Dose-dense Regimen Research Articles

Abstract OT2-22-02: Sequencing of anthracyclines and taxanes during neoadjuvant therapy of locally advanced HER2-negative breast cancer (NEOSAMBA Study/LACOG 0419)

Abstract Background: Breast cancer (BC) is the most frequent cancer in women in Brazil, with more than 60,000 cases estimated annually. Forty percent of patients present with stages III and IV and neoadjuvant chemotherapy (NACT) remains the mainstay of treatment for locally advanced breast cancer (LABC). Taxanes usually follow anthracyclines in breast cancer neo/adjuvant treatment, likely because of their later introduction into clinical practice. However, the potential impact of alternative sequencing remains to be studied. A single-center phase II randomized clinical trial conducted in the Brazilian National Cancer Institute showed an improvement in overall survival with taxane-first compared with anthracycline-first sequencing in HER2-negative LABC (Bines J et al, The Oncologist 2020). As a taxane-before-anthracycline sequence carries neither an incremental cost nor increased toxicity, the optimal sequencing of these agents could have significant implications for clinical practice. To confirm this finding, we are currently conducting a multicenter randomized phase III trial comparing a taxane followed by an anthracycline-based regimen with the reverse sequence in the neoadjuvant setting. Trial Design: This randomized, open-label, phase III trial will be conducted in 15 research centers in Brazil. It was approved by the local ethics committee in 2020 and is registered in Clinicatrials.gov with the identifier NCT04540692. Women with HER2-negative LABC are randomized in a 1:1 ratio to anthracycline-before-taxane (AC-T arm) or taxane-before-anthracycline (T-AC arm), stratified by hormone receptor status (positive vs. negative) and axillary lymph node status (N0 vs. N+). The anthracycline-based therapy recommended in this trial is AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) every three weeks for four cycles, whilst the taxane-based therapy is either weekly paclitaxel 80 mg/m2 weekly for 12 weeks, paclitaxel 175 mg/m2 every three weeks, or docetaxel 75-100 mg/m2 every three weeks. The use of carboplatin concomitantly with taxane for triple-negative tumors and dose-dense regimens is allowed following institutional guidelines. Further therapies (surgery, radiotherapy, and endocrine therapy) are performed according to the physicians’ discretion. Tumor samples are collected and stored for translational studies. Eligibility: Inclusion criteria: women ≥18 years of age; histologically confirmed HER2-negative breast cancer (by ASCO/CAP guidelines); stage ≥ IIB (if TNBC) or ≥ III (if HR-positive); PS ECOG 0-2 and adequate organ function. Exclusion criteria: previous use of anti-cancer therapies; bilateral BC and pregnancy. Specific Aims: The primary objective is invasive disease-free survival (iDFS). Secondary objectives include pathological complete response (pCR) rates, overall survival (OS) and safety. Statistical Methods: Considering an unicaudal type I error of 0.05, a type II error of 0.2, and an estimated iDFS of 50% in 5 years in the control arm, a total of 227 evaluable patients should be included per arm to demonstrate a HR of 0.7 favoring the taxane-first arm. Estimating a dropout rate of 10%, 494 patients will need to be included in the study. Present Accrual and Target Accrual: A total of 9 sites of 15 planned are activated. The first patient was enrolled on January 12, 2021, and as of June 24, 2022, a total of 113 patients have been accrued. The target goal of 494 patients is expected to be achieved by 2025 and initial study results will be reported by 2026. Funding: Brazilian Health MInistry, Programa Nacional de Apoio à Atenção Oncológica (PRONON), NUP 25000.183207/2019-50. Acknowledgements: CURA Project, SAS. Citation Format: Tomás Reinert, Cristiano P. Souza, Pedro Liedke, Gustavo Werutsky, Laura Testa, Vivian Antunes, Carlos Barrios, Vivian Vasconcelos, Heloísa Resende, Geraldo Silva Queiroz, Gisah Guilgen, Yeni Nerón, Lilian Arruda Bastos, Sabina Aleixo, Daniel Cubero, Maria Cristina F. Magalhães, Ana Coradazzi, Daniela Galvão B. de Oliveira, João S. Nunes, Rafaela G. Jesus, Gustavo Gössling, José Bines. Sequencing of anthracyclines and taxanes during neoadjuvant therapy of locally advanced HER2-negative breast cancer (NEOSAMBA Study/LACOG 0419) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-22-02.

