Long-Term Cardiac Safety and Survival Outcomes of Neoadjuvant Pegylated Liposomal Doxorubicin in Elderly Patients or Prone to Cardiotoxicity and Triple Negative Breast Cancer. Final Results of the Multicentre Phase II CAPRICE Study

Miguel J Gil-Gil, Meritxell Bellet, Milana Bergamino, Serafín Morales, Agustí Barnadas, Luís Manso, Cristina Saura, Adela Fernández-Ortega, Elena Garcia-Martinez, Noelia Martinez-Jañez, Mireia Melé, Patricia Villagrasa, Pamela Celiz, X Perez Martin, Eva Ciruelos, Sonia Pernas, Miguel J Gil-Gil, Meritxell Bellet, Milana Bergamino, Serafín Morales, Agustí Barnadas, Luís Manso, Cristina Saura, Adela Fernández-Ortega, Elena Garcia-Martinez, Noelia Martinez-Jañez, Mireia Melé, Patricia Villagrasa, Pamela Celiz, X Perez Martin, Eva Ciruelos, Sonia Pernas

Abstract

Background: The CAPRICE trial was designed to specifically evaluate neoadjuvant pegylated liposomal doxorubicin (PLD) in elderly patients or in those with other cardiovascular risk factors in whom conventional doxorubicin was contraindicated. The primary analysis of the study showed a pathological complete response (pCR) of 32% and no significant decreases in LVEF during chemotherapy. Here, we report important secondary study objectives: 5-year cardiac safety, disease-free survival (DFS), overall survival (OS) and breast cancer specific survival (BCSS).

Methods: In this multicentre, single-arm, phase II trial, elderly patients or those prone to cardiotoxicity and high risk stage II-IIIB breast cancer received PLD (35 mg/m2) plus cyclophosphamide (600 mg/m2) every 4 weeks for 4 cycles, followed by paclitaxel for 12 weeks as neoadjuvant chemotherapy (NAC). Left ventricular ejection fraction (LVEF) monitorization, electrocardiograms and cardiac questionnaires were performed at baseline, during treatment and at 9, 16, 28 and 40 weeks thereafter. The primary endpoint was pCR and 5-year cardiac safety, DFS, BCSS and OS were also analyzed.

Results: Between Oct 2007, and Jun 2010, 50 eligible patients were included. Median age was 73 (35-84) years, 84% were older than 65; 64% of patients suffered from hypertension, and 10% had prior cardiac disease. Most of tumors (88%) were triple negative. No significant decreases in LVEF were observed. The mean baseline LVEF was 66.6% (52-86) and after a median follow-up of 5 years, mean LVEF was 66 (54.5-73). For intention to treat population, 5-year DFS was 50% (95% CI 40.2-68.1) and 5-year OS was 56% (95%CI 41.2-68.4). There were 8 non-cancer related deaths, achieving a 5 years BCSS of 67.74% (CI 95%:54.31%- 81.18%).

Conclusion: At 5-year follow-up, this PLD-based NAC regimen continued to be cardiac-safe and effective in a population of very high-risk breast cancer patients. This scheme should be considered as an option in elderly patients or in those with other risks of developing cardiotoxicity.

Trial registration number: ClinicalTrials.gov reference NCT00563953.

Keywords: cardiotoxicity; elderly; long-term results; neoadjuvant chemotherapy; pegylated liposomal doxorubicin; phase II study; survival; triple negative breast cancer.

Conflict of interest statement

MG-G declares consulting/advisory fees from Pfizer, Daiichi-Sankyo, Novartis and Roche. MB declares consulting/advisory fees from Pfizer, Novartis and Lilly. SM declares consulting/advisory fees from Pfizer, Roche and Lilly. AB declares consulting/advisory fees from Pfizer, Roche, Bristol Muers Squibb, Astra-Zeneca and Lilly. CS declares consulting/advisory fees from Pfizer, Roche, Macrogenics, Piqur therapeutics, Puma, Synthon and Novartis. EG-M declares consulting/advisory fees from Roche; Astra-Zeneca, Clovis, Pharmamr, Celgene and Novartis. EC declares consulting/advisory fees from Puma, Pfizer, Roche, Astra-Zeneca, Celgene, Daiichi-Sankyo, Eisai, Genomyc Health, Novartis Pierre Fabre and Synthon. SP declares consulting/advisory fees from Astra-Zeneca, Daiichi-Sankyo, Novartis, Polyphor, Roche, and Seattle Genetics; and travel/accommodation grants from Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Gil-Gil, Bellet, Bergamino, Morales, Barnadas, Manso, Saura, Fernández-Ortega, Garcia-Martinez, Martinez-Jañez, Melé, Villagrasa, Celiz, Perez Martin, Ciruelos and Pernas.

Figures

Figure 1
Figure 1
Scheme of the Study. PLD, Pegylated liposomal doxorubicin; ER, Estrogen receptors; HER2, Human epidermal growth factor receptor 2; BCS, Breast conservative surgery; TAM, Tamoxifen; N, Node; IA, Aromatase inhibitors.
Figure 2
Figure 2
Consort flow diagram. n, number; PLD, Pegylated liposomal doxorubicin; CPM, Cyclophosphamide; PTX, Paclitaxel; BCS, Breast Conservation Surgery.
Figure 3
Figure 3
Sequential LVEF determinations since baseline to 60 m post-S. LVEF, Left Ventricular Ejection Fraction; M, months; post-S, post surgery.
Figure 4
Figure 4
Kaplan Meier curve for OS. n, number; OS, Overall Survival; CI, Confidence Interval.
Figure 5
Figure 5
Kaplan Meier curves for BCSS. n, number; BCSS, Breast Cancer Specific Survival; CI, Confidence Interval.

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