Francesco Giotta

A prothrombotic state in breast cancer patients treated with adjuvant chemotherapy.

Cancer is often associated with abnormal activation of coagulation leading to a prothrombotic state. Some chemotherapeutic agents used for cancer may induce thrombosis but their biological alterations in the hemostatic system are not yet well understood. This study evaluated alterations of coagulative and fibrinolytic parameters following chemotherapy.In plasma samples of 38 patients (median age: 49 years) receiving CMF (schedule 1–21 or 1–8) for Stage II breast cancer, we evaluated: PT, aPTT, antithrombin III (AT-III), protein C (PC), protein S (PS), thrombinantithrombin complex (TAT), prothrombin fragment F1 + 2 (F1 + 2), fibrinogen (Fbg), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor (PAI - 1) and D-dimer (D-D). PT, aPTT, and Fbg were determined with routine methods; AT-III, PC, and PS were measured with coagulative tests; PC and PS were also evaluated with immunoenzymatic methods. t-PA, PAI-1, D-D, TAT, and F 1 + 2 were measured with immunoenzymatic methods. All tests were performed immediately before starting therapy and after each cycle.A PC antigen decrease appeared soon after beginning therapy and lasted throughout chemotherapy. The lowest values were present after the first treatment both in the CMF 1–21 group (mean ± SD = 72.5 ± 10.8%) and in the CMF 1–8 group (mean ± SD = 77.2 ± 6.9%); PC activity was also decreased. PS antigen decreased after the first administration (mean ± SD = 73.3 ± 10% in CMF 1–21 group, and 72.5 ± 4.9% in CMF 1–8 group); PS activity also decreased. PAI-1 antigen levels increased (mean ± SD = 43.1 ± 20.4 ng/ml in the CMF 1–21 group, and 37.5 ± 12.2 ng/ml in CMF 1–8 group) lasting up to the last cycle.CMF provokes a trend toward hypercoagulability; this effect should be considered when chemotherapy is employed in advanced cancer patients at high risk for thrombosis, or in patients with other risk factors.

First-Line Treatment With Epirubicin and Vinorelbine in Metastatic Breast Cancer

PURPOSEnThis phase II multicenter trial was aimed at investigating the activity of epirubicin-vinorelbine combination as first-line chemotherapy in metastatic breast cancer patients.nnnPATIENTS AND METHODSnNinety-seven patients with metastatic breast cancer and no prior exposure to anthracyclines received the following regimen: epirubicin 100 mg/m(2) by intravenous (IV) bolus infusion on day 1 plus vinorelbine 25 mg/m(2) by 30-minute IV infusion on days 1 and 5, every 3 weeks for up to eight cycles. All patients also received granulocyte colony-stimulating factor (G- CSF) on days 7 to 12 of every cycle.nnnRESULTSnObjective responses, confirmed at least 4 weeks after the first documentation, were observed in 65 out of 92 assessable patients (70.6%; 95% CI, 62% to 80%). Disease remained stable in 17 patients (18.5%). Responses were observed in all disease sites, being 94% in soft tissue, 60% in bone, and 66% in visceral disease. Median time to response, median duration of response, median time to progression, and median overall survival were 2, 9, 10, and 26 months, respectively. The dose-limiting toxicity was neutropenia, which was grade 4 in 36% of the patients, and was accompanied by fever in 26% of the cases. Grade 3 to 4 mucositis was encountered in 28% of the patients. Other toxicities were mild to moderate. No cardiotoxicity was observed.nnnCONCLUSIONnThe epirubicin-vinorelbine combination with G-CSF support has been shown in this study to be highly active as first-line treatment of metastatic breast cancer patients, with significant although transient toxicity. This justifies further evaluation in the neoadjuvant setting and in early-stage breast cancer.

Administration of Angiotensin-Converting Enzyme Inhibitors and β-Blockers During Adjuvant Trastuzumab Chemotherapy for Nonmetastatic Breast Cancer: Marker of Risk or Cardioprotection in the Real World?