Treatment outcomes of neoadjuvant chemotherapy with dose-dense AC-T regimen for patients with stage II, III breast cancer

Objective: To evaluate the treatment outcomes of neoadjuvant chemotherapy with dose-dense AC-T (dd AC-T) regimen on stage II, III breast cancer (BC) patients, and to assess several clinical and subclinical factors associated with treatment response in these patients. Subject and method: This was a cross-sectional, prospective study with longitudinal follow-up, no control group. The study was conducted on 44 stage II, III BC patients receiving NAC with dd AC-T regimen at Department of General Oncology, Institute of Oncology, 108 Military Central Hospital from June 2018 to August 2022. Result: After receiving NAC, CEA, CA15-3 mean concentrations and tumor size decreased statistically (p<0.05). Regarding clinical response according to RECIST ver 1.1 criteria, the overall response rate (ORR) was 97.7%, in which the complete response (CR) rate accounted for 36.4%. All patients underwent surgery after receiving NAC. The rate of pathological complete response (pCR) was 31.8%. Several factors associated with treatment response include: Tumor size, skin involvement status, TNM stage, histopathology grade (p<0.05). Patients achieving clinical CR had a higher rate of pCR than the other group (p<0.001). Conclusion: NAC with ddAC-T regimen in treatment for stage II, III BC patients resulted in high clinical and pathological response. As a result, this is a good NAC option for these patients. Several factors associated with response include: Tumor size, skin involvement status, TNM stage, histology grade. Patients achieving clinical CR had a higher rate of pCR than the other group.

Early Primary Gastric Lymphoma with Adverse Prognosis Factors. Is it Benefit Adding Rituximab to CHOP-14?

Objective: Assess if the addition of rituximab to a dose-dense chemotherapy regimen in patients with primary gastric diffuse large B-cell lymphoma (PGL) in early stage, but, associated with worse prognostic factors. Patients and Methods: Patients with pathological diagnosis of PGL and early stages, but, with elevated levels of beta 2 microglobulin and lactic dehydrogenase, age > 18 years age without upper limit, no gender differences, previously untreated, were recruit in an open label clinical trial, to received CHOP-14 (cyclophosphamide, vincristine, doxorubicin and prednisone, dose dense, every 14 days) and compare with patients that received R-CHOP14 (rituximab + CHOP-14). Results: Between March 2011 to December 2016, 141 patients were taken entry to the study: no statistical differences were observed in clinical and laboratory characteristics. Complete response (CR) was observed in 68 out of 72 (94.4%) patients in the CHOP-R14, and 67 out of 69 (95.1%) patients in the CHOP14 regimen. Actuarial curves at 5-years show that progression-free survival (PFS) was 89% (95%Confidence Interval (CI) in the CHOP-R14, that did not have statistical differences in the CHOP-14 arm: 92% (95%CI: 83% -97%) (p 0.887); the overall survival were: 90% (95% CI:86%-97%) and 93.4% (95% CI: 86% to 97%) (p 0,665). Toxicities were severe granulocytopenia and infection-related, but no dead were observed. Until now, late toxicities as acute leukemia, second neoplasms and cardiac damage has not been observed. Conclusion: The use of dose dense regimen (CHOP-14) confirm that is useful in the treatment of PGL associated to worse prognosis factors, the addition of rituximab did not show any benefit.

Poor Prognosis of Diffuse Large B-Cell Lymphoma of the Breast: The Role of Dose-Dense Chemotherapy

Background: The aim of the study was to define if the use of an intensive regimen (dose-dense) of chemotherapy may improve response rate and outcome in patients with primary breast lymphoma (PBL), whose is considered as lymphoma presentation with an worse prognosis. Methods: Patients with pathological confirmed diagnosis of diffuse large B-cell lymphoma with clinical presentation on breast (PBL) , > 18 years old, stage I and II, negative for immunodeficient syndrome, hepatitis A and B, previously untreated , with non-germinal center cell, were included in a open label clinical trial, phase II, were allocated to received an dose dense regimen of CHOP (cyclophosphamide , doxorubicine, vincristine and prednisone) Results: Between July 2006 to December 2016, seventy eight patients were enrolled in the study. Complete response was achieved in 76 (94.4%), patients. Five patients relapse , thus progression free survival at 5 years was 94.0% (95 % Confidence interval (CI): 87% to 98%%): three patients achieved a second response and are alive, overall survival at 5-years was : 95.3 (96%CI: 89% to 102%).Relapse at central nervous system has not been observed. Severe granulocytopenia was observed in 42.8 (93.0%) cycles, but no death associated to treatment were observed. Conclusion: The use a dose-dense regimen of chemotherapy improve outcome in this setting of patients; although severe acute toxicities were frequent , it well controlled. Relapse in central nervous system has not been observed. Thus, we considered that dose-dense chemotherapy will be employed in this setting of patients.

