Metronomic chemotherapy (mCHT) in metastatic triple-negative breast cancer (TNBC) patients: results of the VICTOR-6 study.

PURPOSE: Triple-negative breast cancer (TNBC) represents a subtype of breast cancer which lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2): TNBC accounts for approximately 20% of newly diagnosed breast cancers and is associated with younger age at diagnosis, greater recurrence risk and shorter survival time. Therapeutic options are very scarce. Aim of the present analysis is to provide further insights into the clinical activity of metronomic chemotherapy (mCHT), in a real-life setting. METHODS: We used data included in the VICTOR-6 study for the present analysis. VICTOR-6 is an Italian multicentre retrospective cohort study, which collected data of metastatic breast cancer (MBC) patients who have received mCHT between 2011 and 2016. Amongst the 584 patients included in the study, 97 were triple negative. In 40.2% of the TNBC patients, mCHT was the first chemotherapy treatment, whereas 32.9% had received 2 or more lines of treatment for the metastatic disease. 45.4% out of 97 TNBC patients received a vinorelbine (VRL)-based regimen, which resulted in the most used type of mCHT, followed by cyclophosphamide (CTX)-based regimens (30.9%) and capecitabine (CAPE)-based combinations (22.7%). RESULTS: Overall response rate (ORR) and disease control rate (DCR) were 17.5% and 64.9%, respectively. Median progression free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.9-7.2) and 12.1 months (95% CI: 9.6-16.7). Median PFS was 6.9 months for CAPE-based regimens (95% CI: 5.0-18.4), 6.1 months (95% CI: 4.0-8.9) for CTX-based and 5.3 months (95% CI: 4.1-9.5) for VRL-based ones. Median OS was 18.2 months (95% CI: 9.1-NE) for CAPE-based regimens and 11.8 months for VRL- (95% CI: 9.3-16.7 and CTX-based ones (95%CI: 8.7-52.8). Tumour response, PFS and OS decreased proportionally in later lines. CONCLUSION: This analysis represents the largest series of TNBC patients treated with mCHT in a real-life setting and provides further insights into the advantages of using this strategy even in this poor prognosis subpopulation.

Metronomic chemotherapy for advanced breast cancer patients in the real world practice: Final results of the VICTOR-6 study.

Metronomic chemotherapy (mCHT) refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen, with no prolonged drug-free breaks, that leads to antitumor activity. Aim of the present study is to describe the use of mCHT in a retrospective cohort of metastatic breast cancer (MBC) patients in order to collect data regarding the different types and regimens of drugs employed, their efficacy and safety. Between January 2011 and December 2016, data of 584 metastatic breast cancer patients treated with mCHT were collected. The use of VRL-based regimens increased during the time of observation (2011: 16.8% - 2016: 29.8%), as well as CTX-based ones (2011: 17.1% - 2016: 25.6%), whereas CAPE-based and MTX-based regimens remained stable. In the 1st-line setting, the highest ORR and DCR were observed for VRL-based regimens (single agent: 44% and 88%; combination: 36.7% and 82.4%, respectively). Assuming VRL-single agent as the referee treatment (median PFS: 7.2 months, 95% CI: 5.3-10.3), the longest median PFS were observed in VRL-combination regimens (9.5, 95%CI 88.8-11.3, HR = 0.72) and in CAPE-single agent (10.7, 95%CI 8.3-15.8, HR = 0.70). The VICTOR-6 study provides new data coming from the real-life setting, by adding new information regarding the use of mCHT as an option of treatment for MBC patients.

Observational study on adjuvant trastuzumab in HER2-positive early breast cancer patients.

AIM: This observational study investigates the use of adjuvant trastuzumab (AT) in HER2-positive breast cancer patients in a real-life setting, focusing on relapse and discontinuation rates. PATIENTS & METHODS: Data on a group of HER2-positive patients collected from 13 oncology centers of northeast Italy were analyzed. RESULTS: In total, 1245 patients were analyzed. 13.1% of patients were excluded from AT because of comorbidities, age, tumor stage, refusal or other reasons; 8.2% of patients who received AT interrupted the therapy, mainly for toxicity. Overall the relapse rate was 10.9% in the AT-treated population versus 22.6% in nontreated patients (follow-up: 37.4 and 62.1 months, respectively). Disease-free survival (DFS) was lower in AT-relapsed patients than in not-relapsed. Statistical analysis showed a correlation between DFS and estrogen receptor status in AT-treated patients. CONCLUSION: Relapse rates are lower in clinical setting compared to clinical trials. Overall, AT is effective in HER2-positive early-stage breast cancer patients.

