Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial.

PURPOSE: Few data are available regarding the influence of adjuvant capecitabine on long-term survival of patients with early breast cancer. METHODS: The Finland Capecitabine Trial (FinXX) is a randomized, open-label, multicenter trial that evaluates integration of capecitabine to an adjuvant chemotherapy regimen containing a taxane and an anthracycline for the treatment of early breast cancer. Between January 27, 2004, and May 29, 2007, 1,500 patients with axillary node-positive or high-risk node-negative early breast cancer were accrued. The patients were randomly allocated to either TX-CEX, consisting of three cycles of docetaxel (T) plus capecitabine (X) followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (CEX, 753 patients), or to T-CEF, consisting of three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF, 747 patients). We performed a protocol-scheduled analysis of overall survival on the basis of approximately 15-year follow-up of the patients. RESULTS: The data collection was locked on December 31, 2020. By this date, the median follow-up time of the patients alive was 15.3 years (interquartile range, 14.5-16.1 years) in the TX-CEX group and 15.4 years (interquartile range, 14.8-16.0 years) in the T-CEF group. Patients assigned to TX-CEX survived longer than those assigned to T-CEF (hazard ratio 0.81; 95% CI, 0.66 to 0.99; P = .037). The 15-year survival rate was 77.6% in the TX-CEX group and 73.3% in the T-CEF group. In exploratory subgroup analyses, patients with estrogen receptor-negative cancer and those with triple-negative cancer treated with TX-CEX tended to live longer than those treated with T-CEF. CONCLUSION: Addition of capecitabine to a chemotherapy regimen that contained docetaxel, epirubicin, and cyclophosphamide prolonged the survival of patients with early breast cancer.

Union is strength: Textbook outcome with perioperative chemotherapy compliance decreases the risk of death in advanced gastric cancer patients.

PURPOSE: Perioperative chemotherapy (POC) in advanced gastric cancer (GC) patients significantly increases the curative resection rate and overall survival (OS). Textbook outcome (TO) represents a composite of surgical quality metrics strongly associated with improved OS. However, the current definition of TO after resection for GC does not include POC. Herein we propose to supplement the current description of TO with an additional feature, POC compliance. The present study aimed to evaluate prognostic impact of thus defined textbook oncological outcome (TOO) among patients undergoing gastrectomy for advanced GC. PATIENTS AND METHODS: We collected data from a prospectively maintained database of all patients operated for GC between 2010 and 2020 in our institution. Patients with histologically confirmed and resectable advanced GC but without distant metastases, in whom multimodal treatment was planned by institutional MDT were included. RESULTS: A total of 194 patients were analyzed. In the multivariate analysis, patients with TOO had a 50 % lower risk of death than patients without TOO (medians: NR vs 42 months; HR = 0.50, p = 0.0109). Patients treated with POC had a 43 % lower risk of death than patients treated with only preoperative chemotherapy (medians: 78 vs 33 months; HR = 0.57, p = 0.0450). Patients with a pathological response (PR) in the primary tumor had a 59 % lower risk of death than patients without PR (medians: NR vs 36 months; HR = 0.41, p = 0.0229). POC combined with TO surgery significantly decreased the risk of death in advanced GC patients (medians: NR vs 42 months; HR = 0.35, p = 0.0258). CONCLUSION: Since TOO is associated with improved survival, it may serve as a multimodal treatment quality parameter in patients with advanced GC.

RGD-targeted redox responsive nano micelle: co-loading docetaxel and indocyanine green to treat the tumor.