Short-term preoperative endocrine therapy allows to estimate and revert patient prognosis with further treatment plan correction in HR+ HER2- early breast cancer patients.

e12628 Background: The anomaly function of ER/PR-dependent molecular cascade is a key driver of ER-positive HER2-negative breast cancer (HR+ HER2- BC) progression. Ki67>10% and/or grade 3 (G3) determine the initial poor patient (pts) prognosis in this group. The short-term pre-operative endocrine therapy (P-ET) simply allows to look ahead to properly the further adjuvant therapy (AT) and to estimate the endocrine therapy (ET) sensibility of each pts in the routine clinical practice. The existing diagnostic methods weaknesses for the baseline lymph nodes invasion, high BC heterogeneity do not allow to accurately estimate the disease stage and tumor phenotype, respectively, with 100% accuracy before surgery. In addition to pre-ET the post-operative IHC is a base method for further pts treatment plan especially for high heterogenicity breast tumors. Our study is focused on pts proportion estimation with P-ET benefit or tumor phenotype reversion in patients with early HR+ HER2- BC. Methods: HR+ HER2- BC pts stages I-II any level of Ki67 independent from grade have received P-ET (letrozole (L)/anastrozole (A)/tamoxifen (TAM)) no less than 2 weeks until surgery in MCSC named after A.S. Loginov. Enrollment period runs from Jun’21 and will end with 1,000 pts. The primary goal of the study was pts’s proportion evaluation with baseline Ki67>10% who experienced suppression of the proliferation marker to 10% or less and/or phenotype change during P-ET followed by AT strategy amendment. Results: At the data cut-off (Jan’22) 832 pts (5 pts were men) with HR+ HER2- BC were enrolled (IIT population) with median age 61 (range:26-85) and ECOG 0-2. 736 (89%) pts have baseline Ki67>10% of whom 100 (14%) pts - with G3, 291 (35%) pts - with baseline Ki67≥30%. Tumors of the 398 (54%) pts suppressed proliferation marker Ki67≤ 10% and 352 (88%) pts among them avoid planned adjuvant chemotherapy followed by ET prolongation independent of ET type (L/A/TAM). The median time of P-ET amounted to 39,5 days (range: 14-90) in focused group. Post-operative evaluation of specimens in 20 (2,4%) pts have resulted in the identification of phenotype change to HER2+ BC and TNBC with subsequent modification of AT decisions (including anti-HER2-based and/or dose dense regimens). Conclusions: In HR+ HER2- early BC pts short-term P-ET simply allows to estimate pts prognosis and further AT strategy proper planning: to identify the pts population of whom CT can be avoided while maintaining treatment efficacy with a better quality of life (42% pts of IIT) (1), to radically change the planned AT to achieve optimal treatment results (2,4% pts of IIT) (2).

Bevacizumab in first-line chemotherapy to improve the survival outcome for advanced ovarian clear cell carcinoma: A multicenter, retrospective analysis.

5502 Background: Advanced ovarian clear cell carcinoma (ACCC, stage III/IV disease) is a rare tumor characterized by chemoresistance. Bevacizumab (Bev) was approved in November 2013 in Japan and became incorporated in the treatment of advanced ovarian cancer. However, the efficacy of Bev against ACCC remain unknown. We investigated the survival outcomes for ACCC, following first-line chemotherapy with or without Bev. Methods: Patients diagnosed with ACCC at seven institutions between 2008 and 2018 were enrolled in this study. Patients underwent cytoreductive surgery and taxane-carboplatin chemotherapy (78: triweekly regimen; 30: weekly regimen; 25: dose-dense regimen; 12: others) with or without concurrent and maintenance Bev (15 mg/kg/3 weeks). We compared the progression-free survival (PFS) and overall survival (OS) before (group A, n = 102) and after (group B, n = 43) Bev approval, using Kaplan–Meier method and Cox regression model. We excluded patients with poor performance status (PS) in group A, and patients who did not receive Bev due to poor PS or thrombosis in group B. Results: There was no significant difference between two groups in terms of age (p = 0.135) and initial CA125 level (p = 0.674). Thirteen (13%) and 11 (26%) patients had stage IV disease (p = 0.058) and 2 (3%) and 7 (16%) patients were of poor PS (PS ≥2) (p = 0.004) in group A and B, respectively (p = 0.058). More patients (29/43, 67%) in group B were achieved complete resection than in A group (52/102, 51%) (p = 0.068). The median cycle of Bev in B group was 16 (interquartile range: 6-21). The median follow-up time was 36 months. The median PFS increased from 12.5months in A group to 29.7 months in B group (log-rank test: p = 0.023, Wilcoxon test: p = 0.006). The median OS increased from 34.7 months in A group to 51.4 months in B group (log-rank test: p = 0.085, Wilcoxon test: p = 0.027). Multivariate analysis revealed that Bev use (Hazard ratio (HR): 0.54, p = 0.011; HR: 0.54, p = 0.019), PS <2 (HR: 0.33, p = 0.013; HR: 0.29, p = 0.006) and completeness of resection (HR: 0.38, p < 0.001; HR: 0.37, p <0.001) were independent prognostic factors for PFS and OS. Conclusions: Incorporating Bev in first-line chemotherapy may improve PFS in patients with ACCC. [Table: see text]

