Anthracycline Pretreatment Research Articles

Anthracyclines Strike Back: Rediscovering Non-Pegylated Liposomal Doxorubicin in Current Therapeutic Scenarios of Breast Cancer.

Simple SummaryAnthracyclines are among the most active chemotherapies in breast cancer (BC). However, they can cause structural and cumulative dose-related cardiac damage; hence, they require careful administration after preliminary functional cardiac assessment and subsequent monitoring, along with a limitation in the cumulative dose delivered. Non-pegylated liposomal doxorubicin (NPLD) has been precisely developed to optimize the doxorubicin toxicity profile, while retaining its therapeutic efficacy, thanks to a reduced diffusion in normal tissues with preserved drug penetrance into cancer sites. This has allowed administration of NPLD beyond a conventional doxorubicin maximum cumulative dose, as well as in patients with cardiac comorbilities or anthracycline pretreatment. At present, NPLD is approved in Europe and Canada in combination with cyclophosphamide as the first line of metastatic HER2-negative BC. However, given the increasing complexity of the therapeutic scenario in this setting, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms.Anthracyclines are among the most active chemotherapies (CT) in breast cancer (BC). However, cardiotoxicity is a risk and peculiar side effect that has been limiting their use in clinical practice, especially after the introduction of taxanes. Non-pegylated liposomal doxorubicin (NPLD) has been developed to optimize the toxicity profile induced by anthracyclines, while maintaining its unquestionable therapeutic index, thanks to its delivering characteristics that increase its diffusion in tumor tissues and reduce it in normal tissues. This feature allows NPLD to be safely administered beyond the standard doxorubicin maximum cumulative dose of 450–480 mg/m2. Following three pivotal first-line phase III trials in HER2-negative metastatic BC (MBC), this drug was finally approved in combination with cyclophosphamide in this specific setting. Given the increasing complexity of the therapeutic scenario of HER2-negative MBC, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms.

Ifosfamide, Carboplatin, and Etoposide (ICE) in Combination with Regional Hyperthermia as Salvage Therapy in Patients with Locally Advanced Nonmetastatic and Metastatic Soft-Tissue Sarcoma

Patients with localized relapse of soft-tissue sarcoma (STS) after anthracycline-based chemotherapy have a dismal prognosis, particularly when surgery is not possible. To facilitate resection and improve long-term tumor control, we applied an intensified perioperative treatment consisting of ICE (ifosfamide 6 g/m2, carboplatin 400 mg/m2, and etoposide 600 mg/m2) in combination with regional hyperthermia (RHT) to maximize local control. Here, we retrospectively evaluate the safety and efficacy of this strategy. Patients aged ≥18 years with locally advanced high-risk STS, either with or without metastasis, treated with ICE + RHT after the failure of first-line anthracycline-based chemotherapy were included in this analysis. Radiographic response, toxicity, progression-free survival (PFS), and overall survival (OS) were assessed. Between 1996 and 2018, 213 sarcoma patients received ICE at our centre. Of these, 110 patients met the selection criteria (progressive disease, suitable high-grade STS histology, anthracycline pretreatment, RHT treatment) for this analysis. Fifty-four patients had locally advanced disease without metastases (LA-STS), and 56 patients had additional metastatic disease (M-STS). Disease control was achieved in 59% of LA-STS patients and in 47% of M-STS patients. For LA-STS, 21% of the patients achieved radiographic response, facilitating resection in 4 patients (7%), compared with 11% of the M-STS patients, facilitating resection in 5 patients (9%). PFS was significantly longer in LA-STS than in M-STS (10 vs. 4 months, p < 0.0001). Median OS was 26 months in LA-STS and 12 months in M-STS. Disease control was the only independent prognostic factor for improved OS in multivariate analysis. Toxicity was high with neutropenic fever occurring in 25% of the patients and three therapy-related deaths (3%). ICE + RHT demonstrated activity in high-risk STS and facilitated resection in selected patients after anthracycline failure. Disease control was associated with improved OS. Based on the observed toxicities, the dose should be reduced to 75%.

