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Background: Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up., Patients and Methods: ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety., Results: At data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib., Conclusions: These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer., Competing Interests: Disclosure VS reports research grants from Novartis, Eli Lilly/Loxo Oncology, Roche/Genentech, Bayer, GlaxoSmithKline, NanoCarrier, VEGENICS, Celgene, Northwest Biotherapeutics, Berg Health, Incyte, Fujifilm, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfasigma, Agensys, Boston Biomedical, Idera Pharmaceuticals, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, National Cancer Institute–Cancer Therapy Evaluation Program, The University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, PharmaMar, and MedImmune; an advisory board/consultant position with Eli Lilly/Loxo Oncology, Helsinn, Incyte, QED Pharma, Daiichi Sankyo, Signant Health, Novartis, Relay Therapeutics, Roche, and MedImmune; travel funds from PharmaMar, Incyte, American Society of Clinical Oncology, and European Society for Medical Oncology; and other support from Medscape. ZAW reports consulting fees from Amgen, AstraZeneca, Daiichi Sankyo, Bayer, Bristol Myers Squibb, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, and Array; support for attending meetings/travel from Daiichi Sankyo; and advisory board participation with Array and Pfizer. JHMS reports stock ownership in and employment with Modra Pharmaceuticals; consulting fees from and advisory board participation with Debiopharm; and a patent on oral taxanes. JCS reports stock in Gritstone Bio and Relay Therapeutics; and employment with Amgen. PYW reports grants from Agios, AstraZeneca/MedImmune, BeiGene, Celgene, Lilly, Roche/Genentech, Kazia, MediciNova, Merck, Nuvation Bio, Oncoceutics, Vascular Biogenics, and VBI Vaccines; and consulting fees from/advisory board participation with Agios, AstraZeneca, Bayer, Boston Pharmaceuticals, CNS Pharmaceuticals, Elevate Bio Immunomic Therapeutics, Imvax, Karyopharm, Merck, Novartis, Nuvation Bio, Vascular Biogenics, VBI Vaccines, Voyager, QED, Celularity, and Sapience. CCZ reports consulting fees from Athenex; payment or honoraria from MSD, Imugene, AstraZeneca, Servier, Lilly, Bristol Myers Squibb, Pfizer, Merck KGaA, Amgen, Takeda, Daiichi Sankyo, Roche, Boehringer Ingelheim, Celgene, and Halozyme; patents with Imugene; and a leadership or fiduciary role with the European Society for Medical Oncology and CECOG. MEC reports grants from Genentech and Merck; payment or honoraria from Exelixis and Lilly; and advisory board participation with Exelixis, Lilly, and Bayer. AB reports stock ownership in and employment with Novartis. IP and TRS report employment with Novartis. PB reports stock ownership in Novartis and GlaxoSmithKline; and employment with Novartis. BK reports research grants from MSD, AstraZeneca, and Ono Pharmaceuticals; consulting fees from AstraZeneca, MSD, ABL Bio, Genexine, Handok, CELiD, Trial Informatics, and CBS Bio; and payment or honoraria from MSD and Merck. All authors acknowledge receipt of medical writing support for this manuscript from ArticulateScience, LLC, funded by Novartis. All other authors have declared no additional conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The PEARL study showed that palbociclib plus endocrine therapy (palbociclib/ET) was not superior to capecitabine in improving progression-free survival in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors, but was better tolerated. This analysis compared patient-reported outcomes., Patients and Methods: The PEARL quality of life (QoL) population comprised 537 patients, 268 randomised to palbociclib/ET (exemestane or fulvestrant) and 269 to capecitabine. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 and EQ-5D-3L questionnaires. Changes from the baseline and time to deterioration (TTD) were analysed using linear mixed-effect and stratified Cox regression models, respectively., Results: Questionnaire completion rate was high and similar between treatment arms. Significant differences were observed in the mean change in global health status (GHS)/QoL scores from the baseline to cycle 3 (2.9 for palbociclib/ET vs. -2.1 for capecitabine (95% confidence interval [CI], 1.4-8.6; P = 0.007). The median TTD in GHS/QoL was 8.3 months for palbociclib/ET versus 5.3 months for capecitabine (adjusted hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Similar improvements for palbociclib/ET were also seen for other scales as physical, role, cognitive, social functioning, fatigue, nausea/vomiting and appetite loss. No differences were observed between the treatment arms in change from the baseline in any item of the EQ-5D-L3 questionnaire as per the overall index score and visual analogue scale., Conclusion: Patients receiving palbociclib/ET experienced a significant delay in deterioration of GHS/QoL and several functional and symptom scales compared with capecitabine, providing additional evidence that palbociclib/ET is better tolerated., Trial Registration Number: NCT02028507 (ClinTrials.gov)., Eudract Study Number: 2013-003170-27., Competing Interests: Conflict of interest statement Z.K. has participated in advisory boards of and received speaker fees or travel support from Pfizer, Roche, AstraZeneca and Novartis. M.G-G.- has received honoraria from Pfizer and Eisai and has participated in advisory boards of Genentech and Daiichi Sankyo. He has received travel support from Pfizer, Novartis, Daiichi Sankyo, Roche and Kern. M.R.B. has received speaker fees and advisory grants from Pfizer, Novartis and Lilly. E.Ca., who has a stock and other ownership interests from Lilly, has received travel and accommodation support from Roche, and her husband, who has participated in consulting and advisory board activities with Bristol Myers Squibb, Novartis, Celgene, Roche Pharma, Janssen, Amgen, Incyte, AbbVie and Pfizer, has received travel and accommodation support from Celgene, Novartis and Bristol Myers Squibb. His institution has received research funding from Celgene, Janssen, Bristol Myers Squibb, Novartis, Roche/Genentech, Amgen, Pfizer and AbbVie. GEICAM has received research funding from Roche/Genentech, Bristol Myers Squibb, Novartis, Pfizer, Celgene, AstraZeneca, Merck Sharp & Dohme, Pierre Fabre and Takeda. E.Ci. has received advisory board honoraria from Lilly, Novartis, MSD, AstraZeneca, Pfizer and Roche and speakers' honoraria from Roche, Lilly and Pfizer, and she has received travel and congress assistance support from Pfizer and Roche. M.Mu. has received travel and congress assistance support from Roche, Novartis, Pfizer and Eisai. B.B. has received advisory board honoraria from Roche, Novartis and MSD and speakers' honoraria from Roche, Novartis, MSD, Pfizer and Pierre Fabre, and she has received travel and congress assistance support from Pfizer. M.Marg. has received advisory board fees from Roche, Novartis, Pfizer and Eisai. Her institution, ICO-Badalona. B-ARGO (Badalona Applied Research Group in Oncology) Hospital Universitari Germans Trias i Pujol, Badalona, has received research funding from Roche, Pfizer, Novartis, Lilly, AstraZeneca, Eisai and Kern, and she has received travel and congress assistance support from Roche. A.A. has received advisory board fees from Bayer, Spain. E.A. has received advisory board fees from Roche, Novartis, Pfizer, Lilly, Bristol Myers Squibb, Genomic Health and Nanostring. He has received travel support from Celgene. His institution, Hospitales Regional y Virgen de la Victoria, Málaga, has received research funding from Roche, Pfizer, Sysmex, Merck Sharp & Dohme and Nanostring. J.d.l.H-R. has received speaker's honoraria from AstraZeneca, Pfizer, Novartis and Lilly. M.R. has received honoraria from Novartis, Roche and Pfizer. I.M.A-L. has received consulting or advisory board honoraria from AstraZeneca, Pfizer, Novartis, Palex and Roche; speakers' honoraria from AstraZeneca, Pfizer, Novartis, Roche and Eisai; travel and congress assistance support from AstraZeneca, Pfizer, Roche and Eisai and research funding from Pfizer, Novartis, AstraZeneca and Roche. E.G-Y. has received honoraria and travel support and has participated in advisory boards for Pfizer, Roche, Novartis and Eli Lilly. S.G-S. has received consulting or advisory board honoraria from Pfizer, MSD, GSK and Roche and speakers' honoraria from AstraZeneca, Pfizer and Novartis. C.A.R. has received consulting or advisory board honoraria from AstraZeneca, Pfizer, Novartis, SeaGen, DaiiChi Sankyo and Roche and speakers' honoraria from MSD, Pfizer, Novartis, Roche, Nanostring, Amgen and Eisai. S.S. has received consulting or advisory board or speakers' honoraria from Roche, Eisai, Daiichi Sankyo, AstraZeneca, MSD and Genomic Health. M.C. is employed by Pfizer and has the company's stock options. X.H. is employed by Pfizer and has the company's stock options. C.Z. has received consulting fees and speaker's honoraria from Roche, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Imugene, Ariad, Pfizer, Merrimack, Merck KGaA, FibroGen, AstraZeneca, Tesaro, Gilead, Servier, Shire, Eli Lilly and Athenex. His institution, Central European Cancer Center, Wiener Privatklinik Hospital, has received fees from Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, AstraZeneca and Merck KGaA. M.Mart. has received consulting fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology and Pfizer; speakers' honoraria from AstraZeneca, Amgen, Roche/Genentech, Novartis, Daiichi Sankyo and Pfizer and contracted research fees from Roche, Novartis and PUMA. All remaining authors have declared no conflicts of interest. A complete list of the PEARL trial collaborators is provided in the Supplementary Appendix., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: This study assessed whether cetuximab 500 mg/m 2 administered every 2 weeks (Q2W), when combined with chemotherapy as a first-line (1L) treatment, was noninferior to the approved dose (400 mg/m 2 followed by 250 mg/m 2 once weekly [Q1W]) for overall survival (OS) in adults with RAS wild-type metastatic colorectal cancer (mCRC)., Methods: This pooled analysis included patients receiving 1L treatment with cetuximab Q1W or Q2W in combination with chemotherapy from post-authorisation studies with patient-level data available to the sponsor. Baseline characteristics were adjusted with a propensity score using inverse probability of treatment weighting (IPTW). Noninferiority in terms of OS was tested with a noninferiority margin for the hazard ratio (HR) of 1.25 using a Cox proportional hazards regression model. Secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and rates of lung/liver metastases resection and serious adverse events., Results: OS time was noninferior in the Q2W cohort (n = 554) compared to the Q1W cohort (n = 763), with a HR after IPTW (95% confidence interval) of 0.827 (0.715-0.956) and median OS times of 24.7 (Q1W) and 27.9 (Q2W) months. There were no major differences in PFS (HR: 0.915 [0.804-1.042]). The odds ratios (ORs) after IPTW for ORR (1.292 [1.031-1.617]) and the rates of lung/liver metastases resection (1.419 [1.043-1.932]) favoured the Q2W regimen. No differences were noted in the occurrence rate of any SAE between groups; the OR after IPTW was 1.089 (0.858-1.382)., Conclusions: The cetuximab Q2W regimen was noninferior to the Q1W regimen for OS in the 1L treatment of mCRC., Competing Interests: Conflict of interest statement SK discloses honoraria (self) from Merck, Amgen, Roche, Sanofi, Aventis, Servier, and Lilly; honoraria (institution) from Merck, Amgen, Roche, and Lilly; advisory/consultancy roles with Merck, Amgen, Roche, Sanofi, Aventis, Servier, and Lilly; research grants/funding (self) from Merck and Lilly; research grants/funding (institution) from Merck and Lilly; travel/accommodation expenses from Merck, Amgen, Roche, Sanofi, Aventis, Servier, and Lilly. FXL and CF are full-time employees of Merck KGaA, Darmstadt, Germany. RE is a full-time employee of Merck KGaA, Darmstadt, Germany, and holds shares of Merck KGaA. WC is a full-time employee of Merck Serono, Shanghai, China, an affiliate of Merck KGaA, Darmstadt, Germany. TB discloses personal fees from Roche (lecture fee), personal fees from Amgen (lecture fee, advisory board), personal fees from Bayer (lecture fee, advisory board), personal fees from Novartis (lecture fee, advisory board), personal fees from PharmaMar (lecture fee, advisory board), personal fees from Eisai (lecture fee, advisory board), and personal fees from Lilly (lecture fee, advisory board), outside the submitted work. CZ discloses consultancy and speaker's honoraria from Roche, Novartis, BMS, MSD, Imugene, ARIAD, Pfizer, Merrimack, Merck KGaA, FibroGen, AstraZeneca, Tesaro, Gilead, Servier, Shire, Lilly, and Athenex. DM and VR were employees of Prometris GmbH at the time the work was performed, which provided statistical services for Merck KGaA. All remaining authors have nothing to disclose., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In December 2017, ESMO Open-Cancer Horizons convened a round-table discussion on the background and latest data regarding cyclin-dependent kinase (CDK)4/6 inhibitors with endocrine therapy (ET) in the treatment of endocrine-sensitive breast cancer (BC). A review on this discussion was published in summer 2018 (https://esmoopen.bmj.com/content/3/5/e000368).Endocrine-sensitive BC with non-visceral disease and limited spread of the metastases.Endocrine-sensitive BC with non-life-threatening visceral involvement. Several open questions were identified, which led to a second ESMO Open discussion on CDK4/6 inhibitors, taking place in December 2018 and covered in this article. The panel discussed two important clinical scenarios and the pro and cons of a treatment approach with CDK4/6 inhibitors for each scenario:Endocrine-sensitive BC with non-visceral disease and limited spread of the metastases.Endocrine-sensitive BC with non-life-threatening visceral involvement. Regarding scenario 1, the panel agreed that CDK4/6 inhibitors should be recommended in first-line therapy for most patients if cost and practicality allow. However, the use of single-agent ET with an aromatase inhibitor in the first-line treatment of these patients is still a possibility for a small group of patients with very limited disease, such as one or two bone lesions or limited lymph node involvement. Regarding scenario 2, chemotherapy is the first approach for patients with endocrine-sensitive metastatic BC with life-threatening visceral involvement because of the need for a faster response. The therapeutic approaches for patients with non-life-threatening visceral involvement are still under debate. Nevertheless, CDK4/6 inhibitors are currently the treatment of choice for most patients with a close follow-up of tumour response. A treatment algorithm has been suggested at the round table., Competing Interests: Competing interests: MP: honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo and Merck Sharp & Dome. JG: research support from Eisai, Genomic Health, Novartis, Pfizer and Roche; travel grants from Eisai, Genomic Health, Novartis, Pfizer and Roche; honoraria for advisory boards and speaker fees from Daiichi, Eisai, Genomic Health, Ipsen, Macrogenics, MSD, Novartis, Onxeo, Pfizer and Roche. GJ: grants, personal fees and non-financial support from Novartis and Roche; personal fees and non-financial support from Pfizer, Lilly, Amgen, BMS, Astra-Zeneca; personal fees from Celgene, Puma Technology, Daiichi Sankyo and Abbvie. AA: advisory boards, travel grants, speaker fees: Novartis, Roche, Lilly, Amgen, Eisai, BMS, MSD, LeoPharma, Genomic Health and Ipsen. CS: honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Novartis, Gerson Lehrman Group, Astra-Zeneca, Lilly, Roche, Amgen, Pfitzer, Merck KGaA, and Tesaro. CCZ: honoraria from Roche, Novartis, BMS, MSD, Imugene, Ariad, Pfizer, Merrimack, Merck KGaA, Fibrogen, AstraZeneca, Tesaro, Gilead, Servier and Shire., (© Author (s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E-mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E-mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.

Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.

Background: The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1·04; 97·5% repeated CI [RCI] -∞ to 1·69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer., Methods: In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1·33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340., Findings: Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30·2 months (95% CI 25·6-32·6 months) versus 26·1 months (22·3-29·0), respectively. The stratified HR was 1·02 (97·5% RCI -∞ to 1·26; repeated p=0·0070), indicating non-inferiority. The unstratified Cox model (HR 1·13 [97·5% RCI -∞ to 1·39]; repeated p=0·061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group., Interpretation: Bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles., Funding: Roche., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Totally implanted access ports (PACs) are valuable tools for the treatment of patients with cancer because they ease the administration of chemotherapy, stem cells, and supportive care by reducing the rate of peripheral vein punctures., Objectives: The purpose of this study was to evaluate the satisfaction and impairments of activities of daily living of ambulatory patients with PAC systems receiving chemotherapy., Methods: This cross-sectional, questionnaire-based study evaluated 202 patients with PAC systems in a comprehensive cancer center and cancer rehabilitation center. From November 2012 to August 2013, patients were invited to answer a questionnaire concerning quality of life and satisfaction with their PAC devices. Data regarding PAC-related complications were collected retrospectively by searching patients' medical history., Findings: A total of 202 patients with 230 PAC devices were included. Median time from PAC implantation to inclusion in the study was nine months. Surgical complications occurred in some cases, with bleeding and hematoma being the most frequently observed events. Late complications consisted of infections, drug extravasation, PAC malposition, PAC malfunction, and thrombosis. A third of the patients reported that their PAC interfered with activities of daily living. However, most agreed that PAC systems alleviated the burden of chemotherapy administration, and the vast majority said they would choose the implantation of a PAC system for chemotherapy administration again.