The efficacy and safety of apatinib combined with paclitaxel and carboplatin dose-dense regimen in neoadjuvant therapy for locally advanced triple-negative breast cancer.

e12602 Background: Triple negative breast cancer (TNBC) has the traits of early onset, high malignancy and no effective molecular targets to act on, neoadjuvant chemotherapy is recommended as the preferred treatment for locally advanced TNBC with highly recurrence risk. The addition of platinum-based agents to conventional taxanes regimens in locally advanced TNBC can significantly improve pathological complete response (pCR) rate. Anti-angiogenic drugs are currently one of the few targeted therapies that have achieved efficacy in TNBC. Apatinib, an inhibitor of VEGFR2, shows significant antitumor activity in the patients with breast cancer. Methods: Pathologically confirmed TNBC patients with clinical stage I-IIIC (per AJCC 8th ed) with no previous surgery or radio-chemotherapy treatment were enrolled in our center from September 2018 to June 2020. Enrolled patients received 4-8 neoadjuvant treatment cycles of apatinib 250mg per day + paclitaxel 175mg/m2 d1 + carboplatin AUC = 4 d2 q14d (Apa+TC), followed by sequential surgery. Enrolled patients who underwent surgery were matched with TNBC patients received paclitaxel and carboplatin intense regimen (TC) contemporarily in our center by propensity score matching (PSM). pCR in breast and axilla (ie. ypT0/Tis ypN0) was the primary endpoint. Objective response rate (ORR), disease control rate (DCR), event-free survival (EFS), overall survival (OS) and adverse events (AEs) are secondary endpoints. Results: 25 locally advanced TNBC patients were enrolled for neoadjuvant therapy of Apa+TC. In radiological evaluation, 2 patients achieved CR, 20 patients achieved PR, 3 patients achieved SD, which indicated an ORR of 88% and a DCR of 100%. 23 of 25 enrolled patients underwent surgery, with a pCR rate of 60.87% (95%CI: 38.54%-80.29%). 69 patients who were treated by TC before surgery were matched by PSM based on baseline stage T and stage N features. A significant higher pCR rate was achieved in Apa+TC arm compared with TC alone (60.87% vs. 30.43%, respectively, P = 0.009). Similar incidence of AEs was observed between two arms. The main AEs were hematologic toxicities fatigue, digestive canal symptoms, transaminase elevation and peripheral neurotoxicity in Apa+TC arm. Grade III-IV AEs included granulocytopia (14/25), thrombocytopenia (4/25), anaemia (3/25), fatigue (1/25), hypertension (1/25) and arrhythmia (1/25). Meanwhile, apatinib-related AEs, including hypertension, proteinuria, and hand-and-foot syndrome, were mild. Due to the limited time, the survival follow-up is still in progress. Conclusions: Apatinib combined with paclitaxel and carboplatin intensive regimen achieved a better efficacy and manageable adverse events in neoadjuvant chemotherapy for locally advanced TNBC, which might be a promising strategy in the treatment of locally advanced TNBC. Clinical trial information: NCT03735082.

Impact of the COVID-19 Pandemic on Breast Cancer Management in Portugal: A Cross-Sectional Survey-Based Study of Medical Oncologists.

IntroductionCancer care providers have faced many challenges in delivering safe care for patients during the COVID-19 pandemic. This cross-sectional survey-based study investigated the impact of the pandemic on clinical practices of Portuguese medical oncologists caring for patients with breast cancer.MethodsAn anonymous online survey comprising 42 questions gathered information regarding COVID-19 testing, treatment in (neo)adjuvant and metastatic settings, and other aspects of breast cancer management. Practices before and during the pandemic were compared, and potential differences in outcomes according to respondents’ regions, case volumes, and practice type were explored.ResultsOf 129 respondents, 108 worked in the public health system, giving a representative national picture of the impact of the COVID-19 pandemic on breast cancer management. Seventy-one percent of respondents reported a reduction in visits for new cases of breast cancer, and there was a shift towards increased use of telemedicine. Clinical decision-making was largely unaffected in the most aggressive indications (i.e., triple-negative, HER2-positive, visceral crisis). The use of neoadjuvant therapy increased when access to surgery was difficult, whereas dose-dense regimens decreased, and cyclin-dependent kinase 4/6 inhibitor treatment decreased for less aggressive disease and increased for more aggressive disease. The use of oral formulations and metronomic chemotherapy regimens increased, and clinical trial participation decreased. Some differences by respondents’ region and case volume were noted.ConclusionMedical oncologists in Portugal implemented many changes during the COVID-19 pandemic, most of which were logical and reasonable responses to the current healthcare emergency; however, the true impact on patient outcomes remains unknown.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40487-022-00191-7.

