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To examine the ex- vivo ability of explanted human tumors and normal tissue to activate liposomal mitomycin C lipidic prodrug (MLP) by releasing the active free drug form, mitomycin C (MMC).We tested conversion of MLP to MMC in an ex vivo assay using explanted tissues obtained during routine surgery to remove primary tumors or metastases. Tumor and adjacent normal tissue were obtained from freshly explanted tumors and were immediately deep frozen at - 70 °C. On test day, the fragments were thawed, homogenized and incubated in the presence of a fixed amount of liposomal MLP at 37 °C for 1 h. We measured MLP and its rate of conversion to MMC by HPLC. Controls included plasma, malignant effusions, red blood cells, tumor cell lines, mouse liver, and buffer with dithiothreitol, a potent reducing agent.Most patients tested (16/20) were diagnosed with colo-rectal carcinoma. The average fraction of MLP cleaved per 100-mg tumor tissue (21.1%, SEM = 1.8) was greater than per 100-mg normal tissue (16.6%, SEM = 1.3). When the tumor and normal tissue samples were paired by patient, the difference was statistically significant (p = 0.022, paired t test). Biological fluids did not activate liposomal MLP, while normal liver tissue strongly does. Interestingly, the omental fatty tissue also greatly activated MLP.Tumor tissue homogenates activate MLP with greater efficiency than the surrounding normal tissues, but far less than liver and adipose tissue. These observations demonstrate the bioavailability of liposomal MLP in human tumors, and its pharmacologic potential in cancer therapy.

Background Pegylated liposomal (PL) mitomycin-c lipidic prodrug MLP) may be a useful agent in patients with metastatic colo-rectal carcinoma (CRC). We report here on the pharmacokinetics and clinical observations in a phase 1A/B study with PL-MLP. Methods Plasma levels of MLP were examined in 53 CRC patients, who received PL-MLP either as single agent or in combination with capecitabine and/or bevacizumab. MLP was determined by an HPLC-UV assay, and its pharmacokinetics was analyzed by noncompartmental methods. The correlation between clinical and pharmacokinetic parameters was statistically analyzed. Results PL-MLP was well tolerated with a good safety profile as previously reported. Stable Disease was reported in 15/36 (42%) of efficacy-evaluable patients. Median survival of stable disease patients (14.4 months) was significantly longer than of progressive disease patients (6.5 months) and non-evaluable patients (2.3 months). MLP pharmacokinetics was stealth-like with long T½ (~1 day), slow clearance, and small volume of distribution (Vd). The addition of capecitabine and/or bevacizumab did not have any apparent effect on the pharmacokinetics of MLP and clinical outcome. High baseline neutrophil count and CEA level were correlated with faster clearance, and larger Vd. Stable disease patients had longer T½ and slower clearance than other patients. T½ and clearance were significantly correlated with survival. Conclusions PL-MLP treatment results in a substantial rate of disease stabilization in metastatic CRC, and prolonged survival in patients achieving stable disease. The correlation of neutrophil count and CEA level with pharmacokinetic parameters of MLP is an unexpected finding that needs further investigation. The association of long T½ of MLP with stable disease and longer survival is consistent with an improved probability of disease control resulting from enhanced tumor localization of long-circulating liposomes and underscores the relevance of personalized pharmacokinetic evaluation in the use of nanomedicines.

1049 Background: This is a single center phase 1b study of a regimen of pembrolizumab (PBZ) and pegylated liposomal doxorubicin (PLD) in endocrine-resistant breast cancer. PLD was chosen as chemotherapy component because it is mildly myelosuppressive and non-immunosuppressive and contains doxorubicin, a strong immunogenic cell death inducer. Methods: Patients with estrogen receptor positive, HER2 negative, metastatic breast cancer, whose disease progressed on hormonal and biological therapy and up to 2 chemotherapy lines were eligible for enrollment. PLD, 30 mg/m2, and PBZ, 200 mg flat dose, were infused on day 1 of every 3-week cycles. The main study objectives were safe dose clearance, characterization of dose-limiting toxicities (DLT), tumor response, and pharmacokinetic analysis of PLD and PBZ during the first 3 cycles of treatment in a 1st cohort of 6 patients and a 2nd confirmatory cohort of 6-9 patients. Patients with partial response (PR) or stable disease (SD) continued on the extended phase of the study consisting of 9 additional cycles during which further safety information was collected. All patients were followed-up for survival. Results: 12 patients were recruited (median age 61 y, range 45-91). 9 patients had received prior doxorubicin treatment. 82 treatments have been administered (median: 7, range 2-13). Overall, treatment was well tolerated. DLT including infusion reactions, grade ≥2 myelosuppression, hair loss and mucocutaneous toxicity were not observed in the first 3 cycles. Subsequently, skin toxicity (grade 2-3 palmar-plantar erythema) was observed forcing treatment delays of 1-2 weeks. Except for 2 cases of subclinical hypothyroidism, there were no other apparent PBZ-related side-effects. There was no evidence of cardiac toxicity. There were 2 early deaths (days 25 and 45) probably related to disease progression. Upon reevaluation on week 9, we observed: 2 patients with PD, 4 with SD, 2 with PR (15+ and 5+ mth), 1 with no measurable disease, and 1 early to evaluate. Three out of 5 patients responded well to post-study chemotherapy with durable improvement or stabilization (range, 5 to 11+ mth). Median follow-up is 14 mth. Median survival has not been reached with 4 deaths and a longest survivor of 19+ mth. Median progression-free survival is 6.0 mth. The clearance of PLD was slow with high Cmax, long T½ and small Vd. There was a significant increase in the AUC of PLD between the 1st and 3rd cycle (median: 2,649 vs 3,422 mg*h/l, p = 0.039). Analysis of PBZ plasma levels is ongoing. Conclusions: The combination of PLD and PBZ is well tolerated and feasible for extended treatment. Dose interval of PLD should be lengthened to 4 weeks after 2-3 cycles to prevent skin toxicity. The late appearance of skin toxicity is probably related to a delay in PLD clearance after 2 treatment cycles with PLD and PBZ. Clinical trial information: NCT03591276 .

Purpose To examine the effect of radiation on in vitro drug activation and release of Promitil, a pegylated liposomal formulation of a mitomycin C (MMC) lipid-based prodrug; and examine the efficacy and toxicity of Promitil with concurrent radiation in colorectal cancer models. Methods and Materials Promitil was obtained from Lipomedix Pharmaceuticals (Jerusalem, Israel). We tested the effects of radiation on release of active MMC from Promitil in vitro. We next examined the radiosensitization effect of Promitil in vitro. We further evaluated the toxicity of a single injection of free MMC or Promitil when combined with radiation by assessing the effects on blood counts and in-field skin and hair toxicity. Finally, we compared the efficacy of MMC and Promitil in chemoradiotherapy using mouse xenograft models. Results Mitomycin C was activated and released from Promitil in a controlled-release profile, and the rate of release was significantly increased in medium from previously irradiated cells. Both Promitil and MMC potently radiosensitized HT-29 cells in vitro. Toxicity of MMC (8.4 mg/kg) was substantially greater than with equivalent doses of Promitil (30 mg/kg). Mice treated with human-equivalent doses of MMC (3.3 mg/kg) experienced comparable levels of toxicity as Promitil-treated mice at 30 mg/kg. Promitil improved the antitumor efficacy of 5-fluorouracil–based chemoradiotherapy in mouse xenograft models of colorectal cancer, while equitoxic doses of MMC did not. Conclusions We demonstrated that Promitil is an attractive agent for chemoradiotherapy because it demonstrates a radiation-triggered release of active drug. We further demonstrated that Promitil is a well-tolerated and potent radiosensitizer at doses not achievable with free MMC. These results support clinical investigations using Promitil in chemoradiotherapy.

