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Background: Mismatch repair-deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited., Methods: We conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses., Results: Of 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease., Conclusions: In patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrials.gov number, NCT03026140.)., (Copyright © 2024 Massachusetts Medical Society.)

Colorectal cancer (CRC) is the fourth cause of death from cancer worldwide mainly due to the high incidence of drug-resistance. During a screen for new actionable targets in drug-resistant tumours we recently identified p65BTK - a novel oncogenic isoform of Bruton's tyrosine kinase. Studying three different cohorts of patients here we show that p65BTK expression correlates with histotype and cancer progression. Using drug-resistant TP53-null colon cancer cells as a model we demonstrated that p65BTK silencing or chemical inhibition overcame the 5-fluorouracil resistance of CRC cell lines and patient-derived organoids and significantly reduced the growth of xenografted tumours. Mechanistically, we show that blocking p65BTK in drug-resistant cells abolished a 5-FU-elicited TGFB1 protective response and triggered E2F-dependent apoptosis. Taken together, our data demonstrated that targeting p65BTK restores the apoptotic response to chemotherapy of drug-resistant CRCs and gives a proof-of-concept for suggesting the use of BTK inhibitors in combination with 5-FU as a novel therapeutic approach in CRC patients. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Purpose: Chemotherapy-resistance remains a major obstacle to effective anti-cancer treatment. We previously showed that platinum analogs cause the release of two fatty acids. These platinum-induced fatty acids (PIFAs) induced complete chemoresistance in mice, whereas co-administration of a COX-1 inhibitor, indomethacin, prevented PIFA release and significantly enhanced chemosensitivity. To assess the safety of combining indomethacin with platinum-based chemotherapy, and to explore its efficacy and associated PIFA levels, a multi-center phase I trial was conducted., Methods: The study was comprised of two arms: oxaliplatin plus capecitabine (CAPOX, arm I) and cisplatin plus gemcitabine, capecitabine or 5FU (arm II) in patients for whom these regimens were indicated as standard care. Indomethacin was escalated from 25 to 75 mg TID, using a standard 3 × 3 design per arm, and was administered orally 8 days around chemo-infusion from cycle two onwards. PIFA levels were measured before and after treatment initiation, with and without indomethacin., Results: Thirteen patients were enrolled, of which ten were evaluable for safety analyses. In arm I, no dose-limiting toxicities were observed, and all indomethacin dose levels were well-tolerated. Partial responses were observed in three patients (30%). Indomethacin lowered plasma levels of 12-S-hydroxy-5,8,10-heptadecatrienoic acid (12-S-HHT), whereas 4,7,10,13-hexadecatetraenoic acid (16:4(n-3)) levels were not affected. Only one patient was included in arm II; renal toxicity led to closure of this cohort., Conclusions: Combined indomethacin and CAPOX treatment is safe and reduces the concentrations of 12-S-HHT, which may be associated with improved chemosensitivity. The recommended phase II dose is 75 mg indomethacin TID given 8 days surrounding standard dosed CAPOX.

