Neutrophil to lymphocyte ratio (NTLR) predicts local control and overall survival after stereotactic body radiotherapy (SBRT) in metastatic sarcoma.

The neutrophil to lymphocyte ratio (NTLR) and absolute lymphocyte count (ALC) recovery are prognostic across many cancers. We investigated whether NLTR predicts SBRT success or survival in a metastatic sarcoma cohort treated with SBRT from 2014 and 2020 (N = 42). Wilcox Signed Rank Test and Friedman Test compare NTLR changes with local failure vs. local control (N = 138 lesions). Cox analyses identified factors associated with overall survival. If local control was successful, NLTR change was not significant (p = 0.30). However, NLTR significantly changed in patients with local failure (p = 0.027). The multivariable Cox model demonstrated higher NLTR before SBRT was associated with worse overall survival (p = 0.002). The optimal NTLR cut point was 5 (Youden index: 0.418). One-year overall survival in SBRT metastatic sarcoma cohort was 47.6% (CI 34.3%-66.1%). Patients with an NTLR above 5 had a one-year overall survival of 37.7% (21.4%-66.3%); patients with an NTLR below 5 had a significantly improved overall survival of 63% (43.3%-91.6%, p = 0.014). Since NTLR at the time of SBRT was significantly associated with local control success and overall survival in metastatic sarcoma treated with SBRT, future efforts to reduce tumor inhibitory microenvironment factors and improve lymphocyte recovery should be investigated.

Neutrophil to Lymphocyte Ratio (NTLR) Predicts Local Control Failure and Overall Survival after Stereotactic Body Radiotherapy (SBRT) In Metastatic Sarcoma.

The neutrophil to lymphocyte ratio (NTLR) and absolute lymphocyte count (ALC) recovery are prognostic across many cancers. We investigated whether NLTR predicts SBRT success or survival in a metastatic sarcoma cohort treated with SBRT from 2014 and 2020 (N = 42). Wilcox Signed Rank Test and Friedman Test compare NTLR changes with local failure vs. local control (N = 138 lesions). Cox analyses identified factors associated with overall survival. If local control was successful, NLTR change was not significant (p = 0.30). However, NLTR significantly changed in patients local failure (p = 0.027). The multivariable Cox model demonstrated higher NLTR before SBRT was associated with worse overall survival (p = 0.002). The optimal NTLR cut point was 5 (Youden index: 0.418). One-year overall survival in SBRT metastatic sarcoma cohort was 47.6% (CI 34.3%-66.1%). Patients with an NTLR above 5 had a one-year overall survival of 37.7% (21.4%-66.3%); patients with an NTLR below 5 had a significantly improved overall survival of 63% (43.3%-91.6%, p = 0.014). Since NTLR at the time of SBRT was significantly associated with local control success and overall survival in metastatic sarcoma treated with SBRT, future efforts to reduce tumor inhibitory microenvironment factors and improved lymphocyte recovery should be investigated.

Early outcomes of ultra-hypofractionated preoperative radiation therapy for soft tissue sarcoma followed by immediate surgical resection.

BACKGROUND: There is increasing interest in shorter courses of radiation therapy (RT) in the management of soft tissue sarcoma (STS). We report our institutional experience for patients undergoing ultra-hypofractionated preoperative RT followed by immediate resection. METHODS: An IRB approved review of patients treated with preoperative 5 fraction, once daily RT followed by immediate resection (within 7 days) for STS of the extremity or trunk was conducted. The primary endpoints are major wound complications and local control (LC). Secondary endpoints include grade ≥ 2 toxicity, metastasis free survival (MFS), and overall survival (OS). RESULTS: Twenty-two patients with a median age of 67 years (range 30-87) and median follow-up of 24.5 months (IQR 17.0-35.7) met eligibility criteria; 18/22 patients (81.8 %) had ≥ 1 year follow-up. Primary tumor location was lower extremity in 15 patients (68.2 %), upper extremity in 5 (22.7 %), and trunk in 2 (9.1 %). All patients received 30 Gy in 5 fractions. The median time to resection following RT was 1 day (range 0-5). The median time from biopsy to resection was 34 days (range 20-69). Local control was 100 %; in patients with localized disease, 2-year MFS and OS were 71.3 % and 76.9 %, respectively. Major wound complications occurred in 9 patients (40.9 %), with wound complications requiring reoperation occurring in 8 patients (36.4 %). Other acute and late grade ≥ 2 toxicities were seen in 0 and 4 patients (18.2 %), respectively. CONCLUSION: Ultra-hypofractionated preoperative RT followed by immediate resection permits expedited completion of oncologic therapy with early results demonstrating excellent local control and acceptable toxicity. Prospective data with long-term follow-up is needed.

