Sean M. McBride

Hypofractionated stereotactic body radiotherapy in low-risk prostate adenocarcinoma: preliminary results of a multi-institutional phase 1 feasibility trial.

Recent reports using extreme hypofractionated regimens in the treatment of low‐risk prostate adenocarcinoma have been encouraging. Here, the authors report on their own multi‐institutional experience with extreme hypofractionated stereotactic radiotherapy for early stage disease.

Proton Radiation Therapy for Pediatric Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumors: Outcomes for Very Young Children Treated With Upfront Chemotherapy

PURPOSE To report the early outcomes for very young children with medulloblastoma or supratentorial primitive neuroectodermal tumor (SPNET) treated with upfront chemotherapy followed by 3-dimensional proton radiation therapy (3D-CPT). METHODS AND MATERIALS All patients aged <60 months with medulloblastoma or SPNET treated with chemotherapy before 3D-CPT from 2002 to 2010 at our institution were included. All patients underwent maximal surgical resection, chemotherapy, and adjuvant 3D-CPT with either craniospinal irradiation followed by involved-field radiation therapy or involved-field radiation therapy alone. RESULTS Fifteen patients (median age at diagnosis, 35 months) were treated with high-dose chemotherapy and 3D-CPT. Twelve of 15 patients had medulloblastoma; 3 of 15 patients had SPNET. Median time from surgery to initiation of radiation was 219 days. Median craniospinal irradiation dose was 21.6 Gy (relative biologic effectiveness); median boost dose was 54.0 Gy (relative biologic effectiveness). At a median of 39 months from completion of radiation, 1 of 15 was deceased after a local failure, 1 of 15 had died from a non-disease-related cause, and the remaining 13 of 15 patients were alive without evidence of disease recurrence. Ototoxicity and endocrinopathies were the most common long-term toxicities, with 2 of 15 children requiring hearing aids and 3 of 15 requiring exogenous hormones. CONCLUSIONS Proton radiation after chemotherapy resulted in good disease outcomes for a small cohort of very young patients with medulloblastoma and SPNET. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and late toxicity.

DNA hypermethylation profiles associated with glioma subtypes and EZH2 and IGFBP2 mRNA expression.

We explored the associations of aberrant DNA methylation patterns in 12 candidate genes with adult glioma subtype, patient survival, and gene expression of enhancer of zeste human homolog 2 (EZH2) and insulin-like growth factor-binding protein 2 (IGFBP2). We analyzed 154 primary glioma tumors (37 astrocytoma II and III, 52 primary glioblastoma multiforme (GBM), 11 secondary GBM, 54 oligodendroglioma/oligoastrocytoma II and III) and 13 nonmalignant brain tissues for aberrant methylation with quantitative methylation-specific PCR (qMS-PCR) and for EZH2 and IGFBP2 expression with quantitative reverse transcription PCR (qRT-PCR). Global methylation was assessed by measuring long interspersed nuclear element-1 (LINE1) methylation. Unsupervised clustering analyses yielded 3 methylation patterns (classes). Class 1 (MGMT, PTEN, RASSF1A, TMS1, ZNF342, EMP3, SOCS1, RFX1) was highly methylated in 82% (75/91) of lower-grade astrocytic and oligodendroglial tumors, 73% (8/11) of secondary GBMs, and 12% (6/52) of primary GBMs. The primary GBMs in this class were early onset (median age 37 years). Class 2 (HOXA9 and SLIT2) was highly methylated in 37% (19/52) of primary GBMs. None of the 10 genes for class 3 that were differentially methylated in classes 1 and 2 were hypermethylated in 92% (12/13) of nonmalignant brain tissues and 52% (27/52) of primary GBMs. Class 1 tumors had elevated EZH2 expression but not elevated IGFBP2; class 2 tumors had both high IGFBP2 and high EZH2 expressions. The gene-specific hypermethylation class correlated with higher levels of global LINE1 methylation and longer patient survival times. These findings indicate a generalized hypermethylation phenotype in glioma linked to improved survival and low IGFBP2. DNA methylation markers are useful in characterizing distinct glioma subtypes and may hold promise for clinical applications.

Intensity modulated proton therapy for postmastectomy radiation of bilateral implant reconstructed breasts: A treatment planning study

BACKGROUND AND PURPOSE Delivery of post-mastectomy radiation (PMRT) in women with bilateral implants represents a technical challenge, particularly when attempting to cover regional lymph nodes. Intensity modulated proton therapy (IMPT) holds the potential to improve dose delivery and spare non-target tissues. The purpose of this study was to compare IMPT to three-dimensional (3D) conformal radiation following bilateral mastectomy and reconstruction. MATERIALS AND METHODS Ten IMPT, 3D conformal photon/electron (P/E), and 3D photon (wide tangent) plans were created for 5 patients with breast cancer, all of whom had bilateral breast implants. Using RTOG guidelines, a physician delineated contours for both target volumes and organs-at-risk. Plans were designed to achieve 95% coverage of all targets (chest wall, IMN, SCV, axilla) to a dose of 50.4 Gy or Gy (RBE) while maximally sparing organs-at-risk. RESULTS IMPT plans conferred similar target volume coverage with enhanced homogeneity. Both mean heart and lung doses using IMPT were significantly decreased compared to both P/E and wide tangent planning. CONCLUSIONS IMPT provides improved homogeneity to the chest wall and regional lymphatics in the post-mastectomy setting with improved sparing of surrounding normal structures for woman with reconstructed breasts. IMPT may enable women with mastectomy to undergo radiation therapy without the need for delay in breast reconstruction.

