Pegylated Liposomal Doxorubicin Monotherapy Research Articles

Pegylated-liposomal Doxorubicin-induced Glomerular Thrombotic Microangiopathy.

Pegylated liposomal doxorubicin (PLD) has emerged as a recent innovation within the realm of antineoplastic agents, distinguished by its incorporation of doxorubicin within the liposomal bilayer. Given the low risk of cardiotoxicity, the clinical use of PLD has been expanding. We encountered a patient who underwent extended PLD therapy for recurrent malignancy and subsequently developed PLD-associated thrombotic microangiopathy, which was diagnosed by a detailed pathophysiological assessment. This case underscores the importance of considering thrombotic microangiopathy as a potential differential diagnosis in patients presenting with unexplained hypertension and renal impairment during prolonged PLD monotherapy.

Role of Pegylated Liposomal Doxorubicin in Heavily Pretreated Relapsed Refractory Hodgkin Lymphoma Eligible for Autologous or Allogeneic Transplantation

In the context of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), various conventional single agents and salvage chemotherapy regimens have been explored, including bendamustine, brentuximab vedotin, nivolumab, and pembrolizumab. However, there is another drug, pegylated liposomal doxorubicin (PLD), which has shown interesting results but is comparatively less recognized and mostly used in combination. For heavily pretreated R/R cHL patients this drug, presenting a reduced cardiac toxicity compared to non-liposomal doxorubicin, may be considered as bridging therapy (BT) to transplantation (both autologous [ASCT] and allogeneic [alloSCT]). The present retrospective study aims to determine the role of PLD monotherapy in terms of safety and effectiveness in heavily pretreated R/R cHL patients as BT to ASCT or alloSCT. Our case series comprises 22 R/R cHL patients who were potentially eligible for transplantation and underwent PLD treatment successfully. These patients had a median of five previous treatments (range, 3-9), including ASCT in 50% of the cases and radiotherapy in 7 out of 22 cases. Of the total, 77% were primary refractory, and 63.6% remained refractory to the last previous therapy before PLD. Additionally, eight patients had advanced stage disease at the time of PLD treatment. PLD was administered at a fixed dose of 60 mg every 21 days with a median of 4 cycles (range, 1-8). No dose reduction was needed. Few toxicities occurred. In detail, four hematological adverse events (AE) were reported in 3 patients (all grade ≥3, drug related but rapidly resolved without sequalae). Only one grade 3 extra-hematological occurred (deep vein thrombosis). Final overall response rate (ORR) was 31.8%, with 4 complete and 3 partial responses (CR, PR). Best ORR of 54.5% was reached at the third cycle (5 CR and 7 PR). Five patients subsequently proceeded to ASCT and 2 to alloSCT with 5 final CR (two patients converted from a PR and 1 from a stable disease). At a median follow-up of 6 years, median overall survival was reached at 4 years. The findings from this retrospective analysis suggest that PLD monotherapy may be effective in treating a subset of patients with multi-relapsed or refractory cHL. PLD could be considered as a strategic and relatively low-toxicity bridging therapy option for patients undergoing transplantation.

Pirfenidone inhibits stromal collagen deposition and improves intra-tumoral delivery and antitumor efficacy of Pegylated liposomal doxorubicin

The effectiveness of cancer nanotherapeutics is greatly restricted by the dense collagen network in solid tumors. Pirfenidone (PFD) is a clinically approved oral antifibrotic agent widely used to treat idiopathic pulmonary fibrosis. To investigate whether PFD can enhance the penetration and tumor delivery efficiency of Pegylated liposomal doxorubicin (PLD), colorectal cancer xenograft mice were administered PFD, PLD, or combined regimens. As expected, high-dose PFD (H-PFD, 270 mg/kg/day) combined with PLD (H-PFD + PLD) exhibited a significantly higher tumor inhibition rate than PLD monotherapy (75.09% vs. 60.87%). Similarly, the intra-tumoral doxorubicin level was markedly elevated using H-PFD pretreatment, which induced over 34% elevation compared to PLD treatment alone (3.37 ± 0.41 vs. 2.51 ± 0.19 µg/mL). Additionally, Masson’s trichrome staining and immunohistochemistry results of the H-PFD + PLD group revealed an attenuation of collagen deposition in vivo, and the in vitro TGF-β1, α-SMA, and collagen protein expression were inhibited using PFD treatment. In contrast, although low-dose PFD (60 mg/kg/day) did not present superior benefits in promoting PLD penetration into tumors, it did downregulate collagen expression in vivo. This study provides a new strategy for PFD combined with chemotherapeutic drugs to improve the antitumor efficacy of nanomedicines.

