Including Brain Metastases Research Articles

Response Assessment in Neuro-Oncology Clinical Trials.

Development of novel therapies for CNS tumors requires reliable assessment of response and progression. This requirement has been particularly challenging in neuro-oncology for which contrast enhancement serves as an imperfect surrogate for tumor volume and is influenced by agents that affect vascular permeability, such as antiangiogenic therapies. In addition, most tumors have a nonenhancing component that can be difficult to accurately quantify. To improve the response assessment in neuro-oncology and to standardize the criteria that are used for different CNS tumors, the Response Assessment in Neuro-Oncology (RANO) working group was established. This multidisciplinary international working group consists of neuro-oncologists, medical oncologists, neuroradiologists, neurosurgeons, radiation oncologists, neuropsychologists, and experts in clinical outcomes assessments, working in collaboration with government and industry to enhance the interpretation of clinical trials. The RANO working group was originally created to update response criteria for high- and low-grade gliomas and to address such issues as pseudoresponse and nonenhancing tumor progression from antiangiogenic therapies, and pseudoprogression from radiochemotherapy. RANO has expanded to include working groups that are focused on other tumors, including brain metastases, leptomeningeal metastases, spine tumors, pediatric brain tumors, and meningiomas, as well as other clinical trial end points, such as clinical outcomes assessments, seizures, corticosteroid use, and positron emission tomography imaging. In an effort to standardize the measurement of neurologic function for clinical assessment, the Neurologic Assessment in Neuro-Oncology scale was drafted. Born out of a workshop conducted by the Jumpstarting Brain Tumor Drug Development Coalition and the US Food and Drug Administration, a standardized brain tumor imaging protocol now exists to reduce variability and improve reliability. Efforts by RANO have been widely accepted and are increasingly being used in neuro-oncology trials, although additional refinements will be needed.

Abstract P1-12-05: Etirinotecan pegol: Survival advantage over standard of care drugs in a model of brain metastases of breast cancer

Abstract BACKGROUND: Brain metastasis of breast cancer is a significant cause of death among women with disseminated breast cancer. Chemotherapy, radiation, and surgery for these metastases provide only minimal benefit with considerable toxicity. The long-acting topoisomerase I inhibitor etirinotecan pegol (EP) is a novel treatment for disseminated breast cancer. EP consists of irinotecan attached to a 20kDa branched polymer via a releasable linker. The large molecular weight of EP results in tumor accumulation, including brain metastases, providing increased and sustained exposure to cytotoxic SN38. In the Phase 3 BEACON study, EP showed a significant survival benefit (HR 0.51; 95% CI 0.30-0.86) in a prespecified subgroup of women with history of treated, stable brain metastases compared to treatment of physicians choice (TPC) consisting of one of seven approved chemotherapy drugs (median OS 10.0 vs 4.8 mo). Nektar has filed a conditional marketing authorization in Europe for EP in patients with advanced breast cancer and brain metastases. A Phase 3 trial in this patient population is being initiated to support a potential U.S. filing. To further support the biological rationale for EP in these patients, an experimental preclinical model of brain metastases of breast cancer was conducted to compare the efficacy of EP to TPC in BEACON and the planned subsequent study. METHODS: Female athymic nude mice were inoculated with 1.75x105 MDA-MB-231-BrLuc cells via intracardiac injection. Starting on day 21, gemcitabine (60 mg/kg) and eribulin (1.5 mg/kg) were dosed IP every 4 days; EP (50 mg/kg), irinotecan (50 mg/kg), paclitaxel (6 mg/kg), vinorelbine (10 mg/kg), docetaxel (10 mg/kg), and vehicle (saline or dextrose) were dosed weekly via tail vein. Efficacy was measured by tumor burden and survival. Tumor burden was determined based on twice weekly bioluminescence measurements. Animals were euthanized according to international animal care guidelines. RESULTS: Median survival for all control arm groups (docetaxel, vinorelbine, eribulin, gemcitabine, irinotecan, and paclitaxel) were 39, 43, 41, 48, 35, and 42 days, respectively, none of which were significantly different from vehicle control median survival of 40 days (p>0.05). No animals receiving these drugs survived until the end of the 90-day trial. Median survival for the EP treatment group was 86 days (p<0.05) with a 40% survival rate at 90 days, the trial endpoint. Tumor burden increased nearly 100-fold in all TPC and vehicle groups, whereas EP significantly inhibited tumor growth. Quantitative autoradiography showed that EP accumulated ~10-fold in brain metastases, while accumulation in non-tumor brain tissue was only ~2-fold compared to irinotecan. EP at 50 mg/kg achieved plasma trough concentrations comparable to those observed in patients receiving the recommended dose of 145 mg/m2 every 21 days. CONCLUSIONS: In this model of brain metastases, EP preferentially accumulates in brain metastases, significantly reduces tumor burden progression and significantly improves survival in brain metastases of breast cancer compared to the most active chemotherapeutic agents available for advanced breast cancer and those used in the BEACON trial and planned subsequent Phase 3 study. Citation Format: Shah N, Mohammad AS, Adkins CE, Dolan EL, Griffith J, Jagannathan R, Hoch U, Lockman PR. Etirinotecan pegol: Survival advantage over standard of care drugs in a model of brain metastases of breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-05.

