Neoadjuvant endocrine therapy with or without palbociclib in low-risk patients: a phase III randomized double-blind SAFIA trial.

BACKGROUND: The most prevalent subtype of breast cancer (BC) is luminal hormonal-positive breast cancer. The neoadjuvant chemotherapy regimens have side effects, emphasizing the need to identify new startegies. OBJECTIVE: Analyze the complete pathologic response (pCR) rate and overall response in a low-risk hormone-positive subset of patients receiving neoadjuvant hormone treatment (NAHT) with or without Palbociclib (a CDK4/CDK6 inhibitor) to boost NAHT effectiveness. MATERIALS AND METHODS: Based on the upfront 21-gene Oncotype DX or low-risk Breast Recurrence Score assay (RS™), the SAFIA trial is designed as a prospective multicenter international, double-blind neoadjuvant phase-III trial that selects operable with luminal BC patients that are HER2-negative for the induction hormonal therapy with Fulvestrant 500 mg ± Goserelin (F/G) followed by randomization of responding patients to palbociclib versus placebo. The pCR rate served as the study's main outcome, while the secondary endpoint was a clinical benefit. RESULTS: Of the 354 patients enrolled, 253 initially responded and were randomized to either F/G fulvestrant with palbociclib or placebo. Two hundred twenty-nine were eligible for the evaluation of the pathologic response. No statistically significant changes were observed in the pCR rates for the patients treated with the F/G therapy with placebo or palbociclib (7% versus 2%, respectively) per the Chevallier classification (Class1 + Class2) (p = 0.1464) and 3% versus 10% assessed per Sataloff Classification (TA, NA/NB) (p = 0.3108). Palbociclib did not increase the rate of complete pathological response. CONCLUSION: Neoadjuvant hormonal therapy is feasible in a selected population with a low RS score of < 31 CLINICAL TRIAL: NCT03447132.

Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients.

UNLABELLED: ESSENTIALS: We performed a pooled analysis of 926 patients with cancer-associated incidental pulmonary embolism (IPE). Vitamin K antagonists (VKA) are associated with a higher risk of major hemorrhage. Recurrence risk is comparable after subsegmental and more proximally localized IPE. Our results support low molecular weight heparins over VKA and similar management of subsegmental IPE. BACKGROUND: Incidental pulmonary embolism (IPE) is defined as pulmonary embolism (PE) diagnosed on computed tomography scanning not performed for suspected PE. IPE has been estimated to occur in 3.1% of all cancer patients and is a growing challenge for clinicians and patients. Nevertheless, knowledge about the treatment and prognosis of cancer-associated IPE is scarce. We aimed to provide the best available evidence on IPE management. METHODS: Incidence rates of symptomatic recurrent venous thromboembolism (VTE), major hemorrhage, and mortality during 6-month follow-up were pooled using individual patient data from studies identified by a systematic literature search. Subgroup analyses based on cancer stage, thrombus localization, and management were performed. RESULTS: In 926 cancer patients with IPE from 11 cohorts, weighted pooled 6-month risks of recurrent VTE, major hemorrhage and mortality were 5.8% (95% confidence interval [CI] 3.7-8.3%), 4.7% (95% CI 3.0-6.8%), and 37% (95% CI 28-47%). VTE recurrence risk was comparable under low molecular weight heparins (LMWH) and vitamin K antagonists (VKAs) (6.2% vs. 6.4%; hazard ratio [HR] 0.9; 95% CI 0.3-3.1), while 12% in untreated patients (HR 2.6; 95% CI 0.91-7.3). Risk of major hemorrhage was higher under VKAs than under LMWH (13% vs. 3.9%; HR 3.9; 95% CI 1.6-10). VTE recurrence risk was comparable in patients with an subsegmental IPE and those with a more proximally localized IPE (HR 1.1; 95% CI 0.50-2.4). CONCLUSION: These results support the current recommendation to anticoagulate cancer-associated IPE with LMWH and argue against different management of subsegmental IPE.

Venous thromboembolism risk stratification in medically-ill hospitalized cancer patients. A comprehensive cancer center experience.