Efficacy and survival outcomes of dose-dense carboplatin plus paclitaxel as neoadjuvant chemotherapy for triple-negative breast cancer

Objective: To evaluate the efficacy and survival outcomes of dose-dense (biweekly) carboplatin plus paclitaxel (PC) as neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC), and to explore an optimal neoadjuvant chemotherapy regimen for TNBC. Methods: Patients diagnosed as TNBC(cT1-4N0-3M0) in Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College Between January 2008 and September 2018 who received dose-dense PC and standard 3-weekly PC as NAC were 1∶1 matched using propensity score matching (PSM) to compare the efficacy, safety and survival outcomes. Results: One hundred of TNBC patients were enrolled (50 patients were divided in dose-dense group, 50 patients in standard group). The objective response rate (ORR) of dose-dense group and standard group were both 90.0% (45/50). The grade 3-4 neutropenia in dose-dense group was less than that of standard group (32.7% vs. 68.0%, P=0.001), while the rate of ALT/AST elevation in dose-dense group was higher than that of standard group (57.1% vs. 32.0%, P=0.012). The pathological complete response (pCR) rates were 34.0% (17/50) in dose-dense group and 38.0% (19/50) in standard group, without statistically significance (P=0.677). The median follow-up time was 55 months (3-150 months). The 5-year recurrence-free survival (RFS) in dose-dense group and standard group were 83.5% and 75.2%, respectively the 5-year overall survival (OS) in dose-dense and standard group were 87.9% and 84.5% the difference were not statistically significant (P=0.322 and 0.647, respectively). Patients with residual disease (tumor size≥1 cm or lymph node positive) had poor prognosis, the 5-year RFS and OS were 59.3% and 68.5%, respectively. Conclusions: Dose-dense PC has similar efficacy with standard 3-weekly PC and has a good safety profile. Since dose-dense regimen can shorten the duration of therapy, it can be an alternative in TNBC.

First Person Profile: Clifford Hudis, MD: The chief executive officer of the American Society of Clinical Oncology previously had an esteemed career as a physician-scientist and executive at the Memorial Sloan Kettering Cancer Center's Breast Medicine Service: The chief executive officer of the American Society of Clinical Oncology previously had an esteemed career as a physician-scientist and executive at the

First Person Profile: Clifford Hudis, MD: The chief executive officer of the American Society of Clinical Oncology previously had an esteemed career as a physician-scientist and executive at the Memorial Sloan Kettering Cancer Center's Breast Medicine Service: The chief executive officer of the American Society of Clinical Oncology previously had an esteemed career as a physician-scientist and executive at the

Real-life Experience With Rituximab-CHOP Every 21 or 14 Days in Primary Mediastinal Large B-cell Lymphoma.

Primary mediastinal large B-cell lymphoma (PMLBCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL), whose prognosis has greatly improved since the incorporation of the anti-CD20 monoclonal antibody rituximab into current therapeutic regimens. Evidence, however, on the optimal time interval between consecutive chemoimmunotherapy (CIT) cycles is still scarce. This study aimed to evaluate the efficacy outcomes of the more commonly administered 3-weekly regimens to the biweekly ones in a PMLBCL patients' population, who were mostly treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP-21) or R-CHOP-14. We retrospectively studied our cohort of consecutively treated PMLBCL patients, focusing on their treatment density, in order to determine possible differences in treatment outcomes. CIT, in the form of both R-CHOP-21 as well as R-CHOP-14 (or similar regimens), is highly active in PMLBCL, with low rates of early treatment failure. In our cohort of patients, R-CHOP-14 did not result in a meaningful improvement of freedom from progression (FFP) or overall survival (OS). Both R-CHOP-14 and R-CHOP-21 are probably equally effective in PMLBCL, yet further, prospective, randomized studies are warranted to clarify whether dose-dense regimens can be associated with better disease control and long-term results.

Low Intensity Ultrasound as an Antidote to Taxane/Paclitaxel-induced Cytotoxicity.

