In a previously published, prospective, randomized trial, patients with pathologically proven prostate cancer in advanced stages (M1), osseous metastasis and resistance to hormone therapy were given two, 7 day courses of oral Apatone (VC at 5 g/m2
/day and VK3
at 50 mg/m2
/day), VC alone, VK3
alone, or a placebo.14
The 7day courses of treatment occurred during the first and fourth week of the study with two weeks of follow up after each treatment period. For the vitamin combination, homocysteine (a marker of tumor cell death induced by Apatone) assays showed an immediate and statistically significant drop (p<<0.01) in tumor cell numbers, while PSA serum levels rose in the two initial weeks and then fell to levels that were significantly different (p
<< 0.01) from the control group. For VC and VK3
alone, a non-significant difference was observed between the serum levels of homocysteine and PSA compared to the control group which suggested that the decreased PSA levels were due to tumor cell death.14
In this study, Apatone was administered daily in a single oral dose which was 2.5 to 3 times higher than the dose employed during the initial 12 weeks of our study. This dose resulted in a significant decrease in patient PSA levels which was ascribed to Apatone- induced tumor cell death by autoschizis. Conversely, the lower Apatone doses employed in the current study, led to increased PSADT without decreasing patient PSA levels.
In the previous study, Apatone was given in a single daily dose.14
However, Apatone was designed as an adjunctive therapy for existing treatment regimens with Apatone being administered intravenously in a bolus immediately prior to chemotherapy or radiotherapy and then in daily oral maintenance doses between therapies to prevent tumor growth following washout of the chemotherapeutic agent. In addition, pharmacokinetic studies indicated serum vitamin C levels returned to steady-state values within 5 to 6 hours of oral administration.15
For these reasons, Apatone was given every 5 to 6 hours in this study. During the 12 week course of the study, PSADT was the primary endpoint. Using this criterion, thirteen of 17 patients had significant increases in PSA doubling time. Following the initial 12 week trial, two of the three “non-responders” in the study who had large body mass index values were given increased Apatone doses adjusted to compensate for their elevated BMI values. Both patients subsequently became “responders”. In addition, 15 of 17 patients opted to continue Apatone therapy following the 12 week trial. The PSA values of these patients were checked at various intervals while on treatment and remained stable. Therapy was not discontinued in any patient due to vitamin toxicity or for other safety reasons.
PSADT has been useful in predicting treatment outcome before definitive therapy. For example, PSADT significantly correlated with biochemical recurrence16
, linearly correlated with the interval to clinical relapse after PSA failure following radiation therapy for prostate cancer17
, and was the most powerful indicator of disease activity in men under observation alone.18
When pretreatment variables in patients with androgen-independent prostate cancer were analyzed to determine the effect on PSA response after initiating maximum androgen blockade, increased PSADT was the only significant predictor of response.19
These results and others have led D'Amico to conclude that PSADT is sufficiently robust as a surrogate marker of prostate cancer survival to serve as a valid endpoint in trials of patients with hormone-refractory disease.17
More recently, PSADT has been used as an effective in vivo method for screening nontoxic agents, such as dihydroxyvitamin D3 (calcitriol), that increase PSADT without concomitantly decreasing PSA and yet become clinically valuable when used in combination with other anticancer agents.11
Our results demonstrate that oral Apatone significantly increased the PSADT of almost all the patients without concomitantly decreasing PSA, while co-administration of Apatone with known chemotherapeutic agents in other cancers resulted in a synergistic increase in antitumor activity.8,20
These results suggest that Apatone may find use in the clinic as a co-adjuvant therapy potentially in addition to docetaxol. Our decision not to include patients with alkaline phosphatase over 200 U/l may have excluded a number of men with osteoblastic bone lesions from metastases. This inherent selection bias does not allow us to examine the potential role of Apatone as salvage therapy, potentially after failure of docetaxol chemotherapy in hormone refractory patients.