BACKGROUNDnAdjuvant trastuzumab therapy improves the outcome of patients with early breast cancer (EBC) and overexpression of human epidermal growth factor receptor 2 (HER2). However, it is potentially cardiotoxic. This study aims to evaluate the relationship between the use of angiotensin-converting enzyme inhibitors/receptor blockers (ACEi/ARBs) and/or β-blockers and development of heart failure (HF) and/or left ventricular dysfunction during 1 year of adjuvant trastuzumab therapy.nnnMETHODSnA total of 499 women receiving adjuvant trastuzumab therapy for EBC entered in a multicenter registry and were divided into four subgroups according to treatment with ACEi/ARBs and/or β-blockers. Occurrence of HF and decrease of left ventricular ejection fraction (LVEF; minimum 10 percentage points) were recorded.nnnRESULTSnHF occurred in 2% of patients who did not take either ACEi/ARBs or β-blockers, 8% of patients receiving ACEi/ARBs alone, 8% receiving β-blockers alone (p = .03), and 19% receiving both medications (p < .01). The prevalence of patients with LVEF that decreased by at least 10 percentage points was similar in all groups. Combined ACEi/ARBs and β-blocker therapy was independently associated with hypertension and a significant reduction of LVEF from baseline to 3-month evaluation. The use of ACEi/ARBs alone or β-blockers alone was predicted only by hypertension. Combined therapy of ACEi/ARBs plus β-blockers predicted LVEF recovery from the 3-month to 12-month evaluation.nnnCONCLUSIONSnIn clinical practice, the degree of hypertension and decrease in LVEF during the first 3 months of adjuvant trastuzumab therapy for EBC are associated with the use of ACEi/ARBs and β-blockers. The combined use of these two medications is associated with a recovery of LVEF during months 3-12 of adjuvant trastuzumab therapy.

Cisplatin and epirubicin plus oral lonidamine as first-line treatment for metastatic breast cancer: a phase II study of the Southern Italy Oncology Group (GOIM).

Lonidamine (LND) is a unique antineoplastic drug derived from indazole-3-carboxylic acid which inhibits oxygen consumption and aerobic glycolysis, interfering with energy metabolism of neoplastic cells. LND has been experimentally shown to potentiate the cytotoxic effects of epirubicin (EPI) in human breast cancer cell lines, cisplatin activity in both platinum-sensitive and -resistant human ovarian carcinoma cell lines, and EPI antineoplastic activity in some recent phase III trials carried out in advanced breast cancer. A multicenter phase II trial was carried out with the combination of cisplatin 60 mg/m2, EPI 100 mg/m2 and LND 450 mg/day p.o. in three refracted doses/day starting 2 days before cisplatin and EPI (day -2 and -1), stopping 2 days after chemotherapy (day 0, +1 and +2). Thirty patients with metastatic breast cancer were enrolled into the study. Twenty-nine patients were evaluable for objective response. The overall response rate accordingly to an intent-to-treat analysis was 73% (95% CL 54-88%). Four patients achieved complete response (13%; 95% CL 4-31%) with a median duration of 9.5 months (range 4-16) and 18 patients had partial response (60%; 95% CL 41-77%) with a median duration of 9.8 months. Stable disease was obtained in five cases (17%) and progressive disease was recorded in three patients. One patient died of progressive cancer before restaging. The overall median survival of the whole series of patients was 14+ months. The most frequent toxicities were represented by gastrointestinal and hematological side effects. The combination of cisplatin + EPI plus oral LND is active against metastatic breast carcinoma. The antineoplastic activity of the cisplatin + EPI + LND regimen is as high as that reported for more aggressive regimens such as the fluorouracil + doxorubicin + cyclophosphamide combinations without an increase in toxic effects.

