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Docetaxel (DTX) is one of the most potent anticancer drugs but its extensive side effects necessitate innovative formulations. In this study, we aimed to investigate the expression pattern of apoptotic proteins, cell cycle arrest, and apoptosis induction after treatment with encapsulated DTX in alginate-chitosan nanoparticles in both breast cancer cells (MCF-7) and peripheral blood mononuclear cells (PBMCs). The characterization of the nanoparticles revealed a spherical shape with a size <50 nm, a hydrodynamic diameter of 200 nm, a Polydispersity Index of 0.5, and an encapsulation efficiency of 98.75 %. The free drug was released completely within 11 h while encapsulated DTX was released only 34 % in 96 h. The encapsulated drug indicated higher cytotoxicity on MCF-7 cells and the half inhibitory concentration (IC 50 ) value was 2 µg/ml after 72 h. Quantitative real-time PCR demonstrated a significant increase in cell death as the expression of apoptosis regulatory protein (Bcl-2) was downregulated with no impact on Bax in the MCF-7 cells. A notable decrease in the expression pattern of pro-inflammatory cytokine (IL-1β) in PBMCs indicated less inflammation induction. Flow cytometry analysis revealed that the newly formulated drug induced less opoptosis in PBMCs than the free DTX. Cell cycle arrest in the sub-G 1 phase was observed for the free drug while the encapsulated drug exhibited no significant changes. Our results suggest the high toxicity of the formulated drug in contrast to the free DTX on the MCF-7 cell line, minimal blood cell side effects, and no inflammation positioning it as a promising alternative to free docetaxel., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Objectives: Pembrolizumab +/- chemotherapy is standard therapy for r/m HNSCC. Despite regulatory approval of platinum/5FU/pembrolizumab, a taxane is often substituted for 5FU for convenience and tolerability. We aimed to characterize nationwide use patterns and compare outcomes between platinum/taxane/pembrolizumab vs platinum/5FU/pembrolizumab., Methods: Patients in a US nationwide database with r/m HNSCC treated from 2017 to 2022 with pembrolizumab plus platinum chemotherapy were included. Demographic and cancer-specific characteristics were summarized. Overall survival (OS) was estimated using Kaplan-Meier methodology, and compared between groups using log-rank test and multivariable Cox regression. Time on treatment, number of cycles, receipt of second-line therapy, and toxicities were compared between groups., Results: Of 438 patients, 320 (73 %) received 5FU and 118 (27 %) received a taxane. Taxane use became more frequent over time and was higher in academic vs community practices (51 % vs 23 %, p < 0.001). OS did not differ between taxane and 5FU groups (mOS 12.2 vs 13.4 months, p = 0.662). On multivariable Cox regression, HR for death associated with taxane vs 5FU was 0.99 (95 %CI 0.71-1.38). Receipt of 2L therapy was numerically higher for 5FU patients (46 %) compared to taxane patients (35 %, p = 0.071). Grade ≥ 3 anemia was more common in taxane patients (33 % vs 20 %, p = 0.003), whereas grade ≥ 3 lymphopenia and thrombocytopenia were numerically higher in 5FU patients., Conclusion: In patients with r/m HNSCC undergoing chemoimmunotherapy, taxane vs 5FU use varies by practice setting and geographical region. Platinum/taxane/pembrolizumab was associated with similar survival as platinum/5FU/pembrolizumab; these results suggest that chemoimmunotherapy with taxane is a reasonable alternative to 5FU., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: We previously reported that S-1 and low-dose docetaxel (DOC) (N-1 study, phase II trial) could be a well-tolerated and effective neoadjuvant chemotherapies (NACs) for patients with operable breast cancer. Herein, we analyzed the long-term outcomes and developed clinicopathological and molecular predictors of pathological complete response (pCR)., Patients and Methods: Eighty-three patients received S-1 (40 mg/m 2 orally on days 1-14) and DOC (40 mg/m 2 intravenously on day 1) every 3 weeks for 4 to 8 cycles. Disease-free survival (DFS) and overall survival (OS) were analyzed for each population with a pCR status. To assess the relationship between pCR and clinicopathological factors such as tumor-infiltrating lymphocytes (TILs, 1+ <10%, 2+ 10%-50%, and 3+ >50%) and nuclear grade (NG), microarray was used to compare the microRNA profiles of the pCR and non-pCR groups using core needle biopsy specimens., Results: With a median follow-up duration of 99.0 (range, 9.0-129.0) months, the 5-year DFS and OS rates were 80.7% and 90.9%, respectively. The 5-year OS rate of the pCR group was significantly better than that of the non-pCR group (100% vs. 86.2%, p = .0176). Specifically, in triple-negative patients, the difference was significant (100% vs. 60.0%, p = .0224). Multivariate analysis revealed that high TILs (≥2-3+) and NG 2-3 independently predicted pCR. Microarray data revealed that 3 miRNAs (miR-215-5p, miR-196a-5p, and miR-196b-5p) were significantly upregulated in the pCR group., Conclusion: Our NAC regimen achieved favorable long-term outcomes and significantly improved OS in the pCR group. High TILs, NG 2-3, and some miRNAs may be predictors of pCR., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: There is currently limited literature assessing the real-world treatment patterns and clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) mutations., Methods: Medical charts were abstracted for mCRPC patients with ≥ 1 of 12 HRR somatic gene alterations treated at US oncology centers participating in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange. Treatment patterns and clinical outcomes were assessed from the initiation of first-line or later (1L+) mCRPC therapy received on or after July 1, 2014., Results: Among 138 patients included in the study, the most common somatic HRR mutations were CDK12 (47.8%), BRCA2 (22.5%), and ATM (21.0%). Novel hormonal therapy and taxane chemotherapy were most commonly used in 1L; taxane use increased in later lines. Median overall survival (95% confidence interval [CI]) was 36.3 (30.7-47.8) months from initiation of 1L therapy and decreased for subsequent lines. Similarly, there was a trend of decreasing progression-free survival and prostate-specific antigen response from 1L to 4L+ therapy., Conclusions: Treatment patterns identified in this study were similar to those among patients with mCRPC regardless of tumor HRR mutation status in the literature., Competing Interests: Disclosure PJ Bobbili, M DerSarkissian, A Muthukumar, T Guo, M Mohan, A Zhang, and MS Duh are employees of Analysis Group, Inc.; a consulting company that has provided paid consulting services to Pfizer, Inc., which funded the development and conduct of this study and manuscript. J Ivanova, B Arondekar, J Chang, and A Niyazov are employees and shareholders of Pfizer, Inc. DB Solit is an employee of Memorial Sloan Kettering Cancer Center; has received payment or honoraria for participation in an advisory board for BridgeBio, Elsie Biotechnologies Inc, Fog Pharma, FORE Therapeutics, Function Oncology, PaigeAI, Pfizer Inc, Rain Therapeutics, Scorpion Therapeutics, and Vividion Therapeutics; has participated on a data safety monitoring board or advisory board for Rain Therapeutics; and is a shareholder in Elsie Biotechnologies Inc, FORE therapeutics, Function Oncology, and Scorpion Therapeutics. R Huq is an employee of Memorial Sloan Kettering Cancer Center. NB Mettu is an employee of Duke Cancer Institute; and has received research funding paid to their institution from Amgen, Amphivena Therapeutics, Aravive Inc, AstraZeneca, BioMed Valley Discoveries, Bristol-Myers Squibb Company, Erytech Pharma, Genentech-Roche, Incyte, Merck, Mereo Biopharma, Repare Therapeutics, and Syros. SJ McCall is an employee of Duke Cancer Institute; has received consulting fees from AstraZeneca; speaker fees from Takeda Pharmaceuticals; and is a part investor in Frameshift MRT software, owned by Duke University and licensed to SciMed Solutions. M Green is a former employee of Duke Cancer Institute and a current employee of Labcop. M Dhawan is an employee of Genentech. M Turski is an employee of UCSF Hellen Diller Cancer Center; and has received speaking fees from Bayer. P Lam is an employee of UCSF Hellen Diller Cancer Center. J Lee is an employee of the American Association for Cancer Research, and has received grants or contracts from AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, BMS, Genentech, Janssen, Novartis, Merck, and Pfizer Inc. WK Oh is an employee of Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai; is the Chief Medical Officer of the Prostate Cancer Foundation; has received consulting fees from Genetic Chemistry Therapeutics and Pfizer Inc; has equity in Sema4/GeneDx, and is an author and editor for UpToDate., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This phase II nonrandomized study evaluated the efficacy and safety of AZD4635 in combination with durvalumab (Arm A) or durvalumab plus cabazitaxel (Arm B) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and ≥1 novel hormonal agent., Patients and Methods: The primary endpoint was radiographic progression-free survival (rPFS) per RECIST v1.1 (soft tissue) or the Prostate Cancer Clinical Trials Working Group 3 (bone). Secondary endpoints included safety, tolerability, overall survival, confirmed prostate-specific antigen (PSA 50 ) response, pharmacokinetics, and objective response rate. Enrollment in Arm A was stopped following a sponsor decision unrelated to safety. The study was stopped based on the planned futility analysis due to low PSA 50 response in Arm B., Results: In the final analysis (1 November 2021), 30 patients were treated (Arm A, n = 2; Arm B, n = 28). The median rPFS in Arm B was 5.8 months (95% confidence interval 4.2-not calculable). Median rPFS was 5.8 months versus 4.2 months for patients with high versus low blood-based adenosine signature. The most common treatment-related adverse events in Arm B were nausea (50.0%), diarrhea (46.4%), anemia and neutropenia (both 35.7%), asthenia (32.1%), and vomiting (28.6%). Overall, AZD4635 in combination with durvalumab or AZD4635 in combination with cabazitaxel and durvalumab showed limited efficacy in patients with mCRPC., Conclusions: Although the safety profile of both combinations was consistent with known safety data of the individual agents, the results of this trial do not support further development of the combinations., Competing Interests: Disclosure TAG: research funding, honoraria, and nonfinancial or other support from IPSEN, Adacap, Pfizer, Sanofi, EISAI, Lilly, Bayer, Janssen, BMS, Astellas, Novartis, Roche. MG: honoraria from Sanofi/Aventis and Alexion Pharmaceuticals for consulting or advisory role; travel, accommodations, expenses provided by AstraZeneca and Genentech; research funding paid to institution from Janssen, AstraZeneca, Genentech. CV: research funding paid to institution from Merck MSD; consulting fees from GSK, Astellas Pharma, Merck MSD, BMS, Leo-Pharma, Janssen, Cilag, Bayer, and AstraZeneca. GR: research funding paid to institution from Bayer; consulting fees from AAA, Astellas, Bayer, Sanofi, Janssen, AstraZeneca, and Pfizer. JZ: honoraria from AstraZeneca for advisory board and speaker bureau; advisory board for Bayer, Pfizer, and Dendreon; speaker bureau for Sanofi. MP: research funding paid to institution from Karyopharm; consulting fees from AstraZeneca, Exelixis, Oncocyte, Signatera, and Janssen. JMP: grants paid to institution from MSD, BMS, Janssen, Merk Serono, BeiGene; consulting fees from Novartis, Sanofi, Janssen, Astellas, BMS, MSD, and Roche. AA: employee of AstraZeneca and may own stock or stock options. GDJ: contractor for AstraZeneca. RC: employee of AstraZeneca and may own stock or stock options. ETG: employee of AstraZeneca and may own stock or stock options. JT: employee of AstraZeneca and may own stock or stock options. GP: employee of AstraZeneca and may own stock or stock options. RK: employee of AstraZeneca and may own stock or stock options. CS: research funding paid to institution by: Janssen, Astellas, Sanofi, Bayer, Sotio, and Dendreon; patents, consulting, or advisory role: Sanofi, Janssen, Astellas, Bayer, Genentech, Pfizer, Lilly; royalties and other intellectual property: Parthenolide (Indiana University); dimethylamino parthenolide (Leuchemix); Exelixis: abiraterone plus cabozantinib combination; FRAS1 SNP and tristetraprolin as biomarkers of lethal prostate cancer; stock or other ownership: Leuchemix., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The reported incidence of platinum resistant recurrence (PRR) (recurrence within 6 months of the last dose of platinum therapy) after interval debulking/cytoreductive surgery (CRS) is high compared to that after primary CRS. The goal was to study PRR following a total parietal peritonectomy (TPP), that addresses occult disease more completely., Methods: This is a prospective multi-center study (CTRI/2018/08/015350). A TPP was performed during interval CRS following a fixed surgical protocol. Patients with a follow-up of 6 months(M) or more were included in this analysis. The incidence and patterns of PRR and factors affecting recurrence were analyzed., Results: From July 2018 to October 2019, 70 patients with serous carcinoma were included. The median surgical PCI was 15 [range 5-37]. A CC-0 resection was obtained in 55 (78.5%); CC-1 in 10 (14.2%). Occult residual disease was seen in 40%. At a median follow-up of 13 months, 17 (24.2%) had developed recurrence/progression. PRR was seen in 5 (7.1%) patients. The sites of progression (>1 in 2 patients) were pleura (n = 1), visceral peritoneum (n = 2), retroperitoneal nodes (n = 2), mediastinal nodes (n = 1) and small bowel mesentery (n = 2). Overall, though the most common site of recurrence was the visceral peritoneum (N = 9), seven (>40%) patients did not develop recurrence in the visceral peritoneum. Patients with high PCI and grade 3-4 complications had a higher probability of developing recurrence., Conclusions: TPP performed during interval CRS resulted in a very low incidence of PRR. These findings need confirmation in a larger series. The benefit of TPP over conventional surgery should be evaluated in a randomized trial., Competing Interests: Declaration of competing interest, (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Introduction: Taxanes are widely used in medical oncology. The aim of our study was to report and analyze the toxicity features of these drugs in Tunisian patients and to determine their impact on treatment response., Methods: Our retrospective study concerned 90 patients treated by taxanes in a medical oncology unit, from January 2014 to January 2017. We collected their epidemiologic and anatomo-clinical data and we detailed toxicity features including types grades and impact on tumor response., Results: Median age was 46 years. 80% of patients had breast cancer. Tumors were metastatic in 23.3% of cases. Nail toxicity was observed in 100% of patients. Grade I-II digestive toxicity was observed in 54.4% of cases. Hematological toxicity was noted in 42.2% of patients and it reached grade III-IV in five patients. Neurological toxicity occurred in 31% of patients and was grade III-IV in 6 cases. Alopecia was observed in 60% of patients. Fatigue was noted in 57.8% of patients. Myalgia was observed in 42.2% of patients. Toxicity did not affect the response to treatment., Conclusion: The taxanes' toxicity profile in Tunisian patients is characterized by more frequent digestive and nail toxicities and less frequent hematological toxicities, dose reduction and treatment delays than other populations., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Endometrial cancer (EC) known prognostic factors are not sufficient to predict either outcome or recurrence rate/site: to investigate EC recurrence patterns according to ESMO-ESGO-ESTRO risk classes, could be beneficial for a more tailored adjuvant treatment and follow-up schedule., Methods: 758 women diagnosed with EC, and a 5-years follow-up, were enrolled: they were divided into the ESMO-ESGO-ESTRO risk classes (low LR, intermediate IR, intermediate-high I-HR, and highrisk HR) and surgically treated as recommended, followed by adjuvants therapies when appropriate., Results: Higher recurrence rate (RR) was significantly detected (p < 0,001) in the HR group (40,3%) compared to LR (9,6%), IR (16,7%) and I-HR (17,1%). Recurrences were detected more frequently at distant sites (64%) compared to pelvic (25,3%) and lymph nodes (10,7%) recurrences (p < 0,0001): only in LR group, no differences were detected between local and distant recurrences. 5-Year distant-free (LR 99%, IR 94%,I-HR 86%, HR 88%) and local-free survivals (LR 99%, IR 100%,I-HR 98%, HR 95%) significantly differ between groups (p < 0,0001 and p = 0,003, respectively). Adjuvant therapy modifies RRs only in LR group (p = 0,01)., Conclusion: To identify biological factors to stratify patients at higher risk of relapse is needed. Distant site relapse could be the main reason of endometrial cancer failure follow-up, independently or in addition to their risk class prognosis., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: To comprehensively describe patient-reported, functional and neurophysiological outcomes to elucidate the phenotypic profile of taxane-induced neuropathy., Methods: Taxane-treated patients (n = 47) completed cross-sectional bilateral clinical and sensory assessments and nerve conduction studies. Patients reported symptom severity via Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx13) questionnaire., Results: Symptoms of neuropathy were reported by 81% of patients. On clinical examination, 62% had 2 or more abnormalities, with 20% indicating significant symptomatic and objective neuropathy. Nerve conduction studies were consistent with a sensory predominant axonal neuropathy. However, features more typical of entrapment neuropathy were also present in > 50%, which were not associated with overall severity of chemotherapy-induced peripheral neuropathy (CIPN) or clinical risk factors., Conclusions: There is considerable variation in CIPN phenotypes associated with taxane-treatment. Understanding their clinical