January, ; Vol2; Issue1

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January, 2018 2018; Vol2; Issue1 http://iamresearcher.

a Single Center Experience Garipoli Claudia 1, D Aveni Alessandro 1, Albanese Nicolò 2 1 Medical Oncology Unit of Messina University, General Pathology Department of Adult and Child, Avenue Gazzi-

1 January, ; Vol2; Issue1 Sustainability of Eribulin Treatment for Patients with Metastatic Breast Cancer: is the of the Drug Related to the Benefit Produced (Effectiveness and Safety)? a Single Center Experience Garipoli Claudia 1, D Aveni Alessandro 1, Albanese Nicolò 2 1 Medical Oncology Unit of Messina University, General Pathology Department of Adult and Child, Avenue Gazzi- Messina,Italy 2 European School of Economics Corresponding Author: Claudia Garipoli cgaripoli@unime.it ABSTRACT Objective: To report the clinical outcomes and health care costs of Metastatic Breast Cancer patients treated with Eribulin, in the Medical Oncology Unit of the Messina University. Method: We retrospectively analyzed the costs associated with eribulin treatment in 15 MBC patients from January 2014 to December 2016 at Messina University Hospital. The PFS, ORR, DCR and the average cost of patient therapy were calculated. Result:15 patients were included in this analysis. They had received a median of 4 lines of therapy previously (including adjuvant treatment) and had significant visceral involvement (median 3 organs). A median of 4 cycles of eribulin was delivered. There were partial responses in 20% patients, stable disease status in 14%, and progressive disease in 66%. The median progression-free survival was 15 weeks (3.5 months), ORR was 20%, DCR was 33%. The most frequent treatmentrelated adverse events were neutropenia (26%), and febrile neutropenia (20%). Therapy for these patients resulted in a cost of euros ,76. Assessing the repayment by the pharmaceutical company equals to euros ,37 for non responders patients, there is a net cost of euros ,39. Conclusion: Our results have shown that treatment with eribulin applied to patients pretreated in III / IV metastatic line and beyond, so the high percentage of nonresponders is determined because of the already expired general conditions at the beginning of treatment. Despite this,eribulin was shown to be an effective and safe therapeutic option in heavily pretreated patients with MBC. The costs associated with eribulin therapy have shown that payment by result contributes to making the cost of therapy more sustainable by the National Health Service. Keywords: breast cancer,eribulin,costeffectiveness,safety