We herein review various pharmacological and clinical aspects of pegylated liposomal doxorubicin (PLD), the first nanomedicine to be approved for cancer therapy, and discuss the gap between its potent antitumor activity in preclinical studies and its comparatively modest achievements in clinical studies and limited use in clinical practice. PLD is a complex formulation of doxorubicin based on pharmaceutical nanotechnology with unique pharmacokinetic and pharmacodynamic properties. Its long circulation time with stable retention of the payload and its accumulation in tumors with high vascular permeability both result in important advantages over conventional chemotherapy. The ability of PLD to buffer a number of undesirable side effects of doxorubicin, including a major risk reduction in cardiac toxicity, is now well-established and confers a major added value in a number of disease conditions. PLD is approved for the treatment of ovarian cancer, breast cancer, multiple myeloma, and Kaposi sarcoma. In addition, clinically significant antitumor activity of PLD has been reported in a number of other cancer types, including lymphomas and soft tissue sarcomas. In spite of this, PLD has not replaced conventional doxorubicin in common applications such as the adjuvant and neoadjuvant treatment of breast cancer, and its use in the clinic has not become as widespread as one may have predicted. Exploiting the unique pharmacology of PLD, analyzing its selective biodistribution and homing to tumors in cancer patients with proper theranostic tools, and harnessing its complex interaction with the immune system, will lead to a more selective and rational use of PLD that may have great impact on future clinical results and may help realize its largely untapped potential.

Here, we present a case of an 84-year-old woman who developed obstructive jaundice and was diagnosed with nonoperable adenocarcinoma originating from the ampulla of Vater, a lethal disease with a median overall survival of less than a year. Her tumor was examined by next-generation sequencing, which showed BRAF and NRAS mutations. To target these mutations, a MEK inhibitor was chosen for treatment. The patient has been treated with a MEK inhibitor for the last 12 months since diagnosis, with clinical and laboratory improvement and manageable side effects. PET-computed tomography imaging has shown stable disease or improvement in the primary and metastatic lesions. This is the first case report of an ampulla of a Vater cancer patient with NRAS and BRAF mutations, identified in next-generation sequencing, and treated successfully with a MEK inhibitor.

Mitomycin C (MMC) has potent cytotoxicity but cumulative toxicity limits widespread use. In animals, pegylated liposomal mitomycin C lipid-based prodrug (PL-MLP) was well tolerated and more effective than free MMC. We evaluated PL-MLP in patients with advanced cancer. Twenty-seven patients were treated in escalating dose cohorts of 0.5–3.5 mg/kg (equivalent to 0.15–1.03 mg/kg MMC) every 4 weeks for up to 12 cycles, unless disease progression or unacceptable toxicity occurred. Pharmacokinetics were assessed during cycles 1 and 3. Per protocol maximum tolerated dose was not reached at 3.5 mg/kg. However, prolonged thrombocytopenia developed after repeated doses of 3 mg/kg or cumulative doses of 10–12 mg/kg. Dose-related grade 3 or higher adverse events included fatigue, anemia, and decreased platelets. Cmax and AUC0-∞ increased linearly over the dose range 0.5–2.0 mg/kg, and greater than linearly from 2.5 to 3.5 mg/kg; there were no significant differences in clearance of MLP between cycles 1 and 3. Median t1/2 was 23 h among dose cohorts, with no trend by dose or cycle. One patient had a partial response. Stable disease was observed in 10 patients across all dose levels. PL-MLP has a long circulation time, was well tolerated, and can be administered to heavily pretreated patients at a single dose of 3.0 mg/kg and cumulative dose of 10–12 mg/kg before development of prolonged thrombocytopenia; this is nearly threefold the equivalent dose of MMC tolerated historically. This formulation may be active in a variety of tumor types and is better tolerated than free MMC.

Anthracyclines are powerful anticancer agents and among the most important tools in the chemotherapy armamentarium of medical oncologists. They are approved for use in the treatment of a broad variety of solid and hematologic neoplasms. However, the usefulness of these agents, particularly doxorubicin, the most widely used anthracycline, is limited by considerable toxicity, especially damage to the cardiac muscle, which is cumulative and mostly irreversible, restricting extended use of this drug. In the last 30 years, extensive research with a variety of drug-delivery systems has attempted to overcome this limitation, with clinical success mostly confined to liposome formulations. Liposomal doxorubicin, and particularly pegylated liposomal doxorubicin, has shown significant pharmacologic advantages and an added clinical value over doxorubicin. Here, we review the mechanisms of action and toxicity of doxorubicin, and ways to reduce toxicity, with a focus on liposome-based drug-delivery systems.

Cancer patients have an increased risk for venous thromboembolism (VTE). Low molecular weight heparin (LMWH) is the mainstay of VTE treatment in these patients. Heparanase, which degrades heparin and LMWH, is an enzyme secreted from a variety of malignant tumors. The objective of this study was to elucidate the pharmacokinetics of LMWH in patients with locally advanced or metastatic cancer. A total of 10 cancer patients with VTE treated with the LMWH enoxaparin at a standard dose of 1 mg/kg every 12 h were enrolled. Blood samples were obtained before the injection of LMWH and at 1, 2, 3, 4, 6, and 8 h after LMWH administration, and they were tested for anti-factor Xa activity and heparanase levels. Peak anti-Xa activity was achieved 2-8 h after subcutaneous administration of LMWH. Six patients did not reach a therapeutic anti-Xa activity target (0.6-1.2 IU/ml) at 4 h after LMWH administration. Four patients did not reach anti-factor Xa values of 0.6 IU/ml throughout the trial. The median anti-Xa activity before LMWH injection was 0.24 IU/ml (range 0.07-0.7 IU/ml), as opposed to 0.52 IU/ml in historical controls. The median anti-Xa activity 4 h after LMWH injection was 0.58 IU/ml (range 0.22-1.23 IU/ml), as opposed to 1.2 IU/ml in historical controls. The blood level of heparanase in patients with malignancy and VTE was 6.24 ± 4.3 ng/ml, compared with 2.67 ± 1.09 ng/ml in cancer-free, age-matched, normal controls. In this pilot study, a substantial proportion of cancer patients suffering from VTE and treated with LMWH had subtherapeutic anti-Xa activity.

Dexrazoxane is indicated as a cardioprotective agent for patients receiving doxorubicin who are at increased risk for cardiotoxicity. Concerns have been raised on the use of dexrazoxane, particularly in adjuvant therapy, because of the risk of interference with the antitumor effect of doxorubicin. Two meta-analyses in metastatic breast cancer have rejected this hypothesis, but have shown an apparent increase in the severity of myelosuppression when dexrazoxane is used. Here, we analyzed retrospectively a cohort of our institute database to assess whether the addition of dexrazoxane causes more bone marrow suppression in breast cancer patients receiving doxorubicin-based adjuvant therapy. The secondary objectives were assessment of the incidence of febrile neutropenia, dose-schedule modifications, recorded cardiac events or cardiac test abnormalities, and overall survival. Eight hundred and twenty-two female patients who received adjuvant (or neoadjuvant) doxorubicin and cyclophosphamide for breast cancer between 2001 and 2013 were included. One hundred and four of these patients also received dexrazoxane concurrently with the adjuvant treatment. Hospital records and, when accessible, community clinic records were reviewed. The median follow-up duration was 7 years for patients receiving dexrazoxane and 7.5 years for patients not receiving dexrazoxane. 85.6% of patients were alive at data lock. Compared with the nondexrazoxane group, patients who received dexrazoxane were older (median age at diagnosis 59 vs. 52 years) and more likely to receive dose-dense AC therapy (73 vs. 59%) and adjuvant trastuzumab treatment (29 vs. 15%). Compared with the nondexrazoxane group, dexrazoxane treatment was associated with a higher rate of hematological side effects: leukopenia (48 vs. 39%), neutropenia (45 vs. 31%, P=0.003), anemia (86 vs. 73%, P=0.005), and thrombocytopenia (37 vs. 22%, P=0.001). There were more febrile neutropenia hospitalizations (20 vs. 10%, P=0.001) and dose reductions (22 vs. 8%, P

The development of stable and long-circulating liposomes provides protection of the drug cargo from degradation and increases tumor drug delivery, leading to the design of liposome formulations with great potential in cancer therapy. However, despite the sound pharmacologic basis, many liposomal as well as other nanoparticle-based drug formulations have failed to meet regulatory criteria for approval. The question that arises is whether we have missed key liposome-host interactions that can account for the gap between the major pharmacologic advantages in preclinical studies and the modest impact of the clinical effects in humans. We will discuss here the nanoparticle-immune system interactions that may undermine the antitumor effect of the nanodrug formulations and contribute to this gap. To overcome this challenge and increase clinical translation, new preclinical models need to be adopted along with comprehensive immunopharmacologic studies and strategies for patient selection in the clinical phase.