Radiation Is an Important Component of Multimodality Therapy for Pediatric Non-Pineal Supratentorial Primitive Neuroectodermal Tumors

PURPOSE To review a historical cohort of pediatric patients with supratentorial primitive neuroectodermal tumors (sPNET), to clarify the role of radiation in the treatment of these tumors. PATIENTS AND METHODS Fifteen children aged <18 years with non-pineal sPNETs diagnosed between 1992 and 2006 were identified. Initial therapy consisted of surgical resection and chemotherapy in all patients and up-front radiotherapy (RT) in 5 patients. Five patients had RT at the time of progression, and 5 received no RT whatever. Kaplan-Meier estimates of overall survival were then calculated. RESULTS The median follow-up from diagnosis for all patients was 31 months (range, 0.5-165 months) and for surviving patients was 49 months (range, 10-165). Of the 5 patients who received up-front RT, all were alive without evidence of disease at a median follow-up of 50 months (range, 25-165 months). Only 5 of the 10 patients who did not receive up-front RT were alive at last follow-up. There was a statistically significant difference in overall survival between the patient group that received up-front RT and the group that did not (p = 0.048). In addition, we found a trend toward a statistically significant improvement in overall survival for those patients who received gross total resections (p = 0.10). CONCLUSIONS Up-front RT and gross total resection may confer a survival benefit in patients with sPNET. Local failure was the dominant pattern of recurrence. Efforts should be made to determine patients most likely to have local failure exclusively or as a first recurrence, in order to delay or eliminate craniospinal irradiation.

Intensity-modulated versus conventional radiation therapy for oropharyngeal carcinoma: long-term dysphagia and tumor control outcomes.

The purpose of this study was to determine the relative clinical benefits of intensity‐modulated radiation therapy (IMRT) versus conventional radiotherapy (CRT) in the treatment of patients with oropharyngeal carcinoma.

Long-term survival after distant metastasis in patients with oropharyngeal cancer.

OBJECTIVES For patients with oropharyngeal squamous cell carcinoma (OPSCC), especially for those with HPV-positive tumors, locoregional control is excellent. Distant metastasis, however, remains a substantial problem. The purpose of our study was to evaluate outcomes and predictors of survival after distant metastasis in OPSCC. MATERIALS AND METHODS Between June 2002 and January 2011, 25 OPSCC patients treated with curative intent subsequently developed distant metastasis. The primary end-points evaluated were time-to-distant metastasis and overall survival after development of distant metastasis. Predictors of outcome were evaluated with median regression analysis or Cox regression. Best subset models were chosen to minimize the Bayesian Information Criterion (BIC). A prognostic index for survival after distant failure was created based on the selected model. RESULTS Median time-to-distant metastasis after completion of radiation was 7.9 months (range, 1.6-25.4). Median overall survival from distant metastasis was 18.3 months (95% CI, 14.3-39.8). The overall survival rates at 1- and 2-year after development of distant metastasis were 72.0% (95% confidence interval [CI], 53.4-89.6) and 40.8% (95% CI, 20.6-61.0), respectively. In multivariate analysis, Karnofsky Performance Status score (KPS) > or = 80 (p=0.01, hazard ratio [HR] 0.15, 95% CI, 0.04-0.52) and limited, single-organ disease (p=0.003, HR 0.13, 95% CI 0.03-0.61) predicted for increased survival from distant metastasis. Patients with both limited disease and good KPS formed the most favorable risk group with a 2-year survival of 100%. Two patients with human papilloma virus (HPV)-positive tumors were alive without any evidence of disease at 64.6 and 60.4 months, respectively, after aggressive local treatment of solitary metastasis. CONCLUSION For OPSCC patients with limited, single-organ disease and good KPS, long-term survival can be achieved.

Proton radiotherapy for solid tumors of childhood.

The increasing efficacy of pediatric cancer therapy over the past four decades has produced many long-term survivors that now struggle with serious treatment related morbidities affecting their quality of life. Radiation therapy is responsible for a significant proportion of these late effects, but a relatively new and emerging modality, proton radiotherapy hold great promise to drastically reduce these treatment related late effects in long term survivors by sparing dose to normal tissues. Dosimetric studies of proton radiotherapy compared with best available photon based treatment show significant dose sparing to developing normal tissues. Furthermore, clinical data are now emerging that begin to quantify the benefit in decreased late treatment effects while maintaining excellent cancer control rates.

Mutation frequency in 15 common cancer genes in high-risk head and neck squamous cell carcinoma.

With prior studies having looked at unselected cohorts, we sought to explore the mutational landscape in a high‐risk group of head and neck squamous cell carcinoma (HNSCC) tumors.

Advances in Radiation Therapy

Recent developments in radiation therapy have largely centered on the improvement in delivering radiation to a highly conformal target with high precision. The increased use of stereotactic body radiotherapy (SBRT) has also introduced another dimension of treatment, potentially replacing surgery in select situations to aggressive treatment of oligometastatic disease to invoking a systemic response using immunomodulators. Simultaneously, advances in systemic therapy ranging from traditional chemotherapy regimens to targeted biologics, and more recently immune modulators, are rapidly affecting the field of radiation oncology. These advances rely on a synergy between significant improvements in radiation delivery, driven by image guidances and more conformal delivery or radiation, and a greater understanding of tumor biology. This chapter will focus on an understanding of advances in these areas and future directions for pediatric brain tumors levering these innovations.