Background: Correlations between development of hand-foot syndrome (HFS) and efficacy in patients receiving capecitabine (CAP)-containing therapy are reported in the literature. We explored the relationship between HFS and efficacy in patients receiving CAP plus bevacizumab (BEV) in the TURANDOT randomised phase III trial., Methods: Patients with HER2-negative locally recurrent/metastatic breast cancer (LR/mBC) who had received no prior chemotherapy for LR/mBC were randomised to BEV plus paclitaxel or BEV-CAP until disease progression or unacceptable toxicity. This analysis included patients randomised to BEV-CAP who received ⩾1 CAP dose. Potential associations between HFS and both overall survival (OS; primary end point) and progression-free survival (PFS; secondary end point) were explored using Cox proportional hazards analyses with HFS as a time-dependent covariate (to avoid overestimating the effect of HFS on efficacy). Landmark analyses were also performed., Results: Among 277 patients treated with BEV-CAP, 154 (56%) developed HFS. In multivariate analyses, risk of progression or death was reduced by 44% after the occurrence of HFS; risk of death was reduced by 56%. The magnitude of effect on OS increased with increasing HFS grade. In patients developing HFS within the first 3 months, median PFS from the 3-month landmark was 10.0 months vs 6.2 months in patients without HFS. Two-year OS rates were 63% and 44%, respectively., Conclusions: This exploratory analysis indicates that HFS occurrence is a strong predictor of prolonged PFS and OS in patients receiving BEV-CAP for LR/mBC. Early appearance of HFS may help motivate patients to continue therapy., Competing Interests: CZ has received honoraria from and acted as a consultant for Roche; SB has received honoraria from and acted as a consultant for Roche, Pfizer, AbbVie, and Novartis; ZK has acted as a consultant for Roche; DV has received honoraria from Roche and Novartis and has acted as a consultant for Roche and Sanofi Aventis; DM is an employee of a contract research organisation that provides services to F. Hoffmann-La Roche; and TB has received honoraria from Amgen, Bayer, GSK, Eli Lilly, Merck, Novartis, PharmaMar, PrimeOncology, and Roche, and has acted as a consultant for Amgen, Bayer, Novartis, and PharmaMar. The remaining authors declare no conflict of interest.

Background: The randomised phase III TURANDOT trial compared first-line bevacizumab-paclitaxel (BEV-PAC) vs bevacizumab-capecitabine (BEV-CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV-PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen., Methods: Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV-PAC (bevacizumab 10 mg kg(-1) days 1 and 15 plus paclitaxel 90 mg m(-2) days 1, 8 and 15 q4w) or BEV-CAP (bevacizumab 15 mg kg(-1) day 1 plus capecitabine 1000 mg m(-2) bid days 1-14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs., Results: The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV-PAC in the TNBC cohort and BEV-CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV-PAC. Grade ⩾3 adverse events were consistently less common with BEV-CAP., Conclusions: A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov NCT00600340).

Background: Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy., Methods: In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov, number NCT01250379., Findings: Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15·9 months (IQR 9·1-21·7) in the chemotherapy-alone group and 16·1 months (10·6-22·7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6·3 months [95% CI 5·4-7·2] vs 4·2 months [3·9-4·7], respectively, stratified hazard ratio [HR] 0·75 [95% CI 0·61-0·93], two-sided stratified log-rank p=0·0068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (<1%) of 238 patients receiving chemotherapy alone. Serious adverse events were reported in 61 (25%) of 245 patients receiving bevacizumab plus chemotherapy versus 44 (18%) of 238 patients receiving chemotherapy alone., Interpretation: These results suggest that continued VEGF inhibition with further bevacizumab is a valid treatment option for patients with locally recurrent or metastatic HER2-negative breast cancer whose disease was stabilised or responded to first-line bevacizumab with chemotherapy., Funding: F Hoffmann-La Roche., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: This randomized phase III trial compared pathologic complete response (pCR) rates of early breast cancer (EBC) following neoadjuvant epirubicin-docetaxel (ED)±capecitabine (C), and evaluated the addition of trastuzumab in HER2-positive tumors., Patients and Methods: Patients with invasive breast cancer (except T4d) were randomly assigned to receive six 3-weekly cycles of ED (both 75 mg/m2)±C (1000 mg/m2, twice daily, days 1-14). Patients with HER2-positive disease were further randomized to receive trastuzumab (8 mg/kg, then 6 mg/kg every 3 weeks) or not. Primary end point: pCR rate at the time of surgery., Results: Five hundred thirty-six patients were randomized to ED (n=266) or EDC (n=270); 93 patients were further randomized to trastuzumab (n=44) or not (n=49). pCR rate was significantly increased with EDC (23.0% versus 15.4% ED, P=0.027), and nonsignificantly further increased with trastuzumab (38.6% EDC versus 26.5% ED, P=0.212). Rates of axillary node involvement at surgery and breast conservation were improved with EDC versus ED, but not significantly; the addition of trastuzumab had no further impact. Hormone receptor status, tumor size, grade, and C (all P≤0.035) were independent prognostic factors for pCR. Trastuzumab added to ED±C significantly increased the number of serious adverse events (35 versus 18; P=0.020), mainly due to infusion-related reactions., Conclusion: These findings show that the integration of C into a neoadjuvant taxane-/anthracycline-based regimen is a feasible, safe, and effective treatment option, with incorporation of trastuzumab in HER2-positive disease., Clinical Trial Number: NCT00309556, www.clinicaltrials.gov.

Background: This randomized phase II study investigated first-line chemotherapy plus cetuximab administered every second week in KRAS wild-type metastatic colorectal cancer., Patients and Methods: Patients received FOLFOX4 plus either standard weekly cetuximab (arm 1) or cetuximab (500 mg/m(2)) every second week (arm 2), until disease progression or unacceptable toxicity. Primary end point was the objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety were also investigated. The study was not powered to establish non-inferiority, but aimed at the estimation of treatment differences., Results: Of 152 randomized eligible patients, 75 were treated in arm 1 and 77 in arm 2; ORRs [53% versus 62%, odds ratio 1.40, 95% confidence interval (CI) 0.74-2.66], PFS [median 9.5 versus 9.2 months, hazard ratio (HR) 0.92, 95% CI 0.63-1.34], OS (median 25.8 versus 23.0 months, HR 0.86, 95% CI 0.56-1.30) and DCR (87%) were comparable. HRs adjusted for baseline factors were 1.01 and 0.99 for PFS and OS, respectively. Frequencies of grade 3/4 adverse events in arms 1 versus 2 were similar: most common were neutropenia (28% versus 34%) and rash (15% versus 17%)., Conclusions: Activity and safety of FOLFOX4 plus either cetuximab administered weekly or every second week were similar.

Background: Randomised phase 3 trials in metastatic breast cancer have shown that combining bevacizumab with either paclitaxel or capecitabine significantly improves progression-free survival and response rate compared with chemotherapy alone but the relative efficacy of bevacizumab plus paclitaxel versus bevacizumab plus capecitabine has not been investigated. We compared the efficacy of the two regimens., Methods: In this open-label, non-inferiority, phase 3 trial, patients with HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease were randomised (by computer-generated sequence; 1:1 ratio; block size six; stratified by hormone receptor status, country, and menopausal status) to receive either intravenous bevacizumab (10 mg/kg on days 1 and 15) plus intravenous paclitaxel (90 mg/m(2) on days 1, 8, and 15) repeated every 4 weeks (paclitaxel group) or intravenous bevacizumab (15 mg/kg on day 1) plus oral capecitabine (1000 mg/m(2) twice daily on days 1-14) repeated every 3 weeks (capecitabine group) until disease progression or unacceptable toxic effects. Treatment allocation was not masked because of the differences in routes of administration and cycle lengths. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel. We report results of an interim overall survival analysis, which was planned for after 175 deaths in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00600340., Findings: Between Sept 10, 2008, and Aug 30, 2010, we randomised 564 patients (paclitaxel group n=285; capecitabine group n=279) from 51 centres in 12 countries. The per-protocol population consisted of 533 patients (paclitaxel group n=268; capecitabine group n=265). After median follow-up of 18·6 months (IQR 14·9-24·7), 181 patients in the per-protocol population had died (89 [33%] in the paclitaxel group; 92 [35%] in the capecitabine group). The hazard ratio [HR] for overall survival was 1·04 (97·5% repeated CI -∞ to 1·69; p=0·059); the non-inferiority criterion of the interim analysis (interim α=0·00105) was not met. More patients who received bevacizumab plus paclitaxel had an objective response than did those who received bevacizumab plus capecitabine (125 [44%] of 285 patients vs 76 [27%] of 279; p<0·0001). Similarly, progression-free survival was significantly longer in the paclitaxel group than in the capecitabine group (median progression-free survival 11·0 months [95% CI 10·4-12·9] vs 8·1 months [7·1-9·2]; HR 1·36 [95% CI 1·09-1·68], p=0·0052). The most common adverse events of grade 3 or higher were neutropenia (51 [18%]), peripheral neuropathy (39 [14%]), and leucopenia (20 [7%]) in the paclitaxel group and hand-foot syndrome (44 [16%]), hypertension (16 [6%]), and diarrhoea (15 [5%]) in the capecitabine group. One treatment-related death occurred in the paclitaxel group; no deaths in the capecitabine group were deemed to be treatment-related., Interpretation: In this planned interim analysis, the non-inferiority criterion was not met and overall survival results are inconclusive. Final results are expected in 2014. Progression-free survival was better, and more patients achieved an objective response, with bevacizumab plus paclitaxel than with bevacizumab plus capecitabine. Efficacy results in both groups were consistent with previous reports., Funding: Central European Cooperative Oncology Group; Roche., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: We report safety data from a randomised, phase III study (CECOG/BC.1.3.005) evaluating first-line bevacizumab plus paclitaxel or capecitabine for locally recurrent or metastatic breast cancer., Patients and Methods: Patients aged ≥18 years with human epidermal growth factor receptor-2-negative breast adenocarcinoma were randomised to Arm A: bevacizumab 10 mg/kg days 1 and 15; paclitaxel 90 mg/m(2) days 1, 8, and 15, every 4 weeks; or Arm B: bevacizumab 15 mg/kg day 1; capecitabine 1000 mg/m(2) b.i.d., days 1-14, every 3 weeks, until disease progression, unacceptable toxicity or consent withdrawal., Results: A post hoc interim safety analysis included 561 patients (Arm A: 284, Arm B: 277). The regimens demonstrated similar frequencies of all-grade and serious adverse events (SAEs), but different safety profiles. Treatment-related events occurred in 85.2% (Arm A) and 78.0% (Arm B) of patients. Fatigue was most common in Arm A (30.6% versus 23.5% Arm B), and hand-foot syndrome (HFS) most common in Arm B (49.5% versus 2.5% Arm A). Diarrhoea (Arm A: 0.4%, Arm B: 1.4%) and pulmonary embolism (Arm A: 0.7%, Arm B: 1.1%) were the most frequently reported SAEs., Conclusion: These findings are in-line with safety data for bevacizumab plus paclitaxel or capecitabine, reported in previous phase III trials., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Resistance to current standard therapies such as anthracyclines or taxanes limits the available options for previously treated patients with metastatic TNBC to a small number of non-cross-resistant regimens, and there is currently no preferred standard chemotherapy. Duration of response is usually short, with rapid relapse very common and median survival of just 13 months. The newly approved agent eribulin has shown a survival benefit in patients who had previously been treated with anthracycline- or taxane-containing regimens, including in patients with TNBC. Platinum-based regimens are an emerging option for patients with BRCA1 mutation, and newer targeted agents such as anti-angiogenic treatment with bevacizumab or anti-epidermal growth factor receptor treatment with cetuximab, have shown some benefit in combination therapy. However, there remains an urgent unmet need for improved targeted agents for this patient population. Improved treatment may be facilitated by biomarker-led understanding of subgroup molecular targets, which may predict benefit from currently approved agents, as well as newer targeted drugs.