P3.02b-015 Impact of Metastatic Status on the Prognosis of Patients Treated with First Generation EGFR-TKIs: Topic: EGFR Biomarkers

First generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib (GEF) or erlotinib (ERL) are effective for patients harboring EGFR mutations positive non-small cell lung cancer (NSCLC). To know the impact of metastatic status on patients treated with EGFR-TKIs is important. The objective of this study is to know the impact of metastatic status including brain metastasis, bone metastasis, liver metastasis and pleural effusion on the prognosis of patients treated with first generation EGFR-TKIs. The pathology files of National Hospital Organization Kinki-chuo Chest Medical Center from 2009 to 2014 were retrospectively reviewed and 533 patients were EGFR mutation positive NSCLC. Patients with stage IA to IIIA and small cell lung cancer were excluded. From 299 stage IIIB, IV and relapsed NSCLC patients, 178 patients treated with GEF or ERL as first line treatment were enrolled for the study. Metastatic status, progression free survival (PFS), overall survival (OS) and response rate (RR) were investigated. We also evaluated the relationship between the number of metastatic organs and prognosis. Fifty-one patients were male and median age at the time of first line treatment was 72 years (range 39-91). Number of patients with adenocarcinoma was 168 and 156 patients were treated with GEF. In log-rank test, PFS and OS were significantly worse in patients with brain metastasis (8.0m vs 13.2m, p= 0.008; 20.2m vs 38.0m, p< 0.001 respectively), bone metastasis (8.8m vs 15.4m, p< 0.001; 24.0m vs 32.1m, p= 0.020 respectively), liver metastasis (6.7m vs 12.5m, p< 0.001; 13.4m vs 32.1m, p< 0.001 respectively) and pleural effusion (10.8m vs 12.2m, p= 0.033; 21.9m vs 34.9m, p= 0.004 respectively) at the time of first line treatment compared with patients without each metastasis. In cox proportional hazards models multivariate analysis, bone metastasis had correlated with worse PFS (HR 2.110, 95% CI 1.437-3.093, p< 0.001) and moreover, brain metastasis had correlated with worse OS (HR 2.414, 95%CI 1.464-3.951, p< 0.001). There were no relationships between metastatic status and RR. Furthermore, the much number of metastasized organs (no metastasis, 1 metastasis and 2 or more metastasis) was significantly related to worse PFS (19.3m vs 12.5m vs 6.6m, p< 0.001) and OS (46.1m vs 29.9m vs 15.1m, p< 0.001). Bone metastasis had correlated with worse PFS and brain metastasis had correlated with worse OS in patients treated with first generation EGFR-TKIs. Moreover, the much number of metastasized organs was related to worse PFS and OS.

Non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases: role of tyrosine kinase inhibitors (TKIs) and evidence in favor or against their use with concurrent cranial radiotherapy.

