A randomized phase 2 study comparing EC or CMF versus nab-paclitaxel plus capecitabine as adjuvant chemotherapy for nonfrail elderly patients with moderate to high-risk early breast cancer (ICE II-GBG 52).

BACKGROUND: Although greater than 40% of breast cancers occur in patients aged ≥65 years, these individuals are frequently undertreated. Taxane-based adjuvant chemotherapy is considered the treatment of choice but to the authors' knowledge has only limited evidence in elderly patients. METHODS: Patients aged ≥65 years with a Charlson comorbidity index ≤2 and pT1/2 pN0/1 disease and either human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor-negative, grade 3 (according to Common Terminology Criteria for Adverse Events [version 3.0]), high uPA/PAI-1 or any stage pT3/4 pN2/3 breast cancer were randomized to receive 4 cycles of adjuvant epirubicin and cyclophosphamide (EC) (epirubicin at a dose of 90 mg/m(2) and cyclophosphamide at a dose of 600 mg/m(2) intravenously [iv] on day 1 every 3 22 days) or 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (cyclophosphamide at a dose of 500 mg/m(2), methotrexate at a dose of 40 mg/m(2), and 5-fluorouracil at a dose of 600 mg/m(2) iv on days 1 plus 8 every 29 days) versus 6 cycles of nab-paclitaxel and capecitabine (nPX) (nab-paclitaxel at a dose of 100 mg/m(2) iv on days 1, 8, and 15 every 21 days with 1 week of rest every 6 weeks plus capecitabine at a dose of 2000 mg/m(2) orally on days 1-14 every 21 days). Primary endpoints were treatment discontinuations and overall frequency of adverse events. RESULTS: Thirteen of 198 patients (6.6%) discontinued EC/CMF and 69 of 193 patients (35.8%) discontinued nPX (P<.001) with 1 and 5 deaths observed during treatment, respectively. Grade 3 to 5 adverse events were more frequent among patients treated with EC/CMF (90.9%) than among those treated with nPX (64.8%) (P<.001), with hematological toxicities being more frequent with EC/CMF (88.4% vs 22.3%; P<.001), but nonhematological toxicities (hand-foot syndrome, diarrhea, mucositis, fatigue, sensory neuropathy, thromboembolisms, and metabolic disorders) being more frequent with nPX (58.5% vs 18.7%; P<.001). None of the geriatric scores (Charlson comorbidity index, Vulnerable Elders Survey [VES-13], Instrumental Activities of Daily Living [IADL], and G8) independently predicted grade 3 to 5 toxic events or treatment discontinuations. No differences in survival between the treatment groups were observed after 22.8 months. CONCLUSIONS: Compared with EC/CMF, treatment with nPX led to more treatment discontinuations and nonhematological toxicities in elderly patients with moderate or high-risk breast cancer.

German adjuvant intergroup node-positive study: a phase III trial to compare oral ibandronate versus observation in patients with high-risk early breast cancer.

PURPOSE: Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use. PATIENTS AND METHODS: The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-ß of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed. RESULTS: Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093). CONCLUSION: Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.

Capecitabine plus paclitaxel versus epirubicin plus paclitaxel as first-line treatment for metastatic breast cancer: efficacy and safety results of a randomized, phase III trial by the AGO Breast Cancer Study Group.

Capecitabine/taxane combinations are highly active in metastatic breast cancer (MBC). We conducted a randomized, phase III, noninferiority trial comparing capecitabine plus paclitaxel (XP) with epirubicin plus paclitaxel (EP) as first-line therapy for MBC, regarding progression-free survival (PFS) as primary efficacy endpoint. Females who had received no prior chemotherapy for MBC were randomized to six 3-weekly cycles of XP (capecitabine 1000 mg/m(2) b.i.d., days 1-14; paclitaxel 175 mg/m(2) 3-h infusion, day 1) or EP (epirubicin 60 mg/m(2) 1-h infusion, day 1; paclitaxel as above). Secondary endpoints included response rate, overall survival, tolerability, and quality of life (QoL). Each arm included 170 patients, most of whom received all six cycles as planned. The difference in means of (logarithmic) PFS times (-0.205) did not meet the pre-defined level for noninferiority (-0.186). However, PFS was similar in the two arms [HR: XP vs. EP: 1.012 (95 % CI 0.785-1.304); median 10.4 months XP vs. 9.2 months EP]. Overall survival was also similar [HR 1.027 (95 % CI 0.740-1.424); median 22.0 vs. 26.1 months], and response rate was 47 % versus 42 %. Both regimens were tolerable: there were more grade 3/4 diarrhea and grade 3 hand-foot syndromes with XP and more grade 3/4 hematologic toxicities with EP. There were no major differences in QoL. Although, noninferiority of XP to EP was formally not proven, first-line XP was active and feasible. XP is a valid first-line alternative to anthracycline/taxane regimens, especially in patients previously treated with adjuvant anthracyclines.

Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial.

BACKGROUND: A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer. METHODS: The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients with HER2-positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) or subcutaneously (fixed dose of 600 mg); 1:1 ratio. Chemotherapy consisted of four cycles of docetaxel (75 mg/m(2)) followed by four cycles of fluorouracil (500 mg/m(2)), epirubicin (75 mg/m(2)), and cyclophosphamide (500 mg/m(2)), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment. Coprimary endpoints were serum trough concentration (C(trough)) at pre-dose cycle 8 before surgery (non-inferiority margin for the ratio between groups of 0·80) and pathological complete response (pCR; non-inferiority margin for the difference between groups of -12·5%), analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00950300. FINDINGS: 299 patients were randomly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab. The geometric mean presurgery C(trough) was 51·8 µg/mL (coefficient of variation 52·5%) in the intravenous group and 69·0 µg/mL (55·8%) in the subcutaneous group. The geometric mean ratio of C(trough) subcutaneous to C(trough) intravenous was 1·33 (90% CI 1·24-1·44). 107 (40·7%) of 263 patients in the intravenous group and 118 (45·4%) of 260 in the subcutaneous group achieved a pCR. The difference between groups in pCR was 4·7% (95% CI -4·0 to 13·4). Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints. The incidence of grade 3-5 adverse events was similar between groups. The most common of these adverse events were neutropenia (99 [33·2%] of 298 patients in the intravenous group vs 86 [29·0%] of 297 in the subcutaneous group), leucopenia (17 [5·7%] vs 12 [4·0%]), and febrile neutropenia (10 [3·4%] vs 17 [5·7%]). However, more patients had serious adverse events in the subcutaneous group (62 [21%] of 297 patients) than in the intravenous group (37 [12%] of 298); the difference was mainly attributable to infections and infestations (24 [8·1%] in the subcutaneous group vs 13 [4·4%] in the intravenous group). Four adverse events led to death (one in the intravenous group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase. Of these, two--both in the subcutaneous group--were deemed to be treatment related. INTERPRETATION: Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non-inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative. FUNDING: F Hoffmann-La Roche.

Comparing guidelines for adjuvant endocrine therapy in postmenopausal women with breast cancer: a coming of age.

Following surgery for early breast cancer, the standard of care for postmenopausal women is adjuvant therapy with any combination of radiation therapy, endocrine therapy, chemotherapy and/or targeted therapy. Clinicians rely on many tools, including guidelines, to make these treatment decisions. Such guidelines include the St Gallen consensus statement, the American Society of Clinical Oncology guidelines and the National Comprehensive Cancer Network guidelines, as well as various regional and national guidelines. Recommendations may vary, because different methods and criteria were used to assess the strength of supporting data. This article provides an overview of global guidelines for the adjuvant treatment of breast cancer and points out the major differences. Ongoing changes are highlighted, particularly those regarding the adjuvant endocrine treatment of postmenopausal women with breast cancer. While previous guidelines recommended tamoxifen alone, all major guidelines now recommend using third-generation aromatase inhibitors either in sequence with tamoxifen or as upfront treatment.

Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study.

PURPOSE Trastuzumab, a humanized antibody against the human epidermal growth factor receptor type 2 (HER2), has shown high efficacy in breast cancer. We prospectively investigated its efficacy given simultaneously with anthracycline-taxane-based neoadjuvant chemotherapy. PATIENTS AND METHODS Patients with operable or locally advanced, HER2-positive tumors were treated preoperatively with four cycles of epirubicin/cyclophosphamide followed by four cycles of docetaxel with or without capecitabine (EC-T[X]) and trastuzumab 6 mg/kg (with a loading dose of 8 mg/kg) every 3 weeks during all chemotherapy cycles. Patients with HER2-negative tumors treated in the same study with the same chemotherapy but without trastuzumab were used as a reference group. Results Of 1,509 participants, 445 had HER2-positive tumors treated with trastuzumab and chemotherapy. Pathologic complete response (pCR; defined as no invasive or in situ residual tumors in the breast) rate was 31.7%, which was 16% higher than that in the reference group (15.7%). HER2-positive patients without response to the first four cycles of EC showed an unexpectedly high pCR rate of 16.6% (3.3% in the reference group). Breast conservation rate was 63.1% and comparable to that of the reference group (64.7%). EC-T(X) plus trastuzumab was associated with more febrile neutropenia and conjunctivitis, but with a comparable short-term cardiac toxicity profile as the reference group. CONCLUSION This trial confirms that combining trastuzumab with anthracycline-taxane-based neoadjuvant chemotherapy results in a high pCR rate without clinically relevant early toxicity. Combination of chemotherapy with trastuzumab should be considered when neoadjuvant treatment is given to patients with HER2-positive breast cancer.

Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study.

PURPOSE Capecitabine can be integrated either concomitantly or sequentially to anthracycline-plus-taxane-based regimens. PATIENTS AND METHODS Patients with large operable or locally advanced tumors, with hormone receptor-negative tumors, or with receptor-positive tumors but also clinically node-positive disease were recruited to receive preoperatively four cycles of epirubicin plus cyclophosphamide (EC; epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2)). Patients were then randomly assigned to four cycles of docetaxel (100 mg/m(2)), four cycles of docetaxel + capecitabine (TX; docetaxel 75 mg/m(2) plus capecitabine 1,800 mg/m(2)), or four cycles of docetaxel (75 mg/m(2)) followed by four cycles of capecitabine (1,800 mg/m(2); T-X). Patients with human epidermal growth factor receptor 2 (HER-2) -positive tumors received trastuzumab concomitantly with all cycles. Primary objectives were to assess the effect of docetaxel by comparing EC plus docetaxel versus EC plus TX and to assess the effect of duration by comparing EC plus TX versus EC plus T-X on pathologic complete response (pCR, without invasive/noninvasive breast tumor, regardless of nodal status) at surgery, irrespective of trastuzumab treatment. Results Of 1,509 patients starting EC, 1,421 were randomly assigned to docetaxel (n = 471), TX (n = 471), or T-X (n = 479). At surgery, pCR rates were 22.3%, 19.5%, and 22.3%, respectively; the difference for docetaxel (EC plus docetaxel v EC plus TX) was 2.8% (95% CI, -2.4% to 8.0%; P = .298).The difference for duration was -2.8% (95% CI, -8.0% to 2.4%; P = .298). Breast conservation rates were 70.1%, 68.4%, and 65.3%, respectively (P = .781 for docetaxel; P = .270 for duration). Concomitant but not sequential treatment with docetaxel was associated with more diarrhea; nail changes, and hand-foot-syndrome, but it was associated with less edema. CONCLUSION Adding capecitabine to or prolonging duration of neoadjuvant EC plus docetaxel does not result in higher efficacy at surgery.

Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial.

BACKGROUND: Among breast cancer patients, nonresponse to initial neoadjuvant chemotherapy is associated with unfavorable outcome. We compared the response of nonresponding patients who continued the same treatment with that of patients who switched to a well-tolerated non-cross-resistant regimen. METHODS: Previously untreated breast cancer patients received two 3-week cycles of docetaxel at 75 mg/m(2), doxorubicin at 50 mg/m(2), and cyclophosphamide at 500 mg/m(2) per day (TAC). Patients whose tumors did not decrease in size by at least 50% were randomly assigned to four additional cycles of TAC or to four cycles of vinorelbine at 25 mg/m(2) and capecitabine at 2000 mg/m(2) (NX). The outcome was sonographic response, defined as a reduction in the product of the two largest perpendicular diameters by at least 50%. A difference of 10% or less in the sonographic response qualified as noninferiority of the NX treatment. Pathological complete response was defined as no invasive or in situ residual tumor masses in the breast and lymph nodes. Toxic effects were assessed. All statistical tests were two-sided. RESULTS: Of 2090 patients enrolled in the GeparTrio study, 622 (29.8%) who did not respond to two initial cycles of TAC were randomly assigned to an additional four cycles of TAC (n = 321) or to four cycles of NX (n = 301). Sonographic response rate was 50.5% for the TAC arm and 51.2% for the NX arm. The difference of 0.7% (95% confidence interval = -7.1% to 8.5%) demonstrated noninferiority of NX (P = .008). Similar numbers of patients in both arms received breast-conserving surgery (184 [57.3%] in the TAC arm vs 180 [59.8%] in the NX arm) and had a pathological complete response (5.3% vs 6.0%). Fewer patients in the NX arm than in the TAC arm had hematologic toxic effects, mucositis, infections, and nail changes, but more had hand-foot syndrome and sensory neuropathy. CONCLUSION: Pathological complete responses to both regimens were marginal. Among patients who did not respond to the initial neoadjuvant TAC treatment, similar efficacy but better tolerability was observed by switching to NX than continuing with TAC.

HER-2-positive metastatic breast cancer: optimizing trastuzumab-based therapy.

