CLINICAL TRIAL published: 09 July 2021 doi: 10.3389/fonc.2021.645026 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 1*, Meritxell Bellet 2, Milana Bergamino 1, Serafı́n Morales 3, Edited by: Agustı́ Barnadas 4, Luı́s Manso 5, Cristina Saura 2, Adela Fernández-Ortega 1, Sirin A. Adham, Elena Garcia-Martinez 6, Noelia Martinez-Jañez 7, Mireia Melé 8, Patricia Villagrasa 9, Sultan Qaboos University, Oman Pamela Celiz 9, X. Perez Martin 10, Eva Ciruelos 5 and Sonia Pernas 1 on behalf of the Reviewed by: SOLTI Breast Cancer Research Group Khalid Al-Baimani, 1 Department of Medical Oncology, Institut Català d’Oncologia, IDIBELL, L’Hospitalet, Spain, 2 Department of Medical Sultan Qaboos University, Oman Oncology, Hospital Vall d’Hebron, Barcelona, Spain, 3 Department of Medical Oncology, Hospital Arnau de Vilanova, Ikram Burney, Lleida, Spain, 4 Department of Medical Oncology, Hospital de Sant Pau, Barcelona, Spain, 5 Department of Medical Sultan Qaboos University, Oman Oncology, Hospital, 12 de Octubre, Madrid, Spain, 6 Department of Medical Oncology Hospital, JM Morales Messeguer, *Correspondence: Murcia, Spain, 7 Department of Medical Oncology, Hospital Ramón y Cajal, Madrid, Spain, 8 Department of Medical Miguel J. Gil-Gil Oncology, Hospital Sant Joan, Reus, Spain, 9 SOLTI Breast Cancer Research Group, Barcelona, Spain, 10 Clinical Research mgilgil@iconcologia.net Unit, Institut Català d’Oncologia, L’Hospitalet, Spain Specialty section: This article was submitted to Background: The CAPRICE trial was designed to specifically evaluate neoadjuvant Women’s Cancer, pegylated liposomal doxorubicin (PLD) in elderly patients or in those with other a section of the journal cardiovascular risk factors in whom conventional doxorubicin was contraindicated. The Frontiers in Oncology primary analysis of the study showed a pathological complete response (pCR) of 32% and Received: 22 December 2020 Accepted: 20 May 2021 no significant decreases in LVEF during chemotherapy. Here, we report important Published: 09 July 2021 secondary study objectives: 5-year cardiac safety, disease-free survival (DFS), overall Citation: survival (OS) and breast cancer specific survival (BCSS). Gil-Gil MJ, Bellet M, Bergamino M, Morales S, Barnadas A, Manso L, Methods: In this multicentre, single-arm, phase II trial, elderly patients or those prone to Saura C, Fernández-Ortega A, cardiotoxicity and high risk stage II-IIIB breast cancer received PLD (35 mg/m2) plus Garcia-Martinez E, Martinez-Jañez N, Melé M, Villagrasa P, Celiz P, Perez cyclophosphamide (600 mg/m2) every 4 weeks for 4 cycles, followed by paclitaxel for 12 Martin X, Ciruelos E and Pernas S weeks as neoadjuvant chemotherapy (NAC). Left ventricular ejection fraction (LVEF) (2021) Long-Term Cardiac Safety and Survival Outcomes of Neoadjuvant monitorization, electrocardiograms and cardiac questionnaires were performed at Pegylated Liposomal Doxorubicin in baseline, during treatment and at 9, 16, 28 and 40 weeks thereafter. The primary Elderly Patients or Prone to endpoint was pCR and 5-year cardiac safety, DFS, BCSS and OS were also analyzed. Cardiotoxicity and Triple Negative Breast Cancer. Final Results of the Results: Between Oct 2007, and Jun 2010, 50 eligible patients were included. Median Multicentre Phase II CAPRICE Study. Front. Oncol. 11:645026. age was 73 (35-84) years, 84% were older than 65; 64% of patients suffered from doi: 10.3389/fonc.2021.645026 hypertension, and 10% had prior cardiac disease. Most of tumors (88%) were triple Frontiers in Oncology | www.frontiersin.org 1 July 2021 | Volume 11 | Article 645026 Gil-Gil et al. Long-Term Safety & Survival Outcomes PLD 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: pegylated liposomal doxorubicin, elderly, neoadjuvant chemotherapy, triple negative breast cancer, long-term results, cardiotoxicity, survival, phase II study INTRODUCTION profile of the liposome-encapsulated anthracyclines. First, this formulation reduces the amount of drug reaching the cardiac Several randomized trials and a meta-analysis confirmed that cells and secondly, it enables a slow release of DOX that