Anthracycline-free or short-term regimen as adjuvant chemotherapy for operable breast cancer: A phase III randomized non-inferiority trial.

BACKGROUND: De-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: It is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1-3N+ or pT2-3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P. FINDINGS: Included in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45-57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79-1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75-1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar. INTERPRETATION: Both TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects. FUNDING: This work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).

Phase II study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA.

OBJECTIVE: Apatinib is an oral TKI targeting VEGFR-2. Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated mBC. Oral vinorelbine also holds promise as a treatment of choice in patients with mBC. This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated mBC. In addition, we detected gene variants in ctDNA to explore the therapeutic implications. METHODS: This study enrolled patients with HER2-negative mBC who were pretreated with anthracycline/taxanes. Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1, 8, and 15 of every cycle (3 weeks). The primary endpoint was PFS. The secondary endpoints were ORR, CBR, OS, and safety. Patients eligible for ctDNA detection were evaluated before and during treatment. RESULTS: Forty patients were enrolled. The median PFS was 5.2 months (95% CI, 3.4-7.0 months), and the median OS was 17.4 months (95% CI, 8.0-27.0 months). The ORR was 17.1% (6/35), and the CBR was 45.7% (16/35). The most common AEs included gastrointestinal reaction, myelosuppression, and hypertension. In 20 patients, ctDNA was detected at baseline and during treatment. A significant difference was found in PFS for undetected vs. detected baseline ctDNA (13.9 months vs. 3.6 months, P = 0.018). CONCLUSIONS: All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative mBC, with acceptable and manageable toxicity profiles. Patients with no gene variant detected and lower variant allele frequencies in ctDNA at baseline showed longer PFS.

Nano-encapsulation of a novel anti-Ran-GTPase peptide for blockade of regulator of chromosome condensation 1 (RCC1) function in MDA-MB-231 breast cancer cells.

Ran is a small ras-related GTPase and is highly expressed in aggressive breast carcinoma. Overexpression induces malignant transformation and drives metastatic growth. We have designed a novel series of anti-Ran-GTPase peptides, which prevents Ran hydrolysis and activation, and although they display effectiveness in silico, peptide activity is suboptimal in vitro due to reduced bioavailability and poor delivery. To overcome this drawback, we delivered an anti-Ran-GTPase peptide using encapsulation in PLGA-based nanoparticles (NP). Formulation variables within a double emulsion solvent evaporation technique were controlled to optimise physicochemical properties. NP were spherical and negatively charged with a mean diameter of 182-277nm. Peptide integrity and stability were maintained after encapsulation and release kinetics followed a sustained profile. We were interested in the relationship between cellular uptake and poly(ethylene glycol) (PEG) in the NP matrix, with results showing enhanced in vitro uptake with increasing PEG content. Peptide-loaded, pegylated (10% PEG)-PLGA NP induced significant cytotoxic and apoptotic effects in MDA-MB-231 breast cancer cells, with no evidence of similar effects in cells pulsed with free peptide. Western blot analysis showed that encapsulated peptide interfered with the proposed signal transduction pathway of the Ran gene. Our novel blockade peptide prevented Ran activation by blockage of regulator of chromosome condensation 1 (RCC1) following peptide release directly in the cytoplasm once endocytosis of the peptide-loaded nanoparticle has occurred. RCC1 blockage was effective only when a nanoparticulate delivery approach was adopted.

Defining the Role of Neoadjuvant Chemotherapy Followed by Surgery in Locally Advanced Cancer Cervix: A Meta-analysis of Phase III Trials.

STUDY OBJECTIVES: This meta-analysis was performed to compare the outcomes between NACT-S and RT for locally advanced cancer cervix. The primary end points were survival benefits. SEARCHING METHOD: The data sources for the search included medline, national library of medicine, and the embase search engines. Inclusion criteria included studies published between 2000 and 2012, and FIGO stages IB2 to IVA. Studies had to be properly randomized, prospective, or retrospective and only phase III. Further, the studies had to be with two arms, including one arm for neoadjuvant chemotherapy then-surgery (NACT-S), and the other arm for radiotherapy (RT). RESULTS: Data were collected from 1171 patients enrolled in seven phase III trials. The 5-year PFS (progression-free survival) for NACT-S and RT were 62 and 45.5 %, respectively. The 5-year OS for NACT-S and RT were 66 and 49 %, respectively. NACT-S was associated with better late toxicities compared to RT. CONCLUSION: NACT-S is a reasonable treatment option for locally advanced cancer cervix. It achieved better results than RT, especially for stages from IB2 to IIB.

