Trainend in gynecology oncology in Hannover Med. Univ. and HSK Wiebaden ASCO member, german breast and ovarian cancer council national and international study participation
Abstract: BACKGROUND: Pegylated liposomal doxorubicin (PLD) is active in metastatic breast cancer. This observational study evaluated the efficacy and safety of PLD in patients treated during routine clinical practice. METHODS: Eligible patients had metastatic breast cancer and were treated with PLD according to the dose and schedule determined by their physician as part of routine practice. The primary objectives were to analyze the efficacy and toxicity of PLD therapy. RESULTS: 125 patients were assessable. Median age was 62 years, 78% had performance status 0-1, and 60% had estrogen-receptor-positive disease. PLD treatment was second- or third-line in 69% of patients. Prior anthracyclines (adjuvant or metastatic) had been used in 56% of patients. The majority of patients (79%) received PLD every 4 weeks at a median dose of 40 mg/m2. Overall response rate was 43% in all patients and 34% in those previously treated with anthracyclines. The most common grade 3/4 adverse events were skin toxicity/hand-foot syndrome (6%), and leukopenia (3%). CONCLUSIONS: This observational study supports the activity and tolerability of PLD in metastatic breast cancer as demonstrated in PLD clinical trials.
Abstract: The FIGO has invited the GCIG to make contributions for possible changes of the FIGO staging system. We report on the consensus within the GCIG committee to propose the following changes in the current FIGO classification. Cervical cancer: Since fertility-preserving surgery is increasingly used in early disease, stage IB1-A may include tumors of up to 2 cm in diameter. Endometrial cancer: Positive peritoneal cytology alone should not classify this patient to be allotted to stage IIIA disease. Lymphadenectomy should be recommended in high-risk clinical stage I patients and in those with adverse histologies. Ovarian cancer: In early stage disease, grading and in advanced disease, the amount of residual disease should be reported. Vulvar cancer: The lymph node status should always be reported. In the case of enlarged inguinal nodes, histology should be obtained by any means. Vaginal cancer: Besides bladder and rectal tumor involvement urethral mucosal involvement should be added. Gestational trophoblastic disease: The modified WHO scoring system which is widely accepted should be adopted.
Abstract: PURPOSE: To compare preoperative intense dose-dense (IDD) chemotherapy with conventionally scheduled preoperative chemotherapy in high-risk primary breast cancer (BC). PATIENTS AND METHODS: In this randomized phase III trial a total of 668 eligible primary BC patients stratified for tumors > or = 3 cm (n = 567) or inflammatory BC (n = 101) were randomly assigned to receive concurrent preoperative epirubicin/paclitaxel every 3 weeks or dose-dense and dose-escalated sequential epirubicin followed by paclitaxel every 2 weeks. All patients received three cycles of cyclophosphamide, methotrexate, and fluorouracil chemotherapy after surgery. RESULTS: IDD treatment significantly improved pathologic complete response rate (18% v 10%; odds ratio [OR] 1.89; P = .008), disease-free survival (DFS; hazard ratio [HR], 0.71; P = .011), and overall survival (OS; HR, 0.83; P = .041) compared to epirubicin/paclitaxel. Patients with inflammatory BC had a particularly poor prognosis and did not appear to benefit from IDD therapy in this trial (DFS HR, 1.10; P = .739; OS HR, 1.25; P = .544). In contrast, patients with noninflammatory BC significantly benefited from IDD treatment (DFS HR, 0.65, P = .005; OS HR, 0.77, P = .013). Treatment effects in multivariate analysis were significant for noninflammatory BC (DFS HR, 0.65, P = .015; OS HR, 0.79, P = .034), but not for all patients (DFS HR, 0.76; P = .088; OS HR, 0.82; P = .059). IDD therapy was associated with significantly more nonhematologic toxicities, anemia, and thrombocytopenia, but with similar neutropenia and infection rates. CONCLUSION: Our results support the efficacy and short-term safety of IDD as preoperative chemotherapy. IDD was less well tolerated compared to standard treatment, but improved clinical outcomes in patients with noninflammatory high-risk primary BC.
Abstract: To ensure targeted treatment, it would be useful to know at the time of diagnosis whether a BRCA mutation is causally related to an individual breast cancer. The aim of this study was to investigate in an unselected series of breast cancer patients the value of incorporating morphological and immunohistochemical features for the selection of patients who may benefit from BRCA1 genetic testing. In a retrospective approach, histopathological results of tumors from 897 women were reevaluated regarding age at diagnosis, subtype of cancer, tumor grade, and estrogen (ER), progesterone (PR), and Her2/neu receptor status, as well as p53 and Ki67 status. In all, 142 tumors fulfilled morphological criteria indicative of a BRCA1 mutation. Of the 59 women willing to participate, 26 women concomitantly showed a positive family history. Pathogenic BRCA1 germline mutations were detected in 7 of 18 women (39%) (95% confidence interval = 0.17-0.64). All BRCA1-associated tumors were of high grade, invasive-ductal subtype, and PR and Her2/neu negative, and 91% of the tumors were negative for ER; 60% of the tumors showed a high expression of p53 and 60% a high expression of Ki67. There was a significant difference with respect to grading (P = 0.001 for G3), ER negativity (P = 0.0075), Ki67 > or = 65% (P = 0.0039), and triple negativity (i.e., ER(-), PR(-), Her2/neu(-)) (P = 0.0019) between tumors of mutation carriers and noncarriers.