Central nervous system (CNS) metastases, including brain metastases (BM) and leptomeningeal metastases (LM) represent a frequent complication of non-small cell lung cancer (NSCLC). Patients with BM comprise a heterogeneous group, with a median survival that ranges from 3 to 14 months. However, in the majority of patients, the occurrence of CNS metastases is usually accompanied by severe morbidity and substantial deterioration in quality of life. Local therapies, such as whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) or surgical resection, either alone or as part of a multimodality treatment are available treatment strategies for BM and the choice of therapy varies depending on patient group and prognosis. Meanwhile, introduction of tyrosine kinase inhibitors (TKIs) in clinical practice has led to individualization of therapy based upon the presence of the exact abnormality, resulting in a major therapeutic improvement in patients with NSCLC who harbor epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) gene rearrangements, respectively. Based on their clinical activity in systemic disease, such molecular agents could offer the promise of improved BM control without substantial toxicity; however, their role in combination with radiotherapy is controversial. In this review, we discuss the controversy regarding the use of TKIs in combination with radiotherapy and illustrate future perspectives in the treatment of BM in NSCLC.

Segmentation of peritumoral oedema offers a valuable radiological feature of cerebral metastasis.

Peritumoral oedema (PTO) is commonly observed on MRI in malignant brain tumours including brain metastasis (bMET) and glioblastoma multiforme (GBM). This study aimed to differentiate bMET from GBM by comparing the volume ratio of PTO to tumour lesion (Rvol). 56 patients with solitary bMET or GBM were enrolled, and MRI was analyzed by a semi-automatic methodology based on MATLAB (Mathworks, Natick, MA). The PTO volume (Voedema) was segmented for quantification using T2 fluid-attenuated inversion-recovery images, while the tumour volume was quantified with enhanced T1 images. The quantitative volume of the tumour, PTO and the ratio of PTO to tumour were interpreted using SPSS(®) (IBM Corp., New York, NY; formerly SPSS Inc., Chicago, IL) by considering different locations and pathologies. The tumour volumes of supratentorial GBM, supratentorial bMET (supra-bMET) and infratentorial bMET were 32.22 ± 21.9, 18.45 ± 17.28 and 11.40 ± 5.63 ml, respectively. The corresponding Voedema were 44.08 ± 25.84, 73.20 ± 40.35 and 23.74 ± 7.78 ml, respectively. The Voedema difference between supratentorial and infratentorial lesions is significant (p-value = 0.002). Supra-bMET has a smaller tumour volume (p-value = 0.032), but a larger PTO (p-value = 0.007). The ratio of Voedema to the tumour volume in bMET is statistically higher than that in GBM (p-value = 0.015). The cut-off ratio for identifying bMET from GBM is 3.9, with a specificity and sensitivity of 90.0% and 68.8%, respectively. Segmentation is an efficient method to quantify irregular PTO. bMET possesses more extensive oedema with smaller tumour volume than does GBM. The Rvol is a valuable index to distinguish bMET from GBM. This study presents a new method for the quantitation of PTO to differentiate bMET from GBM.

Proactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced ALK-positive non-small-cell lung cancer.

Anaplastic lymphoma kinase (ALK) gene fusions occur in 3%–7% of non-small-cell lung cancer (NSCLC) cases. Ceritinib, a once-daily, oral ALK inhibitor, has activity against crizotinib-resistant and crizotinib-naïve NSCLC, including brain metastases. Ceritinib (Zykadia™) was granted accelerated approval by the US Food and Drug Administration in 2014 for treating crizotinib-resistant ALK-positive NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/d and ∼38% of patients require dose interruption or reduction for GI AEs. This case study details our experience with the use of proactive GI AE management regimens in patients treated with ceritinib (750 mg/d) across two study sites. Proactive Regimens A and B were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to ceritinib dose. Regimen B included dicyclomine (taken with the first ceritinib dose), ondansetron (taken 30 minutes prior to ceritinib dose for the first seven doses), and loperamide (taken as needed with the onset of diarrhea). The proactive medications were tapered off depending on patient tolerability to ceritinib. Nine patient cases are presented. Starting Regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in eight of the nine patients. Using these regimens, 78% of patients were able to remain on 750 mg/d fasting. Two patients received 23 months and 16 months of therapy and remain on ceritinib 750 mg/d and 600 mg/d, respectively. Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750 mg/d ceritinib dose.

Nervous system metastases from systemic cancer.