Phase II study of liposome-encapsulated doxorubicin plus cyclophosphamide, followed by sequential trastuzumab plus docetaxel as primary systemic therapy for breast cancer patients with HER2 overexpression or amplification.

PURPOSE OF THE STUDY: Trastuzumab combined with sequential chemotherapy with taxanes and anthracyclines as primary systemic therapy achieved high rates of pathologic complete response (pCR). Non-pegylated liposome-encapsulated doxorubicin (NPLD) has shown equal efficacy but minor cardiotoxicity compared to doxorubicin. This phase II study aimed to evaluate the activity and safety of trastuzumab with sequential chemotherapy for early or locally advanced HER2 positive BC. METHODS: Preoperative treatment included NPLD (60 mg/mq iv) plus cyclophosphamide (600 mg/mq iv) every 3 weeks for 4 cycles followed by docetaxel (35 mg/mq iv) plus trastuzumab (4 mg/mq loading dose iv, then 2 mg/mq iv) weekly for 16 weeks. Primary endpoint was pCR defined as the absence of residual invasive cancer both in the breast and regional nodes. Clinical staging was exploratory evaluated by CT-PET. RESULTS: 43 pts were treated from december 2005 to September 2011, 39 of them were evaluable for the purpose of study. Median age was 53 years (range: 31-78), the majority of pts had tumour stage cT2 (63%), tumour grade 3 (86%), clinical nodes involvement N+ (77%), ER positive (56%) and Ki-67 ≥20% (77%). pCR was reported in 19 (49%) of 39 pts. There was an association between Ki-67 ≥20% at baseline and pCR (p = 0.018). No cardiac toxicity or discontinuation of trastuzumab was reported. CT-PET modified the clinical stage for 10 patients showing new loco-regional lymph nodes. CONCLUSIONS: This study confirms that integrating anti-HER2 therapy in primary treatment for HER2 positive breast cancer is active. NPLD is a safe option to minimize cardiotoxicity.

A phase I/II trial of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab as first-line treatment in HER-2-positive locally advanced or metastatic breast cancer.

AIM: To assess the activity and safety of non-pegylated liposomal doxorubicin (Myocet®) in combination with docetaxel and trastuzumab as first-line treatment of patients with HER-2/neu-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: The maximum tolerated dose of the combination was defined in the phase I part of the study. In the phase II part, 45 HER-2/neu-positive MBC patients were enrolled to receive 6-8 cycles of Myocet® 50 mg/m2 (day 1), docetaxel 30 mg/m2 (days 2 and 9) plus trastuzumab (day 2, 4 mg/kg followed by 2 mg/kg/week) every 21 d until unacceptable toxicity or progression occurred. Objective response (primary end-point) and treatment tolerability were assessed according to World Health Organisation criteria. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure and/or a decrease in left ventricular ejection fraction (LVEF). RESULTS: The overall response rate was 55.6% (complete response 8.9%, partial response 46.7%), with a median time-to-progression of 10.9 months (C.I. 8.7-15.0). Median overall survival was not reached. The most frequent grade 3-4 adverse events were granulocytopaenia (60.0%), leukocytopenia (43.2%) and alopecia (35.6%). Grade 3-4 diarrhoea, pain, oral and skin toxicity (4.4%, each) and nausea/vomiting, thrombocytopenia and elevated alkaline phosphatase (2.2%, each) were also reported. In 2 patients LVEF fell to <50%, with a decrease from baseline>15%. LVEF median values remained stable from baseline to the end of the study (60%). CONCLUSIONS: The combination of Myocet®, docetaxel and trastuzumab is safe and shows promising activity as first-line treatment of HER-2-positive MBC.

Primary chemotherapy with gemcitabine, epirubicin and taxol (GET) in operable breast cancer: a phase II study.

