Motexafin lutetium-photodynamic therapy of prostate cancer: short- and long-term effects on prostate-specific antigen

Abstract

Purpose: The time course of serum prostate-specific antigen (PSA) response to photodynamic therapy (PDT) of prostate cancer was measured.

Experimental design: Seventeen patients were treated in a phase I trial of motexafin lutetium-PDT. PDT dose was calculated in each patient as the product of the ex vivo measured pre-PDT photosensitizer level and the in situ measured light dose. Serum PSA level was measured within 2 months before PDT (baseline), and at day 1; weeks 1 to 3; months 1, 2, and 3; months 4 to 6; and months 7 to 11 after PDT.

Results: At 24 hours after PDT, serum PSA increased by 98% +/- 36% (mean +/- SE) relative to baseline levels (P = 0.007). When patients were dichotomized based on median PDT dose, those who received high PDT dose showed a 119% +/- 52% increase in PSA compared with a 54% +/- 27% increase in patients treated at low PDT dose. Patients treated with high versus low PDT dose showed a median biochemical delay of 82 versus 43 days (P = 0.024), with biochemical delay defined as the length of time between PDT and a nonreversible increase in PSA to a value greater than or equal to baseline.

Conclusions: Results show PDT to induce large, transient increases in serum PSA levels. Patients who experienced high PDT dose showed greater short-term increase in PSA and a significantly more durable PSA response (biochemical delay). These data strongly promote the need for individualized delivery of PDT dose and assessment of treatment effect in PDT of prostate cancer. Information gained from such patient-specific measurements could facilitate the introduction of multiple PDT sessions in patients who would benefit.

Figure 1

Time course of PSA response to PDT in patient 17 (A) and of the patient -averaged (mean ± SE) percent change in PSA after PDT (B). The % change in PSA was calculated as (100*(PSA_{after PDT} − PSA_{before PDT})/PSA_{before PDT}) for each patient using the pre-PDT PSA value closest to the time of treatment and the post-PDT PSA value in the time frame of interest. In plot A, the dashed line indicates when PDT was performed and the numerical insets indicate baseline, post-PDT maximum, and post-PDT minimum PSA values. In plot B, n = 12, 13, 13, 11, 9, 10, and 7 for each respective timeframe, in increasing order. Wk = week; m=month; “*” = p<0.05 for Wilcoxon signed rank test comparing post-PDT PSA values to baseline measurement in the same patient.

Figure 2

The average (mean ± SE) percent change in PSA a function of time after PDT in patients who experienced a PDT dose < (open bars) or ≥ (closed bars) the median dose of 116 $\frac{\mathit{ng}•J}{\mathit{mg}•{\mathit{cm}}^2}$. PDT dose was calculated as the product of tissue photosensitizer concentration and light dose, n = 4-6 (open bars) or 7-8 (closed bars). “+” = p<0.06 for Wilcoxon signed rank test comparing post-PDT PSA values to baseline measurement in the same patient.

Figure 3

Kaplan-Meier estimation of biochemical delay in the PSA response in patients treated with a PDT dose < or ≥ the median dose of 116 $\frac{\mathit{ng}•J}{\mathit{mg}•{\mathit{cm}}^2}$. Duration of biochemical delay was defined as the length of time between PDT and a nonreversible (i.e. not PDT-induced) increase in PSA to a value ≥ baseline. N = 6 and 8 for low and high dose PDT, respectively.

Figure 4

The PDT-induced change in PSA at 24 h after illumination as a function of pre-PDT photosensitizer concentration in the prostate (A); R² = 0.29, p=0.09. MLu concentration in prostatic biopsies collected before (closed symbols) and after (open symbols) PDT (B); times indicate the interval between drug administration and light delivery. MLu concentration was determined by spectrofluorometric assay of drug levels in prostate biopsies.

Figure 5

The average (mean ± SE) maximum percent change in PSA in patients (N=8) who experienced a decrease in prostate MLu concentration during PDT (MLu post/MLu pre <1) vs. those (N= 4) who did not experience a decrease in prostate MLu concentration (MLu post/pre >1). Maximum effect on PSA was calculated as 100*(PSA_{after PDT} − PSA_{before PDT})/PSA_{before PDT}) using the pre-PDT PSA value closest to the time of treatment and the post-PDT PSA value with the largest increase within 1 month of PDT. “*” = p<0.05 for a Wilcoxon signed rank test comparing post-PDT PSA values to baseline measurement in the same patient.