D. Cullurà

Oral Metronomic Cyclophosphamide and Methotrexate Plus Fulvestrant in Advanced Breast Cancer Patients: A Mono‐Institutional Case‐Cohort Report

Abstract:  Fulvestrant is effective in postmenopausal women with estrogen receptor‐positive advanced breast cancer (ABC). So far, no published data exist on fulvestrant combined with chemotherapy. We retrospectively assessed the role of combining oral metronomic cyclophosphamide and methotrexate (CM) to fulvestrant in two cohorts (A and B) of heavily pre‐treated estrogen receptor‐positive advanced ABC patients. From October 2006 to September 2009, 33 postmenopausal patients received fulvestrant 250 mg via i.m. injection q28 days. In A, 20 patients added metronomic cyclophosphamide (50 mg p.o. daily) and methotrexate (2.5 mg p.o. twice daily on day 1 and day 4 weekly) after disease progression, continuing fulvestrant at the same dose. In B, 13 patients started fulvestrant plus metronomic CM upfront. Thirty‐two patients were evaluable for response. Clinical benefit (partial response + stable disease >24 months) for A + B was 56% (95% CI 38–74%). The addition of metronomic CM did not determine relevant toxicities. Treatment with fulvestrant plus metronomic CM was effective in advanced ABC and was minimally toxic providing long‐term disease control in a high proportion of patients. The prolonged clinical benefit, often desirable in such patients, supports this regimen as an additional and useful therapeutic tool.

The incidence and relative risk of cardiovascular toxicity in patients treated with new hormonal agents for castration-resistant prostate cancer

AIM New hormonal agents are available for treating metastatic castration-resistant prostate cancer (mCRPC). We aim to define the incidence and relative risk (RR) of cardiovascular events in mCRPC patients treated with these agents. METHODS Prospective studies were identified by searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts. Combined relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effects methods. RESULTS We included six articles in this meta-analysis covering a total of 6735 patients who were used to evaluate cardiac toxicity. The use of new hormonal agents was associated with an increased risk of all grades of such toxicity (RR=1.32, 95% CI, 1.08-1.60; p=0.006) compared to a placebo, even if the absolute difference in terms of incidence was small at 14.8% versus 11.5%, respectively. No increased risk of grade 3-4 events (RR=1.35, 95% CI, 0.90-2.03; p=0.15) was observed. A total of 7830 patients were used to evaluate hypertension, and it was found that the use of new hormonal agents compared to a placebo was associated with an increased risk of all-grades (RR=1.84, 95% CI, 1.37-2.46; p<0.001) and grade 3-4 events (RR=1.77, 95% CI, 1.13-2.77; p=0.01). The absolute incidence was 12.5% versus 7.5% for all-grades and 3.7% versus 2.4% for grade 3-4. CONCLUSIONS This analysis revealed a significant increase in the incidence and RR of cardiovascular toxicity in mCRPC treated with new hormonal agents as opposed to a placebo, even though the occurrence of all- and grade 3-4 events rose only 14% and 4%, respectively. Follow-ups for the onset of treatment-related cardiovascular events should therefore be considered in these patients.

Are there benefits in routine clinical practice of continuing trastuzumab after progression for metastatic breast cancer patients

The efficacy of trastuzumab beyond metastatic disease progression (PD) is controversial. We retrospectively analyzed 213 patients with HER2-positive metastatic breast cancer treated with trastuzumab-based therapies between November 1998 and December 2010. Out of 213 patients, 134 (58%) had received trastuzumab consecutively for at least 1 year and 154 of 213 patients (67%) had received two or more lines of consecutive trastuzumab-based therapy beyond PD. For these subgroups of patients, we examined the correlation between patients’ survival and time to first tumor progression (TTP). Among 134 patients who received trastuzumab for at least 1 year, 66 (49%) never had PD within the first year of treatment, whereas 68 (51%) had PD at least once within the first year. The estimated 2-year overall survival (OS) after 1 year was 82% for those who had no PD during the first year (median OS 5.1 years) and 70% for those who had PD (median OS 2.6 years) (P<0.0001). Among 154 patients who received two or more lines of consecutive trastuzumab-based therapy beyond PD, we calculated a median first TTP of 8.7 months. In terms of survival after first progression, patients with a longer first TTP (≥8.7 months) had better survival compared with those who had a shorter first TTP (39 months, 95% CI 31–63; vs. 28 months, 95% CI 22–32; P=0.0004). T-based therapy was well tolerated and only five patients experienced a cardiac event. Our retrospective data suggest that treatment with trastuzumab beyond progression is a viable option for patients with advanced HER2-positive breast cancer, whose disease has progressed on previous trastuzumab-based regimens.

