Phase III trial of cyclophosphamide versus cyclophosphamide, doxorubicin, and methotrexate in hormone-refractory prostatic cancer: A hoosier oncology group study

Abstract

Background. Between August 1984 and November 1989, the Hoosier Oncology Group conducted a Phase III study comparing cyclophosphamide (CTX) with cyclophosphamide, doxorubicin, and methotrexate (CAM) in patients with hormone‐refractory metastatic prostatic cancer to determine whether the addition of doxorubicin and methotrexate to the cyclophosphamide regimen conferred any survival advantage. Methods. One hundred three patients were registered and randomized, 99 were evaluable for response, and all were evaluable for survival results. All had histologically confirmed metastatic prostatic cancer and had not responded to hormonal therapy. Fifty‐three patients received CTX alone, and 50 received CAM. Seventy‐one patients (69%) had evaluable disease, and 32 (31%) had measurable disease. Results. There were no complete responses and only four (13%) partial responses in the patients with measurable disease. There was no difference in overall survival time between the two treatment arms in either patients with a Karnofsky performance status (KPS) of 80‐100 (median survival, 9.0 versus 9.5 months; P = 0.93) or in those with a KPS of 50‐70 (median survival, 5.0 versus 6.0 months; P = 0.51). There was no difference in overall time to progression between the two treatment arms (median time to progression; 4.4 versus 6.2 months; P = 0.07). Toxicity was tolerable in both regimens. Conclusions. It was concluded that there was no survival advantage to CAM over CTX alone. New chemo‐therapeutic agents with greater activity against prostatic cancer must be identified.

Interferon‐alpha prevents selection of doxorubicin‐resistant undifferentiated‐androgen‐insensitive metastatic human prostate cancer cells

“…The development of androgen-insensitive prostate cancer metastasis represents the ®nal common pathway for patients dying of prostate cancer. DOX often produces transient responses in such patients [42,43,45] but, unfortunately, the vast majority of patients with androgen-insensitive metastases die of the disease [42±47]. We hypothesized that the development of drug-resistant prostate cancer cells could be related to the emergence of a highly undifferentiated state and that preventing the development of the dedifferentiated phenotype might be a relevant therapeutic strategy.…”

One-Carbon Metabolism in Prostate Cancer: The Role of Androgen Signaling

“…Today, multiple drugs targeting enzymes within the folate cycle are FDA-approved to treat a variety of cancer types [15]; however, these drugs have had mixed reports for the treatment of PCa. While early studies indicated that the antifolate, MTX, might have been beneficial in the treatment of CRPC, subsequent studies failed to support the original findings [213,214,215]. Because AR inhibition during ADT decreases polyamine synthesis, which may in turn increase methyl group availability in the folate cycle, it has been suggested that MTX may be more beneficial in the treatment of PCa at earlier stages of the disease [63,160].…”

Prolonged Remission of Fulminant Castrate-Resistant Prostate Cancer: A Case Report

“…Oral cyclophosphamide is active against CRPC both alone and in combination regimens 19 , and vincristine has modest single-agent activity against it. 20 Dexamethasone has significantly reduced PSA levels, and a substantial percentage of patients whose PSA decreased also had radiographic evidence of disease regression 21 , as did our patient.…”