This trial was conducted to assess the activity and tolerability of the gemcitabine, epirubicin, taxol triplet combination in patients with operable breast cancer. After core biopsy, 43 women with stage II-IIIA breast cancer were treated with gemcitabine 1000 mg m(-2) over 30 min on days 1 and 4, epirubicin 90 mg m(-2) as an intravenous bolus on day 1, and taxol 175 mg m(-2) as a 3-h infusion on day 1, every 21 days for four cycles. The primary end point was the percentage of pathological complete responses (pCR) in the breast; secondary end points were tolerability, clinical response rates, overall and progression-free survival, tumour biomarkers before and after primary chemotherapy (PCT). All patients were included in safety and survival analyses; 41 eligible patients were evaluated for response. The overall clinical response rate was 87.8% (95% CI 77.8-97.8), with 26.8% complete responses (95% CI 13.3-40.3). A pCR in the breast was observed in six patients (14.6%; 95% CI 3.8-25.4); 15 patients (36.6%; 95% CI 21.9-51.3) had negative axillary lymph nodes. Grade 4 neutropenia was observed in 67.4% of the patients; febrile neutropenia occurred in 1.9% of cycles (granulocyte colony-stimulating factor was used in 3.2% of the cycles to shorten the duration of neutropenia). A statistically significant difference between Mib-1 at baseline (> or =20% in 71.4% of the patients) and at definitive surgery (28.6%, P < 0.05) was observed. The gemcitabine, epirubicin, taxol regimen is active and well tolerated as PCT for operable breast cancer. This combination allows the administration of full doses of active agents with a low incidence of febrile neutropenia.

Topoisomerase I inhibitors combination chemotherapy in non-small cell lung cancer.

In the last years, the main topoisomerase I inhibitors (TP1-I) (i.e. topotecan and irinotecan) have been used in combination chemotherapy in non-small cell lung cancer. Several drugs (also alternative to cisplatin) have been used in combination with TP1-I, but to date the higher remission rate obtained with combinations is not translated into a more prolonged survival in comparison with TP1-I given alone. On the other hand, the toxicity of TP1-I combinations is greater than those of TP1-I used alone. The superior efficacy of combinations versus TP1-I used alone remains an open question. Furthermore, the best schedule for TP1-I has not been completely elucidated. Randomised studies are few (only two phase III trials) and only controlled studies will be able to clarify the best TP1-I combination regimen.

Tumor markers in breast cancer monitoring should be scheduled according to initial stage and follow-up time: a prospective study on 859 patients.

PURPOSE: The purpose of this study was to identify and standardize optimal decision criteria for maximizing the effectiveness of tumor markers in clinical use during the follow-up of patients operated on for breast cancer. MATERIALS AND METHODS: The study was prospectively performed on 859 patients enrolled in 10 institutions. A total of 13,337 determinations of CEA and 14,330 determinations of CA15.3 were available. The median number of samples per patient was 16 for CEA and 17 for CA15.3. The median follow-up was 7 years. Receiver-operating characteristic analysis was used to evaluate the ability of CEA and CA15.3 to discriminate relapses from patients who had no evidence of disease. The diagnostic performances of the two markers were evaluated using decision criteria based on both dichotomic cut-off points and dynamic variations among serial samples. RESULTS: We selected decision levels corresponding to preset levels of 90% and 99% specificity. Patients with CEA and/or CA15.3 levels above the cut-off values were considered positive only if a 1.5-fold increase occurred among the last sample and the mean of the first three samples. According to the different cut-offs used, specificity ranged from 94% to 99% and sensitivity from 48% to 63%. We calculated predictive values using the prevalence expected with reference to the stage of primary tumor and the length of follow-up. Positive predictive values ranged from 1.6% to 93.7%, and negative predictive values from 88.9% to 100%, according to the clinical scenarios and the decision criteria used. The choice of the decision criteria significantly affected positive predictive values within each patient subset. Differences related to time from surgery were still remarkable for every decision criteria (i.e., positive predictive values ranged from 36.6% to 2.8% in node-negative patients according to the year of observation, although the same cut-off point was used). DISCUSSION: The results of the present prospective study show that different decision criteria may provide different diagnostic performances for the same tumor marker and in the same patient. Therefore, we suggest that different decision criteria be settled and used according to the clinical goals.

Pharmacokinetics and tolerance of vinorelbine in elderly patients with metastatic breast cancer.