Effects of Pegylated Liposomal Doxorubicin and CA125 Level Variability Analysis in Platinum-refractory/resistant Recurrent Ovarian Cancer.

Ovarian cancer is a disease with significant impact, because more than half of cases exhibit recurrence despite platinum therapy. The choice of drug for cases of recurrence remains controversial, but the current option is pegylated liposomal doxorubicin (PLD). We retrospectively reviewed the use of PLD in patients with ovarian cancer refractory or resistant to platinum-based therapy at our Department. We also examined efficacy, predictive indices of efficacy, and adverse events as well. In this study of PLD monotherapy for 60 platinum-refractory/resistant recurrent ovarian cancers, there was a median progression-free survival (PFS) of 4 months, median overall survival (OS) of 11 months, and the disease control rate (DCR) was 71.7%. The treatment effect can be predicted by the reduction of CA125 level after 2 courses. Patients with an increase and decrease in CA125 after 2 cycles of PLD, respectively, had a median OS of 14.5 (2-60) and 8 (2-51) months and a median PFS of 6 (2-38) months and 3 (0-47) months. PLD is clinically effective and useful because it provides a high DCR and is tolerable to adverse events. These findings can help support the use of PLD and guide physicians in their choice of treatment when encountering such cases.

Cardiac safety of trabectedin monotherapy and in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer.

11547 Background: Trabectedin (T) is an established option as monotherapy for advanced soft tissue sarcomas (STS; Leiomyosarcomas and Liposarcomas in the USA) and in combination with pegylated liposomal doxorubicin (PLD) for recurrent ovarian cancer (ROC). This retrospective analysis evaluated the cardiac safety profile in over 1500 patients (pts) from clinical trials administering T monotherapy for STS or in combination with PLD (T+PLD) for ROC. Methods: Integrated cardiac safety data was analyzed from ten Phase 2 trials and one Phase 3 trial in STS (T) and two Phase 3 ROC trials (T+PLD). Cardiac-related treatment-emergent adverse events (TEAEs) were summarized using MedDRA terminology and by Kaplan-Meier analysis for time-to-event variables. Subgroup analyses were performed for cardiac-related TEAEs, including any significant decrease in LVEF. Results: Integrated data on T monotherapy included 982 pts (Table). Of these, 110 (11.2%) pts who received ≥1 dose of T experienced a cardiac-related TEAE, including tachycardia (3.1%), palpitations (1.5%), LVEF decrease (1.3%), sinus tachycardia (1.0%), and/or congestive cardiac failure (1.0%). A multivariate analysis revealed factors associated with increased risk to be cardiovascular medical history (risk ratio [RR]: 1.90; 95% CI: 1.24-2.91; p = 0.003) and age > 65 years (RR: 1.78; 95% CI: 1.12,2.83; p = 0.014). Cardiac-related TEAEs were reported in 78 (12.6%) of 619 pts receiving T+PLD (Table). Incidence of cardiac-related TEAEs was greater with T+PLD compared with PLD monotherapy (12.6% vs 5.6%). A multivariate analysis showed that pts were at increased risk for experiencing cardiac-related TEAEs when treated with T+PLD compared to PLD monotherapy (RR: 2.70; 95% CI: 1.75,4.17; p < 0.0001) and when there was a history of prior cardiac medication (RR: 1.88; 95% CI: 1.16,3.05; p = 0.010). Conclusions: Although infrequent, patients receiving T after prior anthracyclines or in combination with PLD are at risk for cardiac dysfunction, and appropriate clinical awareness and monitoring is encouraged to optimize patient outcomes. [Table: see text]

A phase 3 randomized, open-label, multicenter trial for safety and efficacy of combined trabectedin and pegylated liposomal doxorubicin therapy for recurrent ovarian cancer