avoid chemotherapy regimens that include anthracyclines are more peak plasma concentrations. PLD has longer half-life (50-80 hours) effective than those without them (1). Despite their high than non-pegylated liposomal DOX (10-16 hours) and antitumor activity profile, their use in clinical practice is conventional DOX (10 minutes) (10, 11). PLD has demonstrated limited due to potential cardiotoxicity (2). Conventional to have equivalent efficacy but significantly less cardiotoxicity than doxorubicin (DOX) can induce myofibrillar damage with a conventional DOX in a phase III non-inferiority trial in patients decrease in Left Ventricular Ejection Fraction (LVEF), leading with metastatic breast cancer (12). In addition, a meta-analysis to irreversible congestive heart failure (CHF) (3). The including data from nine randomized trials of different tumors, mechanisms of cardiotoxicity of DOX are mainly caused by compared the efficacy and safety profile of liposomal formulations the pro-apoptotic effect of the topoisomerase II inhibition in the versus conventional anthracyclines. In this meta-analysis, cardiomyocytes resulting in loss of functional myocytes and liposomal DOX and PLD demonstrated favorable toxicity irreversible heart injury (4). The risk of developing chronic profiles with better cardiac safety and less myelosuppression, anthracycline-induced cardiotoxicity is strongly related to alopecia, nausea, and vomiting compared to conventional several factors. The main risk factor is the cumulative dose anthracyclines, without compromising effectiveness (13). of this agent, but one prospective study revealed that only Given the projected substantial increase of the elderly 240 mg/m2 of accumulated DOX caused grade 1 cardiotoxicity population over the following years, it is necessary to develop in 17% patients and grade 2 in 6.6% (5). Some retrospective new chemotherapy regimens with equivalent efficacy, and better studies showed that in addition to the accumulated dose, the risk tolerability, for this vulnerable subset of patients. We conducted a of CHF correlate with the age of the patient and with the scheme phase II, single-arm, multicenter clinical trial to evaluate the efficacy of administration (6). Continuous infusion schemes have been and safety of a NAC based on PLD plus cyclophosphamide reported to be less cardiotoxic compared with rapid infusion of followed by paclitaxel in patients with breast cancer and at high DOX (7). Other independent risk factors for developing risk of developing cardiotoxicity: the SOLTI-CAPRICE study cardiomyopathy are pre-existing cardiac disease and history (NCT00563953). The results of complete pathological response of hypertension. (pCR), breast conserving surgery (BCS) and acute toxicity have Pegylated liposomal doxorubicin (PLD), trademark Caelyx/ already been published (14). This is an update on the cardiotoxicity Doxil®, is an encapsulated anthracycline that was designed to and survival outcomes at five years of follow-up which were reduce toxicity of DOX while preserving its antitumor efficacy by secondary objectives of the study. altering its tissue distribution and pharmacokinetics. It is associated with a significantly reduced incidence of cardiotoxicity (8, 9). There are at least two known factors that contribute to the less cardiotoxic PATIENTS AND METHODS Abbreviations: BCS, Breast Conserving Surgery; BCSS, Breast Cancer Specific Study Design Survival; CHF, Congestive Heart Failure; DFS, Disease Free Survival; DOX, Phase II, Open-Label, Multicentre Clinical Trial aimed to Doxorubicin; ECG, Electrocardiogram; ER, Estrogen receptor; HFS, Hand-Foot evaluate PLD plus Cyclophosphamide followed by paclitaxel as Syndrome; ITT, Intent-to-treat; LVEF, Left Ventricular Ejection Fraction; NAC, Neoadjuvant Chemotherapy; ORR, Overall Response Rate; OS, Overall Survival; NAC for breast cancer patients with risk of developing pCR, Pathologic complete response; PLD, Pegylated Liposomal Doxorubicin; RFS, cardiotoxicity. The protocol was designed and approved by the Relapse-free survival. ethics committee at each participating center in 