25 patients older than 65 years with metastatic breast cancer were treated with vinorelbine 30 mg/m2 i.v. days 1 and 8 every 3 weeks; the pharmacokinetics were studied in 10 of them. Vinorelbine showed a large apparent volume of distribution (mean 23.4 l/kg), a long terminal half-life (mean 26.2 h) and a large systemic clearance rate (mean 1.2 l/kg). These results are similar to those reported in younger patients. No correlation has been found between toxicity, age and drug exposure. We observed 6 partial responses out of 20 evaluable patients despite a relatively low mean dose intensity (67%). Severe neutropenia occurred in 37% of the patients; other side-effects were acceptable. This study does not provide a pharmacokinetic rationale for reducing the dosage of vinorelbine in selected elderly patients.

Tumor markers in breast cancer follow-up: a potentially useful parameter still awaiting definitive assessment. Forza Operativa Nazionale sul Carcinoma Mammario (FONCaM).

BACKGROUND: Although tumor markers are frequently used in the follow-up of patients with breast cancer, two points are still being debated: 1) their cost/effectiveness has been neither demonstrated nor disproved; 2) the reliability of the currently used dichotomous division into a positive/negative cut-off should be definitely validated. Dynamic criteria of interpretation based on serial serum samples would probably be more effective for early detection of relapse. PATIENTS AND METHODS: The aim of the present study was to compare the dichotomous cut-off based decision criteria to a dynamic serial sample based assessment of tumor markers. Since 1989, 794 patients have been followed in 11 institutions. CEA and CA15.3 were measured once a month for three months before every clinical examination. The present paper concerns the evaluation variability in 405 patients without evidence of disease in the first three institutions joining the study. RESULTS: In patients without evidence of disease, the coefficient of variation of all samples for every patient showed a median value of 19 for CEA and 21 for CA15.3. Variability was negatively associated with the antigen level and was most likely due to the analytical component. This was also confirmed by the significant difference in variability among the three institutions evaluated. The median value of the critical difference was 53% for CEA and 57% for CA15.3. CONCLUSIONS: 1) Individually tailored dynamic decision criteria are applicable in about 50% of the cases. 2) The problem of improving the precision of tumor marker assays in the low dose range must be urgently addressed to the manufacturers of tumor markers by the scientific community in order to apply individually tailored decision criteria for patients in whom the serum level of biological markers is low.

Evaluation of critical differences of CEA and CA 15.3 levels in serial samples from patients operated for breast cancer.

In the present investigation we evaluated the variability of tumor marker levels in the follow-up of patients without evidence of disease after resection of primary breast cancer. CEA and CA15.3 were measured using commercially available methods in serial blood samples collected from 170 patients. The coefficient of variation among all samples from each patient, which accounts for the total variability (analytical variability+biological variability), was widely scattered (from 4 to 99% for CEA; from 4 to 52% for CA15.3). The critical difference was calculated using the formula designed by Fraser [CD = 2.77. (CVa2 + CVb2)1/2]. It ranged from 11 to 276 for CEA and from 11 to 144 for CA15.3. From the present findings we conclude that: 1) it is possible to identify individually tailored decision criteria to evaluate tumor marker variations in the follow-up of breast cancer patients; 2) in a considerable number of cases the non-tumor-related variability is too high to allow the early identification of minor tumor marker variations that are of clinical relevance.

Variability of tumor markers in the follow-up of patients radically resected for breast cancer.

The biological and analytical components of variability of tumor markers should be distinguished from the variations due to tumor progression. The aim of the present study was to evaluate tumor marker variability in the follow-up of patients resected for breast cancer. So far, we have carried out 2,085 CEA and 2,550 CA 15-3 determinations in 435 patients. The total variability of both CEA and CA 15-3 was widely scattered among different subjects (CEA coefficient of variation 0-105%; CA 15-3 coefficient of variation 0-89.2%). The biological variability of CA 15-3, which was calculated in a limited number of cases, was scattered between 0 and 23% and was higher than the intra-assay variability. From these findings we conclude that when evaluating serial marker assays the intra-individual variability should be assayed initially to obtain a reference value of individual variability in relapse-free conditions.

Evaluation of two consecutive regimens in advanced gastric cancer.

