Non-pegylated Liposomal Doxorubicin Research Articles

New approaches in the management of advanced breast cancer – role of combination treatment with liposomal doxorubicin

Metastatic breast cancer (MBC) remains a major cause of morbidity and mortality in women worldwide. For three decades doxorubicin, alone or in combination with other cytotoxic agents, has been a mainstay of systemic therapy for MBC. However, its use is limited by cumulative cardiotoxicity. More recently liposomal formulations of doxorubicin have been developed which exhibit equal efficacy but reduced cardiotoxicity in comparison to conventional doxorubicin. The novel toxicity profile of liposomal doxorubicins has prompted their evaluation with various cytotoxic agents in patients with MBC. In addition, their favorable cardiac safety profile has prompted re-evaluation of concomitant therapy with doxorubicin and trastuzumab, a regimen of proven efficacy in MBC but previously considered to be associated with significant cardiotoxicity. We review clinical trial data addressing combination therapy with both pegylated and non-pegylated liposomal doxorubicin in patients with MBC.

Nonpegylated liposomal doxorubicin is highly active in patients with B and T/NK cell lymphomas with cardiac comorbidity or higher age

We used nonpegylated liposomal doxorubicin (NPLD) in cytostatic drug combinations to treat 37 patients with non-Hodgkin's lymphoma and pre-existing cardiac disorder or elderly patients with reduced physical state who were ineligible for conventional anthracycline-containing therapy. High remission rates were observed in this poor-risk population: Complete remission rates were 75% for diffuse large B cell lymphoma (DLBCL) and 55% for T/NK cell neoplasm (overall response rate of 80% and 89%, respectively). Twenty-seven patients (73%) are still alive after a median observation time of 14 months. No major cardiac or gastrointestinal toxicity was observed. Extravasation of NPLD in two patients resulted in mild inflammation without tissue damage. Hematologic toxicity was comparable to that of conventional anthracycline-containing regimens. We conclude that NPLD is highly active in combination chemotherapy for lymphoma with low cardiac toxicity in patients with pre-existing cardiac disorders or higher age. Moreover, we also observed remarkable efficacy in T/NK cell lymphomas.

Phase I study of non-pegylated liposomal doxorubicin in combination with ifosfamide in adult patients with metastatic soft tissue sarcomas

The aim of this study was to evaluate the maximum tolerated dose (MTD) and safety of the combination of non- pegylated liposomal doxorubicin (Myocet) and ifosfamide in patients with metastatic soft tissue sarcomas. Cohorts of four patients with metastatic soft tissue sarcomas received up to five cycles of intravenous ifosfamide 3000 mg/m2 on days 1- 3 in combination with escalating doses of intravenous Myocet on day 1 every 3 weeks until dose limiting toxicity (DLT) in at least one patient. Starting dose of Myocet was 40 mg/m2 to be escalated through 10 mg/m2 increase up to 80 mg/m2. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria v3.0 (NCI-CTC v3.0). Ten patients were enrolled in the study and 8 of them received the treatment. Median age was 45 years, 3 patients were male and 5 were female. DLT, consisting of neutropenic fever, was reached in one patient at dose level 2 (Myocet 50 mg/m2). Therefore, the MTD and the recommended phase II dose is 40 mg/m2. The combination of intravenous Myocet 40 mg/m2 on day 1 and ifosfamide 3,000 mg/m2 on days 1-3 every 3 weeks is safe and feasible; a phase II study is ongoing.

Non-Pegylated Liposomal Doxorubicin in Combination with Cyclophosphamide or Docetaxel as First-Line Therapy in Metastatic Breast Cancer: A Retrospective Analysis

Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer. Unfortunately, the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure. In order to limit anthracycline-related cardiotoxicity, liposomal formulations of doxorubicin have been developed. This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer. Patients received non-pegylated liposomal doxorubicin in combination with either cyclophosphamide (n = 14) or docetaxel (n = 20) for up to eight cycles, and efficacy and safety were assessed according to standard criteria. The overall response rate was 71%. The median progression-free survival was 8 months in patients receiving non-pegylated liposomal doxorubicin plus cyclophosphamide and 13.8 months in those receiving non-pegylated liposomal doxorubicin plus docetaxel (P = 0.2). The most commonly observed toxicities were grade 1-2 leucopenia, alopecia, nausea and vomiting; no grade 3-4 toxicities were observed. Overall, three patients (9%) experienced grade 1 cardiac toxicity. Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer.

