Background: This paper evaluates the prognostic and predictive impact of protein expression of various molecular markers in high-risk breast cancer (HRBC) patients with >9 involved lymph nodes, who ...received different chemotherapy dose-intensification strategies within a prospective randomized WSG AM-01 trial. Materials and methods: Paraffin-embedded tumors from 236 patients, who were randomly assigned to dose-dense conventional chemotherapy with four cycles of E90C600 followed by three cycles of C600M40F600 every 2 weeks (DD) or a rapidly cycled tandem high-dose regimen with two cycles of E90C600 every 2 weeks followed by two cycles of E90C3000Thiotepa400 every 3 weeks (HD), were available for retrospective central pathological review (116 HD/120 DD). Expression of estrogen receptor (ER), progesterone receptor (PR), MIB-1, epidermal growth factor receptor, and Her-2/neu was evaluated immunohistochemically using tissue microarrays. Results were correlated with follow-up data and treatment effects by proportional hazard Cox regression models (including interaction analysis). Results: After a median follow-up of 61.7 months, 5-year event-free survival (EFS) as well as overall survival (OS) rates for the 236 patients were significantly better in the HD arm: EFS: 62% versus 41% hazard ratio (HR) = 0.60, 95% CI 0.43–0.85, P = 0.004; OS: 76% versus 61% (HR = 0.58, 95% CI 0.39–0.87, P = 0.007). In multivariate analysis, HD, tumor size <3 cm, positive PR, negative MIB-1 staining, and grade 1/2 were associated with favorable outcome. Interaction analysis showed that regarding predictive effects, triple negative (ER/PR/Her-2/neu) and G3 tumors derived most benefit from HD. Conclusion: Tandem HD improves both EFS and OS in HRBC. This therapy effect may be partly attributable to superior efficacy in the subgroup of triple-negative tumors and/or G3 with their poor prognostic marker profile.
Abstract Objectives Evidence suggests that continued trastuzumab therapy beyond progression (TBP) may provide additional survival benefit. Within the framework of an observational prospective study ...of patients with advanced/metastatic breast cancer receiving trastuzumab in routine clinical practice, we had the opportunity to examine the effect of TBP in a large population. Patients and methods Among a total of 1843 trastuzumab-treated patients, a sub-cohort of 418 fulfilled the selection criteria for the TBP analysis: 261 continued trastuzumab and 157 discontinued. Logrank tests and Cox models were used to compare survival and identify prognostic factors. Results Survival from progression was significantly longer in those patients continuing trastuzumab treatment beyond disease progression (TBP: median 22.1 months; no TBP: median 14.9 months; HR = 0.64; P = 0.00021). In addition to TBP, a positive endocrine receptor status, a longer relapse-free interval, no visceral metastasis, no concomitant chemotherapy during first-line treatment, and first-line response were independently significant prognostic variables for longer survival on multivariate analysis. Conclusion The hitherto limited evidence for TBP benefit from randomized studies was confirmed. While a number of strong disease-related predictors for survival after first progression could be identified, the positive effect of trastuzumab continuation retained statistical significance in a multivariate model.
Background: Response to the first two cycles of preoperative chemotherapy might differentiate subgroups of breast cancer patients with high or minimal chances for a pathologic complete response (pCR) ...and may be used as an in vivo chemosensitivity test. Methods: Breast cancer patients were treated with two cycles of TAC (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 every 21 days). Patients whose tumors showed a response received four more cycles. Patients whose tumors did not respond were randomized to four additional cycles TAC or NX (vinorelbine 25 mg/m2 days 1 and 8, capecitabine 2000 mg/m2 days 1–14, every 21 days). The primary end point was pCR at surgery. Results: Two hundred and eighty-five patients showed a clinical response, in 73.0% after two cycles, in 88.4% at surgery, and a pCR was seen in 17.9%. Breast conservation was possible in 72.2%. Responding patients obtained a pCR in 22.6% whereas non-responding patients reached a pCR in 7.3% and 3.1% with TAC or NX, respectively. Grade III/IV neutropenia and febrile neutropenia were observed during TAC in 70.2% and 13.5%, respectively. Significantly less toxicity were observed with NX. Conclusion: Early response to TAC can reliably identify patients with a high chance of achieving a pCR. New effective treatments need to be explored for patients without an early response.
Abstract
A subcutaneous formulation of trastuzumab to treat patients with HER2-positive breast cancer is available since August 2013. The subcutaneous formulation is administered as a fixed dose of ...600 mg over a period of up to 5 minutes. The HannaH trial compared subcutaneous with intravenous administration and found comparable pharmacokinetics, efficacy and tolerability for both administration forms of trastuzumab in the neoadjuvant setting. The randomized crossover study PrefHer reported a clear preference from the patientʼs point of view for subcutaneous over intravenous administration of trastuzumab. The accompanying time-and-motion study reported a reduction concerning the total time spent for the institution as well as for the patient receiving trastuzumab s. c.. The experience of 7 German centers largely corresponded with the results of these studies. Patients expressed a clear preference for subcutaneous trastuzumab administration, with the time saved by the subcutaneous administration route cited as the greatest benefit. Although the existing reimbursement terms mean that centers will receive a lower remuneration, the centersʼ overall evaluation of the subcutaneous administration route for trastuzumab was overwhelmingly positive. The greatest benefit cited by the centers was the flexibility in scheduling patient appointments. This increased flexibility improved conditions in some centers which were experiencing pressures due to a shortage of staff, particularly at peak times. The general consensus, however, was that the remuneration systems for oncological treatments urgently need to be amended to ensure that the real costs of treatment are covered, even if the administration route has changed.