Weekly Paclitaxel Versus Three-Weekly Paclitaxel in Recurrent Platinum-Resistant Epithelial Ovarian and Peritoneal Cancers: A Phase III Study.

INTRODUCTION: Treatment of recurrent platinum-resistant ovarian and peritoneal cancers represents a therapeutic challenge. The aim of this Phase III prospective study was to compare the survival benefits, objective response rate, and toxicities among patients treated by weekly paclitaxel with those who underwent three-weekly paclitaxel in recurrent platinum-resistant ovarian and peritoneal cancers. METHOD: Patients with recurrent platinum-resistant ovarian and peritoneal cancer were allocated to receive either weekly paclitaxel (arm 1) at 80 m/m(2) or three-weekly paclitaxel (arm 2) at 175 mg/m(2). RESULTS: Fifty-five patients were enrolled (30 arm 1, 25 arm 2). The mean age was 56.7 years, and the median performance status was 0 (Eastern Cooperative Oncology Group [ECOG]). For arms 1 and 2, the objective response rates were 27% and 16%, the median progression-free survival were 7 and 4.5 months, and the median overall survival were 15.5 and 12.5 months, respectively. Treatments also significantly improved the quality of life. Treatment was associated with mild toxicities, and while neuropathy was slightly higher for weekly paclitaxel over three-weekly paclitaxel, hematological toxicities were significantly lower for the former than the latter. CONCLUSION: Paclitaxel rechallenge showed antitumor activity in recurrent platinum-resistant ovarian and peritoneal cancers. Weekly paclitaxel achieved better results than three-weekly paclitaxel in terms of survival benefits, quality of life, and toxicities.

Metronomic methotrexate and cyclophosphamide after carboplatin included adjuvant chemotherapy in triple negative breast cancer: a phase III study.

BACKGROUND: Despite being chemosensitive, the majority of triple negative breast cancer (TNBC) patients recur. The primary study objectives were to compare disease free survival (DFS), and overall survival (OS) for TNBC after adjuvant chemotherapy, who underwent maintenance metronomic chemotherapy versus no maintenance therapy. METHODS: TNBC patients were eligible for enrolment if they had TNM stages II-III and fit with our inclusion criteria. Patients were assigned to either: group 1, 3 cycles FEC-100 then 3 cycles docetaxel, carboplatin, followed by maintenance metronomic chemotherapy for 1 year; and group 2, 3 cycles FEC-100 then 3 cycles docetaxel. RESULTS: Between November 2008 and December 2014, 158 patients (78 group 1, and 80 group 2) were enrolled. The mean age was 46 years. The median DFS for groups 1,2 were 28 and 24 months, respectively; P value 0.05. The median OS for groups 1,2 were 37 and 29 months, respectively; P values 0.04. Additionally, during the follow-up period, the overall distant metastasis recurrence rates for groups 1,2 were 26% and 37% respectively. Finally, treatment protocol was tolerated well in both groups with mild toxicity profiles. CONCLUSIONS: Extended adjuvant metronomic chemotherapy achieved significant improvement in the survival and was well tolerated.

Obesity Correlation With Metastases Development and Response to First-Line Metastatic Chemotherapy in Breast Cancer.

STUDY OBJECTIVES: To compare breast cancer metastases between obese and nonobese women and to evaluate the effect of first-line metastatic chemotherapy in each group. METHOD: A retrospective study was performed in an educational institute in Ireland. The study consisted of two parts: the first part was a comparative analysis of metastases development in obese (arm A) and nonobese patients (arm B). The second part was a comparison between both arms in relation to their response to first-line metastatic chemotherapy and their survival data. RESULTS: Between 2009 and 2014, we reviewed 118 patients with metastatic breast cancer. All the patients fulfilled our inclusion criteria. In all, 48% of patients were obese and 52% were nonobese. There were no statistically significant differences between the two groups. For arms A and B, the median interval between initial cancer diagnosis and distant metastases development (distant metastases-free survival) was 5.8 versus 7.6 years, respectively (Pvalue 0.04). Earlier visceral (liver and lung) metastases were observed in obese compared to nonobese women (Pvalues were 0.05 and 0.04, respectively). The most commonly used chemotherapy was weekly paclitaxel. Our treatments showed significantly better treatment response and better survival results in nonobese women than in obese ones, who were premenopausal with performance state 2, pathological grade 3, and four or more positive lymph nodes. CONCLUSION: Obesity is linked with visceral metastases development, especially lung and liver metastases. Furthermore, first-line metastatic chemotherapy achieved better results in nonobese patients.