Cancer, also known as a malignant tumor, has developed into a type of disease with the highest fatality rate, seriously threatening the lives and health of people. Chemotherapy is one of the most important methods for the treatment of cancer. However, chemotherapy drugs have some problems, such as low solubility and lack of targeting, which severely limit their clinical applications. To solve these problems, we designed a block copolymer that has a disulfide bond response. The polymer uses RGD peptide (arginine-glycine-aspartic acid) as the active targeting group, PEG (polyethylene glycol) as the hydrophilic end, and PCL (polycaprolactone) as the hydrophobic end. Then we utilized the amphiphilic polymer as a carrier to simultaneously deliver DOC (docetaxel) and ICG (indocyanine green), to realize the combined application of chemotherapy and photothermal therapy. The antitumor efficacy in vivo and histology analysis showed that the DOC/ICG-loaded micelle exhibited higher antitumor activity. The drug delivery system improved the solubility of DOC and the stability of ICG, realized NIR-guided photothermal therapy, and achieved an ideal therapeutic effect.

Active Tumoral/Tumor Environmental Dual-Targeting by Non-Covalently Arming with Trispecific Antibodies or Dual-Bispecific Antibodies on Docetaxel-Loaded mPEGylated Nanocarriers to Enhance Chemotherapeutic Efficacy and Minimize Systemic Toxicity.

PURPOSE: This study was aimed at developing the trispecific antibodies (anti-EGFR/anti-FAP/anti-mPEG, TsAb) or dual bispecific antibodies (anti-EGFR/anti-mPEG and anti-FAP/anti-mPEG) docetaxel (DTX)-loaded mPEGylated lecithin-stabilized micelles (mPEG-lsbPMs) for improving the targeting efficiency and therapeutic efficacy. METHODS: mPEG-lsbPMs were simply prepared via thin film method. The trispecific antibodies or bispecific antibodies bound the mPEG-lsbPMs by anti-mPEG Fab fragment. The formulations were characterized by DLS and TEM; in vitro and in vivo studies were also conducted to evaluate the cellular uptake, cell cytotoxicity and therapeutic efficacy. RESULTS: The particle sizes of mPEG-lsbPMs with or without the antibodies were around 100 nm; the formulations showed high encapsulation efficiencies of 97.12%. The TsAb and dual bispecific antibodies were fabricated and demonstrated their targeting ability. Two EGFR-overexpressed cell lines (HT-29 and MIA PaCa-2) were co-cultured with FAP-overexpressed WS1 cells (HT-29/WS1; MIA PaCa-2/WS1) to mimic a tumor coexisting in the tumor microenvironment. Cellular binding study revealed that the binding of anti-FAP micelles to three co-culture ratios (4:1, 1:1, and 1:4) of HT-29/EGFR to WS1/FAP was significantly higher than that for TsAb micelles and dual (1:1) micelles, and the binding of those targeting antibodies to WS1/FAP and MIA PaCa-2/EGFR was equally efficacious resulting in a similar binding amount of the TsAb and dual BsAbs (1:1) with the co-culture of MIA PaCa-2/EGFR and WS1/FAP at a 1:1 ratio. Antitumor efficacy study showed that treatment with DTX-loaded mPEG-lsbPMs modified with or without BsAbs, dual BsAbs (1:1), and TsAbs was enhanced in inhibiting tumor growth compared with that for Tynen® while showing fewer signs of adverse effects. CONCLUSION: Active targeting of both tumors and TAF-specific antigens was able to increase the affinity of DTX-loaded mPEG-lsbPMs toward tumor cells and TAFs leading to successive uptake by tumor cells or TAFs which enhanced their chemotherapeutic efficacy against antigen-positive cancer cells.

Staged laparoscopic management of locally advanced gastric cancer with outlet obstruction.

BACKGROUND: The prognosis of patients with locally advanced gastric cancer with outlet obstruction is poor. Gastrectomy with curative intent is often initially impossible or difficult. OBJECTIVE: We report our experience of curative distal gastrectomy after laparoscopic gastrojejunostomy and fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy to examine the feasibility and safety of this modified strategy for locally advanced gastric cancer with outlet obstruction, initially deemed unresectable. METHODS: Between October 2017 and June 2019, 15 patients diagnosed with locally advanced gastric cancer with outlet obstruction sequentially underwent gastrojejunostomy, received four cycles of FLOT chemotherapy, and underwent laparoscopic distal gastrectomy with curative intent (R0 resection + D2 lymphadenectomy). Clinical data were retrospectively collected and analyzed. RESULTS: R0 resection was possible in 12/15 patients, laparoscopically in 11, and one conversion to laparotomy was necessary. There was no perioperative mortality in the 12 patients. Pathologic evaluation of the resected specimens revealed that complete tumor grade regression 1a (TRG1a), TRG1b, TRG2, and TRG3 occurred in 3, 2, 4, and 3 patients, respectively. CONCLUSION: This case series showed that curative surgical resection was feasible as a staged approach for patients with locally advanced gastric cancer with outlet obstruction, after initial staged gastrojejunostomy and chemotherapy.

