Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer.

BACKGROUND: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. PATIENTS AND METHODS: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. RESULTS: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015). CONCLUSIONS: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.

Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study‡.

Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. Results: A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001). Conclusions: This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial Registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM (Gruppo Oncologico Italia Meridionale) 9902 study.

BACKGROUND: The Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide (EC) with four cycles of docetaxel (Taxotere, D) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to EC (E 120 mg/m(2), C 600 mg/m(2), arm A) for four cycles or four cycles of D (100 mg/m(2)) followed by four cycles of EC (arm B), both regimens every 21 days. Hormone receptor-positive patients were given hormonal therapy for 5 years. Primary end point was 5-year disease-free survival (DFS). Secondary objectives were overall survival (OS) and safety. RESULTS: There were 750 patients enrolled. With a median follow-up of 64 months, 5-year DFS was 73.4% in both arms, and 5-year OS was 89.5% versus 90.7% in arm A and B [hazard ratio was 0.99 (95% confidence interval for DFS 0.75-1.31; P = 0.95)], respectively. Grade 3-4 toxicity was more common in arm B. CONCLUSIONS: This study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer. The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms.

A multicenter phase II randomized trial of docetaxel/gemcitabine versus docetaxel/capecitabine as first-line treatment for advanced breast cancer: a Gruppo Oncologico Italia Meridionale study.

OBJECTIVE: To evaluate two docetaxel-based regimens as first-line treatment in advanced breast cancer patients. METHODS: Patients were randomly assigned to docetaxel/gemcitabine (arm A: docetaxel 75 mg/m(2) on day 1, gemcitabine 1,000 mg/m(2) on days 1 and 8) or docetaxel/capecitabine (arm B: docetaxel 75 mg/m(2) on day 1, capecitabine 1,250 mg/m(2) twice daily on days 1-14); both chemotherapy regimens were repeated every 21 days. The primary objective of the study was to evaluate the response rate. RESULTS: Seventy-two patients were enrolled (36 each in arms A and B). Responses according to intention-to-treat analysis were as follows: arm A, 41.7% [95% confidence interval (CI) 25.6-57.8]; arm B, 38.9% (95% CI 23-54.8). Median progression-free survival was 10.9 months (95% CI 8.1-13.7) in arm A and 10 months (95% CI 8.8-11.2) in arm B. Overall survival was 26 months (95% CI 22.0-30.0) in arm A and 28 months (95% CI 23.4-32.6) in arm B. Both treatments were well tolerated; myelosuppression was the dose-limiting toxicity, with grade 3-4 neutropenia in 13.8 and 19.4% of the patients in arms A and B, respectively. No relevant differences in other toxicities were observed in the two arms, except for diarrhea (13.9%) and hand-foot syndrome (11.1%), which occurred only in arm B. CONCLUSIONS: Both regimens were active and well tolerated in advanced breast cancer.

A Gradient-Based Approach for Breast DCE-MRI Analysis.

Breast cancer is the main cause of female malignancy worldwide. Effective early detection by imaging studies remains critical to decrease mortality rates, particularly in women at high risk for developing breast cancer. Breast Magnetic Resonance Imaging (MRI) is a common diagnostic tool in the management of breast diseases, especially for high-risk women. However, during this examination, both normal and abnormal breast tissues enhance after contrast material administration. Specifically, the normal breast tissue enhancement is known as background parenchymal enhancement: it may represent breast activity and depends on several factors, varying in degree and distribution in different patients as well as in the same patient over time. While a light degree of normal breast tissue enhancement generally causes no interpretative difficulties, a higher degree may cause difficulty to detect and classify breast lesions at Magnetic Resonance Imaging even for experienced radiologists. In this work, we intend to investigate the exploitation of some statistical measurements to automatically characterize the enhancement trend of the whole breast area in both normal and abnormal tissues independently from the presence of a background parenchymal enhancement thus to provide a diagnostic support tool for radiologists in the MRI analysis.

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.

Post-traumatic Growth in the Italian Experience of Long-term Disease-free Cancer Survivors.

