Chlorambucil and lomustine (CL56) in absolute hormone refractory prostate cancer: re-induction of endocrine sensitivity an unexpected finding

Abstract

The management of androgen independent prostate cancer is increasingly disputed. Diethylstilbestrol and steroids have useful second-line activity in its management. The value of chemotherapy still remains contentious. This paper reports a phase 2 study of two orally active chemotherapy drugs in patients who are absolutely hormone refractory having failed primary androgen blockade and combined oestrogens and corticosteroids. In total, 37 patients who were biochemically castrate with absolute hormone refractory prostate cancer and performance status of 0 -3 were enrolled. Therapy consisted of chlorambucil 1 mg kg À1 given as 6 mg a day until the total dose was reached and lomustine 2 mg kg À1 given every 56 days (CL56). During this time all hormone therapy was stopped. One patient normalised his PSA with a further two having a greater than 50% decline leading to an objective response rate of 10%. The median time to progression was 3.6 months with an overall survival of 7.1 months. The median survival of this group of patients from first becoming androgen independent was 23.5 months. Eight of 17 (47%) patients who were subsequently rechallenged with hormonal therapy following failure of chemotherapy had a further PSA reduction, three (17%) of which were 450%. The median progression-free interval for the eight patients was 4 months. In conclusion, CL56 has a low objective response rate in the management of absolute hormone refractory prostate cancer. Toxicity was mild. Re-induction of hormone sensitivity following failure of chemotherapy was an unexpected finding that requires further study.

Re-induction of hormone sensitivity to diethylstilboestrol in androgen refractory prostate cancer patients following chemotherapy

“…A criticism of the study by Shamash et al (2005), is that the patients were not androgen suppressed during chemotherapy, and therefore responses to the reinduction of hormone therapy may have been due to the growth of androgen-dependent clones. However, two patients with a previous orchidectomy, and therefore castrate during chemotherapy, responded to rechallenge with DES in their study.…”

“…Recently, Shamash et al (2005) reported on the reinduction of hormone-sensitivity in androgen refractory prostate cancer patients following chemotherapy with lomustine and chlorambucil. In their prospective study, eight out of 17 (47%) patients who were rechallenged with hormonal therapy following the failure of chemotherapy had a prostate specific antigen (PSA) response.…”

A phase II study investigating the re-induction of endocrine sensitivity following chemotherapy in androgen-independent prostate cancer

“…All patients received oral chemotherapy with chlorambucil 1 mg kg À1 starting day 1, lomustine 2 mg kg À1 day 1, etoposide 50 mg daily from day 22 -28 and 36 -42, with the cycle repeating every 56 days. This treatment was based on a previously published regimen (Shamash et al, 2005). Patients were biochemically castrate (testosterone o1.5 nmol l À1 or failed maximum androgen blockade (MAB)) before starting the chemotherapy.…”

“…In a previous chemotherapy study involving castrate patients AIPC, we anecdotally observed that re-induction of hormone sensitivity was possible if endocrine therapy was stopped during chemotherapy (Shamash et al, 2005). Therefore, a prospective phase II study was designed to investigate this observation.…”

Whole Blood Stem Cell Reinfusion and Escalated Dose Melphalan in Castration-Resistant Prostate Cancer: A Phase 1 Study

“…Cabazitaxel has now been approved by the U.S. Food and Drug Administration though many consider the toxicities unacceptable (8,9); alkylating agents have also been used in the management of prostate cancer for many years although no effects on survival have been observed (10,11). In one phase 2 study of intravenous melphalan using 30 mg/m 2 every 4 weeks in 27 patients, there were no objective responses although one quarter received more than 4 months of therapy due to overall disease stabilization (12).…”