Oncological Outcomes After Hippocampus-Sparing Whole-Brain Radiotherapy in Cancer Patients With Newly Diagnosed Brain Oligometastases: A Single-Arm Prospective Observational Cohort Study in Taiwan

BackgroundPromisingly, the technique of hippocampus sparing during WBRT (HS-WBRT) might preserve NCFs. In this research, we examined oncological outcomes, with emphasis on neurologic/non-neurologic causes of death, CNS progression, and leptomeningeal disease (LMD) recurrence in cancer patients who underwent HS-WBRT.MethodsOne hundred and fourteen cancer patients with newly diagnosed brain oligometastases underwent HS-WBRT were consecutively enrolled. The cumulative incidence of cancer-specific deaths (neurologic or non-neurologic), LMD recurrence, and the composite endpoint of CNS progression (CNS-CE) as the first event were computed with a competing-risks approach to characterize the oncological outcomes after HS-WBRT.ResultsPatients with intact brain metastases had a significantly increased likelihood of dying from non-neurologic causes of death associated with early manifestation of progressive systemic disease (hazard ratio for non-neurologic death, 1.78; 95% CI, 1.08–2.95; p = 0.025; competing-risks Fine–Gray regression), which reciprocally rendered them unlikely to encounter LMD recurrence or any pattern of CNS progression (HR for CNS-CE as the first event, 0.13; 95% CI, 0.02–0.97; p = 0.047; competing-risks Fine–Gray regression). By contrast, patients with resection cavities post-craniotomy had reciprocally increased likelihood of CNS progression which might be associated with neurologic death eventually.ConclusionsPatterns of oncological endpoints including neurologic/non-neurologic death and cumulative incidence of CNS progression manifesting as LMD recurrence are clearly clarified and contrasted between patients with intact BMs and those with resection cavities, indicating they are clinically distinct subgroups.Trial RegistrationClinicalTrials.gov, Identifier: NCT02504788, NCT03223675.

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Competing causes of death in NCIC CTG MA.17, a placebo-controlled trial of letrozole as extended adjuvant therapy for breast cancer patients

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.540 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 540-540

Author(s):

J. Chapman ◽

D. Meng ◽

L. Shepherd ◽

W. Parulekar ◽

J. N. Ingle ◽

...

Keyword(s):

Breast Cancer ◽

Cardiovascular Disease ◽

Cancer Patients ◽

Competing Risks ◽

Causes Of Death ◽

Nodal Status ◽

Breast Cancer Patients ◽

Baseline Trial ◽

Risk Of Death ◽

Baseline Factors

540 Background: Risk of death from other malignancies (OM) and other causes (OC) than breast cancer (BC) increases with age. Effects of baseline factors on type of death were assessed with competing risks analyses. Methods: In NCIC CTG MA.17, 5,187 women free of recurrent breast cancer after 5 years of tamoxifen were randomized to letrozole (L, 2,593 women) or placebo (P, 2,594 women). The primary endpoint was disease free survival (DFS), and secondary, overall survival (OS). Follow-up was to October 9, 2005: median 3.9 years, range <0.1 to 7.0 years. Effects of competing risks were examined for endpoints of BC, OM, and OC for 11 baseline trial factors: treatment, age, menopausal status, duration of prior tamoxifen, adjuvant radiotherapy, bone fracture, osteoporosis, cardiovascular disease, hormone receptor status, nodal status, adjuvant chemotherapy. Lagakos’ hierarchical method (Lagakos, Appl. Statist. 1978; 27:235–241) was used to test for differential effects of baseline factors on type of death (BC, OM, OC). Results: Rate of censoring was 97.8%, with 256 deaths (BC, 102; OM, 50; OC, 100; unknown, 4). Non-breast cancer deaths accounted for 60% of known deaths; 72%, for those ≥70 years; and 48%, for those <70 years. Two baseline factors differentially affected type of death. Women with cardiovascular disease were more likely to die from OC (p=0.02), while those with osteoporosis were more likely to die of OM (p=0.03). Age and nodal status had directionally similar effects. Older women had shorter survival from all 3 causes of death (p=0.01). Lymph node positivity was associated with worse survival (p=0.003). Conclusions: Extended L provides similar proportional benefit in improving DFS for all ages of women (Muss ref abstract SABCS 2006). However, the magnitude of competing non-breast cancer, and non-treatment related, causes of death needs to be considered more frequently, since with early detection and improved therapies, breast cancer patients may increasingly be expected to survive their disease to die from another cause. The novel association between baseline osteoporosis and other malignancies is being explored quantitatively. No significant financial relationships to disclose.