2007. Frontiers in Oncology | www.frontiersin.org 2 July 2021 | Volume 11 | Article 645026 Gil-Gil et al. Long-Term Safety & Survival Outcomes PLD Eligibility Criteria Statistical Analysis Histologically confirmed stage II-IIIB invasive breast cancer, The primary end point of the study was the pCR rate in breast. To estrogenic receptor (ER) below 50% and at least one of the determine the sample size, the expected proportion of complete following cardiotoxicity risk conditions: > 65 years old, pre- pathological responses (pCR) was assumed to be higher than 18%. existing heart disease, LVEF <55%, clinical history of It was also established that the investigational regimen would be hypertension requiring pharmacological treatment, previous of no further interest if the true pCR rate was < 8% (H0). The mediastinal irradiation or previous treatment with alternate hypothesis (HA) assumed that a true pCR rate ≥ 18% anthracyclines. Full eligibility criteria are published online would be of considerable interest in breast cancer patients with (Table S1). high risk of developing cardiotoxicity. The hypothesis test was resolved with a risk a = 0.05, using a conformance test of a Treatment Plan and Evaluations proportion (p = 0.08) versus unilateral alternative (ß = 0.08) NAC regimen was based on 4 cycles of PLD 35 mg/m2 plus based on the Normal approximation. They provided the lower cyclophosphamide 600 mg/m2 on day 1 every 4 weeks followed limit of the confidence interval (unilateral) of 95% for the by paclitaxel 80 mg/m2/week for 12 weeks (Figure 1). Dose proportion of pCR. Assuming a 10% drop out rate, the sample reduction criteria is summarized in Table S2. needed was calculated in 66 patients. Physical examination, LVEF monitorization, electrocardiogram Secondary end points of the study were: Cardiac safety (ECG) and cardiac questionnaire were performed at the beginning measured by decrease in LVEF, overall response rate (ORR) of the study and during weeks 9, 16, 28; then every 3 months for 2 after PLD plus Cyclophosphamide, ORR at the end of the NAC, years and then every 6 months until the 5th year. Cell blood count, BCS rate, pCR in breast and axilla, and 5-year relapse free chemistry profile, physical examinations, and toxicity assessments survival (RFS) and overall survival (OS). More information can were performed every 4 weeks during treatment. Toxicities were be found in Table S3. graded using the Common Terminology Criteria for Adverse Events (CTCAE) 3.0 common toxicity criteria. The type of surgery indicated by the surgeon prior to NAC RESULTS initiation was recorded, and surgery treatment was performed between 2-5 weeks after the last infusion of NAC Between October 2007 and June 2010, 51 patients signed the informed consent. The sample size was lower than initially Response Criteria foreseen due to slow recruitment. One patient was excluded Surgical specimens were evaluated for pathological tumour before treatment initiation because of metastatic disease response according to the NSABP guidelines (15). pCR was identified at baseline. Therefore, 50 patients were included in defined as no evidence of residual invasive cancer (ypT0/is) in the intent-to-treat (ITT) analysis. the breast specimen while breast and axilla pCR was defined as Patient and tumors characteristics are summarized in the absence of invasive disease in the breast and axillary nodes Table 1. It is noteworthy that 84% of the patients were older (ypT0/Tis ypN0). Radiological response was evaluated according than 65 years old and that 88% of the tumors were triple to WHO criteria. negative. At baseline only 13 patients (26%) were candidates 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. Frontiers in Oncology | www.frontiersin.org 3 July 2021 | Volume 11 | Article 645026 Gil-Gil et al. Long-Term Safety & Survival Outcomes PLD TABLE 1 | Patient and tumor baseline characteristics. (n=44) pCR was 33.3%. Two out of seven (28.7%) inflammatory n % breast carcinoma achieved a pCR. pCR in breast and nodes was 24% for ITT patients (95% CI 12.1-35.8%) (Table S4). Patients in ITT 50 100 No significant decreases in LVEF were observed. The mean Age: <60 years 6 12 baseline LVEF was 66.6 (52-86). After 16, 28, and 40 weeks LVEF 60-64 years 2 4 65-69 years 11 22 was 66.7 (51-88), 62.2 (48-75), and 64.7 (50-74), respectively 70-74 years 11 22 (Figure 3). Mean LVEF after 5 years follow-up was 66 (54.5-73). 