associations may assist in identification of patients at risk of severe neurotoxicity. This would enable treatment modification decisions but also limit early cessation of effective anti-cancer treatment in patients with less severe neurological sequelae., Significance: Understanding the CIPN phenotype may inform treatment decisions which could impact clinical and survival outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Clinical trials have demonstrated the efficacy of several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC); however, real-world data on their use, survival effect, and safety are limited. Using electronic health record data from the Flatiron Health database, we studied real-world treatment patterns and health outcomes in patients with mCRPC., Patients and Methods: We conducted a retrospective, non-interventional cohort analysis of electronic health record data of patients with confirmed mCRPC between January 2013 and September 2017. The primary objective was to describe real-world treatment patterns, including treatment type, duration, and sequencing. Secondary objectives included describing patient characteristics and clinical outcomes., Results: Of 2559 patients with mCRPC, 1980 (77%) received at least 1 line of life-prolonging therapy (abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223). Of patients receiving first-line therapy, 49% received second-line therapy, and of these, 43% received third-line therapy. Abiraterone/prednisone and enzalutamide accounted for 65% of first-line therapies and 54% of second-line therapies. Docetaxel was the most common third-line therapy (24%). Back-to-back use of abiraterone/prednisone and enzalutamide was common. Radium-223 monotherapy use was 2% in the first-line setting, 3% in the second-line setting, and 8% in the third-line setting. The median overall survival was longer in patients who received life-prolonging therapies (23.7 months; 95% confidence interval: 22.3-25.1 months) than in those who did not (10.1 months; 95% confidence interval: 9.1-11.5 months)., Conclusion: These real-world insights on over 2500 patients with mCRPC supplement findings from randomized controlled trials and may help to inform clinical trial design, treatment guidelines, and clinical decision-making., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: We investigated the quantification of the response shift-adjusted treatment effect on quality-of-life (QOL) data in a randomized controlled trial of taxane versus S-1 for patients with metastatic breast cancer (SELECT-BC)., Methods: This study was a secondary data analysis of a previously published trial. The response shift-adjusted treatment effect on health-related QOL (HRQOL) data measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was estimated using structural equation modeling techniques in addition to quantifying the "true" treatment effect. Measurement invariances in the values of the common factor loadings, intercepts, and residual variances between before treatment and at the 3-, 6-, and 12-month visits were considered the response shift effects., Results: In the taxane group, we observed positive recalibration effects for role functioning and positive reprioritization and negative recalibration effects for emotional functioning. The observed change of -4.56 for role functioning comprised +2.26 response shifts and -6.82 "true" change. The observed change of +9.41 for emotional functioning comprised +12.43 response shifts and -1.17 "true" change. In the S-1 group, we observed positive reprioritization and negative recalibration effects for emotional functioning and positive reprioritization effects for social functioning. The observed change of +10.54 for emotional functioning comprised +10.07 response shifts and +0.47 "true" change. The observed change of +2.43 for social functioning comprised +3.50 response shifts and -1.07 "true" change., Conclusion: Detailed analysis of the response shift effects will improve the evaluation reliability of observed HRQOL data during clinical trials., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aims to compare two induction chemotherapy regimens, TPF and GP, for patients with locally advanced nasopharyngeal carcinoma (NPC)., Materials and Methods: We analyzed patients with newly diagnosed stage III-IVA NPC (excluding T3/T4N0, AJCC) between December 2010 and May 2015 who were treated with TPF or GP induction chemotherapy (IC) followed with concurrent chemoradiotherapy (CCRT) and those treated with CCRT alone. Treatment compliance, survival outcomes and grade 3-4 side effects were compared among these three groups., Results: A total of 189 patients were eligible for this study, with 87 (46.0%), 71 (37.6%) and 31 (16.4%) in the TPF, GP and CCRT alone groups. All patients were followed for 3 years. There was no difference in the 3-year survival rate between GP- and TPF-treated patients. Disease-free survival (DFS) and overall survival (OS) were significantly improved in both IC groups compared with those in the CCRT alone group. Multivariable analysis suggested that patients with N3 had a higher risk of distant metastasis than those with N1-2. GP is not inferior to TPF regardless of different N categories. There were significant more grade 3-4 treatment-related toxicity in TPF group than in GP group., Conclusion: Our study found that in locally advanced NPC, the GP induction chemotherapy regimen is equivalent to TPF in treatment outcomes, but with significant less grade 3-4 acute toxicity. Further studies are needed to validate our findings., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cabazitaxel has been shown to improve overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel in the TROPIC trial. However, trial populations may not reflect the real-world population. We compared patient characteristics and outcomes of cabazitaxel within and outside trials (standard of care, SOC)., Patients and Methods: mCRPC patients treated with cabazitaxel directly after docetaxel therapy before 2017 were retrospectively identified and followed to 2018. Patients were grouped on the basis of treatment within a trial or SOC. Outcomes included OS and prostate-specific antigen (PSA) response., Results: From 3616 patients in the CAPRI registry, we identified 356 patients treated with cabazitaxel, with 173 patients treated in the second line. Trial patients had favorable prognostic factors: fewer symptoms, less visceral disease, lower lactate dehydrogenase, higher hemoglobin, more docetaxel cycles, and longer treatment-free interval since docetaxel therapy. PSA response (≥ 50% decline) was 28 versus 12%, respectively (P = .209). Median OS was 13.6 versus 9.6 months for trial and SOC subgroups, respectively (hazard ratio = 0.73, P = .067). After correction for prognostic factors, there was no difference in survival (hazard ratio = 1.00, P = .999). Longer duration of androgen deprivation therapy treatment, lower lactate dehydrogenase, and lower PSA were associated with longer OS; visceral disease had a trend for shorter OS., Conclusion: Patients treated with cabazitaxel in trials were fitter and showed outcomes comparable to registration trials. Conversely, those treated in daily practice showed features of more aggressive disease and worse outcome. This underlines the importance of adequate estimation of trial eligibility and health status of mCRPC patients in daily practice to ensure optimal outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Cervical cancer is one of the most common malignancies diagnosed during pregnancy. Taxanes administration has been established as theurapetic regimen in non pregrant women., Objectives: This systemic review and meta-analysis aims to synthesize all available data from cervical cancer series in pregnant women and evaluate the efficacy and safety of taxanes during pregnancy., Search Strategy: Eligible articles were identified by a search of ClinicalTrial.gov and MEDLINE databases for the period 01/01/2000 up to 31/11/2017; The algorithm consisted of a predefined combination of the words "cervical", "cancer", "taxanes" and "pregnancy"., Selection Criteria: PRISMA guidelines were applied in this study. The literature search and data extraction from all studies that examined the efficacy and safety of taxanes in pregnancy, were done by two independent investigators. Quantitative synthesis of the published articles was performed., Data Collection and Analysis: Overall eight articles were retrieved. In all cases (14 pregnancies, 14 newborns) the use of taxanes in combination with platinum derivatives resulted in the birth of alive neonates, with not any miscarriage. The taxane derivative used in all cases was paclitaxel, combined with Cisplatin (13 pregnancies) and Carboplatin (one pregnancy)., Results: Complete and partial response was achieved in 7.2% and 92.9% of cervical cancer patients. In the majority of cases chemotherapy was well tolerated. The median progression-free survival was 48.5 months., Conclusion: Taxanes administration during the 2nd and 3rd trimester of pregnancy is a safe choice., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting., Patients and