Background: A phase 1A/1B study was conducted to investigate the safety of Promitil, a liposomal formulation of a lipidic prodrug of mitomycin-c (MLP) within an open, dose-escalating, phase (1A, n=27) followed by an expanded phase (1B, n=61) restricted to metastatic colorectal cancer (mCRC) patients after failure to two or more lines of therapy. We report here on the correlation between pharmacokinetic (PK) parameters and clinical observations in patients with mCRC. Methods: PK analysis of plasma MLP levels was obtained in 53 mCRC patients (F=26, M=27), who received Promitil every 4 weeks either as single agent (n=28), in combination with capecitabine (Cap) (n=12), or in combination with Cap and bevacizumab (Bev) (n=13). The MLP dose range was 0.5-3.5 mg/kg with most patients (N=29) receiving 2.0-2.5 mg/kg. Out of 53 patients analyzed, 39 patients completed the 3rd cycle (study week 12) and were efficacy-evaluable by CT scan and Recist criteria. PK of plasma MLP levels was analyzed by noncompartmental methods. For statistical analysis and correlations of T½ and Clearance (CL) with age, sex, BMI, baseline neutrophil/lymphocyte ratio (NLR), CEA, and survival, we used t test and Pearson or Spearman coefficients. Results: The PK of MLP was stealth-like with long T½ (~1 day), slow CL, and small Volume of distribution. Stable Disease (SD) was reported in 14 patients (36%), and Progressive Disease (PD) in 25 patients. Median survival of all 39 patients (SD+PD) was 8.3 months. SD patients had significantly longer median survival than PD patients (14.3 vs 6.5 months, p=0.0002). SD patients had significantly longer T½ and slower CL than non-SD patients. A longer T½ and slower CL were significantly correlated with longer survival. A high NLR and high CEA were correlated with shorter T½ and/or faster CL. Dose of MLP, addition of Cap and/or Bev, age and BMI did not have any apparent effect on response or survival. Conclusions: SD was indicative of extended survival. The longer circulation time of the liposomal prodrug in SD patients and its correlation with longer survival are consistent with the well-known correlation between liposome circulation time and localization in tumors. A high NLR may signal inflammatory macrophage activation resulting in shorter liposomal circulation half-life and reducing the chances of disease control. Citation Format: Alberto A. Gabizon, Esther Tahover, Ruth Perets, Talia Golan, Ravit Geva, Yasmine Amitay, Hilary Shmeeda, Patricia Ohana. Clinical and pharmacokinetic study with a lipidic prodrug of mitomycin-c entrapped in liposomes in metastatic colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT054.

The aim of the present retrospective study was to evaluate the efficacy and safety of diethylstilbestrol (DES) as treatment for patients with castration-resistant prostate cancer (CRPC) and to identify predicting factors of response to DES. Patients treated with DES during the castration-resistant phase following the failure of prior treatment with LH-RH analogs during the castration-sensitive phase were retrieved from a prostate cancer database of our institution. Patients were treated with a daily dose of DES of 1-4 mg (mean, 2.6 mg) and anticoagulants for thromboembolic prophylaxis until disease progression. We analyzed their medical records, biochemical prostate-specific antigen (PSA) response and time to disease progression (TDP). Disease response and progression were identified according to the PCWG2 criteria. Patient data were examined using Kaplan-Meier survival analysis and statistical correlation tests with intra-patient comparison of the LH-RH and DES treatment phases. Forty-three DES-treated CRPC patients were found in our database through July 2011. The median age was 66 years. Sixty-three percent of the patients achieved a ≥50% decline in their serum PSA levels during DES therapy. Median TDP was 20.4 months for LH-RH analog treatment in the castration-sensitive phase, and 7.1 months for DES treatment in the castration-resistant phase. Durable responses (>1 year) were observed in 31% of the patients. Median overall survival was 57 months from the start of the DES therapy. There was no significant correlation between the TDP under LH-RH analogs and under DES therapy among the 38 patients eligible for correlation analysis. However, the magnitudes of serum PSA responses under DES and LH-RH analogs were significantly correlated with each other, and with the TDP under DES therapy. There were no treatment-related deaths. Four patients (9%) developed thromboembolic complications while under treatment, some of which appeared to be related to a discontinuation of thromboprophylaxis. In conclusion, DES confers substantial clinical benefit in the treatment of CRPC, with a relatively good safety profile when administered with thromboprophylaxis. The use of DES may be effective in CRPC, irrespective of the length of the hormone-sensitive period with LH-RH treatment. The magnitude of PSA response to previous treatment with LH-RH analogs, as well as to DES, was predictive of the duration of response to DES.

Pegylated liposomal doxorubicin (PLD; Doxil or Caelyx) has been shown to be as effective as conventional doxorubicin, and to have a significantly better cardiac safety profile. The aim of this study was to assess the safety of delivering doses exceeding 700 mg/m of PLD to patients with solid tumors. A review of the medical records of 149 patients with a variety of solid tumors treated with PLD was performed. The findings in 12 patients who had reached or exceeded cumulative doses of 700 mg/m (median=1.071 mg/m, range 712-1856 mg/m) were reviewed. Changes in left ventricular ejection fraction (LVEF), and in clinical cardiac status were analyzed. The median age of the patients was 53.9 years and the median follow-up from the start of PLD treatment was 44.6 months. None of the 12 patients had clinical congestive heart failure secondary to cardiomyopathy. Seven of the 12 patients underwent further assessment of LVEF by echocardiography or multiple gated acquisition scan, which revealed a stable or improved ejection fraction.PLD is cardiac safe for long-term treatment of metastatic solid tumors. Its maximal cumulative dose remains undefined. Frequent determinations of LVEF, as routinely done for other anthracyclines, do not appear to have any clinical value in patient follow-up. In metastatic patients with no evidence of cardiac risk factors, it may be sufficient to measure LVEF at baseline.

There are approximately 40,000 new cases of pancreatic adenocarcinoma diagnosed in the USA each year. It is estimated that 5–10% of all patients with pancreatic cancer have a first-degree relative with the disease, while up to 20% of cases have a hereditary component. Individuals who carry a germline mutation in the BRCA 1 or 2 genes have an increased lifetime risk of developing pancreatic adenocarcinoma when compared with the general population. Here, we present a case of metastatic pancreatic adenocarcinoma arising in a 67-year-old carrier of a BRCA 1 germline mutation. In patients with known BRCA 1 or 2 mutation-associated pancreatic adenocarcinoma, the addition of a DNA cross-linking agent such as cisplatin, oxaliplatin, or mitomycin to a standard gemcitabine chemotherapy backbone should be considered. Poly ADP-ribose inhibitors are a novel class of drug, which have demonstrated promising efficacy in trials of BRCA 1 and 2 mutant breast and ovarian cancer, and are currently undergoing prospective evaluation in advanced pancreatic cancer.

