Faculty Bibliography

OBJECT/OBJECTIVE:Radiation therapy is known to impair wound healing. Higher dose per fraction is believed to increase this risk. This study sought to quantify rates of wound complication in patients receiving preoperative conventionally fractionated radiotherapy (XRT) or high-dose hypofractionated image-guided radiation therapy (IGRT) for spinal metastasis, and to identify predictors of wound complication. METHODS:The records of 165 consecutive patients who underwent spine surgery for metastasis at Memorial Sloan-Kettering Cancer Center between 1999 and 2010, with a history of prior radiation therapy, were reviewed. Patients with primary spine tumors, 2 courses of prior radiation therapy to the surgical site, total dose < 9 Gy, or radiation therapy adjacent to or partially overlapping the surgical site, were excluded. One hundred thirty patients received XRT (≤ 3 Gy/fraction) and 35 received IGRT (> 3 Gy/fraction). The total dose prescribed to the 100% isodose line to treat the planning target volume was 18-30 Gy in 1-5 fractions. Clinical factors evaluated included age, Karnofsky Performance Scale score, body mass index, presence of diabetes, smoking, ambulatory status, prior surgery at same spinal site, preoperative laboratory results (hemoglobin, lymphocyte count, and albumin), perioperative chemotherapy or steroids, estimated blood loss, extent of stabilization hardware, time between radiation therapy and surgery, number of vertebral bodies irradiated, total radiation dose, and dose per fraction of radiation therapy. Wound complication was defined as poor healing, dehiscence, or infection. Potential predictors of wound complication were assessed by univariate analyses using competing-risk methods to adjust for risk of death. results: For XRT patients, median dose was 30 Gy (range 11.5-70 Gy) with 72% of them receiving 3 Gy × 10 fractions. For IGRT patients, 66% received 18-24 Gy × 1 fraction and 23% received 6 Gy × 5 fractions. Groups differed only by the mean number of vertebral bodies treated (4.6 XRT and 1.8 IGRT, p < 0.0001). Wound complications occurred at a median of 0.95 months (range 0.4-3.9 months). A total of 22 wound events occurred in the XRT group and 2 in the IGRT group. The 6-month cumulative incidence of wound complications for XRT was 17% and for IGRT was 6%. There was no significant difference in wound complications between groups (IGRT vs XRT: hazard ratio 0.31, 95% CI 0.08-1.3; p = 0.11). Higher dose per fraction appeared to be associated with a lower risk of wound complication (hazard ratio 0.27, 95% CI 0.06-1.15; p = 0.08), which trended toward significance. Univariate analyses did not reveal any significant predictors of wound complications. CONCLUSIONS:Patients who underwent XRT or IGRT did not have significantly different rates of postoperative wound complications. This finding may be explained by the treatment of fewer vertebral bodies in IGRT patients, or by the low overall number of total events. With a wound complication rate of 6%, preoperative IGRT, a highly conformal treatment, resulted in a very low rate of surgical wound complication.

HER2-positive breast cancer is a known risk factor for CNS metastases, and the use of trastuzumab in the adjuvant setting does not prevent brain metastases. The purpose of this study is to compare outcomes in HER2-positive and HER2-negative intracranial disease treated with stereotactic radiosurgery (SRS). Among 57 breast cancer patients with brain metastases, 28 patients were HER2-positive. All patients were treated with SRS as their first treatment modality for CNS metastases. The median dose was 20 Gy (range 12-20 Gy). Statistical analysis was performed using the Kaplan-Meier method and chi (2) test. With a median follow-up of 11.0 months, the median time to progression in the HER2-positive group compared with the HER2-negative group was 7 versus 11 months (p = 0.080), respectively. Salvage therapy was performed in 50 % of HER2-positive patients compared with 21 % of HER2-negative patients (p = 0.02). The median OS for the HER2-positive group compared with the HER2-negative group was 22 versus 12 months (p = 0.053). Stereotactic radiosurgery results in excellent local control in the treatment for breast cancer brain metastases. Compared with HER2-negative disease, HER2-positive disease appears to show higher rates of intracranial relapse despite better overall survival rates. This data suggests that we need effective adjuvant therapy to prevent and treat brain metastases in HER2-positive patients.

Objectives/UNASSIGNED:Excellent local-regional control can be achieved for major salivary gland tumors treated with surgery and post-operative radiotherapy. We evaluated the cumulative incidence and predictors of distant metastasis in high-risk major salivary gland tumors. Methods/UNASSIGNED:Between 1990 and 2011, 200 patients with major salivary gland tumors received post-operative radiotherapy at our center. The patients' median age was 60 years. Patients had primary tumors of the parotid gland (84%), submandibular (16%), and one sublingual gland. Among the patients, 34% had T3-T4 tumors, 32% had nodal involvement. Other high-risk features included close/positive margins and high grade tumors. The median RT dose was 63 Gy. Results/UNASSIGNED:With a median follow-up of 50 months, the 5-year local control and regional control were 88% and 94%, respectively. The 5-year freedom from distant metastasis was 73%. The median overall survival was 14.6 years corresponding to a 5 and 10-year overall survival of 77% and 59%, respectively. T category and nodal involvement were independent predictors of distant metastasis. Nodal involvement was also an independent predictor of overall survival. Conclusions/UNASSIGNED:Distant relapse was the predominant mode of failure despite excellent local-regional control in high-risk major salivary gland tumors. Both advanced T category and nodal involvement were independent predictors of distant metastasis. More effective systemic therapy is needed to combat distant relapse.