Purpose: This study investigated the safety, clinical activity, and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas. Experimental Design: The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2,000 mg plus cetuximab or erlotinib according to standard posology, respectively. The effect of HRG mRNA and HER3 mRNA and protein expression were investigated in a dedicated extension cohort of squamous non-small cell lung cancer (sqNSCLC) patients treated with lumretuzumab and erlotinib. Results: Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and two DLTs in the erlotinib part were reported. The most frequent adverse events were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor HRG and HER3 mRNA levels were associated with a numerically higher disease control rate but not ORR. Conclusions: The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable, but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher HRG mRNA expression levels. Clin Cancer Res; 23(18); 5406-15. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Importance: To our knowledge, this is the first randomized clinical trial evaluating an alternating treatment regimen in an attempt to delay disease progression in clear cell renal cell carcinoma., Objective: To test our hypothesis that an 8-week rotating treatment schedule with pazopanib and everolimus delays disease progression, exhibits more favorable toxic effects, and improves quality of life when compared with continuous treatment with pazopanib., Design, Setting, and Participants: This was an open-label, randomized (1:1) study (ROPETAR trial). In total, 101 patients with treatment-naive progressive metastatic clear cell renal cell carcinoma were enrolled between September 2012 and April 2014 from 17 large peripheral or academic hospitals in The Netherlands and followed for at least one year., Interventions: First-line treatment consisted of either an 8-week alternating treatment schedule of pazopanib 800 mg/d and everolimus 10 mg/d (rotating arm) or continuous pazopanib 800 mg/d (control arm) until progression. After progression, patients made a final rotation to either pazopanib or everolimus monotherapy (rotating arm) or initiated everolimus (control arm)., Main Outcome and Measures: The primary end point was survival until first progression or death. Secondary end points included time to second progression or death, toxic effects, and quality of life., Results: A total of 52 patients were randomized to the rotating arm (median [range] age, 65 [44-87] years) and 49 patients to the control arm (median [range] age, 67 [38-82] years). Memorial Sloan Kettering Cancer Center risk category was favorable in 26% of patients, intermediate in 58%, and poor in 15%. Baseline characteristics and risk categories were well balanced between arms. One-year PFS1 for rotating treatment was 45% (95% CI, 33-60) and 32% (95% CI, 21-49) for pazopanib (control). Median time until first progression or death for rotating treatment was 7.4 months (95% CI, 5.6-18.4) and 9.4 months (95% CI, 6.6-11.9) for pazopanib (control) (P = .37). Mucositis, anorexia, and dizziness were more prevalent in the rotating arm during first-line treatment. No difference in quality of life was observed., Conclusions and Relevance: Rotating treatment did not result in prolonged progression-free-survival, fewer toxic effects, or improved quality of life. First-line treatment with a vascular endothelial growth factor inhibitor remains the optimal approach in metastatic clear cell renal cell carcinoma., Trial Registration: clinicaltrials.gov Identifier: NCT01408004.

TAS-102 is a novel oral formulation of trifluridine (TFT) and tipiracil hydrochloride (TPI), a thymidine phosphorylase inhibitor. TFT was originally synthesized in the 1960s and is a nucleoside analogue that impedes DNA synthesis by inhibition of thymidylate synthase. TFT's main mechanism of action, however, seems to be its incorporation into DNA, which distinguishes TFT from current well-known antimetabolites like 5-fluorouracil (5-FU). The rapid degradation of TFT brought initial clinical development to a halt, but TFT reentered clinical trials when addition of a TPI was found to improve the bioavailability of TFT. The combined TFT-TPI formulation was tested in patients with treatment-refractory metastatic colorectal cancer in the randomized phase III RECOURSE study. Compared with placebo, TAS-102 was associated with an overall survival (OS) and progression-free survival (PFS) benefit and a 32% reduction in risk of death [median OS, 7.1 (95% CI, 6.5-7.8) vs. 5.3 months (95% CI, 4.6-6.0); median PFS, 2.0 (95% CI, 1.9-2.1) vs. 1.7 months (95% CI, 1.7-1.8); HR for death, 0.68 (95% CI, 0.58-0.81, P < 0.001)]. Based on the results of this pivotal trial and supported by results from an earlier phase II study, TAS-102 recently gained FDA approval. This article reviews the development of TAS-102 and its therapeutic value for the proposed indication. Clin Cancer Res; 22(12); 2835-9. ©2016 AACR., (©2016 American Association for Cancer Research.)