2 1. INTRODUCTION Metastatic breast cancer (MBC) remains an incurable disease. Treatment approaches for metastatic breast cancer have evolved in recent years; however chemotherapy remains a core component for the majority of patients. Current therapeutic goals for MBC are to control symptoms with an improved quality of life, and to prolong survival. Anthracycline or taxane is considered first line chemotherapy for MBC in patients who have not been exposed to these agents as adjuvants (1). However, the disease progression ultimately encountered is often attributed to primary or acquired resistance to these regimens (2).Traditional chemotherapeutic agents: gemcitabine (3,4), liposomal-doxorubicin (5,6), vinorelbine (3), platinum (7) (especially in the Triplo Negative Breast Cancer subgroup), have been used in the metastatic setting, with response rates between 10% and 35%.Therefore,there are few therapeutic possibilities that may be present in patients with anthacyclineresistant and taxane-resistant or refractory Metastatic Breast Cancer.Eribulin therapy is one of the few chemotherapy regimens shown to prolong OS of 2.5 months and the PFS of 1.5 months compared to other chemotherapy contributing to OS in women with heavily pretreated MBC. Its use may however be hampered by its cost,which is up to three times the cost of other standard drugs pretreated MBC.We report here on the safety and effectiveness of eribulin in women with MBC,placing particular attention to the costs of somministration of the drug,in relation to the results. 2. MATERIAL AND METHOD This retrospective analysis included women with MBC who were treated with eribulin at Messina University Hospital,by Junary 2014 to December 2016 and safety,effectiveness and cost of eribulin were evaluated. Patients diagnosed with advanced breast cancer and candidate for treatment with eribulin according to EMA criteria were considered for the study. Patients treated at the approved dose of 1.4 mg/m2 eribulin mesylate infused over 2 5 min intravenously on days 1 and 8, every 3 weeks were accrued. Dose reduction or cycles delayed were described. A total of 17 patients with MBC underwent eribulin therapy in our department were evaluated but only 15 were eligible for this study and have been object of our study(2 were excluded due to lack of sufficient news). The median age was 62 years (44 67),, ER-positive 53%, (8/15), Her2 amplified 34% (5/15), and triple negative subtype in 13% (2/15). 46% (7/15) of patients had more than 3 sites of disease, with the most common sites of disease being the liver (66%),bone (66%) lymph nodes ( 47%), lung (33%),skin (26%),brain (13%). The median number of eribulin cycles received in these patients was 4 (range: 1 18). Six (40%) patients received eribulin as third line therapy,six ( 40% )as fourth line, three ( 20% ) as further line of treatment. Table 1and 2. To evaluate the toxicity were used the National Cancer Institute Common Terminology Criteria for Advers Events (NCICTCAE version 4).The therapy costs (spending, reimbursement of the National Health System and Payment by result, equal to 100% of the cost of vials for non-responders within the first 3 months of therapy) have been extrapolated from database of a centralized Unit for cytotoxic drug preparations [Unità Farmaci Antiblastici (UFA)] of our University Polyclinic. Table 1:Patients characteristic Baseline characteristics N 15 Age, years, median (range) 62 (44-67) Menopause at the time of the first diagnosis, 7 (47) n (%) ECOG performance status, n (%) 0 10 (66) 1 4 (27) 2 1 (6) Metastatic site, n (%) Liver 10 (66) Bone 10 (66) Lymph node 7 (47) Lung 5 (33) Skin 4 (26) Brain 2 (13) Prior chemotherapy, n (%) Taxanes 15 (100) Anthracycline 15 (100) Capecitabine 9 (60) Vinorelbine 5 (33) Others 5 (33) Neoadjuvant-chemoterapy, n (%) Yes 4 (36) No 11 (73) Prior endocrine therapy, n (%) 8 (53) Prior radiation therapy, n (%) 12 (80) Treatment line* with Eribulin, n(%) 3 rd 6 (40) 4 th 6 (40) >4 th 3 (20) Total number of chemotherapy cycles 88 Number of courses of eribulin, median (range) 4 (range 1-18) *Refers to chemotherapy for metastatic disease, ECOG= Eastern Cooperative Oncology Group; MBC= metastatic breast

3 Table 2: Histopathological Characteristic of primary tumor in patients with breast cancer treated with eribulin Estrogen receptor status, n (%) Positive 8 (53) Negative 7 (47) Her 2 status, n(%) Positive 5 (34) Negative 10 (66) Ki 67, n(%) Low 11 (73) High 4 (27) TN*, n (%) Yes 2 (13) No 13 (87) *Triple negative PFS median study group PFS median Embrace 3. RESULTS We included 15 MBC patients.median European Cooperative Oncology Group performance status of 1 (ECOG), a number of metastatic sites 3. Adverse events were: neutropenia in four (26%) patients, fatigue in two (6%), costipation in two (6%), neurotoxicity in one (6%), stomatitis in one (6%). Table 3. Efficacy analysis: progressive disease were 66% (10/15), stable disease 14% (2/15), partial response 20% (3/15). ORR was 20% (3/15), DCR was 33% (5/15) Table 4. In particular ORR and DCR were rispectively: 66% (2/3) and 50% (1/2) in third line of treatment, 34% (1/3) and 50% (1/2 ) in fourth line of treatment. The median PFS was 3.5 months ( EMBRACE 3.7 months ). Graph.1 Table 3: Eribulin treatment related adverse events, n (%) Neutropenia 4 (26) Febrile neutropenia 3 (20) Fatigue 2(13 Constipation 2 (13) Neurotoxicity 1 (7) Stomatitis 1 (7) Table 4: Results (Efficacy analysis) Tumor responses, n (%) Progressive disease (PD) 10 (66) Stable disease (SD) 2 (14) Partial response (PR) 3 (20) Complete response (CR) 0 ORR 3 (20) DCR 5 (33) PFS (months) 3.5 months Graphic 1: PFS median study group vs PFS median Embrace Therapy for these patients resulted in a cost of euros ,76. Graph. 2. Total cost AIFA recalculated reimbursement(pay after repayment by result 100%) Graphic 2: s of Therapy (Euros) For each patient in our sample the average cost of therapy is equal to euros ,65 for each cycle is equal to euros 1.798,23 Considering the PFS, the average cost of a day of progressive free life equals to euros 100,47. Assessing the repayment by the pharmaceutical company equals to euros ,37 for non responders patients, in accordance with the pay by result, there is a decrease in costs for other treatments at a net average cost per patient of euros 9.200,42 (- 1349,23), a net cost x cycle of euros 1.568,25 (- 229,98) and a net cost for each day of free life of progression of euros 87,62 (- 12,85). Graph.3,4,5 180,00 160,00 140,00 120,00 100,00 80,00 60,00 40,00 20,00