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Anticoagulation in Cancer Patients with Atrial Fibrillation and Grade 3-4 Thrombocytopenia

Blood ◽

10.1182/blood-2021-150782 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4272-4272

Author(s):

Genady Drozdinsky ◽

Noam Arad ◽

Galia Spectre ◽

Nir Livneh ◽

Itamar Poran ◽

...

Keyword(s):

Atrial Fibrillation ◽

Acute Leukemia ◽

Cancer Patients ◽

Major Bleeding ◽

Cumulative Incidence ◽

Competing Risk ◽

Newly Diagnosed ◽

Thrombotic Risk ◽

Significant Difference ◽

Grade 3

Abstract Introduction: Atrial fibrillation (AF) is not uncommon in cancer patients with grade 3-4 thrombocytopenia (platelets <50x10 9/L). The risk of bleeding appears to outweigh the risk of thrombosis in acute leukemia patients. There are no published data regarding management of anticoagulation (AC) and rates of bleeding and thrombosis in other cancer types. Aim: To assess AC management and incidence of bleeding and thrombosis in thrombocytopenic cancer patients with AF. Methods: Single-center retrospective cohort study. The study included adults with active cancer, grade 3-4 thrombocytopenia (platelets <50x10 9/L) and AF with CHA 2DS 2-VASc ≥1, irrespective of AC status prior index. Patients with acute leukemia were excluded. Patients were indexed when platelets <50x10 9/L. AC management was classified as either "No-AC", if AC was withheld (i.e., stopped or not started) at index, or "Continue-AC", if AC was continued. Arterial thromboembolism (ATE; ischemic stroke, transient ischemic attack or systemic embolism) and ISTH-defined major bleeding were recorded over 30 days. The 30-day cumulative incidence of composite and individual outcomes with corresponding 95% confidence intervals (CI) was calculated for each management group (death as competing risk). A Cox proportional hazards model was used to calculate hazard ratios (HR) and corresponding 95% CI for outcomes between the No-AC and Continue-AC groups, with death as a competing risk (Fine and Gray model). Results: The eligibility criteria were met by 131 patients. At study index, AC was not given in 90 (69%) patients and continued in 41 (31%). Table 1 shows patient characteristics overall and stratified for management. The median age was 80 years )IQR 70-82) and 55 (42%) were females. Most patients were inpatients at index (70%) and had newly diagnosed cancer (70%). 64% had solid malignancy, and the remainder had hematological malignancy. The majority (92%) had AF prior to study index, while 8% had AF newly diagnosed at index. The median CHA 2DS 2-VASc score was 4 [IQR 3-5] and 18% had a prior stroke. Median platelet counts were 42 x 10 9/L at index and the median HASBLED score was 5 [3-5]. Only 44% of the No-AC group were receiving AC prior index, compared with 95% in the Continue-AC group, at shorter median duration. The type of prior AC differed between groups. Antiplatelet therapy (54%) and major bleeding prior index (13%) were more frequent in the No-AC group. There was a median [IQR] of 4 [0-60] and 4 [1-26] days of grade 3-4 thrombocytopenia in the No-AC and Continue-AC groups, respectively. Platelet nadirs (x10 9/L) were numerically higher in the No-AC group (31 [3-50] vs. 21 [6-50]; p=0.09). A median [IQR] of 12 [6-17.25] and 10 [5-12] platelet transfusions were given to 29 (32.2%) patients in the No-AC group and 11 (26.8%) in the Continue-AC group, respectively (p>0.2). In the Continue-AC group, AC was subsequently held in 12/41 (29%) and dose-reduced in 4/41 (10%) during the 30 days post-index. The 30-day cumulative incidence [95% CI] of the composite outcome (major bleeding or ATE) was 10% [4.88-17.27] in the No-AC group and 4.88% [0.86-14.7] in the Continue-AC group (HR 2.142 [0.47-9.609]). The 30-day cumulative incidence of ATE (Figure 1A) was 3.33% [0.88-8.66] in the No-AC group (n=3), and 4.88% [0.85-14.7] in the Continue-AC group (n=2), corresponding with a HR of 0.70 [0.12-4.10]. The 30-day cumulative incidence of major bleeding (Figure 1B) was 7.8% [3.40-14.52] in the No-AC group, and 2.44% [0.18-11.22] in the Continue-AC group (HR 3.29 [0.42-26.04]). The 30-day overall survival was 64.4% in the No-AC and 73.2% in the Continue-AC groups (HR 1.39 (95% CI 0.7-2.76). Conclusions: In a cohort of cancer patients with grade 3-4 thrombocytopenia (<50x10 9/L) and AF (median CHA 2DS 2-VASc = 4), the majority had anticoagulation held. Baseline thrombotic and bleeding risk factors were generally balanced, but a higher rate of prior bleeding and lower rates of anticoagulation prior index in the No-AC group, suggest confounding by indication. No statistically significant difference in outcomes was detected between management groups, but 95% CI's were wide. The high bleeding and low ATE incidence in the No-AC group suggests that holding AC during time-limited periods of grade 3-4 thrombocytopenia may be a reasonable approach in many cancer patients with AF. Continuing AC should be investigated in a subset of patients with lower bleeding and higher thrombotic risk. Figure 1 Figure 1. Disclosures Falanga: Pfizer: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Leo Pharma: Honoraria. ten Cate: Bayer AG: Other; Pfizer: Other; LEO Pharma: Other; Gideon Pharmaceuticals: Other; Alveron Pharma: Other. Leader: Bayer: Honoraria; Leo Pharma: Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Honoraria.