Purpose: LY2334737 is an orally available prodrug of gemcitabine. The objective of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of daily administration of LY2334737 with or without erlotinib., Experimental Design: Patients with advanced or metastatic cancer were treated with escalating doses of LY2334737 monotherapy or in combination with continuous daily administration of 100 mg erlotinib. LY2334737 was given once daily for 14 days of a 21-day cycle. The study was extended with a bioequivalence trial to investigate a novel LY2334737 drug formulation., Results: A total of 65 patients were treated in this study. The MTD was 40 mg LY2334737. Fatigue was the most frequent DLT for LY2334737 monotherapy (4 patients) followed by elevated transaminase levels (2 patients), both observed at the 40- to 50-mg dose levels. Among the 10 patients in the combination arm, 2 had DLTs at the 40-mg dose level. These were fatigue and elevated liver enzyme levels. The most common adverse events were fatigue (n = 38), nausea (n = 27), vomiting (n = 24), diarrhea (n = 23), anorexia (n = 20), pyrexia (n = 18), and elevated transaminase levels (n = 14). The pharmacokinetics showed dose proportional increase in LY2334737 and gemcitabine exposure. The metabolite 2',2'-difluorodeoxyuridine accumulated with an accumulation index of 4.3 (coefficient of variation: 20%). In one patient, complete response in prostate-specific antigen was observed for 4 cycles, and stable disease was achieved in 22 patients overall. Pharmacokinetic analysis showed that the 2 investigated LY2334737 drug formulations were bioequivalent., Conclusions: LY2334737 displays linear pharmacokinetics and the MTD is 40 mg with or without daily administration of 100 mg erlotinib. Signs of antitumor activity warrant further development., (©2011 AACR)

Background: Ovarian cancer overexpresses ET-1, and in vitro studies have shown that ET-1 confers resistance to anthracycline-containing chemotherapy. Atrasentan has been developed as an oral selective endothelin-A receptor antagonist. The objective of the study was to investigate the feasibility and toxicity of adding increasing doses of atrasentan (to a maximum of 10 mg/d) and liposomal doxorubicin in patients with progressive ovarian cancer, refractory for platinum and paclitaxel., Methods: Patients with platinum-resistant ovarian cancer were treated with pegylated liposomal doxorubicin (PLD) 50 mg/m(2) on day 1 (and repeated every 4 weeks) in combination with escalating doses of atrasentan once daily. The starting dose was 2.5 mg and escalated in cohorts of three patients from 5 to 10 mg., Results: Twenty-six patients (mean age = 60 years, range = 42-74 years) were treated at the three dose levels. Atrasentan could be safely administered in combination at a dose of 10 mg. All patients were evaluable for toxicity, and 19 patients, included in the phase 2 period, were evaluable for response. Adverse events included nausea, vomiting, mucositis, skin toxicity, and rhinitis. Clinical cardiac toxicity, intensively monitored, was not observed, although two patients had a decrease in cardiac ejection fraction. Three objective responses were observed and another six patients had stable disease with a median time to progression of 14 weeks and an overall survival of 13.1 months., Conclusions: The addition of atrasentan to standard dose PLD in platinum-resistant ovarian cancer is feasible with some suggestion of prolonged survival.

Background: About 50% of patients with colorectal cancer are destined to develop hepatic metastases. Radical resection is the most effective treatment for patients with colorectal liver metastases offering five year survival rates between 36-60%. Unfortunately only 20% of patients are resectable at time of presentation. Radiofrequency ablation is an alternative treatment option for irresectable colorectal liver metastases with reported 5 year survival rates of 18-30%. Most patients will develop local or distant recurrences after surgery, possibly due to the outgrowth of micrometastases present at the time of liver surgery. This study aims to achieve an improved disease free survival for patients after resection or resection combined with RFA of colorectal liver metastases by adding the angiogenesis inhibitor bevacizumab to an adjuvant regimen of CAPOX., Methods/design: The Hepatica study is a two-arm, multicenter, randomized, comparative efficacy and safety study. Patients are assessed no more than 8 weeks before surgery with CEA measurement and CT scanning of the chest and abdomen. Patients will be randomized after resection or resection combined with RFA to receive CAPOX and Bevacizumab or CAPOX alone. Adjuvant treatment will be initiated between 4 and 8 weeks after metastasectomy or resection in combination with RFA. In both arms patients will be assessed for recurrence/new occurrence of colorectal cancer by chest CT, abdominal CT and CEA measurement. Patients will be assessed after surgery but before randomization, thereafter every three months after surgery in the first two years and every 6 months until 5 years after surgery. In case of a confirmed recurrence/appearance of new colorectal cancer, patients can be treated with surgery or any subsequent line of chemotherapy and will be followed for survival until the end of study follow up period as well. The primary endpoint is disease free survival. Secondary endpoints are overall survival, safety and quality of life., Conclusion: The HEPATICA study is designed to demonstrate a disease free survival benefit by adding bevacizumab to an adjuvant regime of CAPOX in patients with colorectal liver metastases undergoing a radical resection or resection in combination with RFA., Trial Registration: ClinicalTrials.gov Identifier NCT00394992.