A multicenter randomized phase II study of nonpegylated liposomal doxorubicin plus vinorelbine versus nonpegylated liposomal doxorubicin plus cyclophosphamide as first line in locally advanced breast cancer (LABC) or metastatic breast cancer (MBC): Safety results

1116 Background: We conducted a multicenter randomized phase II trial to assess activity and tolerability of the combination of nonpegylated liposomal doxorubicin plus vinorelbine versus standard nonpegylated liposomal doxorubicin plus cyclophosphamide. Methods: This multicenter randomized phase II study was planned to enrol 140 patients (pts). Elegibile pts must have LABC or MBC, PS (ECOG) ≤ 2, and measurable disease. Adjuvant or neoadjuvant chemotherapy with anthracyclines was allowed as well as prior endocrine therapy. Pts assigned to arm A received nonpegylated liposomal doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1 of a 21-day cycle. Pts assigned to arm B received nonpegylated liposomal doxorubicin 50 mg/m2 plus vinorelbine 25 mg/m2 iv on day 1, and 60 mg/m2 on day 8 po, every 3 weeks. The primary outcome measure was response rate (RR), whereas safety was one of the secondary endpoints. Results: Between July 2006 and July 2008 110 women were treated; for 80 of these, safety results are available. Patient characteristics: Arm A pts (N=41): median age, 59 (range 37–69); ER status ±/unk, 26/15/0; Her-2 status ±/unk, 5/34/2; PS 0/1/2, 26/14/1; prior adjuvant treatment with anthracyclines 10 pts (24%); dominant site of disease visceral 31 pts (76%). Arm B pts (N=39): median age, 61 (range 25–70); Er status ±/unk, 29/10/0; Her-2 status ±/unk, 3/35/1; prior adjuvant treatment with anthracyclines 14 pts (36%); dominant site of disease visceral in 28 pts (72%). There was no study discontinuation due to AE either in arm A or in arm B, nor study-related deaths. Conclusions: The combination regimen of nonpegylated liposomal doxorubicin plus vinorelbine appears to be associated with a slight increase of hematological and nonhematological toxicity when compared with nonpegylated liposomal doxorubicin plus cyclophosphamide. No increase in cardiotoxicity was seen. The trial is ongoing and we plan to give preliminary efficacy results at the time of the Meeting. [Table: see text] No significant financial relationships to disclose.

Phase I Study of Nonpegylated Liposomal Doxorubicin plus Trastuzumab in Patients with HER2-Positive Breast Cancer

Background This was an open-label, nonrandomized, multicenter, 2-stage phase I trial of safety and preliminary efficacy of nonpegylated liposomal doxorubicin (NLD) in combination with trastuzumab in advanced breast cancer, with emphasis on cardiac toxicity. Patients and Methods Forty patients (median age, 48 years; range, 30–74 years) with HER2/ neu 2+ or 3+ tumors (by immunohistochemistry) were recruited December 1999 to November 2002. Patients were eligible if they received ≤ 1 previous trastuzumab regimen, ≤ 2 cytotoxic regimens for advanced breast cancer, and lifetime cumulative anthracycline doses ≤ 240 mg/m 2. The study regimen comprised NLD 60 mg/m 2 every 3 weeks and trastuzumab loading dose 4 mg/kg followed by 2 mg/kg weekly. Treatment cycles lasted 21 days. Clinical cardiac assessments were performed with multigated acquisition scans every 2 cycles. Patients were evaluated for cardiac toxicity after receiving ≥ 1 cycle. Cardiac safety was assessed after completing ≥ 4 full treatment cycles. Results Thirty out of 40 patients (75%) received ≥ 4 treatment cycles and were evaluable for cardiac safety. Five patients (13%), 4 who were doxorubicin pretreated, developed left ventricular ejection fraction reductions to < 50%, and 2 (5%) of these patients experienced clinical cardiac toxicity. Fifty percent of the patients had objective tumor responses; median progression-free survival was approximately 21 weeks. Twenty-six patients (65%) had grade 3/4 neutropenia; 2 patients experienced febrile neutropenia. Conclusion Nonpegylated liposomal doxorubicin plus trastuzumab is active in HER2-positive patients with advanced breast cancer and is associated with a lower risk of cardiac toxicity than conventional doxorubicin plus trastuzumab.