NT-proBNP correlates with LVEF decline in HER2-positive breast cancer patients treated with trastuzumab

BackgroundEarly identification of cardiac dysfunction by non-invasive imaging in HER2-positive breast cancer patients treated with trastuzumab is challenging. In particular multigated acquisition (MUGA) scan, which is most widely used, is unable to detect subclinical cardiac changes. The use of N-terminal pro-brain natriuretic peptide (NT-proBNP), a serum biomarker of myocardial stress, might improve timely diagnosis.MethodsThis prospective, single-center, cohort study included patients with HER2-positive breast cancer who started trastuzumab therapy. Echocardiography was scheduled at regular intervals every 3 months during one year follow-up for cardiac function monitoring. For research purposes, NT-proBNP was determined at the same time points. Trastuzumab-induced cardiotoxicity (TIC) was the primary study endpoint, defined as a left ventricular ejection fraction (LVEF) < 45%, and/or an absolute decline in LVEF > 10% since inclusion, and/or the incidence of a clinical cardiac event.ResultsA total of 135 patients were enrolled between April 2008 and June 2016, with a median age of 54 years (IQR: 47–61). By three-dimensional echocardiography (3DE), the median LVEF at baseline was 62% (IQR: 58–65). At a median of 6 months (IQR: 5–11), 45 patients (33%) reached the study endpoint of TIC. Patients with TIC had a mean change of − 9.5% in LVEF (95% CI -7.2 to − 11.7; p = 0.001) during 1 year of trastuzumab treatment. Both NT-proBNP at baseline (HR 1.04, 95% CI 1.02–1.07; p = 0.003) and LVEF decline during anthracycline treatment prior to the start of trastuzumab (HR 1.16, 95% CI 1.07–1.25; p < 0.001) were independently associated with development of TIC. The level of NT-proBNP during follow-up was associated too with development of TIC (HR 1.06 per 10 pmol/l difference, 95% CI 1.02–1.10; p = 0.008). No steadily or sudden increase in NT-proBNP prior to TIC was observed.ConclusionsNT-proBNP cannot be used as a surrogate monitoring tool for trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients during the first year of treatment. Patients showing an LVEF decline during anthracycline pre-treatment appeared vulnerable for trastuzumab-induced cardiotoxicity.

Trastuzumab Single-Drug Therapy after Failure of Cytotoxic Treatment for Metastatic Breast Cancer

Background: Trastuzumab is an established component of breast cancer combination regimens, but data on the safety and efficacy of single-agent therapy is sparse. Patients and Methods: 70 patients with HER2-overexpressing breast cancer after failure of at least one chemotherapy regimen for metastatic disease were recruited from 28 institutions. HER2 overexpression was 3+ in 96% and 2+/FISH+ in 4%. Treatment consisted of a loading dose of 4 mg/kg trastuzumab in the first week and 2 mg/kg per week thereafter, continued until progression. Results: Trastuzumab treatment duration ranged from 1 to 66 weeks (median: 12). Objective responses (complete response (CR)/partial response (PR)) were seen in 12/62 fully evaluable patients (19%; 2 CR) while another 29% showed stabilization of the disease. Half of the patients had experienced progression after 13 weeks while median duration of response reached 44 weeks. Median survival was 68 weeks with nearly one-third of the patients still alive after more than 3 years. The most frequent adverse reaction was infusion-related syndrome arising during the first administration. Significant cardiovascular problems were detected in 3 cases, all with anthracycline pretreatment. Conclusions: Patients with metastatic breast cancer overexpressing HER2 may benefit from trastuzumab single-drug treatment, predominantly due to its favourable safety profile.

Incorporation of a Comprehensive Geriatric Assessment (CGA) into a randomized phase III trial for metastatic breast cancer: The PELICAN Study

9551 Background: The PELICAN trial is a randomized phase III trial evaluating efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line therapy in patients (pts) with metastatic breast cancer who are not considered candidates for combination chemotherapy. Randomisation was stratified according to age (cut-off 65 years) and anthracycline pretreatment. CGA results and adverse events (AEs), dose reductions, and number of applied cycles were evaluated. Methods: CGA comprised data on activities of daily living (ADL), instrumental activities of daily living (IADL), ECOG and Karnofsky performance score, comorbidity (CIRS-G), and number of comedication. According to CGA, pts were classified into groups 1–3 (Balducci 2000). Associations of CGA groups and single CGA items with outcome measures were assessed using Fisher's exact test, Wilcoxon test, and logistic regression. Results: Results of 210 pts, mean age 61 years (SD 11; range 22–85) were analysed. According to CGA, 102 pts were considered fit (group 1, 72%), 21 compromised (group 2, 15%), and 19 frail (group 3, 13%). Age was associated neither with overall AEs, nor with dose reductions or number of applied cycles. However, the following significant associations were observed: any AE and number of comedication (p=0.026); less hand foot syndrome (HFS) and CGA group 2/3 (p=0.032); and more constitutional symptomes and age &gt;=65 as well as CGA group 2/3 (p=0.002 and 0.015, respectively). Comedication was the variable most frequently associated with single AEs (dermatology other than HFS, p=0.038; gastrointestinal, p=0.035; constitutional symptomes, p=0.002; pain, p=0.001; pulmonary, p&lt;0.0001; fatigue, p=0.01). Whereas no association between any item and dose reduction was found, CIRS-G grade 3–4 was associated with a reduced number of applied cycles (p=0.049). Conclusions: Incorporation of CGA into a phase III trial is feasible and yields information that would otherwise have been missed. Results of CGA should be validated prospectively in treatment algorithms for this population. [Table: see text]

