BRAF inhibitors and radiotherapy for melanoma brain metastases: potential advantages and disadvantages of combination therapy.

Melanoma is an aggressive malignancy that frequently spreads to the brain, resulting in rapid deterioration in both quality and quantity of life. Historically, treatment options for melanoma brain metastases (MBM) have predominantly consisted of surgery and radiotherapy. While these options can help provide local control, the majority of patients still develop intracranial progression. Indeed, novel therapeutic options, including molecularly targeted agents and immunotherapy, have improved outcomes and are now changing the role of radiotherapy. Up to 50% of melanomas contain an activating BRAF mutation, resulting in hyperactive cellular proliferation and survival. Drugs that target BRAF have been introduced for the treatment of metastatic melanoma and offer hope in improving disease outcomes; however, many of these trials either excluded or had a limited amount of patients with MBM. Recent studies have revealed that melanoma cell lines become more radiosensitive following BRAF inhibition, thus providing a potential synergistic mechanism when combining BRAF inhibitor (BRAFi) and radiotherapy. However, neurotoxicity concerns also exist with this combination. This article reviews the efficacy and limitations of BRAFi therapy for MBM, describes current evidence for combining BRAFis with radiation, discusses the rationale and evidence for combination modalities, and highlights emerging clinical trials specifically investigating this combination in MBM.

The influence of postoperative lymph node radiation therapy on overall survival of patients with stage III melanoma, a National Cancer Database analysis.

Recently, TROG 02.01 results showed that in stage III melanoma patients with nodal metastasis, adjuvant radiation to lymph node basin after nodal dissection improves lymph node field relapse without an overall survival (OS) benefit. However, this trial was neither designed nor powered to detect an OS difference. In the present study, we analyzed patients in the National Cancer Database (NCDB) with stage III melanoma with pathologically involved nodes and compared survival outcomes of adjuvant radiation and no-radiation cohorts. Inclusion criteria were as follows: age at least 18 years; diagnosed 2003-2011; surgery to regional lymph nodes; pathologically involved lymph nodes; and American Joint Committee on Cancer stage (IIIA-C). We used propensity score matching analysis to compare the OS of patients with similar baseline demographic, clinical, and pathologic characteristics who received adjuvant radiation and no adjuvant radiation. Overall, 912 patients were analyzed with an average age at diagnosis of 54.4 years and a median follow-up time of 5.5 years. In this cohort, the 5-year OS was 69.0, 51.1, and 30.6% for stage IIIA, IIIB, and IIIC, respectively. On propensity score-adjusted multivariate analysis, we found that adjuvant radiation had no statistically significant impact on OS (hazard ratio: 1.09, 95% confidence interval: 0.75-1.58, P=0.640). Furthermore, age older than 60 years, number of nodes, increasing pathologic stage, and absence of immunotherapy correlated with worse OS. In this NCDB analysis, we found that the adjuvant radiotherapy for node-positive, stage III melanoma patients did not improve OS. This is consistent with TROG 02.01; however, there may be patient selection bias not accounted for by the NCDB.

Validation of cutaneous lymphoma international prognostic index (CLIPI) for mycosis fungoides and Sézary syndrome.

We sought to evaluate the performance of the cutaneous lymphoma international prognostic index (CLIPI), a prognostic index for mycosis fungoides (MF), and Sézary syndrome (SS), in our cohort of patients seen at Emory University between 1998 and 2013. Additionally, we examined the prognostic significance of lactate dehydrogenase (LDH), B0a/b, and CD30 status. A total of 390 patients were included in analysis: 78.2% early stage (IA-IIA), 7.2% with SS, 53.1% male, mean age 53.5 years. CLIPI stratified patients into low, intermediate, and high-risk groups for overall survival (OS) and progression free survival (PFS) for early stage patients (p < 0.0001), but was not significant for late stage patients. On multivariable analysis for early stage patients, age >60, plaques, folliculotropic disease was significant for OS and age >60, plaques, N1/Nx was significant for PFS. In the overall cohort, CD30+, elevated LDH, and B0b were significant for worse OS and PFS.