Nonpegylated liposomal doxorubicin in the treatment of B-cell non-Hodgkin’s lymphoma: where we stand

Anthracyclines, including doxorubicin, are widely used in the treatment of B-cell non-Hodgkin’s lymphoma (NHL). However, their clinical potential is limited by their cardiotoxic adverse effects, which include cardiomyopathy and congestive heart failure. Anthracycline-induced cardiotoxicity is cumulative and irreversible. Liposomal doxorubicin has been developed with the aim of improving the therapeutic index of doxorubicin by reducing the drug’s cardiotoxicity. Nevertheless, liposomal conjugation of doxorubicin results in preferential distribution of the drug in the tumor compared with normal tissue, maintaining its anti-tumor efficacy. Nonpegylated liposomal doxorubicin produced a promising response rate when substituted for conventional doxorubicin in the cyclophosphamide, doxorubicin, vincristine and prednisolone regimen in the treatment of patients with NHL either at diagnosis or at relapse. The ability of nonpegylated liposomal doxorubicin to overcome excessive drug efflux due to P-glycoprotein (MDR-1) overexpression in NHL might confer on this drug a curative potential for patients with a bad prognosis (e.g., MDR-1 overexpressing, the elderly or frail).

A multicenter phase II study of non-pegylated liposomal doxorubicin (MYOCET®) in combination with trastuzumab and docetaxel as first line therapy in metastatic breast cancer.

Abstract Abstract #3156 The objective of the phase II study is to evaluate the cardiotoxicity, general safety, and efficacy of non-pegylated liposomal doxorubicin, in combination with docetaxel and trastuzumab, as first line treatment of metastatic breast cancer.&amp;#x2028; Patients and methods: Patients (n = 31) with metastatic HER2-overexpressing breast cancer, who had not previously received chemotherapy for metastatic disease, received non-pegylated liposomal doxorubicin (50 mg/m2), docetaxel (75 mg/m2) every 3 weeks and trastuzumab (2 mg/kg/week) for up to eight cycles, followed by trastuzumab alone for up to 52 weeks. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure (CHF) and/or an absolute decrease in left ventricular ejection fraction (LVEF) of ≥ 20 units or a decline to ≤ 45%. Patients were allowed to receive adjuvant doxorubicin or epirubicin to cumulative doses up to 240 mg/m2 or 450 mg/m2, respectively.&amp;#x2028; Results: The mean LVEF at baseline was 62.8 ± 7.1% and decreased to 60.2 ± 6.5% at cycle 2, but did not change significantly during the rest of the study; mean values at cycle 8 and at the end of the study were 58.7 ± 7.0% and 57.3 ± 9.5% respectively. One case of symptomatic CHF occurred during the study.&amp;#x2028; The most common adverse events were hematologic toxicities, alopecia, asthenia and fever. The Overall Response Rate was 65.5% (CR 31%, PR 34.5%).The median progression free survival was 15.5 months (95% CI 11-24 months). The average overall survival was 27.9 months.Conclusions: These results suggest that the combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab has shown a good cardiac safety profile at a long term follow up, comparatively to recent published results data in HET study. A promising efficacy including CR and PFS has been noted in 1st line MBC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3156.

Phase II study of liposomal doxorubicin (Myocet®), docetaxel and trastuzumab combination as first line treatment of patients with her-2/neu positive locally advanced or metastatic breast cancer.