Trastuzumab with a taxane as first-line therapy is now the standard of care for patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer (MBC). The search for additional and more effective trastuzumab-based therapies continues. Novel combinations of trastuzumab with chemotherapeutic agents, including vinorelbine, gemcitabine, and capecitabine, and hormonal therapy agents, such as tamoxifen and aromatase inhibitors, are currently under investigation in clinical trials. Available data suggest these combinations will provide additional treatment options that may ultimately lead to better outcomes for patients with HER-2-positive MBC. Evidence is growing for the use of trastuzumab treatment beyond disease progression and retreatment after (neo)adjuvant relapse is being explored to assist in clinical decision making. Already, the use of trastuzumab in the metastatic setting has changed HER-2-positive status from a marker of poor prognosis to one of better overall outcome, and ongoing studies should expand further the treatment options for patients with HER-2-positive MBC.

Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG.

PURPOSE: Most patients with advanced ovarian cancer develop recurrent disease. For those patients who recur at least 6 months after initial therapy, paclitaxel platinum has shown a modest survival advantage over platinum without paclitaxel; however, many patients develop clinically relevant neurotoxicity, frequently resulting in treatment discontinuation. Thus, an alternative regimen without significant neurotoxicity was evaluated by comparing gemcitabine plus carboplatin with single-agent carboplatin in platinum-sensitive recurrent ovarian cancer patients. METHODS: Patients with platinum-sensitive recurrent ovarian cancer were randomly assigned to receive either gemcitabine plus carboplatin or carboplatin alone, every 21 days. The primary objective was to compare progression-free survival (PFS). RESULTS: Three hundred fifty-six patients (178 gemcitabine plus carboplatin; 178 carboplatin) were randomly assigned. Patients received a median of six cycles in both arms. With a median follow-up of 17 months, median PFS was 8.6 months (95% CI, 7.9 to 9.7 months) for gemcitabine plus carboplatin and 5.8 months (95% CI, 5.2 to 7.1 months) for carboplatin. The hazard ration (HR) for PFS was 0.72 (95% CI, 0.58 to 0.90; P = .0031). Response rate was 47.2% (95% CI, 39.9% to 54.5%) for gemcitabine plus carboplatin and 30.9% (95% CI, 24.1% to 37.7%) for carboplatin (P = .0016). The HR for overall survival was 0.96 (95% CI, 0.75 to1.23; P = .7349). While myelosuppression was significantly more common in the combination, sequelae such as febrile neutropenia or infections were uncommon. No statistically significant differences in quality of life scores between arms were noted. CONCLUSION: Gemcitabine plus carboplatin significantly improves PFS and response rate without worsening quality of life for patients with platinum-sensitive recurrent ovarian cancer.

A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer.

BACKGROUND: Despite considerable improvement in the treatment of advanced ovarian cancer, the optimization of efficacy and tolerability remains an important issue. Therefore, we performed a randomized, phase III non-inferiority trial comparing paclitaxel plus cisplatin (PT) with paclitaxel plus carboplatin (TC) in patients with advanced ovarian cancer. METHODS: A total of 798 patients with International Federation of Gynecology and Obstetrics stage IIB-IV were randomly assigned to receive six courses of either PT or TC at 3-week intervals. The primary endpoint was the proportion of patients without progression at 2 years. Secondary endpoints included toxicity, response to treatment, quality of life, and overall and progression-free survival time. Quality of life was evaluated using the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30, version 2.0. Survival curves were calculated using the Kaplan-Meier method, and hazard ratios were estimated using the Cox proportional hazards model. RESULTS: The proportion of patients without progression at 2 years was not statistically significantly different between the two treatment arms (40.0% for PT versus 37.5% for TC, difference = 2.5%, one-sided 95% confidence interval [CI] = - infinity to 8.2%). Median progression-free survival time in the TC arm (17.2 months, 95% CI = 15.2 to 19.3 months) and the PT arm (19.1 months, 95% CI = 16.7 to 21.5 months) were also not statistically significantly different; the same was true of median overall survival time (43.3 months, 95% CI = 37.2 to 47.8 months versus 44.1 months, 95% CI = 40.2 to 49.4 months, for the TC and PT arms, respectively). The TC regimen was associated with a higher frequency of hematologic toxicity, but a lower frequency of gastrointestinal and neurologic toxicity, than the PT regimen. Mean global quality-of-life scores at the end of treatment were statistically significantly better in the TC arm than in the PT arm (65.25 versus 51.97, respectively; difference = -13.28, 95% CI = -18.88 to -7.68). CONCLUSION: The TC regimen achieved comparable efficacy to the PT regimen but was associated with better tolerability and quality of life, and should, therefore, be considered as an important alternative for standard first-line chemotherapy in patients with advanced ovarian cancer.