Methods: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8 mg/kg loading dose, then 6 mg/kg every 3 weeks (q3w)] and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS)., Results: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%)., Conclusions: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile., Clinicaltrials.gov: NCT01572038., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC., Patients and Methods: Eligible patients had centrally confirmed mTNBC, ≥1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1-positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), progression-free survival, and overall survival., Results: All enrolled patients (N = 170) were women, 61.8% had PD-L1-positive tumors, and 43.5% had received ≥3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7-9.9) in the total and 5.7% (2.4-12.2) in the PD-L1-positive populations. Disease control rate (95% CI) was 7.6% (4.4-12.7) and 9.5% (5.1-16.8), respectively. Median duration of response was not reached in the total (range, 1.2+-21.5+) and in the PD-L1-positive (range, 6.3-21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9-2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6-11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs., Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile., Clinical Trial Registration: ClinicalTrials.gov, NCT02447003., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy., Patients and Methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety., Results: A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001)., Conclusions: This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse., Trial Registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Background: Metastatic germ cell tumors remain potentially curable when treated with salvage chemotherapy at first relapse. In the present phase I/II study, we sought to improve on the response rate and duration of the TIP (paclitaxel, ifosfamide, cisplatin) regimen by adding gemcitabine (Gem-TIP)., Materials and Methods: Twenty patients were recruited after failure of first-line cisplatin-containing chemotherapy. The primary objectives were to determine the maximum tolerated dose of gemcitabine when combined with TIP and to establish the dose intensity of the TIP drugs in this combination. The secondary objectives were the response rates, failure-free survival, and overall survival., Results: The maximum tolerated dose of gemcitabine was 1200 mg/m 2 . The mean relative dose intensity was 95% (95% confidence interval [CI], 90.2%-99.2%) for gemcitabine, 96% (95% CI, 92.9%-98.7%) for paclitaxel, 92% (95% CI, 84.5%-98.8%) for ifosfamide, and 94% (95% CI, 89.3%-99.0%) for cisplatin. The overall complete response rate was 50%; another 30% of the patients achieved a partial response. The 1-year failure-free survival and overall survival rates were 68% (95% CI, 43%-84%) and 89.5% (95% CI, 64%-97%), respectively., Conclusion: Gemcitabine can be added to TIP chemotherapy at the full dose, with manageable toxicity and no detrimental effect on the dose intensity of the TIP drugs. The response rate and duration were improved compared with those reported from the Medical Research Council TIP trial; further evaluation is warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Lapatinib is an oral small molecule tyrosine kinase epidermal growth factor receptor-1/HER2 inhibitor that crosses the blood-brain barrier and is active against central nervous system (CNS) metastases. Cabazitaxel is a taxoid that is effective against taxane-resistant metastatic breast cancer (MBC) and has distinguished itself by its ability to cross the blood-brain barrier. The present phase II study (ClinicalTrials.gov identifier, NCT01934894) evaluated the combination of these agents to treat HER2 + MBC patients with CNS metastases., Materials and Methods: Patients with HER2 + MBC and ≥ 1 untreated or progressive, measurable CNS metastasis were eligible. Using a 3+3 dose escalation design, patients were treated with escalating doses of intravenous cabazitaxel every 21 days and oral lapatinib daily in 21-day treatment cycles. Intracranial disease restaging was performed every 2 cycles for the first 8 cycles and then every 3 cycles until progression or unacceptable toxicity., Results: Eleven patients were treated at 2 dose levels. Six patients were treated at dose level 1 (intravenous cabazitaxel 20 mg/m 2 plus oral lapatinib 1000 mg daily), and five were treated at dose level 2 (intravenous cabazitaxel 25 mg/m 2 plus oral lapatinib 1000 mg daily). The most common treatment-related adverse events were myelosuppression, diarrhea, fatigue, and skin toxicity. A total of 5 dose-limiting toxicity events occurred. No intra- or extracranial objective responses were observed., Conclusion: The combination of cabazitaxel plus lapatinib was not feasible because of toxicity and because no objective CNS activity was seen in the 5 evaluable patients. The role of cabazitaxel to treat breast cancer patients with CNS metastases remains undefined., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor-targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC)., Patients and Methods: Records of 574 consecutive patients treated (2012-2016) at 44 centers in 6 countries were retrospectively examined., Results: A total of 267 patients received ADT → DOC → CABA (group 1), 183 patients ADT → DOC → ART → CABA (group 2), and 124 patients ADT → DOC → CABA → ART (group 3), with respective median OS from diagnosis of mCRPC of 38.3, 44.45, and 53.9 months (P = .012 for group 3 vs. group 1). Multivariate analysis showed response to first ADT ≤ 12 months, Gleason score of 8 to 10, clinical progression, and high prostate-specific antigen levels at mCRPC diagnosis were associated with worse OS. Prior receipt of ART did not influence activity of CABA., Conclusion: OS appeared to increase with the number of life-extending therapies, with a sequence including DOC, CABA, and an ART providing the greatest OS benefit., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: The addition of carboplatin (Cb) to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) has been demonstrated to improve pathologic complete response (pCR) at the expense of increased toxicity. We aimed to evaluate the effectiveness and tolerability of dose-dense anthracycline & cyclophosphamide (ddAC) followed by weekly paclitaxel (wT) in combination with weekly Cb., Methods: Retrospective data was collected on patients with clinical stage I-III TNBC treated with neoadjuvant ddAC-wTCb (four cycles of ddA 60 mg/m 2 and ddC 600 mg/m 2 every 2 weeks followed by 12 cycles of wT 80 mg/m 2 with Cb AUC 1.5). Indices of tolerability and pCR were evaluated and compared to a historical cohort (n = 76) treated with ddAC-T. A secondary objective was to evaluate the rates of pCR by BRCA status., Results: For 43 eligible patients, mean age was 41.5 years, 51% had clinical stage II disease, 81.4% were clinically node positive and 32.6% carried a deleterious BRCA1 mutation. Only 35% completed all scheduled doses of chemotherapy. Grade 3/4 neutropenia was observed in 42.5% of patients. Overall pCR was 51.2%; 44.8% in BRCA wild-type compared to 64.3% in BRCA-associated TNBC (p = 0.232). pCR rates with ddAC-wTCb were similar to historic institutional rates with ddAC-T (51.2% vs. 51.3%, p = 0.987) and were comparable when stratified by BRCA status. In pooled multivariate analysis, only BRCA status (HR 4.00, 95%CI 1.65-9.75, p = 0.002) was significantly associated with pCR., Conclusion: Neoadjuvant ddAC-wTCb is less tolerable in clinical practice compared to most clinical trials, with a pCR comparable to historic rates using non-platinum regimen. The role of Cb in neoadjuvant chemotherapy for BRCA mutated TNBC remains uncertain., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Most men with advanced prostate cancer will develop bone metastases, which have a substantial impact on quality of life. Bone metastases can lead to skeletal-related events (SREs), which place a burden on patients and healthcare systems. For men with castration-resistant prostate cancer (CRPC) and bone metastases, the treatment landscape has evolved rapidly over the past few years. The relatively recent approvals of the hormonal agents abiraterone acetate and enzalutamide, second-line chemotherapy cabazitaxel, and the radiopharmaceutical radium-223 dichloride (radium-223), have provided clinicians with a greater choice of treatments. These compounds have benefits in terms of overall survival based on the results of pivotal phase 3 studies. The bisphosphonate zoledronic acid and the RANK ligand inhibitor denosumab are indicated for the prevention of SREs in men with metastatic CRPC but studies of these compounds have not demonstrated a survival benefit. The important question of the role of bisphosphonates or denosumab in combination with these new agents has thus materialised. Current and emerging evidence from clinical studies of abiraterone acetate, enzalutamide and radium-223, suggest that addition of bisphosphonates or denosumab to these new therapies may provide further clinical benefits for patients with prostate cancer and bone metastases. This evidence may help to