Both capecitabine and bevacizumab are established agents in the treatment of metastatic breast cancer, but until recently clinical data supporting their use in combination were limited. We review available data on the capecitabine-bevacizumab combination in breast cancer, particularly results from the RIBBON-1 trial in the first-line setting, and we discuss these findings in light of previous studies. We also examine ongoing trials investigating capecitabine-bevacizumab combination therapy., (Copyright © 2012. Published by Elsevier Ltd.)

Background: Continuation of trastuzumab plus capecitabine (XH) showed a significantly improved overall response rate and time to progression compared with capecitabine (X) alone in women with HER2-positive breast cancer progressing during trastuzumab treatment. Here, we report the final analysis on overall survival., Patients and Methods: Patients with HER2-positive, advanced breast cancer who progressed during treatment with trastuzumab with or without 1st-line metastatic chemotherapy were prospectively randomised to X (2500mg/m(2) on days 1-14, q3w) or XH (6 (8)mg/kg, q3w). Overall survival was a pre-specified secondary end-point., Results: Median follow-up at June 2010 was 20.7months. Fifty nine of 74 and 60 of 77 patients died in the X and XH arm, respectively. Median overall survival was 20.6 and 24.9months with X and XH, respectively (HR=0.94 [0.65-1.35]; p=0.73). Performance status and metastatic site were independent prognosticators for overall survival. No difference between treatment arms was observed for patients who achieved clinical response or clinical benefit, respectively. Patients who continued/restarted anti-HER2 treatment (trastuzumab or lapatinib) after 2nd progression (N=52) had a post-progression survival of 18.8 compared with 13.3months for those who did not receive 3rd line treatment with anti-HER2 agents (N=88) (HR 0.63; p=0.02)., Conclusions: Final overall survival analysis of the GBG-26 study did not demonstrate a significant survival benefit for treatment beyond progression with trastuzumab. However, in a post-hoc analysis, patients receiving anti-HER2 treatment as 3rd line therapy showed a better post-progression survival than those not receiving this targeted treatment., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Bortezomib belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma. Preclinical studies suggest that bortezomib has synergistic activity with rituximab, which provides a rationale for the exploration of treatment combinations., Design and Methods: The activity and safety of bortezomib in combination with rituximab and dexamethasone were investigated in patients with relapsed or chemotherapy-refractory mantle cell lymphoma. A treatment cycle consisted of bortezomib (1.3 mg/m² on days 1, 4, 8, and 11; six 21-day cycles), rituximab (375 mg/m², day 1) and dexamethasone (40 mg orally, days 1 to 4). Responding patients received four consolidating doses of rituximab. Sixteen patients with progressive mantle cell lymphoma after a median of three prior lines of therapy were enrolled., Results: The overall response rate was 81.3% (13 patients), with seven patients achieving a complete response (43.8%). Six of these patients were also negative for disease activity by positron emission tomography scanning. The median progression-free survival and overall survival were 12.1 and 38.6 months, respectively. In patients achieving a complete response, the median progression-free survival and overall survival have not yet been reached. Adverse events (greater than grade II) included thrombocytopenia (37.5%), fatigue (18.8%) and peripheral neuropathy (12.5%). Two patients discontinued bortezomib because of grade III neuropathy., Conclusions: Bortezomib combined with rituximab and dexamethasone has promising activity and manageable toxicity in patients with heavily pretreated mantle cell lymphoma. Achievement of complete response emerged as an important factor for sustained disease control. This trial was registered at www.clinicaltrials.gov as #NCT00261612.

Background: Chemotherapy dose delay and/or reduction lower relative total dose intensity (RTDI) and may affect short- and long-term outcome of metastatic breast cancer (MBC) patients., Methods: Based on 933 individual patients' data of from 3 randomized MBC trials using an anthracycline and taxane we examined the impact of RTDI on efficacy and determined the lowest optimal RTDI for MBC patients., Results: Median time to disease progression (TTDP) and overall survival (OS) of all patients were 39 and 98 weeks. Overall higher RTDI was correlated with a shorter TTDP (log-rank p = 0.0525 for 85% RTDI cut-off). Proportional hazards assumption was violated, there was an early drop in the TTDP-curve for the high RTDI group. It was explained by the fact that patients with primary disease progression (PDP) do have a high RTDI per definition. Excluding those 114 patients with PDP the negative correlation between RTDI and TTDP vanished. However, non-PDP patients with RTDI-cut-off levels <85% showed a shorter OS than patients with higher RTDI levels (p = 0.0086)., Conclusions: Optimizing RTDI above 85% appears to improve long-term outcome of MBC patients receiving first-line chemotherapy. Lowering RTDI had no negative influence on short term outcome like OR and TTDP.

Background: Neoadjuvant chemotherapy can facilitate pancreatic resection in patients with initially unresectable pancreatic cancer (PC). We report the results of a phase II trial of gemcitabine-oxaliplatin neoadjuvant chemotherapy for patients with locally advanced, nonmetastatic PC., Methods: A prospective, phase II clinical trial using neoadjuvant chemotherapy, consisting of gemcitabine (900 mg/m(2)) and oxaliplatin (60 mg/m(2)) given as intravenous infusion once a week at day 1 of each treatment cycle (NeoGemOx protocol). Patients received 6-9 cycles of chemotherapy. Those patients with sufficient tumor regression subsequently underwent pancreatic resection and were followed postoperatively to assess long-term survival., Results: A total of 33 patients were eligible and were included in the intent-to-treat and evaluable population. On centralized review of the imaging studies, 18 patients had unresectable disease at inclusion, and 15 patients had borderline resectable PC. Eventually, 13 patients (39%) had a curative resection after neoadjuvant therapy. The R0 resection rate was 69%. Median overall survival of patients who underwent tumor resection was 22 months (95% confidence interval [CI], 14-30) compared with 12 months (95% CI, 9-15) for those without resection (P = .046). The median recurrence-free survival rate after resection was 10 months (95% CI, 4-17)., Conclusion: Neoadjuvant gemcitabine plus oxaliplatin is well tolerated and safe. Substantive tumor regression occurs in some patients with locally advanced PC treated with this neoadjuvant protocol, offering the potential for curative resection and improvement in overall survival. Additional studies involving the NeoGemOx protocol should be considered to further evaluate the safety and efficacy of this combination., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Bortezomib-dexamethasone (Btz/Dex) is an active regimen in patients with multiple myeloma and has been used in few patients with amyloidosis. Here, we report a retrospective evaluation of the efficacy and toxicity of Btz/Dex in 26 patients with AL amyloidosis (AL). Eighteen patients (69%) received Btz/Dex as first-line treatment. Organs most frequently involved were kidneys (100%) and heart (35%); five patients (19%) had less than two organs involved. The overall response rate was 54% (14 of 26 patients), with eight patients (31%) achieving a hematologic complete remission (CR). All patients who reached a CR received Btz/Dex as first-line therapy. Median time to response was 7.5 weeks. Improvement in organ function was noticed in three patients (12%). Median progression-free survival (PFS) and overall survival (OS) was 5.0 and 18.7 months, respectively; in CR patients, however, median PFS and OS have not yet been reached. Toxicities were manageable, with hematological side effects being most common. No grade 3/4 neuropathy was observed. Our results confirm the activity of bortezomib/dexamethasone in patients with AL amyloidosis and suggest that patients achieving a CR have a marked benefit for survival.