Metastatic complications affecting the nervous system, including brain metastases, leptomeningeal metastases, dural metastases, metastatic epidural spinal cord compression, intramedullary spinal cord metastases, and neoplastic plexopathy, are associated with significant morbidity and poor prognoses. Early recognition and management are vital to minimizing neurologic decline and maintaining quality of life. Several recent randomized clinical trials in patients with brain metastases emphasize the importance of quality of life. Results from the European Organisation for Research and Treatment of Cancer (EORTC) 22952-26001 study suggest that adjuvant whole-brain radiation therapy after surgery or radiosurgery in patients with limited brain metastases may negatively impact some aspects of health-related quality of life, even if the negative effects are only transitory. In a separate study, Radiation Therapy Oncology Group (RTOG) 0614, memantine delayed cognitive decline in patients undergoing whole-brain radiation therapy for brain metastases. This article summarizes the main clinical features of cancer metastases affecting the nervous system and highlights recent updates in treatment and symptomatic management.

ET-53 * IPILIMUMAB FOR RECURRENT GLIOBLASTOMA (GBM)

Available treatments for recurrent glioblastoma (GBM) are inadequate, and median survival is approximately 6 months. Ipilimumab (ipi) is an immune modulator that inhibits CTLA-4 and is active in refractory melanoma, including brain metastases. We retrospectively reviewed records of patients treated with ipi for recurrent GBM, and explored safety, response, and survival using Kaplan-Meier methodology. There were 10 patients (6 men), median age 55 years (range 41-65). All received prior radiotherapy and temozolomide, and 9 received prior bevacizumab. Ipi (3mg/kg/dose) was administered for 1st (1), 2nd (4), 3rd (4), or 6th (1) recurrence. Bevacizumab was administered concurrently to all patients to reduce corticosteroid requirements that can blunt ipi effect. Other concurrent therapies included GM-CSF (8), nitrosoureas (5), carboplatin (1), temozolomide (1), or lapatinib (1). Corticosteroids (dexamethasone, 0.75 - 4.0 mg/day) were administered concurrently in 4. All patients were evaluated for toxicity. One experienced fever, elevated LDH, and transaminitis. One experienced rash and fatigue. There were no other significant toxicities, specifically no endocrinopathies or electrolyte abnormalities. Responses included stable disease (5) and progressive disease (5). Median progression-free survival (PFS) was 2.8 months and overall survival (OS) was 5.1 months, although 5 patients remain alive. Results were the same for those (9) treated for bevacizumab-refractory disease. Historical control suggests results are similar in bevacizumab-failure patients treated with salvage chemotherapy (PFS 1-3 moths, OS 4-6 months), and superior to those in patients who receive no further treatment following progression on bevacizumab. Comparison of immunologic effects in pre-ipi and post-ipi tumor tissue for one case is underway. Ipi can be administered safely to patients with GBM concurrently with GM-CSF, bevacizumab, nitrosoureas, and other therapies. In patients treated for bevacizumab-refractory disease, ipi may prolong PFS and OS as compared to historical controls. Concurrent bevacizumab may reduce corticosteroid requirements. Treatment earlier in the disease course merits investigation.

Paraneoplastic neurologic syndromes: Clinical presentation and management

This chapter gives a review of gastrointestinal cancers and their neurological complications, including brain metastasis, cord compression, plexopathy, leptomeningeal carcinomatosis, and paraneoplastic syndromes. It provides an update on current treatment regimens for GI cancers and their neurological side effects.

Ipilimumab for recurrent glioblastoma (GBM).

e13026 Background: Currently available treatments for recurrent glioblastoma (GBM) are inadequate, and median survival is approximately 6 months. Ipilimumab (ipi) is an immune modulator that inhibits CTLA-4 and is active in refractory melanoma, including brain metastases. Methods: We retrospectively reviewed medical records of patients treated with ipi for recurrent GBM, and explored safety, response, and survival using Kaplan-Meier methodology. Results: There were 10 patients (6 men), median age 55 years (range, 41-65). All received prior radiotherapy and temozolomide, and 9 received prior bevacizumab. Ipi (3mg/kg/dose) was administered for 1st (1), 2nd (4), 3rd (4), or 6th(1) recurrence. Bevacizumab was administered concurrently to all patients to reduce corticosteroid requirements that can blunt ipi effect. Eight patents received concurrent GM-CSF. Other concurrent chemotherapy included nitrosoureas (5), carboplatin (1), temozolomide (1), or lapatinib (1). Corticosteroids (dexamethasone, 0.75 – 4.0 mg/...

