- Email: [email protected]
Dosimetric quality endpoints for low-dose-rate prostate brachytherapy using biological effective dose (bed) vs. conventional dose
Medical Dosimetry, Vol. 28, No. 4, pp. 255⫺259, 2003 Copyright © 2003 American Association of Medical Dosimetrists Printed in the USA. All rights reserved 0958-3947/03/$–see front matter
doi:10.1016/j.meddos.2003.04.001
DOSIMETRIC QUALITY ENDPOINTS FOR LOW-DOSE-RATE PROSTATE BRACHYTHERAPY USING BIOLOGICAL EFFECTIVE DOSE (BED) VS. CONVENTIONAL DOSE RACHANA SINGH, M.D., HANIA AL-HALLAQ, PH.D., CHARLES A. PELIZZARI, PH.D., GREGORY P. ZAGAJA, M.D., ANDREW CHEN, M.D., and ASHESH B. JANI, M.D., M.S.E.E. Departments of Radiation and Cellular Oncology and Urology, University of Chicago Hospitals, Chicago, IL (Received 30 May 2002; accepted 15 April 2003)
Abstract—The purpose of this study was to compare conventional low-dose-rate prostate brachytherapy dosimetric quality parameters with their biological effective dose (BED) counterparts. To validate a model for transformation from conventional dose to BED, the postimplant plans of 31 prostate brachytherapy patients were evaluated using conventional dose-volume histogram (DVH) quality endpoints and analogous BED-DVH endpoints. Based on CT scans obtained 4 weeks after implantation, DVHs were computed and standard dosimetric endpoints V100 (volume receiving 100% of the prescribed dose), V150, V200, HI (1ⴚ[V150/V100]), and D90 (dose that 90% of the target volume received) were obtained for quality analysis. Using known and reported transformations, dose grids were transformed to BED-early (␣/ ⴝ 10 Gy) and BED-late (␣/ ⴝ 3 Gy) grids, and the same dosimetric endpoints were analyzed. For conventional, BED-early and BED-late DVHs, no differences in V100 were seen (0.896, 0.893, and 0.894, respectively). However, V150 and V200 were significantly higher for both BED-early (0.582 and 0.316) and BED-late (0.595 and 0.337), compared with the conventional (0.539 and 0.255) DVHs. D90 was significantly lower for the BED-early (103.1 Gy) and BED-late transformations (106.9 Gy) as compared with the conventional (119.5 Gy) DVHs. The conventional prescription parameter V100 is the same for the corresponding BED-early and BED-late transformed DVHs. The toxicity parameters V150 and V200 are slightly higher using the BED transformations, suggesting that the BED doses are somewhat higher than predicted using conventional DVHs. The prescription/quality parameter D90 is slightly lower, implying that target coverage is lower than predicted using conventional DVHs. This methodology can be applied to analyze BED dosimetric endpoints to improve clinical outcome and reduce complications of prostate brachytherapy. © 2003 American Association of Medical Dosimetrists. Key Words: Prostate cancer, Brachytherapy, Biological effective dose, Dose-volume histogram.
