Immunohistochemistry study of tumor vascular normalization and anti-angiogenic effects of sunitinib versus bevacizumab prior to dose-dense doxorubicin/cyclophosphamide chemotherapy in HER2-negative breast cancer

Purpose Tumor angiogenesis controlled predominantly by vascular endothelial growth factor and its receptor (VEGF-VEGFR) interaction plays a key role in the growth and propagation of cancer cells. However, the newly formed network of blood vessels is disorganized and leaky. Pre-treatment with anti-angiogenic agents can “normalize” the tumor vasculature allowing effective intra-tumoral delivery of standard chemotherapy. Immunohistochemistry (IHC) analysis was applied to investigate and compare the vascular normalization and anti-angiogenic effects of two commonly used anti-angiogenic agents, Sunitinib and Bevacizumab, administered prior to chemotherapy in HER2-negative breast cancer patients. Methods This prospective clinical trial enrolled 38 patients into a sunitinib cohort and 24 into a bevacizumab cohort. All received 4 cycles of doxorubicin/cyclophosphamide chemotherapy and pre-treatment with either sunitinib or bevacizumab. Tumor biopsies were obtained at baseline, after cycle 1 (C1) and cycle 4 (C4) of chemotherapy. IHC was performed to assess the tumor vascular normalization index (VNI), lymphatic vessel density (LVD), Ki67 proliferation index and expression of tumor VEGFR2. Results In comparison to Bevacizumab, Sunitinib led to a significant increase in VNI post-C1 and C4 (p < 0.001 and 0.001) along with decrease in LVD post-C1 (p = 0.017). Both drugs when combined with chemotherapy resulted in significant decline in tumor proliferation after C1 and C4 (baseline vs post-C4 Ki67 index p = 0.006 for Sunitinib vs p = 0.021 for Bevacizumab). Bevacizumab resulted in a significant decrease in VEGFR2 expression post-C1 (p = 0.004). Conclusion Sunitinib, in comparison to Bevacizumab showed a greater effect on tumor vessel modulation and lymphangiogenesis suggesting that its administration prior to chemotherapy might result in improved drug delivery. Trial registry ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).

Impact of Complete Pulmonary Metastasectomy on the Prognosis of Children with Metastatic Hepatoblastoma: A Single Center Experience

Background The survival rate of patients with hepatoblastoma (HB) with distant metastases is unsatisfactory. Although dose-dense chemotherapy with a high incidence of ototoxicity improves the prognosis of these patients, surgical metastasectomy may provide an alternative treatment option avoiding drug side effects. The aim of this study was to examine the efficacy of “complete” pulmonary metastasectomy for the treatment of children with metastatic HB. Methods This retrospective study retrieved data from 2004 to 2015 on 22 children with metastatic HB. Separated into two groups; children who underwent only hepatectomy (group H, 14 cases), and children who underwent primary or rescue liver transplantation (group T, eight cases). Each patient was administered initial chemotherapy according to JPLT-2, SIOPEL3 or PLADO protocols. Over the course of this study, we performed metastasectomies for all detectable pulmonary metastases. Indocyanine green fluorescent navigation was used for 15 patients to detect tiny metastases. The follow-up period for survivors after the last metastasectomy ranged from 36 to 186 months. Results The cumulative disease-free 5-year survival rate was 84% in group H and 33% in group T. The median number of resected pulmonary metastatic lesions was 10.5 (range: 1-42) in group H and 3.5 (range: 1–97) in group T. None of the survivors developed hearing or respiratory impairment. Conclusions Complete pulmonary metastasectomy improves the prognosis of patients with metastatic HB with conventional chemotherapy, especially in the patients with primary HB lesions removed without liver transplantation.

Neoadjuvant chemotherapy for HER2-positive breast cancer using dose-consolidated regimens and dual anti-HER2 blockade with pertuzumab and trastuzumab (preliminary results)

The main goal of neoadjuvant chemotherapy (NACT) in aggressive breast cancer (BC) subtypes (triple-negative, HER2-positive) is to achieve complete pathological response (pCR), since it is associated with a significant decrease in the likelihood of recurrence and death. Currently, the standard approach for HER2+ BC stage II–III is NACT with the inclusion of a double anti-HER2 blockade, since this significantly increases the frequency of pCR. To date, it remains unclear whether the intensification of modern anthracycline-taxane-containing regimens of NACT affects the incidence of pCR in different BC subtypes, including HER2-positive, provided that a double anti-HER2 blockade is used.The aim of our prospective observational study from daily clinical practice was to assess the efficacy (according to the RCB system and the frequency of pCR) and tolerability of dose-dense NACT in stage II–III HER2-positive BC.Materials and methods. The study included 86 patients, mean age 45 years (26–74 years), in 96.5% of cases, the tumor was represented morphologically by invasive cancer of a nonspecific type, in 53.5% of the tumors had a positive luminal B HER2 phenotype, in 46.5% – non-luminal HER2+. The majority of patients (67.4%) had locally advanced inoperable breast cancer; in 80.2% of cases, metastatic lesions of regional lymph nodes were determined. NACT included anthracyclines and taxanes: four cycles of AC in a dose-dense regimen (once every 2 weeks), then four cycles of docetaxel 75 mg/m2 once every 3 weeks + trastuzumab + pertuzumab.Results. The frequency of pCR = RCB0 in the entire group was 54.7% (47/86), in locally advanced breast cancer – 55.9%, in operable breast cancer – 51.9%. In the luminal HER2+ subtype, the frequency of pCR was lower than in the non-luminal HER2+ subtype – 43.5% vs 67.5%, however, the differences were statistically insignificant (p = 0.09). The frequency of RCB0–I in ER+ HER2+ subtype was 60.9%, as in ER-HER2+ – 80%. Conclusions. In our study, for the first time, the efficacy of dose-dense NACT in HER2+ breast cancer was assessed; it was shown that the frequency of pCR and RCB0–I correspond to those in standard anthracycline-taxane-containing regimens. In the context of the use of double anti-HER2 blockade, the anthracycline stage, most likely, does not need to be escalated, since this does not lead to an increase in the frequency of complete pathomorphological regressions.