Prognostic role of the cumulative toxicity in patients affected by metastatic renal cells carcinoma and treated with first-line tyrosine kinase inhibitors

Tyrosine kinase inhibitor-related toxicities have been reported to be predictive and/or prognostic factors in patients affected by metastatic renal cell carcinoma (mRCC). We aim to investigate the incidence of cumulative toxicity and its prognostic role in mRCC patients treated with sunitinib or pazopanib. mRCC patients treated with sunitinib or pazopanib at the European Institute of Oncology in Milan were reviewed for the incidence of adverse events. Cumulative toxicity was defined as the presence of more than one selected adverse event of any grade. Prognoses were evaluated by the International mRCC Database Consortium criteria. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and Cox analysis. A total of 104 patients were included in the final analysis. Only 18.3% did not experience any of the selected toxicities: 26.9% had one, 35.6% had two and 19.2% all three toxicities. Accordingly, 54.8% of patients experienced cumulative toxicity. In those with or without cumulative toxicity, the median PFS was 27.6 versus 7.2 months and the median OS was 61.2 versus 18.7 months, respectively. When cumulative toxicity was adjusted for International mRCC Database Consortium prognostic groups, it maintained its prognostic role for both PFS (hazard ratio: 0.31, 95% confidence interval, 0.20–0.49; P<0.001) and OS (hazard ratio: 0.27, 95% confidence interval, 0.15–0.48; P<0.001). A major limitation was the retrospective and monocentric nature of the analysis. We reported the prognostic role of cumulative toxicity because of hypertension, hypothyroidism and hand–foot syndrome in patients affected by mRCC and treated with sunitinib or pazopanib.

Serum HER2 extracellular domain levels and HER2 circulating tumor cell status in patients with metastatic breast cancer

AIM To shed light on the clinical role of HER2 status in serum as extracellular domain (ECD) and corresponding circulating tumor cells (CTCs) in metastatic breast cancer patients. METHODS 68 patients were analyzed. Serum HER2 was determined by ADVIA Centaur(®) Serum HER2 test. CellSearch System was performed for CTC quantification. RESULTS HER2 was overexpressed in 21 primary tumors. In total, 19 patients had ECD >15 ng/ml (the cut-off used), 48 patients had at least one CTC. ECD positivity was associated with CTC number (p = 0.01), HER2-positive CTC (p = 0.01) and the ratio HER2-positive CTC/total CTC (p = 0.02). ECD was not associated with survival. CONCLUSION ECD in combination with HER2 CTC status would deserve further investigation in larger series for addressing its putative prognostic relevance.

Is there still a role for sorafenib in metastatic renal cell carcinoma? A systematic review and meta-analysis of the effectiveness of sorafenib over other targeted agents

BACKGROUND The treatment of metastatic renal cell carcinoma (mRCC) has largely improved over the last decade, due to the availability of several targeted agents (TAs). Sorafenib was the first TA to report a benefit in terms of PFS in this disease, and it has largely been used as a comparator in randomized trials. We tested its activity compared to other TAs by performing a systematic review and meta-analysis. METHODS MEDLINE/PubMed, the Cochrane library, and the ASCO university websites were searched for randomized phase II or III trials that compared other TAs to sorafenib in mRCC. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The measured outcomes were progression free survival (PFS), overall survival (OS), and the overall response rate (ORR). Sub-analyses were performed for MSKCC prognostic groups and lines of therapy. RESULTS A total of 3094 patients were evaluable for PFS. Other TAs significantly reduce the risk of progression compared to sorafenib (HR=0.78; 95% CI, 0.72-0.85; p<0.001). This difference remains significant in patients in a good prognostic group with respect to both first- (HR=0.61; 95%CI, 0.44-0.85; p=0.003) and second-line therapy (HR=0.58; 95% CI, 0.42-0.79; p<0.001). No significant differences were, however, found in patients with an intermediate prognosis in terms of both first- (HR=0.80; 95% CI, 0.60-1.00; p=0.05) and second-line treatment (HR=0.89; 95% CI, 0.73-1.07; p=0.21). In 2922 patients evaluable for OS, no significant difference was found between other TAs and sorafenib (HR=1.07; 95% CI, 0.97-1.18; p=0.18). A benefit was also not identified when the analysis was limited to patients treated with first or subsequent lines of therapy or in patients previously treated with sunitinib. Significant differences were found in terms of the ORR in the 2963 evaluable patients favoring other TAs (RR=1.48; 95% CI, 1.24-1.76; p<0.001). This difference remain significant when a sub-analysis was performed per line of therapy. CONCLUSIONS Other TAs improve PFS but not OS when compared to sorafenib. The use of sorafenib in patients with an intermediate prognosis, especially in second-line therapy, does not have a detrimental effect on PFS and might be an option for certain patients.