stage patients,2– 8 brachytherapy is an established treatment option in varied stages of prostate cancer. While the multiple uses of brachytherapy in prostate cancer are well established, they all rely on optimal and uniform dosimetric coverage of the target volume. The assessment of dosimetric quality of an implant relies on postimplant dose-volume histogram (DVH) analysis, most commonly using CI images,9,10 and involves correlation with the CT with the preplan ultrasound prostate volume. The common endpoints of postimplant analysis include D90 (the dose delivered to 90% of the target volume), V100 (the volume receiving 100% of the prescribed dose), and, similarly, V150 and V200. The homogeneity index (HI) (defined as [1 ⫺ (V150/V100)]) is also commonly assessed. These dosimetric endpoints are used ubiquitously in evaluating the quality of the implant, and quantifying the delivery of physical dose to the target.11,12 Biological effective dose (BED) is defined by both physical and radiobiologic factors, and reflects the amount of lethal damage sustained by accounting for the dose received by a given tissue over time and its biological response.13,14 As a result, using BED-DVH-based
INTRODUCTION Prostate cancer is the most common malignancy for which health care intervention is sought in the United States.1 Widespread screening efforts, using the combination of digital rectal exam (DRE) and prostate-specific antigen (PSA) have allowed prostate cancer to be diagnosed earlier in its natural history and, in turn, has allowed a number of treatment options to become available for early-stage prostate cancer. Transperineal prostate brachytherapy has become widely accepted as a form of curative therapy for selected early-stage patients, with clinical and biochemical results comparable to modern external beam and prostatectomy series in similar patients.2–7 With recent reports demonstrating similar biochemical outcomes between external beam radiation therapy and brachytherapy in well-selected early-stage patients and others demonstrating outcome improvement with dose escalation with external beam radiotherapy with or without hormone therapy in unfavorable laterReprint requests to: Ashesh B. Jani, M.D., M.S.E.E., University of Chicago Hospitals, Department of Radiation and Cellular Oncology, 5758 S. Maryland Avenue, MC 9006, Chicago, IL 60637. E-mail: [email protected] 255
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endpoints as an alternative to conventional-DVH-based endpoints may yield a more realistic and precise quality analysis of prostate brachytherapy. BED-based analysis may better correlate with toxicity and outcome data by accounting more accurately for responses based on the ␣/-based responses of various tissues and changes in dose rate secondary to constant falloff of the implanted sources.15–18 In a previous investigation from our institution,19 BED-DVHs correlated better than conventional DVHs of external beam radiation in predicting late gastrointestinal (GI) and genitourinary (GU) toxicities. In a separate investigation, BED-DVHs have allowed for the successful quantitative merging of external beam and brachytherapy treatment plans.20 This investigation concentrates on exploring the relationship between BED-DVH quality endpoints and their conventional DVH counterparts and examining whether BED-DVHs can accurately be used in assessing brachytherapy quality in the clinic. We report our preliminary experience with the application of BED transformation of conventional implant quality endpoints obtained from postimplant CT scans. METHODS The model used for transformation from conventional to BED dose in described below. For interstitial brachytherapy, BED incorporates, among other factors, initial dose rate, isotope half-life, tissue type, and repopulation terms.13–18 Although the model can be expanded to include any of many different isotopes, the current investigation was limited to Iodine-125 (125I). Analytically,
再
冉 冊冎 冉
BED ⫽ D 1⫹2(d 0*)(/␣)ⴱ
⫺
⫺
冊
0.693*T ␣ ⴱTp
with ⫽
冉 冊 再冉 1 ⴱ 1⫺
冊 冋
册冎
1 ⫺ 2 1 ⫺ 共ⴱe ⫺Teff) ⫺ 2* ⫹
and 1 Teff ⫽ ⴱln关共1.44*d0兲*共 ␣ *Tp兲兴
(1)
where: D ⫽ total conventional (prescription) dose in Gy do ⫽ initial dose rate in Gy/h ⫽ 0.693/t1/2 ⬇ 0.01166/day [t1/2 ⫽ half-life of 125 I ⫽ 60 days] ⫽ 0.693/t1/2 (repair) ⬇ 11.09/day [t1/2 (repair) ⫽ 1.5 h] ⬇ 45.10/day ␣/ ⫽ 10 Gy (early toxicity or tumor control) or 3 Gy (late toxicity) ␣ ⫽ 0.3/Gy ⫽ e⫺Teff ⫽ 0.0541
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Fig. 1. BED and scaled conventional dose vs. conventional dose for early effects (␣/ ⫽ 10). Plotted dose (BED-early dose [solid line] and scaled conventional dose [dashed line]) against conventional dose. The scaled conventional dose was chosen to intersect at the prescription dose (in this case, 100 Gy).
