Effective oral combination metronomic chemotherapy with low toxicity for the management of castration-resistant prostate cancer

Abstract

Abstract. Prostate cancer (PC) was previously believed to be a chemoresistant disease. In recent years taxane-based chemotherapy has been shown to prolong survival in patients with castration-resistant prostate cancer (CRPC). It remains to be shown, however, which type of chemotherapy provides the most beneficial effect with the least amount of side effects. Seventeen patients with chemonaive CRPC were enrolled in a pilot study evaluating an orally administered chemo-hormonal treatment regimen using a weekly sequential combination called KEES; consisting of ketoconazole in combination with cyclophosphamide or etoposide in combination with estramustine administered on alternate weeks. Prednisone was administered throughout the treatment period. Prostate-specific antigen (PSA) response and acute and chronic toxicities were evaluated. Seventeen patients with CRPC were treated; eleven patients demonstrated a median reduction in PSA of 87% (range 26-99%). Ten (59%) patients responded with a decrease in PSA >50%. Thrombocytopenia and anaemia were the most common side effects. One study fatality was reported, however, it was unclear whether this was treatment related. In conclusion, KEES may be a promising option for patients with CRPC, resulting in a clear reduction in PSA with limited toxicity. Further clinical evaluation of this metronomic chemohormonal combination is underway.

Population-based study on use of chemotherapy in men with castration resistant prostate cancer

“…Based on this assumption, a total of 465/556 (84%) men had received some docetaxel containing regimen. A small group, 66/556 men (12%) received only peroral chemotherapy out of which single cyclophosphamide was most common followed by single estramustine and KEES (peroral combination therapy regimen including ketoconazole, estramustine, etoposide and cyclophosphamide (Table II) [17]. The majority of men, 75/105 (71%), who received chemotherapy less than two months prior to death received docetaxel, 14/105 (13%) men received mitoxantrone, 1/105 (1%) man received docetaxel and mitoxantrone and 15/105 (14%) men received other types of chemotherapy.…”

Metronomic chemotherapy from rationale to clinical studies: A dream or reality?

“…Thrombocytopenia and anemia were the most common side effects. The authors concluded that KEES might be a promising option for patients with CRPC, resulting in a clear reduction in PSA with limited toxicity [79]. In a phase II study, Gebbia et al investigated the activity and toxicity of metronomic chemotherapy with lowdose oral cyclophosphamide (50 mg/day) and methotrexate (2.5 mg twice/week), without rest periods, in 58 patients with metastatic CRPC that progressed after docetaxel.…”

Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience

“…No grade 4 toxicities were reported, with grade 3 toxicities being neutropenia (5%), thrombocytopenia, diarrhea, and stomatitis (2.5%) [119]. Another modified scheme consisting of ketoconazole in combination with estramustine, cyclophosphamide, or etoposide administered on alternate weeks, suggested by Jellvert et al, achieved a 59% decrease in PSA >50% [120]. In another multicenter trial with oral etoposide and estramustine 15 mg/kg daily in 55 patients, 22% of PSA response was reported [121].…”