shape clinical practice but are based largely on post hoc analyses of clinical trial data. It is therefore apparent that further data are required from both clinical studies and real-world settings to enable physicians to understand the efficacy and safety of combination therapy with the new agents plus bisphosphonates or denosumab., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: A retrospective study to evaluate the efficacy and safety of the addition of neoadjuvant chemotherapy to concurrent chemoradiotherapy in the treatment of nasopharyngeal carcinoma., Patients and Methods: Data from 62 patients treated for non-metastatic nasopharyngeal carcinoma were analyzed by comparing two groups of patients: a first group of 32 patients treated with 3 cycles of neoadjuvant chemotherapy based on docetaxel, cisplatin and 5-fluoro-uracil every 21 days followed by concurrent chemoradiotherapy (weekly cisplatin 40mg/m 2 with radiotherapy 70Gy, 2Gy per session, 5 sessions per week) and a second group of 30 patients treated with the same concurrent chemoradiotherapy., Results: After a median follow-up of 53.5 months, neoadjuvant chemotherapy showed a significant reduction in the rate of a distant metastatic relapses (3.3% vs. 10%, P=0.03). No significant difference in disease-free survival at 5 years (65.6% vs. 68.8%, P=0.46) or overall survival at 5 years (68.8% vs. 73.3%, P=0.46) was noted between the two groups. Induction chemotherapy was associated with febrile neutropenia of 15.6%. During concurrent chemoradiotherapy, hematological complications were greater in the first chemotherapy group (53% vs. 33%)., Conclusion: Induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil is a safe and effective option in the treatment of nasopharyngeal carcinoma. A better definition of high risk of relapse group would optimize the indications of this chemotherapy in the therapeutic arsenal., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: In advanced gastric cancer, doublet regimen including platinum salts and fluoropyrimidine is considered as a standard first-line treatment. The addition of docetaxel (75 mg/m 2  q3w) to cisplatin (75 mg/m 2  q3w) and 5-fluorouracil has been shown to improve efficacy. However, this regimen (DCF) was associated with frequent severe toxicities (including more complicated neutropenia), limiting its use in clinical practice. Interesting alternative docetaxel-based regimens have been developed that need to be validated., Aim: GASTFOX study is a randomized phase III trial comparing FOLFOX alone or with docetaxel at 50 mg/m 2 (TFOX regimen) in first-line treatment for advanced gastric cancer. In both arms, cycle is repeated every 2 weeks until disease progression or unacceptable toxicity., Materials and Methods: Main eligibility criteria: histologically proven locally advanced or metastatic gastric or esogastric junction adenocarcinoma, HER negative status, measurable disease, ECOG performance status 0 or 1, and adequate renal, hepatic and bone marrow functions., Results: The primary endpoint is radiological/clinical progression-free survival (PFS). A difference of 2 months for the median PFS in favor of TFOX is expected (HR = 0.73) Based on a two-sided α risk of 5% and a power of 90%, 454 events are required to show this difference. Secondary endpoints included overall survival, overall response rate, safety, quality of life and the therapeutic index., Conclusion: This study is planned to include 506 patients to demonstrate the superiority of TFOX over FOLFOX in first-line advanced gastric cancer treatment (NCT03006432)., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: Given their inclusion and exclusion criteria, randomized clinical trials (RCT) might not include a population that truly mirrors real life (RL). This raises concerns about the applicability of RCT results in clinical practice. We evaluated the efficacy of anti-HER2 treatment with pertuzumab combined with trastuzumab and a taxane as first-line treatment for HER2-positive metastatic breast cancer in a RL setting, and compared the safety results obtained in our population versus the experimental cohort of the CLEOPATRA RCT, which led to the approval of this therapy., Materials and Methods: Patients treated with trastuzumab, pertuzumab and a taxane were enrolled in this retrospective study. We compared the tumor features and the patients' characteristics of the RL cohort to those of the CLEOPATRA cohort. We also compared the median progression-free survival (PFS) in the RL population versus specific patients' subgroups., Results: RL patients were more frequently HR-positive, less likely to have visceral metastases (P < .001 for both) and had more frequently received (neo)adjuvant hormone therapy or trastuzumab than CLEOPATRA patients (P = .004 and P < .001, respectively). The median number of anti-HER2 cycles was 8 vs 24 and the median number of cycles was 7 vs 8 for docetaxel in the RL versus CLEOPATRA population, respectively. Adverse reactions of all grades were less frequent in RL. Median PFS was 27.8 months in the RL population and the treatment was equally effective in all patients' subgroups., Conclusion: This study provides compelling evidence that pertuzumab, trastuzumab and a taxane are effective and safe also in a clinical scenario., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This research was motivated due to substantial requirement of improved treatment for breast cancer which accounts for over 0.52 million deaths annually worldwide. Utilizing nanoparticles carrying active medicaments as targeted delivery carrier is emerging as a promising approach. For a drug to be clinically effective, it needs to be suitably protected in the biological fluid till it is delivered to the targeted site. Keeping above in mind, we prepared and optimized polymeric nanoparticles by polyhydroxybutyrate-co-hydroxyvalerate (PHBV) a biodegradable polymer utilizing modified emulsification solvent evaporation method. The optimized formulation had particle size of 349±3.51nm with entrapment efficiency of 69±1.28%. Nanoparticle formation and its surface morphology were confirmed by various electron microscopes. The in vitro and pharmacokinetic studies demonstrated a sustained release of drug in a non-biological system and into rat's bloodstream respectively. Also, the in vitro cytotoxicity and in vivo toxicological evaluation at the therapeutic dose demonstrated the safety and antitumor efficacy of the formulation. Due to formulation characteristic properties, it was found to be effective in enveloping and chaperoning the drug to the suitable site of action. The PHBV-TPGS combination causes the drug to be released in controlled and sustained modes, thereby reducing drug dose and toxicity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A novel redox-sensitive system for co-delivering hydrophobic drugs and hydrophilic siRNA or shRNA was developed by conjugating gambogic acid (GA) with poly(amido amine)s (PAAs) through amide bonds, which is called GA-conjugated PAAs (PAG). PAG can self-assemble into micelles as amphiphilic block copolymers, which exhibits an excellent loading ability for the co-delivery of docetaxel (DTX) and MMP-9 shRNA with adjustable dosing ratios. In addition, confocal microscopy, flow cytometry and in vitro transfection analyses demonstrated more efficient cellular internalization of DTX and MMP-9 shRNA after incubation with PAG/DTX- MMP-9 shRNA micelles (PAG/DTX-shRNA) than with free drugs. Unlike traditional amphiphilic copolymer micelles, GA conjugated in PAG possesses an intrinsic anticancer efficacy. The presence of disulfide bonds in PAAs enables rapid disassembly of PAG micelles in response to reducing agents, inducing the release of loaded drugs (DTX, GA and MMP-9 shRNA). In vitro cellular assays revealed that PAG/DTX-shRNA micelles inhibited MCF-7 cell proliferation more efficiently than the single drug or single drug-loaded micelles. In vivo biodistribution and anti-tumor effect studies using an MCF-7 breast cancer xenograft mouse model have indicated that PAG/DTX-shRNA micelles can enhance drug accumulation compared with the free drug, thereby sustaining the therapeutic effect on tumors. Additionally, PAG/DTX-shRNA micelles displayed a greater anti-tumor efficacy than Taxotere® and PAG-shRNA micelles. These results suggest that the redox-sensitive PAG platform is a promising co-delivery system for combining drugs and gene therapy for the treatment of cancer., Statement of Significance: The PAG micelles were designed by conjugating gambogic acid (GA) with poly(amido amine)s (PAAs), which would serve dual purposes as both gene and drugs co-delivery carrier and an anti-tumor prodrug. Unlike traditional amphiphilic micelles, GA conjugated in PAG could exert its intrinsic efficacy and provide synergistic antiproliferative effects with docetaxel (DTX) on MCF-7 cells. Disulfide bonds in PAG enables a rapid disassembly of PAG micelles in response to reducing agents and to release all loaded drugs (DTX, GA and MMP-9 shRNA) at tumor sites. PAG/DTX-shRNA micelles displayed greater anti-tumor efficacy than that of Taxotere®, indicating the design concept for PAG works well. And the strategy for PAG could be used to develop a series of similar co-delivery systems through conjugations of other small-molecule drugs with PAAs, such as doxorubicin, methotrexate and other drugs with carboxy groups in their structure., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Anti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer., Patients and Methods: BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive., Results: Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively)., Conclusion: Treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab., Clinical Trial Information: NCT02132949.