The folate receptor (FR) is overexpressed in a broad spectrum of malignant tumors and represents an attractive target for selective delivery of anti-cancer agents to FR-expressing tumors. Targeting liposomes to the FR has been proposed as a way to enhance the effects of liposome-based chemotherapy. Folate–polyethylene glycol–distearoyl–phosphatidyl–ethanolamine conjugate was inserted into pegylated liposomal doxorubicin (PLD). The therapeutic activity of folate-targeted (FT-PLD) and non-targeted (PLD) pegylated liposomal doxorubicin was tested in two human tumor models (KB, KB-V) and in one mouse ascitic tumor model (FR-expressing J6456) by the i.v. systemic route in all models, and by the i.p. intracavitary route in the ascitic tumor model only. Consistent with previous studies, PLD was clearly superior to free doxorubicin in all tumor models. When targeted and non-targeted liposome formulations were compared, FT-PLD was more effective than PLD in the KB and KB-V xenograft models, and in the J6456 intra-cavitary therapy model. The therapeutic effect was dose-dependent in the KB model and schedule-dependent in the J6456 intra-cavitary therapy model. In some experiments, toxic deaths aggravated by folate-depleted diet were a major confounding factor. In a non-FR expressing J6456 model, FT-PLD was as active as PLD indicating that its activity is not limited to FR-expressing tumors. Folate-targeting confers a significant albeit modest therapeutic improvement to PLD in FR-expressing tumor models, which appears particularly valuable in intracavitary therapy. The potential clinical added value of this approach has yet to be determined.

Doxorubicin and ifosfamide are currently considered the cornerstones of treatment for advanced soft tissue sarcomas (STSs). Pegylated liposomal doxorubicin (PLD) has been shown to have equivalent activity to doxorubicin and an improved toxicity profile. A review of the medical records of 11 patients with a variety of STSs treated with PLD was performed. The median age of the patients was 54.8 years. Of the 11 patients, seven received no earlier systemic therapy for their sarcoma. The initial dose per course was 40-60 mg/m2 every 4 weeks with dose reduction to 40 mg/m2 in the second or third cycle. A median of 11 cycles was given (range, two to 29 cycles). Treatment was generally well tolerated. We did observe some toxic effects as described earlier with PLD, including mild myelosuppression, skin toxicity and fatigue. No cardiotoxicity was observed. Of the 11 treated patients, six had a partial response, two had a best response of stable disease and three had progressive disease. All six patients with a partial response had an extended time to progression. To date, two patients continue on treatment (15 and seven cycles); one patient has stable disease 60 months after withdrawal of PLD (after eight cycles) and one patient had progression of disease 7 months after the withdrawal of therapy after 20 cycles. Of the two patients with stabilization of their disease, one had progression after 29 months and one continues on treatment for 6 months. PLD is active and safe for long-term treatment of metastatic STSs and may be important in maintaining response.

Imatinib mesylate (IM), a small molecule that is a selective inhibitor of the ABL, platelet derived growth factor receptor (PDGFR-R) and stem cell ligand receptor (c-kit) tyrosine kinases (TK). IM was also found to inhibit the TK activity of BCR/ABL fusion protein produced in chronic myelogenous leukemia, with marked clinical activity against the disease. Since both PDGF-R and c-kit both having a putative role in tumorigenesis, we investigated the efficacy and safety of the use of IM in patients with endocrine tumors unresponsive to conventional therapies that expressed c-kit and/or PDGF-R (within the framework of a comprehensive phase II multi-center study of IM in patients with solid tumors). IM was initiated at a dose of 400 mg/day, with possible dose escalation within 1 week to 600 mg/day and an option to raise the dose to 800 mg/day in the event of progression and in the absence of safety concerns for a period of up to 12 months. Between September 2002 and July 2003, 15 adult patients with disseminated endocrine tumors were recruited as follows: medullary thyroid carcinoma (MTC, n = 6); adrenocortical carcinoma (ACC, n = 4); malignant pheochromocytoma (pheo, n = 2); carcinoid (non-secreting, n = 2), neuroendocrine tumor (NET, n = 1). No objective responses were observed. MTC – disease progression in 4 patients, and treatment discontinuation in 2 patients due to adverse events; ACC – disease progression in 3 patients, and treatment discontinuation in 1 patient due to severe psychiatric adverse event; Pheo – disease progression in 2 patients; Carcinoid – stable disease in 1 patient (6.5 months), and disease progression in 1 patient; NET – disease progression in 1 patient. IM does not appear to be useful for treatment of malignant endocrine tumors, also causing significant toxicity in this patient population.

Purpose: A lipid-based prodrug of mitomycin C [MMC; 2,3-(distearoyloxy)propane-1-dithio-4′-benzyloxycarbonyl-MMC] was designed for liposome formulation. The purpose of this study was to examine the in vitro cytotoxicity, pharmacokinetics, in vivo toxicity, and in vivo antitumor activity of this new lipid-based prodrug formulated in polyethylene glycol–coated (pegylated) liposomes. Experimental Design: MMC was released from the MMC lipid–based prodrug (MLP) by thiolytic-induced cleavage with a variety of thiol-containing reducing agents. MLP was incorporated with nearly 100% efficiency in cholesterol-free pegylated liposomes with hydrogenated phosphatidylcholine as the main component and a mean vesicle size of ∼90 nm. This formulation was used for in vitro and in vivo tests in rodents. Results: In vitro, the cytotoxic activity of pegylated liposomal MLP (PL-MLP) was drastically reduced compared with free MMC. However, in the presence of reducing agents, such as cysteine or N-acetyl-cysteine, its activity increased to nearly comparable levels to those of free MMC. Intravenous administration of PL-MLP in rats resulted in a slow clearance indicating stable prodrug retention in liposomes and long circulation time kinetics, with a pharmacokinetic profile substantially different from that of free MMC. In vivo, PL-MLP was ∼3-fold less toxic than free MMC. The therapeutic index and absolute antitumor efficacy of PL-MLP were superior to that of free MMC in the three tumor models tested. In addition, PL-MLP was significantly more active than a formulation of doxorubicin in pegylated liposomes (DOXIL) in the M109R tumor model, a mouse tumor cell line with a multidrug-resistant phenotype. Conclusions: Delivery of MLP in pegylated liposomes is a potential approach for effective treatment of multidrug-resistant tumors while significantly buffering the toxicity of MMC.

Conventional anthracyclines are active against many tumor types, but cardiotoxicity related to the cumulative dose may limit their use; this is particularly problematic for patients with risk factors for increased toxicity, for those who have received any anthracycline in the past, or for those who are to receive other cardiotoxic agents. Preclinical studies determined that encapsulating conventional anthracyclines in liposomes reduced the incidence and severity of cumulative dose-related cardiomyopathy while preserving antitumor activity. In controlled clinical trials, the risk of cardiotoxicity was significantly lower when nonpegylated liposomal doxorubicin (Myocet [NPLD]) was substituted for conventional doxorubicin, but the risk was not significantly different when NPLD was used in place of conventional epirubicin. Direct comparisons to conventional doxorubicin therapy showed comparable efficacy but significantly lower risk of cardiotoxicity with pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]) therapy. Retrospective and prospective trials have not identified a maximum "cardiac safe" dose of PLD, despite use of cumulative doses exceeding 2,000 mg/m2 in some patients. Liposomal daunorubicin (DaunoXome [DNX]) may be associated with a lower risk of cardiotoxicity than conventional anthracyclines, but comparative trials are not available. With respect to combination chemotherapy, early results of clinical trials suggest that combining trastuzumab or a taxane with NPLD or PLD instead of a conventional anthracycline significantly reduces cardiotoxicity risk without reducing chemotherapeutic efficacy. Further results are eagerly awaited from ongoing controlled trials of cardiac safety with long-term liposomal anthracycline therapy, either alone or in combination with other potentially cardiotoxic agents.