Treatment of gastric cancer still presents a challenge in cancer chemotherapy. In our Institute, from January 1981 to November 1984, 45 patients were given 5-fluorouracil (5FU) 600 mg/m2 Days 1, 8, 29, and 36; doxorubicin (A) 30 mg/m2 Days 1 and 29; mitomycin-C 10 mg/m2 Day 1 (FAM regimen) every 8 weeks. From December 1984 to October 1986, 26 patients were treated with 5FU 300 mg/m2 on Days 1-5, A 40 mg/m2 on Day 1, cisplatin (P) 100 mg/m2 on Day 1 (FAP regimen) every 3 weeks. In the FAM group, 42 patients are evaluable for response; 5 (12%) partial remission (PR), 9 stable disease (SD), and 28 progressions (PRO) were observed. Median duration of response (MDR) was 21 weeks (range 13-45) and the median survival (MS) in the whole group was 27 weeks. In the FAP group, 23 patients are evaluable: 2 CR (9%), 11 PR (47%), 2 SD (9%), and 8 PRO (34%) were observed; CR duration was 24 and 107+ weeks, respectively, MDR of PR was 22 weeks (5-35). The MS of all patients was 16 weeks. Toxicity (WHO criteria) was mild in the FAM group and severe in the FAP group. In spite of a higher objective response rate, the short MS and the severe toxicity observed in the FAP group do not merit recommendation of this regimen in patients with gastric cancer; therefore neither FAM nor FAP appear to be an ideal standard therapy.

Persistent generalized lymphadenopathy syndrome vs "AIDS"--unrelated malignant lymphoma: comparison of presenting clinical and laboratory findings in 88 patients. AIDS and Related Syndromes Study Group.

The purpose of this report is to document and compare the presenting clinical and laboratory findings of 38 patients, all intravenous drug abusers, with pathologically documented persistent generalized lymphadenopathy (PGL), and of 50 patients with AIDS-unrelated malignant lymphoma (30 with Hodgkin's disease and 20 with non-Hodgkin's lymphoma). All patients, aged 40 years or less, consecutively seen since May 1984 in a single institution in Italy, have prospectively undergone a similar clinico-pathologic approach. In addition to a history of intravenous drug abuse and HIV serology, the results indicate that a history of infection in the previous year, night sweats, weight loss, generalized lymphadenopathy, beta 2 microglobuline, transaminase, T4/T8 ratio less than 1, and polyclonal hypergamma-globulinemia significantly increased among PGL patients compared with patients with AIDS-unrelated malignant lymphoma. In contrast, patients with malignant lymphoma had a significant increase in mediastinal lymph nodes, sedimentation rate, LDH, fibrinogen and anemia. Therefore, at this time of an AIDS epidemic, after histologic diagnosis of reactive lymphadenopathy has been performed in young patients presenting with generalized lymphadenopathy, a request for a second biopsy and other invasive procedures may be avoided if clinical and laboratory data suggest a PGL syndrome. If not already performed, HIV antibody detection should be carried out in this setting.

Risk factors for human immunodeficiency virus (HIV) infection among homosexual and bisexual men in a region at low risk for AIDS: the northeastern part of Italy. AIDS and Related Syndromes Study Group.

Prevalence and determinants of HIV infection were assessed in 127 homosexual and bisexual men in the northeastern part of Italy. The overall prevalence of HIV seropositivity was still rather low: 20% (95% confidence interval -CI- 13-27%). The most important risk factor for acquiring HIV infection turned out to be having has sexual intercourses in high-risk areas. Relative risks (RRs) for those who have travelled and had sex in North Europe and in the U.S., were, respectively, 2.7 (95% CI: 1.0-7.3) and 5.6 (95% CI: 1.2-25.9). A significantly increased risk was also seen for having a steady sexual partner (RR = 3.1, 95% CI: 1.3-7.5). Use of nitrite inhalants, high number of occasional sexual partners and habitual receptive anal intercourses were also associated with elevation of risk, whereas prostitution was not. The present study confirms the patterns of HIV spread among homosexual and bisexual men from high-risk areas to low-risk areas and prompts urgent educational intervention, in order to prevent the epidemics of AIDS among Italian homosexuals from reaching the size documented in other countries.