Quality of life, fatigue and depression in Italian long-term breast cancer survivors

Data from the European Cancer Registries show an increase in survival in the last decade: the 5-year age-standardised relative survival rate for breast cancer has reached 79 % for women diagnosed in 1995–1999 [1], which is higher from the 76 % for those diagnosed in 1990–1994 [2]. Nevertheless, most survivors experience adverse effects that can negatively affect their quality of life [3–5]. Risk factors for long-term cancer and treatment-related sequelae may differ by time from completion and type of treatment, age at diagnosis, comorbid conditions and biological factors as well as psychosocial or behavioural factors such as healthy or unhealthy lifestyle. All these aspects may affect both physical and psychological functioning [5]. Among physical late effects in breast cancer survivors (BCS), arm/shoulder complaints, cardiovascular disease, gonadal dysfunction and fatigue are the most common [6]. Fatigue is a distressing symptom in breast cancer patients both during treatments and during the survivorship phase. Long-term BCS tend on average to be more fatigued than the general population, but, until now, evidence of greater fatigue severity compared to healthy controls is mixed [7]. Incidence and prevalence rates for fatigue in long-term BCS range from 24 to 62 %, with most studies reporting rates of approximately 40 % [8–10]. In reality, both the diverse definitions of survivorship and the various fatigue measurement tools implied complicate the ability to make adequate data comparison and to draw clear conclusions on fatigue incidence and prevalence. Regarding psychological sequelae, it was found that in long-term BCS, depression is one of the most distressing and disabling symptoms, even more than anxiety and posttraumatic stress disorder [11]. In a recent US populationbased study [12], including 4,636 adult long-term survivors diagnosed five or more years earlier, the prevalence of significant psychological distress was found to be significantly higher compared to the healthy peers and similar data were also found in European studies [13, 14]. Fatigue and depression have been found to be closely related both in cancer patients and in cancer survivors [e.g. 15, 16]. The concept of health-related quality of life (HRQOL) includes aspects of physical and mental health as a subjective perception and is usually considered a valid indicator of the impact of health on peoples quality of life. In some previous studies on long-term BCS, it was surprisingly found that BCS reported better health compared to the general female population [17] even if reporting more frequent use of health care facilities [18]. When studying cancer late effects in cancer survivors, the intercultural variations across countries should also be mentioned: different cultures and health systems may contribute to diverse adaptation in the survivorship phase. For example, many European countries, such as France, Italy and the F. Romito (*) : C. Cormio :V. Mattioli Experimental Unit of Psychological Oncology, Department of Critical Area and Surgery, National Cancer Center “Giovanni Paolo II”, Via O. Flacco 65, 70126 Bari, Italy e-mail: francescaromito@yahoo.com

A multicenter prospective phase II randomized trial of epirubicin/vinorelbine versus pegylated liposomal doxorubicin/vinorelbine as first-line treatment in advanced breast cancer. A GOIM study

BackgroundTo evaluate activity and tolerability of two anthracycline-containing regimens as first-line treatment for anthracycline-naïve relapsed breast cancer patients.MethodsPatients with relapsed breast cancer not previously treated with adjuvant anthracyclines were randomly assigned to epirubicin/vinorelbine (arm A: EPI/VNB, EPI 90 mg/m2 on day 1, VNB 25 mg/m2 on days 1,5 plus G-CSF subcutaneously on days 7-12, with cycles repeated every 21 days), or to pegylated liposomal doxorubicin/VNB (arm B: PLD/VNB, PLD 40 mg/m2 on day 1, VNB 30 mg/m2 on days 1, 15, with cycles repeated every 4 weeks). Primary objective was to evaluate the efficacy of the two regimens in terms of response rate, secondarily toxicity, progression free survival and overall survival.ResultsOne hundred and four patients have been enrolled (arm A 54, arm B 50): characteristics were well balanced between the 2 arms. Responses were as follows: arm A, 3 (5.6%) CR, 20 (37%) PR, (ORR 42.6%, 95%CI 29.3%-55.9%); arm B, 8 (16%) CR, 18 (36%) PR, (ORR 52%, 95%CI 38.2%-65.8%). Median progression free survival was 10.7 months in arm A (95% CI, 8.7-12.6), and 8.8 months in arm B (95% CI, 7.1-10.5). Median overall survival was 34.6 months in arm A (95%CI, 19.5-49.8) and 24.8 months in arm B (95%CI, 15.7-33.9). As toxicity concerns, both treatment regimens were well tolerated; myelosuppression was the dose-limiting toxicity, with G3-4 neutropenia occurring in 18.5% and 22% of the patients of arm A and B, respectively. No relevant differences in main toxic effects have been observed between the two arms, except for alopecia, more common in arm A, and cutaneous toxicity, observed only in arm B. No clinical congestive heart failures have been observed, one case of tachyarrhythmia was reported after the last EPI/VNB cycle, and two reversible ≥ 20% LVEF decreases have been observed in arm A.ConclusionsBoth anthracycline- containing regimens evaluated in the present study seem to be active and with a satisfactory tolerability in anthracycline-naïve relapsed breast cancer patients.