For Stage II Node-Positive Breast Cancer, is it Worthwhile to Consider Adjuvant Radiotherapy Following Mastectomy?

PURPOSE: To evaluate overall survival (OS), progression-free survival (PFS), loco-regional recurrence (LRR), and toxicities for early breast-cancer patients with one to three positive axillary lymph nodes, by the addition of radiotherapy to adjuvant chemotherapy. PATIENTS AND METHODS: Patients were eligible for enrollment into the study if they had pathologically proven stages II breast cancer, with one to three positive axillary lymph nodes. Patients were assigned to one of the two groups; Group 1; adjuvant chemotherapy then radiotherapy, and group 2; adjuvant chemotherapy only. RESULTS: Between September 2008 and August 2014, 75 patients were enrolled. Forty patients group 1, and 35 group 2. The 4-year OS for group 1, and two were 77.5 and 71.4%, respectively. The 4-year PFS for group 1 and 2 were 72.5 and 60%, respectively. During the 54 months follow-up period, 11 patients from group 1 had recurrence (three locoregional, seven metastatic, and one both), and 14 patients from group 2 had recurrence (seven locoregional, three metastatic, and four both). The distant metastasis rate was the same in the two groups. However, the metastasis sites were different in the two groups. CONCLUSION: The addition of radiotherapy in stage II breast cancer with one to three positive lymph nodes improved the PFS, and LRR. Radiotherapy improved OS in patients with high-risk features.

Phase II trial of temozolomide and reirradiation using conformal 3D-radiotherapy in recurrent brain gliomas.

PURPOSE: This phase II trial was designed to assess the response rate, survival benefits and toxicity profile of temozolomide, and brain reirradiation using conformal radiotherapy (RT) for treatment of recurrent high grade glioma. DESIGN: Open-label phase II trial. PATIENTS: Twenty-nine patients had been enrolled in the study between February 2006 and June 2009. Patients had to show unequivocal evidence of tumour recurrence on gadolinium-enhanced magnetic resonance imaging (MRI) after failing conventional RT with or without temozolomide and surgery for initial disease. Histology included recurrent anaplastic astrocytoma, glioblastoma multiforme. INTERVENTIONS: Patients were treated by temozolomide at a dose of 200 mg/m(2)/day for chemonaïve patients, and at a dose of 150 mg/m(2)/day to previously treated patients, for 4-5 cycles. Then, patients underwent reirradiation by conformal RT at a dose of 30-40 Gy by conventional fractionation. MAIN OUTCOME MEASURES: The primary end point of the study was response. The secondary end points included survival benefit. RESULTS: All the 29 patients were treated with temozolomide and reirradiation. Two patients achieved complete remission (CR), 4 achieved partial remission (PR), with an overall objective response rate of 20.6%, and further 10 patients had stable disease (SD), with a SD rate of 34.4%. The mean progression free survival (PFS) was 10.1 months, and the mean overall survival (OS) was 11.4 months. Additionally, treatment significantly improved quality of life (QOL). Treatment was tolerated well with mild grade 1, 2 nausea/vomiting in 40% of cycles, and mild grade 1, 2 haematological toxicities (neutropenia/thrombocytoprnia) in 8.6% of cycles. CONCLUSIONS: Temozolomide and conformal RT had an anti-tumor activity in recurrent high grade glioma, and represented a good treatment hope for patients with recurrent brain glioma.

Neoadjuvant chemotherapy versus cystectomy in management of stages II, and III urinary bladder cancer.

