Extracranial Disease Sites Research Articles

Treatment patterns and outcomes in BRAF V600E-mutant melanoma patients with brain metastases receiving vemurafenib in the real-world setting.

Brain metastases are a common and serious complication among patients with metastatic melanoma. The selective BRAF inhibitor vemurafenib has demonstrated clinical efficacy in patients with BRAF V600E-mutant melanoma brain metastases (MBM). We examined the real-world application and clinical outcomes of vemurafenib in this patient population. Demographic, treatment patterns, response, and survival data were collected from medical charts. Clinical data on 283 patients with active BRAF V600E-mutant MBM treated with vemurafenib were provided by 70 US oncologists. Mean age was 57.2 years, 60.8% were male, 67.5% had ECOG performance status of 0–1, and 43.1% used corticosteroids at vemurafenib initiation. Median follow-up was 5.7 months. Following vemurafenib initiation, 48.1% of patients experienced intracranial response and 45.6% experienced extracranial response. The Kaplan–Meier estimate for overall survival was 59% at 12 months. Multivariate analyses showed associations between intracranial response and both corticosteroid use and vemurafenib as initial therapy after MBM diagnosis. Larger size (5–10 mm vs. <5 mm) and number of brain metastases (≥5 vs. <2) and progressive extracranial disease at treatment initiation were associated with decreased intracranial response and increased risk of disease progression. Multiple extracranial sites (2 vs. <2) and the absence of local treatments were also associated with increased risk of progression. Increased risk of death was associated with ≥2 extracranial disease sites, progressive extracranial disease, and ≥5 brain metastases. Subgroups of MBM patients may derive more benefit with vemurafenib, warranting prospective investigation.

Abstract P6-16-12: Graded prognostic assessment for triple negative breast cancer brain metastases

Abstract Background: Brain metastases is a serious complication of triple negative breast cancer (TBCBM). We evaluated prognostic factors for overall survival (OS) in contemporary cohort of TBCBM patients treated at a tertiary care institution. Methods: With IRB approval, Cleveland Clinic’s database was used to identify BCBM patients treated between 2000 and 2013. OS from the diagnosis of TBCBM was the primary end point. Cox proportional hazards models with stepwise variable selection were used for data analysis. Results: One hundred forty three female patients were included for this analysis. Karnofsky performance scale (KPS) was 90-100 in 52 patients (39%), 70-80 in 50 (38%) and &amp;lt;70 in 30 (23%) patients. Sixty eight (49%) patients were treated with whole brain radiation therapy (WBRT), 26 (19%) with stereotactic radiosurgery (SRS), 18 (13%) with WBRT and SRS, 13 (9%) underwent surgery and WBRT, 5 (4%) underwent surgery and SRS. Seventy nine percent (113/143) of patients are reported to have died. Overall survival was 8.3 months (95% C.I. 5.5-10.6). Disease specific graded prognostic assessment (GPA) for breast cancer brain metastases is based on KPS, age at diagnosis, and subtype. By definition triple negative patients fall into the lowest two GPA score groups. GPA was prognostic for survival (p=.05), however separation between groups was variable. Starting de-novo, KPS (but different coding than in the GPA), leptomeningeal disease, and the number of extracranial sites of disease at the time of diagnosis of TBCBM were found to be independently prognostic for survival (proportional hazards model, stratified by when brain metastases were diagnosed, and a stepwise selection algorithm). A new GPA was formulated by assigning "points" (weights) to the levels within each of these three factors that are proportional to the regression coefficient estimates in the final model and then adding the total number of points present. Prognostic Factors Impacting Survival of TBCBMFactorNumber of pointsHazard RatiopKPS0.31 (0.21-0.48)&amp;lt;.000180-1003 &amp;lt;/= 700 No. Extra-Cranial Mets0.42 (0.28-0.64)&amp;lt;.00010 or 12 &amp;gt;/= 20 Leptomeningeal Disease0.43 (0.26-0.71)0.001No2 Yes0 The new GPA consists of three groups: unfavorable, intermediate and favorable with OS of 2.7, 9.1 and 13.6 months respectively. New GPAGPANumber of pointsNumberMedian OS ( months)PFavorable736 (27%)13.6 Intermediate4-559 (45%)9.1 Unfavorable&amp;lt;/= 336 (27%)2.7 &amp;lt;0.0001 Conclusions: A novel GPA for TBCBM is proposed. Citation Format: Ming Chi, Vyshak Alva Venur, Jame Abraham, Thomas G Budd, Paul Elson, Manmeet S Ahluwalia. Graded prognostic assessment for triple negative breast cancer brain metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-16-12.