ObjectiveThis phase 3 study aimed to compare overall survival (OS) of women with platinum-sensitive, recurrent ovarian cancer (ROC) treated with third-line trabectedin (T) + pegylated liposomal doxorubicin (PLD) vs. PLD monotherapy. MethodsWomen with advanced-relapsed epithelial ovarian cancer were randomly assigned 1: 1 to intravenous infusions of either T + PLD (trabectedin 1.1 mg/m2 for 3 h; PLD 30 mg/m2 for 1.5 h, every 3 weeks) or PLD (50 mg/m2 for 1.5 h, every 4 weeks). Primary endpoint was OS. Secondary endpoints included investigator-assessed progression free survival (PFS) and objective response rates (ORR). At randomization, patients were stratified by time from last dose of first-line platinum therapy to disease progression, ECOG grade 0 or 1, BRCA1/2 germline mutational status, and prior PLD therapy. Exploratory endpoints included OS, PFS, and ORR in the stratified subgroups (PFI, ECOG, BRCA1/2 status, and prior PLD therapy). This trial is registered with ClinicalTrials.gov, number NCT01846611. Results576 patients were randomized (T + PLD, n = 289; PLD, n = 287). Median OS was 23.8 months with T + PLD vs. 22.2 months with PLD (HR:0.92, 95%CI:0.73–1.18; p = 0.52). Median PFS was 7.52 vs. 7.26 months (HR:0.93, 95%CI:0.76–1.15; p = 0.52); ORR was 46% vs. 35.9% (OR:1.52, 95%CI:1.07–2.16; p = 0.01). Patients with BRCA1/2 mutations had median OS of 34.2 months with T + PLD vs. 20.9 months with PLD (HR:0.54, 95%CI:0.33–0.90; p = 0.016). Patients with BRCA1/2 mutations had median PFS of 10.1 months with T + PLD vs. 7.6 months with PLD (HR:0.72, 95%CI:0.48–1.08; p = 0.039). Patients with BRCA1/2 mutations and a 6–12 months platinum-free interval (PFI), median OS was 31.5 vs. 14.9 months, respectively (HR:0.37, 95%CI:0.17–0.82; p = 0.011). Grade 3–4 AEs were higher in T + PLD (79%) vs. PLD (54%). ConclusionCombination of T and PLD did not show favorable OS benefit nor safety; however, patients with germline BRCA1/2 mutations and/or a PFI of 6–12 months appear to have clinically relevant survival benefit with T + PLD. No new safety signals were identified.

Therapeutic efficacy of combined PEGylated liposomal doxorubicin and radiofrequency ablation: Comparing single and combined therapy in young and old mice

Antitumor therapy in the elderly is particularly challenging due to multiple, often chronic diseases, poly-therapy, and age-related physiological changes that affect drug efficacy and safety. Furthermore, tumors may become more aggressive and drug-resistant with advanced age, leading to poor patient prognosis. In this study, we evaluated in mice bearing medulloblastoma xenografts the effect of age on tumor progression and tumor therapy. We focused on therapeutic efficacy of two treatment modalities alone radiofrequency ablation therapy (RFA), PEGylated liposomal doxorubicin (PLD) equivalent to Doxil, and their combination. We demonstrated that tumor growth rate was higher and survival was lower in old versus young mice (p<0.05). Likewise, tumors in old mice were less susceptible to either PLD or RFA monotherapy. However, combined therapy of PLD and RFA succeeded to eliminate the age-related differences in anti-cancer treatment efficacy (p>0.05) by the two monotherapies. The results on PLD therapy are supported by preferable PEGylated nano-liposomes accumulation in tumors of young mice compared to old mice, as determined by near-infrared imaging with indocyanine green (ICG)-labeled PEGylated nano-liposomes. Taken together, our findings suggest that age effects on tumor progression and tumor monotherapy outcome may potentially be related to changes in tumor microenvironment, and that these changes can be overcome by RFA as this technique abolishes these differences and significantly improves success of PLD treatment.