Gemcitabine and docetaxel every 2 weeks in advanced non-small cell lung cancer: a phase II study of the Gruppo Oncologico Italia Meridionale

INTRODUCTIONnPlatinum-based chemotherapy is the gold standard in advanced non-small cell lung cancer (NSCLC), although with relevant toxic effects. Both docetaxel (DCT) and gemcitabine (GEM) have shown activity as single agent in advanced NSCLC with a different toxicity profile and a lack of cross-resistance.nnnMATERIALS AND METHODSnFrom April 2000 to May 2001, 47 consecutive patients were enrolled in a multicenter phase II trial. Main inclusion criteria included untreated patients with histologically confirmed NSCLC, age</=70 years, stage IIIB/IV, Eastern Cooperative Oncology Group performance status (PS) 0-2, measurable disease, adequate hematologic, cardiac, hepatic and renal functions, and written informed consent. Treatment schedule consisted of DCT at the dosage of 50 mg/m(2) with conventional steroid premedication and GEM at the dosage of 2,000 mg/m(2). Both drugs were administered every 2 weeks without prophylactic use of growth factors.nnnRESULTSnEnrolled patients included 40 males and seven females with a median age of 65 years, and a median PS 1. There were 26 squamous carcinomas, 13 adenocarcinomas, and eight others, 13 stage IIIB and 34 stage IV. A total of 371 cycles were administered. Overall 18 partial responses were observed (38.3%); 14 patients were considered as stable disease and 13 showed progressive disease. Two treatment-not related deaths occurred before the first disease evaluation was performed. Median duration of response was 6 months (range 2-10) and median duration of survival was 10.5 months (range 1-25+). One year survival probability was 38% (95% CI 25-54%). In a statistical analysis responses were independent to histology or stage. Grade 3-4 toxicity, according NCI criteria, was mild with neutropenia in eight patients (17%), anemia in two patients (4%). Asthenia affected two patients and mucositis occurred in one patient.nnnCONCLUSIONSnIn our experience the biweekly combination of DCT and GEM is active and well tolerated and can be administered without G-CSF primary prophylaxis reducing treatment costs. It should be considered as a promising alternative to more toxic platinum-based regimens.

Outcomes of HER2-positive early breast cancer patients in the pre-trastuzumab and trastuzumab eras: a real-world multicenter observational analysis. The RETROHER study