Tumor characteristics and clinical outcome of peritoneal metastasis of gastric origin treated with a hyperthermic intraperitoneal chemotherapy procedure in the PERISCOPE I trial.

INTRODUCTION: The PERISCOPE I (Treatment of PERItoneal dissemination in Stomach Cancer patients with cytOreductive surgery and hyPErthermic intraperitoneal chemotherapy) study was conducted to investigate the safety and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer patients with limited peritoneal dissemination. In this study, tumor characteristics and clinical outcome of the patients treated in the PERISCOPE I trial were investigated. METHODS: Patients who had undergone the full study protocol were selected; that is, preoperative systemic chemotherapy, followed by a surgical procedure consisting of a (sub)total gastrectomy, cytoreductive surgery, and HIPEC with oxaliplatin (460 mg/m2 ) and docetaxel (in escalating doses). RESULTS: Twenty-five PERISCOPE I patients underwent the full study protocol. Most patients had an ypT3-4 tumor (96%) and the diffuse-type histology was predominant (64%). Seven patients (28%) had a microscopically irradical (R1) resection. In all patients, a complete cytoreduction was achieved. Median follow-up was 37 (95% confidence interval [CI]: 34-39) months. Disease recurrence was detected in 17 patients (68%). Median disease-free and overall survival were 12 and 15 months, respectively. CONCLUSION: In this series of gastric cancer patients with limited peritoneal dissemination who underwent HIPEC surgery, unfavorable tumor characteristics were common. Survival might be encouraging but disease recurrence was frequent. The efficacy of an HIPEC procedure in improving prognosis is currently being investigated in the PERISCOPE II trial.

Association of high TUBB3 with resistance to adjuvant docetaxel-based chemotherapy in gastric cancer: translational study of ITACA-S.

BACKGROUND: No predictive markers for chemotherapy activity have been validated in gastric cancer (GC). The potential value of class III ß-tubulin (TUBB3) as biomarker for prognosis and resistance to taxane-based therapy was reported. METHODS: We analyzed GC samples of patients enrolled in the Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S), a randomized adjuvant study comparing 5-fluorouracil/leucovorin (5-FU/LV) and docetaxel-based sequential chemotherapy. TUBB3 was quantitated by selected reaction monitoring mass spectrometry and patients were stratified using a threshold of 750 attomoles per microgram (amol/µg). Cox proportional modeling and Kaplan-Meier survival analysis were used to assess the impact of TUBB3 expression on overall survival (OS) and disease-free survival. RESULTS: Patients with TUBB3 protein levels >750 and <750 amol/µg were 21.9% and 78.1%, respectively, and were well-balanced between treatment arms. TUBB3 protein levels were not prognostic. Whereas no survival differences according to the 2 arms were observed in the subgroup with low TUBB3 expression (5-year OS 47% vs 40%; p = 0.44), patients with high TUBB3 had a clinically meaningful poorer OS when receiving docetaxel-based versus 5-FU/LV chemotherapy (5-year OS 31% vs 54%; p = 0.09), with a statistically significant interaction between TUBB3 and treatment (p = 0.049). CONCLUSIONS: The quantification of TUBB3 might be considered as a negative predictive biomarker of benefit from taxane-based therapy in GC. Studies are needed to evaluate its role in the neoadjuvant setting.

Hyperthermia During Intraperitoneal Chemotherapy With Paclitaxel or Docetaxel for Ovarian Cancer: Is There Any Benefit?