Stereotactic radiosurgery (SRS) for brain metastases: a systematic review.

In many patients with brain metastases, the primary therapeutic aim is symptom palliation and maintenance of neurologic function, but in a subgroup, long-term survival is possible. Local control in the brain, and absent or controlled extracranial sites of disease are prerequisites for favorable survival. Stereotactic radiosurgery (SRS) is a focal, highly precise treatment option with a long track record. Its clinical development and implementation by several pioneering institutions eventually rendered possible cooperative group randomized trials. A systematic review of those studies and other landmark studies was undertaken. Most clinicians are aware of the potential benefits of SRS such as a short treatment time, a high probability of treated-lesion control and, when adhering to typical dose/volume recommendations, a low normal tissue complication probability. However, SRS as sole first-line treatment carries a risk of failure in non-treated brain regions, which has resulted in controversy around when to add whole-brain radiotherapy (WBRT). SRS might also be prescribed as salvage treatment in patients relapsing despite previous SRS and/or WBRT. An optimal balance between intracranial control and side effects requires continued research efforts.

A phase II trial of second-line erlotinib in combination with stereotactic body radiation therapy (SBRT) for patients with metastatic non-small cell lung cancer (NSCLC).

8074 Background: Stage IV NSCLC patients who progress through first-line therapy have poor progression-free survival (PFS) and overall survival (OS), most commonly failing in existing sites of gross disease after systemic therapy. Cytoreduction with SBRT may aid systemic agents in prolonging survival. We decided to test this hypothesis in a multi-institutional phase II study with SBRT and erlotinib. Methods: Stage IV NSCLC patients with ≤ 6 sites of extracranial disease who failed first-line systemic therapy were eligible to receive SBRT to all sites of clinically apparent disease, utilizing equipotent fractionation schemes based on location of disease and risk of toxicity to critical normal structures, and erlotinib given daily (150 mg OD) until disease progression. Frequent SBRT fractionation schemes used included 33 Gy in 11 Gy fractions and 40 Gy in 8 Gy fractions. Safety and clinical endpoints were evaluated. Results: 23 patients (12 M: 11 F) with a median age of 67 (56-86) were enrolled in this trial with median follow-up of 14.7 months. All patients progressed through platinum-based chemotherapy, 14 with paclitaxel and 7 with pemetrexed as part of the doublet regimen. 20/23 patients received SBRT to 3 or fewer sites. Lung parenchyma and mediastinal lymph nodes represented most common sites of irradiation. Median PFS was 10.7 months and median OS was 20.8 months.A majority of patients progressed in new sites with only 4 patients failing locally. Most distant failures manifested in the liver. Only one grade 3 toxicity, pneumonitis, was radiation-related. The trial commenced before molecular profiling became standard; 5/10 patient tumors tested, however, had EGFR alterations by IHC/FISH, 0/10 were positive for an EGFR mutation. Conclusions: Use of SBRT with erlotinib for unselected stage IV NSCLC patients as a second-line therapy was well tolerated and resulted in significant PFS and OS, substantially greater than historical values for patients who only received second-line systemic agents. Debulking gross disease with local therapy results in a median PFS of nearly a year with patients relapsing most commonly in new rather than existing sites. Clinical trial information: NCT00547105.