Cancer and its treatment are recognized risk factors for VTE. Compliance rate with published VTE prophylaxis guidelines is low. Decision on when to offer prophylaxis for hospitalized cancer patients is difficult to make. This paper describes current clinical practice in offering VTE prophylaxis to hospitalized cancer patients. Prophylaxis rate and rate of VTE will be correlated with the risk level. We prospectively followed all consecutive adult cancer patients admitted to medical units over a 5-month period. Caprini risk assessment model, with some modifications, was utilized to determine risk of VTE. Six hundred and six patients (51% males, median age 52 years, range 18-91) were included. Reasons for admission included infections (25%), chemotherapy (22%) and palliative care (10%). In addition to cancer, the most frequently encountered risk factors for VTE were: Immobilization (35%), age > 60 years (31%) and body mass index > 30 in (20%). Patients were grouped according to their total risk score: low (9%), moderate (44%) and high risk (47%). VTE prophylaxis rate was 55.1% for the whole study group. Following discharge, patients were followed for 60 days. The incidence of VTE was 3.4% in the moderate and 4.2% in the high risk groups, while none in the low risk group developed VTE. Many additional risk factors for VTE are usually encountered in hospitalized cancer patients. Cancer alone may not be an enough reason for VTE prophylaxis. Risk assessment model able to stratify patients into different risk categories will simplify decision making and enhance VTE prophylaxis rate.

A randomized study of multi-day infusion of autologous peripheral blood progenitor cells.

Peripheral blood progenitor cells (PBPC) are increasingly used as the source of stem cells in both the autologous and allogeneic settings. Based on previous early non-randomized studies reporting enhanced engraftment following fractionated autologous PBPC infusion, some centers and study groups infuse PBPC over 3 days. To study the possible benefit of multiple day PBPC infusion, 60 patients receiving high-dose chemotherapy and autologous progenitor cell transplantation (ABMT) were randomized to receive their PBPC divided over 1, 2 or 3 days. Stem cells were mobilized with G-CSF 5 microg/kg for 7 days and PBPC were collected on days 5-7. Patients received daily G-CSF 5 microg/kg i.v. over 30 min beginning 4 h after the infusion of the first aliquot of PBPCs. Toxicity was similar for the 1, 2 and 3 day infusion groups. The median time to achieve 500 neutrophils/mm3 was 10, 11 and 11 days in the groups receiving PBPCs over 1, 2 or 3 days, respectively. The median time to achieve a platelet count of 20 x 10(9)/l was 11 days for the group receiving their cells as a single infusion and 12 days in the other two groups. We conclude that expanding PBPC infusion over 2 or 3 days does not enhance engraftment or reduce toxicity.

Comparative analysis of interphase FISH and RT-PCR to detect bcr-abl translocation in chronic myelogenous leukemia and related disorders.

The t(9;22)(q34;q1 1) between the abl and bcr genes plays a pivotal role in the diagnosis and pathogenesis of chronic myelogenous leukemia (CML). Its detection is routinely accomplished by Southern blot analysis and karyotyping. Interphase fluorescence in situ hybridization (FISH) and reverse transcriptase-polymerase chain reaction (RT-PCR) are emerging molecular techniques that offer viable alternatives. We analyzed 40 samples of peripheral blood and bone marrow (CML, 16; acute myelogenous leukemia, 6; acute lymphoblastic leukemia [ALL], 1; chronic lymphoblastic leukemia, 2; myelodysplasias, 4; myeloproliferative disorders, unclassified, 3; nonleukemic hematologic malignancies, 3; hypercellular bone marrow, 1; normal control samples, 2; and K562 cell line samples, 2) for the presence of bcr-abl fusion gene and its messenger RNA (mRNA) transcript by FISH and RT-PCR, respectively. We compared the results with results of Southern blot analysis and karyotyping when available. Cost analysis was performed. Thirty-three samples were evaluable by FISH; 14 of 14 evaluable CML samples and one ALL sample were positive for bcr-abl by FISH (100%). The other 15 evaluable samples were negative; 16 of 16 (100%) and 13 of 16 (81%) of CML cases were positive for bcr-abl mRNA by RT-PCR (chemiluminescent blot method) and RT-PCR (colorimetric method), respectively. The ALL sample was positive by both RT-PCR methods. All other samples were negative by RT-PCR (chemiluminescent blot method), and all but 1 case of myeloproliferative disorder tested negative by RT-PCR (colorimetric method). We conclude the utility of FISH and RT-PCR is associated with certain limitations, such as insufficient RNA for RT-PCR and the occasional absence of internal positive FISH control signals. However, each procedure offers (with a high concordance rate) a specific and cost-effective alternative to Southern blot analysis and karyotyping and improved turnaround time for the detection of bcr-abl fusion gene or its mRNA transcript.