BACKGROUND/AIM: Intraperitoneal chemotherapy with taxanes provides high locoregional drug concentrations. Regarding their synergy with hyperthermia, results have been inconclusive. In this in vitro study, the thermal enhancement of the effect of paclitaxel and docetaxel on ovarian cancer cells under conditions mimicking those during hyperthermic intraperitoneal chemotherapy (HIPEC) is evaluated. MATERIALS AND METHODS: Cisplatin-resistant SKOV-3 and OVCAR-3 ovarian cancer cells were exposed for 2 h to 0.1, 1 and 3 µΜ of paclitaxel and docetaxel at 37°C (normothermia) and 41.5°C (hyperthermia). Cell proliferation and cell-cycle distribution were evaluated after 24 h, 3 days and 7 days. RESULTS: A concentration-dependent cytotoxic effect on cell proliferation was observed. Concurrent hyperthermia caused an increased arrest of cells in the G2/M phase. At 7 days, thermal enhancement of drug effect was shown only for treatment of OVCAR-3 cells with 1 µM paclitaxel. CONCLUSION: The concentration-dependent cytotoxic effect of paclitaxel and docetaxel supports their intraperitoneal use. Due to the lack of or only minimal thermal enhancement, normothermic may be as effective as hyperthermic intraoperative intraperitoneal chemotherapy with taxanes, avoiding, however, potential oncological and treatment-related adverse effects of concurrent hyperthermia.

Novel T7-Modified pH-Responsive Targeted Nanosystem for Co-Delivery of Docetaxel and Curcumin in the Treatment of Esophageal Cancer.

BACKGROUND: Although single-drug chemotherapy is still an effective treatment for esophageal cancer, its long-term application is limited by severe side-effects, poor bioavailability, and drug-resistance. Increasing attention has been paid to nanomedicines because of their good biological safety, targeting capabilities, and high-efficiency loading of multiple drugs. Herein, we have developed a novel T7 peptide-modified pH-responsive targeting nanosystem co-loaded with docetaxel and curcumin for the treatment of esophageal cancer. METHODS: Firstly, CM-ß-CD-PEI-PEG-T7/DTX/CUR (T7-NP-DC) was synthesized by the double emulsion (W/O/W) method. The targeting capacity of the nanocarrier was then investigated by in vitro and in vivo assays using targeted (T7-NP) and non-targeted nanoparticles (NP). Furthermore, the anti-tumor efficacy of T7-NP-DC was studied using esophageal cancer cells (KYSE150 and KYSE510) and a KYSE150 xenograft tumor model. RESULTS: T7-NP-DC was synthesized successfully and its diameter was determined to be about 100 nm by transmission electron microscopy and dynamic light scattering. T7-NP-DC with docetaxel and curcumin loading of 10% and 6.1%, respectively, had good colloidal stability and exhibited pH-responsive drug release. Good biosafety was observed, even when the concentration was as high as 800 µg/mL. Significant enhancement of T7-NP uptake was observed 6 hours after intravenous injection compared with NP. In addition, the therapeutic efficacy of T7-NP-DC was better than NP-DC and docetaxel in terms of growth suppression in the KYSE150 esophageal cancer model. CONCLUSION: The findings demonstrated that T7-NP-DC is a promising, non-toxic, and controllable nanoparticle that is capable of simultaneous delivery of the chemotherapy drug, docetaxel, and the Chinese Medicine, curcumin, for treatment of esophageal cancer. This novel T7-modified targeting nanosystem releases loaded drugs when exposed to the acidic microenvironment of the tumor and exerts a synergistic anti-tumor effect. The data indicate that the nanomaterials can safely exert synergistic anti-tumor effects and provide an excellent therapeutic platform for combination therapy of esophageal cancer.

Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer-results from the randomized phase III SUCCESS-A trial.

BACKGROUND: When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients. METHODS: A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety. RESULTS: No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively. CONCLUSION: Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting. TRIAL REGISTRATION: Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.