Association between biologically effective dose and local control after stereotactic body radiotherapy for metastatic sarcoma.

Introduction: Stereotactic body radiation therapy (SBRT) is increasingly utilized for patients with recurrent and metastatic sarcoma. SBRT affords the potential to overcome the relative radioresistance of sarcomas through delivery of a focused high biological effective dose (BED) as an alternative to invasive surgery. We report local control outcomes after metastatic sarcoma SBRT based on radiation dose and histology. Methods: From our IRB-approved single-institution registry, all patients treated with SBRT for metastatic sarcoma between 2014 and 2020 were identified. Kaplan-Meier analysis was used to estimate local control and overall survival at 1 and 2 years. A receiver operating characteristic (ROC) curve was generated to determine optimal BED using an α/ß ratio of 3. Local control was compared by SBRT dose using the BED cut point and evaluated by histology. Results: Forty-two patients with a total of 138 lesions met inclusion criteria. Median imaging follow up was 7.73 months (range 0.5-35.0). Patients were heavily pre-treated with systemic therapy. Median SBRT prescription was 116.70 Gy BED (range 66.70-419.30). Desmoplastic small round cell tumor, Ewing sarcoma, rhabdomyosarcoma, and small round blue cell sarcomas were classified as radiosensitive (n = 63), and all other histologies were classified as radioresistant (n = 75). Local control for all lesions was 66.7% (95% CI, 56.6-78.5) at 1 year and 50.2% (95% CI, 38.2-66.1) at 2 years. Stratifying by histology, 1- and 2-year local control rates were 65.3% and 55.0%, respectively, for radiosensitive, and 68.6% and 44.5%, respectively, for radioresistant histologies (p = 0.49). The ROC cut point for BED was 95 Gy. Local control rates at 1- and 2-years were 75% and 61.6%, respectively, for lesions receiving >95 Gy BED, and 46.2% and 0%, respectively, for lesions receiving <95 Gy BED (p = 0.01). On subgroup analysis, local control by BED > 95 Gy was significant for radiosensitive histologies (p = 0.013), and trended toward significance for radioresistant histologies (p = 0.25). Conclusion: There is a significant local control benefit for sarcoma SBRT when a BED > 95 Gy is used. Further investigation into the dose-response relationship is warranted to maximize the therapeutic index.

In vivo assessment of the safety of standard fractionation Temporally Feathered Radiation Therapy (TFRT) for head and neck squamous cell carcinoma: An R-IDEAL Stage 1/2a first-in-humans/feasibility demonstration of new technology implementation.

INTRODUCTION: Prior in silico simulations of studies of Temporally Feathered Radiation Therapy (TFRT) have demonstrated potential reduction in normal tissue toxicity. This R-IDEAL Stage 1/2A study seeks to demonstrate the first-in-human implementation of TFRT in treating patients with head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Patients with HNSCC treated with definitive radiation therapy were eligible (70 Gy in 35 fractions) were eligible. The primary endpoint was feasibility of TFRT planning as defined by radiation start within 15 business days of CT simulation. Secondary endpoints included estimates of acute grade 3-5 toxicity. RESULTS: The study met its accrual goal of 5 patients. TFRT plans were generated in four of the five patients within 15 business days of CT simulation, therefore meeting the primary endpoint. One patient was not treated with TFRT at the physician's discretion, though the TFRT plan had been generated within sufficient time from the CT simulation. For patients who received TFRT, the median time from CT simulation to radiation start was 10 business days (range 8-15). The average time required for radiation planning was 6 business days. In all patients receiving TFRT, each subplan and every daily fraction was delivered in the correct sequence without error. The OARs feathered included: oral cavity, each submandibular gland, each parotid gland, supraglottis, and posterior pharyngeal wall (OAR pharynx). Prescription dose PTV coverage (>95%) was ensured in each TFRT subplan and the composite TFRT plan. One of five patients developed an acute grade 3 toxicity. CONCLUSIONS: This study demonstrates the first-in-human implementation of TFRT (R-IDEAL Stage 1), proving its feasibility in the modern clinical workflow. Additionally, assessments of acute toxicities and dosimetric comparisons to a standard radiotherapy plan were described (R-IDEAL Stage 2a).