The efficacy and safety of pegylated liposomal doxorubicin monotherapy and combination therapy with carboplatin in Korean patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer: a single-institution experience

ObjectiveThis study aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) with or without carboplatin in Korean patients with recurrent ovarian cancer (ROC), fallopian tube, or primary peritoneal cancer.MethodsThis retrospective study included 52 patients with ROC, fallopian tube, or primary peritoneal cancer who received PLD (50 mg/m2) between 1st December 2014 and 31th July 2016.ResultsThe mean number of chemotherapy cycles was 3.8 (range, 2 to 9) in the PLD monotherapy group and 7 (range, 2 to 13) in the PLD combined with carboplatin (PLD-C) group. In overall response rates and clinical beneficial rates, PLD monotherapy group shows 5.0% and 17.5%, and PLD-C group shows 33.3% and 75.0%. The mean progression-free survival (PFS) was 5 and 13 months in the PLD monotherapy and PLD-C groups, respectively. At 6 months after treatment initiation, absence of disease progression was confirmed in 6 (15%) and 10 (83.3%) patients in the PLD monotherapy and PLD-C groups. Hematological adverse events (e.g., neutropenia and thrombocytopenia) were more common in the PLD-C group (P<0.001, P=0.004). The incidence of anemia and non-hematological adverse events, including mucositis, hand-foot syndrome, and allergic reactions, was similar in both groups.ConclusionThis study demonstrated the efficacy and safety of PLD monotherapy and PLD-C combination in Korean patients with ROC. This study would be helpful to consider the degree of worry about side effects and treatment expectations after treatment. Further retrospective studies with larger samples are required to confirm the efficacy of PLD monotherapy in Asian patients with platinum-resistant ROC.

TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin: TOP2A as marker of response to PLD in ovarian cancer

ObjectiveThe treatment of platinum resistant/refractory epithelial ovarian cancer (EOC) is a challenge for oncologists. One of the most utilized drugs in these patients is pegylated liposomal doxorubicin (PLD). As PLD is active only in a small subset of patients and causes side effects, selection of responsive patients is an unmet need and might be guided by the status of the DNA topoisomerase II alpha (TOP2A) that is poisoned by the drug. MethodsFrom 176 ovarian cancers treated in three institutions, we selected 38 patients treated with PLD monotherapy as second/third line of treatment. TOP2A gene copies were measured using Fluorescent In Situ Hybridization (FISH) and expression evaluated using immunohistochemistry. Patients' derived xenografts (PDXs) of ovarian cancers were used to assess the correlation between TOP2A protein expression and response to PLD. ResultsClinical data showed that TOP2A gene gain that is paralleled by increased expression of the protein, was associated with a higher probability of clinical benefit from PLD. Treatment of PDXs demonstrated that only xenografts showing a high percentage of TOP2A expressing cells underwent tumor shrinkage when treated with PLD. ConclusionsThese data show that TOP2A gene gain and protein over-expression might predict activity of PLD in platinum resistant/refractory EOC.

The Role of Pegylated Liposomal Doxorubicin in Ovarian Cancer: A Meta-Analysis of Randomized Clinical Trials

Recent studies suggest that carboplatin with pegylated liposomal doxorubicin (C+PLD) is as efficacious as carboplatin with paclitaxel (C+P) and possibly is more tolerable for ovarian cancer therapy. Pegylated liposomal doxorubicin (PLD) may also be efficacious and tolerable as monotherapy in recurrent or platinum-resistant disease. We performed a meta-analysis of randomized trials in order to elucidate the role of PLD in ovarian cancer. We searched PubMed, Scopus, and ISI Web of Knowledge for studies comparing C+PLD with C+P and comparing PLD with another monotherapy. Summary hazard ratios (HRs) and relative risks with their corresponding 95% confidence intervals (CIs) were calculated using a fixed-effects model. Three trials were included in the doublet regimen analysis, and five trials were included in the monotherapy regimen analysis. C+PLD provided superior progression-free survival (PFS) (HR, 0.87; 95% CI, 0.78-0.96) and similar overall survival (OS; HR, 0.95; 95% CI, 0.84-1.07) compared with C+P. There was no evidence of improved tolerability: C+PLD had more gastrointestinal toxicity, anemia, thrombocytopenia, cutaneous toxicity, and mucositis/stomatitis, although there was less neutropenia, neuropathy, and alopecia. PLD monotherapy had similar PFS (HR, 0.99; 95% CI, 0.89-1.11) and OS (HR, 0.99; 95% CI, 0.88-1.11) to other monotherapies, but it was more tolerable. There was less neutropenia, anemia, thrombocytopenia, and gastrointestinal toxicity, although cutaneous toxicity was increased. C+PLD had better PFS and similar OS compared with C+P and had a very different toxicity profile. Therapy selection could be based on patient risks for side effects. PLD is as efficacious as other monotherapies and is more tolerable.

