Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis.

Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.

Weighing Risk of Cardiovascular Mortality Against Potential Benefit of Hormonal Therapy in Intermediate-Risk Prostate Cancer.

Background: The purpose of this study is to determine the optimal strategy for men with newly diagnosed intermediate-risk prostate cancer by age and cardiac risk. Methods: A Markov model was calibrated to the EORTC 22991 trial, which randomly assigned men with intermediate-risk prostate cancer to radiation therapy (RT) with or without six months of hormonal therapy (HT). We compared quality-adjusted life-years (QALYs) in men age 50, 60, and 70 years by age decile and cardiac risk group. Competing risks of cardiovascular mortality were estimated from the published literature. Sensitivity analyses were used to assess the impact of varying model assumptions. Results: HT was associated with a net decrease of 0.3 to 0.4 QALYs in men with a history of myocardial infarction. However, for all other men, HT improved QALYs (range = 0.4-2.6 QALYs). Younger men with fewer cardiac risk factors experienced the largest benefit from HT. In sensitivity analyses, the model was only found to be sensitive to the probability of biochemical failure. Men at low risk for biochemical failure (≤8.7% at five years) did not benefit from HT. Further, the benefits of HT did not begin to manifest until after 7.3 years of follow-up. Conclusions: The optimal choice of therapy depends upon age, cardiac risk, and disease recurrence risk. Young men with intermediate-risk prostate cancer with no cardiac risk factors benefit most from HT. Men with a history of myocardial infarction who are at very low risk for biochemical failure may be negatively impacted by the addition of HT.

Emerging Technologies and Techniques in Radiation Therapy.

The past decade has brought an improved ability to precisely target and deliver radiation as well as other focal prostate-directed therapy. Stereotactic body radiotherapy (SBRT), proton beam radiation, high-dose-rate (HDR) brachytherapy, as well as nonradiotherapy treatments such as cryoablation and high-intensity focused ultrasound are several therapeutic modalities that have been investigated for the treatment of prostate cancer in an attempt to reduce toxicity while improving cancer control. However, high-risk prostate cancer requires a comprehensive treatment of the prostate as well as areas at risk for cancer spread. Therefore, most new radiation treatment (SBRT, HDR, and proton beam radiation) modalities have been largely investigated in combination with regional radiation therapy. Though the evidence is evolving, the use of SBRT, HDR, and proton beam radiation is promising. Nonradiation focal therapy has been proposed mainly for partial gland treatment in men with low-risk disease, and its use in high-risk prostate cancer patients remains experimental.

Cost-effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for up to 10 brain metastases.

OBJECTIVE The JLGK0901 study found that stereotactic radiosurgery (SRS) is a safe and effective treatment option for treating up to 10 brain metastases. The purpose of this study is to determine the cost-effectiveness of treating up to 10 brain metastases with SRS, whole-brain radiation therapy (WBRT), or SRS and immediate WBRT (SRS+WBRT). METHODS A Markov model was developed to evaluate the cost effectiveness of SRS, WBRT, and SRS+WBRT in patients with 1 or 2-10 brain metastases. Transition probabilities were derived from the JLGK0901 study and modified according to the recurrence rates observed in the Radiation Therapy Oncology Group (RTOG) 9508 and European Organization for Research and Treatment of Cancer (EORTC) 22952-26001 studies to simulate the outcomes for patients who receive WBRT. Costs are based on 2015 Medicare reimbursements. Health state utilities were prospectively collected using the Standard Gamble method. End points included cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). The willingness-to-pay (WTP) threshold was $100,000 per QALY. One-way and probabilistic sensitivity analyses explored uncertainty with regard to the model assumptions. RESULTS In patients with 1 brain metastasis, the ICERs for SRS versus WBRT, SRS versus SRS+WBRT, and SRS+WBRT versus WBRT were $117,418, $51,348, and $746,997 per QALY gained, respectively. In patients with 2-10 brain metastases, the ICERs were $123,256, $58,903, and $821,042 per QALY gained, respectively. On the sensitivity analyses, the model was sensitive to the cost of SRS and the utilities associated with stable post-SRS and post-WBRT states. In patients with 2-10 brain metastases, SRS versus WBRT becomes cost-effective if the cost of SRS is reduced by $3512. SRS versus WBRT was also cost effective at a WTP of $200,000 per QALY on the probabilistic sensitivity analysis. CONCLUSIONS The most cost-effective strategy for patients with up to 10 brain metastases is SRS alone relative to SRS+WBRT. SRS alone may also be cost-effective relative to WBRT alone, but this depends on WTP, the cost of SRS, and patient preferences.

Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensive medications that have been reported to affect aberrant angiogenesis and the dysregulated inflammatory response. Because of such mechanisms, it was hypothesized that these medications might affect the tumor response to neoadjuvant radiation in patients with rectal cancer. METHODS: One hundred fifteen patients who were treated with neoadjuvant radiation at the University of Wisconsin (UW) between 1999 and 2012 were identified. Univariate analyses were performed with anonymized patient data. In a second independent data set, 186 patients with rectal cancer who were treated with neoadjuvant radiation at the Queen's Medical Center of the University of Hawaii (UH) between 1995 and 2010 were identified. These data were independently analyzed as before. Multivariate analyses were performed with aggregate data. RESULTS: Among patients taking ACEIs/ARBs in the UW data set, a significant 3-fold increase in the rate of pathologic complete response (pCR) to neoadjuvant therapy (52% vs 17%, P = .001) was observed. This finding was confirmed in the UH data set, in which a significant 2-fold-increased pCR rate (24% vs 12%, P = .03) was observed. Identified patient and treatment characteristics were otherwise balanced between patients taking and not taking ACEIs/ARBs. No significant effect was observed on pCR rates with other medications, including statins, metformin, and aspirin. Multivariate analyses of aggregate data identified ACEI/ARB use as a strong predictor of pCR (odds ratio, 4.02; 95% confidence interval, 2.06-7.82; P < .001). CONCLUSIONS: The incidental use of ACEIs/ARBs among patients with rectal cancer is associated with a significantly increased rate of pCR after neoadjuvant treatment. Cancer 2016;122:2487-95. © 2016 American Cancer Society.

Impact of Deferring Radiation Therapy in Patients With Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Who Develop Brain Metastases.

PURPOSE: To perform a retrospective analysis of patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma who developed brain metastases (BM) to evaluate our hypothesis that the use of upfront EGFR-tyrosine kinase inhibitors (TKIs), and deferral of radiation therapy (RT), would result in inferior intracranial progression-free survival but similar overall survival (OS). METHODS AND MATERIALS: Of 202 patients diagnosed with EGFR-mutant NSCLC between July 1, 2008, and December 31, 2014, 71 developed BM. Twenty-one patients were excluded owing to prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after whole-brain radiation therapy (WBRT)/stereotactic radiosurgery (SRS) or <6 months' follow-up. Of the remaining 50 patients, 17 received upfront EGFR-TKI followed by SRS or WBRT, 17 WBRT then EGFR-TKI, and 16 SRS followed by EGFR-TKI. Disease-specific-graded prognostic assessment was similar among all 3 groups. RESULTS: The median OS was longer in the upfront RT group compared with the upfront EGFR-TKI group (34.1 vs 19.4 months; P=.01). On subgroup analysis, the SRS group had longer OS than the upfront EGFR-TKI group (58.4 vs 19.4 months; P=.01), but the WBRT group did not (29.9 vs 19.4 months; P=.09). Intracranial progression-free survival was improved in patients receiving upfront RT compared with those receiving upfront EGFR-TKI (37.9 vs 10.6 months; P<.001). CONCLUSIONS: The present study suggests that the use of upfront EGFR-TKI, and the deferral of SRS or WBRT, may result in inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. A prospective, multi-institutional, randomized trial of upfront EGFR-TKI with RT at intracranial progression versus upfront RT followed by EGFR-TKI is urgently needed.

Impact of Node Negative Target Volume Delineation on Contralateral Parotid Gland Dose Sparing Using IMRT in Head and Neck Cancer.

There is considerable practice variation in treatment of the node negative (N0) contralateral neck in patients with head and neck cancer. In this study, we examined the impact of N0 neck target delineation volume on radiation dose to the contralateral parotid gland. Following institutional review board approval, 12 patients with head and neck cancer were studied. All had indications for treatment of the N0 neck, such as midline base of tongue or soft palate extension or advanced ipsilateral nodal disease. The N0 neck volumes were created using the Radiation Therapy Oncology Group head and neck contouring atlas. The physician-drawn N0 neck clinical target volume (CTV) was expanded by 25% to 200% to generate volume variation, followed by a 3-mm planning target volume (PTV) expansion. Surrounding organs at risk were contoured and complete intensity-modulated radiation therapy plans were generated for each N0 volume expansion. The median N0 target volume drawn by the radiation oncologist measured 93 cm(3) (range 71-145). Volumetric expansion of the N0 CTV by 25% to 200% increased the resultant mean dose to the contralateral parotid gland by 1.4 to 8.5 Gray (Gy). For example, a 4.1-mm increase in the N0 neck CTV translated to a 2.0-Gy dose increase to the parotid, 7.4 mm to a 4.5 Gy dose increase, and 12.5 mm to an 8.5 Gy dose increase, respectively. The treatment volume designated for the N0 neck has profound impact on resultant dose to the contralateral parotid gland. Variations of up to 15 mm are routine across physicians in target contouring, reflecting individual preference and training expertise. Depending on the availability of immobilization and image guidance techniques, experts commonly recommend 3 to 10 mm margin expansions to generate the PTV. Careful attention to the original volume of the N0 neck CTV, as well as expansion margins, is important in achieving effective contralateral gland sparing to reduce the resultant xerostomia and dysguesia that may ensue after radiotherapy.

Impact of adjuvant pelvic radiotherapy in stage I uterine sarcoma.