Preclinical studies have established the pharmacologic advantages of liposomal anthracyclines, including pharmacokinetic profiles after bolus dosing that resemble continuous infusion of conventional anthracyclines, increased drug concentrations in tumor cells compared with the surrounding tissues, and reduced toxicity relative to conventional anthracycline treatment. Based on these studies, many phase I and phase II clinical trials were conducted to assess the safety and potential activity of liposomal anthracyclines in the management of both solid and hematologic tumors. These studies provided valuable insight into the safety of pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), nonpegylated liposomal doxorubicin (Myocet [NPLD]), and liposomal daunorubicin (DaunoXome [DNX]) over a range of doses, either as single-agent therapy or in combination with other cytotoxic agents. Other liposomal anthracyclines in development may be well tolerated but their activity remains to be elucidated by clinical trials. The available data also suggest that liposomal anthracyclines have activity not only against tumor types with known sensitivity to conventional anthracyclines, but also potentially for tumors that are typically anthracycline-resistant. Despite the availability of clinical data from a wide variety of tumor types and patient populations, further studies of liposomal anthracycline therapy are needed to fully establish their safety, efficacy, and dosing in the treatment of these patients.

Metastatic meningioma is a rare disease, which has no effective chemotherapy. We report on a treatment of this condition with Doxil, a liposomal doxorubicin formulation. A 60-year-old woman with massive pleuro-pulmonary metastases from recurrent cranial meningioma was treated with Doxil (50-37.5 mg/m 2 ) for 18 months with near-complete resolution of metastases and disappearance of pleural fluid. The only significant toxicities observed were stomatitis and hand-foot syndrome, which resolved with dose reduction and increase of dosing intervals. Doxil was cleared very slowly in this patient with a monoexponential half-life of 108 h. The patient remains in near-complete response for 6 months after treatment discontinuation. This is the first report on an effective chemotherapy in a patient with typical metastatic meningioma. The exact mechanism accounting for such an effective drug action is not clear, but may be related to a particularly high microvascular permeability to the liposome carriers in these metastatic lesions.

Liposomes have raised considerable interest as drug carriers in cancer chemotherapy [1] given their ability to alter the biodistribution and control the release rate of encapsulated drugs. Their ve...

"Personalized medicine" has become a generic term referring to techniques that evaluate either the host or the disease to enhance the likelihood of beneficial patient outcomes from treatment interventions. There is, however, much more to personalization of care than just identifying the biotherapeutic strategy with the highest likelihood of benefit. In its new meaning, "personalized medicine" could overshadow the individually tailored, whole-person care that is at the bedrock of what people need and want when they are ill. Since names and definitional terms set the scope of the discourse, they have the power to define what personalized medicine includes or does not include, thus influencing the scope of the professional purview regarding the delivery of personalized care. Taxonomic accuracy is important in understanding the differences between therapeutic interventions that are distinguishable in their aims, indications, scope, benefits, and risks. In order to restore the due emphasis to the patient and his or her needs, we assert that it is necessary, albeit belated, to deconflate the contemporary term "personalized medicine" by taxonomizing this therapeutic strategy more accurately as "biologically personalized therapeutics" (BPT). The scope of truly personalized medicine and its relationship to biologically personalized therapeutics is described, emphasizing that the best of care must give due recognition and emphasis to both BPT and truly personalized medicine.

BACKGROUND Stealth liposomes hold promise as a mode of delivering cytotoxic agents selectively to tumors in cancer patients. The objective of this study was to determine whether stealth liposomal doxorubicin accumulates selectively in bone metastases based on clinical material obtained from two patients with breast carcinoma. METHODS Tumor tissue was obtained from two women (ages 33 years and 41 years, respectively) with metastatic breast carcinoma who responded to treatment with stealth liposomal doxorubicin and later underwent a surgical fixation procedure to treat a pathologic fracture of the femur. Drug levels in the tumor and adjacent muscle were examined by high performance liquid chromatography analysis in both patients and by fluorescence microscopy in one of the patients. RESULTS Bone tumor fragments obtained during surgery performed 6 days after the administration of the 12th course of stealth liposomal doxorubicin in 1 patient and 12 days after the administration of the 16th course of stealth liposomal doxorubicin in the second patient had a 10-fold greater concentration of liposomal doxorubicin than tumor free muscle. Doxorubicin fluorescence and specific nuclear staining showed good colocalization, thus confirming the presence of the liposome-delivered drug in the nuclei of tumor cells. CONCLUSIONS Using skeletal muscle as a comparator, stealth liposomal doxorubicin accumulates selectively in metastatic breast carcinoma cells within bone. Cancer 1999;86:72–8. © 1999 American Cancer Society.

Enhanced permeability of the tumor vasculature allows macromolecules to enter the tumor interstitial space, whereas the suppressed lymphatic filtration allows them to stay there. This phenomenon, enhanced permeability and retention (EPR), has been the basis of nanotechnology platforms to deliver drugs to tumors. However, progress in developing effective drugs using this approach has been hampered by heterogeneity of EPR effect in different tumors and limited experimental data from patients on effectiveness of this mechanism as related to enhanced drug accumulation. This report summarizes the workshop discussions on key issues of the EPR effect and major gaps that need to be addressed to effectively advance nanoparticle-based drug delivery. Cancer Res; 73(8); 2412–7. ©2013 AACR.

Long-circulating (stealth) liposomes coated with polyethylene glycol (PEG), which show reduced uptake by the reticuloendothelial system (RES) and enhanced accumulation in tumours, were used for conjugation to monoclonal antibodies (MAbs) as a drug-targeting device. A MAb (N-12A5) directed against erbB-2 oncoprotein, a functional surface antigen, was used. Amplification and overexpression of the erbB-2 gene product, being unique to malignancy, confer onto this antibody-mediated therapy high tumour specificity. In vitro binding of [3H]cholesteryl ether ([3H]Chol ether) labelled anti-erbB-2 conjugated liposomes to N-87 cells (erbB-2-positive human gastric carcinoma) was compared with the binding of non-targeted liposomes and indicated a 16-fold increase in binding for the targeted liposomes. No difference in binding to OV1063 cells (erbB-2-negative human ovary carcinoma) was observed. These results indicate highly selective binding of antibody-targeted liposomes to erbB-2-overexpressing cells. Despite increased cell binding, doxorubicin (DOX) loaded in anti-erbB-2-conjugated liposomes did not cause increased in vitro cytotoxicity against N-87 cells, suggesting lack of liposome internalisation. In vivo, the critical factor needed to decrease the non-specific RES uptake and prolong the circulation time of antibody-conjugated liposomes is a low protein to phospholipid ratio ( < 60 micrograms mumol-1). Using these optimised liposome preparations loaded with DOX and by monitoring the drug levels and the [3H]Chol ether label, biodistribution studies in nude mice bearing subcutaneous implants of N-87 tumours were carried out. No significant differences in liver and spleen uptake between antibody-conjugated and plain liposomes were observed. Nevertheless, there was no enhancement of tumour liposome levels over plain liposomes. Both liposome preparations considerably enhanced DOX concentration in the tumour compared with free drug administration. Therapeutic experiments with N-87 tumour-bearing nude mice indicated that anti-tumour activity of targeted and non-targeted liposomes was similar, although both preparations had an increased therapeutic efficacy compared with the free drug. These studies suggest that efficacy is dependent on drug delivery to the tumour and that the rate-limiting factor of liposome accumulation in tumours is the liposome extravasation process, irrespective of liposome affinity or targeting to tumour cells.