Multiple Site SBRT in Pediatric, Adolescent, and Young Adult Patients With Recurrent and/or Metastatic Sarcoma.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is increasingly used for patients with recurrent and or metastatic tumors. Sarcomas are generally considered not sensitive to radiotherapy and SBRT may allow for increased biological effectiveness. We report intermediate outcomes and toxicity for pediatric, adolescent, and young adult patients treated with SBRT to sites of recurrent and or metastatic sarcoma. PROCEDURE: We queried an Institutional Review Board-approved registry of patients treated with SBRT for metastases from pediatric sarcomas. Patients age 29 and below were assessed for local control, survival, and toxicity. RESULTS: Thirty-one patients with a total of 88 lesions met eligibility criteria. Median patient age was 17.9 years at treatment. Sixteen patients were treated with SBRT to >1 site of disease. The median dose was 30 Gy in 5 fractions. The median follow-up time was 7.4 months (range: 0.2 to 31.4 mo). Patients were heavily pretreated with systemic therapy. In 57 lesions with >3 months of radiographic follow-up, the 6-month and 12-month local control rates were 88.3%±4.5% and 83.4%±5.5%, respectively. Radiographic local failures were rare (6/57 in-field, 4/57 marginal). Only 1/88 treated lesions was associated with a radiation-related high-grade toxicity; late grade 3 intestinal obstruction in a re-irradiated field while on concurrent therapy (gemcitabine and docetaxel). No acute grade ≥3 toxicity was observed. CONCLUSIONS: SBRT was well tolerated in the majority of patients with favorable local control outcomes. Additional studies will be required to determine the optimal SBRT dose and fractionation, treatment volume, and appropriate concurrent therapies.

Treatment paradigms for oligometastatic pediatric cancers: a narrative review with a focus on radiotherapy approaches.

There is a growing body of prospective evidence describing an oligometastatic phenotype in adults for whom local metastasis-directed therapy can improve outcomes in select patients. However, a relative paucity of data for pediatric patients with oligometastatic disease creates challenges in choosing optimal treatment. The purpose of this review is to evaluate the literature surrounding pediatric oligometastatic disease and treatment, specifically focusing on the role of radiotherapy. A review of studies ranging from 2008 to 2020 was performed. The radiotherapy techniques evaluated included conventionally fractionated radiotherapy, stereotactic body radiotherapy (SBRT), and stereotactic radiosurgery (SRS). Our search yielded 6 studies evaluating conventionally fractionated radiotherapy, 9 studies of SBRT, and 3 studies of spine SRS. Metastasis-directed therapy for treatment of pediatric oligometastasis is generally well-tolerated, is associated with favorable local control, and is shown to improve event-free survival and progression-free survival (PFS) outcomes in select pediatric patients. Pediatric patients with oligometastatic disease may benefit from aggressive local therapy to metastatic sites in conjunction with a comprehensive treatment paradigm. Retrospective data have led to promising prospective trials that will further clarify patient selection and management. Additional data are needed to elucidate long term oncologic and toxicity outcomes.

Early Outcomes of Preoperative 5-Fraction Radiation Therapy for Soft Tissue Sarcoma Followed by Immediate Surgical Resection.