Abstract Abstract #3149 Objective: the aims of the study are to assess activity and safety of liposomal doxorubicin (Myocet®) in combination with Docetaxel and Trastuzumab as first-line treatment of patients with HER-2/neu positive MBC.&amp;#x2028; Methods: forty-six (46) non treated patients with metastatic HER2-overexpressing BC were planned to receive Myocet 50 mg/m2 (d1) and Docetaxel 30 mg/m2 (d2 and d9) plus Trastuzumab (d2, 4 mg/kg followed by 2 mg/kg weekly) for at least 6 cycles (up to a maximum of 8 unless occurrence of unacceptable toxicity or PD). Cycles were repeated every 21 days. Objective response was assessed according to WHO criteria every 3 cycles. To evaluate the tolerability WHO grading toxicity events were assessed at each cycle. Cardiotoxicity was defined as signs and/or symptoms of CHF and/or a decrease in LVEF below normal limit (&amp;lt; 50%) or a decline ≥ 15% from baseline value. To evaluate LVEF an echocardiography was done at baseline and at cycles 3, 6 and 8.&amp;#x2028; Results: we reported preliminary results of 46 patients enrolled. 41 patients completed at least 3 cycles and at first response evaluation Complete Response was seen in 2 pts (CR=4,9%), Partial Response in 22 pts (PR=53,7%), Stable Disease in 15 pts (SD=36,6%) and Progression Disease in 2 pts (PD=4,9%). The Overall Response Rate (ORR) was 58,6%.&amp;#x2028; 36 pts completed the planned chemotherapy (6 cycles): Complete Response was seen in 4 pts (CR=11,1%), Partial Response in 15 pts (PR=41,7%), Stable Disease in 9 (SD=25,0%) and Progression Disease in 8 pts (PD=22,2%). The Overall Response Rate (ORR) was 52,8%. 12 pts were entered in the follow up and for this subgroup median TTP was 13 months.&amp;#x2028; All 46 enrolled patients were included in the safety analysis. Most frequent toxicity events occurred during the study were: granulocytopenia Grade 4 in 16 pts (30.4%), leukocytopenia Grade 3 in 15 pts (32.6%), increase of transaminase levels Grade 1 in 14 pts (30.4%), alopecia Grade 4 in 16 pts (34.8%) and nausea Grade 2 in 13 pts (28.3%). In 2 patients LVEF dropped &amp;lt; 50% and other 2 pts registered a decrease of LVEF &amp;gt;15% with respect to baseline value. In the whole population LVEF mean value changed from 62.6 ± 4.9 at baseline to 61.0 ± 5.5 at cycle 3, to 62.9 ± 6.4 (cycle 6) and to 60.0 ± 8.1 (cycle 8).&amp;#x2028; Conclusion: these preliminary results suggest that the combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab has shown a promising activity in first line MBC. The combination is safe with no significant change in LVEF values from baseline to the end of therapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3149.

Nonpegylated Liposomal Doxorubicin (TLC-D99), Paclitaxel, and Trastuzumab in HER-2-Overexpressing Breast Cancer: A Multicenter Phase I/II Study

To determine the recommended dose, cardiac safety, and antitumor activity of nonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and the anti-HER-2 monoclonal antibody trastuzumab in patients with HER-2-overexpressing locally advanced nonoperable breast cancer (LABC) and metastatic breast cancer (MBC). Women with measurable, previously untreated, HER-2-overexpressing LABC and MBC with a baseline left ventricular ejection fraction (LVEF) >50% received weekly trastuzumab in combination with escalating doses of weekly paclitaxel and TLC-D99 every 3 weeks for 6 cycles. LVEF monitoring was done every 3 weeks for the first 18 weeks and every 8 weeks thereafter. Sixty-nine patients participated, 15 in the dose escalating part and 54 at the recommended phase II dose (28 patients with LABC and 26 patients with MBC). The recommended doses of TLC-D99 and paclitaxel were 50 mg/m(2) every 3 weeks and 80 mg/m(2)/wk, respectively. Twelve (17%) patients developed asymptomatic declines in LVEF. In 8 of these patients, LVEF recovered to >or=50% after a median time of 9 weeks (range, 3-38 weeks). In the rest of patients, LVEF ranged from 44% to 49%. No patients developed symptomatic cardiac heart failure. The overall response rate was 98.1% (95% confidence interval, 90.1-99.9) with a median time to progression not reached in LABC and of 22.1 months (95% confidence interval, 16.4-46.3) in MBC patients. Nonpegylated doxorubicin, paclitaxel, and trastuzumab combination is safe, does not result in clinically manifest cardiac toxicity, and has a high rate of durable responses in HER-2-overexpressing breast cancer patients. Further exploration of this combination is warranted.

Non-pegylated liposomal doxorubicin and docetaxel in metastatic breast cancer: final results of a phase II trial

Non-pegylated liposomal doxorubicin (NPLD) has demonstrated equivalent antitumor activity to conventional doxorubicin and a significantly lower risk of cardiotoxicity when given as single agent or in combination with cyclophosphamide, but there is limited experience with the combination of NPLD and taxanes. This phase II study was performed to evaluate the efficacy and safety of the NPLD and docetaxel in patients with metastatic breast cancer. A total of 51 patients were treated with NPLD (60 mg/m(2)) and docetaxel (75 mg/m(2)) in 3-weeks intervals for up to eight cycles. The overall response rate was 50% and 78% of patients derived a clinical benefit. Median time to progression and overall survival were 10.0 months (95% CI, 6.9-13.1 months) and 25 months (95% CI, 22.1-29.8 months), respectively. Median duration of response was 12.0 months (95% CI 7.1-16.9). The treatment was generally well tolerated and associated with toxicities that were consistent with the known side-effects of the individual agents and of anthracycline/taxane combinations. There were no symptomatic cardiac averse events and mild asymptomatic LVEF changes were reported in five patients. The combination of NPLD and docetaxel is well tolerated and has high antitumour activity in MBC patients.

