HOW LOW IS THE / RATIO FOR PROSTATE CANCER?

Purpose: It has been suggested recently that the / ratio for human prostate cancer is low (around 1.5 Gy), and much debate on the evidence for such a low value is ongoing. Analyses reported so far ignored the contribution of tumor repopulation. Extremely low values and unrealistic cell numbers of tumor clonogens are found in these studies. In this paper, we present a comprehensive analysis of the updated clinical data to derive a self-consistent set of parameters for the linear-quadratic (LQ) model. Methods and Materials: The generalized LQ model, considering the effects of dose rate, sublethal damage repair, and clonogenic proliferation, was used to analyze the recently reported clinical data for prostate cancer using either external-beam radiotherapy or brachytherapy. Three LQ parameters, , /, and the repair time, were determined based on the clinical finding that the external-beam radiotherapy and the 125 I and 103 Pd permanent implants are biologically equivalent. The tumor control probability model was used also to analyze the clinical data to obtain an independent relationship of / vs. and to estimate clonogenic cell numbers for patients in different risk groups. Results: Based on the analysis of clinical data and a consideration of repopulation effect, we have derived a self-consistent set of LQ parameters for prostate cancer: 0.15 0.04 Gy 1 , / 3.1 0.5 Gy. Our analysis indicates the half-time of sublethal damage repair to be in the range from 0 to 90 min with a best estimate of 16 min. The best estimate of clonogenic cell numbers in prostate tumors is found to range from 10 6 to 10 7 according to the patient risk level. These values are more realistic than those derived previously (only 10 ‐100). Conclusions: The effect of tumor repopulation is not negligible in determining the LQ parameters for prostate cancer, especially for the low-dose-rate permanent implants. Analysis of clinical data for prostate cancer with corrections for damage repair and repopulation effects results in a low / ratio of 3.1 Gy. Unrealistic clonogenic cell numbers and extremely small values of reported in the literature can be resolved by correcting for repopulation effect. The LQ parameters derived presently from the clinical data are consistent with reports of intrinsic radiosensitivity in vitro. © 2003 Elsevier Science Inc. Prostate cancer, Radiotherapy, Linear-quadratic model, Tumor repopulation.

[1]  D J Brenner,et al.  Fractionation and protraction for radiotherapy of prostate carcinoma. , 1999, International journal of radiation oncology, biology, physics.

[2]  S. Webb.  The Physics of Conformal Radiotherapy: Advances in Technology , 1997 .

[3]  R G Dale,et al.  The application of the linear-quadratic dose-effect equation to fractionated and protracted radiotherapy. , 1985, The British journal of radiology.

[4]  I. Rosen,et al.  4 Preliminary results of a randomized dose-escalation study comparing 70 GY to 78 GY for the treatment of prostate cancer , 1999 .

[5]  A. Horwich,et al.  The dose-rate effect in human tumour cells. , 1987, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[6]  H D Thames,et al.  Time-dose factors in radiotherapy: a review of the human data. , 1990, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[7]  A. Pollack,et al.  External beam radiotherapy dose response of prostate cancer. , 1997, International journal of radiation oncology, biology, physics.

[8]  R. Dale,et al.  A theoretical investigation into the role of tumour radiosensitivity, clonogen repopulation, tumour shrinkage and radionuclide RBE in permanent brachytherapy implants of 125I and 103Pd , 2001, Physics in medicine and biology.

[9]  D. Brenner,et al.  Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy. , 1991, International journal of radiation oncology, biology, physics.

[10]  H. Kampinga,et al.  Correlation between slowly repairable double-strand breaks and thermal radiosensitization in the human HeLa S3 cell line. , 1997, International journal of radiation biology.

[11]  R. Stock,et al.  A dose-response study for I-125 prostate implants. , 1998, International journal of radiation oncology, biology, physics.

[12]  William R. Fair,et al.  DOSE ESCALATION WITH THREE-DIMENSIONAL CONFORMAL RADIATION THERAPY AFFECTS THE OUTCOME IN PROSTATE CANCER , 1998 .

[13]  J. Fowler.  The linear-quadratic formula and progress in fractionated radiotherapy. , 1989, The British journal of radiology.