Combination chemotherapy with docetaxel and gemcitabine in anthracycline pretreated patients with metastatic breast cancer (MBC)

792 Background: There is a need for more effective 2nd line treatment options for MBC. Both docetaxel (D) and gemcitabine (G) have shown efficacy in MBC as single agents. Combination-chemotherapy, even in 2nd line, may have advantages over single agent therapy. Methods: This multicenter phase II study evaluated the efficacy and safety of D and G in patients with anthracycline pretreated MBC. Eligibility criteria included measurable disease, adequate performance status and organ- and hematological functions. Patients received i.v. G 1000 mg/m2 d1 and d8 and on day 8 immediately followed by D 75 mg/m2 every 3 weeks for 6 cycles up to a maximum of 9 cycles. Premedication for D consisted of oral dexamethason 16 mg for 3 days starting the day before D infusion. Response evaluation was performed every 3rd cycle. Results: 34/40 pts have been enrolled, 26 are evaluable for response and toxicity. Anthracycline pretreatment was given for adjuvant purposes (10/26) or for palliative purposes (16/26 patients). This la...

Open label, randomized, phase II study of pertuzumab (P) in patients (pts) with metastatic breast cancer (MBC) with low expression of HER2

3068 Background: P is the 1st of a new class of targeted therapeutics known as HER-dimerization inhibitors (HDI). It blocks ligand-associated heterodimerization of HER2 with other HER kinase family members, thereby inhibiting intracellular signaling. Preclinical activity of P in breast cancer has been shown to be independent of the HER2 expression level. In this study the primary endpoint was response rate according to RECIST. Secondary endpoints were: rate of stable disease (SD), toxicity profile, pharmacokinetics (PK). Methods: 79 pts in total were randomized to receive P every 3 weeks as an IV infusion either at 420 mg with a loading dose of 840 mg (arm A) or at 1050 mg (arm B). Selection criteria were: progressing MBC with low HER2 expression, anthracycline pretreatment, ≤ 2 chemotherapy regimens for MBC and LVEF ≥ 50%. Results: Out of 79 recruited pts, 78 were included in the intent to treat population. In arm A 2 partial responses (PR) and 18 SD were observed in 41 pts. In arm B 14 SD were observed in 37 pts. Overall, 6 out of 78 pts responded or had SD for > 6 months. Most frequent adverse events were: diarrhea grade (G) 1 & 2 51%, G3 8%, fatigue G 1 & 2 35%, G3 2%, nausea G 1 & 2 31%, G3 1% and vomiting G 1 & 2 23%, G3 4%. Drops in LVEF of ≥10% and to below 50% were observed in 3 pts (1 case of congestive heart failure) in arm A & 3 pts in arm B. PK data supports a fixed dose of P administered every 3 weeks. Conclusions: No obvious relationship between dose and activity or toxicity was observed. The monoclonal antibody P administered IV every 3 weeks is safe and well tolerated but there is evidence of limited activity in this BC study. A combination (either chemo or hormonal) or patient selection strategy may be investigated in the future. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, Nordic, Roche Genentech, Roche Aventis, Lilly Oncology, Pierre Fabre, Roche Roche

Combination chemotherapy with docetaxel and gemcitabine in anthracycline pretreated patients with metastatic breast cancer (MBC)

792 Background: There is a need for more effective 2nd line treatment options for MBC. Both docetaxel (D) and gemcitabine (G) have shown efficacy in MBC as single agents. Combination-chemotherapy, even in 2nd line, may have advantages over single agent therapy. Methods: This multicenter phase II study evaluated the efficacy and safety of D and G in patients with anthracycline pretreated MBC. Eligibility criteria included measurable disease, adequate performance status and organ- and hematological functions. Patients received i.v. G 1000 mg/m2 d1 and d8 and on day 8 immediately followed by D 75 mg/m2 every 3 weeks for 6 cycles up to a maximum of 9 cycles. Premedication for D consisted of oral dexamethason 16 mg for 3 days starting the day before D infusion. Response evaluation was performed every 3rd cycle. Results: 34/40 pts have been enrolled, 26 are evaluable for response and toxicity. Anthracycline pretreatment was given for adjuvant purposes (10/26) or for palliative purposes (16/26 patients). This last group received 2nd line palliative chemotherapy. 21/26 Received at least 6 cycles, treatment was discontinued prior to 6 cycles due to progressive disease (PD) in 3/26. Two complete responses and 14 partial responses were observed, leading to an overall response rate of 61% (16/26). Stable disease was observed in 7 patients and 3 patients had PD. The mean response duration was 6.1 months. Mean time to progression was 7.7 months. Hematological toxicity was modest with grade 3–4 (NCI-CTC) leucopenia in 23/184 cycles, febrile leucopenia (grade 3) in 1/184 cycles and grade 3–4 thrombocytopenia in 2/184 cycles. Non-hematological toxicity(grade 3/4): edema 2/184 and diarrhea 1/184 cycles. Conclusions: Combination chemotherapy with gemcitabine 1000 mg/m2 d1 and d8 and docetaxel 75 mg/m2 on d 8 is feasible in anthracycline pretreated MBC and shows promising efficacy. No significant financial relationships to disclose.