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancer

Anthracyclines, including doxorubicin, are the mainstay of therapy for breast cancer. However, doxorubicin can cause dose-dependent cardiotoxicity, limiting the cumulative dose. Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues. Nonpegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity, with anti-tumor responses comparable to those of conventional doxorubicin. The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity, while allowing a higher cumulative dose. This allows patients who have already received the maximum cumulative dose of doxorubicin to receive further doxorubicin, as well as those with risk factors for anthracycline-induced cardiotoxicity. The favorable cardiac safety profile of NPLD may allow it to be combined with newer therapies, such as trastuzumab.

Interest of liposomal doxorubicin as a radiosensitizer in malignant glioma xenografts

Malignant glioma patients have a life expectancy reduced to about 15 months despite aggressive surgery, radiotherapy (RT), and chemotherapy. Doxorubicin has shown a marked cytotoxic effect against malignant glioma cells in vitro. The brain exposure to this drug is, however, hindered by the blood-brain barrier. Encapsulation of doxorubicin in liposomal carriers has been shown to reduce toxicities and to improve brain tumors exposure to doxorubicin. In this study, we evaluated the radiosensitizing properties of a nonpegylated liposomal doxorubicin (Myocet, MYO) on two subcutaneous (U87 and TCG4) and one intracranial (U87) malignant glioma models xenografted on nude mice. Doxorubicin biodistribution was assessed by a high-performance liquid chromatography method. Antitumor efficacy was investigated by tumor volume measurements and mice survival determination. We showed that (i) encapsulation of doxorubicin ensured a preferential deposition of doxorubicin in tumoral tissue in comparison with free doxorubicin; (ii) doxorubicin accumulated in both subcutaneous and intracranial tumors during repeated injections of MYO and this accumulation was linked to the potentiation of RT efficacy on two subcutaneous models; (iii) MYO was unable to improve the antitumoral efficacy of RT on an intracranial glioma model. Finally, this study emphasizes the importance of performing preclinical studies on models closer as possible of human tumors and localization to be more predictive of therapeutic effects observed in humans.

Non-pegylated liposomal doxorubicin combined with gemcitabine as first-line treatment for metastatic or locally advanced breast cancer. Final results of a phase I/II trial

Doxorubicin and gemcitabine are active as single agents in breast cancer, have different mechanisms of action, and mainly have non-overlapping side effects. Dose-dependent doxorubicin-related cardiac toxicity is the principal limitation in the metastatic setting. This open, multicenter, single-arm phase I/II study assessed the safety and activity of gemcitabine in combination with non-pegylated liposomal doxorubicin (Myocet), a more cardiac-friendly anthracycline, in the first-line treatment of patients with advanced breast cancer. We aimed to determine the optimal recommended dose (RD) of gemcitabine combined with Myocet in a population, with performance status >or=2 and LVEF >or=50%. A formal phase II study was performed afterwards. A total of 53 patients were recruited. Gemcitabine 900 mg/m(2) intravenously day 1 and 8 combined with Myocet 55 mg/m(2) intravenously day 1, every 21 days, was the final RD. The principal toxicity observed was hematological, and 48% of patients developed grade 3-4 neutropenia. Other toxicities were mild and infrequent, including nausea and vomiting. There were no symptomatic cardiac events despite the fact that 36% of the patients had received prior treatment with adjuvant anthracyclines. Objective responses were observed in 51.1% of 47 evaluable patients (95% CI: 36-66%), including two complete response. In addition, 14 patients (29.8%) demonstrated stable disease. The combination of Myocet and gemcitabine at the RD is safe and has encouraging clinical activity in patients with advanced breast cancer, without apparent cardiac toxicity in anthracycline-pretreated patients. These data support further development of this combination.