PURPOSE: There are limited data regarding the use of hypofractionated radiation therapy (RT) for soft tissue sarcoma. We report early oncologic outcomes and wound complications of patients undergoing preoperative hypofractionated (5 fraction) RT followed by immediate surgical resection. METHODS AND MATERIALS: An institutional review board-approved database of patients treated with preoperative RT for soft tissue sarcoma was queried. Patients treated with a hypofractionated dosing regimen followed by immediate (within 7 days) planned wide surgical resection were identified. RESULTS: Between 2016 and 2019, 16 patients met eligibility criteria. The median patient age was 64 years old (range, 33-88). Ten of the sarcomas were located in the lower extremity, 4 in the upper extremity, and 2 were located in the trunk. Four patients had metastatic disease at diagnosis. The majority of the patients received a total radiation dose of 30 Gy in 5 fractions (range, 27.5-40 Gy) on consecutive days. All patients were planned with intensity modulated radiation therapy or volumetric arc therapy. The median time to surgical resection after the completion of RT was 1 day (range, 0-7 days). The median time from initial biopsy results to completion of primary oncologic therapy was 20 days (range, 16-35). Ten patients achieved R0 resection, whereas the remaining 6 patients achieved R1 resection. Of the 13 patients assessed for local control, no patients developed local failure. Within the median follow-up time of 10.7 months (range, 1.7-33.2), 5 patients developed wound healing complications (31%), of which only 3 patients (19%) required return to the operating room. CONCLUSIONS: Treatment of soft tissue sarcoma with preoperative hypofractionated RT followed by immediate resection resulted in a median of 20 days from biopsy results to completion of oncologic therapy. Early outcomes demonstrate favorable wound healing. Further prospective data with long-term follow-up is required to determine the oncologic outcomes and toxicity of hypofractionated preoperative RT.

Technical Note: A step-by-step guide to Temporally Feathered Radiation Therapy planning for head and neck cancer.

PURPOSE: Prior in silico simulations propose that Temporally Feathered Radiation Therapy (TFRT) may reduce toxicity related to head and neck radiation therapy. In this study we demonstrate a step-by-step guide to TFRT planning with modern treatment planning systems. METHODS: One patient with oropharyngeal cancer planned for definitive radiation therapy using intensity-modulated radiation therapy (IMRT) techniques was replanned using the TFRT technique. Five organs at risk (OAR) were identified to be feathered. A "base plan" was first created based on desired planning target volumes (PTV) coverage, plan conformality, and OAR constraints. The base plan was then re-optimized by modifying planning objectives, to generate five subplans. All beams from each subplan were imported onto one trial to create the composite TFRT plan. The composite TFRT plan was directly compared with the non-TFRT IMRT plan. During plan assessment, the composite TFRT was first evaluated followed by each subplan to meet preset compliance criteria. RESULTS: The following organs were feathered: oral cavity, right submandibular gland, left submandibular gland, supraglottis, and OAR Pharynx. Prescription dose PTV coverage (>95%) was met in each subplan and the composite TFRT plan. Expected small variations in dose were observed among the plans. The percent variation between the high fractional dose and average low fractional dose was 29%, 28%, 24%, 19%, and 10% for the oral cavity, right submandibular, left submandibular, supraglottis, and OAR pharynx nonoverlapping with the PTV. CONCLUSIONS: Temporally Feathered Radiation Therapy planning is possible with modern treatment planning systems. Modest dosimetric changes are observed with TFRT planning compared with non-TFRT IMRT planning. We await the results of the current prospective trial to seeking to demonstrate the feasibility of TFRT in the modern clinical workflow (NCT03768856). Further studies will be required to demonstrate the potential benefit of TFRT over non-TFRT IMRT Planning.

223-Radium for metastatic osteosarcoma: combination therapy with other agents and external beam radiotherapy.

BACKGROUND: Bone-seeking radiopharmaceuticals can deposit radiation selectively to some osteosarcoma tumours because of the bone-forming nature of this cancer. OBJECTIVES: This is the first report of using 223-radium, an alpha-emitting calcium analogue with a high therapeutic index, in combination therapy with other agents in 15 patients with metastatic osteoblastic osteosarcoma. METHODS: Candidates for alpha-radiotherapy if 99mTc-MDP bone scan had avid bone-forming lesions and no therapy of higher priority (eg, definitive surgery). Monthly 223-radium infusions (1.49 µCi/kg or 55.13 kBq/kg) were given. RESULTS: The median infusion number was three and the average time to progression was 4.3 months for this cohort receiving 223-radium+other agents. Agents provided during 223-radium included (1) drugs to reduce skeletal complications: monthly denosumab (n=13) or zolendronate (n=1); (2) agents with antivascular endothelial growth factor activity, pazopanib (n=8) or sorafenib (n=1), (3) alkylating agents: oral cyclophosphamide (n=1) or ifosfamide, given as a 14-day continuous infusion (n=1, two cycles), (4) high-dose methotrexate (n=1), pegylated liposomal doxorubicin (n=1); and (5) two other combinations: nivolumab and everolimus (n=1) and rapamycin and auranofin (n=1). Radiation therapy, including stereotactic body radiotherapy (SBRT), was also given to 11 patients concurrently with 223-radium (n=2), after 223-radium completion (n=3), or both concurrently and then sequentially for other sites (n=6). After 223-radium infusions, patients without RT had a median overall survival of 4.3 months compared with those with SBRT and/or RT, who had a median overall survival of 13.5 months.Conclusion Although only 1/15 of patients with osteoblastic osteosarcoma still remain alive after 223-radium, overall survival.