Timing of Failure in Limited Disease (Stage I-III) Small-Cell Lung Cancer Patients Treated with Chemoradiotherapy: A Retrospective Analysis

Follow-up in limited disease (stage I-III) small cell lung cancer could be further optimized by assessment of the temporal and locational distribution of treatment failure after completion of chemoradiotherapy. Follow-up was retrospectively analyzed in 125 limited disease (stage I-III) small cell lung cancer patients with initial performance status WHO <3 who had successfully completed chemoradiotherapy. Thoracic irradiation was applied in the concurrent or sequential mode. Time from initial pathological diagnosis and treatment end to local, distant and brain recurrence was documented. One- and two-year progression-free survival rates were 50% and 27.2% in patients treated with concurrent and 45.2% and 14.2% in those treated with sequential chemoradiotherapy, respectively. Local relapse was documented in 14% patients treated with concurrent and 16% with sequential chemoradiotherapy. The distant failure rate was 43% in both subgroups. Up to the end of the follow-up period, more patients treated with concurrent chemoradiotherapy had developed brain metastases than those treated sequentially (37% vs 20%, P = 0.049). Median time (in days) to local relapse was 376 and 401 from the initial diagnosis, 200 and 309 from the end of chemotherapy, and 316 and 196 from the end of thoracic irradiation; to distant failure was 275 and 298 from the initial diagnosis, 151 and 157 from the end of chemotherapy and 180 and 84 from the end of thoracic irradiation; to brain relapse was 330 and 273 from the initial diagnosis, 123 and 151 from the end of chemotherapy and 213 and 73 from the end of thoracic irradiation in patients treated with concurrent and sequential chemoradiotherapy, respectively. There was no significant difference in the temporal distribution of treatment failure in either subgroup. In more than half of the patients who developed a distant recurrence, including brain metastases, treatment failure occurred in the first year after the initial diagnosis. Intensified follow-up can be recommended at least in the first year, because no sufficient eradication of the systemic small cell lung cancer with the applied chemoradiotherapy protocol could be achieved.

Novel Therapies for Metastatic HER2 Positive Breast Cancer

The clinical course of HER2 positive (HER2+) breast cancer has changed since the introduction of trastuzumab, the first approved HER2 targeted agent. However, a significant number of patients relapse because of either de novo or acquired resistance to trastuzumab, imposing a need for other targeted agents. Lapatinib, the first targeted agent to demonstrate efficacy after trastuzumab progression, is licensed in combination with chemotherapy or with trastuzumab and has shown efficacy post-trastuzumab progression. Newer, recently approved agents include pertuzumab, an antibody preventing dimerization of HER2 and HER3, and T-DM1, an antibody-drug conjugate capable of delivering a highly cytotoxic agent into the cancer cells. Both agents have modest systemic toxicity. The dual combination of pertuzumab and trastuzumab given in combination with docetaxel is the current standard first-line treatment for HER2+ MBC. T-DM1 is now approved for second-line treatment. Specific clinical scenarios, including brain metastases, still lack good therapeutic options. Newer targeted agents are being tested with an exciting future for the treatment of HER2+ MBC although there are challenges to develop them in today’s environment. Clinicians now have a number of options for treatment of metastatic HER2 advanced breast cancer although access to some drugs may be limited globally, often because of economic realities.

Usage of EGFR-TKI and WBRT in NSCLC patients with brain metastases.

Central nervous system (CNS) metastases, including brain metastases (BM) and leptomeningeal metastases (LM), represent a common manifestation in patients with non-small-cell lung cancer (NSCLC). About 10% to 20% of NSCLC patients have BM and/or LM in their initial diagnosis of lung cancer. Approximately 20% to 30% of the remaining NSCLC patients will eventually have CNS metastases at some point during the course of the disease (1-5). The appearance of CNS metastases is often accompanied by disabling neurological symptoms, a decrease in quality of life, and a dismal outlook for survival; the patients usually died of CNS failure before other organ failure (2,3). As such, an optimization of the treatment algorithms for NSCLC-related CNS metastases would be of major relevance for these patients.