Anemia Requiring Transfusion in Breast Cancer Patients on Dose-dense Chemotherapy: Prevalence, Risk Factors, Cost and Effect on Disease Outcome.

Purpose: Dose dense chemotherapy improves survival but also increases toxicity and treatment related cost. Here we report the prevalence of anemia, understand the risk factors of chemotherapy related anemia and determine the cost and time-delay associated with transfusion requirement in Indian non-metastatic breast cancer patients on dose dense preoperative chemotherapy.Methods: In this study, 116 triple negative breast cancer (TNBC) patients were treated preoperatively with Docetaxel and Cyclophosphamide alternating with Epirubicin and Cisplatin every 2-weekly. Patients were evaluated for anemia pre- and post-chemotherapy. We examined trends in the cell counts, transfusion requirement, time to transfusion as well as risk factors associated with transfusion during treatment, along with delay in treatment due to anemia and the additional cost incurred.Results: One hundred and sixteen women with high-risk non-metastatic TNBC were treated. Median age was 44.5 years. 56.1% had stage III disease. Delivery of 6/8 planned doses was achieved in 98.3% of patients, and all 8 doses in 86% patients. Anemia was detected at baseline in 54(46.5%) patients with mild(10-12g/dl) anemia in 42(36.2%) patients and moderate(8-10g/dl) in 12(10.3%) patients. Forty-four patients (37.9%) required transfusion during chemotherapy with 55(47.4%) patients having grade 1-2 anemia and 40(34.5%) patients having grade 3 anemia. The factors associated with transfusion were low grade of tumor (OR 2.48 (95% CI 1.08 - 5.68), p = 0.025), hemoglobin post 2 cycles of chemotherapy (OR 1.74 (95% CI 1.21- 2.51), p = 0.003), thrombocytopenia grade 3 or 4 (OR 4.35 (95% CI 1.062-17.827), p = 0.034) and drop in hemoglobin after 2 cycles (OR 1.65 (95% CI 1.09-2.48), p = 0.017). Nearly one fourth of the study population had a delay between two cycles of chemotherapy due to anemia. A median additional cost of Rs 7000 (IQR-Rs 7000 – Rs 14000) was incurred on transfusion.Conclusion: Anemia is a common toxicity associated with dose dense chemotherapy during curative breast cancer treatment leading to delay in treatment and increased cost. Low grade tumor, grade 3 or 4 thrombocytopenia and Grade 2 or higher anemia after 2 cycles of chemotherapy are risk factors for blood transfusions during treatment.

Neoadjuvant chemotherapy with dose dense MVAC is associated with improved survival after radical cystectomy compared to other cytotoxic regimens: A tertiary center experience

Introduction Neoadjuvant chemotherapy has become standard of care for cisplatin-eligible patients with muscle-invasive bladder cancer qualified to radical cystectomy, providing a modest increase in 5-year overall survival rate. Several regimens are being employed for neoadjuvant treatment, largely because of their efficacy in metastatic setting. There is however a scarcity of evidence on the optimal cytotoxic regimen for neoadjuvant chemotherapy. Objectives We evaluated the efficacy of different protocols of neoadjuvant chemotherapy amongst patients who underwent radical cystectomy at our institution. Methods This is a single-center, retrospective, observational study including a cohort of 220 patients who underwent radical cystectomy between 2014 and 2020. The neoadjuvant chemotherapy cohort included 79 patients and was compared to the cohort of historical controls including 141 patients operated prior to routine administration of neoadjuvant chemotherapy and those who opted for upfront surgery. Results Administration of neoadjuvant chemotherapy decreased the risk of overall and cancer-specific mortality HR = 0.625 (95% CI 0.414–0.944), p = 0.025 and HR = 0.579 (95% CI 0.348–0.964), p = 0.036. Rates of downstaging, complete responses, lymph node metastasis, extravesical extension and positive surgical margins significantly favored neoadjuvant chemotherapy. Out of cytotoxic regimens, dose-dense MVAC and gemcitabine-cisplatin were similarly efficacious providing 46.9% and 50% of downstaging to <ypT2N0 respectively, including 30.6% and 25% of complete remissions. However, only dose-dense MVAC was associated with reduction of all-cause and cancer specific mortality risk HR = 0.385 (95% CI 0.214–0.691) p = 0.001 and HR = 0.336 (95% CI 0.160–0.703), p = 0.004 respectively. Conclusions Our study implies that neoadjuvant chemotherapy with subsequent radical cystectomy provides significant improvement over upfront surgery in locoregional control and long-term prognosis of muscle-invasive bladder cancer. The urologic community should strive to maximize utilization of neoadjuvant chemotherapy, yet further research, including randomized control trials, is needed to validate superiority of dose-dense MVAC as the preferred regimen for cisplatin-eligible patients.