Docetaxel Loaded Pomegranate Seed Oil Based Nanostructured Lipid Carriers: A Potential Alternative to Current Formulation.

The current work is focused on the development of docetaxel loaded pomegranate seed oil based lipid nanosystem. Docetaxel loaded pomegranate seed oil nanostructured lipid carriers (DTX-PSO-NLCs) were formulated by the melt emulsification method for parenteral delivery. The developed formulation was characterized in terms of their physicochemical parameters, solid-state characterization, in vitro drug release, in vitro cytotoxicity studies, and in vivo pharmacokinetics and biodistribution studies. Stability studies were carried out as per ICH guidelines Q1A. Melt emulsification method resulted in the formulation of stable DTX-PSO-NLCs with a particle size in the range of 150-180 nm and an entrapment efficiency of 63-65%. The in vitro release showed a slow and sustained release of the drug from the formulation compared to the marketed formulation (i.e., Daxotel®). The formulation was found to be stable for a period of 12 months at conditions of 4°C ± 2°C, 25°C ± 2°C/60% RH ± 5%RH, and 40°C ± 2°C/75% RH ± 5%RH. The developed nanosystem exhibited promising antitumor activity against various types of cancerous cell lines (i.e., MCF7, DU145, U87MG, and NCI-H460) relative to the marketed formulation. The pharmacokinetic evaluation revealed that DTX-PSO-NLCs had a better kinetic profile compared to the marketed formulation. Graphical abstract.

Phase I study to evaluate the maximum tolerated dose of the combination of SH003 and docetaxel in patients with solid cancer: A study protocol.

INTRODUCTION: Cancer is the second leading cause of death, and the burden of cancer continues to grow globally. Research on the efficacy of combined administration of herbal medicine and anticancer drugs is also increasing. SH003 is a new herbal medicine composed of Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii. SH003 alone up to 4800 mg daily was found to be safe. Preclinical studies have shown SH003 to have a synergistic effect with coadministration of anticancer drugs. This study aimed to determine the maximum tolerated dose of SH003 combined with docetaxel in patients with lung or breast cancer. METHODS: This is an open-label, dose-escalation study to evaluate the safety of SH003 combined with docetaxel. Patients with lung or breast cancer will be recruited. The participants will be divided into 3 groups based on SH003 daily dose (2400, 3600, and 4800 mg); the medication will be taken orally for 21 days. The traditional 3 + 3 design will be adopted for the dose escalation. Dose-limiting toxicities are defined as grade 3 or 4 adverse events according to the Common Terminology Criteria for Adverse Events. The highest dose at which no more than 1 of the 6 patients experience dose-limiting toxicity will be determined as the maximum tolerated dose of SH003 combined with docetaxel. DISCUSSION: This study investigates the safety of SH003 when combined with docetaxel. The results of this study will provide a safe dose range for conducting therapeutic exploratory trials. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT04360317.

Differential Benefit of Adjuvant Docetaxel-Based Chemotherapy in Patients With Early Breast Cancer According to Baseline Body Mass Index.