Background: Data from meta-analyses support the use of induction or adjuvant platinum-based chemotherapy for locally advanced non-small cell lung cancers (NSCLCs). This phase 2 study assessed the role of induction cisplatin and docetaxel followed by surgery in patients with resectable stage I to III NSCLCs, followed by 12 months of adjuvant erlotinib., Methods: Patients with resectable stage I to III NSCLCs received cisplatin 80 mg/m 2 , docetaxel 75 mg/m 2 every 21 days for 3 cycles, followed by surgery, followed by adjuvant erlotinib for 12 months. The primary endpoint included safety. Long-term efficacy outcomes and exploratory analysis of intermediary endpoints are also reported (NCT00254384)., Results: Forty-seven eligible patients received a median of 3 cycles of induction treatment, 37 underwent surgical resection, and only 21 received adjuvant erlotinib. Two patients died in the perioperative period (1 sepsis during chemotherapy, 1 acute respiratory distress syndrome postoperatively). Most common grade 3 to 5 toxicities during chemotherapy included hypokalemia (8%), infection (7%), and granulocytopenia (25%). During adjuvant erlotinib, 14% of patients experienced grade 2 rash. Median overall survival was 3.4 years. Major pathologic responses in the primary tumor were observed in 19% (7 of 37) of patients and correlated with improved long-term overall survival. Complete pathologic response in mediastinal/hilar nodes also correlated with superior survival., Conclusions: Induction cisplatin and docetaxel was well tolerated. Adjuvant erlotinib did not improve outcomes compared with historical controls. Major pathologic response predicted for improved long-term survival and is a suitable intermediary endpoint for future phase 2 studies., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Clinically, codelivery of chemotherapeutics has been limited by poor water-solubility and severe systemic toxicity. In this work, we developed a new reduction-sensitive mixed micellar system for self-codelivery of doxorubicin (DOX) and docetaxel (DTX). Biodegradable methoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) was coupled with DOX and DTX by a reduction-sensitive disulfide bond, resulting in mPEG-PCL-SS-DOX and mPEG-PCL-SS-DTX, respectively. mPEG-PCL-SS-DOX was mixed with mPEG-PCL-SS-DTX at a mole ratio of 1:1 in water, forming a mixed micellar system. The mixed micelles had a diameter of 223.7nm and a low critical micelle concentration. Reductive-triggered drug release revealed a "smart" characteristic of the mixed micelles. A cellular uptake and cytotoxicity assay in vitro showed that the mixed micelles could efficiently accumulate in MCF-7 cells and suppress the growth of tumour cells. The proposed reduction-sensitive mixed micelles assembled from amphiphilic prodrugs can be used as a promising drug codelivery system for cancer therapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Microabstract: Women treated with chest radiation for Hodgkin lymphoma (HL) have significantly higher risk of developing breast cancer, and little is known about how these patients tolerate chemotherapy for breast cancer. This small retrospective study identified 15 patients, noting that these patients tolerate proposed chemotherapy regimens for breast cancer in rates similar to those without prior HL and therapeutic radiation., Purpose: Women treated for Hodgkin lymphoma (HL) with chest radiation have significantly higher risk of developing breast cancer, and little is known about how these patients tolerate chemotherapy for breast cancer., Methods: Women with breast cancer diagnosed from 1986-2015 after radiation for HL were identified from hospitals and clinics in St. Paul and Minneapolis, Minnesota. Patient, tumor and treatment characteristics, and clinical outcomes were abstracted from medical records and summarized using descriptive statistics. Chemotherapy was defined as tolerated if all scheduled doses and cycles were completed without deviation from the initial plan, with lack of grade 3 or higher toxicity attributable to chemotherapy in categories including blood, cardiac, gastrointestinal, fatigue and pain., Results: Forty-two patients with breast cancer and prior radiation for HL were identified, 15 of which received chemotherapy for breast cancer. We noted 75% tolerability of taxane-based and 100% tolerability of anthracycline-based chemotherapy, suggesting that most patients with prior radiation for HL tolerate chemotherapy for breast cancer. A subset of patients (N = 7) in this study were also treated with chemotherapy for HL prior to breast cancer diagnosis, and 86% (6 of 7) also tolerated chemotherapy for breast cancer., Conclusions: Treatment of breast cancer is strongly influenced by prior treatment of HL. Although this study was small and did not meet statistical significance, the data suggest that these patients tolerate proposed chemotherapy regimens for breast cancer in rates similar to those without prior HL and therapeutic radiation. Larger studies comparing specific chemotherapy dosing schedules are needed to address this complicated population., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Phase 2 trials evaluating new agents for metastatic castration-resistant prostate cancer (mCRPC) have relied on bone scan and prostate-specific antigen changes to assess activity. Given the increasing detection of measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST) changes warrant consideration to evaluate activity. We validated the association of RECIST 1.0 changes with survival in men with mCRPC receiving docetaxel., Patients and Methods: Data for men with measurable disease from the Southwest Oncology Group (SWOG) S0421, a phase 3 trial in men with mCRPC receiving docetaxel and prednisone plus placebo or atrasentan, were used. Cox proportional hazards regression was used to evaluate the association of RECIST 1.0 outcomes within 120 days, ie, unconfirmed partial response (uPR), stable disease, and progressive disease (PD), with overall survival (OS) from day 120, adjusted for prognostic factors., Results: Overall, 326 men were evaluable for landmark analysis, of whom 23 had PD, 230 stable disease, and 73 uPR. OS beyond day 120 was significantly different (P = .004) among these subgroups, with median (95% confidence interval) OS of 7.1 (3.5-8.8), 13.4 (11.4-15.6), and 16.3 (10.0-19.6) months for those with PD, stable disease, and uPR, respectively. In a multivariable model, the hazard ratio (95% confidence interval) for patients with PD was 2.47 (1.42-4.29) compared to patients with an uPR (P = .002)., Conclusion: The association of RECIST 1.0 changes with OS in men with mCRPC receiving docetaxel was validated. Given limitations of bone scan and prostate-specific antigen alterations, improvements in objective RECIST 1.0 changes should be reported in phase 2 trials before launching phase 3 trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC., Patients and Methods: Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations., Results: A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified., Conclusion: The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported., Trial Identifier: Clinicaltrials.gov NCT01750281., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