PURPOSE: This phase III trial was de - signed to compare the survival benefit, surgical respectability, and toxicities among patients treated by neoadjuvant chemotherapy followed by radical cystectomy (arm A), with those treated by radical cystectomy (arm B) in the management of stage II, III urinary bladder cancer. PATIENTS AND METHODS: For inclusion, patients should have pathologically proven urothelial carcinoma in urinary bladder, clinical stages from T2N0M0 to T4aN0M0, patient age less than 65 years, and performance state ≤ 2. Additionally, patients should have adequate hematological, renal, and liver functions. Arm A patients underwent 3 cycles of neoadjuvant cisplatin and gemcitabine followed by radical cystectomy, while arm B patients underwent radical cystectomy directly. RESULTS: Thirty patients had been enrolled in each arm between September 2009 and April 2014 in 3 educational institutes in Egypt. The 3 year OS (overall survival) for arm A, and B were 60% and 50% respectively. The median OS for arm A was 36+ months and that for arm B was 32.5 months. The 3 year progression-free survival (PFS) for arm A, and B were 57% and 43% respectively. The median PFS for arm A was 36+ months and for arm B was 28 months. A subgroup analysis was performed to correlate between 3 year OS and predetermined prognostic factors including age, tumor size, pathological stage, and the response to neoadjuvant chemotherapy. The later was performed only in arm A. Both treatment arms were tolerated well with mild toxicities profiles. CONCLUSION: Neoadjuvant chemotherapy achieved better survival, surgical respectability, with nearly equivalent toxicities when compared with radical cystectomy.

Temozolomide and Reirradiation in Recurrent Grade II Brain Glioma.

BACKGROUND: This phase II trial was designed to assess the response rate, survival benefits and toxicity profile of temozolomide, and brain reirradiation using conformal radiotherapy (CRT) for recurrent grade II brain glioma. Between February 2006 and June 2009, 18 patients with recurrent low grade glioma, and two with recurrent ependymoma were enrolled in the study. Patients had to show unequivocal evidence of tumor recurrence on gadolinium-enhanced magnetic resonance imaging after failing conventional radiotherapy for initial disease. METHODS: Patients were treated by temozolomide at a dose of 200 mg/m2/day for chemonaive patients, and at a dose of 150 mg/m2/day for previously treated patients, for 4 - 5 cycles. Then, patients underwent reirradiation by CRT at a dose of 30 - 40 Gy by conventional fractionation. RESULTS: All the 20 patients were treated with temozolomide and reirradiation. Two patients achieved complete remission, and six achieved partial remission, with an overall objective response rate of 40%. The mean overall survival (OS) was 16 months (range, 6 - 24 months). The median OS was 15.5 months. Additionally, treatment significantly improved quality of life. Treatment was tolerated well with mild grade 1, 2 hematological toxicities, and nausea/vomiting in 15% and 39% of cycles, respectively. CONCLUSIONS: Temozolomide and CRT had an anti-tumor activity in recurrent grade II brain glioma, and represented a good treatment hope for such patients.

Intestinal absorption and presystemic disposition of sildenafil citrate in the rabbit: evidence for site-dependent absorptive clearance.

Sildenafil citrate is the first oral treatment for erectile dysfunction. Its oral bioavailability is about 40%. This research investigated the intestinal transport parameters of sildenafil citrate in rabbit using an in situ intestinal perfusion technique. This was studied in four different anatomical sites, namely duodenum, jejunoileum, ascending colon and rectum. The results revealed the highest absorptive clearance in the jejunoileum. The values of the permeability area product normalized to segment length (ml/min.cm) were 0.0101, 0.0063, 0.0059 and 0.0023 and those of the percentage absorbed were 68.0, 32.3, 23.0 and 5.0 in jejunoileum, duodenum, ascending colon and rectum, respectively. The values of the length (cm) required for complete absorption were 87.6, 137, 153 and 384 for each anatomical site in the same order. The absorptive clearance did not correlate with the net water flux in the four anatomical regions studied, indicating a mainly passive diffusion mechanism through a transcellular pathway. The plasma sildenafil concentrations achieved during intestinal perfusion experiments and sildenafil total body clearance in the rabbit were used to calculate the fraction of sildenafil that reached the systemic circulation relative to the amount that disappeared from the intestinal segment. Only 34% of sildenafil that disappeared from the intestinal segment appeared in the systemic circulation indicating that the presystemic elimination of sildenafil is 66%. These results confirm that the incomplete bioavailability of sildenafil is mainly due presystemic elimination.