HER2-positive recurrent breast cancer and metastases of breast cancer, including life-threatening metastases to the brain and dura mater: a case effectively treated with lapatinib plus capecitabine before whole brain radiotherapy

Lapatinib is a new small molecule tyrosine kinase inhibitor. It targets both ErbB1 and ErbB2 (HER2) receptors and directly and reversibly acts on them to inhibit signaling. Since lapatinib has a low molecular weight, it can cross the blood–brain barrier. Thus, there is much interest in its potential effectiveness against brain metastases. Our patient was a 57-year-old postmenopausal woman with a non-contributory medical history. In September 2006, she underwent a partial mastectomy and axillary dissection for right breast cancer. Pathological diagnosis was solid-tubular carcinoma, n+ (6/23), nuclear grade 3, ly1, v0, ER+, PgR−, and HER2 3+ (pT1cN2aM0-stageIIIA). Adjuvant chemotherapy consisted of 6 cycles of epirubicin and cyclophosphamide (EC) and subsequent oral anastrozole. In May 2009, the patient developed choroidal, lung, liver, bone, and lymph node metastases. She underwent radiation therapy (choroids 40 Gy and cervical vertebrae 40 Gy), and the oral drug was changed to high-dose toremifene. In July 2009, the patient developed headache, vomiting, and seizures. MRI revealed multiple brain metastases and dura mater metastases. Administration of glycerol and steroid was begun. In addition, administration of lapatinib (1,250 mg/body, daily) plus capecitabine (2,000 mg/m2, day 1–14, every 3 weeks) was begun for treatment of brain and systemic metastatic lesions. Neurological symptoms improved on day 14. In January 2010, examinations revealed partial response of all metastatic lesions, including brain metastases. The patients continued the same treatment but exhibited progressive disease in March 2010. Thus, the treatment was discontinued as per the patient’s request. In May 2010, the patient developed generalized seizures again and underwent whole brain radiotherapy (30 Gy). However, the patient’s general condition gradually deteriorated and the patient died in June 2010.

Management of Melanoma Brain Metastases in the Era of Targeted Therapy

Disseminated metastatic disease, including brain metastases, is commonly encountered in malignant melanoma. The classical treatment approach for melanoma brain metastases has been neurosurgical resection followed by whole brain radiotherapy. Traditionally, if lesions were either too numerous or surgical intervention would cause substantial neurologic deficits, patients were either treated with whole brain radiotherapy or referred to hospice and supportive care. Chemotherapy has not proven effective in treating brain metastases. Improvements in surgery, radiosurgery, and new drug discoveries have provided a wider range of treatment options. Additionally, recently discovered mutations in the melanoma genome have led to the development of “targeted therapy.” These vastly improved options are resulting in novel treatment paradigms for approaching melanoma brain metastases in patients with and without systemic metastatic disease. It is therefore likely that improved survival can currently be achieved in at least a subset of melanoma patients with brain metastases.

Retrospective study of the efficacy and safety of fotemustine in 170 patients with metastatic melanoma.

e19011 Background: Fotemustine is a third-generation nitrosourea authorized in Europe for the treatment of metastatic melanoma. Fotemustine crosses the brain-blood barrier with a relevant activity on brain metastases (BM) and it is authorized in some European countries for primary brain tumors. Methods: We assessed the pattern of use, efficacy (tumor response, median progression-free survival [PFS], and median overall survival [OS]) and toxicity of fotemustine in Spain through a retrospective study on medical record data of 170 patients (pts) (56% male, 44% female). Median age: 61 years (range 20–87). ECOG PS: 0 in 28% of pts, 1 in 55%, ≥ 2 in 17%. High LDH values: 42 pts. Results: The most used scheme was induction at a 100 mg/m2 i.v. dose (days 1, 8, 15), 4-5 weeks of therapeutic rest and maintenance (100 mg/m2 i.v. every 3 weeks). 41% of pts were treated in first line, 38% in second, and 21% in third or higher. The median number of cycles was 3 (range 1-10). 160 pts were evaluable for efficacy. Tumor response: 3% complete response (CR), 14% partial response (PR), 31% stable disease (SD), 52% progression disease (PD). The clinical benefit in first line was 61% (CR=5%, PR=14%, SD=42%) and 39% (CR=3%, PR=14%, SD=22%) in second line. PFS was 84 days (95% CI 71-109), 100 days (95% CI 72-127) in first line and 77 days (95% CI 63-110) in second line. OS was 200 days (6.5 months) (95% CI 172–284). In 17 pts (10.3%) with BM the tumor response was CR=6% (1 pt), PR=18% (3 pts), SD=35% (6 pts), PD=41% (7 pts). 165 pts were evaluable for toxicity. The most common grade 3/4 toxicities were hematological and included neutropenia (40 pts, 24.2%), thrombocytopenia (39 pts, 23.6%), and anemia (14 pts, 8.5%). Conclusions: Fotemustine is an active and well-tolerated agent in metastatic melanoma, including brain metastases. Tumor response n % CR 5 3 PR 23 14 SD 49 31 Clinical benefit (CR+PR+SD) 77 48 PD 83 52 Total 160 100 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Italfarmaco, S.A.