Cancer survivors often report post-traumatic growth. Since culture influences the development of post-traumatic growth, the aims of this study were to measure the prevalence of post-traumatic growth in Italian long-term disease-free and treatment-free cancer survivors (≥5 years) and explore the relationship between post-traumatic growth and sociodemographic and clinical variables. Three hundred sixty long-term disease-free and treatment-free cancer survivors were assessed with Post-traumatic Growth Inventory (PTGI), Brief COPE and Multidimensional Scale of Perceived Social Support (MSPSS). Mean age was 58.6 years, and mean survival was 11 years (range 5-32). The PTGI average total score was higher in younger survivors, in those without comorbidities, in survivors engaged in physical activity. Positive correlation between PTGI and Brief COPE and between PTGI and MSPSS were found. The variables more associated with post-traumatic growth were age, comorbidity, physical activity and two coping subscales. The prevalence of post-traumatic growth in this sample of cancer survivors was lower than previous studies. We discussed some possible explanations, including the consideration that cultural differences may affect the development of post-traumatic growth in cancer survivors. Having less comorbidities, receiving social support from friends, having the ability to adaptively cope and engaging in physical activity were found to be strongly associated with post-traumatic growth.

Novel association with gemcitabine and docetaxel as salvage chemotherapy in metastatic breast cancer previously treated with anthracyclines: results of a multicenter phase II study.

The goals of this study were to evaluate the efficacy and toxicity of the gemcitabine/docetaxel combination in metastatic breast cancer previously treated with anthracyclines. Fifty-three patients with metastatic breast cancer who had failed or relapsed after anthracycline-based chemotherapy entered the study and were evaluable. Patients received gemcitabine (1,000 mg/m(2) days 1 and 8) and docetaxel (80 mg/m(2) day 8), every 3 weeks. The regimen was generally well tolerated with good feasibility. A complete response occurred in six patients (9.4%) and partial response in 23 (43.4%) for an overall response rate of 53% (95% confidence interval, 38.9% to 66.7%). Median survival rate was 70%; and the duration of response, time to progression, and overall survival were 6, 7.5, and 16.5 months, respectively. We conclude that the gemcitabine/docetaxel combination constitutes a manageable and tolerable combination as salvage chemotherapy in metastatic breast cancer and may represent a valid treatment option in patients previously treated with anthracyclines.

Mitomycin C and lonidamine as second-line treatment of advanced colorectal cancer patients.

To date no effective salvage regimens have been reported for progressive or relapsed patients with advanced colorectal cancer, and new potentially active drugs or combinations should be evaluated for these situations. In vitro studies have suggested that lonidamine (LND) positively modulates the cytotoxic activity of mitomycin (MMC) in human colon cancer cell lines. From November 1993 to February 1995, 29 colorectal cancer patients previously treated with first line chemotherapy were admitted to the study. Treatment consisted of a combination of MMC at 12 mg/m2 administered intravenously on day 1, and LND at 150 mg per os three times daily for five consecutive days, starting two days before MMC; the treatment was repeated every four weeks for a total of 109 cycles. All patients were fully evaluable for response and toxicity. Two partial responses (7%), 10 stable disease, and 17 progressive disease were observed. Median survival duration was 212 days. Toxicity was mild, with no WHO grade 3-4 toxicity. MMC + LND combination therapy does not seem to be effective in previously treated advanced colorectal cancer patients.

5-Fluorouracil plus high dose levofolinic acid and oral hydroxyurea for the treatment of primary hepatocellular carcinomas: results of a phase II multicenter study of the Southern Italy Oncology Group (G.O.I.M.).

A phase II trial of 5FU in modulation with intravenous high-dose levofolinic acid and oral hydroxyurea (HU) in advanced unresectable hepatocellular carcinoma (HCC). A total of 50 consecutive patients, 38 males (76%) and 12 females (24%), with a mean age of 62 years (range 30-74) and a mean performance status of 80 (KI, range 60-90) were enrolled. The vast majority of patients were therapy-naive, although two patients (4%) had previous surgery and showed progressive disease at entry. No patient had been previously treated with chemotherapy. Five patients had previous hormonotherapy with tamoxifen. Most patients had disease limited to the liver while 12 patients (24%) had also metastatic deposits outside the liver. The treatment plan included: levofolinic acid 100 mg/m2 diluted in 500 cc of normal saline over 2 hour infusion followed by 5FU 600 mg/m2 i.v. bolus. HU 1,000 mg/m2 was given by mouth in three refracted doses starting 6 hours after 5FU. A PR was recorded in only 5 patients (10%; 95% CL 1%-34%) with a median duration of 5.7+ months (range 4.0/6.2 months), a stabilization in 15 (30%) with a median duration of 3.8 months, while 30 patients progressed (60%). PR were seen at liver primary tumor in 4 cases and at soft tissue in 1 case. The median survival was 5.8 months (range 2.0/12.0+). The most frequent toxicities were leukopenia (32%), which however was mild (grade 1-2) in all cases, and grade 1-2 thrombocytopenia observed in 15% of cases. Mild grade 1-2 vomiting was recorded in one third of patients, and grade 1-2 stomatitis in 15%. The combination of 5FU with levofolinic acid and oral HU on a weekly schedule is largely inactive against unresectable or metastatic HCC and results are no better than historical data reported for 5FU alone.