PURPOSE: Lipophilic drugs, such as taxanes, have a high affinity for adipose tissue and a resulting higher volume of distribution. Here, we reanalyzed clinical trial data to investigate whether the efficacy of docetaxel-based chemotherapy differs from non-docetaxel-based chemotherapy in patients with breast cancer according to their baseline body mass index (BMI). PATIENTS AND METHODS: We retrospectively analyzed data from all of the patients in the adjuvant BIG 2-98 trial (ClinicalTrials.gov identifier: NCT00174655; N = 2,887) comparing non-docetaxel- to docetaxel-containing chemotherapy. BMI (kg/m2) was categorized as follows: 18.5 to < 25, lean; 25 to < 30, overweight; and ≥ 30, obese. Disease-free survival (DFS) was the primary endpoint, and overall survival (OS) was the secondary endpoint. A second-order interaction was assessed among treatment, BMI, and estrogen receptor (ER) status. RESULTS: There was no difference in DFS or OS according to BMI in the non-docetaxel group, while reduced DFS and OS were observed with increasing BMI category in the docetaxel group. Adjusted hazard ratios for DFS and OS were, respectively, 1.12 (95% CI, 0.98 to 1.50; P = .21) and 1.27 (95% CI, 1.01 to 1.60; P = .04) for overweight versus lean groups and were 1.32 (95% CI, 1.08 to 1.62; P = .007) and 1.63 (95% CI, 1.27 to 2.09; P < .001), respectively, for obese versus lean groups. Similar results were obtained when considering ER-negative and ER-positive tumors separately and when considering only patients who received a relative dose intensity ≥ 85% for docetaxel. A joint modifying role of BMI and ER status on treatment effect was evident for DFS (adjusted P = .06) and OS (adjusted P = .04). CONCLUSION: This retrospective analysis of a large adjuvant trial highlights a differential response to docetaxel according to BMI, which calls for a body composition-based re-evaluation of the risk-benefit ratio of the use of taxanes in breast cancer. These results now must be confirmed in additional series.

FLOT Neoadjuvant Chemotherapy Followed by Laparoscopic D2 Gastrectomy in the Treatment of Locally Resectable Advanced Gastric Cancer.

Background: The prognosis of patients with advanced gastric cancer remains unsatisfactory, highlighting the need for improved therapeutic strategies. We analyzed 23 resectable advanced gastric cancer patients who received FLOT followed by laparoscopic gastrectomy with D2 lymphadenectomy to evaluate the efficacy and safety. Methods: Patients aged 18-75 years with gastric adenocarcinoma (stage cT3-4 and/or N + M0) underwent neoadjuvant FLOT therapy (four preoperative and four postoperative 2-week cycles) at Shanghai East Hospital. Laparoscopic gastrectomy was scheduled 3-4 weeks after completion of the last cycle of preoperative chemotherapy. The type of surgical procedure was determined by the location and extent of the primary tumor. Results: 23 patients were reviewed in the study. 20 patients (81.2%) received four courses of FOLT therapy, while 3 patients (18.8%) received three courses of treatment. There were 3 (13.0%) complete responses, 13 (56.5%) partial responses, 4 (26.1%) of stable disease, and 1 (4.3%) of progressive disease. The clinical efficacy response rate was 69.6%. The R0 resection rate was 91.3%. Only one patient exhibited grade III postoperative complications. The pathologic complete remission was 13%. The common grade 3/4 adverse events from chemotherapy were leucopenia (17.4%), neutropenia (30.4%), anemia (13%), anorexia (13%), and nausea (17.4%). Postoperative complications occurred in 5 patients (26.1%). There was no treatment-related mortality or reoperation. The most reason for not completing chemotherapy was the patient's request. Conclusions: These findings suggest that FLOT neoadjuvant chemotherapy, followed by laparoscopic D2 gastrectomy, is effective and safe in advanced, resectable advanced gastric cancer.

Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models.

HER2 is a transmembrane tyrosine kinase receptor that mediates cell growth, differentiation, and survival. HER2 is overexpressed in approximately 20% of breast cancers and in subsets of gastric, colorectal, and esophageal cancers. Both antibody and small-molecule drugs that target HER2 and block its tyrosine kinase activity are effective in treating HER2-driven cancers. In this article, we describe the preclinical properties of tucatinib, an orally available, reversible HER2-targeted small-molecule tyrosine kinase inhibitor. In both biochemical and cell signaling experiments, tucatinib inhibits HER2 kinase activity with single-digit nanomolar potency and provides exceptional selectivity for HER2 compared with the related receptor tyrosine kinase EGFR, with a >1,000-fold enhancement in potency for HER2 in cell signaling assays. Tucatinib potently inhibits signal transduction downstream of HER2 and HER3 through the MAPK and PI3K/AKT pathways and is selectively cytotoxic in HER2-amplified breast cancer cell lines in vitro. In vivo, tucatinib is active in multiple HER2+ tumor models as a single agent and shows enhanced antitumor activity in combination with trastuzumab or docetaxel, resulting in improved rates of partial and complete tumor regression. These preclinical data, taken together with the phase-I tucatinib clinical trial results demonstrating preliminary safety and activity, establish the unique pharmacologic properties of tucatinib and underscore the rationale for investigating its utility in HER2+ cancers. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/19/4/976/F1.large.jpg.