A phase I, dose escalation trial to assess the safety and biological activity of recombinant human interleukin-18 (SB-485232) in combination with pegylated liposomal doxorubicin in platinum-resistant recurrent ovarian cancer.

5065 Background: SB-485232, a recombinant human form of interleukin-18 (IL-18), is being studied as a novel cytokine for tumor immunotherapy. IL-18 has been shown to increase the anti-tumor activity of doxorubicin in other cancer mouse models. Methods: This multi-center study enrolled 16 patients (pts), and evaluated four cycles (28 days each) of standard pegylated liposomal doxorubicin (PLD) (40 mg/m2 day 1) in combination with increasing doses of IL-18 (1, 3, 10, 30, and 100 mg/kg) on days 2 and 9 of each cycle with a 1 yr follow-up to further evaluate safety and efficacy. Results: Of the 16 pts, 10 (63%) completed study treatment and 6 (37%) did not because of disease progression (5 pts) and PLD hypersensitivity (1 pt). Thirteen (82%) were platinum resistant/refractory having received a median of &gt; 3 prior lines of therapy. SB-485232 up to 100 mg/kg in combination with PLD had an acceptable safety profile. All 16 pts experienced at least 1 AE including chills (81%), nausea (75%), anemia (63%), fatigue (56%), hyperglycemia, and pyrexia (50% each). Eight of 16 pts had Grade 3 AEs including anemia (19%), and 6% each for abdominal pain, asthenia, dehydration, PLD hypersensitivity, edema, fatigue, hyperglycemia, hyperkalemia, jaundice, pain, nausea, vomiting, and pyelonephritis. There were no grade 4/5 AEs. Four subjects experienced 10 non-fatal SAEs with 3 related to study drug: anemia, PLD hypersensitivity, and cytokine release syndrome. Maximal SB-485232 biological activity, assessed by peripheral blood NK and T cell markers, was observed at 10mg/kg-100mg/kg. This drug combination resulted in a 6% partial response rate (RR) and a 38% stable disease rate using RECIST 1.0. Median (95% CI) time of progression-free survival (PFS) was 4.50 (3.52,--) months. Conclusions: The SB-485232/PLD combination was tolerable with minimal toxicity. These preliminary efficacy data are comparable to the historical RR and PFS observed with PLD monotherapy in platinum-resistant ovarian cancer. However, given the small sample size, this combination warrants further investigation.

Technetium-99m sulfur colloid (TSC) as a phenotypic probe for predicting pharmacokinetics (PK) and palmar-plantar erythrodysesthesia (PPE) toxicity of pegylated liposomal doxorubicin (PLD) in patients (pts) with recurrent epithelial ovarian cancer (EOC).

5050 Background: There is significant variability in the PK and PD (efficacy and toxicity) of PLD. Clearance (CL) of PLD has been proposed to occur primarily via uptake by cells of the mononuclear phagocyte system (MPS) mainly located in the liver, spleen, and blood. TSC is a radioactive colloid used clinically for diagnostic and functional imaging of the MPS. Our aim is to evaluate TSC as a phenotypic probe of MPS activity, which may predict PLD PK and PPE toxicity in pts (n=9) with EOC. Methods: Prior to administration of PLD on cycle 1 day 1 (C1D1), TSC was administered at 10 mCi IVP × 1. Dynamic planar and SPECT/CT images of the liver, spleen and hands were acquired using a gamma camera. Blood samples were collected up to 60 min after TSC and analyzed for radioactivity using a gamma counter. On C1D1, PLD was administered at 40 mg/m2 alone or at 30 mg/m2 in combination with carboplatin IV over 1 to 3 h. Serial PK samples were obtained from 0h to 672h post PLD dose. Plasma was processed to measure encapsulated and released doxorubicin (dox) using solid phase separation and HPLC. CL of PLD and TSC were calculated by non-compartmental analysis. The grade of PPE toxicity was determined by NCI CTCAE (v4.03) criteria. Results: Nine patients have undergone TSC imaging and eight patients completed TSC blood PK and PLD plasma PK studies. There was a positive linear relationship between TSC CL and encapsulated dox CL (R2 = 0.61, p=0.02). When patients were subdivided, there was a stronger relationship between TSC CL and encapsulated dox CL (R2 = 0.81, p=0.03) in pts receiving PLD monotherapy. A positive relationship using Spearman’s correlation (ρ=0.84, p=0.006) was also found between maximum grade PPE toxicity developed and estimated AUC of encapsulated dox in hands [(TSC AUCBlood)/(TSC AUCHand)*Encapsulated Dox AUCPlasma]. Conclusions: These results suggest that TSC is a probe for MPS function and PLD PK and PD and may be used to individualize PLD therapy in pts with EOC. In addition, our findings suggest TSC may be able to predict the development of PPE in patients.