4 12,00 10,00 8,00 6,00 4,00 2,00 months), so a high percentage of non-responder patients is determined.within the constraints of such a small cohort, we have some data regarding eribulin, to be considered interesting. While PFS is comparable to western data, the ORR, and DCR in our analysis was lower than other studies evaluating eribulin (8,9,10,11). The costs associated with eribulin therapy have proved acceptable if we consider eribulin a lifeextending, end-of-life treatment. Respect for the budget and the ability to choose the best path based on the cost/benefit criterion necessarily affects the specialist s choice of activity when accessing therapies. Graphic 3: Average cost for patient AIFA reimbursement (Euros) 1,80 1,60 1,40 1,20 1, Graphic 4: Average cost for cycle AIFA reimbursement (Euros) Graphic 5: 1 day PFS (Euros) 4. DISCUSSION Our patient population involved 15, heavily pretreated (an average of 3 lines of prior therapy) MBC, who had progressed rapidly on prior therapy (60% within 3 5. CONCLUSION The life expectancy of the patients to whom Eribulin is given is short and the goals of treatment in MBC continue to remain symptomatic palliation and disease control, with quality of life issues being of paramount importance as disease is incurable.however, as of date, there is growing evidence that up to 40% of patients may benefit for up to 6 months on the 3rd line or further lines of therapy (12). Despite the multiple options available, there is no consensus as to which drug is to be preferred in pretreated MBC (9,13,14). Innovative and expensive drugs often appear to be the main cost drivers in cancer treatment, particularly for MBC. There is an urgent need to assess clinical practice benefit. The overall economic burden of treating patients with MBC,however,has increased,as newer treatments are considerably more costly (15).Therefore, it is not surprising that breast cancer is one of the most expensive cancers to treat (16,17,18,19,20). In summary, in the 15 patients with MBC, the subject of our study,previously treated with two or more chemotherapy lines, eribulin was shown to achieve good disease control rates both in visceral and non-visceral metastases. The toxicity profile was favourable and, as expected, neutropaenia and febrile neutropenia, were the common adverse events.in conclusion, with the limitations due to the observational nature of our findings, eribulin once again was shown to be an effective and safe therapeutic option for third and further lines of treatment in patients with advanced MBC. Negotiated clinical evaluation models guarantee access to new health technologies and produce potential postmarketing evidence to renegotiate pricing and redemption conditions.the Pay By Result, indeed, contributes to making the cost of therapy more sustainable for the National Health Service.

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Cancer du sein métastatique et amélioration de la survie Pr. X. Pivot Date of preparation: November 2015. EU0250i TTP/PFS Comparaisons First line metastatic breast cancer Monotherapy Docetaxel Chan 1999