Aim: Cediranib is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. Preclinical and clinical data suggest that inhibition of the VEGFR and epidermal growth factor receptor (EGFR) pathways may be synergistic. Combination treatment with cediranib and gefitinib, an EGFR signalling inhibitor, was evaluated in patients with advanced solid tumours., Patients and Methods: Ninety patients received treatment in this four-part, open-label study (NCT00502060). The patients received once-daily oral doses of cediranib (20-45mg) and gefitinib 250mg (part A1; n=16) or 500mg (part B1; n=44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30mg with gefitinib 250mg (part A2; n=15) or 500mg (part B2; n=15). The primary objective was to assess the safety and tolerability of cediranib with gefitinib. Secondary assessments included pharmacokinetics, efficacy and pharmacodynamics., Results: Combination treatment was generally well tolerated; the protocol-defined maximum-tolerated dose of cediranib was 30mg/day with gefitinib 250mg/day (part A1) and cediranib 45mg/day was the maximum dose investigated with gefitinib 500mg/day (part B1). The most common adverse events were diarrhoea (84 [93%]), anorexia (63 [70%]) and fatigue (60 [67%]). Cediranib pharmacokinetic parameters were not substantially different when given alone or in combination with gefitinib. Gefitinib pharmacokinetic parameters were similar to those seen previously with gefitinib monotherapy. Efficacy results included eight (9%) confirmed partial responses (6 renal; 1 lung; 1 osteosarcoma) and 38 (42%) patients with stable disease. Pharmacodynamic assessments demonstrated changes in levels of VEGF and soluble VEGFR-2 following treatment., Conclusions: Combination treatment was generally well tolerated and showed encouraging antitumour activity in patients with advanced solid tumours. These results merit further exploration., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Introduction: PTK/ZK is a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptor, colony-stimulating factor 1 receptor, and cytokine stem cell factor receptor. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combining inhibition of VEGF and EGF signaling might act additive or synergistically., Methods: In phase 1 design, patients with advanced solid tumors were treated with PTK/ZK daily (cohort 1, 750 mg once daily; cohort 2, 1250 mg once daily; cohort 3, 250 mg [morning] and 500 mg [evening]; and cohort 4, 500 mg [morning] and 750 mg [evening]) in combination with cetuximab 250 mg/m(2) weekly in cycles of 28 days in cohorts of three patients. Toxicity was evaluated conform the Common Terminology Criteria for Adverse Events classification 3.0. Pharmacokinetics and pharmacodynamics consisting of circulating endothelial (progenitor) cell (CE[P]C) analysis by flow cytometry were performed., Results: Safety and tolerability was evaluated in 16 patients. The most frequently reported adverse events were acne, dry skin, fatigue, nausea, dizziness, vomiting, headache, and diarrhea. One dose-limiting toxicity occurred in cohort 3 consisting of a grade 3 transaminitis. Pharmacokinetic analysis revealed no significant changes in PTK/ZK exposure on coadministration with cetuximab and in bioavailability at equivalent total daily doses. Biomarker analysis showed no significant change in the number of CE(P)Cs during treatment. One of 14 evaluable patients showed a partial response for at least 11.5 months, and 7 patients (50%) stable disease for at least 2 months., Conclusions: This study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has antitumor activity.