A phase II study to assess the efficacy and impact of BIBW 2992 on QTc interval in patients with solid tumors, including brain metastases and recurrent glioblastoma multiforme (GBM).

TPS187 Background: BIBW 2992 is an oral, irreversible inhibitor of EGFR/HER1 and HER2. EGFR and HER2 are amplified and overexpressed in most epithelial cancers as well as 50%–60% of GBMs. In a phase I study, one patient with NSCLC and brain metastases showed a response in both systemic and CNS disease. Preclinical and retrospective ECG analyses did not suggest an effect of BIBW 2992 on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. The primary objectives of this study are to evaluate the effect of BIBW 2992 on QTc interval and the efficacy in patients with GBM, and patients with eligible tumors with and without brain metastases. Methods: In this phase II open label study, patients ≥18 years, with tumors known to historically overexpress EGFR or HER2, including those with brain metastases, and GBM at 1st recurrence, adequate organ function and ECOG PS 0–2, are eligible for treatment with BIBW 2992 50 mg PO OD q28. Patients with a QTcF-interval >470 ms, a PR-interval >230 ms, a QRS-interval >120 ms and ST-segment and T/U-wave abnormalities at screening, as assessed by central cardiology review, are excluded. All concomitant medications and dose changes within the initial 14 days on BIBW 2992 treatment are recorded. Up to 60 patients are to be recruited and treated until disease progression. Time-matched 24-h electrocardiograms are being performed at baseline, prior to drug exposure, after single dose and at steady state, i.e. Days -1, +1 and +14. PK samples are to be drawn at single dose and at steady state coincident with ECGs The primary endpoints are QTcF interval and objective tumor response according to the Macdonald criteria for GBM patients and for patients with brain metastases, and the RECIST 1.0 for other patients. Secondary endpoints include prolongation of QTcF, PR and QRS interval of ECG, heart rate, T wave and U wave morphology, disease control rate, PFS, molecular determinants of response, adverse events and PK characteristics of BIBW 2992 after single dose and at steady state. To date, 40 patients have been treated and 33 patients have completed ECG assessments on Days -1, +1 and +14. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Boehringer Ingelheim Boehringer Ingelheim Boehringer Ingelheim Boehringer Ingelheim

Triple Negative Breast Cancer: From Molecular Portrait to Therapeutic Intervention

Triple negative breast cancer is a subtype of breast cancer that lacks expression of an estrogen receptor (ER), a progesterone receptor (PR), and HER2. It is characterized by its unique molecular profile, aggressive behavior, and distinct pattern of metastasis. Epidemiological studies show a high prevalence of triple negative breast cancer among younger women and those of African descent. Although sensitive to chemotherapy, early relapse is common, and a predilection for visceral metastasis, including brain metastasis, has been described. Gene-expression profiling approaches demonstrated that triple negative breast cancer is a heterogeneous group of diseases composed of different, molecularly distinct subtypes. Although not synonymous, the majority of triple negative breast cancers carry the "basal-like" molecular profile on gene-expression arrays. However, several studies have shown that triple negative breast cancer includes tumors with a non-basal expression profile and, in particular, the "normal-breast," the "multiple marker negative," and the recently identified "claudin-negative" subtypes. Target-based agents, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and poly-ADP-ribose polymerase (PARP) inhibitors, are currently in clinical trials and hold promise in the treatment of this aggressive disease.