Efficacy of the association of folinic acid and 5-fluorouracil alone versus folinic acid and 5-fluorouracil plus 4-epidoxorubicin in the treatment of advanced gastric carcinoma.

A total of 71 patients with advanced gastric carcinoma were randomized to receive either folinic acid + fluorouracil (arm A) or the same combination with the addition of 4-epidoxorubicin (arm B). Of the 62 evaluable patients (31 in both arms), six patients achieved a CR (10%) and 16 a PR (25.5%) with an overall response rate of 35.5% (29% in arm A and 42% in arm B; p = .28). Median duration of response was 6 and 7 months for arm A and B, respectively (p = .6). Responder patients showed a significantly better median survival duration than nonresponders (p = .01); in arm B the median survival duration was 16 months for responder patients in contrast to 7 months for nonresponders (p = .004). Toxicity was mild without significant differences between the two groups. There was one death due to hematological toxicity (arm A). The EPI-FA-FU combination appears effective and well tolerated with the additional advantage of being able to be administered in the outpatient clinic.

Prinzmetal's Variant Angina during cis-diamminodichloroplatinum (CDDP) administration: case report.

We report a rare case, the second in the literature, of Prinzmetal's Variant Angina (VA) caused by cis-diamminodichloroplatinum (CDDP) infusion. We also discuss the possible underlying mechanism of ischemia.

Sequential treatment with high-dose methotrexate and fluorouracil in advanced colorectal cancer. Experience of the Southern Italian Oncology Group (GOIM).

A total of 101 patients with advanced colorectal cancer in two consecutive Southern Italian Oncology Groups (GOIM) studies (8501 and 8801--arm A) were treated with a sequential combination of high dose methotrexate (HDMTX) and fluorouracil (FU). Of the 92 eligible patients, 2 achieved complete response (2%) and 27 partial response (30%), with a median duration of 7 months. When classified according to the time interval between administration of the two drugs, retrospective analysis showed significant improvement (p = 0.04) in overall survival in the shorter time interval group (6 hours). The observed toxicities were generally mild and transient. Our data confirm the efficacy of the synergism between the two chemotherapeutic agents, in particular when administered with a 6-hour interval. Further studies are necessary to establish the possibility of enhancing the efficacy of sequential treatment with the modulation of FU with high-dose folinic acid.

Carboplatin and etoposide in previously treated colorectal cancer patients.

AIMS AND BACKGROUND: Salvage treatment of advanced colorectal cancer patients has not been well defined as yet, and new potentially active drugs or combinations should be evaluated for these situations. METHODS: From February 1993 to September 1993, the combination of carboplatin (CBDCA) and etoposide (VP-16), both as 100 mg/m2 for three consecutive days, was administered to 17 colorectal cancer patients who had been previously subjected to FA-FU combination chemotherapy. The CBDCA + VP-16 treatment was repeated every 3 weeks. A total of 58 cycles was administered, and 16 patients were evaluable for response. RESULTS: There was no objective response, but 2 stable diseases and 14 progressive diseases were observed. Toxicity was mild, with no WHO 3-4 grade toxicity. CONCLUSION: This combination chemotherapy was judged ineffective for pretreated colorectal cancer patients.

Primary Hodgkin's disease of the stomach. A case report.

Primary gastric Hodgkin's disease is rare and has been reported in only 2% of patients with primary gastric lymphomas. Its existence is quite controversial, and new immunohistochemical techniques and flow cytometry have reduced the frequency of diagnosis of this pathology. The authors describe a case of primary gastric Hodgkin's disease in a 61-year-old woman.