CD30+ Cutaneous T Cell Lymphoma: Response to Rotational Total Skin Electron Irradiation.

INTRODUCTION: Rotational total skin electron irradiation (RTSEI) is an effective therapy for cutaneous T cell lymphoma (CTCL). CD30 expression has been identified as a prognostic factor in CTCL. Therefore, we investigated CD30 status, treatment response, and survival in our cohort of patients with CTCL treated with RTSEI. METHODS: Patients with CTCL treated with RTSEI (≥30 Gy) between 2000 and 2013 at our institution were identified, and clinical and pathologic data were retrospectively reviewed. Primary outcomes were complete clinical response (CCR; >90% reduction of skin disease burden), relapse-free survival (RFS), and overall survival (OS). RESULTS: Sixty-eight patients with CTCL treated with RTSEI were identified. Median age at diagnosis was 51 years with median follow-up of 61 months. Median OS was 76 months and median RFS was 11 months. Thirteen patients (19%) had CD30+ lymphocytes on initial pathology. In the CD30+ cohort, there were no T2, eight T3, and five T4 cases. In comparison, in the CD30- cohort, there were 18 T2, 29 T3, and 8 T4 cases (P = 0.01). Six weeks post-RTSEI, CCR was 85% in CD30+ and 81% in CD30- cases (P = 1). Six months post-RTSEI, CCR was 23% in CD30+ and 50% in CD30- cases (P = 0.083). CONCLUSION: RTSEI resulted in excellent CCR at 6 weeks in our cohort of patients with CTCL, with a median RFS of 11 months. We found CD30+ patients presented with significantly higher T stage at time of RTSEI and trended towards decreased CCR at 6 months post-RTSEI compared with the CD30- group.

Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) as a prognostic marker for local control in T1-2 N0 breast cancer treated with breast-conserving surgery and radiation therapy (BCS + RT).

Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) expression, involved in the regulation of translation, has been implicated to mediate resistance to chemotherapy and radiation in cancer cells in vitro. The purpose of this study was to evaluate the prognostic significance of IFIT1 protein expression in patients with breast cancer treated with Breast-Conserving Surgery and Radiation Therapy (BCS + RT). A tissue microarray was constructed with specimens from 282 women with node-negative, early-stage (I/II) breast cancer who were treated with BCS + RT. Immunohistochemistry was used to stain for the IFIT1 protein. Cytoplasmic IFIT1 protein expression levels were correlated with clinicopathologic factors, local relapse-free survival (LRFS), disease-free survival (DFS), and overall survival (OS). IFIT1 positivity was found in 123 (49%) of cases. The median follow-up time was 7.3 years. Eighty percent of the patients had T1 disease, 88% were human epidermal growth factor receptor 2 (HER2) negative, and 20% had triple-negative breast cancer (TNBC). IFIT1 positivity was associated with estrogen receptor negative status (p = 0.002), progesterone receptor negative status (p = 0.02), TNBC (p = 0.01), and HER2-positive status (p = 0.006). In univariate and multivariate analysis, IFIT1 positivity was associated with improved LRFS (p = 0.055 and p = 0.04, respectively). Using a log-rank test, IFIT1 positivity was found to be associated with improved LRFS (94% versus 85%, p = 0.046) but not DFS or OS at 10 years. On subset analysis of the TNBC patients, IFIT1 positivity was found to correlate with improved LRFS (100% versus 53%, p = 0.004) and DFS in (87% versus 49%, p = 0.048) at 10 years. Elevated IFIT1 protein expression is associated with improved LRFS. In addition, our data suggest that IFIT1 expression may help risk stratify patients with TNBC who may benefit from more aggressive therapy. As there is limited data on IFIT1 in breast cancer, additional work is needed to ascertain its significance.