Chemotherapy-induced neutropenia is a major risk factor for infection-related morbidity and mortality and also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact the success of treatment, particularly when treatment intent is either curative or to prolong survival. In Europe, prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim (including approved biosimilars), lenograstim or pegfilgrastim is available to reduce the risk of chemotherapy-induced neutropenia. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. The need for generally applicable, European-focused guidelines led to the formation of a European Guidelines Working Party by the European Organisation for Research and Treatment of Cancer (EORTC) and the publication in 2006 of guidelines for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. A new systematic literature review has been undertaken to ensure that recommendations are current and provide guidance on clinical practice in Europe. We recommend that patient-related adverse risk factors, such as elderly age (≥65 years) and neutrophil count be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy. It is important that after a previous episode of FN, patients receive prophylactic administration of G-CSF in subsequent cycles. We provide an expanded list of common chemotherapy regimens considered to have a high (≥20%) or intermediate (10-20%) risk of FN. Prophylactic G-CSF continues to be recommended in patients receiving a chemotherapy regimen with high risk of FN. When using a chemotherapy regimen associated with FN in 10-20% of patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Clinical evidence shows that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications where indicated. Filgrastim biosimilars are also approved for use in Europe. While other forms of G-CSF, including biosimilars, are administered by a course of daily injections, pegfilgrastim allows once-per-cycle administration. Choice of formulation remains a matter for individual clinical judgement. Evidence from multiple low level studies derived from audit data and clinical practice suggests that some patients receive suboptimal daily G-CSFs; the use of pegfilgrastim may avoid this problem., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Introduction: Recently, histology has emerged as a predictive factor for pemetrexed efficacy in non-small cell lung cancer (NSCLC). These analyses evaluate whether the differential efficacy of pemetrexed by NSCLC histology is reproducible and consistent across three registration studies of different lines of therapy (first-line/second-line and maintenance settings)., Methods: The reported studies for patients with advanced NSCLC were pemetrexed versus docetaxel in previously treated patients (N = 571), cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients (N = 1725), and maintenance pemetrexed plus best supportive care versus placebo plus best supportive care (N = 663). Cox models of overall survival (OS) and progression-free survival (PFS) were used to test for a significant treatment-by-histology interaction (THI). A significant THI indicates that the efficacy benefit for pemetrexed relative to the control arm is greater in patients with nonsquamous histology than in those with squamous histology. Subsequent Cox models were used to estimate hazard ratios for OS and PFS according to histology., Results: Histology was well balanced between treatment arms in each study. Across all three studies, no clinically relevant differences were observed for the safety profile of pemetrexed among histologic groups. THIs were statistically significant in all three studies for OS (p = 0.001, 0.002, and 0.033, respectively) and PFS (p = 0.004, 0.002, and 0.036, respectively)., Conclusions: These analyses demonstrate a statistically significant interaction between treatment effect and NSCLC histology, indicating superior efficacy of pemetrexed in nonsquamous patients compared with other standard treatment options. Thus, histology is consistently predictive of the improved efficacy of pemetrexed in patients with nonsquamous NSCLC.

Aim: Peritoneal mesothelioma (PM) has rarely been studied. The Expanded Access Program (EAP) provided access to 109 patients with PM., Methods: This was a nonrandomized, open-label study conducted in chemo-naïve or previously treated patients with PM not amenable to curative surgery. Patients received pemetrexed (PEM) 500 mg/m2 alone or with cisplatin (CIS) 75 mg/m2 or carboplatin (CARBO) AUC 5 every 21 days, supplemented with standard vitamin B(12), folate, and dexamethasone., Results: Response rates (95% CI) for PEM, PEM/CIS, and PEM/CARBO were 12.5% (3.5, 29.0), 20.0% (7.7, 38.6), and 24.1% (10.3, 43.5), respectively. Median survival for PEM was 10.3 months. One-year survival rates for PEM/CIS and PEM were 57.4% (95% CI: 10.3, 100) and 41.5% (95% CI: 4.6, 78.4), respectively, and were not available for PEM/CARBO. Anemia was the most common serious adverse event (6.4%). Neutropenia (34.6%) was the most frequent CTC grade 3 or 4 toxicity reported., Concluding Statement: PEM with or without a platinum agent was both active and well tolerated in patients with peritoneal mesothelioma.

Purpose: Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression., Methods: Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m(2) body-surface area on days 1 through 14 [1,250 mg/m(2) semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression., Results: We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus-trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity., Conclusion: Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastuzumab treatment.

Purpose: Patients with colorectal cancer (CRC) and liver metastases have a poor prognosis, but can benefit from perioperative chemotherapy and disease resection. Bevacizumab improves outcomes in patients with metastatic CRC; however, its impact on surgical complications and hepatic regeneration after liver resection remains to be determined., Patients and Methods: Fifty-six patients with metastatic CRC with liver metastases potentially curable by resection were eligible for this single-center, nonrandomized phase II trial. Eligibility criteria defined patients at high risk of early recurrence. Patients received biweekly bevacizumab plus capecitabine and oxaliplatin for six cycles. The sixth cycle of therapy did not include bevacizumab, resulting in 5 weeks between the last administration of bevacizumab and surgery., Results: Objective response to neoadjuvant chemotherapy was achieved in 41 patients (73%). Fifty-two patients underwent liver resection including 11 with synchronous primary tumor resection. No increased intraoperative bleeding events or wound-healing complications were observed and only three patients (6%) required perioperative blood transfusions. Further surgery was necessary in a single patient. Postoperative liver function and regeneration were normal in all but one patient. No postoperative mortality occurred and morbidity was encountered in 11 patients (20%). The mean length of postoperative hospitalization was 9 days (+/- 4.0)., Conclusion: These data suggest that bevacizumab can be safely administered until 5 weeks before liver resection in patients with metastatic CRC without increasing the rate of surgical or wound healing complications or severity of bleeding. To our knowledge, they are also the first to show that neoadjuvant bevacizumab does not affect liver regeneration after resection.

Background: As patients with B-cell lymphomas suffering from an underlying autoimmune condition undergoing therapy with the CD20 antibody rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) offer the unique possibility of monitoring effects of therapy on various rheumatologic parameters, we have evaluated serologic autoimmune markers and the clinical outcome of patients with autoimmune diseases (ADs) who received lymphoma treatment with R-CHOP during the course of their disease., Patients and Methods: We have retrospectively analysed 13 patients with non-Hodgkin's lymphoma who concurrently suffered from ADs and were treated with the R-CHOP regimen. Subjective parameters along with rheumatoid factor (RF) and antinuclear antibodies (ANA) were serially measured., Results: The median levels of RF were 901 IU/ml [inter-quartile-range (IQR) 189-2520] before and 75 IU/ml (IQR 45-644) after therapy (P = 0.028). The median levels of ANA were 800 (IQR 140-2560) before and 100 (40-1280) after therapy (P = 0.027). Ten (77%) patients showed clinical improvement of their autoimmune symptoms, two (15%) reported no difference and one (7%) patient with rheumatoid arthritis-related worsening symptoms during therapy with R-CHOP. The autoimmune-related symptoms recurred after a median time of 7 weeks (IQR 6-8) in seven patients. In terms of lymphoma response, 11 patients achieved a complete remission and two a partial remission., Conclusions: This analysis indicates that R-CHOP given for lymphoma treatment is also effective for therapy of concurrent rheumatoid diseases. Both rheumatoid parameters as well as clinical symptoms showed a significant decrease during treatment with this immunochemotherapy. The effects on the rheumatic diseases, however, seem to be of limited duration.