AbstractAddition of trastuzumab to adjuvant chemotherapy has dramatically reduced the risk of recurrence and has become the standard of care for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer patients. Since most data on trastuzumab benefits come from clinical trials, conducted in selected patient populations, we performed a retrospective analysis of HER2-positive early breast cancer patients treated in the “pre-trastuzumab” and “trastuzumab” eras, with the aim to determine patients outcomes in real-world practice. 925 consecutive HER2-positive breast cancer patients treated with adjuvant chemotherapy in ten Italian oncologic centers were identified. Patients who had received adjuvant chemotherapy alone (cohort A, 352 patients), and patients who had received adjuvant chemotherapy followed or combined with trastuzumab (cohort B, 573 patients) were analyzed. Relapse rate at 3xa0years, relapse-free survival, and overall survival were significantly more unfavorable in the cohort A than in the cohort B (pxa0<xa00.0001). In multivariate analysis, factors related to relapse were younger age, advanced stage at diagnosis, absence of hormonal and of trastuzumab therapy. The benefit derived from the addition of trastuzumab was independent of nodal status and hormonal receptors expression. A subgroup analysis including 163 “triple positive” tumors with high levels of estrogen and progesterone receptor (TP50) suggested that addition of trastuzumab to adjuvant chemotherapy and hormonal therapy did not translate into better outcomes. In our analysis, trastuzumab benefit was confirmed in all but a small subset of TP50 tumors subgroups. In this subset further investigations are needed.n

A phase II trial of docetaxel and vinorelbine in patients with advanced breast cancer previously treated with anthracyclines

Background: It was the aim of this study to evaluate the efficacy of docetaxel and vinorelbine combination in well-defined anthracycline-‘exposed’ or -‘resistant’ advanced breast cancer patients. Patients and Methods: A phase II trial was carried out enrolling 43 advanced breast cancer patients, all previously treated with anthracyclines, both in an adjuvant or advanced setting. Docetaxel 75 mg/m2 as 1-hour infusion and vinorelbine 25 mg/m2 as 30-min infusion were administered on day 1, every 3 weeks. Results: According to an intent-to-treat analysis, the response rate was 37.2% (95% CI 22.8–51.6) in 43 patients, whereas responses were observed in 16 (1 complete response, 15 partial response) out of 39 evaluable patients (41%, 95% CI 25.6–56.5); there were 50% with first-line and 33% with second-line therapy, and 50 and 29% of patients were considered anthracycline ‘exposed’ and ‘resistant’, respectively; responses by estrogen receptor (ER) status were given in 48% (ER positive) and 25% (ER negative), and by HER2 status, in 21% (HER2 positive) and 52% (HER2 negative). Median time to progression and median overall survival were 7.7 and 28.7 months, respectively. Toxicity was generally acceptable, with grade 3 neutropenia encountered in 15 (35%) patients and grade 4 neutropenia in 1 (2%) patient. Neutropenic fever occurred in 7 patients (16%), usually short-lasting. Grade 3 mucositis was encountered in 2 patients (5%). Conclusions: The combination of docetaxel and vinorelbine as a 3-weekly schedule is active and manageable in advanced breast cancer patients previously treated with anthracyclines.

Clinical and prognostic role of matrix metalloproteinase-2, -9 and their inhibitors in breast cancer and liver diseases: A review.

Matrix metalloproteinases are a family of zinc endopeptidases with proteolytic activity against the extracellular matrix components. In particular, two members of this family named Gelatinase A and B, as amply documented in the literature, play a key role in the process of tumor growth/metastasis in breast and hepatocellular carcinoma. Their activity is regulated by Tissue Inhibitor of metalloproteinases-1 and -2, which are the physiological inhibitor of Gelatinases A and B respectively. The aim of this review is to determine the current understanding of the clinical and prognostic role of Metalloproteinases-2 and -9 and their inhibitors in the course of breast cancer and liver diseases. Forty-one articles were selected from PubMed by entering the following keywords: liver diseases, breast cancer, MMP-2, TIMP-2; all articles were read and notes were made regarding the number of enrolled patients, pathology, measures, results and these data were used to write this review. Over-expression of both gelatinases is associated with the relapse of disease, metastasis, shorter overall survival in breast cancer and hepatocellular carcinoma and invasion and progression to tumors in chronic liver diseases, and MMPs/TIMPs ratio could be useful in the follow-up of these patients.