75-79 years 14 28 No relevant changes were observed in the ECG follow up either. >79 years 6 12 A total of 406 adverse events (37 grades 3-4) were reported in 38 ECOG PS 0 43 86 patients (Table 2). Four patients (8%) developed early 1 7 14 Menopausal status cardiotoxicity (≥G3 in two cases): one sudden death in a 82- Pre 4 8 year-old patient three months after completion of NAC, one Post 46 92 episode of atrial fibrillation and CHF during paclitaxel treatment, Mean tumor size in mm (range) 33.7 (5-123) one case of palpitations and one case with a decrease in LVEF Histological Grade G1 4 8 <15% versus prior value (toxicity grade 1). G2 10 20 G3 36 72 Overall, 24 patients died during the follow-up. Seventeen ER–status 0% 42 84 were cancer-related deaths and eight were 8 non-cancer related 1-9% 2 4 deaths (16%). Three out of these 8 non-cancer related deaths >10% 6 12 occur early in time, and all were in patients older than 80 years: HER2/neu negative 49 98 positive 1 2 a sudden death one month after surgery, a hemorrhagic stroke Disease stage II 24 48 30 days after completing paclitaxel, and a non-neutropenic III 26 52 pneumonia during paclitaxel course. An Independent T clinical T2-T3 29 54 Multidisciplinary Safety Committee evaluated the cause of T4 a-c 14 28 death in the three cases and concluded that it was probably T4d 7 14 N clinical N0 23 46 due to old age and not directly related to the study treatment. N1 14 28 There were subsequently five non-cancer related deaths during N2 11 22 the follow-up: a case of amyotrophic lateral sclerosis (ALS), an N3 2 4 stroke, an intestinal ischemia, a heart failure due to valvular Cardiotoxicity risk factors age > 65 42 84 disease in a 85-year-old patient and an unknown-cause death in hypertension 32 64 prior cardiac disease 6 12 a 83-year-old woman after nine years of the study treatment end. lipid metabolic disorder 23 46 At 60 months of follow-up, median DFS was 50% (95% CI diabetes 12 24 40.2-68.1), median OS was 56% [IC95%: 41.2-68.4] (Figure 4) Brain Transient Ischemic 2 4 and breast cancer-specific survival (BCSS) was 67.74% (CI 95%: Attack 54.31% - 81.18%) (Figure 5) in the ITT patients. For those Type of surgery indicated in baseline patients who underwent surgery, 5 years RFS was 54.4%. [95% Mastectomy 37 74 CI: 38.3-67.9]. BCS 13 26 ITT, intention to treat. ECOG PS, Easter Cooperative Oncology Group Perfomance Status. BCS, breast conserving surgery. DISCUSSION In this prospective phase II trial, PLD 35mg/m 2 plus for BCS. Twenty-six (52%) breast cancer cases were stage III, cyclophosphamide 600mg/m2 every 4 weeks followed by including 7 (14%) inflammatory breast carcinomas and 14 (28%) paclitaxel 80mg/m2 as NAC was an effective and cardiac safe T4b-c. regimen in a population of breast cancer patients for whom DOX Forty-eight patients (96%) completed the 4 cycles of PLD plus was contraindicated. To our knowledge, this is the first study cyclophosphamide, in whom eight patients (16%) required analyzing cardiac safety, DFS, RFS, OS and BCSS with PLD as delayed or reduced doses. Only 26 patients (52%) were able to NAC for breast cancer at long-term follow-up. Our study complete the 12 weeks of paclitaxel (Figure 2). demonstrates that this scheme has low risk for cardiotoxicity Forty-six patients (92%) underwent surgery: BCS was and is effective in this fragile sub-population, mostly elderly, with performed in 27 (58.7%) and mastectomy in 19 cases (41.3%). very high-risk breast cancer as 88% were triple negative tumors Thirty-nine patients (84%) underwent axillary lymphadenectomy and half of them locally advanced. and seven sentinel lymph node biopsies. The optimal NAC scheme is not well established yet, but In the ITT analysis, the pCR rate in breast was 32% (95% CI combinations of anthracyclines and taxanes have shown the 19.5-46.7%). This