Background: The objectives of this phase III trial were to compare the time to progressive disease (TtPD), overall response rate (ORR), overall survival, and toxicity of gemcitabine, epirubicin, and paclitaxel (GET) versus fluorouracil (FU), epirubicin, and cyclophosphamide (FEC) as first-line therapy in patients with metastatic breast cancer (MBC)., Patients and Methods: Female patients aged 18 to 75 years with stage IV and measurable MBC were enrolled and randomly assigned to either gemcitabine (1,000 mg/m(2), days 1 and 4), epirubicin (90 mg/m(2), day 1), and paclitaxel (175 mg/m(2), day 1) or FU (500 mg/m(2), day 1), epirubicin (90 mg/m(2), day 1), and cyclophosphamide (500 mg/m(2), day 1). Both regimens were administered every 21 days for a maximum of eight cycles., Results: Between October 1999 and November 2002, 259 patients (GET, n = 124; FEC, n = 135) were enrolled. Baseline characteristics were well balanced across treatment arms. After a median of 20.4 months of follow-up, median TtPD was 9.1 months and 9.0 months in the GET and FEC arms, respectively (P = .557). The ORR was 62.3% in the GET arm (n = 114) and 51.2% in the FEC arm (n = 129; P = .093). Grade 3 and 4 toxicities, including neutropenia, thrombocytopenia, anemia, stomatitis, neurosensory toxicity, and allergy, occurred significantly more often in the GET arm., Conclusion: No significant differences in terms of TtPD and ORR were observed between the two treatment arms. Treatment-related toxicity was higher in the GET arm.

It has been established that high-dose chemotherapy (HDT) improves the therapeutic outcome of patients with multiple myeloma (MM) as compared with standard-dose therapy (SDT); however, little is known about the impact of HDT on different prognostic groups of MM patients. We therefore compared the survival times of 77 patients with previously untreated MM who were enrolled in HDT regimens with those of 64 similar patients <65 years old, who would be eligible for HDT but were treated by SDT. Overall, HDT was superior to SDT with respect to achievement of complete remissions (28% versus 2%; P <0.0001) and improvement of progression-free survival (PFS) (30.2 versus 21.2 months; P = 0.01) as well as overall survival (OS) (median 54.9 versus 49.4 months; P = 0.048). According to the chromosome 13q14 status as determined by fluorescence in situ hybridization and serum levels of beta(2)-microglobulin (beta(2)M), MM patients were separated into a standard-risk group (normal chromosome 13q14 and beta(2)M 4 mg/l). Among patients of the high-risk group, both PFS (26.4 versus 10.7 months; P = 0.004) and OS times (40 versus 23 months; P = 0.05) were longer in patients receiving HDT compared with patients treated by SDT. In the standard-risk group, PFS and OS times were not significantly different between HDT patients and SDT patients. Results of this retrospective analysis suggest that the beneficial effects of HDT are greater in MM patients with high-risk features than in patients with absence of such poor prognostic indicators.

Five human soft tissue sarcoma (STS) cell lines (HTB-82 rhabdomyosarcoma, HTB-91 fibrosarcoma, HTB-92 liposarcoma, HTB-93 synovial sarcoma and HTB-94 chondrosarcoma) were analysed for their sensitivity to tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and the function of the TRAIL apoptotic pathway in these cells. TRAIL induced significant apoptosis (>90%) in HTB-92 and HTB-93 cells, whereas no effect was observed in HTB-82, HTB-91 and HTB-94 cells. TRAIL-Receptor 1 (TRAIL-R1) was expressed in TRAIL-sensitive HTB-92 and HTB-93 cell lines, but not in TRAIL-resistant HTB-91 and HTB-94 cells. HTB-82 cells, which expressed the long (c-FLIP(L)) and short (c-FLIP(S)) splice variants of the FLICE-like inhibitory protein (FLIP), were resistant to TRAIL in spite of the presence of TRAIL-R1. TRAIL-R2,-R3,-R4 and osteoprotegerin (OPG) expression did not correlate with TRAIL sensitivity. Coincubation of TRAIL and doxorubicin led to the overexpression of TRAIL-R2 resulting in a synergistic effect of doxorubicin and TRAIL in TRAIL-sensitive cell lines and in the overcoming of TRAIL-resistance in all of the TRAIL-resistant cell lines, except HTB-91, which lacked caspase 8 expression. These data suggest that TRAIL, either as a single agent or in combination with cytotoxic agents, might represent a new treatment option for advanced STS, which constitutes a largely chemotherapy-resistant disease.

Background: This phase II study evaluated the feasibility and efficacy of alternating and sequential regimens of docetaxel and doxorubicin as first-line chemotherapy for metastatic breast cancer (MBC)., Patients and Methods: Women with MBC requiring first-line chemotherapy for progressive disease (n = 106) were randomized and received 3-weekly monotherapy with docetaxel (T, 100 mg/m2, 1-h i.v. infusion) and doxorubicin (A, 75 mg/m2, 20-30-min i.v. infusion) either on a cycle-by-cycle alternating basis (ATATATAT, n = 51) or sequentially each for four cycles (TTTTAAAA, n = 55)., Results: For both regimens, the median number of cycles administered was the maximum of eight. The alternating and sequential groups achieved similar objective tumor response rates (60% and 67%, respectively) and similar median duration of response (47 and 44 weeks, respectively). With a median follow-up of 31 months, median survival times were estimated at 20 and 26 months in the alternating and sequential groups, respectively. No unexpected toxicities were reported. Compared with alternating therapy, patients receiving sequential therapy were more likely to complete the planned eight chemotherapy cycles (69% versus 63%), and had a lower incidence of febrile neutropenia (2% versus 14%)., Conclusions: Alternating and sequential docetaxel-doxorubicin regimens are viable alternatives to simultaneous combination therapy in MBC, with sequential therapy achieving slightly higher response rates and improved tolerability compared with alternating therapy.

Background: Recent data suggest that chemotherapy with the cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen is a highly effective treatment for localised primary gastric lymphoma of diffuse large B-cell histology (DLBCL). We have reported that the large majority of patients achieve complete remission (CR) following three cycles of treatment, and now provide an updated series with special emphasis on patients receiving only short-term chemotherapy., Patients and Methods: All patients with a histologically verified diagnosis of gastric DLBCL in stages EI and EII(1) undergoing chemotherapy with the CHOP regimen were evaluated. Data analysed included clinical stage, histology [presence of an additional mucosa-associated lymphoid tissue (MALT) component], evidence of Helicobacter pylori infection, H. pylori eradication, time to CR, survival and regular restaging (i.e. after three and six cycles, respectively)., Results: A total of 37 patients with DLBCL of the stomach with localised disease were identified, five of whom also had a MALT component. Twenty-two patients presented with stage EI and 15 with stage EII(1) disease. All patients were given chemotherapy as sole management of their lymphoma; 36 patients received CHOP, while one patient was given CHOP along with rituximab. Thirty-two (86%) achieved a CR after a maximum of three cycles, while only four patients had to be given six cycles for CR. In total, nine of 37 patients (24%) discontinued therapy earlier than scheduled: one patient received one cycle, two received two, six received three and one patient received four cycles. Two of these patients stopped treatment due to toxicity, i.e. protracted thrombocytopenia or chemotherapy extravasation. One additional patient died after one cycle of treatment; autopsy disclosed no signs of remaining lymphoma. Three patients have died after a median follow-up of 39 months (including the one patient who discontinued therapy after one cycle of treatment), while the remaining 34 patients are alive without evidence of disease. Twenty-four out of 37 patients (65%) had also undergone H. pylori eradication (including six of nine patients receiving only short-term treatment)., Conclusions: DLBCL of the stomach appears to be a highly chemosensitive disease. Our data question the need for full-term CHOP treatment in patients achieving CR upon first follow-up. However, recent data suggest that additional H. pylori eradication might have contributed to the excellent results achieved in our series.

Purpose: The aim of this study was to investigate the severity and time-course of alterations in gastroduodenal and intestinal permeability in relation to nausea/emesis following administration of the highly emetogenic polydrug regimen IFADIC (ifosfamide, Adriamycin, dacarbazine) using a differential lactulose/mannitol absorption (SLM) test. We also assessed the ease of administration and patients' tolerance of the SLM test., Methods: The SLM test was performed in seven patients with soft tissue sarcomas on days 1, 3 and 14 of cycle I and cycle III of chemotherapy; seven healthy volunteers served as controls. The degree of correlation between the clinical grade of nausea/emesis according to WHO criteria and gastroduodenal permeability, expressed in terms of urinary sucrose excretion, and intestinal permeability, expressed in terms of the permeability index (urinary lactulose to mannitol permeability ratio), was also assessed., Results: The permeability index values were significantly different (P < or =0.01) on days 1, 3 and 14 during both cycles of chemotherapy. The median permeability index on day 3 was higher (P < =0.01) in patients with nausea/emesis than in those without symptoms. Additionally, the permeability index when nausea was present (day 3) was higher (P < or =0.01) than when nausea/emesis was absent (days 1 and 14). In 59% of patients the increased permeability index on day 3 was accompanied by nausea/emesis of WHO grade 3. Gastroduodenal permeability did not alter consistently following chemotherapy., Conclusions: Our study confirms an acute, transient increase in intestinal permeability following the polydrug regimen IFADIC, accompanied by nausea/emesis of WHO grade 3 in the majority of patients. Normal intestinal permeability was achieved on day 14 in all patients, thus allowing intensified 2-weekly treatment administration. The SLM test may be recommended as a feasible test for the objective assessment of alterations in intestinal permeability following chemotherapy administration.