WE‐G‐BRB‐01: Safety and Quality Assurance in SRS and SBRT

Stereotactic radiosurgery (SRS) has been an effective modality for the treatment of benign and malignant cranial disease for over 50 years. Increasingly, the stereotactic approach is being applied in a number of extracranial disease sites. Stereotactic body radiation therapy (SBRT) holds significant potential for improving tumor control rates across a range of locations and histologies. SRS / SBRT are fundamentally different from conventional radiotherapy in that the intent is to deliver an ablative dose that overcomes all of the abilities of a cancer cell to defend itself. It is inherently aggressive, much like a surgical approach, and therefore an increased rate of acute complications compared with conventional radiotherapy could be expected. Both SRS and SBRT require specialized technology, meticulous procedures, and dedicated personnel. Several recent high‐profile medical radiation events have generated considerable attention within the media, and serve to remind the profession that close attention to safety and ongoing quality improvement is a fundamental responsibility. The main aim of this symposium will be to address safety and quality in SRS and SBRT, highlighting the errors that have occurred in the past and determining how they can be minimized in a systematic way, starting from patient simulation, to planning and verification, immobilization and localization, delivery, and patient follow‐up, and to provide some recommendations for SRS / SBRT processes and procedures that may be beneficial in understanding and reducing risks inherent to the modalities. Specific issues to be addressed include:‐ An overview of the accuracy requirements and the need for high levels of safety and quality in SRS/SBRT, as summarized in recent AAPM, ASTRO and ACR reports.‐ Highlights from recent media events related to SRS, examining what went wrong and why; what could go wrong; and what nominal safety procedures, commissioning and routine QA and testing are needed for SRS and SBRT programs to ensure errors are minimized.‐ Verification requirements for accurate image‐based localization and delivery in both rigid sites (e.g. CNS, spine) and moving targets (e.g. thorax (lung), liver, pancreas, etc.).

Phase II trial of chemotherapy with temozolomide in combination with topotecan for central nervous system (CNS) metastases of solid tumors.

TPS145 Background: Patients with brain metastases of solid tumors have a poor prognosis, despite improvements in survival achieved with modern neurosurgical and radiation techniques. Chemotherapy does not play any significant role in this disease, but may have application in salvage of patients who have failed radiation therapy. In patients who are not surgical candidates, do not require immediate XRT to relieve symptoms and have controlled systemic disease, effective chemotherapy as an alternative to XRT might decrease the risk of radiation induced neurotoxicity. Both temozolomide and topotecan have good blood-brain barrier penetration and have shown activity in CNS malignancies. Preclinical studies suggest synergy of this drug combination. This is a single-arm, open-label phase II drug study. All patients will receive the chemotherapy combination. Up to 35 patients will be accrued over 2-3 years and followed for up to 5 years. Patients will receive up to 8 cycles of chemotherapy. The primary endpoint is the rate of radiologic response of brain metastases and secondary endpoints are median overall survival, progression-free survival, time to progression of brain metastases and toxicity. Methods: Each cycle is defined as a 28-day period. Patients will take oral temozolomide at bedtime nightly for 5 days on days 1 through 5 of each cycle. A chemotherapy-trained nurse will administer topotecan intravenously daily for 5 days on days 2 through 6 of each cycle. Contrast-enhanced MRI or CT scan of the brain and the sites of extracranial disease will be performed at baseline and every 2 cycles, until completion of the therapy or progression to evaluate response. Patients achieving complete remission (CR) will receive 2 more cycles of combined chemotherapy after CR is documented, but no less than 6 and no more than 8 cycles total. To be eligible: 1) Have failed prior WBRT or 2) not be candidates for surgical intervention and not require immediate radiation therapy to relieve symptoms, and have controlled systemic disease. No significant financial relationships to disclose.