Long-term (up to 16 months) health-related quality of life after adjuvant tailored dose-dense chemotherapy vs. standard three-weekly chemotherapy in women with high-risk early breast cancer.

PURPOSE: To prospectively compare HRQoL effects of two modern adjuvant chemotherapy breast cancer treatment regimens at six time-points up to 16 months after random assignment. METHODS: The open-label, randomized, Phase 3 "Panther trial" was conducted between February 2007 and September 2011. 760 women, aged 65 years and younger, after surgery for non-metastatic node-positive or high-risk node-negative breast cancer were randomized 1:1 to the experimental group (four cycles of tailored and dose-dense adjuvant epirubicin and cyclophosphamide/2 weeks followed by four cycles of tailored dose-dense docetaxel/2 weeks) or standard group (three cycles of fluorouracil and epirubicin-cyclophosphamide/3 weeks followed by three cycles of docetaxel/3 weeks). HRQoL was assessed at all Swedish centres using EORTC QLQ-C30 and EORTC QLQ-BR23 at six points during 16 months before randomization. RESULTS: Response rates to questionnaires were highest at baseline 728/780 (93%) and lowest 16 months after randomization, 557/750 (74%). HRQoL declined during treatment in both groups. At the end of treatment, the experimental group reported statistically significantly lower HRQoL (P < 0.001) than the standard group on global health status, physical functioning, role functioning, social functioning, fatigue, sexual functioning, and systemic therapy effects. No differences were found for emotional functioning, body image, and arm and breast symptoms. There were no statistically significant differences between the groups at the first follow-up and at subsequent assessments. HRQoL levels at the 16-month follow-up were similar to baseline values. CONCLUSIONS: Negative HRQoL impact of the dose-dense and tailored strategy appears to be prominent during treatment, but HRQoL recover once treatment ends. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.

[Analysis of follow-up results of chrono-chemotherapy or conventional chemotherapy combined with intensity modulated radiotherapy in locally advanced nasopharyngeal carcinoma].

Objective: To evaluate the long-term effect and safety of chrono-chemotherapy combined with intensity modulated radiotherapy (IMRT) in locally advanced nasopharyngeal carcinoma (NPC). Methods: 160 patients with locally advanced NPC were randomly divided into a chrono group and conventional group according to random number table. In the first stage, all patients underwent two cycles of induced chemotherapy, consisting of docetaxel, cisplatin and 5-Fu every 21 days. Notably, patients received chrono-moduated chemotherapy according to circadian rhythm in the chrono group, and conventional chemotherapy in the conventional group. Then, 21 days after the completion of first stage, three cycles of concurrent cisplatin chemotherapy every 21 days were given to all patients during IMRT. The median follow-up after the completion of radiotherapy was 31 months. Long-term side effects and the survival of patients were observed. Results: Patients in the chrono group had significantly lower rates of hearing loss (22.72%), dysphagia (0) and neck fibrosis (4.54%) compared with those in the conventional group (39.13%、8.69%, 15.94%, respectively, all P<0.05). Meanwhile, the 1- year overall survival rates (97.0% vs 92.8%), 3-year overall survival rates (80.3% vs 81.2%), 1-year progression free survival rates (95.5% vs 87.0%), 3-year progression free survival rates (71.2% vs 73.9%), 1-year locoregional relapse-free survival rates (97.0% vs 95.7%), 1-year locoregional relapse-free survival rates (92.4% vs 92.8%), 1-year distant metastasis-free survival rates (97.0% vs 98.6%) and 3-year distant metastasis-free survival rates (90.9% vs 91.3%) between the chrono group and the conventional group were not statistically significant (all P>0.05). Conclusions: Compared with conventional chemotherapy, chrono-chemotherapy combined with IMRT didn't affect long-term survival, but reducing the incidence of adverse events in patients with locally advanced NPC.