A phase II trial of etoposide, folinic acid, fluorouracil and epirubicin in advanced pancreatic carcinoma.

PURPOSE: Pancreatic carcinoma is generally considered a chemotherapy-resistant malignant neoplasm and to date there is no established chemotherapeutic treatment for patients with advanced disease. Many new combination regimens have been investigated to improve results. Modiano et al. (ASCO 1993; 12: 303) with ELF regimen (etoposide, folinic acid, and 5-fluorouracil) plus interferon obtained 6/7 partial remission in patients with advanced pancreatic cancer. Considering these interesting results and the therapeutic activity of epirubicin in this disease, we started a study (GOIM 9405) to verify the efficacy and safety of the ELFE (ELF + Epirubicin) regimen. PATIENTS AND METHODS: Twenty-three patients with advanced pancreatic cancer received etoposide 80 mg/m2 day 1-3, folinic acid (levo-isomer form) 100 mg/m2 day 1-3, 5-fluorouracil 340 mg/m2 day 1-3, and epirubicin 60 mg/m2 day 1. Treatment was repeated every three weeks. RESULTS: We obtained 3 PR, 4 SD and 13 PD. Overall response rate was 15% (95% CI: 3% to 38%) (intent to treat analysis: 13%; 95% CI: 3% to 34%). The median durations of response and survival were 9 and 5 months, respectively. Grade 3-4 WHO toxicity included diarrhoea (17%), mucositis (22%), leukopenia (17%). CONCLUSIONS: The ELFE regimen demonstrates scarce activity in patients with advanced pancreatic cancer, with mild toxicity.

Non-pegylated liposome-encapsulated doxorubicin citrate plus cyclophosphamide or vinorelbine in metastatic breast cancer not previously treated with chemotherapy:a multicenter phase III study.

We conducted a phase III multicenter randomized trial to compare the efficacy of the combination of liposome encapsulated doxorubicin (Myocet(©)) plus either cyclophosphamide (MC) or vinorelbine (MV). Since July 2006, 233 patients affected with metastatic breast cancer were randomized to receive the combination of Myocet (M) 60 mg/m(2) i.v. plus cyclophosphamide (C) 600 mg/m2 on Day 1 of a 21­day cycle (Arm A) or Myocet (M) at 50 mg/m2 plus vinorelbine (V) 25 mg/m2 i.v. on Day 1 and V 60 mg/m2 orally on Day 8 on a 21­day cycle (Arm B). The primary endpoints of the study was time to progression (TTP); secondary endpoints were RR, toxicity and OS. Response was observed in 53/116 (45.7%) evaluable patients of Arm A vs. 51/112 (45.5%) of Arm B, respectively (P=NS). Median TTP was 41 weeks (95% CI, 32­51) and 34 weeks (95% CI, 26­39), for M/C and M/V, respectively (P=0.0234). The difference in median OS was not statistically significant (131 vs. 122 weeks; P=0.107). With regard to toxicity, patients treated with MV showed a slight increase of neutropenia and constipation, as compared to those treated with MC. No clinical signs of cardiotoxicity were observed. The MC combination remains as an unbeaten 'standard' in first line treatment of MBC.

Angiogenetic axis angiopoietins/Tie2 and VEGF in familial breast cancer.

Angiogenesis leads to the formation of blood vessels from pre-existing ones, allowing tumor growth. Vascular endothelial growth factor (VEGF) and Angiopoietins (Ang-1, Ang-2) have a pivotal role in tumor angiogenesis but few data regarding their role in hereditary breast cancer are available. The aim of the present study was to analyze Ang-1, Ang-2, tyrosine-protein kinase receptor Tie2 and VEGF expression and their correlation in a cohort of familial and sporadic breast cancers in order to verify whether the presence of germline mutations in BRCA may have a role in tumor microenvironment regulation. Tumor samples from a cohort of 41 patients with a first diagnosis and a family history of breast cancer and 19 patients with sporadic breast cancers were enrolled. The expression of Tie2, Ang-1, Ang-2 and VEGF were analyzed by quantitative real-time PCR. Patients harboring BRCA mutations had higher levels of Ang-1 (P=0.05), Ang-2 (P=0.02) and VEGF (P=0.04) mRNA compared with those without BRCA mutations (BRCAX). The same was observed in triple-negative breast cancer (TNBC). Moreover, a positive correlation between Ang-2 and VEGF was found in both the familial breast cancer group (BRCA carriers: r=0.83; P<0.0001 and BRCAX: r=0.58; P=0.008) and in TNBC (r=0.62; P=0.007). The higher levels of Ang-1, Ang-2 and VEGF mRNA found in BRCA carriers and TNBCs suggest that they could be attractive angiogenic therapeutic targets in these breast cancers.