Introduction: Liposomes are commonly used as drug carriers and the majority of approved anticancer nanoparticles utilize this platform. We have reported that liposomes similar to those used in patients can enhance tumor growth through inhibition of the antitumor immune response. However, it is not clear how the drug cargo impacts the immune modulatory effects of the carrier. The primary purpose of this study was to determine how loading of alendronate, an immune modulatory drug, into liposomes affects tumor progression and functionality of immune cells in tumor and spleen. Methods: Tumor free C57BL/6 mice (n = 12) and mice bearing s.c. TC-1 tumors (n = 24) were treated with up to 2 weekly i.v. injections of empty liposomes similar to the pegylated liposomal carrier used in Doxil, liposomes containing alendronate (PLA), or vehicle control. Tumor size was monitored biweekly and mice were sacrificed at endpoint to obtain tumors and spleens for single cell suspensions. To enumerate myeloid and lymphoid cell populations, cells were stained for CD11b, CD11c, Gr1, and F4/80, or TCR-β, CD8b and CD4 respectively. Separate aliquots of cells were also stimulated ex vivo with CpG (myeloid cells) or PMA/ionomycin (T cells), with monensin followed by intracellular staining for IL-2, IFN gamma, perforin and TNF alpha. All assays included Fc-blocking, CD45 stain, viability dye, and were analyzed by flow cytometry (BD LSR Fortessa). Results: In tumor free mice, liposomes increased the infiltration of macrophages and MDSC's in the spleen with lowered iNOS production, and increased IL-2, IFN gamma, and perforin production in CD8+ and CD4+ T cells. Loading alendronate into the liposomes mitigated the splenic infiltration of both macrophages and MDSC's and potentiated the T cell cytokine responses (IL-2, IFNg, perforin and TNF alpha). In tumor bearing mice, liposomes increased the infiltration of TAMs and inhibited tumor CTLs. Loading Alendronate (PLA) decreased the iNOS and arginase producing TAMs and mitigated the liposome-associated inhibition of CTL infiltration. Importantly, we found that mean tumor volumes were significantly smaller in PLA treated mice (288.9 mm3) as compared with liposomes (885.7 mm3). Conclusions: We found that loading alendronate into liposomes mitigates the tumor-promoting potential of the carrier through modulation of macrophage, MDSC, and T cell infiltration and functionality in spleen and tumor. Ongoing studies will identify the mechanisms underlying the interactions between the carrier, drug cargo, and tumor immunologic milieu. This will be especially critical to the successful translation of carrier-mediated immunotherapies into the clinic. Citation Format: Robin Rajan, Manoj K. Sabnani, Laurence M. Wood, Vikram Mavinkurve, Alberto A. Gabizon, Ninh M. La-Beck. Pegylated liposomal alendronate: The impact of the drug cargo on carrier-induced immune modulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4008.

To assess the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) and carboplatin in patients with recurrent epithelial ovarian carcinoma (ROC), following disease progression on single agent PLD.An analysis of the medical records of 10 patients with ROC, treated in our institution with a combination of PLD and carboplatin following progression on single-agent PLD therapy was performed. The median age was 59.1 years (range, 45 to 77 years). All diagnoses were histological-proven. Eight of the 10 patients were platinum-resistant. Following disease progression on single-agent PLD treatment, carboplatin area under the curve (AUC)-5 was added to PLD in all 10 patients. In order to assess disease status, Ca-125 was assessed before each PLD/carboplatin treatment. Relative changes in Ca-125 values were calculated, and response defined as a greater than 50% reduction in Ca-125 from baseline. Radiographic studies were re-evaluated and responses to therapy based on computer tomography (CT) scans carried out on a regular basis every 2-3 mo in each patient. Statistical analysis was performed using SPSS (V19).A median of 10 cycles (range, 2-26) of the carboplatin-PLD combination was given. Of the 10 treated patients, 6 had50% reduction in Ca-125 levels from baseline, 4 of these had a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and the other 2 patients had no measurable disease. In a further 2 patients with a best response of disease stabilization and50% reduction of Ca-125 levels, one had progression of disease after 26 cycles, and the second progressed with brain metastases following 12 cycles. Seven of the eight patients who were platinum-resistant showed evidence of clinical benefit on carboplatin-PLD combination therapy; 5 of these had50% reduction in Ca-125 level, 4 also showed a partial response on CT scan. The treatment was generally well-tolerated by the patients.Addition of carboplatin to PLD, after disease progression on single-agent PLD therapy, is both effective and safe in patients with ROC, even in those with Platinum-resistant disease.

Learning Objectives After completing this course, the reader will be able to: Describe the need for additional vigilance regarding renal dysfunction when platinums, pegylated liposomal doxorubicin, bevacizumab, and gemcitabine are used for prolonged treatment of recurrent ovarian cancer in combination or sequentially following pre-existing renal damage.Describe and quantify the risk of chronic kidney disease in patients treated for ovarian cancer. CME This article is available for continuing medical education credit at CME.TheOncologist.com Background and Objective. Ovarian cancer is usually diagnosed at an advanced stage, with most patients undergoing surgery followed by platinum- and taxane-based chemotherapy. After initial clinical remission, the majority recur, leading to additional treatments, including not only platinums and taxanes but also pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and, more recently, bevacizumab, which may extend survival times. PLD, in particular, has been extensively studied by our group, with encouraging therapeutic results. We, however, observed instances of chronic kidney disease (CKD) developing among patients who received long-term treatment for recurrent ovarian cancer. To document the frequency and contributing factors to the emergence of CKD, we initiated a retrospective review at two institutions. Patients and Methods. Fifty-six consecutive patients with recurrent ovarian cancer receiving treatment at New York University Cancer Institute were reviewed for the presence of renal disease in 1997–2010. At Shaare Zedek Medical Center, 73 consecutive patients with ovarian cancer were reviewed in 2002–2010. Patients were diagnosed with CKD if they had an estimated GFR 3 months and were staged according to the National Kidney Foundation guidelines. Results. Thirteen patients (23%) developed stage ≥3 CKD. Three patients had renal biopsies performed that showed thrombotic microangiopathy. Conclusions. CKD is emerging as a potential long-term consequence of current chemotherapy for recurrent ovarian cancer.

Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA +) benefit from platinum-based treatment more than noncarriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA + predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Tel Aviv, New York, Padua, and Jerusalem) were subjected to retrospective comparisons between 40 (25.8%) patients who were BRCA +, and 115 (74.2%) deemed nonhereditary (NH). Median age was 59 years (range 31–83); 111 (72%) had a platinum-free interval more than 6 months [PLD alone (n = 65) and PLD plus platinum (n = 90)]; 104 received PLD in second-line and 51 in third-line. BRCA + versus NH comparisons: median time to treatment failure (TTF) 15.8 months [95% confidence interval (CI): 11.4–21.6] versus 8.1 months (95% CI: 6.1–10.3; P = 0.009); overall survival (OS) 56.8 months (95% CI: 32.5–indeterminate) versus 22.6 months (95% CI: 17.0–34.1; P = 0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR = 1.66; 95% CI: 1.08–2.55; P = 0.02) and OS (adjusted HR 2.07; 95% CI: 1.18–3.60; P = 0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95% CI: 0.93–2.68; P = 0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result seemed to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other EOCs to DNA-damaging agents such as PLD, even after acquiring platinum resistance. Mol Cancer Ther; 10(10); 2000–7. ©2011 AACR.

There is significant inter-patient variability in the pharmacokinetics of pegylated liposomal doxorubicin (PLD). Identification of factors affecting the pharmacokinetics of PLD would enable personalization of therapy. We previously reported that age, gender, body composition, and monocytes affect the clearance of other liposomal agents. Therefore, we evaluated how these factors affect the pharmacokinetics of PLD.Pharmacokinetic studies of PLD were performed as part of phase I and II studies in 70 patients with solid tumors or Kaposi's sarcoma. The effects of monocyte count, age, gender, and body composition on PLD clearance were examined.There was a 15.3-fold variability in PLD clearance. Body surface area-based dosing did not significantly reduce the variability in PLD clearance. The mean ± SD clearance for patients60 years old and ≥60 years old were 54.6 ± 28.5 and 23.3 ± 10.8 mL/h/m(2), respectively (P 0.0001), and for female and male patients were 23.7 ± 18.8 and 55.6 ± 26.8 mL/h/m(2), respectively (P 0.0001). A reduction in pre-cycle monocyte count was associated with a greater reduction in PLD clearance.Age, gender, and monocyte counts appear to correlate with PLD clearance. Further investigation of the association between these factors, PLD pharmacokinetics, and clinical outcomes (efficacy and toxicity) is warranted. These effects on the pharmacokinetics of PLD may be an approach for personalizing PLD therapy and may affect other pegylated liposomes and nanoparticle agents.