Evaluation of clinical cardiotoxicity of nonpegylated liposomal doxorubicin in the treatment of patients with metastatic breast cancer (MBC) who had received prior adjuvant anthracyclines

1132 Background: The cumulative use of anthracyclines in MBC is often limited by cardiomyopathy and the risk of developing congestive heart failure (CHF). Nonpegylated liposomal doxorubicin (M) was designed to reduce the risk of cardiotoxicity associated with doxorubicin while preserving its antitumor efficacy. This analysis ascertains, on a daily basis, the cardiotoxicity of M in pts with MBC previously treated with anthracyclines. Methods: To participate in this retrospective analysis, pts were required to have an ECOG PS 0–2, an adequate organ function and a basal left ventricular ejection fraction (LVEF) > 50%, which was repeated at least once while on therapy with M. A cardiac event was defined as TYPE A in case of signs and/or symptoms consistent with CHF plus grade 3/4 LVEF decline. TYPE B cardiac events implied asymptomatic LVEF decline, defined as an absolute drop ≥10% resulting in a final LVEF 20%, or LVEF < 40%. A maximum dose of 600 mg/m2 of M was permitted. Previous ...

R-COMP 21 for frail elderly patients with aggressive B-cell non-Hodgkin lymphoma: A pilot study

We evaluated the toxicity and efficacy of nonpegylated liposomal doxorubicin (Myocet®) when substituted for conventional doxorubicin in the CHOP-21 regimen in the treatment of frail elderly patients with aggressive non-Hodgkin lymphoma. Twenty frail patients (median age, 73 years), as defined by Balducci et al., with diffuse large B cell or grade IIIb follicular lymphoma, either at diagnosis (15 patients) or relapsed (five patients), were prospectively enrolled. Nine out of 20 (45%) had a World Health Organisation (WHO) performance status ≥2. Fifteen out of 20 patients (75%) had an International Prognostic Index (IPI) score ≥3. Thirteen out of 20 (65%) evaluable patients obtained a complete response. Five additional patients (25%) achieved a partial response. With a median follow-up of 24 months (range 18–27), 15/18 responding patients (83%) are alive and disease free, as well as 3/18 are alive with active disease. Toxicity was mainly hematological with grade 3/4 neutropenia in 26% of cycles and febrile neutropenia in 5%. However, 3/20 patients presented a grade III–IV WHO toxicity (one fatal pulmonary embolism, one congestive, and one ischemic heart failure) while receiving R-COMP chemotherapy. In conclusion, R-COMP-21 is an effective regimen with promising response rates for frail and elderly patients with aggressive non-Hodgkin lymphoma.

Reduced Dose of Non-Pegylated Liposomal Doxorrubicin with Cyclophosphamide, Vincristine and Prednisone ± Rituximab for Elderly Patients with Aggressive Lymphoma Non Candidates to Standard Chemotherapy.

BACKGROUND: CHOP± Rituximab regimen is the standard regimen for elderly patients with aggressive lymphoma. However, many of these patients present formal contraindication for this type of treatment due to severe associated comorbidities. The aim of the study is to retrospectively evaluate the safety and clinical profile of a modified CHOP (with low dose non-pegylated liposomal doxorrubicin) ± Rituximab in elderly patients with clinically aggressive lymphoma which are not tributary to standard chemotherapy.PATIENTS AND METHODS. Retrospective analysis of 15 consecutively patients (pts) with previously untreated aggressive lymphoma. Gender: 9 men/6 women; median age: 76 years (62–85y). 6 pts had stage I–II (IPI=1–2) and 9 pts stage IV (IPI=2–5). Median baseline left ventricular ejection fraction (LVEF) was 60.2% (31–80%). Comorbidities: active chronic liver disease (1 pt), severe chronic obstructive pulmonary disease (3 pts), severe cardiomiopathy (4 pts) and others (7 pts). Schedule: non pegylated liposomal doxorubicin 30 mg/m2, cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, prednisone 100 mg/d d1-5 ± rituximab 375mg/m2 d1) every 21 days, as a first line therapy. Pegfilgrastim was used on day 2 at standard dose.RESULTS. Nine pts are evaluable for efficacy at the time of this report (2 pts died early due to infectious complications and are not evaluable for response). Median number of cycles was 4 (range 4–6). Total number of cycles administered was 43. A complete response (CR) was achieved in 8 pts (88.8%) and partial response in 1 pt (11.1%) after chemotherapy. CR was achieved in this last patient after involved field radiotherapy. Two pts have relapsed during follow-up, all dying with active disease. OS at 12 months: 70% (CI95%: 42–98%) and PFS at 12 months: 60% (CI95%: 30–90%), with a median time of follow-up for surviving pts of 18 months (4–35 m). Treatment was well tolerated with grade III–IV neutropenia was 39.5% with 14% episodes of febrile neutropenia. No other relevant toxicities were observed. Of note, median LVEF was not significantly different between before and after treatment with one patient showing a clinical significant improve in his LVEF.CONCLUSION. This preliminary data indicate that low dose non-pegylated liposomal doxorubicin in modified CHOP regimen was active and well tolerated in patients with formal contraindications to standard therapy due to severe comorbidities. Further exploration of this regimen administered every 14 days is warranted.