As current tumor chemotherapy faces many challenges, it is important to develop drug delivery systems with increased tumor-targeting ability, enhanced therapeutic effects and reduced side effects. In this study, a pH-sensitive liposome was constructed containing CHEMS-anchored PEG2000 for extended circulation and NGR peptide as the targeting moiety. The NGR-modified docetaxel-loaded pH-sensitive extended-circulation liposomes (DTX/NGR-PLL) prepared possess suitable physiochemical properties, including particle size of approximately 200nm, drug encapsulation efficiency of approximately 70%, and pH-sensitive drug release properties. Experiments performed in vitro and in vivo on human fibrosarcoma cells (HT-1080) and human breast adenocarcinoma cells (MCF-7) verified the specific targeting ability and enhanced antitumor activity to HT-1080 cells. The results of intravenous administration demonstrated that NGR-modified liposomes can significantly and safely accumulate in tumor tissue in xenografted nude mice. In conclusion, the liposomes constructed hold promise as a safe and efficient drug delivery system for specific tumor treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The potential predictive value of genetic polymorphisms in ovarian cancer first-line treatment is inconsistently reported. We aimed to review ovarian cancer pharmacogenetic studies to update and summarize the available data and to provide directions for further research., Methods: A systematic review followed by a meta-analysis was conducted on cohort studies assessing the involvement of genetic polymorphisms in ovarian cancer first-line treatment response retrieved through a MEDLINE database search by November 2016. Studies were pooled and summary estimates and 95% confidence intervals (CI) were calculated using random or fixed-effects models as appropriate., Results: One hundred and forty-two studies gathering 106871 patients were included. Combined data suggested that GSTM1-null genotype patients have a lower risk of death compared to GSTM1-wt carriers, specifically in advanced stages (hazard ratio (HR), 0.68; 95% CI, 0.48-0.97) and when submitted to platinum-based chemotherapy (aHR, 0.61; 95% CI, 0.39-0.94). ERCC1 rs11615 and rs3212886 might have also a significant impact in treatment outcome (aHR, 0.67; 95% CI, 0.51-0.89; aHR, 1.28; 95% CI, 1.01-1.63, respectively). Moreover, ERCC2 rs13181 and rs1799793 showed a distinct ethnic behavior (Asians: aHR, 1.41; 95% CI, 0.80-2.49; aHR, 1.07; 95% CI, 0.62-1.86; Caucasians: aHR, 0.10; 95% CI, 0.01-0.96; aHR, 0.18; 95% CI, 0.05-0.68, respectively)., Conclusion(s): The definition of integrative predictive models should encompass genetic information, especially regarding GSTM1 homozygous deletion. Justifying additional pharmacogenetic investigation are variants in ERCC1 and ERCC2, which highlight the DNA Repair ability to ovarian cancer prognosis. Further knowledge could aid to understand platinum-treatment failure and to tailor chemotherapy strategies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population., Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m 2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125., Findings: Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96-4·47] vs 2·76 months [2·60-2·96]; hazard ratio [HR] 0·757, 95% CI 0·607-0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8-30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4-18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1-2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab., Interpretation: To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma., Funding: Eli Lilly and Company., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: The efficacy of various chemotherapy regimens in nasopharyngeal carcinoma (NPC) remains under debate. We compared the efficacy and toxicity of a taxane-based regimen and regimen including fluorouracil in NPC., Materials and Methods: Eight-hundred and six patients with stage II-IVB NPC from four institutions in China were pair-matched (1:1 ratio) to the cisplatin plus fluorouracil (PF) group or cisplatin plus taxanes (TP) group using eight clinical factors. Overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method and Cox regression model. Toxicities were assessed in all patients., Results: Three-year DFS was significantly better in the TP group than PF group (82.5% vs. 72.7%, P=0.002), with no significant difference in OS, LRRFS or DMFS. TP led to significantly better DFS compared to PF in the subgroups advanced stage NPC, patients aged ≤45-years-old and female patients. In multivariate analysis, chemotherapy regimen was an independent prognostic factor for DFS [hazard ratio, 0.591, 95% CI 0.444-0.786, P=0.000]. Grade 3-4 leukopenia, neutropenia and anemia were significantly more common in the TP group; grade 3-4 mucositis, vomiting, vasculitis and diarrhea were more common in the PF group., Conclusion: Taxane-based regimens have a higher efficacy in NPC than regimens including fluorouracil, especially in patients with advanced stage, patients aged≤45-years-old and female patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: This phase II study was conducted to assess clinical efficacy of tasquinimod maintenance therapy in patients with metastatic castrate-resistant prostate cancer not progressing during first-line docetaxel-based therapy., Patients and Methods: Patients were randomly assigned (1 : 1) to receive tasquinimod (0.25-1.0 mg/day orally) or placebo. The primary end point was radiologic progression-free survival (rPFS); secondary efficacy end points included: overall survival (OS); PFS on next-line therapy (PFS 2) and symptomatic PFS, assessed using the Brief Pain Inventory (BPI) questionnaire and analgesic use. Quality of life was measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and by the EuroQol-5 Dimension Quality of Life Instrument (EQ-5D). Adverse events were recorded., Results: A total of 219 patients were screened and 144 patients randomized. The median duration of treatment was 18.7 weeks (range 0.6-102.7 weeks) for the tasquinimod arm and 19.2 weeks (range 0.4-80.0 weeks) for the placebo arm. Median (90% CI) rPFS was 31.7 (24.3-53.7) and 22.7 (16.1-25.9) weeks in the tasquinimod and placebo arms, respectively [HR (90% CI) 0.6 (0.4-0.9), P = 0.0162]. The median OS was not reached because only 14 deaths occurred by the cut-off date. No statistically significant differences between treatment arms were noted for symptomatic PFS, PFS 2, BPI score, FACT-P score, or EQ-5D. The incidence of any treatment emergent adverse event (TEAE) was similar in the tasquinimod and placebo arms (97.2% versus 94.3%, respectively), whereas severe TEAEs (NCI-CTC Grade 3-5) incidence was higher in the tasquinimod group (50.7% versus 27.1%)., Conclusions: Randomized trials testing new drugs as maintenance can be successfully conducted after chemotherapy in castrate-resistant prostate cancer. Maintenance tasquinimod therapy significantly reduced the risk of rPFS by 40%., Clinicaltrials: gov identifier NCT01732549., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC., Patients and Methods: Patients with advanced NSCLC previously treated with ≥1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m2 in Japan, 75 mg/m2 at all other study sites; day 1 in a 3-week cycle) or S-1 (80-120 mg/day, depending on body surface area; days 1-28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2., Results: A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833-1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913-1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm., Conclusion: S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC., Clinical Trial Number: Japan Pharmaceutical Information Center, JapicCTI-101155., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Premenopausal women undergoing chemotherapy are at high risk for premature ovarian failure and its long-term consequences. Data on potential markers to evaluate ovarian reserve pre- and posttreatment are limited. Anti-Müllerian hormone (AMH) known for ovarian reserve in reproductive medicine could be a surrogate marker and was assessed in premenopausal breast cancer patients of the SUCCESS A study (EUDRA-CT no. 2005-000490-21)., Methods: We identified 170 premenopausal patients, age ≤ 40 years at trial entry, who received FEC-Doc as taxane-anthracylince based chemotherapy. Blood samples were taken at three time points: Before, four weeks after and two years after adjuvant chemotherapy. Serum AMH-levels were evaluated in a central laboratory by a quantitative immunoassay AMH Gen II ELISA (Beckman Coulter, Brea, USA)., Results: Median age was 36 years (21-40 years). Median serum AMH-level before chemotherapy was 1.37 ng/ml (range < 0.1-11.3 ng/ml). Four weeks after chemotherapy AMH-levels dropped in 98.6% of the patients to <0.1 ng/ml (range < 0.1-0.21 ng/ml). After two years, 73.3% (n = 101) showed no evidence of ovarian function recovery (AMH <0.1 ng/ml, range < 0.1-3.9 ng/ml). Permanent chemotherapy induced amenorrhea occurred only in 50.6% of the patients., Conclusions: In this analysis, premenopausal patients showed a high rate of ovarian impairment reflected by low AMH-levels after chemotherapy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Induction chemotherapy must be integrated in a global approach for locally advanced head and neck cancer. Its use has theoretical advantages but should not compromise locoregional radiotherapy. Induction chemotherapy is a standard for organ preservation with the use of the TPF scheme to avoid total laryngectomy without compromising survival data. It is more controversial in other locally advanced head and neck cancer because concurrent chemoradiotherapy is the standard of care. It may be an option for patients with significant lymph node invasion to reduce the occurrence of distant metastasis., (Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Background: EORTC 24971 was a phase III trial demonstrating superiority of induction regimen TPF (docetaxel, cisplatin, 5-fluorouracil) over PF (cisplatin/5-fluorouracil), in terms of progression-free (PFS) and overall survival (OS) in locoregionally advanced unresectable head and neck squamous cell carcinomas. We conducted a retrospective analysis of prospectively collected data aiming to evaluate whether only HPV(-) patients (pts) benefit from adding docetaxel to PF, in which case deintensifying induction treatment in HPV(+) pts could be considered., Patients and Methods: Pretherapy tumor biopsies (blocks or slides) were assessed for high-risk HPV by p16 immunohistochemistry, PCR and quantitative PCR. HPV-DNA+ and/or p16+ tumors were subjected to in situ hybridization (ISH) and HPV E6 oncogene expression qRT-PCR analysis. Primary and secondary objectives were to evaluate the value of HPV/p16 status as predictive factor of treatment benefit in terms of PFS and OS. The predictive effect was analyzed based on the model used in the primary analysis of the study with the addition of a treatment by marker interaction term and tested at two-sided 5% significance level., Results: Of 358, 119 pts had available tumor samples and 58 of them had oropharyngeal cancer. Median follow-up was 8.7 years. Sixteen of 119 (14%) evaluable samples were p16+ and 20 of 79 (25%) evaluable tumors were HPV-DNA+. 