result allows us to reject the pre-specified null highest rates of pCR (10-31%) (16). hypothesis (pCR ≤ 8%) with p < 0.0001 and proven alternative The major late adverse effect of anthracyclines is hypothesis (pCR rate ≥ 18%). Among triple-negative tumours cardiotoxicity. The incidence of CHF secondary to DOX can Frontiers in Oncology | www.frontiersin.org 4 July 2021 | Volume 11 | Article 645026 Gil-Gil et al. Long-Term Safety & Survival Outcomes PLD FIGURE 2 | Consort flow diagram. n, number; PLD, Pegylated liposomal doxorubicin; CPM, Cyclophosphamide; PTX, Paclitaxel; BCS, Breast Conservation Surgery. manifest even some years after the treatment was administered factors for cardiotoxicity act as a “snowball effect” in elderly (17). According to the guidelines of the American Society of patients with cancer, as described by Reddy et al. (20). For all Clinical Oncology (ASCO), the risk of developing DOX these reasons, the elderly patients or those that have a prior cardiotoxicity increases 1.6 to 6.8 times in patients over 65 history of heart disease do not usually receive anthracyclines in years of age (18). One of the reasons the old heart is clinical practise. Furthermore, one of the main caveats of clinical particularly vulnerable to cardiotoxicity by chemotherapy is trials in oncology is the limited information available regarding probably the age-related loss of cardiomyocytes. In addition, it the elderly. Typically, clinical trials with DOX, including PLD, is noteworthy that pharmacokinetics of anthracyclines appears to are limited to women up to 70 years old and in optimal be altered in the elderly, resulting in significant increased DOX performance status (21). concentrations, particularly evident in the heart (19). Finally, The encapsulation of DOX in liposomes alters its aging is generally accompanied by the development of pharmacokinetic properties and is associated with less comorbidities, such as hypertension, high blood levels of cardiotoxicity (8–13). There is no standardized test for the cholesterol and diabetes mellitus. Thus, those additional risk assessment of anthracycline-induced cardiotoxicity. The most Frontiers in Oncology | www.frontiersin.org 5 July 2021 | Volume 11 | Article 645026 Gil-Gil et al. Long-Term Safety & Survival Outcomes PLD FIGURE 3 | Sequential LVEF determinations since baseline to 60 m post-S. LVEF, Left Ventricular Ejection Fraction; M, months; post-S, post surgery. widespread clinical practice is to conduct a LVEF baseline study plus paclitaxel, in the metastatic setting, was also used by Vorobiof and repeat the same exploration periodically during treatment, et al. who described one asymptomatic LVEF drop > 20% in but long-term LVEF assessment is not common. The role of 26 patients (4%) (25) and Rigatos et al. (26) who reported cardiac damage plasmatic markers is not completely established. cardiotoxicity in 2 of the 24 treated patients (8%). Combination of PLD plus cyclophosphamide has In the neoadjuvant setting, several small studies and two demonstrated little or no cardiotoxicity in three phase II trials in single-arm phase II trials with liposomal anthracyclines have advanced breast cancer patients (22–24). The combination of PLD been published showing high response rates, good tolerability and low acute cardiac toxicity (27–29). A recent retrospective study has compared a small cohort of patients treated with PLD regimens such as NAC versus another matched cohort treated TABLE 2 | Most frequent toxicities. with conventional epirubicin-based regimens, showing similar Adverse Event All grades Grade 3-4 efficacy and less cardiotoxicity evaluated during a 6 month- period (30). Docetaxel 100 mg/m2 for 4 cycles, followed by non-pegylated liposomal DOX (Myocet®) 60 mg/m2 combined n % n % Fatigue 42 84 3 6 with cyclophosphamide 600 mg/m2 was analysed in a phase II Alopecia 35 70 0 0 trial without significant decreases in LVEF during NAC Neurology (sensitive) 31 62 3 6 (31). Results of a non-comparative phase II study with Stomatitis 29 58 0 0 Nausea/Vomiting 25 50 1 2 the combination of PLD plus cyclophosphamide followed