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Phase II trial of sunitinib as adjuvant therapy after stereotactic radiosurgery (SRS) in patients with 1-3 newly diagnosed brain metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2018 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2018-2018

Author(s):

David M. Peereboom ◽

Samuel T. Chao ◽

John H. Suh ◽

Ding Wang ◽

Tom Mikkelsen ◽

...

Keyword(s):

Adjuvant Therapy ◽

Brain Metastases ◽

Systemic Disease ◽

Neuropsychological Testing ◽

Local Therapy ◽

Whole Brain Radiotherapy ◽

Growth Factor Signaling ◽

Newly Diagnosed ◽

Brain Radiotherapy ◽

Primary Disease

2018 Background: For patients with 1-3 brain metastases, standard therapy after SRS is adjuvant whole brain radiotherapy (WBRT). SRS without WBRT carries a higher rate of brain relapse. Due to concerns about neurologic sequelae of WBRT, however, many patients and physicians opt to defer WBRT until the time of central nervous system (CNS) progression. This trial used sunitinib as an alternative to WBRT for post-SRS adjuvant therapy. Sunitinib inhibits vascular endothelial growth factor signaling, and we hypothesized that it would prevent growth of microscopic brain metastases presumed to be present. The objective was to use adjuvant sunitinib after SRS to prevent the emergence of new or progressive disease in the brain or at the site of SRS and to preserve neurocognitive function. Methods: Eligible patients had 1-3 newly diagnosed brain metastases, RTOG RPA class 1-2, and started sunitinib < 1 month after SRS and baseline neuropsychological testing (NPT). Patients with controlled systemic disease were allowed to continue chemotherapy for their primary disease according to a list of published regimens (therapy + sunitinib) included in the protocol. Patients received sunitinib 37.5 or 50 mg/d days 1-28 every 42 days until CNS progression. NPT and MRIs were obtained every 2 cycles. The primary endpoint was the rate of CNS progression at 6 months (PFS6) after SRS. Results: Fourteen patients enrolled. The median age was 59 (range 46-80). Main histologies: lung 36%, breast 21%, melanoma 14%. Toxicities: Grade 4: neutropenia [ANC] (1 pt); Grade 3: fatigue (5), ANC (2), rash (1). Dose reduction due to toxicity: 1 pt (to 37.5 mg/d). The CNS PFS6 and PFS12 were 50% + 13% and 43% + 13%, respectively. The median PFS was 6.6 months (95% C.I. 1.5-19). NPT results will be reported at the meeting. Conclusions: Sunitinib after SRS for 1-3 brain metastases was well tolerated with a PFS6 of 50%. The use of novel agents to prevent progressive brain metastasis after SRS requires the incorporation of chemotherapy regimens to control the patient’s primary disease. Future trials should continue to explore the paradigm of secondary chemoprevention of brain metastases after definitive local therapy (surgery or SRS).