Vascular disrupting agents preferentially target the established but abnormal tumor vasculature, resulting in extensive intratumoral hypoxia and cell death. However, a rim of viable tumor tissue remains from which angiogenesis-dependent regrowth can occur, in part through the mobilization and tumor colonization of circulating endothelial progenitor cells (CEP). Cotreatment with an agent that blocks CEPs, such as a vascular endothelial growth factor pathway-targeting biological antiangiogenic drug, results in enhanced antitumor efficacy. We asked whether an alternative therapeutic modality, low-dose metronomic chemotherapy, could achieve the same result given its CEP-targeting effects. We studied the combination of the vascular disrupting agent OXi4503 with daily administration of CEP-inhibiting, low-dose metronomic cyclophosphamide to treat primary orthotopic tumors with the use of the 231/LM2-4 breast cancer cell line and MeWo melanoma cell line. In addition, CEP mobilization and various tumor characteristics were assessed. We found that daily p.o. low-dose metronomic cyclophosphamide was capable of preventing the CEP spike and tumor colonization induced by OXi4503. This was associated with a decrease in the tumor rim and marked suppression of primary 231/LM2-4 growth in nude as well as severe combined immunodeficient mice. Similar results were found in MeWo-bearing nude mice. The delay in tumor growth was accompanied by significant decreases in microvessel density, perfusion, and proliferation, and a significant increase in tumor cell apoptosis. No overt toxicity was observed. The combination of OXi4503 and metronomic chemotherapy results in prolonged tumor control, thereby expanding the list of therapeutic agents that can be successfully integrated with metronomic low-dose chemotherapy.

Background: Cancer of the esophagus and gastro-esophageal junction is a disorder with a poor prognosis and increasing incidence., Objective: To provide a critical evaluation of current treatment strategies and new developments including targeted therapy for esophageal cancer., Methods: Published clinical trials as well as abstracts were selected regarding chemoradiation or targeted therapy for esophageal cancer., Results/conclusions: Preoperative chemotherapy may offer a survival advantage compared to surgery alone, but the evidence is inconclusive. For preoperative chemoradiation, only 2 of 10 randomized trials showed advanced survival compared to surgery alone, and, therefore, more Phase III trials and, consequently, meta-analyses are needed. Until now, for palliative chemotherapy, no survival benefit has been shown. This is largely due to a lack of studies and difficulties in performing randomized trials. The application of targeted therapy is widespread and reported for several tumor types. For esophageal cancer, most studies have been performed with EGFR inhibitors, including cetuximab, gefitinib, erlotinib and trastuzumab. Limited experience is available with angiogenesis inhibitors, apoptosis inhibitors and COX-2 inhibitors. As yet, targeted therapies are proven to be safe often in combination with chemoradiation, but modestly effective for esophageal cancer. Phase III trials have not been published yet and, therefore, for targeted therapies also, possibly using new concepts, more studies are needed.

Background: Fluoropyrimidine-based chemotherapy plus the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is standard first-line treatment for metastatic colorectal cancer. We studied the effect of adding the anti-epidermal growth factor receptor (EGFR) antibody cetuximab to a combination of capecitabine, oxaliplatin, and bevacizumab for metastatic colorectal cancer., Methods: We randomly assigned 755 patients with previously untreated metastatic colorectal cancer to capecitabine, oxaliplatin, and bevacizumab (CB regimen, 378 patients) or the same regimen plus weekly cetuximab (CBC regimen, 377 patients). The primary end point was progression-free survival. The mutation status of the KRAS gene was evaluated as a predictor of outcome., Results: The median progression-free survival was 10.7 months in the CB group and 9.4 in the CBC group (P=0.01). Quality-of-life scores were lower in the CBC group. The overall survival and response rates did not differ significantly in the two groups. Treated patients in the CBC group had more grade 3 or 4 adverse events, which were attributed to cetuximab-related adverse cutaneous effects. Patients treated with cetuximab who had tumors bearing a mutated KRAS gene had significantly decreased progression-free survival as compared with cetuximab-treated patients with wild-type-KRAS tumors or patients with mutated-KRAS tumors in the CB group., Conclusions: The addition of cetuximab to capecitabine, oxaliplatin, and bevacizumab resulted in significantly shorter progression-free survival and inferior quality of life. Mutation status of the KRAS gene was a predictor of outcome in the cetuximab group. (ClinicalTrials.gov number, NCT00208546.), (2009 Massachusetts Medical Society)