Heterogenous Dose-escalated Prostate Stereotactic Body Radiation Therapy for All Risk Prostate Cancer: Quality of Life and Clinical Outcomes of an Institutional Pilot Study.

OBJECTIVES: Previous prostate stereotactic body radiation therapy studies delivered uniform doses of 35 to 40 Gy/5 fx. Attempts at uniform dose escalation to 50 Gy caused high rates of gastrointestinal (GI) toxicity. We hypothesize that heterogeneous dose escalation to regions nonadjacent to sensitive structures (urethra, rectum, and bladder) is safe and efficacious. MATERIALS AND METHODS: Patients were enrolled on a prospective pilot study. The primary endpoint was treatment-related GI and genitourinary (GU) toxicity. The secondary endpoints included quality of life (QOL) assessed by the EPIC-26 questionnaire and biochemical control. The target volume received 36.25 Gy/5 fx. The target >3 mm from sensitive was dose escalated to 50 Gy/5 fx. RESULTS: Thirty-five patients were enrolled. Three patients had low, 14 intermediate, and 18 high-risk disease. The mean initial prostate specific antigen was 15.1 ng/mL. Androgen deprivation therapy was given to 19 patients. Median follow-up was 46 months. Urinary irritation/obstructive and urinary bother scores declined by minimal clinically important difference threshold from baseline at 6 weeks, but subsequently recovered by 4 months. No differences in QOL scores were observed for urinary incontinence, bowel domain, bloody stools, or sexual domain. One patient developed acute grade 4 GU toxicity and acute grade 4 GI toxicity. The incidence of late high grade toxicity was 1/35 for GU toxicity and 2/35 for GI toxicity. Freedom from biochemical failure at 3 years was 88.0%. CONCLUSIONS: Heterogeneous dose-escalated prostate stereotactic body radiation therapy is feasible with low rates of acute and late toxicities and favorable QOL outcomes in patients with predominantly intermediate-risk and high-risk prostate cancer.

Aggressive Local Control With Multisite Stereotactic Body Radiation in Metastatic Ewing Sarcoma: A Literature Review and Case Report.

Ewing sarcoma (ES) is an undifferentiated small round blue cell tumor most commonly originating in the bone of adolescents 10-20 years of age, although 30% are diagnosed in adults. The most important prognostic factor is the presence of metastatic disease. Results of the EURO-EWING 99 trial of ES patients showed that local treatment of not only the primary, but also of the sites of metastatic disease should be considered to improve event-free survival. The use of stereotactic body radiotherapy (SBRT) has been extensively reported for tumors of lung, liver, pancreas, and spine. The use of SBRT in these sites is well-accepted. Here, we report a detailed case of SBRT to multisite metastatic ES. We demonstrate the feasibility, safety, and efficacy of aggressive local control with multisite SBRT for the treatment of metastatic ES.

Spine radiosurgery in adolescents and young adults: early outcomes and toxicity in patients with metastatic Ewing sarcoma and osteosarcoma.