The taxane family of compounds, including Taxol/paclitaxel and Taxotere/docetaxel, are surprisingly successful drugs used in combination or alone for the treatment of most major solid tumors, especially metastatic cancer. The drugs are commonly used in regimen with other agents (often platinum drugs) as frontline treatment, or used as a single agent in a dose dense regimen for recurrent cancer. The major side effects of taxanes are peripheral neuropathy, alopecia, and neutropenia, which are grave burden for patients and limit the full potential of the taxane drugs. Especially in the current treatment protocol for peripheral neuropathy, taxane dosage is reduced once the symptoms present, resulting in the loss of full or optimal cancer killing activity.Substantial efforts have been made to address the problem of cytotoxic side effects of taxanes, though strategies remain very limited. Following administration of the taxane compound by infusion, taxane binds to cellular microtubules and is sequestered within the cells for several days. Taxane stabilizes and interferes with microtubule function, leading to ultimate death of cancer cells, but also damages hair follicles, peripheral neurons, and hemopoietic stem cells. Currently, cryo-treatment is practiced to limit exposure and side effects of the drug during infusion, though the effectiveness is uncertain or limited.A recent laboratory finding may provide a new strategy to counter taxane cytotoxicity, that a brief exposure to low density ultrasound waves was sufficient to eliminate paclitaxel cytotoxicity cells in culture by transiently breaking microtubule filaments, which were then relocated to lysosomes for disposal. Thus, ultrasonic force to break rigid microtubules is an effective solution to counter taxane cytotoxicity. The discovery and concept of low intensity ultrasound as an antidote may have the potential to provide a practical strategy to counter paclitaxel-induced peripheral neuropathy and alopecia that resulted from chemotherapy.Taxanes are a class of important drugs used in chemotherapy to treat several major cancers. This article reviews a new laboratory discovery that ultrasound can be used as an antidote for the peripheral cytotoxicity of taxane drugs and discusses the potential development and application of low intensity ultrasound to prevent side effects in chemotherapeutic treatment of cancer patients.

KẾT QUẢ SỐNG THÊM KHÔNG BỆNH VÀ MỘT SỐ YẾU TỐ LIÊN QUAN TRÊN BỆNH NHÂN UNG THƯ VÚ BỘ BA ÂM TÍNH ĐƯỢC HÓA TRỊ BỔ TRỢ TRƯỚC 4AC-4T LIỀU MAU TẠI BỆNH VIỆN K

Objectives: Evaluation of disease-free survival and analysis of some additional factors related to disease-free survival in triple negative breast cancer patients who were treated with neoadjuvant by dose dense 4AC-4T regimen. Method: Retrospective, descriptive study on 48 patients in stage II and III, triple negative breast cancer, were treated with neoadjuvant dose-dense 4AC-4T regimen at National Cancer Hospital. Result: Triple-negative breast cancer (TNBC) is most common in the age group 30-49 years old, accounting for 69, the incidence of patients had stage II and stage III disease were 12,5% and 87,5% respectively. The pathological complete response rate (pCR) with neoadjuvant treatment was 47,9%. The results of long-term follow-up showed that the 12-month and the 36-month progression-free survival rate were 85,2% and 82,9% respectively. Progression-free survival was higher in the group of patients who achieved complete response on histopathology than in the group of patients who did not achieve complete response on histopathology and the group of patients with tumor size < 5 cm higher than remaining, p>0.05. The majority of patients had metastasis recurrence in the first 2 years, most of the metastatic sites were visceral (liver, lung) accounting for 83.3%, one patient with bone metastases, and no cases of the chest wall or lymph node recurrence were recorded. Conclusion: In patients with triple negative breast cancer, dose-dense 4AC-4T regimen in neoadjuvant settting yielded high clinical response rates and provided a feasible and safe short-duration. Keywords: Dose-dense 4AC-4T neoadjuvant chemotherapy, triple negative breast cancer

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.

Dose-Dense Docetaxel versus Weekly Paclitaxel following Dose-Dense Epirubicin and Cyclophosphamide as Adjuvant Chemotherapy in Node-Positive Breast Cancer Patients: A Retrospective Cohort Analysis.

Methods This study included patients from two prospective studies conducted in our institute from April 2007 to March 2009. Ninety-one women with axillary lymph node-positive breast cancer who had received four cycles of dose-dense epirubicin and cyclophosphamide were treated with either weekly paclitaxel (80 mg/m2) for 12 doses or biweekly docetaxel (75 mg/m2) for four cycles. Results After a median follow-up of 88 and 109 months, 11 (23.4%) and 10 (22.7%) patients had experienced disease recurrence (p = 0.16), while 10 (21.3%) and 5 (11.4%) patients had died in the paclitaxel and docetaxel arm, respectively (p = 0.56). No significant difference could be seen in 5-year DFS or OS among groups (HR: 0.58; 95% CI: 0.19–1.81, p = 0.35; HR: 0.58; 95% CI: 0.19–1.81, p = 0.35, respectively). Conclusion In conclusion, both evaluated adjuvant chemotherapy regimens have comparable effectiveness regarding DFS and OS.