The present phase II trial was performed to assess the efficacy and toxicity of polychemotherapy with gemcitabine and cisplatin in patients with locally advanced or metastatic carcinoma of the pancreas. Sixteen patients received six courses of an i.v. cytotoxic regimen consisting of gemcitabine (1000 mg/m2, days 1, 8 and 15) and cisplatin (35 mg/m2, days 1, 8 and 15) administered in 28-day intervals. Complete remission (CR) occurred in one patient (6%), partial remission (PR) in four patients (25%) and stable disease in seven patients (44%), whereas four patients (25%) developed progressive disease resulting in an overall response rate of 31%. Mean duration of responses (CR+PR) was 3.6 (range 0.7-8.5) months and mean time to progression was 7.4 (range 3.8-12.6) months. After a mean observation period of 11.5 months the overall survival was 9.6 months with 12 patients (75%) still being alive, which compares favorably with historical data of the administration of gemcitabine alone. The performance status improved in three (19%) and stabilized in eight (50%) out of 16 patients for 4 weeks or longer. Treatment-associated toxicity included alopecia of WHO grade III in all cases, leukopenia of WHO grades I and II in 10 patients (63%), grade III in five patients (31%), and thrombocytopenia grades I and II in four patients (25%), and grades III and IV in 10 patients (63%). We conclude that the administered dosage and schedule of gemcitabine and cisplatin in patients with locally advanced or metastatic cancer of the pancreas constitutes an active cytotoxic regimen associated with moderate toxicity.

Background: Because of the known efficacy of several cytokines in the treatment of advanced renal cell cancer (RCC), we have conducted a phase II trial of the efficacy and toxicity of subcutaneous interferon gamma (IFNgamma) and interleukin-2 (IL-2)., Methods: 63 patients with progressive metastatic RCC were treated with 100 microg recombinant IFNgamma1b administered three times weekly during weeks 1 and 2 and with 4.5 MU recombinant IL-2 administered on 4 consecutive days during weeks 3 and 4, every 6 weeks., Results: 11% of patients had an objective response (CR: 3%, PR: 8%), 33% had SD. Toxicity was generally mild. The median duration of remissions (CR + PR) was 9.6 months; the median duration of SD 8 months. A significant survival benefit was evident at a median observation time of 51 months for patients (44%) responding to therapy (P < 0.0001)., Conclusions: we conclude that sequential treatment with IFNgamma and IL-2 may prolong survival in patients with metastatic RCC responding to therapy.

The aim of this phase II study was to investigate the therapeutic value of second-line treatment with oxaliplatin, irinotecan (CPT-11) and mitomycin C (MMC) in patients with metastatic colorectal cancer pretreated with 5-fluorouracil (5-FU)-based chemotherapy. A total of 10 patients with metastatic colorectal cancer, all of whom had developed progressive disease from advanced or metastatic colorectal cancer while receiving or within 6 months after discontinuing first-line chemotherapy with 5-FU and leucovorin, were entered in this study. At the time of relapse, cytotoxic chemotherapy consisting of oxaliplatin 80 mg/m2 plus CPT-11 80 mg/m2 given i.v. on therapeutic day 1, and MMC 6 mg/ m2 given i.v. on day 15, respectively, was initiated. Treatment courses were repeated every 4 weeks for a total of six courses unless there was prior evidence of progressive disease. The overall response rate was 30% with three partial responses for all 10 assessable patients. Two additional patients (20%) had stable disease and five patients (50%) progressed. The median overall survival duration has not been reached yet and is longer than 7.1 months (range 2-23.5+) from the beginning of second-line therapy. Four patients are currently alive with progressive disease. The tolerance of second-line treatment was generally mild to moderate and easy to treat. Our data suggest that the combination of oxaliplatin, CPT-11 and MMC in patients with metastatic colorectal cancer pretreated with 5-FU-based chemotherapy is feasible and has substantial antitumor activity. Further evaluation of this regimen seems warranted.

Purpose: Glutathione has been shown to be an effective chemoprotector against cisplatin-induced side effects in patients with ovarian cancer. In view of this fact, we performed a randomized clinical pilot-trial in the management of other solid tumors in order to compare application of Glutathione to intensive hydration in patients undergoing chemotherapy with a regimen including cisplatin., Patients and Methods: Twenty patients suffering from advanced non small cell lung cancer (n = 6) or head- and neck cancer (n = 14) were enrolled in the study. All patients received 80 mg/m2 cisplatin along with etoposide or 5-fluorouracil every 4 weeks. Patients randomized to application of Glutathione (n = 11) received 5 g of Glutathione immediately before application of cisplatin followed by 2000 ml of normal saline. Patients in the control group (n = 9) received 2000 ml electrolyte infusion before and 2000 ml of normal saline with forced diuresis after cisplatin., Results: The intensity of hematologic toxicity was significantly less pronounced in patients treated with Glutathione than in the control group (hemoglobin: 10.7 vs 9.5 mg% respectively, p = 0.039; white blood cell count 3.3 vs 2.2 x 103/microliter respectively, p = 0.004; platelets 167 vs 95 x 103/microliter respectively, p = 0.02), whereas in terms of non-hematologic toxicity no difference was observed. Objective remission occurred in 6 out of 11 evaluable patients from the group receiving Glutathione (55%; complete remission: 9%; partial remission: 46%), and in 4 out of 8 evaluable patients from the control group (partial remission: 50%). However, there was no statistical difference in terms of response and overall survival (13.5 months vs. 10.5 months) between the two groups., Conclusions: Application of Cisplatin and Glutathione seems to be safe and feasible and the antitumoral efficacy of cisplatin is apparently not impaired by the concomitant use of Glutathione in patients with solid tumors.

Objectives: To investigate the impact of polychemotherapy on cellular immunity in patients with testicular cancer., Methods: Lymphocyte subpopulations, lymphoproliferative responses to mitogenic stimulation, and mitogen-induced release of soluble interleukin-2 receptor from peripheral blood mononuclear cells were investigated in 15 patients with testicular germ cell tumors a median of 61 months (range 7 to 73) after polychemotherapy with bleomycin, etoposide, and cisplatin (BEP)., Results: The numbers of peripheral blood T cells (CD3+), CD4+ and CD8+ subsets, and lymphoproliferative responses to pokeweed mitogen, phytohemagglutinin, and concanavalin A in patients were comparable to those of healthy control subjects. When two groups of patients were formed according to elapsed time from BEP polychemotherapy and study onset (group A, 12 months and group B, 69 months after termination of BEP), a significant increase in lymphoproliferative response to concanavalin A (P <0.05) was found in group A 1 year after chemotherapy., Conclusions: BEP chemotherapy administered to patients with testicular cancer does not result in impairment of cellular immunity but rather leads to a significant increase in the capacity of patients' lymphocytes to respond to mitogenic stimulation up to 1 year after polychemotherapy. Moreover, the increased T-cell activity found after BEP therapy may contribute to the high rate of long-term complete remission.

Despite standard-dose adjuvant chemotherapy, the prognosis for patients with breast cancer and extensive axillary lymph node involvement at diagnosis is poor. The efficacy of a paclitaxel-containing, high-dose chemotherapy protocol in 21 high-risk breast cancer patients is assessed. After standard-dose chemotherapy followed by peripheral blood stem cell (PBSC) mobilization, high-dose therapy with paclitaxel, carboplatin, and cyclophosphamide and CD34-selected PBSC rescue was given. Hematologic reconstitution after high-dose therapy was rapid. Main toxicity included diarrhea grade I or II in about half of the patients and infections were observed in 19%. Five-year probabilities for relapse and failure-free survival were 32% and 62%, respectively. High-dose consolidation with paclitaxel, carboplatin, and cyclophosphamide achieves a high failure-free survival in patients with high-risk breast cancer with acceptable toxicities and stable, long-term hematopoietic reconstitution. Evaluation of the benefit of high-dose therapy in these patients in larger prospective, randomized trials is warranted and currently under way.