OBJECTIVE: There are limited data on spine stereotactic radiosurgery (SRS) in treating adolescent and young adult (AYA) patients. SRS has the advantages of highly conformal radiation dose delivery in the upfront and retreatment settings, means for dose intensification, and administration over a limited number of sessions leading to a decreased treatment burden. In this study, the authors report the oncological and toxicity outcomes for AYA patients with metastatic sarcoma treated with spine radiosurgery and provide clinicians a guide for considerations in dose, volume, and fractionation. METHODS: An institutional review board-approved database of patients treated with SRS in the period from October 2014 through December 2018 was queried. AYA patients, defined by ages 15-29 years, who had been treated with SRS for spine metastases from Ewing sarcoma or osteosarcoma were included in this analysis. Patients with follow-ups shorter than 6 months after SRS were excluded. Local control, overall survival, and toxicity were reported. RESULTS: Seven patients with a total of 11 treated lesions were included in this study. Median patient age was 20.3 years (range 15.1-26.1 years). Three patients had Ewing sarcoma (6 lesions) and 4 patients had osteosarcoma (5 lesions). The median dose delivered was 35 Gy in 5 fractions (range 16-40 Gy, 1-5 fractions). The median follow-up was 11.1 months (range 6.8-26.0 months). Three local failures were observed within the follow-up period. No acute grade 3 or greater toxicity was observed. One patient developed late grade 3 toxicity consisting of radiation enteritis. This patient had previously received radiation to an overlapping volume with conventional fractionation. SRS re-irradiation for this patient was also performed concurrently with chemotherapy administration. No late grade 4 or higher toxicities were observed. No pain flare or vertebral compression fracture was observed. Three patients died within the follow-up period. CONCLUSIONS: SRS for spine metastases from Ewing sarcoma and osteosarcoma can be considered as a treatment option in AYA patients and is associated with acceptable toxicity rates. Further studies must be conducted to determine long-term local control and toxicity for this treatment modality.

Outcomes of stereotactic radiosurgery for pilocytic astrocytoma: an international multiinstitutional study.

OBJECTIVE: The current standard initial therapy for pilocytic astrocytoma is maximal safe resection. Radiation therapy is considered for residual, recurrent, or unresectable pilocytic astrocytomas. However, the optimal radiation strategy has not yet been established. Here, the authors describe the outcomes of stereotactic radiosurgery (SRS) for pilocytic astrocytoma in a large multiinstitutional cohort. METHODS: An institutional review board-approved multiinstitutional database of patients treated with Gamma Knife radiosurgery (GKRS) between 1990 and 2016 was queried. Data were gathered from 9 participating International Radiosurgery Research Foundation (IRRF) centers. Patients with a histological diagnosis of pilocytic astrocytoma treated using a single session of GKRS and with at least 6 months of follow-up were included in the analysis. RESULTS: A total of 141 patients were analyzed in the study. The median patient age was 14 years (range 2-84 years) at the time of GKRS. The median follow-up was 67.3 months. Thirty-nine percent of patients underwent SRS as the initial therapy, whereas 61% underwent SRS as salvage treatment. The median tumor volume was 3.45 cm3. The tumor location was the brainstem in 30% of cases, with a nonbrainstem location in the remainder. Five- and 10-year overall survival rates at the last follow-up were 95.7% and 92.5%, respectively. Five- and 10-year progression-free survival (PFS) rates were 74.0% and 69.7%, respectively. On univariate analysis, an age < 18 years, tumor volumes < 4.5 cm3, and no prior radiotherapy or chemotherapy were identified as positive prognostic factors for improved PFS. On multivariate analysis, only prior radiotherapy was significant for worse PFS. CONCLUSIONS: This represents the largest study of single-session GKRS for pilocytic astrocytoma to date. Favorable long-term PFS and overall survival were observed with GKRS. Further prospective studies should be performed to evaluate appropriate radiosurgery dosing, timing, and sequencing of treatment along with their impact on toxicity and the quality of life of patients with pilocytic astrocytoma.

Splenic oligometastasis: Report of a patient successfully treated with stereotactic body radiation therapy.

The use of SRS/SBRT has been extensively reported on for tumors of the lung, liver, pancreas, adrenal gland, brain, and spine. Tumor control and associated toxicities of treatment are well understood and the use of SBRT in these sites is well-accepted. Here we uniquely report a detailed case of SBRT to the spleen and demonstrate pre- and post-treatment imaging along with treatment planning implications. We demonstrate excellent local control at 4 year follow-up with no development of late toxicity.

Stereotactic radiosurgery with concurrent lapatinib is associated with improved local control for HER2-positive breast cancer brain metastases.