Pneumonectomy for Lung Cancer After Preoperative Concurrent Chemotherapy and High-Dose Radiation

We studied the clinical characteristics and outcomes of patients undergoing pneumonectomy after preoperative concurrent chemoradiation for non-small cell lung cancer. Clinical records of patients with non-small cell lung cancer who underwent pneumonectomy at our institution between 1995 and 2005 after preoperative concurrent chemoradiation were reviewed retrospectively. Twenty-nine patients underwent pneumonectomy after preoperative concurrent chemoradiation. Of the 21 men and 8 women who were treated, 1 had stage IIB (T3N0M0) and the remainder had stage IIIA or IIIB non-small cell lung cancer. Mean patient age at surgery was 53.4 years. There were 15 right pneumonectomies, of which 2 were for pancoast tumors. All patients received concurrent preoperative chemoradiation. Mean total radiation dose was 61.1 Gy. All patients went on to have complete (R0) resection by pneumonectomy. Pathologic complete response was found in 16 patients (55.2%). All patients were discharged alive from the hospital after pneumonectomy. Median hospital length of stay was 5 days (mean 8.6). Ninety-day mortality after surgery was 3.4% (n = 1). Recurrences have been found in 11 patients (38%), including brain metastases (n = 6), bone metastases (n = 4), liver metastases (n = 2), and cervical lymph node metastases (n = 2). One patient had a contralateral new primary lung cancer develop 70 months after undergoing pneumonectomy. Estimated 5-year disease-free survival is 48%. Median survival time has not been reached. Pneumonectomy can be performed safely after preoperative concurrent chemoradiation, even with high-dose radiation. The frequency of disease recurrence in the brain underscores the need to evaluate the role of prophylactic cranial radiation in non-small cell lung cancer.

Triple Negative Breast Cancer Patients with Brain Metastasis Are Associated with More Concurrent Lung Metastases.

Abstract Background: Breast cancer is a heterogeneous disease with different molecular subtypes. It is known that triple negative breast cancer and the HER-2 positive breast cancer subtypes are associated with more brain metastases. We further explored different subtypes of breast cancer patients with brain metastasis and analyzed their clinical behaviour with particular reference to the Hong Kong Chinese population. Methodology: We reviewed all breast cancer patients with brain metastasis presented to the Department of Clinical Oncology in the Queen Mary Hospital, the University of Hong Kong which is a teaching hospital during January 2004 to June 2008. Sociodemographic factors, date of primary breast cancer diagnosis and the tumour features, clinical behaviour at presentation, treatment received such as surgery, chemotherapy, hormonal therapy and targeted therapy, time of local recurrence, metastasis including brain metastasis, the recursive partitioning analysis (RPA) classes and treatment for the brain metastasis were all recorded. We classified the patients into 3 main subtypes, hormone positive, triple-negative (TNC) and HER-2 positive subtypes and further studied the clinical features and brain metastasis behaviour. Statistical analysis using SPSS 16.0 version was applied. Results: Altogether, there were 60 breast cancer patients with brain metastasis occurred during January 2004 to June 2008 requiring further management in our Department. Hormone positive patients constituted 46.6% while TNC accounted for 15.5% and HER-2 positive patients accounted for 37.9% of the cohort. The majority presented with symptoms at the time of the brain metastasis (93.1%) with headache being the most common symptom (43.1%), and 54 patients received whole brain radiotherapy (WBRT) and 8 patients received surgical resection of the brain metastasis. There were no significant statistical significance between the breast cancer subtypes and the metastatic behaviour except that the TNC patients were associated with concurrent lung metastasis when they first presented with brain metastasis (p = 0.03) when compared to the hormone positive and HER-2 positive patients. The ANOVA analysis showed there was a statistically significant difference between the RPA Classes of the patients and their time of survival after the brain metastasis (p = 0.002). Further ANOVA Post Hoc showed the RPA Class 3 patients were associated with shorter time of survival after brain metastasis when compared to the Class 1 patients (2.4 months vs 11.8 months, p = 0.001). However, patients with brain metastasis and different breast cancer subtypes did not have statistically significant different time of survival after their brain metastases. Conclusion: Hong Kong Chinese triple negative breast cancer patients with brain metastasis were associated with more concurrent lung metastasis. The RPA Classification still serves as a prognostic indicator with reference to the survival after brain metastasis in the breast cancer patients when compared to the breast cancer subtypes. Further large-scale multi-centre epidemiology study is warranted to confirm the above findings. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3072.