Abstract 2673: Relationship between serum hormone levels and pharmacokinetics (PK) of PEGylated liposomal doxorubicin (PLD) in patients with refractory ovarian cancer

Abstract Background: Pharmacokinetics (PK) of nanoparticle agents, such as PEGylated liposomes, are dependent upon the carrier and not the encapsulated drug. Previous studies have demonstrated a high degree of interpatient variability in the PK of PEGylated liposomal doxorubicin (PLD). We have previously demonstrated that circulating monocytes play a major role in clearance (CL) of PEGylated liposomes in patients. Estrogen and testosterone, which are largely secreted via the gonads, have been shown to modulate monocyte function and chemotaxis. In addition, estrone is converted from other steroid hormones in adipose tissue. Thus, we evaluated the relationship between serum hormone concentrations in blood samples and PK of PLD in patients with refractory ovarian cancer. Methods: PLD was administered at 30 or 40mg/m2 IV every 28 days with or without concurrent carboplatin at an AUC = 5 in patients (n = 10) with recurrent ovarian cancer. All patients had undergone bilateral salpingo-oophorectomy (BSO). Serial PK samples were obtained from time 0 h to 168 h and day 28 post PLD dose. Plasma was processed to measure encapsulated and released doxorubicin using solid phase separation and HPLC with fluorescence detection. CL of encapsulated doxorubicin in plasma was calculated by non-compartmental methods. Prior to administration of PLD, serum samples were collected and concentrations of estrone, estrogen, testosterone, and dihydrotestosterone were measured. Results: There was a direct linear relationship between encapsulated doxorubicin CL and both testosterone (R2 = 0.72) and estrone concentrations (R2 = 0.54) in all patients. When patients were subdivided based on PLD monotherapy (n = 6) or PLD + carboplatin (n = 4), there was a stronger relationship between encapsulated doxorubicin CL and both testosterone (R2 = 0.88) and estrone concentrations (R2 = 0.86) in patients receiving PLD monotherapy. Estrogen and dihydrotestosterone concentrations were below quantification limits for the majority of patients and thus were not evaluated. There was no relationship between patient body weight and BMI and estrone concentrations (R2 = 0.25 and R2 = 0.13 respectively). Conclusions: These findings indicate that serum hormone concentrations are associated with encapsulated doxorubicin CL and thus may be useful for individualizing PLD therapy in patients with ovarian cancer and other malignancies. Patient body weight and BMI were not associated with estrone concentrations in patients with ovarian cancer, suggesting phenotypic and/or genotypic differences in estrone production in adipose tissue. Low estrogen concentrations are consistent with the patients undergoing BSO surgery as standard treatment of ovarian cancer. The relationship between hormone levels and PK of nanoparticles needs to be further evaluated as a method to individualize nanoparticle therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2673. doi:1538-7445.AM2012-2673

Epidemiologic study to evaluate the treatment of palmar-plantar erythrodysesthesia (PPE) in patients (pts) with ovarian cancer (OC) or metastatic breast cancer (MBC) treated with pegylated liposomal doxorubicin (PLD).