OBJECTIVE: With increasing survival for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer in the trastuzumab era, there is an increased risk of brain metastasis. Therefore, there is interest in optimizing intracranial disease control. Lapatinib is a small-molecule dual HER2/epidermal growth factor receptor inhibitor that has demonstrated intracranial activity against HER2+ breast cancer brain metastases. The objective of this study was to investigate the impact of lapatinib combined with stereotactic radiosurgery (SRS) on local control of brain metastases. METHODS: Patients with HER2+ breast cancer brain metastases who underwent SRS from 1997-2015 were included. The primary outcome was the cumulative incidence of local failure following SRS. Secondary outcomes included the cumulative incidence of radiation necrosis and overall survival. RESULTS: One hundred twenty-six patients with HER2+ breast cancer who underwent SRS to 479 brain metastases (median 5 lesions per patient) were included. Among these, 75 patients had luminal B subtype (hormone receptor-positive, HER2+) and 51 patients had HER2-enriched histology (hormone receptor-negative, HER2+). Forty-seven patients received lapatinib during the course of their disease, of whom 24 received concurrent lapatinib with SRS. The median radiographic follow-up among all patients was 17.1 months. Concurrent lapatinib was associated with reduction in local failure at 12 months (5.7% vs 15.1%, p < 0.01). For lesions in the ≤ 75th percentile by volume, concurrent lapatinib significantly decreased local failure. However, for lesions in the > 75th percentile (> 1.10 cm3), concurrent lapatinib did not significantly improve local failure. Any use of lapatinib after development of brain metastasis improved median survival compared to SRS without lapatinib (27.3 vs 19.5 months, p = 0.03). The 12-month risk of radiation necrosis was consistently lower in the lapatinib cohort compared to the SRS-alone cohort (1.3% vs 6.3%, p < 0.01), despite extended survival. CONCLUSIONS: For patients with HER2+ breast cancer brain metastases, the use of lapatinib concurrently with SRS improved local control of brain metastases, without an increased rate of radiation necrosis. Concurrent lapatinib best augments the efficacy of SRS for lesions ≤ 1.10 cm3 in volume. In patients who underwent SRS for HER2+ breast cancer brain metastases, the use of lapatinib at any time point in the therapy course was associated with a survival benefit. The use of lapatinib combined with radiosurgery warrants further prospective evaluation.

Overall survival and response to radiation and targeted therapies among patients with renal cell carcinoma brain metastases.

OBJECTIVE: The object of this retrospective study was to investigate the impact of targeted therapies on overall survival (OS), distant intracranial failure, local failure, and radiation necrosis among patients treated with radiation therapy for renal cell carcinoma (RCC) metastases to the brain. METHODS: All patients diagnosed with RCC brain metastasis (BM) between 1998 and 2015 at a single institution were included in this study. The primary outcome was OS, and secondary outcomes included local failure, distant intracranial failure, and radiation necrosis. The timing of targeted therapies was recorded. Multivariate Cox proportional-hazards regression was used to model OS, while multivariate competing-risks regression was used to model local failure, distant intracranial failure, and radiation necrosis, with death as a competing risk. RESULTS: Three hundred seventy-six patients presented with 912 RCC BMs. Median OS was 9.7 months. Consistent with the previously validated diagnosis-specific graded prognostic assessment (DS-GPA) for RCC BM, Karnofsky Performance Status (KPS) and number of BMs were the only factors prognostic for OS. One hundred forty-seven patients (39%) received vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Median OS was significantly greater among patients receiving TKIs (16.8 vs 7.3 months, p < 0.001). Following multivariate analysis, KPS, number of metastases, and TKI use remained significantly associated with OS.The crude incidence of local failure was 14.9%, with a 12-month cumulative incidence of 13.4%. TKIs did not significantly decrease the 12-month cumulative incidence of local failure (11.4% vs 14.5%, p = 0.11). Following multivariate analysis, age, number of BMs, and lesion size remained associated with local failure. The 12-month cumulative incidence of radiation necrosis was 8.0%. Use of TKIs within 30 days of SRS was associated with a significantly increased 12-month cumulative incidence of radiation necrosis (10.9% vs 6.4%, p = 0.04). CONCLUSIONS: Use of targeted therapies in patients with RCC BM treated with intracranial SRS was associated with improved OS. However, the use of TKIs within 30 days of SRS increases the rate of radiation necrosis without improving local control or reducing distant intracranial failure. Prospective studies are warranted to determine the optimal timing to reduce the rate of necrosis without detracting from survival.