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The management of BRAF mutant melanoma brain metastases upon tyrosine kinase failure.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e21020 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e21020-e21020

Author(s):

Rahul Ladwa ◽

Victoria Atkinson

Keyword(s):

Brain Metastases ◽

Tyrosine Kinase ◽

Kinase Inhibitor ◽

Systemic Disease ◽

Whole Brain Radiotherapy ◽

Mortality Data ◽

Leptomeningeal Disease ◽

Number Of Patients ◽

The Brain ◽

Braf Mutant

e21020 Background: Brain metastases (BM) failure on tyrosine kinase inhibitor (TKI) is a frequent complication in patients with BRAF mutant metastatic melanoma (MM) and is associated with a poor prognosis. We aimed to explore the outcome of these patients with modern therapeutic options. Methods: We retrospectively analysed 55 patients with treated BRAF mutant mm diagnosed with BM on TKI at a single site in Brisbane, QLD, Australia during 2009-2016. Basic clinico-pathological parameters, treatments used and mortality data were collected. Results: Patient characteristics included a median age of 53 (17-82) years, presence of seizures (N = 7), LDH > 250 (N = 23) and presence of systemic disease (N = 54). BM were categorised as solitary (N = 8), 2-6 (N = 23), more than 6 (N = 13) and leptomeningeal disease (N = 11). Management of BM included surgical resection (N = 6), stereotactic radiosurgery (SRS) (N = 14), whole brain radiotherapy (N = 13) and best supportive care (N = 16). BRAF use post progression with BM was used (N = 10). Immunotherapy with Ipilimumab (N = 17) and PD1 inhibitor (N = 24) was used. With a median follow up of 5 months, 47 (85%) patients had died from MM. Death occurred due to progressive disease in the brain (N = 24), systemically (N = 5) or both (N = 18). The number of patients surviving over 6 months (N = 27) were associated with < 6 BM, use of radiotherapy, use of anti PD1 antibodies and the use of ablative therapies with immunotherapy. Statistically improved overall survival (OS) were found with < 6 BM, SRS use and PD1 inhibitor use. Ablative treatments (resection or SRS) with subsequent immunotherapy confers a median OS of 13 months in select patients. Conclusions: Despite improvements in systemic treatment for mm the outcomes of those with BRAF mutant mm on TKI who develop BM remains poor. Death is frequently due to PD within the brain. The use of ablative techniques and immunotherapy are optimal treatment options in this poor prognostic group.

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Thrombotic Risk Assessment in a Prospective Cohort of Newly Diagnosed Ambulatory Cancer Patients Candidate to Chemotherapy

Blood ◽

10.1182/blood-2019-129901 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3642-3642

Author(s):

Anna Falanga ◽

Cristina Verzeroli ◽

Marina Marchetti ◽

Cinzia Giaccherini ◽

Laura Russo ◽

...