13 of 40 pts (33%) assessed with HPV-DNA ISH and 12 of 28 pts (43%) assessed for HPV E6 mRNA were positive. The preplanned analysis showed no statistical evidence of predictive value of HPV/p16 status for PFS (P = 0.287) or OS (P = 0.118)., Conclusions: The incidence of HPV positivity was low in the subset of EORTC 24971 pts analyzed. In this analysis only powered to detect a large treatment by marker interaction, there was no statistical evidence that treatment effect found overall was different in magnitude in HPV(+) or HPV(-) pts. These results do not justify selection of TPF versus PF according to HPV status., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy., Materials and Methods: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level)., Results: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF., Conclusions: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy., Clinical Trial Number: NCT01086826, www.clinicaltrials.gov., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Our aim was to test the safety of cetuximab added to chemoradiation with either cisplatin or carboplatin after prior induction chemotherapy., Methods: Patients with stage III/IV unresectable, squamous cell carcinoma of the head and neck received up to four cycles of TPF-E (cisplatin and docetaxel 75 mg/m2 on day 1 followed by 5-FU 750 mg/m2/day as a continuous infusion on days 1-5 plus cetuximab at a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2), with prophylactic antibiotics but no growth factors. Patients not progressing after four cycles of TPF-E were randomly assigned to radiotherapy (70 Gy over 7 weeks in 2 Gy fractions) and weekly cetuximab with either weekly cisplatin 40 mg/m2 or carboplatin, AUC of 1.5 mg/ml/min. Primary endpoint was feasibility., Results: Forty-seven patients were recruited. One patient did not start TPF (hypersensitivity reaction during the cetuximab loading dose). Induction TPF-E was discontinued in 12 patients due to toxicity (6 patients), medical decision (2), death (1), patient refusal (1), protocol violation (1), co-morbidity (1). Three further patients were not randomized [progressive disease (1), protocol violation (1), toxicity and co-morbidity (1)]. Of particular interest are three patients who suffered from bowel perforation, one patient who died as results of pneumonia and septic shock, and a second patient who was found dead at home 12 days after starting TPF-E (cause of death unknown). Weekly cisplatin and carboplatin was stopped early in seven and four patients, respectively. Radiotherapy was stopped in two patients with cisplatin and interrupted in one patient with cisplatin and four patients with carboplatin., Conclusions: The addition of cetuximab to full dose TPF induction chemotherapy led to unacceptable complications and premature closing of the study. Only 34 out of 46 patients completed four cycles of TPF-E and only 30 started biochemoradiation., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Neoadjuvant chemotherapy (NAC) is a promising method of improving the survival of resectable gastric cancer. Cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) are both effective against metastatic gastric cancer. This report clarified the impact of these regimens on early endpoints, including the pathological responses, chemotherapy-related toxicities, and surgical results., Methods: Patients with M0 and either T4 or T3 in case of junctional cancer or scirrhous type received two or four courses of cisplatin (60 mg/m2 at day 8)/S-1 (80 mg/m2 for 21 days with 1 week rest) or docetaxel (40 mg/m2 at day 1)/cisplatin (60 mg/m2 at day 1)/S-1 (80 mg/m2 for 14 days with 2 weeks rest) as NAC. Patients then underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was the 3-year overall survival., Results: Between October 2011 and September 2014, 132 patients were assigned to receive CS (n = 66; 33 in 2 courses and 33 in 4 courses) or DCS (n = 66; 33 in 2 courses and 33 in 4 courses). The respective major grade 3 or 4 hematological toxicities (CS/DCS) were leukocytopenia (14.1%/26.2%), neutropenia (29.7%/47.7%), anemia (14.1%/12.3%), and platelet reduction (3.1%/1.5%). The rate of pathological response, defined as a complete response or < 10% residual cancer remaining, was 19.4% in the CS group and 15.4% in the DCS group, and 15.6% in the two-course group and 19.0% in the 4-course group. The R0 resection rate was 72.7% in the CS group and 81.8% in the DCS group and 80.3% in the two-course group and the 74.2% in the four-course group. No treatment-related deaths were observed., Conclusions: Our results do not support three-drug therapy with a taxane over two-drug therapy, or any further treatment beyond two cycles as an attractive candidate for the test arm of NAC., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Recent retrospective studies suggest that beta-adrenergic blocking drugs (BB) are associated with improved outcomes in patients with a range of cancers. Although limited and discordant data suggest that BB may increase overall survival (OS) in localized breast cancer (BC), there is no information on the effects of BB in women with advanced BC., Patients and Methods: To explore the association between BB use and BC outcomes, we retrospectively reviewed ROSE/TRIO-012, a double-blinded, multinational phase III trial that randomized 1144 patients with HER2-negative advanced BC to first-line docetaxel in combination with ramucirumab or placebo. We compared progression-free survival (PFS), OS, overall response rate, and clinical benefit rate in patients who received BB to those who did not., Results: 153/1144 (13%) patients received BB; 62% prior to enrolment and 38% began after enrolment. Median PFS in BB treated patients was longer than in patients who did not receive them (10.3 versus 8.3 months; HR 0.81; 95% CI 0.66-0.99; P = 0.038). Patients treated with BB only after enrolment had even higher median PFS (15.5 versus 8.3 months, P < 0.001). In the TNBC subset, median PFS was 13.0 months with BB, compared to 5.2 months without BB (HR 0.52; 95% CI 0.34-0.79; P = 0.002). The benefit of BB intake in PFS was independent of treatment-emergent hypertension (P = 0.476) but associated with treatment arm (P = 0.037). The test for interactions between BB and treatment arm was not significant (P = 0.276). No differences were seen in OS, overall response rate, or clinical benefit rate. A validation dataset analysis had consistent but less substantial improved outcomes for women with node positive operable breast cancer receiving BB in the BCIRG-005 trial., Conclusions: In this exploratory analysis, BB intake was associated with significant improvement in PFS, particularly in patients with TNBC and patients not previously exposed to BB., Clinical Trial Number: NCT00703326., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Triple negative breast cancer has the highest relapse risk of all the clinical subsets, although the escalation of chemotherapy has benefited this subset substantially over recent years. Systemic options are limited to chemotherapy, which makes meaningful de-escalation or escalation of therapy more challenging but possible. Observational cohorts suggest a less than 10% risk of relapse and minimal if any benefit of chemotherapy in very small (<1 cm), node-negative triple negative disease. In higher risk, particularly node-positive disease, anthracycline/taxane-based regimens remain standard. Neoadjuvant chemotherapy clearly de-escalates surgery, although there are insufficient data to give less than standard chemotherapy on the basis of response to neoadjuvant therapy. Efforts to meaningfully escalate therapy in high-risk disease have included incorporating platinums into Neoadjuvant therapy, with clear benefit in pCR but uncertain impact on relapse and survival at this time. Residual disease after neoadjuvant chemotherapy carries a particularly poor prognosis; a recent randomized trial of 6 months' capecitabine in this setting suggested a survival advantage to this approach in higher risk residual disease. While not validated at this time, future directions are likely to include biologic prognostication with tumor and immune variables, as well as targeted non-cytotoxic approaches leveraging the molecular heterogeneity of triple negative disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)