Nuclear NHERF1 expression as a prognostic marker in breast cancer.

Our purpose was to investigate whether Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) expression could be linked to prognosis in invasive breast carcinomas. NHERF1, an ezrin-radixin-moesin (ERM) binding phosphoprotein 50, is involved in the linkage of integral membrane proteins to the cytoskeleton. It is therefore believed to have an important role in cell signaling associated with changes in cell cytoarchitecture. NHERF1 expression is observed in various types of cancer and is related to tumor aggressiveness. To date the most extensive analyses of the influence of NHERF1 in cancer development have been performed on breast cancer. However, the underlying mechanism and its prognostic significance are still undefined. NHERF1 expression was studied by immunohistochemistry (IHC) in a cohort of 222 breast carcinoma patients. Association of cytoplasmic and nuclear NHERF1 expression with survival was analyzed. Disease-free survival (DFS) and overall survival (OS) were determined based on the Kaplan-Meier method. Cytoplasmic NHERF1 expression was associated with negative progesterone receptor (PgR) (P=0.017) and positive HER2 expression (P=0.023). NHERF1 also showed a nuclear localization and this correlated with small tumor size (P=0.026) and positive estrogen receptor (ER) expression (P=0.010). Multivariate analysis identified large tumor size (P=0.011) and nuclear NHERF1 expression (P=0.049) to be independent prognostic variables for DFS. Moreover, the nuclear NHERF1(-)/ER(-) immunophenotype (27%) was statistically associated with large tumor size (P=0.0276), high histological grade (P=0.0411), PgR-negative tumors (P<0.0001) and high proliferative activity (P=0.0027). These patients had worse DFS compared with patients with nuclear NHERF1(+)/ER(+) tumors (75.4% versus 92.6%; P=0.010). These results show that the loss of nuclear NHERF1 expression is associated with reduced survival, and the link between nuclear NHERF1 and ER expression may serve as a prognostic marker for the routine clinical management of breast cancer patients.

Liposomal-encapsulated doxorubicin plus cyclophosphamide as first-line therapy in metastatic breast cancer: a phase II multicentric study.

BACKGROUND: The objective of this study is to evaluate the efficacy and toxicity of the liposome-encapsulated doxorubicin (TLC D-99) plus cyclophosphamide (CTX) as first-line treatment of metastatic breast cancer in light of the potential cardioprotective effect of TLC D-99 as compared with conventional doxorubicin. MATERIALS AND METHODS: Sixty-seven patients as defined according Simon's two-stage phase II design were enrolled. They received TLC D-99 at the dosage of 60 mg/m2 plus CTX 600 mg/m2, with cycles repeated every 3 weeks. Cardiac function was assessed by ultrasonography at baseline and every two cycles. RESULTS: The principal characteristics of the 67 enrolled patients were as follows: median age 60 years (range 33-75), median World Health Organization performance status of 1 (range 0-2) and dominant disease site (viscera/bone/soft tissue): 47/15/15 There were nine complete responses and 32 partial responses for an overall response rate of 64%; a further 14 patients had stable disease and the remaining nine patients progressed. Median number of administered cycles was six. Median duration of response was 10 and 9 months, respectively, for complete responders and partial responders. Median duration of survival was 17+ months (range 3 to 33+). Hematological toxicity consisted in leucopenia (G1-G2) in 21 patients and anemia (G1-G2) in 20 patients; G1 thrombocytopenia was observed only in 2 patients. Non-hematological toxicity was generally mild with G1-G2 nausea/vomiting in 23 patients and G1-G2 mucositis in 10. Hair loss was registered in 30 patients and it was G2 in 14 patients. As to concern cardiac toxicity, one patient developed an asymptomatic 20% decline of left ventricular ejection fraction from the baseline value. CONCLUSIONS: The results of our study show that the combination of TLC D-99 plus CTX is active and well tolerated, with no unexpected toxicity.