded for lack of adequate data. RESULTS: The median age was 28 years. The histologic diagnoses were as follows: embryonal 54%, alveolar 33%, pleomorphic 12%, and not otherwise specified 2%. The tumor site was unfavorable in 67% of patients. Thirty-three patients (24%) were at low risk, 61 (44%) at intermediate risk, and 44 (32%) at high risk. Forty-six percent were treated on or according to a prospective RMS protocol. The 5-year rate of overall survival (OS) was 45% for patients with nonmetastatic disease. The failure rates at 5 years for patients with nonmetastatic disease were 34% for local failure and 42% for distant failure. Among patients with nonmetastatic disease (n=94), significant factors associated with OS were histologic diagnosis, site, risk group, age, and protocol treatment. On multivariate analysis, risk group and protocol treatment were significant after adjustment for age. The 5-year OS was 54% for protocol patients versus 36% for nonprotocol patients. CONCLUSIONS: Survival in adult patients with nonmetastatic disease was significantly improved for those treated on RMS protocols, most of which are now open to adults.