600P Final results of phase I/II trial of fractionated dose 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC)

Safety and initial efficacy results of a phase I dose-escalation study of a fractionated (dose-dense) regimen were previously described, without short-term dose-limiting toxicity [ESMO 2019]. Here, we report results of the complete phase I/II study.

A Systematic Literature Review of Overall Survival and Delivered Dose Intensity in Cancer Patients Receiving Chemotherapy and G-CSF in Randomized Control Trials

IntroductionAdvances in cancer diagnosis, treatment and supportive care have contributed to improvements in overall survival (OS) in recent decades. Granulocyte colony-stimulating factor (G-CSF) has been shown to reduce neutropenic complications associated with chemotherapy. G-CSF support may improve disease control and survival by minimizing dose reductions and treatment delays as well as enabling administration of dose-dense regimens, dose escalation and additional chemotherapeutic agents when indicated. With the introduction of biosimilar G-CSFs, the impact of G-CSF on OS reported in recent randomized clinical trials is of considerable interest. We undertook an updatedsystematic literature review to determine the impact of G-CSFon delivered dose intensity and OS in cancer patients receiving chemotherapy for solid tumors or malignant lymphoma.MethodsFollowing our previous review (Lyman G et al, Ann Oncol 2013;24:2475-84), relevant publications between September 1, 2012 and March 20, 2017 were identified according to best-practice principles and reported in compliance with PRISMA requirements. Randomized, controlled trials comparing primary G-CSF support vs no initial G-CSF and reporting survival measures or occurrence of secondary tumors including acute myeloid leukemia [AML] or myelodysplastic syndrome [MDS]) with a minimum follow-up of 24 months were identified. Following the initial treatment cycle, control subjects may have received no G-CSFs, G-CSFs at the discretion of the treating physician, or secondary use of G-CSFs. Exclusion criteria included non-random assignment to the treatment group; G-CSF administered from the start in all study arms; use of granulocyte macrophage colony-stimulating factor; patients receiving stem cell or bone marrow transplantation, or a prior diagnosis of leukemia of any type.Full electronic search was undertaken of of Embase, Medline In-Process and Cochrane libraries. No language restrictions were imposed on the literature search. Abstracts of papers initially identified were evaluated independently by two investigators for eligibility using specified inclusion/exclusion criteria. All potentially relevant papers were evaluated in detail. Bibliographies of all identified relevant studies were used to perform a recursive search. Full papers were assessed independently by two investigators according to the predefined eligibility criteria. Any disagreement between investigators was resolved by discussion.A meta-analysis was conducted to estimate the relative risk (RR) and risk difference for OS between patients who did or did not receive primary G-CSF support. As previously reported, four prospectively-defined study designs reflecting differing dosing schedules were evaluated for impact of primary G-CSF support.Statistical software R was utilized for these analyses.ResultsA total of2604 publications were identified. After removing duplicate reports and further screening, 14 recent studies met the inclusion criteria. Nine studies reported OS and 2 reported incidence of AML/MDS. Sample sizes ranged from 85 to 2091 patients with solid tumors or lymphoma at various stages.The updated meta-analysis showed that OS was significantly improved in patients receiving primary G-CSF vs patients who did not (relative risk [RR] of death during follow-up = 0.92; 95% confidence intervals [CI]: 0.90, 0.95; p<0.0001) [Table]. Study design groups 2, 3 and 4 also had significant RRs favoring G-CSF (see table). Based on the reported and extracted data, it was not possible to make any conclusions regarding OS differences between originator and biosimilar G-CSF formulations.Of the 2 studies evaluating AML/MDS, 1 reported no cases during follow-up in either arm and the other reported 9 occurrences in the G-CSF arm and 2 in the control arm: RR = 1.85; 95% CI: 1.19, 2.88; p=0.0064.ConclusionsResults of this systematic literature review and meta-analysis confirm a modest but statistically significant increase in OS in patients undergoing chemotherapy with primary G-CSF support for solid tumors and lymphoma. [Display omitted] DisclosuresYau:Hexal: Employment. Nakov:Hexal: Employment. Krendyukov:Hexal: Employment.