R-COMP 21 (Prednisone, Cyclophosphamide, Vincristine, Myocettm and Rituximab) for Frail and Elderly Patients with Aggressive B-Cell Non-Hodgkin Lymphoma: A Pilot Study.

CHOP chemotherapy is the gold standard treatment for patients with indolent and aggressive non-Hodgkin Lymphomas. However, CHOP is frequently poorly tolerated by frail and elderly patients resulting in dose reductions and consequently lower response and cure rates compared to younger patients. The toxicity and efficacy of nonpegylated liposomal doxorubicin (Myocet™) when substituted for conventional doxorubicin in the CHOP 21 regimen (Doxorubicin, Cyclophosphamide, Vincristine, Prednisone given every 3 weeks) were evaluated in the treatment of frail elderly patients with aggressive non-Hodgkin's lymphoma. Twenty patients (median age: 73 years, range 61–82) with diffuse large B cell non-Hodgkin lymphoma, either at diagnosis (15 patients) or relapsing (5 patients), were enrolled in the study. At baseline 14/20 (72%) patients had stage III–IV disease. All patients had one or more comorbidity. Eighteen out of 20 patients (90%) had an intermediate or high risk International Prognostic Index score. The median left ventricular ejection fraction (LVEF) before starting chemotherapy was 62% (range 43–73). A total of 111 chemotherapy cycles were administered, with a median of 6 cycles (range 1–8). Of the cycles administered, 19 (17%) were delayed by haematological toxicity. The relative dose intensity for the regimen was 83%. Toxicity was mainly haematological with grade 3 or 4 neutropenia in 16% of cycles and febrile neutropenia in 5%. However, 3/20 patients presented a grade III–IV WHO toxicity (one fatal pulmonary embolism, one congestive heart failure, one ischemic heart failure) while receiving R-COMP chemotherapy. All but one patient were evaluable for response. 13 out of 19 (68%) had a complete response and an additional 5 patients (26%) achieved a partial response. Of the evaluable patients, only 1/19 (5%) did not respond at all to chemotherapy and rapidly died due to progressive disease. With a median follow-up of 14 months (range 7–18) as of July 2007, 15/18 responding patients (83%) are alive and disease free, as well as 3/18 are alive with active disease. In conclusion, the R-COMP 21 is a very effective regimen with promising response rates in frail and elderly patients with high risk aggressive non-Hodgkin lymphoma. Further studies with a larger cohort of patients are warranted to better define the impact of non pegylated liposomal doxorubicin on overall survival of this setting of elderly and particularly frail patients.

Biweekly nonpegylated liposomal doxorubicin (M) and docetaxel (T) as neoadjuvant treatment in patients with stage II-III breast cancer