Oxaliplatin has been shown to be valuable in the treatment of patients with colorectal cancer. Many of these patients will develop liver metastases during the course of their disease, with, in some cases, severe hepatic dysfunction. Although single agent oxaliplatin can be administered safely in patients with severely compromised liver function (as it is not metabolized by the liver), little is known of its safety in these patients when administered in the preferred combination with 5-fluorouracil (which is metabolized by the liver) and leucovorin (FOLFOX protocol). We report on a very sick patient with major liver dysfunction, a bilirubin of 11.2 mg/dl (190 micromol/dl) and an open abdominal wound, for whom palliative hospice care alone was originally proposed, who responded dramatically to the combination. His bilirubin fell to 0.6 mg/dl (10.2 micromol/dl) and his liver function tests returned to near normal levels. The combination was well tolerated and clinical improvement continued for more than 11 months before disease progression was observed.

Pharmacokinetic and imaging studies in 19 patients receiving liposome-entrapped adriamycin (L-ADM) were carried out within the framework of a Phase I clinical trial (Gabizon et al., 1989a). The formulation of L-ADM tested consisted of 0.2 microM-extruded multilamellar vesicles composed of egg phosphatidylcholine, egg-derived phosphatidyl-glycerol (PG), cholesterol, and ADM intercalated in the fluid lipid bilayer. Plasma clearance of total drug extracted from the plasma after L-ADM infusion followed a biexponential curve with a pattern similar to that reported for free ADM. The plasma concentration of drug circulating in liposome-associated from was also measured in a subgroup of seven patients. Liposome-associated drug was found to be rapidly cleared from plasma. Its ratio to non-liposome-associated drug appeared to correlate with liver reserve, with highest ratios in patients with normal liver function. Liposome clearance, as measured by the plasma concentration of PG in three patients was slower than the clearance of liposome-associated ADM, suggesting that liposomes lose part of their drug payload during circulation. To learn about the liposome organ distribution, imaging studies were carried out with 111Indium-deferoxamine labelled liposomes of the same composition. Liposomes were cleared predominantly by liver and spleen and to a lesser extent by bone marrow in seven out of nine patients. In two patients with active hepatitis and severe liver dysfunction, there was minimal liver uptake and increased spleen and bone marrow uptake. Except for one hepatoma patient, intrahepatic and extrahepatic tumours were not imaged by liposomes, suggesting that liposome uptake is restricted to cells of the reticulo-endothelial system (RES).(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 6 Figure 7 Figure 8 Figure 9 Figure 10

Primary malignant melanoma of the vagina is extremely rare, accounting for 0.3-0.8% of all malignant melanomas. True amelanotic vaginal melanoma showing no melanin on histological examination is exceedingly rare, accounting for only 2% of all vaginal melanomas.We describe a 31-year-old female patient who presented with locally advanced amelanotic melanoma of the vagina, with no evidence of metastatic spread on the computerized tomography (CT) scan, but who was subsequently diagnosed as suffering from metastatic disease by positron emission tomography (PET)-CT performed a few weeks following posterior pelvic exenteration.Specific immunohistochemical staining with melanoma markers should be performed to confirm or exclude a diagnosis of amelanotic melanoma in all patients presenting with a vaginal mass composed of undifferentiated epithelioid malignant cells. Fluorodeoxyglucose (FDG)-PET-CT should be performed as part of the preoperative evaluation, to identify the presence or absence of metastatic disease in all patients with vaginal melanoma.

Pegylated liposomal doxorubicin (PLD) is a liposomal formulation with a distinct pharmacokinetic profile characterized by an extended circulation time and a reduced volume of distribution. Biodistribution animal studies indicate preferential accumulation of PLD into various implanted mouse-human tumors, with an enhancement of liposomal drug tumor levels compared with free drugs. The extended circulation time of pegylated liposomes and their ability to extravasate through the leaky vasculature of tumors results in the enhanced delivery of liposomal drug and/or radiotracers to the tumor site in patients with cancer. In malignant effusions, Kaposi sarcoma skin lesions, and a variety of solid tumors there is evidence of selective tumor uptake detected by various methods. Pegylated liposomal doxorubicin has been approved for clinical use in a variety of neoplastic conditions because of its antitumor efficacy and unique safety profile with an impressive reduction of cardiac toxicity in comparison with conventional doxorubicin.

There are no definitive data in humans on the dose dependence and/or cycle dependence of the pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD). This study examined the PK of PLD across a twofold dose variation and along 3 cycles.Fifteen patients received PLD in successive doses of 60, 30, and 45 mg/m(2) (Arm A) and 30, 60, and 45 mg/m(2) (Arm B), every 4 weeks. Twelve patients, six on each arm, completed all three cycles and were fully evaluable. Plasma levels of doxorubicin were analyzed by HPLC and fluorimetry. PK analysis was done by non-compartmental method. Repeated measures ANOVA and paired tests were used for statistical analysis.There was no significant difference in the PK parameters examined when the dose was increased from 30 to 60 mg/m(2). However, when we analyzed the effect of cycle number on the PK, we found a gradual and significant inhibition of clearance (P0.0001) from the 1st through the 3rd cycle of PLD, with a geometric mean increase of 43% in dose-normalized AUC (P = 0.0003). Dose-normalized C(max) and T(1/2) mean values increased by 17 and 18%, respectively between the 1st and 3rd cycles, but only the increase in T(1/2) was statistically significant (P = 0.0017).While the PK of PLD is not dose-dependent within the dose range of 30-60 mg/m(2), there is evidence of a cycle-dependent effect that results in inhibition of clearance when patients receive successive cycles of PLD. These results suggest the need for dose adjustments of PLD upon retreatment to minimize the risk of toxicity.

Brain metastases are a frequent finding in patients with advanced non-small cell lung cancer and concomitant administration of antiepileptic and chemotherapeutic drugs or epidermal growth factor receptor (EGFR) inhibitor is necessary in many cases. Anticonvulsants have clinically significant interactions with other drugs used in brain tumor patients. We report a case in which a potential drug interaction resulted in elevated phenytoin levels after initiation of erlotinib therapy in a patient who was receiving phenytoin.

e13525 Background: Mitomycin C (MMC) is a potent radiosensitizer and a well-established agent in chemoradiotherapy (CRT) for anal cancer and localized bladder cancer. However, its use is often limi...

The folate receptor is overexpressed in a broad spectrum of malignant tumors and represents an attractive target for selective delivery of anticancer agents to folate receptor–expressing tumors. This study examines folate-lipid conjugates as a means of enhancing the tumor selectivity of liposome-encapsulated drugs in a mouse lymphoma model. Folate-derivatized polyethylene glycol (PEG3350)-distearoyl-phosphatidylethanolamine was post-loaded at various concentrations into the following preparations: radiolabeled PEGylated liposomes, PEGylated liposomes labeled in the aqueous compartment with dextran fluorescein, and PEGylated liposomal doxorubicin (PLD, Doxil). We incubated folate-targeted radiolabeled or fluorescent liposomes with mouse J6456 lymphoma cells up-regulated for their folate receptors (J6456-FR) to determine the optimal ligand concentration required in the lipid bilayer for liposomal cell association, and to examine whether folate-targeted liposomes are internalized by J6456-FR cells in suspension. Liposomal association with cells was quantified based on radioactivity and fluorescence-activated cell sorting analysis, and internalization was assessed by confocal fluorescence microscopy. We found an optimal ligand molar concentration of ∼0.5% using our ligand. A substantial lipid dose-dependent increase in cell-associated fluorescence was found in folate-targeted liposomes compared with nontargeted liposomes. Confocal depth scanning showed that a substantial amount of the folate-targeted liposomes are internalized by J6456-FR cells. Binding and uptake of folate-targeted PLD by J6456-FR cells were also observed in vivo after i.p. injection of folate-targeted PLD in mice bearing ascitic J6456-FR tumors. The drug levels in ascitic tumor cells were increased by 17-fold, whereas those in plasma were decreased by 14-fold when folate-targeted PLD were compared with nontargeted PLD in the i.p. model. Folate-targeted liposomes represent an attractive approach for the intracellular delivery of drugs to folate receptor–expressing lymphoma cells and seem to be a promising tool for in vivo intracavitary drug targeting. [Mol Cancer Ther 2006;5(4):818–24]