Myocardial expression of HER2 and HER4 in anthracycline-pretreated breast cancer patients

652 Background: Therapeutic benefits of the powerful combination of Trastuzumab and anthracyclines in the management of HER2-overexpressing metastatic breast cancer are limited by a dramatic increase in cardiac side effects. Many data indicate an important role of HER2 and its preferred cardiac heterodimerisation partner HER4 in mediating essential myocytes survival pathways. Gene targeting of either receptor leads to cardiomyocyte apoptosis and cardiomyopathy. An interaction between Trastuzumab and HER2/HER4 mediated signaling might therefore contribute to the cardiotoxic side effects. We therefore have examined possible changes in the protein expression levels of HER2 and HER4 after anthracycline treatment. Methods: We examined HER2 and HER4 protein expression as well as HER2 gene amplification in 35 cardiac specimens obtained from autopsy material of breast cancer patients with a history of anthracycline treatment. The mean cumulative Epirubicin dose was 662 mg. In addition 10 patients with anthracycline- free pretreatment were assessed. Three of them had received immunotherapy with Trastuzumab. HER2 and HER4 expression were analyzed immunohistochemically using the HercepTest (DAKO) and the polyclonal antibody c-18 (SantaCruz) respectively. Copy numbers of the HER2 gene were determined by fluorescence in situ hybridisation (Inform-Kit Ventana). Results: In the 54 cardiac biopsies with and without anthracycline pretreatment no HER2 staining could be detected. In addition, no HER2 gene amplification was observed in all specimens. A HER4 expression could be detected in 13 of the 25 anthracycline pretreated specimens witch was not significantly different from the cases without anthracycline history (6/10). No relation of HER4 expression with the cumulative anthracycline dose could be noticed. Conclusions: This study shows that an anthracycline treatment does not result in changes of the HER2 or HER4 expression levels nor in amplification of the HER2 gene in the myocardium as suspected to probably underlie the onset of heart failure in anthracycline pretreated patients receiving Trastzumab therapy. No significant financial relationships to disclose.

Treatment of Anthracycline-Resistant Breast Cancer

The anthracyclines are commonly used for the treatment of early stage and advanced stage breast cancer, but many patients develop resistance to therapy. The definition of anthracycline resistance varies considerably in the literature, but in most cases includes disease progression during or within 6–12 months after completion of anthracycline therapy. Some authors have distinguished true anthracycline resistance (defined as progression during anthracycline therapy) from anthracycline pretreatment (defined as progression after completion of therapy).

Docetaxel in Patients with Anthracycline-Resistant Advanced Breast Cancer

Objective: To better determine docetaxel activity in patients with well-defined anthracycline-resistant breast cancer. Methods: From October 1996, we carried out a phase II trial in 69 heavily pretreated patients with advanced breast cancer with docetaxel 100 mg/m² by a 1-hour infusion on day 1, with cycles repeated every 3 weeks. Patients were classified as having primary anthracycline resistance (n = 32), secondary anthracycline resistance (n = 7), anthracycline pretreatment (n = 22) or no anthracycline pretreatment (n = 8). Results: Among 68 evaluable patients, we observed 6 (9%) complete responses and 27 (40%) partial responses, for an overall response rate of 49% (95% confidence interval 37–61%); the disease remained stable in 17 patients (25%). Responses according to the above subgroups were as follows: primary anthracycline resistance 41%, secondary anthracycline resistance 43%, anthracycline pretreatment 64% and no anthracycline pretreatment 43%. The median time to response, median time to progression and median overall survival were 2, 7 and 10 months, respectively. Myelosuppression was the dose-limiting toxicity, with grade 4 neutropenia occurring in 47% of the patients and neutropenic fever in 12%. G-CSF was added in the case of grade 4 febrile neutropenia; a 25% reduction in the dose of docetaxel was required in 4 patients. Other side effects were mild. Conclusions: The results of the present trial confirm the high activity of docetaxel in heavily pretreated patients with advanced breast cancer, including those with strictly defined anthracycline resistance.