Background and Objectives: Surgery is the main treatment for extra-abdominal desmoid tumors, but the results of further management remain uncertain. Therefore, a retrospective analysis was undertaken to evaluate the toxicity and efficacy of treatment with interferon-alpha (IFN-alpha) +/- tretinoin in this setting., Methods: Thirteen patients with extra-abdominal desmoid tumors and a median age of 32 years (range, 15-73) received IFN-alpha. Seven of these patients received a combination of IFN-alpha and tretinoin in order to test further enhancement., Results: After a mean observation period of 27 +/- 15 months (mean +/- standard deviation) under treatment with IFN-alpha +/- tretinoin, local control was seen in 11 of 13 patients (85%). Seven patients had no evidence of disease at a mean disease-free interval of 22 +/- 18 months; in two patients progressive disease occurred after only 7 and 9 months, respectively, of observation. In another four patients, progression of the desmoid tumor was stabilized., Conclusions: The data of this retrospective, nonrandomized study on therapy with IFN-alpha +/- tretinoin suggest that such treatment may be effective in prolonging the disease-free interval of patients after intralesional or marginal surgery. Because of the encouraging response rate, this regimen appears to be another nonsurgical treatment alternative., (Copyright 2000 Wiley-Liss, Inc.)

Objectives: The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) is currently considered the most effective chemotherapy for metastatic transitional cell cancer (TCC) of the urinary tract, but because of its considerable toxicity, alternative regimens appear very interesting. We evaluated the efficacy and toxicity of a combination of paclitaxel and carboplatin as first-line therapy for metastatic TCC., Methods: Thirty-two patients (8 women, 24 men; mean age 67.03 years, range 50 to 79) with metastatic TCC of the bladder or upper urinary tract were included in the study. Paclitaxel (175 mg/m2) was given as a 3-hour intravenous infusion, carboplatin was dosed to an area under the plasma concentration curve of 5 mg/m/min calculated according to the Calvert formula [(creatinine clearance + 25) x 5] as a 30-minute intravenous infusion immediately after paclitaxel. Response evaluation was performed after every 2 cycles and additional therapy depended on response. The maximum number of cycles was 6., Results: With a mean follow-up of 13.1 months (range 2 to 28), 23 of 32 patients responded to treatment (response rate 71.9%), with 31.3% complete remission (CR) (10 of 32) and 40.6% partial remission (PR) (13 of 32). Four patients (12.5%) had stable disease, and 5 patients (15.6%) showed progression. These results compare well with the outcome after MVAC. Toxicity was mainly characterized by neurotoxicity grade 3 and 4 in 9.4%, grade 3 and 4 leukopenia in 37.5%, and grade 3 thrombocytopenia in 3.1% of the patients. No nephrotoxicity was observed, but all patients developed alopecia. Time to progression after CR was a mean of 7.0 months (range 4 to 13) and after PR a mean of 5.9 months (range 2 to 9)., Conclusions: Paclitaxel/carboplatin is an effective therapy for metastatic TCC, with low toxicity.

The present phase II trial was undertaken to assess the efficacy and toxicity of a combination of paclitaxel and carboplatin as first-line chemotherapy in patients with metastatic transitional cell carcinoma of the urothelium. Twenty patients (age range 50-79 years; inclusion criteria: WHO performance status 0-2, no previous cytotoxic treatment) with metastatic transitional cell carcinoma of the urothelium were recruited and received cytotoxic treatment with paclitaxel at a dosage of 175 mg m(-2) administered over a 3-h infusion and carboplatin given at an AUC of 5 mg ml(-1) min (according to creatinine clearance) administered every 21 days. A total of 65% of patients achieved remissions (CR+PR), with CR occurring in 40% of patients. A further 15% of patients experienced stable disease. Remissions occurred after 2.4 +/- 0.8 (mean +/- standard deviation; range two to four) treatment cycles. The mean duration of responses (CR+PR) was 8.5 +/- 5.5 months. After a mean observation period of 11.4 +/- 4.8 months, 16 patients (80%) are alive. Toxicity included alopecia of WHO grade 3 in all patients, leucopenia of WHO grades 1 and 2 in ten patients, grade 3 in eight and grade 4 in two patients and, finally, severe thrombocytopenia grade 3 in only three patients. Non-haematological toxicity consisted of polyneuropathy of WHO grade 1 in 13 patients and grade 2 in five patients. We thus conclude that a combination of paclitaxel and carboplatin at the given dosage and schedule constitutes an active, well-tolerated first-line cytotoxic treatment for patients with metastatic urothelial cancer.

A randomised phase II/III study was conducted in patients with advanced breast cancer to determine the dose intensity achievable through an acceleration of administration of chemotherapy with epidoxorubicin and cyclophosphamide (EC) alone, as compared with the combination of this regimen with two different schedules of granulocyte-macrophage colony stimulating factor (GM-CSF). 73 patients received EC intravenous (i.v.) (epidoxorubicin 100 mg/m2, cyclophosphamide 600 mg/m2) on day 1 (group A), or the same chemotherapy plus sub-cutaneous (s.c.) GM-CSF (5 micrograms/kg/day) either from days 3 to 12 (group B) or from days -6 to -3 (group C). The primary objective of the study was the investigation of dose intensity delivered in the three treatment arms, whereas the secondary objective was response rate. A significant increase (P = 0.006) in dose intensity of 21% was observed for treatment group B, whereas the increase in dose intensity achieved in group C (7%) was not significant (P = 0.086). Response rates (complete response (CR) + partial response (PR)) of 56% were observed in group A, 65% in group B, and 57% in group C, respectively. This difference in response rates did not reach statistical significance (P = 0.271). We thus conclude that an acceleration of the EC regimen over the standard schedule could be accomplished with postchemotherapeutic GM-CSF support, leading to an increase in dose intensity, whereas pretherapeutic short-term GM-CSF administration did not reach this goal.

Purpose: A phase III study was performed in patients with metastatic breast cancer (MBC) to evaluate the effect on response rate and survival of a doubling of the epirubicin dose intensity., Patients and Methods: Four hundred fifty-six patients were randomised to receive either epirubicin 100 mg/m2 or 50 mg/m2 in combination with 5-FU (500 mg/m2) and cyclophosphamide (500 mg/m2) (FEC 100 vs. FEC 50) i.v., every 21 days for a maximum of six cycles (eight in case of CR)., Results: Of 456 patients, 390 were evaluable for efficacy. Objective response (CR + PR) was seen in 57% (FEC 100) vs. 41% (FEC 50) of the evaluable patients (P = 0.003). The CR rate was higher in the FEC 100 arm (12% vs. 7%, P = 0.07). FEC 100 produced significantly higher response rates in patients with visceral localisation (50% vs. 34%, P = 0.011) and in patients with more than two metastatic organ sites (64% vs. 37%, P = 0.001). Median time to progression (7.6 vs. 7 months) and overall survival (18 months vs. 17 months) were similar. Myelosuppression was the principal toxic effect, with grade IV neutropenia observed in 57% of the patients treated with FEC 100 vs. 9% of those on FEC 50. Grade IV infection or febrile neutropenia were observed in 8% (FEC 100) vs. 0.4% (FEC 50), but the incidence of septic death was the same in the two arms (two patients each). Cardiac toxicity was similar in the two treatment groups, with 5% vs. 3% of the patients taken off study due to cardiac events, primarily due to a decline in LVEF. Only three patients (two in FEC 100) experienced congestive heart failure., Conclusion: This trial shows that FEC with epirubicin at 100 mg/m2 can be administered for repeated cycles without bone marrow support with increased, though acceptable, toxicity and with a significant increase of antitumor effect (especially in visceral and/or high-burden disease), but no increased survival.

Background: Patients with testicular cancer can be cured by cisplatin-based chemotherapy in many cases. Thus, concern about possible late toxicities of treatment is warranted., Methods: In this investigation, the absolute number of natural killer (NK) cells according to their CD56+ phenotype, NK cell activity, and antibody dependent cellular cytotoxicity (ADCC) were investigated in 29 patients with seminomas or nonseminomatous germ cell tumors (NSGCT) a median of 31 months (range, 5-73 months) after termination of chemotherapeutic treatment., Results: No difference in the absolute number of NK cells, NK cell activity, and ADCC was found between patients with testicular cancer after either standard polychemotherapy consisting of bleomycin, etoposide, and cisplatin (BEP) or monotherapy with carboplatin and healthy control subjects. When patients were analyzed further using multivariate analysis, a significant (P < 0.05) detrimental influence of BEP polychemotherapy versus carboplatin monotherapy on NK cell activity was found. Moreover, NK cell activity also depended significantly (P < 0.05) on the time elapsed after chemotherapy was administered, but normalized with time. Because the absolute number of NK cells was not affected, is was assumed that polychemotherapy induced a functional defect. In a subanalysis of patients with NSGCTs, metastases at diagnosis resulted in a significant (p < 0.05) and persistent stimulation of NK cell activity but not of ADCC., Conclusion: Cytostatic chemotherapy in patients with testicular cancer did not lead to compromised lytic effector cell function as assessed by NK cell activity and ADCC. However, a short, time-dependent reduction was found that also depended on the intensity of chemotherapeutic treatment. This finding related to the observation of a long-lasting stimulus of NK cell activity by initial metastases in patients with NSGCTs.