11049 Background: We have previously reported (ASCO 2006) the efficacy and toxicity of 4 courses of M (75mg/m2) and T (75mg/m2) with G-CSF support in a 21 day schedule as neoadjuvant treatment in patients with resectable breast cancer. Aim: To evaluate the clinical and pathological response rate (RR) and toxicity of biweekly M and T given prior to surgery in patients with breast cancer. Methods: Patients with histological confirmation of breast cancer (stage II-III and inflammatory), age &gt;18 years, left ventricular ejection fraction &gt; 45% and adequate bone marrow, renal and hepatic function were included in the study. Prior systemic therapy, radiotherapy or surgery for breast cancer were not allowed. The treatment was: M (60 mg/m2) and T (60mg/m2) each in 1 hour infusion, with subcutaneous G-CSF (5 mcg/kg) support on days 4–9. Courses were repeated every 14 days. Patients received 6 courses prior to surgery. Results: To date 45 patients have been enrolled; 20 who have completed therapy and underwent surgery (except for patients with progression) were included in this interim analysis. Median age: 48 years (38–63), ECOG PS 0: 90%, ECOG PS1: 10%, postmenopausal: 35%. Histology was infiltrating ductal carcinoma in 80%. Patients received a total of 110 courses (median 6, range 2–6). Efficacy: Of 19 evaluable patients, 4 achieved a clinical complete response (cCR) (21%), 12 partial response (cPR) (63%), 1 stable disease (cSD) (5%) and 2 progressive disease (cPD) (10%), resulting in a clinical response rate (cRR) of 84%. Surgery was performed in 17 (85%) patients, 4 (23%) of them had pathological complete response (pCR), 12 (70%) partial response (pPR), 1 (6%) stable disease (pSD), resulting in a pathological RR of 93%. Median time to progression and overall survival have not been reached. Toxicity: Hematological grade III/IV toxicities per patient were neutropenia (10%), febrile neutropenia (10%) and thrombocytopenia (5%). Non-hematological grade III/IV toxicities per patient were mucositis (10%), nausea/vomiting (10%) and epigastralgia (10%) Conclusions: Six courses of T and M every 14 days with G- CSF support as induction treatment in stage II and III breast cancer are active and well tolerated. No significant financial relationships to disclose.

Liposomal Doxorubicin in the Treatment of Elderly, Cardiopatic, or Pretreated Patients with Aggressive Lymphomas: Comparison with an Historical Series.

The majority of patients (pts) with diffuse large-B cell lymphoma (DLBCL) are elderly and may have limited tolerance to chemotherapy due to concomitant diseases. Non-pegylated liposomal doxorubicin has an improved therapeutic index in comparison to doxorubicin, resulting in less myelosuppression, lower GI toxicity and reduced risk of cardiotoxicity at dose level equivalent to standard formulations of doxorubicin. The aim of this study was to assess the efficacy and feasibility of the combination of cyclophosphamide, vincristine, prednisone and liposomal doxorubicin with rituximab every three weeks (R-COMP21) in DLBCL elderly pts with concomitant disease or relapsed pts pre-treated with anthracyclines containing regimens. We analysed twenty-five not consecutive pts from June 2003 to December 2005 according to following negative characteristics: 5 pts over 75 years (20%), 8 pts pretreated with anthracyclines (32%), 12 pts (48%) with heart disease (5 ischemic, 2 hypokinetic and 5 hypertensive cardiomiopathy). Median age was 71 years (range 54–76). 3 pts were stage I, 6 stage II, 5 stage III and 11 stage IV. According to IPI score 8 pts were low risk, 9 low-intermediate, 7 intermediate-high and 1 high risk. The median left ventricular ejection fraction (LVEF) at diagnosis was 59% (range 42%–75%). All pts were evaluable for response to therapy: 18 (72%) obtained a complete remission (62,5% in pre-treated pts), 5 (20%) obtained a partial remission with an overall response rate of 92%. Two pts did not respond to therapy. After a total of 126 cycles we observed three toxic event (congestive heart failure, stroke and gastrointestinal bleeding). No significant hematological toxicity was recorded. Four percent of cycles were delayed. Median final LVEF was 57% (47%–65%). All pts but one had no change in LVEF, one patient developed a congestive heart failure resolved with medical therapy: he was withdrawn due to decrease of LVEF. After a median observation period of 2 years (range 2–68 months), 71% of pts are alive, five pts died two due toxicity and three due to progressive disease. We compared these outcomes with an historical control of 26 aggressive NHL pts treated from February 2001 to June 2005; these pts received no doxorubicin (10 pts) or a mitoxantrone-based scheme devised for elderly (16 pts) due to age or concomitant disease. Case matching was performed with respect to clinical stage, IPI, sex, symptoms, bulky disease, LVEF, with the exception of age (which was greater in control group: median 76 vs 71 p=.001) and heart disease which was more frequent in experimental group (48% vs 31% p=.02). Allowing for the limitations of studies using historic controls, the R-COMP regimen was associated with higher CR (72% vs 42%) and OS rates (71% vs 42%). These results did not change when only pts treated with rituximab are considered. We conclude that the general tolerability and the low incidence of cardiac events of liposomal doxorubicin warrants further studies in a subset of pts with concomitant disease limiting the use of conventional anthracyclines.