The clinical value and usage of inflammatory and nutritional markers in survival prediction for gastric cancer patients with neoadjuvant chemotherapy and D2 lymphadenectomy.

BACKGROUND: The clinical values of inflammatory and nutritional markers remained unclear for gastric cancer with neoadjuvant chemotherapy (NACT). METHODS: The inflammatory, nutritional markers and their changes were analyzed for locally advanced gastric cancer with NACT. The predictive value was evaluated by the Cox proportional hazards regressions under three hypothesized scenarios. The nomograms including independent prognostic factors were plotted for survival prediction. RESULTS: A total of 225 patients were included in the study. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index, and hemoglobin (Hgb) were significantly reduced, and the body mass index was significantly increased after NACT (all P < 0.05). The pre-NACT NLR [hazard ratio (HR) = 1.176, P = 0.059] showed a trend to correlate with the overall survival (OS) when only pre-NACT markers available; The post-NACT Hgb (HR = 0.982, P = 0.015) was the independent prognostic factor when only post-NACT markers available; The post-NACT Hgb (HR = 0.984, P = 0.025) and the change value of LMR (HR = 1.183, P = 0.036) were the independent prognostic factors when both pre- and post-NACT markers available. The nomogram had a similar Harrell's C-statistic compared to ypTNM stage (0.719 vs. 0.706). CONCLUSION: For locally advanced gastric cancer, the NACT could significantly decrease some inflammatory markers. The pre-NACT NLR, the post-NACT Hgb and the change value of LMR had some values in survival prediction combined with age, sex, tumor location and the clinical stages under different clinical scenarios. The elevated initial NLR, the preoperative anemia and the greater change value of LMR implied a poor prognosis.

Predictive Biomarkers for Adjuvant Capecitabine Benefit in Early-Stage Triple-Negative Breast Cancer in the FinXX Clinical Trial.

PURPOSE: Recent studies have demonstrated a benefit of adjuvant capecitabine in early breast cancer, particularly in patients with triple-negative breast cancer (TNBC). However, TNBC is heterogeneous and more precise predictive biomarkers are needed. EXPERIMENTAL DESIGN: Tumor tissues collected from TNBC patients in the FinXX trial, randomized to adjuvant anthracycline-taxane-based chemotherapy with or without capecitabine, were analyzed using a 770-gene panel targeting multiple biological mechanisms and additional 30-custom genes related to capecitabine metabolism. Hypothesis-generating exploratory analyses were performed to assess biomarker expression in relation to treatment effect using the Cox regression model and interaction tests adjusted for multiplicity. RESULTS: One hundred eleven TNBC samples were evaluable (57 without capecitabine and 54 with capecitabine). The median follow-up was 10.2 years. Multivariate analysis showed significant improvement in recurrence-free survival (RFS) favoring capecitabine in four biologically important genes and metagenes, including cytotoxic cells [hazard ratio (HR) = 0.38; 95% confidence intervals (CI), 0.16-0.86, P-interaction = 0.01], endothelial (HR = 0.67; 95% CI, 0.20-2.22, P-interaction = 0.02), mast cells (HR = 0.78; 95% CI, 0.49-1.27, P-interaction = 0.04), and PDL2 (HR = 0.31; 95% CI, 0.12-0.81, P-interaction = 0.03). Furthermore, we identified 38 single genes that were significantly associated with capecitabine benefit, and these were dominated by immune response pathway and enzymes involved in activating capecitabine to fluorouracil, including TYMP. However, these results were not significant when adjusted for multiple testing. CONCLUSIONS: Genes and metagenes related to antitumor immunity, immune response, and capecitabine activation could identify TNBC patients who are more likely to benefit from adjuvant capecitabine. Given the reduced power to observe significant findings when correcting for multiplicity, our findings provide the basis for future hypothesis-testing validation studies on larger clinical trials.