Keyword(s):

Risk Assessment ◽

High Risk ◽

Cancer Patients ◽

Cumulative Incidence ◽

Prospective Cohort ◽

Tumor Site ◽

Newly Diagnosed ◽

Thrombotic Risk ◽

D Dimer

Introduction: The occurrence of venous thromboembolism (VTE) during chemotherapy may result in treatment delays with unfavorable effects on cancer outcome, therefore VTE prevention is a relevant issue. Current guidelines recommend primary thromboprophylaxis in select high-risk cancer outpatients undergoing chemotherapy. Hence, the use of risk assessment models involving both clinical and biological parameters is increasingly important. In this analysis, in a large prospective cohort of patients with newly diagnosed metastatic non-small cell lung (NSCLC), colorectal (CRC), gastric (GC) or breast (BC) cancers, we assessed whether pre-chemotherapy levels of thrombotic biomarkers may help to stratify patients at different risk levels of VTE during the first 6 months of anti-tumor therapy. Methods: The study cohort included patients with advanced cancer enrolled from January 2012 to December 2017 in the HYPERCAN study (ClinicalTrials.gov, ID# NCT02622815), an ongoing Italian prospective, multicenter, observational study (Falanga et al, Thromb Res 2016). Clinical data and blood samples were collected at enrollment and during scheduled follow-up visits. Baseline plasma levels of fibrinogen (Clauss method), d-dimer (immunoturbidimetric assay), prothrombin fragment F1+2 (ELISA), FVIIa-AT (ELISA) and thrombin generation (TG, CAT assay) were measured. The study protocol was approved by the local Ethics Committee. Informed written consent was obtained from all study subjects. The outcome measure of the current analysis is the time to the occurrence of first symptomatic and/or incidental VTE, objectively confirmed. Results: A cohort of 922 patients [median age: 66 (30-92) years] with metastatic NSCLC (n=416), CRC (n=262), GC (n=105) and BC (n=139) was available for analysis. After a median follow-up of 327 days (range 44-1,548), VTE occurred in 122 (76 M/46 F) patients [median age 64 y (range 40-85)] providing a cumulative incidence of 19.7% (CI 95%: 16-23). According to tumor site, VTE frequency was: NSCLC (n= 64, 15.3%) > CRC (n= 38, 14.5%) > GC (n= 12, 11.4%) > BC (n= 8, 5.7%). Biomarkers' analysis of baseline plasma samples from 598 patients showed significantly higher levels of fibrinogen, d-dimer and TG in the cancer cohort compared to healthy control subjects (p<0.01). NSCLC patients had significantly (p<0.001) higher levels of d-dimer compared to CRC and BC patients, and of fibrinogen (p<0.001) compared to CRC, BC and GC patients. Cumulative incidence of VTE at 6 months was 10% (CI 95% 8-12). In particular, patients who had VTE in 6 months presented with significantly higher pre-chemotherapy levels of D-Dimer than VTE-free subjects (p<0.05). Cox-multivariate analysis identified as independent risk factors for VTE, high d-dimer (HR: 2.1, CI 95% 1.2 - 3.7; p=0.008), high peak of TG (HR: 1.8, CI 95% 0.99 - 3.2; p=0.052), and site of primary tumor (non-BC vs BC) (HR: 3.3, CI 95% 1.01 - 10.5; p=0.048). A score for VTE prediction was created with these variables and three risk categories (low, intermediate, and high) were generated. The cumulative incidence of VTE at 6 months in each risk category was 3.9%, 9.8%, and 19%, respectively (low vs high HR: 2.36 p=0.005; intermediate vs high HR 2.16 p=0.006). Differently, the application of the Khorana score failed to identify high risk patients. Conclusions: Our prospective study in a large cohort of metastatic cancer patients shows the high burden of VTE during the first 6 months of chemotherapy. Furthermore, laboratory data from this analysis enable us to create a risk scoring system based on d-dimer and TG together with tumor site, that significantly identifies patients at the highest VTE risk. Further investigation are worth to externally validate this score for clinical use. Project funded by AIRC "5xMILLE multiunit extension program" n. 12237 grant from the "Italian Association for Cancer Research (AIRC)". Disclosures Santoro: Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; MSD: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy; Abb-Vie: Speakers Bureau; Roche: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; BMS: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Lilly: Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Speakers Bureau.

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