[14]  C. Mayo,et al.  Is the prostate α/β ratio of 1.5 from Brenner & Hall a modeling artifact?1 , 2000 .

[15]  F. Vicini,et al.  The importance of adequate follow-up in defining treatment success after external beam irradiation for prostate cancer. , 1999, International journal of radiation oncology, biology, physics.

[16]  D. Brenner,et al.  Direct evidence that prostate tumors show high sensitivity to fractionation (low α/β ratio), similar to late-responding normal tissue , 2002 .

[17]  B. Wouters,et al.  Substructure in the radiation survival response at low dose in cells of human tumor cell lines. , 1996, Radiation research.

[18]  G. Hanks,et al.  Radiation inactivation of human prostate cancer cells: the role of apoptosis. , 1996, Radiation research.

[19]  C C Ling,et al.  Fitting tumor control probability models to biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer: pitfalls in deducing radiobiologic parameters for tumors from clinical data. , 2001, International journal of radiation oncology, biology, physics.

[20]  William H. Press,et al.  Numerical Recipes: FORTRAN , 1988 .

[21]  Duchesne Gm,et al.  What is the alpha/beta ratio for prostate cancer? Rationale for hypofractionated high-dose-rate brachytherapy. , 1999 .

[22]  A. Hercbergs,et al.  Radiobiological studies of PC-3 and DU-145 human prostate cancer cells: x-ray sensitivity in vitro and hypoxic fractions of xenografted tumors in vivo. , 1993, International journal of radiation oncology, biology, physics.

[23]  C. King,et al.  Optimal radiotherapy for prostate cancer: predictions for conventional external beam, IMRT, and brachytherapy from radiobiologic models. , 2000, International journal of radiation oncology, biology, physics.

[24]  R K Sachs,et al.  The link between low-LET dose-response relations and the underlying kinetics of damage production/repair/misrepair. , 1997, International journal of radiation biology.

[25]  G. Hanks.  Conformal radiotherapy for prostate cancer , 2000, Annals of medicine.

[26]  S. Stokes,et al.  Comparison of biochemical disease-free survival of patients with localized carcinoma of the prostate undergoing radical prostatectomy, transperineal ultrasound-guided radioactive seed implantation, or definitive external beam irradiation. , 2000, International journal of radiation oncology, biology, physics.

[27]  D. Brenner,et al.  In response to Drs. King and Mayo: low α/β values for prostate appear to be independent of modeling details1 , 2000 .

[28]  J. Fowler,et al.  A comment on proliferation rates in human prostate cancer. , 2000, International journal of radiation oncology, biology, physics.

[29]  R. Dale.  Radiobiological assessment of permanent implants using tumour repopulation factors in the linear-quadratic model. , 1989, The British journal of radiology.

[30]  T. DeWeese,et al.  Sensitivity of human prostatic carcinoma cell lines to low dose rate radiation exposure. , 1998, The Journal of urology.

[31]  J. Fowler,et al.  The prospects for new treatments for prostate cancer. , 2002, International journal of radiation oncology, biology, physics.

[32]  S Webb,et al.  A model for calculating tumour control probability in radiotherapy including the effects of inhomogeneous distributions of dose and clonogenic cell density. , 1993, Physics in medicine and biology.

[33]  J. Fowler,et al.  A simple analytic derivation suggests that prostate cancer α/β ratio is low , 2001 .

[34]  A. Hanlon,et al.  Dose selection for prostate cancer patients based on dose comparison and dose response studies. , 2000, International journal of radiation oncology, biology, physics.

[35]  T E Schultheiss,et al.  Optimization of conformal radiation treatment of prostate cancer: report of a dose escalation study. , 1997, International journal of radiation oncology, biology, physics.

[36]  Warren D. D'Souza,et al.  Is the α/β ratio for prostate cancer low? , 2001 .

[37]  Rick Chappell,et al.  Is α/β for prostate tumors really low? , 2001 .

[38]  D. Brenner.  Toward optimal external-beam fractionation for prostate cancer. , 2000, International journal of radiation oncology, biology, physics.

[39]  J F Williamson,et al.  Recommendations of the American Association of Physicists in Medicine on 103Pd interstitial source calibration and dosimetry: implications for dose specification and prescription. , 2000, Medical physics.