BACKGROUND/AIM: The optimal adjuvant therapy for stage I uterine sarcoma remains unresolved and may consist of radiotherapy (RT), chemotherapy, hormonal therapy or observation. We analyzed the impact of adjuvant pelvic RT on overall survival (OS), cause-specific survival (CSS), disease-free survival (DFS), pelvic control (PC) and patterns of failure. PATIENTS AND METHODS: A retrospective analysis of 157 patients with International Federation of Gynecology and Obstetrics FIGO stage I uterine sarcoma was performed. RT was given postoperatively to a dose of 45-51 Gy in 28-30 fractions. RESULTS: The 5-year OS, CSS, DFS and PC was 58%, 62%, 47% and 72%, respectively. Adjuvant RT significantly improved PC (85% for RT group vs. 64% for non-RT group; p=0.02) but did not impact OS, CSS or DFS. CONCLUSION: The addition of adjuvant pelvic RT significantly improved PC for patients with stage I uterine sarcoma. As systemic therapies continue to improve, optimal locoregional control may result in improved patient outcomes.

Survival following gamma knife radiosurgery for brain metastasis from breast cancer.

BACKGROUND: Breast cancer is the second most common cause of brain metastases in the United States. Although breast cancer induced brain metastases represent an incurable condition, some patients experience prolonged survival. In this retrospective study, we examine a cohort of patients with brain metastases from breast cancer treated with Gamma Knife stereotactic radiosurgery to identify factors that predict better outcomes. METHODS: A retrospective database of 100 patients treated for brain metastases due to breast cancer via Gamma Knife radiosurgery (GKS) from July 1998 through March 2009 was reviewed. Patients who received radiosurgery as sole treatment, as a planned boost after whole brain radiotherapy or surgical resection, or as salvage after prior whole brain radiation therapy (WBRT) or surgical resection were included. Prognostic factors identified to be significant for survival in previous brain metastasis studies were analyzed for significance by univariate and multivariate Cox analysis. RESULTS: Overall, the median brain progression-free survival time was 7.1 months and the median survival time was 12.3 months. No prognostic variables were significant for brain progression-free survival. For patients treated with a planned GKS after WBRT, GKS as sole treatment, GKS salvage after WBRT, GKS boost after surgery, or GKS for surgical salvage the median survival times (MSTs) were as follows: 12.2 months, 12.4 months, 9.5 months, 27.6 months and 33.4 months respectively. Differences between the groups were not significant (p = 0.06); however, GKS boost after surgery and GKS for salvage after surgery did have a trend toward better overall survival. CONCLUSION: Stereotactic radiosurgery offers good local control and prolonged survival in selected patients. Age and number of lesions are strong predictors of overall survival.

Successful management of female urethral carcinoma with radiation therapy and concurrent chemotherapy.

► Successful treatment of locally advanced urethral carcinoma with chemoradiation as evidenced by patients alive NED at 90 and 47 months. ► 45 Gy of external beam RT followed by 15-25 Gy of interstitial brachytherapy. ► Concurrent chemotherapy with 5-fluorouracil and cisplatin.

Successful treatment of melanoma metastatic to the left atrium using external beam radiation therapy.

The successful treatment of a patient with primary nasal melanoma metastatic to the lung, pulmonary vein, and left atrium using radiation therapy is described. The patient was effectively treated with a conventional external beam radiation fractionation scheme (rather than a more commonly used hypofractioned regimen) that was utilized to minimize risk of arterial embolus of the tumor or rupture of a vessel wall. A post-treatment CT demonstrated a significant decrease in the caliber of the right pulmonary vein and tumor thrombus. The patient never developed cardiac valvular dysfunction or acute life-threatening massive embolism of tumor from the atrium. Unfortunately, the patient experienced clinical decline secondary to the massive progression of intra-abdominal disease and subsequently died from multiple liver metastases and liver failure. Numerous studies and this case report demonstrate that radiation therapy can be very effective in the treatment of malignant melanoma, especially when only small volumes of disease need to be treated and adequate total doses are used. Therefore, radiation therapy appears to play an important yet underutilized role in the treatment of metastatic melanomas.

Hounsfield unit density accurately predicts ESWL success.

Extracorporeal shockwave lithotripsy (ESWL) is a commonly used non-invasive treatment for urolithiasis. Helical CT scans provide much better and detailed imaging of the patient with urolithiasis including the ability to measure density of urinary stones. In this study we tested the hypothesis that density of urinary calculi as measured by CT can predict successful ESWL treatment. 198 patients were treated at Alaska Urological Associates with ESWL between January 2002 and April 2004. Of these 101 met study inclusion with accessible CT scans and stones ranging from 5-15 mm. Follow-up imaging demonstrated stone freedom in 74.2%. The overall mean Houndsfield density value for stone-free compared to residual stone groups were significantly different ( 93.61 vs 122.80 p < 0.0001). We determined by receiver operator curve (ROC) that HDV of 93 or less carries a 90% or better chance of stone freedom following ESWL for upper tract calculi between 5-15mm.