Background: Abagovomab is a murine anti-idiotypic antibody against the antigen CA-125 which has been shown to elicit humoral and cellular immune responses against ovarian cancer (oc). Patients and ...methods: This phase I trial included 36 patients with recurrent oc comparing two subcutaneous (s.c.) vaccination schedules: nine (group L) versus six injections (group S), 18 patients in each group. Four injections of 2.0 mg abagovomab were administered every 2 weeks and then two or five additional doses monthly. Primary endpoint was drop-out rate due to toxicity, and the secondary endpoint was analysis of immunological response. Results: Treatment was completed in eight (44%) and 16 (89%) patients in groups L and S, respectively. Premature termination occurred due to patient withdrawal or disease progression. No treatment-limiting toxicities occurred in either group. The most common toxicity related to the vaccine was grade 1/2 local injection site reaction. Induction of Ab3 was observed in all evaluable patients. There were no differences between the groups with regard to induction of human anti-mouse antibody (P = 0.1006). IFNγ-expressing CA125-specific CD8+ T-cells were significantly more frequent in group L, while there was no significant difference between CD4+ T-cells in the two groups. Conclusions: Abagovomab s.c. vaccination is safe and well tolerated. The long vaccination schedule tended to be more effective with regard to AB3-induction and cellular cytotoxicity.
Abstract Objective. A multicenter non-randomized phase II study was initiated to evaluate tolerability and efficacy of pegylated liposomal doxorubicin (PLD) in combination with carboplatin in ...gynecologic malignancies. Methods. One hundred forty women with recurrent or advanced endometrial ( n = 31), cervical or vaginal cancer ( n = 31), uterine sarcomas ( n = 11), or recurrent platinum-sensitive ovarian cancer ( n = 67) received six courses of PLD 40 mg/m2 and carboplatin (AUC 6) every 28 days. Results. Hematological toxicities with NCI-CTC grade 3/4 were anemia in 8%, thrombocytopenia in 14%, neutropenia in 24%, and febrile neutropenia in 2% of 652 cycles. Grade 3/4 non-hematological toxicities included fatigue (14% of patients), pain (10%), dyspnea (9%), palmar–plantar erythrodysesthesia (7%), and nausea/vomiting (7%). Dose intensity reached 87.2% for PLD and 88.2% for carboplatin. Seventy-four percent of all non-progressive patients received at least 5 cycles. Overall response rates were (116 patients evaluable for response): ovarian cancer ( n = 54) 68%, endometrial cancer ( n = 27) 44%, uterine sarcomas ( n = 9) 33%, and cervical/vaginal cancer ( n = 26) 12%. Median progression-free survival was 11.6 months (95%CI 9.6–14.1) for ovarian cancer and 9.5 months (95%CI 6.6–12.6) for endometrial cancer. Median overall survival was 23.8 months (95%CI 19.0–30.2) and 21.4 months (95%CI 11.9–), respectively. Conclusions. The combination of PLD and carboplatin was well tolerated and feasible in patients with gynecologic malignancies. Efficacy was low in cervical/vaginal cancer, but promising in patients with endometrial cancer. Efficacy was within the expected range in recurrent platinum-sensitive ovarian cancer and is currently under further investigation in a prospective randomized phase III trial comparing PLD/carboplatin with paclitaxel/carboplatin (CALYPSO-trial; AGO-OVAR 2.9).
To investigate the effect of adding tamoxifen to a preoperative dose-dense doxorubicin and docetaxel regimen on the pathologic response of primary operable breast cancer.
Patients (tumor size > or = ...3 cm, N0 to 2, M0) were prospectively randomized to receive every 14 days a total of four cycles of doxorubicin 50 mg/m2 and docetaxel 75 mg/m(2), either with (ADocT) or without (ADoc) simultaneous tamoxifen. Granulocyte colony-stimulating factor (G-CSF) was routinely given on days 5 to 10. Surgery followed 8 to 10 weeks after the start of treatment.
Within 14 months, 250 patients were included in the study at 56 centers. Of 992 planned cycles, 97.9% were administered. Pathologically complete remission (pCR) with no detectable viable tumor cells was achieved in 9.7%. There was a nonsignificant difference of -1.2% in favor of ADoc, with a 95% confidence interval of -8.6% to 6.2%. A further 2.4% had only noninvasive tumor residues, and 13.8% had focal invasive residues. Complete and partial responses detected by palpation were observed in 28.9% and 52.4%, respectively. The response rates (complete and partial) by best appropriate imaging methods were 77.5% and 67.5% for ADocT and ADoc, respectively. Breast conservation was possible in 68.8% of the patients. A tendency toward more frequent toxic events was observed with ADocT treatment. Significant predictors of pCR to chemotherapy were negative lymph node and negative estrogen receptor status.
A dose-dense regimen of ADoc with G-CSF offers high compliance, moderate toxicity, and rapid efficacy as a form of preoperative chemotherapy in operable breast cancer. Concurrent treatment with tamoxifen for 8 weeks could not improve the pathologic response rate.
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