Effect of sequencing of androgen deprivation and radiotherapy on prostate cancer growth.
OBJECTIVE
Androgen deprivation (AD) is frequently combined with radiotherapy (RT); however, the optimal sequence in vivo is currently unknown. Previous published work from our laboratory demonstrated that AD with RT was consistent with at least an additive, and possibly supra-additive, effect with the combined approach. We, therefore, performed additional experiments to elucidate the optimal sequence.


METHODS
R3327-G Dunning rat prostate tumor cells were grown s.c. in the flanks of Copenhagen rats. Treatment was initiated when the tumor reached approximately 1 cm(3). Temporary AD was performed by a transscrotal orchiectomy followed 14 days later with androgen restoration using s.c. testosterone implants. RT was delivered using (60)Co to 7 Gy. Seven groups, including the controls, were analyzed: Group 1, sham control (Day 0: AD + testosterone); 2, AD control (Day 0: AD, Day 14: testosterone); 3, RT alone on Day 7 (Day 0: AD + testosterone, Day 7 RT); 4, RT alone on Day 3 (Day 0: AD + testosterone, Day 3: RT); 5, RT during AD (Day 0: AD, Day 7: RT, Day 14: testosterone); 6, RT before AD (Day 0: RT, Day 3: AD, Day 17: testosterone); and Group 7, RT after AD (Day 0: AD, Day 14: testosterone, Day 17: RT). The doubling times for tumor growth were calculated for the seven groups from the end of treatment plus 1 day. Differences in doubling time were assessed using analysis of variance, with pair-wise comparisons accomplished using post-hoc Bonferroni tests.


RESULTS
An analysis of the differences in the tumor volume doubling time as measured from the end of treatment suggests that Groups 1 and 7 were statistically different from the other groups (p = 0.02). As expected, the sham control group had the shortest doubling time at 5.4 days and Group 7 (14 days of AD administered before RT) had the longest doubling time at 32.6 days. The findings were similar even after excluding an outlying doubling time of 85 days from Group 7 (p < 0.0001). To assess the effect of sequencing further, only Groups 5 through 7 (excluding the outlier) were compared in an analysis of variance with post-hoc Bonferroni tests. Group 7 (RT after AD) demonstrated a significantly longer doubling time than Groups 5 and 6 (p = 0.0024).


CONCLUSIONS
The results suggest that neoadjuvant AD may result in prolonged suppression of tumor growth, even after testosterone replacement.
Kaminski
Joseph M L
JM
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Hanlon
Alexandra L
AL
Joon
Daryl Lim
DL
Meistrich
Marvin
M
Hachem
Paul
P
Pollack
Alan
A
D000818:Animals; D004195:Disease Models, Animal; D016015:Logistic Models; D008297:Male; D008954:Models, Biological; D009367:Neoplasm Staging; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D018714:Radiotherapy, Adjuvant; D051381:Rats; D013739:Testosterone / Q000008:administration & dosage; D016896:Treatment Outcome
D013739:Testosterone