Abstract: OBJECTIVE: Effective therapies with a low rate of side effects are warranted in the 2nd-line setting in ovarian cancer. Both topotecan and the alkylating agent treosulfan have demonstrated efficacy in this patient group and are broadly used in Germany. Therefore, we started a prospectively randomized phase III trial comparing these two drugs in early recurrent ovarian cancer. METHODS: Patients having relapsed after platinum-taxane therapy were randomized to receive either topotecan or treosulfan. Stratification depended on platinum sensitivity (stratum 1: up to 6 months after primary chemotherapy, stratum 2: 6 to 12 months). RESULTS: A total of 274 patients were treated either with topotecan (136 patients) or treosulfan (138). Hematologic toxicity was significantly more frequent with topotecan but without severe clinical consequences. Non hematologic toxicity was similar in both study arms. Overall survival was significantly longer with topotecan (p=0.0023), with a median of 55.0 weeks versus 41.0 weeks as well as progression-free survival (p=0.0020) with a median of 23.1 weeks versus 12.7 weeks. Similar results were found for stratum 2 subgroup. Overall response rate was 27.5% for topotecan and 16.0% for treosulfan (p=0.0307). In stratum 1 progression-free survival was 18.1 weeks for topotecan and 9.4 weeks for treosulfan (p=0.0476), but there was no difference in overall survival in this prognostic poor subgroup. CONCLUSIONS: This randomized phase III trial could detect superiority of topotecan versus treosulfan in patients with recurrent disease after platinum-paclitaxel combination therapy. Our experience indicates that optimization of systemic treatment could improve outcome even in this poor prognostic subgroup of patients with relapsed ovarian cancer.
Abstract: BACKGROUND: Carboplatinum-based retreatment can be regarded as a standard option in the so-called platinum-sensitive ovarian cancer, but its use can be limited by the occurrence of sometimes severe hypersensitivity reactions (HSRs). This study analyzes the value of carboplatin skin testing and desensitization. PATIENTS AND METHODS: Between 2004 and 2006, all patients with carboplatin reinduction chemotherapy received an intradermal injection of 0.2 microL of carboplatin and saline as negative control before chemotherapy. Carboplatin was administered in the standard way if the test was negative. If positive, carboplatin was administered after an already published desensitization protocol. RESULTS: Fifty-four patients received retreatment with carboplatinum and were submitted to skin test. Seven patients (13%) had positive skin test, whereas 4 patients developed HSRs although they had negative skin test (8.5% false-negative rate). Skin test predicted HSRs in only 64% of the afflicted patients. Desensitization was performed in all patients with positive skin test, and 5 (71%) of 7 could receive 3 to 11 further carboplatinum courses. Repeated HSRs occurred in 2 of 7 patients despite desensitization; however, none of the HSRs after desensitization were severe. CONCLUSIONS: Skin test did not reliably predict carboplatinum-induced HSR, but desensitization was demonstrated to be a rather successful strategy. Taking the low predictive value into account, we started another prospective series of administering antiallergic medication to all patients with carboplatinum retreatment and offer desensitization if any HSR occurs.
Abstract: BACKGROUND: Chemotherapy with epirubicin is approved in women with breast cancer and is associated with a certain degree of cardiotoxicity. HYPOTHESIS: Epirubicin changes stroke volume, cardiac output and systemic vascular resistance, while liposomal doxorubicin does not. METHODS: 75 patients with HER-2-positive metastatic breast cancer were continuously measured with CW-Doppler ultrasound for stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR) before, during and after drug infusion in combination with NT-pro-BNP before and 10 min after drug infusion. RESULTS: Epirubicin infusion increased stroke volume significantly in low-level NT-pro-BNP (62+/-23 ml vs. 74+/-29 ml, p=0.004) and high-level NT-pro-BNP (48+/-5 ml vs. 64+/-20 ml, p=0.131), while liposomal doxorubicin infusion increased stroke volume significantly in low-level NT-pro-BNP (54+/-16 ml vs. 67+/-22 ml, p=0.001) and high-level NT-pro-BNP (65+/-22 ml vs. 82+/-27 ml, p=0.001). Cardiac output was significantly increased in epirubicin (p=0.004) by 20% (NT-pro-BNP<125 pg/ml) and not significantly 38% (NT-pro-BNP>125 pg/ml; p=0.144), while in liposomal doxorubicin cardiac output was significantly increased by 23% (NT-pro-BNP<125 pg/ml; p=0.023) and 33% (NT-pro-BNP>125 pg/ml; p=0.001). In liposomal doxorubicin cardiac index was significantly increased by 26% (NT-pro-BNP<125 pg/ml; p=0.021) and 33% (NT-pro-BNP>125 pg/ml; p=0.0001). SVR was significantly reduced during and after epirubicin therapy. CONCLUSION: Using the CW-Doppler USCOM a different hemodynamic response to epirubicin vs. liposomal doxorubicin is evident. Epirubicin leads to a significant upregulation of stroke volume and cardiac output, which is even more pronounced in the high-level NT-pro-BNP group, while liposomal doxorubicin does not change immediate hemodynamics. No deterioration of cardiac function using the real-time CW-Doppler ultrasound USCOM or an increase in NT-pro-BNP levels was evident during epirubicin or liposomal doxorubicin therapy.
