Incorporating clinical measurements of hypoxia into tumor local control modeling of prostate cancer: implications for the alpha/beta ratio.
OBJECTIVE
The recently obtained low value of approximately 1.5 for the alpha/beta of prostate cancer has led us to reexamine the optimal prostate tumor biology parameters, while taking into account everything known about the radiation response of prostate clonogens for use in a predictive dose-response model.


METHODS
Averages of the literature values of the alpha- and beta-inactivation coefficients for human prostate cancer cell lines were calculated. A robust tumor local control probability (TLCP) model was used that required average alpha and beta, as well as sigma(alpha), for the interpatient variation in single-hit killing (alpha). Median PO(2) values <or=1 mm Hg in the prostates of Fox Chase Cancer Center brachytherapy patients had been found in 21% of 115 cases. The oxygen enhancement ratios of 1.75 and 3.25 for alpha- and beta-inactivation, respectively, measured for tumor cells in vitro, were incorporated into the TLCP model, together with a clonogen density of approximately 10(5) cells/cm(3). Severe hypoxia and radioresistance were estimated for a proportion of tumors that was increased with PSA level.


RESULTS
For asynchronous human prostate cell lines irradiated in air, alpha(mean) was 0.26 +/- 0.07 (standard error) Gy(-1), sigma(alpha) = 0.06 Gy(-1), and beta(mean) was 0.0312 Gy(-2) +/- 0.0064 (standard error) Gy(-2). The TLCP data indicated that most tumors that contained aerobic cells would be cured, whereas most tumors that contained hypoxic cells would not be cured by total doses of 76 to 80 Gy. Clinical response data from the literature for external beam dose escalation, stratified by PSA value, and for low-dose-rate brachytherapy, were well predicted by the model, where the alpha/beta ratio was 8.5 and 15.5 for well-oxygenated and hypoxic clonogens, respectively.


CONCLUSIONS
Neither alpha/beta ratio nor clonogen number need be extremely low to explain the response of prostate cancer to brachytherapy and external beam therapy, contradicting other recent analyses. It is strongly suggested that severe hypoxia in the prostates of certain patients limits the overall cancer cure rate by conventional radiation therapy.
Nahum
Alan E
AE
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Movsas
Benjamin
B
Horwitz
Eric M
EM
Stobbe
Corinne C
CC
Chapman
J Donald
JD
D001918:Brachytherapy / Q000379:methods; D015687:Cell Hypoxia; D002470:Cell Survival; D019583:Dose Fractionation, Radiation; D006801:Humans; D008297:Male; D008954:Models, Biological; D010100:Oxygen / Q000032:analysis; D010313:Partial Pressure; D011336:Probability; D011471:Prostatic Neoplasms / Q000503:physiopathology* / Q000532:radiotherapy*; D011836:Radiation Tolerance; D011853:Radiobiology; D011879:Radiotherapy Dosage; D014407:Tumor Cells, Cultured
D010100:Oxygen