e12014 Background: PLD is a highly active agent for OC and MBC. Liposome encapsulation and pegylation of PLD alters the pharmacokinetic and side effect (SE) profiles of conventional doxorubicin, improving its therapeutic ratio. PPE is a common SE of PLD and may be related to the pressure-dependent extravasation of liposomes into the skin. Methods: Pts with OC or MBC being treated with PLD were observed. The primary objectives were frequency of PPE as well as the curative pharmacologic and/or prophylactic treatment for PPE. Secondary objectives were numbers of pts that required change in PLD treatment dose/schedule due to PPE and pts compliance to PPE treatment. Results: 154 pts from 16 Spanish hospitals were evaluable. The mean age was 62.4 y (range: 39-83). 73 pts had MBC and 81 had OC. 140 pts (90.9%) received PLD monotherapy with a mean of 3.9 cycles. The mean accumulated dose and dose intensity of PLD were 95.4 mg/m2 (15-331.5) and 9.7 mg/m2/week (4.4-23.3), respectively. At time of study enrollment, 65 pts presented with PPE (grade 1 n = 42; grade 2 n = 15; grade 3 n = 8; no grade 4). The median duration of PPE was 23 days (0-226). PLD treatment was adjusted in 18 pts (11.7%): delayed in 10 pts and dose reduced (to mean of 35 mg/m2 [30-40]) in 8 pts. PLD had to be interrupted in 4 pts. 14 pts (9.1%) received curative therapy for PPE, 52 (33.8%) received prophylaxis, and 6 (3.9%) received both. Most pts (n=55, 76.4%) received one treatment for PPE. Common pharmacologic strategies were oral dexamethasone (n = 10; 71.4%), pyridoxine (n = 8, 57.1%), topical corticosteroids (n = 8, 57.1%), and topical DMSO 99% (n = 3, 21.4%). Nonpharmacologic strategies were avoid excessive heat/water (n = 14, 100%), keep skin hydrated (n = 12, 85.7%), avoid sweating and physical activity (n = 7, 50%), avoid tight fitting clothing (n = 12, 85.7%), and local cooling of hands/feet (n = 6, 42.9%). Compliance with each educational recommendation was low (< 45%). Conclusions: While PPE was an observed SE of PLD in these MBC and OC pts, it was manageable. Patient education to ensure compliance with PPE preventive measures and treatments is important in controlling this SE. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough

Pegylated Liposomal Doxorubicin in Primary Cutaneous Lymphomas: Efficacy, Safety, and Low Rate of Palmar-Plantar Erythrodysesthesia