Abstract: PURPOSE: Overall survival (OS) can be observed only after prolonged follow-up, and any potential effect of first-line therapies on OS may be confounded by the effects of subsequent therapy. We investigated whether tumor response, disease control, progression-free survival (PFS), or time to progression (TTP) could be considered a valid surrogate for OS to assess the benefits of first-line therapies for patients with metastatic breast cancer. PATIENTS AND METHODS: Individual patient data were collected on 3,953 patients in 11 randomized trials that compared an anthracycline (alone or in combination) with a taxane (alone or in combination with an anthracycline). Surrogacy was assessed through the correlation between the end points as well as through the correlation between the treatment effects on the end points. RESULTS: Tumor response (survival odds ratio [OR], 6.2; 95% CI, 5.3 to 7.0) and disease control (survival OR, 5.5; 95% CI, 4.8 to 6.3) were strongly associated with OS. PFS (rank correlation coefficient, 0.688; 95% CI, 0.686 to 0.690) and TTP (rank correlation coefficient, 0.682; 95% CI, 0.680 to 0.684) were moderately associated with OS. Response log ORs were strongly correlated with PFS log hazard ratios (linear coefficient [rho], 0.96; 95% CI, 0.73 to 1.19). Response and disease control log ORs and PFS and TTP log hazard ratios were poorly correlated with log hazard ratios for OS, but the confidence limits of rho were too wide to be informative. CONCLUSION: No end point could be demonstrated as a good surrogate for OS in these trials. Tumor response may be an acceptable surrogate for PFS.
Abstract: PURPOSE: Taxanes (paclitaxel or docetaxel) have been sequenced or combined with anthracyclines (doxorubicin or epirubicin) for the first-line treatment of advanced breast cancer. This meta-analysis uses data from all relevant trials to detect any advantages of taxanes in terms of tumor response, progression-free survival (PFS), and survival. PATIENTS AND METHODS: Individual patient data were collected on eight randomized combination trials comparing anthracyclines + taxanes (+ cyclophosphamide in one trial) with anthracyclines + cyclophosphamide (+ fluorouracil in four trials), and on three single-agent trials comparing taxanes with anthracyclines. Combination trials included 3,034 patients; single-agent trials included 919 patients. RESULTS: Median follow-up of living patients was 43 months, median survival was 19.3 months, and median PFS was 7.1 months. In single-agent trials, response rates were similar in the taxanes (38%) and in the anthracyclines (33%) arms (P = .08). The hazard ratios for taxanes compared with anthracyclines were 1.19 (95% CI, 1.04 to 1.36; P = .011) for PFS and 1.01 (95% CI, 0.88 to 1.16; P = .90) for survival. In combination trials, response rates were 57% (10% complete) in taxane-based combinations and 46% (6% complete) in control arms (P < .001). The hazard ratios for taxane-based combinations compared with control arms were 0.92 (95% CI, 0.85 to 0.99; P = .031) for PFS and 0.95 (95% CI, 0.88 to 1.03; P = .24) for survival. CONCLUSION: Taxanes were significantly worse than single-agent anthracyclines in terms of PFS, but not in terms of response rates or survival. Taxane-based combinations were significantly better than anthracycline-based combinations in terms of response rates and PFS, but not in terms of survival.
Abstract: BACKGROUND: Breast cancers arising in women with germline BRCA1 mutations are most likely to be estrogen receptor (ER), progesterone receptor (PR), and HER2/neu negative (so-called triple negative or basal-like breast cancers). Metaplastic carcinoma with pure squamous differentiation is a very rare histological subtype (0.1% of all breast cancers) and is usually ER, PR, and HER2/neu negative by immunohistochemistry. A BRCA1 germline mutation in squamous cell breast cancer has never been reported. CASE REPORT: A 25-year-old woman was diagnosed with squamous cell cancer of the breast. Three years later, she developed contralateral breast cancer, also of the squamous cell subtype. Both tumors were triple negative. Because of the patient's history and her strong family history, genetic testing was recommended. The patient was found to be carrier of a BRCA1 germline mutation. CONCLUSION: We report, to our knowledge, the first case of a BRCA1 mutation in a woman with metaplastic squamous cell breast cancer.