Previously we have shown that our routine portal imaging (PI) of the craniofacial region in pediatric brain tumor patients contributed an additional 2%-3% of the prescribed dose and up to 200 cGy to the planning target volume (PTV) and nearby organs at risk (OARs). The purpose of this study is to quantify the reduction in dose to PTV and OARs from portal imaging (PI) of the craniofacial region of pediatric patients treated after the implementation of changes in our portal imaging practices. Twenty consecutive pediatric patients were retrospectively studied since the implementation of changes to our portal imaging procedure. Each received portal imaging of treatment fields and orthogonal setup fields to the craniofacial region. PI modifications included a reduction in the field size of setup orthogonal fields without loss of radiographic information needed for treatment verification. In addition, treatment fields were imaged using a single exposure, rather than double exposure. Dose-volume histograms were generated to quantify the dose to the target and critical structures through PI acquisition. These results were compared with our previous cohort of 20 patients who were treated using the former portal imaging practices. The mean additional target dose from portal imaging following the new guidelines was 1.5% of the prescribed dose compared to 2.5% prior to the new portal image practices (p < 0.001). With the new portal imaging practices, the percentage decrease in portal imaging dose to the brainstem, optic structures, cochlea, hypothalamus, temporal lobes, thyroid, and eyes were 25%, 35%, 35%, 51%, 45%, 80%, and 55%, respectively. Reductions in portal imaging doses were significant in all OARs with exception of the brainstem, which showed a trend towards significance. Changes to portal imaging practices can reduce the radiation dose contribution from portal imaging to surrounding OARs by up to 80%. This may have implications on both late toxicity and second cancer development in pediatric brain tumors.

Brain metastases in malignant melanoma carries a poor prognosis with minimal response to any therapy. The purpose of this pilot analysis was to find the effectiveness of vemurafenib, an oral BRAF inhibitor, and radiation therapy in V600 mutated melanoma with brain metastases. BRAF mutation status of the melanoma patients was determined by real-time PCR assay. Retrospective analysis was performed on twelve patients who had the mutation and were treated with either stereotactic radiosurgery or whole brain radiation therapy prior to or along with vemurafenib at a dose of 960 mg orally twice a day. Clinical and radiological responses, development of new brain metastases, overall survival and toxicity were assessed. Improvement in neurological symptoms was seen in 7/11 (64 %) following therapy. Radiographic responses were noted in 36/48 (75 %) of index lesions with 23 (48 %) complete responses and 13 (27 %) partial responses. Six month local control, freedom from new brain metastases and overall survival were 75, 57 and 92 %. Four patients had intra-tumoral bleed prior to therapy and two patients developed steroid dependence. One patient experienced radiation necrosis. This retrospective study suggests that melanoma patients with brain metastases harboring BRAF mutation appear to be a distinct sub-group with a favorable response to vemurafenib and radiation therapy and acceptable morbidity.

The anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab has been shown to improve survival in patients with metastatic non-CNS melanoma. The purpose of this study was to investigate the efficacy of CTLA-4 inhibitors in the treatment of metastatic melanoma with limited brain metastases treated with stereotactic radiosurgery (SRS). Between January 2008 and June 2011, 58 patients with limited brain metastases from melanoma were treated with SRS with a median dose of 20 Gy delivered to the 50% isodose line (range, 15-20 Gy). In 25 patients, ipilimumab was administered intravenously at a dose of 3 mg/kg over 90 min every 3 weeks for a median of four doses (range, 1-8). Local control (LC), freedom from new brain metastases, and overall survival (OS) were assessed from the date of the SRS procedure. The median LC, freedom from new brain metastases, and OS for the entire group were 8.7, 4.3, and 5.9 months, respectively. The cause of death was CNS progression in all but eight patients. Six-month LC, freedom from new brain metastases, and OS were 65, 35, and 56%, respectively, for those who received ipilimumab and 63, 47, and 46% for those who did not (P=NS). Intracranial hemorrhage was noted in seven patients who received ipilimumab compared with 10 patients who received SRS alone (P=NS). In this retrospective study, administration of ipilimumab neither increased toxicity nor improved intracerebral disease control in patients with limited brain metastases who received SRS.

Background Whole brain radiation therapy (WBRT) reduces local recurrence in patients after surgical resection of brain metastases without improving overall survival. Involved field radiation therapy (IFRT) has been used at our center to avoid delayed neurotoxicity associated with WBRT in well-selected patients with surgically resected single brain metastases. The purpose of this study was to evaluate the long-term outcomes of these patients. Methods Thirty-three consecutive patients with single brain metastases from a known primary tumor were treated with gross total resection followed by IFRT between 2006 and 2011. The postoperative surgical bed was treated to 40.05 Gy in 15 fractions of 2.67 Gy with conformal radiation therapy. Patients received serial MRIs and neurological exams in follow-up. Surgery, WBRT, or stereotactic radiosurgery was performed as salvage treatment when necessary. Results The median follow-up was 16 months (range: 2-65 months). Local control, distant brain recurrence-free survival, and overall survival at 12 and 24 months were 90.3% and 85.8%, 60.7% and 51.4%, and 65.6% and 61.5%, respectively. Overall, 5 (15%) patients developed recurrence at the resection cavity, and 13 (39%) patients experienced recurrence at a new intracranial site. Two patients received WBRT, 8 stereotactic radiosurgery, 2 surgery, and 2 both chemotherapy and IFRT as salvage. Four patients died from CNS disease progression. Conclusion For patients with newly diagnosed single brain metastases treated with surgical resection, postoperative IFRT to the resection cavity achieves reasonable rates of local control and is an excellent alternative to WBRT.