Prospective randomized Phase II trial of pegylated doxorubicin in the management of symptomatic hormone‐refractory prostate carcinoma

Abstract

BACKGROUNDLiposomal encapsulation of doxorubicin has been shown to reduce nonspecific delivery of this agent to normal tissue and to increase specific delivery to malignant cells. On the basis of doxorubicin's demonstrated clinical efficacy against hormone‐refractory prostate carcinoma (HRPCA), the authors conducted a prospective, randomized Phase II clinical trial to evaluate the feasibility, toxicity, and therapeutic efficacy associated with the pegylated form of this agent.METHODSForty‐eight patients with symptomatic HRPCA were randomized to receive pegylated liposomal doxorubicin at either 25 mg/m2 every 2 weeks for 12 cycles (Group A) or 50 mg/m2 every 4 weeks for 6 cycles (Group B). Thirty‐eight of these 48 patients (79%) presented with severe pain (corresponding to a pain score of 7.5 on a visual analog scale [VAS] ranging from 0 to 10) due to osseous metastases. Therapeutic efficacy was assessed by serial evaluation of serum prostate‐specific antigen (PSA) concentrations and by serial measurement of pain levels (using a VAS ranging from 0 to 10). Toxicity data were obtained using the National Cancer Institute of Canada/Cancer and Leukemia Group B criteria and the 30‐item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.RESULTSThe median patient age was 68.9 years (range, 58–79 years), and the mean follow‐up duration was 42 months. The mean pretreatment PSA level was 660.4 ng/mL (mean, 8–6340 ng/mL); an objective decrease in PSA levels (i.e., a decrease of > 50%) was observed in 8 of 31 patients (25.8%) in Group B, whereas no other patient in either group experienced such a decrease. The mean time to disease progression was 6.5 months, and the mean survival duration was 13.4 months. Patients in Group B had a significantly higher rate of response with respect to pain (52.6% vs. 28.6%; P = 0.04), and the mean 1‐year survival rate also was significantly higher in Group B (42% vs. 15%; P = 0.02). Severe side effects were observed, with 24 patients (50%) experiencing World Health Organization Grade 3/4 toxicity. Toxicity types differed significantly between Group A and Group B; palmar‐plantar erythrodysesthesia developed in 60% of patients in the former group (P < 0.0005), whereas tachycardia was more common in the latter group (39% of patients; P < 0.0005). No dose‐limiting cardiotoxicities or hematotoxicities were documented.CONCLUSIONSPegylated liposomal doxorubicin yielded a noteworthy objective palliative response rate and a mean survival of 13 months for patients with symptomatic HRPCA. The dosage tested in the current study should be used in future Phase II and Phase III trials of pegylated liposomal doxorubicin–containing combination regimens for patients with HRPCA. Cancer 2004. © 2004 American Cancer Society.

Impact of PSA flare-up in patients with hormone-refractory prostate cancer undergoing chemotherapy

“…Data suggest that AR mutations are present in approximately 10% of patients with prostate cancer who experience treatment failure with hormone therapy that included an antiandrogen. We described the flare-up in about 10% of our patients, other reported a similar frequency of the flare-up phenomenon [11,12]. The flare-up phenomenon is to our knowledge only described for cytotoxic regimens including co-medication with dexamethasone/prednisolone and/or estramustine.…”

“…An initial PSA elevation was first described after initiation of androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) agonists for advanced prostate cancer [9]. Beside this, PSA elevations shortly after induction of chemotherapy in HRPC were observed in patients treated with liposomal doxorubicin [10,11]. A PSA rise followed by a decrease of PSA below the baseline level can be considered a temporary flareup.…”

Therapeutic Efficacy Evaluation of 111In-Labeled PEGylated Liposomal Vinorelbine in Murine Colon Carcinoma with Multimodalities of Molecular Imaging

“…Polyethylene glycol (PEG) modification of the liposomes (PEGylated liposomes) was initially developed to resist opsonization, evade rapid clearance by the RES, and allow the liposomes to remain in the circulation for a prolonged period after systemic administration (6,7). The PEGylated liposomal formulation of doxorubicin has been applied as a treatment for AIDS-related Kaposi sarcoma (8,9), ovarian carcinoma (10,11), breast carcinoma (12,13), mullerian carcinoma (14), and prostate cancer (15,16). Furthermore, this approach has gained regulatory approval for use as a clinical therapy (8)(9)(10)(11)(12)(13).…”

Chemotherapy for prostate cancer

“…Der Zeitpunkt des Einsatzes dieser palliativen Therapieoption ist allerdings kritisch, da eine zu frühe Strontium-oder Samariumtherapie aufgrund der dadurch ausgelösten Myelosuppression den Einsatz einer nachfolgenden Chemotherapie erschweren kann [40,41].…”