For patients whose breast cancers are not responsive to endocrine therapy, there are a large number of cytotoxic drugs that will induce a response. In spite of the introduction of new, very active drugs such as the taxanes, vinorelbine, capecitabine, gemcitabine, and trastuzumab, the anthracyclines are still as active as any--and more active than most--drugs used to treat breast cancer. Their inclusion in combinations to treat early and advanced disease prolongs survival. However, they cause nausea, vomiting, alopecia, myelosuppression, mucositis, and cardiomyopathies. There is no evidence that increasing the dose of conventional anthracyclines or any other of the cytotoxics beyond standard doses will improve outcomes. Schedule may be more important than dose in determining the benefit of cytotoxics used to treat breast cancer. Weekly schedules and continuous infusions of 5-fluorouracil and doxorubicin may have some advantages over more intermittent schedules. Liposomal formations of doxorubicin reduce toxicity, including cardiotoxicity; theoretically they should also be more effective because of better targeting of tumor over normal tissues. Both pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]) and liposomal doxorubicin (Myocet [NPLD]) appeared to be as effective as conventional doxorubicin and much less toxic in multiple phase II and phase III studies. PLD has been evaluated in combinations with cyclophosphamide, the taxanes, vinorelbine, gemcitabine, and trastuzumab, and NPLD has been evaluated in combination with cyclophosphamide and trastuzumab. Both liposomal anthracyclines are less cardiotoxic than conventional doxorubicin. The optimal dose of PLD is lower than that of conventional doxorubicin or NPLD. Patients treated with PLD have almost no alopecia, nausea, or vomiting, but its use is associated with stomatitis and hand-foot syndrome, which can be avoided or minimized with the use of proper dose-schedules. In contrast, the optimal dose-schedule of NPLD is nearly identical to that of conventional doxorubicin. The toxicity profile of NPLD is similar to that of conventional doxorubicin, but toxicities are less severe and NPLD is better tolerated than conventional doxorubicin at higher doses.

Although conventional doxorubicin demonstrates broad activity, its clinical use is limited by cardiotoxicity. A more recent analysis suggests conventional doxorubicin-related cardiotoxicity occurs more frequently and at lower cumulative doses than previously reported. Pegylated liposomal doxorubicin, designed to maintain or improve conventional doxorubicin activity while reducing toxicities, has demonstrated improved cardiac safety versus conventional doxorubicin. In this prospective study, we evaluated endomyocardial biopsies to determine the cardiac effects of pegylated liposomal doxorubicin in patients with advanced malignancies receiving doxorubicin-equivalent dosesor = 550 mg/m2 (including pegylated liposomal doxorubicin) oror = 400 mg/m2 pegylated liposomal doxorubicin alone. Eight patients were enrolled, and 10 biopsy scores were obtained (two patients had two biopsies). Median biopsy score (Billingham scale) was 0.75 (range, 0-1.5) after a median pegylated liposomal doxorubicin dose of 707.5 mg/m2 and median total anthracycline exposure of 908.5 mg/m2. These results suggest that pegylated liposomal doxorubicin minimizes doxorubicin-related cardiotoxicity, even at doses exceeding the recommended lifetime cumulative conventional dose (450-550 mg/m2).

(2002). Liposomal Drug Carrier Systems in Cancer Chemotherapy: Current Status and Future Prospects. Journal of Drug Targeting: Vol. 10, No. 7, pp. 535-538.

Introduction Cancer patients have an increased risk of developing venous thrombo-embolism (VTE). Treatment of VTE involves the administration of heparin, low molecular weight heparin (LMWH) or coumarin derivatives. Heparin resistance is a situation in which the administration of heparin does not result in an increase of the activated partial thromboplastin time (APTT) and blood anticoagulation. While heparin resistance is a known entity, LMWH resistance is not well documented, and anti factor Xa activity is not tested routinely in cancer patients treated with LMWH. Here, we report the pharmacokinetics of LMWH in cancer patients suffering from VTE and receiving treatment with enoxaparin at standard doses of 1 mg/kg twice daily. Patients/methods Patients suffering from malignancy and VTE, and treated with the LMWH, enoxaparin at standard dose of 1mg/kg q12 hr were enrolled. Ambulatory patients were admitted to the oncology day care unit for 8 hours in order to facilitate repeated blood testing. Blood samples were obtained before the injection of LMWH and 1, 2, 3, 4, 6 and 8 hours after LMWH subcutaneous administration, and tested for anti Xa activity as a surrogate marker of bioavailable LMWH levels. The trial was approved by the ethics committee of Shaare Zedek Medical Center. ClinicalTrials.gov Identifier: NCT00716898. Study funding: Israel Cancer Association. Results Eleven patients were enrolled; one was excluded from analysis due to complete remission at time of VTE diagnosis. Peak anti Xa activity was achieved after 2, 3, 4, 6, and 8 hours in 2, 3, 2, 2, and 1 patient respectively. 60% of the patients (n = 6) did not reach the therapeutic anti Xa activity target (0.6 -1.0 IU/ml) at 4 hours after subcutaneous administration of LMWH. Average anti Xa activity at 4 hours was 0.62 ± 0.29 IU/ml as opposed to 1.1 IU/ml in historical controls of non-oncology patients. Conclusions Our results show that a substantial number of cancer patients suffering from VTE and treated with standard dose enoxoparin do not reach therapeutic target anti Xa activity. If confirmed in a larger study, our results suggests that cancer patients suffering from VTE should be tested for anti Xa activity and LMWH dose should be titrated accordingly in order to achieve effective anticoagulation. Disclosure All authors have declared no conflicts of interest.

Disclosure A.A. Gabizon: I am the founder and Chief Scientist of Lipomedix Inc., a company with a vested interest in the product discussed in this presentation. Y. Amitay: Paid employee of Lipomedix, a product of which is discussed here. All other authors have declared no conflicts of interest. We have developed a formulation of a mitomycin-C lipid-based prodrug (MLP) in pegylated liposomes (PL) in which MLP is activated by thiolytic cleavage to mitomycin C (MMC). PL-MLP (PROMITIL™) was previously reported to have reduced toxicity and an improved therapeutic index as compared to MMC in human and mouse tumor models. In the following studies, we examined the pharmacokinetics, toxicity, and therapeutic activity of scaled-up batches of PL-MLP (prepared under the same protocol design as for clinical batches) in rodent and miniswine species. PL-MLP is a liquid suspension of vesicles of ∼100 nm diameter with MLP entrapped in the lipid bilayer at 10% molar ratio. Pharmacokinetic studies revealed major (>100-fold) differences in Cmax, AUC, plasma clearance and volume of distribution between MMC (i.v. 3 mg/kg) and PL-MLP (i.v. 6 mg/kg in MMC-equivalents). While MMC is cleared from blood within minutes and extensively distributed to peripheral tissues, PL-MLP is cleared very slowly with a mono-exponential half-life of ∼15 hours in rats and has a limited volume distribution roughly equivalent to the blood volume. In rat toxicity studies in rats, the MTD of PL-MLP was two to three-fold higher than that of MMC in mg-equivalent doses. Therapeutic studies in BALB/c mice inoculated i.p. with C26 tumor cells show a clear survival advantage for treatment with PL-MLP over free MMC at all dose levels tested, whether treatment was administered by the i.v. or by the i.p. route. In the porcine model, no acute infusion reaction to i.v. administration of PL-MLP was observed. PL-MLP appears to be a stable formulation with minimal prodrug activation and release of MMC in circulation, yet significant antitumor activity, indicating in vivo prodrug activation in tumors. PL-MLP may represent an effective therapeutic tool in a broad spectrum of malignancies, including multi-drug resistant tumors, with improved safety over free MMC, and is due to be tested in a human phase I study in 2012.