by Pain 21 42 0 0 docetaxel as NAC in breast cancer have recently been published Diarrhoea 17 34 2 4 (29). There was no evidence of a significant decrease in mean Nail Changes 17 34 0 0 LVEF values during the 24 weeks of treatment. However, long- Anorexia 17 34 0 0 term cardiac toxicity and efficacy have not been reported yet in Skin reaction (rash) 16 32 2 4 Neutropenia 11 22 1 2 any of those studies. Hand-Food Syndrome 7 14 0 0 Our study is the first to report 5-year follow-up of clinical Oedema 7 14 0 0 outcome, LVEF monitorization and ECG data. Overall, there was Constipation 7 14 0 0 no significant decrease in the median LVEF, no relevant changes Fever 7 14 1 2 Haemolysis 6 12 1 2 in the ECG or late cardiac symptoms. Only 4 patients (8%) Infection 6 12 1 2 presented severe early adverse events from which 2 were ≥G3. Cardiac Event 5 10 3 6 In addition, the median age of the patients included in the trial Pulmonary 4 8 2 4 was 73 years old, being 84% over 65. Most of them had high Neurology (other) 4 8 1 2 blood pressure (64%) and 10% had history of heart disease. Anaemia 3 6 2 4 Hypersensitivity 3 6 1 2 These results support the uphold of the use of PLD in this subset Haemorrhage 3 6 2 4 of patients. Age and comorbidities are substantial differences Renal Failure 2 4 1 2 from the rest of the studies published to date; in which the Frontiers in Oncology | www.frontiersin.org 6 July 2021 | Volume 11 | Article 645026 Gil-Gil et al. Long-Term Safety & Survival Outcomes PLD FIGURE 4 | Kaplan Meier curve for OS. n, number; OS, Overall Survival; CI, Confidence Interval. FIGURE 5 | Kaplan Meier curves for BCSS. n, number; BCSS, Breast Cancer Specific Survival; CI, Confidence Interval. Frontiers in Oncology | www.frontiersin.org 7 July 2021 | Volume 11 | Article 645026 Gil-Gil et al. Long-Term Safety & Survival Outcomes PLD median age ranges between 47 and 54 years old and patients over strategy allowed doubling the BCS rate (26% to 58%) in this very 70 or with history of heart disease were exclusion criteria (9, fragile cohort of patients. 17, 18). Although another alternative would have been to treat It is noteworthy that although 96% of patients of this trial patients in our study with carboplatin and/or nab-paclitaxel completed all four cycles of PLD plus cyclophosphamide, but schedules, these drugs were not the standard of care at the only 52% of patients could complete the 12 weeks planed of time when this study was planned. Indeed, the addition of paclitaxel mostly due to neurotoxicity, asthenia and HFS. This neoadjuvant carboplatin to a regimen based on taxanes has fact reflects the good tolerance to PLD-cyclophosphamide, but shown to significantly increase the proportion of patients probably poor tolerance to sequentially administration of achieving a pCR in triple negative breast cancer (33, 34). paclitaxel. Other studies including younger population such as However, the improvement in OS remains unclear. Li et- study have shown that up to 86% of patients were able to One limitation of this study is that it is a single-arm phase II complete the treatment with docetaxel but median age was trial and therefore we do not have a direct comparison with a remarkably lower (46 years old) and patients over their 70’s non-anthtracycline chemotherapy regimen. A second limitation were excluded (28). The hand-foot syndrome (HFS) and skin of this regimen is the paclitaxel dose-intensity. Only 52% of the reactions are typical toxicities associated with PLD (12, 28). A patients were able to complete the paclitaxel regimen after PLD median dose of 10 mg/m2 per week has shown to reduce the plus cyclophosphamide, mainly due to cutaneous and incidence and severity of mucositis and HFS. We chose the dose neurological cumulative toxicity. Whether the administration of 35mg/m2 of PLD every 4 weeks in an attempt to reduce the of the drugs in the reverse order would have prevented cutaneous mucositis and HFS associated with PLD. In our study skin and neurological toxicities and if the administration of paclitaxel reactions were documented in 32% of patients but only 2 were would have resulted