Principles and practice of high-dose rate penile brachytherapy: Planning and delivery techniques.

PURPOSE: To allow for organ preservation, high-dose rate (HDR) brachytherapy may be used in the treatment of localized penile cancer. Penile cancer is a rare malignancy that accounts for <1% of cancers in men in the United States. The standard treatment for localized disease is partial amputation of the penis. However, patients with T1b or T2 disease <4 cm in maximum dimension and confined to the glans penis may be treated with brachytherapy as an organ-sparing approach. Previous works have described the technique involved for low-dose rate brachytherapy; however, we detail the techniques involved with HDR brachytherapy. METHODS AND MATERIALS: Circumcision should precede brachytherapy. Interstitial brachytherapy needles are placed in the operating room under general anesthesia with the goal to allow for appropriate target coverage. Target definition is done via computed tomography-based simulation and planning. Radiation is delivered using a prescription dose of 3840 cGy in 12 fractions twice daily over a course of 6 days. RESULTS: Acute toxicities peak upon completion of the radiation therapy and may include dermatitis, sterile urethritis, and adhesions in the urethra. These toxicities are reversible and generally take 2 to 3 months to heal. The two most common and significant late complications of radiation therapy for penile cancer are soft tissue necrosis and meatal stenosis. An increased risk of necrosis has been reported with T3 tumors and higher-volume implants (>30 cm3). Erectile function is generally maintained because the erectile tissues including the penile shaft and corpora have not been irradiated. CONCLUSIONS: Organ preservation is feasible using HDR brachytherapy with favorable acute and late toxicities.

Temporally feathered intensity-modulated radiation therapy: A planning technique to reduce normal tissue toxicity.

PURPOSE: Intensity-modulated radiation therapy (IMRT) has allowed optimization of three-dimensional spatial radiation dose distributions permitting target coverage while reducing normal tissue toxicity. However, radiation-induced normal tissue toxicity is a major contributor to patients' quality of life and often a dose-limiting factor in the definitive treatment of cancer with radiation therapy. We propose the next logical step in the evolution of IMRT using canonical radiobiological principles, optimizing the temporal dimension through which radiation therapy is delivered to further reduce radiation-induced toxicity by increased time for normal tissue recovery. We term this novel treatment planning strategy "temporally feathered radiation therapy" (TFRT). METHODS: Temporally feathered radiotherapy plans were generated as a composite of five simulated treatment plans each with altered constraints on particular hypothetical organs at risk (OARs) to be delivered sequentially. For each of these TFRT plans, OARs chosen for feathering receive higher doses while the remaining OARs receive lower doses than the standard fractional dose delivered in a conventional fractionated IMRT plan. Each TFRT plan is delivered a specific weekday, which in effect leads to a higher dose once weekly followed by four lower fractional doses to each temporally feathered OAR. We compared normal tissue toxicity between TFRT and conventional fractionated IMRT plans by using a dynamical mathematical model to describe radiation-induced tissue damage and repair over time. RESULTS: Model-based simulations of TFRT demonstrated potential for reduced normal tissue toxicity compared to conventionally planned IMRT. The sequencing of high and low fractional doses delivered to OARs by TFRT plans suggested increased normal tissue recovery, and hence less overall radiation-induced toxicity, despite higher total doses delivered to OARs compared to conventional fractionated IMRT plans. The magnitude of toxicity reduction by TFRT planning was found to depend on the corresponding standard fractional dose of IMRT and organ-specific recovery rate of sublethal radiation-induced damage. CONCLUSIONS: TFRT is a novel technique for treatment planning and optimization of therapeutic radiotherapy that considers the nonlinear aspects of normal tissue repair to optimize toxicity profiles. Model-based simulations of TFRT to carefully conceptualized clinical cases have demonstrated potential for radiation-induced toxicity reduction in a previously described dynamical model of normal tissue complication probability (NTCP).