Outcome of Immediate Breast Reconstruction in Patients With Nonendocrine-Responsive Breast Cancer: A Monoinstitutional Case-Control Study.

BACKGROUND The long-term prognostic relevance of immediate breast reconstruction (IBR) for patients with estrogen receptor (ER)-negative breast cancer (BC) has not been fully elucidated. PATIENTS AND METHODS The study population included 444 patients with ER-negative BC who underwent total mastectomy with complete axillary dissection between 1995 and 2006, 339 patients with and 105 patients without IBR. The median follow-up was 8.6 years. RESULTS Patients treated with IBR were younger (P < .001) and received surgery more recently (2003-2006: 53.1% vs. 39%; P = .0003), and had a lower number of metastatic lymph nodes (>4 lymph nodes involvement: 29.5% vs. 45.7%; P = .0026), smaller tumors (pT1/2: 15% vs. 26.7%; P = .0007), and lower extent of peritumoral vascular invasion (15.9% vs. 21%; P = .032). The 5-year cumulative incidence of locoregional recurrence was 7.1% in the IBR group and 11.7% in the no IBR group (hazard ratio [HR], 0.81; P = .63). The 5-year cumulative incidence of distant metastases were similar in the 2 groups (P = .79). The 5-year overall and disease-free survival proportions were 79.9% versus 69.5% (HR, 1.11; P = .67) and 66.6% versus 54.1% (HR, 1.04; P = .83) in the IBR group and no IBR group, respectively. CONCLUSION IBR intervention does not significantly affect prognosis of ER-negative BC patients.

Abstract P6-11-14: Long-Term Disease Control with Vinorelbine, Cisplatin and Continuous Infusion of 5-Fluorouracil -ViFuP Regimen-in Metastatic Triple Negative Breast Cancer Patients

Background: Triple negative breast cancers (TNBCs) are characterized by lack of estrogen, progesterone, HER-2-neu receptors expression and comprise 15% to 20% of all breast cancers. Studies have suggested that TNBCs may be more sensitive to DNA damaging agents like cisplatin. Our previous experience had identified a combination chemotherapy -the ViFuP regimen-with noteworthy efficacy and safety as a first or subsequent line treatment for metastatic breast cancer (MBC) patients (pts). In this view we retrospectively examined the activity of ViFuP regimen in 2 cohorts (A and B) of metastatic TNBC pts. Material and Methods: From January 2000 to December 2008, 115 pts with MBC were treated with ViFuP regimen, at the European Institute of Oncology, Milan, Italy. Among these, 35 pts (30%) had TNBC. Pts received continuous infusion 5-fluorouracil 200 mg/m2/day, vinorelbine 20 mg iv on days 1 and 3 and cisplatin 60 mg/m2on day 1. Therapy was given every three weeks. In A 22 pts (63%) were triple negative on primary tumor and in B 13 pts (37%) were triple negative in metastatic site. Median age was 54 years (range 35-73), 11 pts (31%) were pre-treated for MBC and 21 pts (60%) had ≥3 metastatic sites. Results: Thirty three pts were evaluable for response and 34 pts were assessable for toxicity. Median duration of treatment was 3.57 months (range 1-5.7). Four pts (12%) had complete responses, 14 pts (42%) had partial responses and 11 pts (33%) had stable disease with a clinical benefit (CB) of 73% (95% CI, 55%-87%). Four pts (12%) had progressive disease. Median time to progression was 6 months (95% CI, 5-8 months). Main toxicity was haematological with 62% of the pts showing grade 3/4 leuco-neutropenia. Alopecia was almost absent. Discussion: Treatment with ViFuP regimen was effective and safe in metastatic TNBC providing long-term disease control in a high proportion of pts. The prolonged CB supports this regimen as an additional therapeutic opportunity in this category of pts. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-14.