in an increase of the pCR rate, DFS and OS grade 3 (4%). This toxicity generally began with weekly infusions is unclear and deserves further investigation. of paclitaxel. The cutaneous toxicity derived from PLD is a consequence of microtrauma in the blood vessels, which leads to extravasation of the cytostatics into the tissues. This fact may account for the poor skin tolerance to sequentially administered CONCLUSIONS paclitaxel after PLD. Li et al. report 45% of HFS with PLD plus Our study demonstrated that a PLD-based NAC chemotherapy cyclophosphamide followed by docetaxel (29). Most patients in scheme can lead to equivalent long-term efficacy but with our trial experienced fatigue (84%) but it was ≥ G3 in only 6% of significantly less cardiotoxicity than regimens that include cases. Peripheral sensorial neuropathy, mainly due to paclitaxel conventional DOX. The good tolerability profile of PLD was also seen in 62% patients. without compromising effectiveness makes it a favourable Some phase II studies have shown efficacy of PLD as NAC, choice over conventional anthracyclines in elderly patients or in combination with cyclophosphamide (22–24, 28) or with patients with risk factors for cardiac disease. This regimen should paclitaxel (25–27) with ORR ranging from 38% to 80% be considered as a neoadjuvant treatment option for elderly or (Table S5). The pCR rate in previously published phase II cardiotoxicity-prone patients with high-risk breast cancer. studies ranges from 8% to 36% (27, 30). The pCR in our study was remarkably high: 32% in the ITT population and 33.3% in triple negative breast cancer patients, as previously published (14). These rates are especially relevant considering that 26 cases DATA AVAILABILITY STATEMENT were stage III and seven were inflammatory breast carcinoma The raw data supporting the conclusions of this article will be (28.7% of whom achieved pCR). These results seem superior to made available by the authors, without undue reservation. the trial by Li et al, where breast pCR rate was 18.75% (95% CI 11.5-26%) using a very similar scheme to us but administering a higher dose of PLD (40 mg/m2) combined with docetaxel instead of paclitaxel (29). This lower pCR rate in their study is probably ETHICS STATEMENT due to the fact that the population included was much more heterogeneous than that from our study. This is reflected by the The studies involving human participants were reviewed and fact that the pCR rate amongst the 16 triple negative tumors in approved by Hospital Vall de Hebron Ethics Committee on that series was 43.75%. Clinical Research. The patients/participants provided their For the 46 patients who underwent surgery, 5-year RFS was written informed consent to participate in this study. 54.4% [95% CI: 38.3-67.9] and 5-year OS for ITT was 56% (IC95%: 41.2-68.4). Long-term OS was probably limited by the elderly population and the significant association with AUTHOR CONTRIBUTIONS comorbidities. In addition, most of the tumors were triple negative and half of them were locally advanced breast cancers. MG-G: Conception, study design, data collection, analysis, 5-year BCSS was 67.74% (CI 95%:54.31%- 81.18%). This RFS interpretation of results, figure design, article draft writing. and BCSS is in line with what has been published in patients with MiB: Data collection, analysis, interpretation of results, figure bulky triple negative tumors (32). Furthermore, this therapeutic design. MeB: Drafted the manuscrit. SM, AB, CS, AF, EG-M, Frontiers in Oncology | www.frontiersin.org 8 July 2021 | Volume 11 | Article 645026 Gil-Gil et al. Long-Term Safety & Survival Outcomes PLD NM-J, MM, EC and SP participated in data collection. TP and JC ACKNOWLEDGMENTS participated in data analysis. XP participated in data analysis and figure design. All authors contributed to the article and approved We thank CERCA Programme/Generalitat de Catalunya for the submitted version. institutional support. PDL as well as the rest of cytostatics was provided by Schering-Plough Labs. SUPPLEMENTARY MATERIAL FUNDING The Supplementary Material for this article can be found