Clinical study of apatinib plus temozolomide for the treatment of recurrent high-grade gliomas

ObjectivesRecurrent high-grade glioma, a malignant tumor of the brain or spinal cord associated with poor prognosis with a median survival of <6 months. Recurrent high-grade glioma does not have standard treatment even if some strategies have some effect in recurrent gliomas. Apatinib, as a tyrosine kinase inhibitor shown to be effective in treating the lung and gastric cancer. The present study investigated the efficacy and safety of apatinib in combination with dose-dense regimens of temozolomide for treating recurrent glioma. Patients and methodsEighteen patients with recurrent high-grade glioma were enrolled and treated with apatinib (500 mg/day) and TMZ (50 mg/m2/day). Patients who achieved partial response or stable disease continued treatment. Administration of drug was terminated for patients with progressive disease, who could not tolerate toxicity, and who required discontinuation due to other medical conditions. ResultsFrom the 18 cases, only 17 were included in the evaluation of the curative effect of the drug and in that four showed partial responses, ten had stable disease, remaining three exhibited progressive disease. The disease control rate was 82.3% (14/17). Progression-free and overall survival was found to be 4 months and 9.1 months, respectively. Three patients became transiently capable of self-care (Karnofsky performance status >70). Cognition and quality of life improved after treatment and from the safety perspective, three most common adverse reactions included epilepsy (24.1%), hypertension (20.7%), and fatigue (17.2%). ConclusionApatinib and TMZ may represent an alternative treatment option for patients with recurrent high-gradeglioma, especially those with a low Karnofsky performance status. However, studies using a larger sample size are required to confirm these findings.

Comparison of treatment effect and long-term outcomes for pediatric and adult Ewing sarcoma patients in British Columbia, Canada.

11531 Background: Treatment of Ewing Sarcoma (EWS) is challenging. While it is known to be sensitive to chemotherapy and radiation, the number of lines of therapy available are limited. This disease affects pediatric patients (PP) more often than adults (AP), and reported outcomes are worse for AP onset EWS in the literature. It is unclear if this is due to difference in the biology of disease in AP compared to PP, or if this is due to differences in treatment approach. Furthermore, optimal treatments and real world impact of treatment is unclear in both the PP and AP populations. This study identifies the features of therapy received by AP and PP with EWS in a large, mutli-institutional cohort, and provides real world evidence for the expected outcomes in both AP and PP with EWS. Methods: A cohort study analysis of the Sarcoma Outcomes Unit database at BC Cancer was conducted to identify patients diagnosed with EWS in British Columbia from January 1, 2000 to December 31, 2018. Data on the frequency, amount, and regimen of chemotherapy were collected. Baseline Charlson comorbidity index, age at diagnosis, progression free survival and overall survival were collected. Results: 108 patients with EWS were identified, 66 AP and 42 PP Median age at diagnosis for adults was 37 (19-86) and median age for diagnosis of pediatric patients was 14 (1-18). Real world median PFS and OS for AP were 23 mos and 79 mos, and for the PP were 32 mos and NE. Five year overall survival was 54% in AP and 77% in PP. Overall, there was no difference in the number of lines of therapy received between PP and AP, but the type of therapy was more dose-dense in the PP than in the AP, (85% vs 28% for dose dense chemo). 5 year overall survival was longer for PP who received dose dense regimens compared to non-dose dense regimens (HR 0.87), but was not different in the AP receiving dose dense regimens (HR 0.95), even when controlling for comorbidities. The most common chemotherapy regimen for AP was Vincristine, Adriamycin, cyclophosphamide alternating with Ifosfamide and Etoposide q3weeks, whereas in the pediatric population the most common chemotherapy regimen was the same but alternating q2weeks. Conclusions: The treatment plans for PP with EWS were more often dose dense compared to the AP. Outcomes for PP were vastly better than for APs, despite overall similarities in the number of lines of therapy and types of agents used. Given the lack of difference between dose dense and non-dose dense regimens for APs, this is not the likely cause of difference in survival between PPs and APs. Extrapolating pediatric protocols to the adult setting may not be appropriate given the differences in outcomes. Further work to identify effective therapies and predictive biomarkers in this disease are needed, and my further identify reasons for discrepant outcomes in pediatric and adult populations.

Improving early breast cancer treatment: the role of granulocyte colony-stimulating factor

Breast cancer is still the leading cause of death in patients with malignant tumors. Among women with breast cancer, standard combination chemotherapy with anthracyclines and taxanes reduces mortality from this disease by about one third compared to patients not receiving chemotherapy and is the standard for neoadjuvant or adjuvant chemotherapy of breast cancer. Understanding the patterns of tumor growth has made it possible to improve the current paradigms of the treatment of early forms of breast cancer and to use dose-dense chemotherapy regimens to achieve better treatment results. Nowadays, chemotherapy in a dose-dense regimen for breast cancer is the preferred option in all world and Russian clinical guidelines. However, the use of such chemotherapy regimens significantly increases the incidence of side effects, primarily febrile neutropenia. The appearance of more effective methods of supportive care, particularly short-acting and long-acting granulocyte colony-stimulating factor, in clinical practice has made it possible to use dose-dense chemotherapy regimens to increase the effectiveness of the treatment.