Pegylated liposomal doxorubicin (PLD) is approved in breast cancer, ovarian cancer, Kaposi's sarcoma. Its skin-tropism suggests a role in the therapy of primary cutaneous lymphomas (PCLs). Among the cutaneous toxicities of PLD, the palmar-plantar erythrodysesthesia (PPE) is characterized by tingling, dysesthesia, erythema, swelling and, in severe cases desquamation, crusting, ulceration and necrosis. PPE is dose- and schedule-dependent and is usually reversible. Different pathophysiologic mechanisms are suggested:PLD, excreted from sweat glands, penetrates into the corneum stratum with local oxidative and inflammatory reactions;direct cytotoxic effect;extravasation of PLD from the deep microvessels through the local pressure.At our knowledge no specific reports on PPE in patients (pts) with PCLs treated with PLD were presented. We report 31 PCL pts treated with PLD: 26 affected by primary cutaneous T-cell lymphomas (PCTCL) and 5 by primary cutaneous B-cell lymphomas (PCBLC). Among PCTLC, 21 pts (16 M, 5 W, median age 67 yrs) received PLD in monotherapy at the dosage of 20 mg/m2 every 3–4 weeks. They were affected by relapsed or refractory PCTCLs: Mycosis Fungoides (MF) (52%), transformed MF in large cell lymphoma (20%), Sèzary Syndrome (SS) (14%), peripheral T-cell lymphoma unspecified (PTCL–U) (14%). After 6 courses, 47% achieved a CR, with ORR of 81%. The median time to the max response was 3 mo.s. After a median follow-up of 36 months 5 pts had progression of disease (PD) and 5 relapsed. To date 9 pts are alive and 12 dead, 4 for PD and 8 for non-related causes. Median OS, EFS and PFS are 36, 17 and 19 mo.s respectively; OS, EFS and PFS rates at 66 mo.s are 33%, 16% and 37%, respectively. Among the remaining 5 PCTLC pts one with transformed MF in large cell lymphoma was treated with PLD in monotherapy and then intensified with bortezomib and dexamethasone obtaining a VGPR. Another pt with PTCL-U received PLD plus rituximab with a CR and the last 3 pts (MF, MF transformed and SS) underwent CBVD scheme obtaining a PR. Among the 5 PCBCLs a woman was affected by marginal zone lymphoma (PCMZL) and 4 men by large B-cell lymphoma (PCLBCL) (all in stage: T3,N0,M0). All pts showed a CR with PLD monotherapy, in a short period (median 2,5 mo.s), even when heavily pretreated. One of them experienced a relapse. One died for PD; to date the others are still in CR after 5, 52, 63 and 69 mo.s. PLD was well tolerated. In PCTLC adverse effects were observed in 6 pts (23%) and grade III–IV toxicity occurred in 2 (8%): capillary leakage syndrome and neutropenia. Nobody required dose modifications or delays. Grade II gastrointestinal toxicity was present in 2 pts. Only two showed a grade I PPE. In these cases we delayed the dose up to 1 week, obtaining a complete resolution, thus returning to the original interval. Even in the five pts affected by PCBCL, PLD was well tolerated and no one decreased or delayed the dose. A pt showed a reversibile grade I neurotoxicity; the hematological toxicity was mild with one case of grade III neutropenia treated with G-CSF. Nobody experienced PPE. PPE is frequently reported in pts with cancer treated with PLD: about 50% off all pts who received the currently approved dose of 50 mg/m2 every 4 weeks experienced PPE and about 20% grade III PPE. When PPE develops, PLD dose reduction, schedule modification, ultimately drug withdrawal are considered. In our pts affected by PCLs, PPE occurred rarely, with mild grade (2 case of grade I). It is probably due to low dosages of Peg-Doxo, compared to the commonly used in other solid neoplasms. Besides oral prophylaxis with pyridoxine 300 mg daily was administered from the beginning of the treatment until 1 month after its discontinuation in all pts, as suggested by some authors. This is the first report of PLD in PCBCL; as regarding the other few studies (Wollina, Cantonetti, Di Lorenzo, Lybaek, Quereux) concerning PLD in PCTLC the incidence of PPE resulted always low. In conclusion, it emerges that PLD shows a significantly high clinical activity and a good safety profile in PCLs. Our data seem to confirm the dose dependent toxicity effect of PLD, since three-four weekly schedule of PLD at the dose of 20 mg/m2 has less PPE compared to the classical schedule of 50 mg/m2 every 4 weeks. Some studies in ovarian and breast cancer demonstrated that PLD dose intensity reduction can prevent PPE. The administration of prophylactic pyridoxine seems to be useful in the reduction of the incidence and severity of PPE.

Single-agent treatment with pegylated liposomal doxorubicin for metastatic breast cancer

Anthracyclines and taxanes are among the most active substances used in the treatment of metastatic breast cancer (MBC). Their frequent use in the adjuvant setting and in cumulative toxicities including cardiotoxicity, however, often limit their use in MBC. The trend towards the use of adjuvant trastuzumab-containing regimens, which can also produce cardiotoxicity, adds further support to the need for effective agents with improved tolerability in the metastatic setting. Pegylated liposomal doxorubicin (PLD) can be an effective alternative to conventional anthracyclines for certain women with MBC. In phase III clinical trials, PLD was as effective as doxorubicin and produced significantly less cardiotoxicity in women with MBC. The incidences of myelotoxicity, nausea/vomiting, and alopecia were also lower with PLD, whereas hand-foot syndrome and stomatitis occurred more frequently. Phase II and III trials conducted in women with MBC support the use of PLD monotherapy in patients relapsing after adjuvant anthracycline-containing therapy, in heavily pretreated patients with taxane-refractory disease, in patients with cardiovascular risk factors (e.g. hypertension and mediastinal irradiation), in elderly patients, and in patients for whom specific acute doxorubicin toxicities, such as alopecia, are particularly worrying.