Presentation and outcome in cancer patients with extensive spread to the brain

BackgroundControversy exists around the preferred management of patients with brain metastases and limited survival expectation, e.g. because of extensive brain involvement. Few studies have focused on this particular group of patients.FindingsA group of 24 patients with a large number of brain metastases, defined as 10 or more on computed tomography scans, who were managed with palliative whole-brain radiotherapy (WBRT), typically 30 Gy in 10 fractions, were analyzed. The median number of lesions was 14. The patient characteristics were comparable to those of studies in the general population with brain metastases, except for the fact that all patients had active sites of extracranial disease. Clinical benefit, imaging response and overall survival were lower than expected. Median survival, for example was 2 months. Trends towards better survival were found in patients with brain metastases detected at first cancer diagnosis (synchronous manifestation, treatment naïve) and those with better prognostic features according to the graded prognostic assessment (GPA) score.ConclusionsThe benefit of WBRT did not meet the expectations, suggesting that consideration should be given to best supportive care including corticosteroid administration, especially if a patient belongs to the lowest GPA class.

Breast cancer subtypes and survival in patients with brain metastases

IntroductionBrain metastases (BM) occur in up to one third of patients with metastatic breast cancer (MBC), whose incidences and prognoses by breast cancer subtypes in BM have not been well delineated.MethodsRetrospective survival analyses were performed in 126 BM patients from 805 MBC patients treated at the National Cancer Center between August 2001 and April 2006, according to clinical characteristics, breast cancer subtypes, and receipt of trastuzumab. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor-2 (HER2) statuses were tested by immunohistochemical (IHC) staining, and HER2 FISH analysis conducted for IHC 2+.ResultsThe proportion of HER2+/ER- (29% vs 16%) and triple-negative (37% vs 25%) tumors was higher in the 126 BM patients than those without BM. While median survival after recurrence was longer in patients with luminal A disease (median survival of luminal A vs luminal B vs HER2+/ER- vs triple-negative: p = 0.0246; 39.6 vs 27.4 vs 20.9 vs 15.5 months), survival was shorter from BM to death in luminal A and triple negatives (median survival: p = 0.0113; 4.0 vs 9.2 vs 5.0 vs 3.4 months). Receipt of trastuzumab after BM was a significant variable for survival in HER2+ patients. Multivariate analyses identified ER-negative, HER2-negative, or triple-negative, as well as older age, presence of leptomeningeal disease, and three or more extracranial disease sites, as poor prognostic factors for survival after BM.ConclusionMBC patients who developed BM had higher proportions of triple-negative and HER2+/ER- tumor status. Triple receptor status is a useful prognostic marker for predicting survival after BM in metastatic breast cancer patients.

Survival differences in patients with brain metastases according to breast cancer subtypes

11507 Background: Brain metastases (BM) occur in as many as one-third of patients with metastatic breast cancer (MBC). Incidences and prognoses by triple receptor subtypes in BM have not been well delineated. Methods: Retrospectively, prognoses were assessed according to clinical characteristics, triple receptor subtypes, and receipt of trastuzumab therapy by univariate and multivariate analyses. ER/PR/HER2 were tested by IHC with HER2 FISH for IHC 2+ and for all 118 consecutive primary BC. Results: Between 8/2001 and 4/2006, 138 of 805 pts (17.1%) with MBC presented with BM at NCC Korea. More pts with triple negative and HER2+ tumors developed BM (see table ). The median age was 47 years. They were single (9%), multiple (80%), or leptomeningeal disease with or without multiple BM (11%). As initial therapy, 104 pts received WBRT, 8, intrathecal therapy (IT), 9, WBRT with IT, and 17 others. Of 56 HER2+ pts, 45 received trastuzumab either before (n=25) or after (n=13), or continuously before and after BM diagnosed (n=7). By 10/2006, 117 pts died with a median survival of 4.5 months. Multivariate analyses indicated age, tumor receptor subtypes, leptomeningeal presentation and number of extracranial disease sites as significant factors. Receipt of trastuzumab therapy after BM was a significant variable for survival in HER2+ diseases (3.8 vs. 13.4 mo, p=0.0000). Pts with triple negative subtype lived shortest compared with other types (p=0.0035). Conclusions: More pts with triple negative and HER2+ disease developed BM. HER2+ disease gained a significant survival benefit by trastuzumab therapy. Supported by NCC Grant 0610240 and 0510520. [Table: see text] No significant financial relationships to disclose.

Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases.

The authors determined the safety and efficacy of recombinant high-dose interleukin-2 administration in patients with brain metastases. This retrospective review included 1,069 patients with metastatic melanoma or renal cell carcinoma who received high-dose interleukin-2 alone or in combination with other immunotherapy or chemotherapy from July 1985-July 2000. All patients were evaluated for both toxicity and response. Only the first exposure to interleukin-2 was considered. Parameters evaluated among the groups included toxicity profiles, reasons for stopping treatment, number of interleukin-2 doses per cycle, and response to therapy. Three patient groups were compared. Group I (n = 27) comprised patients with previously treated brain metastases (surgery or radiation), group 2 (n = 37) comprised patients with untreated brain metastases, and group 3 (n = 1,005) comprised patients without brain metastases. For most comparisons between patients with brain metastases and those without, no significant differences were noted in toxicity profiles or reasons for stopping interleukin-2 therapy. Patients with previously treated brain metastases received fewer interleukin-2 doses per cycle (median, 6.5) than patients with previously untreated brain metastases (median, 7.5) or patients without brain metastases (median, 7.5). Patients with previously treated brain metastases demonstrated an 18.5% overall clinical response to interleukin-2 treatment. However, patients with evaluable (previously untreated) brain metastases had an overall 5.6% response rate, which was less than the 19.8% response rate of patients without brain metastases. Two of thirty-six patients with evaluable brain metastases demonstrated objective regression of intracranial and extracranial disease after receiving interleukin-2. Carefully selected patients with brain metastases can safely receive high-dose interleukin-2, and some can experience a response to treatment at intracranial and extracranial disease sites.

Brain metastasis after immunotherapy in patients with metastatic melanoma or renal cell cancer: is craniotomy indicated?

The purpose of this study was to evaluate the outcome of surgical treatment of brain metastasis in patients with metastatic melanoma or renal cell cancer after interleukin-2 (IL-2) therapy. A retrospective analysis was conducted at the Surgery Branch, National Cancer Institute. All patients with a diagnosis of metastatic melanoma or renal cell cancer who received IL-2 from January 1, 1985 to January 1, 1996 (n = 1385) were screened for the development of brain metastasis. Forty patients underwent surgical treatment of brain metastasis that developed after initiating IL-2 therapy. Thirty-six were rendered free of disease after resection of a single metastasis and were the focus of this study. Twenty-two of the 36 patients achieved a clinical response (10 complete responses and 12 partial responses) at extracranial sites of disease after IL-2-based immunotherapy and before the development of brain metastasis. The median disease-free interval in the brain after resection of a single metastasis was 21, 7, and 3 months for patients achieving a complete response, partial response, and no response (CR, PR, and NR) to IL-2 therapy, respectively. The median survival after craniotomy for these three groups of patients was 23, 17, and 7 months, respectively. The disease-free interval in the brain and the overall survival after craniotomy were significantly longer for patients achieving a CR to previous immunotherapy when compared with patients achieving a PR or NR. Of the 10 patients who had achieved a prior CR, 8 remained disease free in the brain at last follow-up, 6 remained alive beyond 1 year, and 3 > 4 years. Twenty-five patients experienced neurologic symptoms before craniotomy and all had complete resolution of their symptoms after surgery. Surgical treatment of single brain metastasis in patients with metastatic melanoma or renal cell cancer is indicated in carefully selected patients. The benefits of resection include palliation of symptoms and the potential for a prolonged disease-free interval in the brain.