online at: The rest of the study was supported by the collaborative https://www.frontiersin.org/articles/10.3389/fonc.2021.645026/ group SOLTI. full#supplementary-material 14. Gil-Gil MJ, Bellet M, Morales S, Ojeda B, Manso L, Mesia C, et al. Pegylated REFERENCES Liposomal Doxorubicin Plus Cyclophosphamide Followed by Paclitaxel as 1. Cole MP, Todd IDH, Wilkinson PM. A Preliminary Trial of Doxorubicin in Primary Chemotherapy in Elderly or Cardiotoxicity-Prone Patients With Advanced Breast Cancer and Other Malignant Disease. Br J Cancer (1974) High-Risk Breast Cancer: Results of the Phase II CAPRICE Study. Breast 29:114. doi: 10.1038/bjc.1974.47 Cancer Res Treat (2015) 151:597–606. doi: 10.1007/s10549-015-3415-2 2. Early Breast Cancer Trialist’s Collaborative Group (EBCTCG). Effects of 15. Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, et al. 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MB declares consulting/advisory fees from Pfizer, Oncology Group. Ann Oncol (2002) 13:1737–42. doi: 10.1093/annonc/mdf284 Novartis and Lilly. SM declares consulting/advisory fees from Pfizer, Roche and 29. Li R, Tian F, Qi Y, Ma L, Zhou T, Li Y, et al. Pegylated Liposomal Doxorubicin Lilly. AB declares consulting/advisory fees from Pfizer, Roche, Bristol Muers Plus Cyclophosphamide Followed by Docetaxel as Neoadjuvant Squibb, Astra-Zeneca and Lilly. CS declares consulting/advisory fees from Pfizer, Chemotherapy in Locally Advanced Breast Cancer (Registration Number: Roche, Macrogenics, Piqur therapeutics, Puma, Synthon and Novartis. EG-M Chictr1900023052). Sci Rep 9 (2019) 9(1):18135. doi: 10.1038/s41598-019- declares consulting/advisory fees from Roche; Astra-Zeneca, Clovis, Pharmamr, 54387-5 Celgene and Novartis. EC declares consulting/advisory fees from Puma, Pfizer, 30. Dong M, Luo L, Ying X, Lu X, Shen J, Jiang Z, et al. Comparable Efficacy and Roche, Astra-Zeneca, Celgene, Daiichi-Sankyo, Eisai, Genomyc Health, Novartis Less Toxicity of Pegylated Liposomal Doxorubicin Versus Epirubicin for Pierre Fabre and Synthon. SP declares consulting/advisory fees from Astra- Neoadjuvant Chemotherapy of Breast Cancer: A Case-Control Study. Onco Zeneca, Daiichi-Sankyo, Novartis, Polyphor, Roche, and Seattle Genetics; and Targets Ther (2018) 11:4247–52. doi: 10.2147/OTT.S162003 travel/accommodation grants from Novartis. 31. Garcıá -Mata J, Calvo L, Ló pez R, Ramos M, Castellanos J, Heras L. Non- Randomized, Open Label Phase II Trial Evaluating the Safety and Efficacy of The remaining authors declare that the research was conducted in the absence of Taxotere (T) Followed by Myocet (M) + Cyclophosphamide (C) as First-Line any commercial or financial relationships that could be construed as a potential Treatment for HER2–Negative Breast Cancer (Bc). Cancer Res (2011) 71(24 conflict of interest. suppl). doi: 10.1158/0008-5472.SABCS11-P3-14-15 32. Bignon L, Fricker JP, Nogues C, Mouret-Fourme E, Stoppa-Lyonnet D, Caron Copyright © 2021 Gil-Gil, Bellet, Bergamino, Morales, Barnadas, Manso, Saura, O, et al. Efficacy of Anthracycline/Taxane-Based Neo-Adjuvant Fernández-Ortega, Garcia-Martinez, Martinez-Jañez, Melé, Villagrasa, Celiz, Perez Chemotherapy on Triple-Negative Breast Cancer in BRCA1/BRCA2 Martin, Ciruelos and Pernas. This is an open-access article distributed under the Mutation Carriers. Breast J (2018) 24:269–77. doi: 10.1111/tbj.12887 terms of the Creative Commons Attribution License (CC BY). The use, distribution or 33. Von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, et al. reproduction in other forums is permitted, provided the original author(s) and the Neoadjuvant Carboplatin in Patients With Triple-Negative and HER2- copyright owner(s) are credited and that the original publication in this journal is Positive Early Breast Cancer (Geparsixto; GBG 66): A Randomised Phase 2 cited, in accordance with accepted academic practice. No use, distribution or Trial. Lancet Oncol (2014) 15:747–56. doi: 10.1016/S1470-2045(14)70160-3 reproduction is permitted which does not comply with these terms. Frontiers in Oncology | www.frontiersin.org 10 July 2021 | Volume 11 | Article 645026