Purpose: Enzastaurin targets the protein kinase C and phosphatidylinositol 3-kinase/AKT pathways to reduce tumor angiogenesis and cell proliferation and to induce cell death. A phase I trial was conducted to evaluate the feasibility of combining enzastaurin with gemcitabine and cisplatin., Experimental Design: Patients with advanced cancer received a 14-day lead-in treatment with oral enzastaurin followed by subsequent 21-day cycles of daily enzastaurin, gemcitabine on days 1 and 8, and cisplatin on day 1. Enzastaurin doses were escalated between 350 mg once daily to 500 mg twice daily, whereas gemcitabine doses were either 1,000 or 1,250 mg/m(2) and cisplatin doses were either 60 or 75 mg/m(2). Circulating endothelial cell numbers and CD146 and CD133 mRNA expression were evaluated as pharmacodynamic markers., Results: Thirty-three patients (median age, 58 years) were enrolled in seven dose levels. The maximum tolerated dose was not identified. Two dose-limiting toxicities (grade 2 QT interval corrected for heart rate prolongation and grade 3 fatigue) were reported. Other toxicities included grade 3/4 neutropenia (3 of 6 patients), thrombocytopenia (1 of 6 patients), grade 3 leukopenia (2 patients), and fatigue (5 patients). Enzastaurin twice daily (> or =250 mg) resulted in more discontinuations and low-grade toxicities. In the combination, enzastaurin exposures decreased slightly but remained above the target of 1,400 nmol/L, whereas gemcitabine/cisplatin exposures were unaltered. Three patients (9.1%) had partial responses and 13 (39.4%) had stable disease. Measurement of circulating endothelial cell numbers and CD146 and CD133 mRNA expression did not contribute to decision-making on dose escalation., Conclusions: Recommended phase II dose is 500 mg enzastaurin once daily, 1,250 mg/m(2) gemcitabine, and 75 mg/m(2) cisplatin. This regimen is well tolerated with no significant alterations in the pharmacokinetic variables of any drug.

Background: The use of high-dose adjuvant chemotherapy for high-risk primary breast cancer is controversial. We studied its efficacy in patients with 4 to 9 or 10 or more tumor-positive axillary lymph nodes., Methods: Patients younger than 56 years of age who had undergone surgery for breast cancer and who had no distant metastases were eligible if they had at least four tumor-positive axillary lymph nodes. Patients in the conventional-dose group received fluorouracil, epirubicin, and cyclophosphamide (FEC) every three weeks for five courses, followed by radiotherapy and tamoxifen. The high-dose treatment was identical, except that high-dose chemotherapy (6 g of cyclophosphamide per square meter of body-surface area, 480 mg of thiotepa per square meter, and 1600 mg of carboplatin per square meter) with autologous peripheral-blood hematopoietic progenitor-cell transplantation replaced the fifth course of FEC., Results: Of the 885 patients, 442 were assigned to the high-dose group and 443 to the conventional-dose group. After a median follow-up of 57 months, the actuarial 5-year relapse-free survival rates were 59 percent in the conventional-dose group and 65 percent in the high-dose group (hazard ratio for relapse in the high-dose group, 0.83; 95 percent confidence interval, 0.66 to 1.03; P=0.09). In the group with 10 or more positive nodes, the relapse-free survival rates were 51 percent in the conventional-dose group and 61 percent in the high-dose group (P=0.05 by the log-rank test; hazard ratio for relapse, 0.71; 95 percent confidence interval, 0.50 to 1.00)., Conclusions: High-dose alkylating therapy improves relapse-free survival among patients with stage II or III breast cancer and 10 or more positive axillary lymph nodes. This benefit may be confined to patients with HER-2/neu-negative tumors., (Copyright 2003 Massachusetts Medical Society)