Tp ⫽ potential doubling time ⫽ 34 days T ⫽ Teff ⬇ 250.2 days* For this investigation, D ⫽ 144, 110, or 108 Gy, and the corresponding do ⫽ 1.69 Gy/day (for D ⫽ 144 Gy), 1.29 Gy/day (for D ⫽ 110 Gy), and 1.27 Gy/day (for D ⫽ 108 Gy). For the above BED model, there is considerable controversy as to the actual values to be used above for many of the parameters,21–25 and, furthermore, there are many different BED models in existence;26 however, the robustness of the model is not central to the goals of the current investigation. Because Eq. (1) is highly nonlinear, it is a formidable task to predict intuitively what effects the BED transformations would have on the chosen dosimetric quality endpoints (V100, V150, V200, HI, and D90). To facilitate the predictions, the authors found it useful to plot the conventional dose vs. the transformed dose. These plots are shown in Fig. 1 (BED-early vs. conventional dose) and Fig. 2 (BED-late vs. conventional dose). As shown in Fig. 1, the scaled conventional dose was chosen to intersect at the prescription dose (in this case chosen as 100 Gy). The underlying assumption is that V100 should not change as a function of BED transformation. Intuitively, this implies that the prescribed dose, when transformed, is still the prescribed dose after the BED transformation; therefore the volume receiving this prescribed dose should not change. Figure 1 can also be used to predict changes in V150 because the BED dose increases faster than conventional dose at values of dose above the prescribed dose (i.e., the solid line is above the dashed line for values above 100% of the prescribed dose). Intuitively, this implies that the volume receiving 150% of the prescribed dose will be higher after the BED transformation than for the conventional dose, and thus V150 would be expected to be higher after the BED-early transformation than on the
BED vs. conventional prostate brachy dose endpoints ● R. SINGH et al.
Fig. 2. BED and scaled conventional dose vs. conventional dose for late effects (␣/ ⫽ 3). Plotted dose (BED-late dose [solid line] and scaled conventional dose [dashed line]) against conventional dose. The scaled conventional dose was chosen to intersect at the prescription dose (in this case, 100 Gy).
conventional DVH. This argument can be logically extended for V200 —as the difference between the solid and dashed curves increases with increasing dose, the increase in V200 after the BED transformation would be expected to be even greater than the increase for V150. With regard to HI, because it is arithmetically related to V150 and V100 (i.e., HI ⫽ (1 ⫺ [V150/V100])), if V100 remains the same and V150 increases after the BED transformation, the HI would be expected to be lower. Figure 1 can also be used to predict the effect of the BED transformation on D90. Because the BED transformation shows a lower dose at the 90% level than conventional dose (i.e., the solid curve is below the dashed curve for values below the prescription dose), D90 would be expected to be lower after the BED transformation than it was on the conventional DVH. Figure 2 shows the identical analysis for BED-late transformation. This figure predicts that V100 would also be the same after the BED-late transformation. Using the difference in the solid and dashed curves, the effects on V150, V200, D90, and HI would be similar to that for BED-early transformation described above, but would be of a slightly greater magnitude (as the difference between the solid and dashed curves are in the same direction as seen on Fig. 1 but are amplified; that is, for Fig. 2, the solid curve is higher than the dashed curve in Fig. 1 for values above the prescription dose, and the solid curve is lower than the dashed curve in Fig. 1 for values below the prescription dose). This model was applied to 31 patients who had undergone permanent transperineal prostate brachytherapy at our institution from 2000 to 2001 for whom postimplant CT scan was available for dosimetric analysis. Reflecting the diverse applications of brachytherapy in prostate cancer, all patients had T1c-T2b disease, with PSA values ranging from 4.5 to 20, and Gleason scores of 5 to 7. Patients received external beam radiation
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therapy (EBRT) or neoadjuvant hormonal therapy (NAHT) prior to brachytherapy, based on the disease and anatomical characteristics of the individual, at the discretion of the attending radiation oncologist. Brachytherapy doses ranged from 108 to 110 Gy for boost doses (n ⫽ 20) following EBRT to 144 Gy for implant monotherapy (n ⫽ 11). Permanent NycomedAmersham Iodine-125 (125I) seeds were used for 24 implants while Imagyn Isostar 125I seeds were used for the remaining 7 implants. Uniform seed activities ranging from 0.27 mCi (brachytherapy following external beam radiation therapy) to 0.355 mCi (brachytherapy monotherapy) were used to plan the implant. Modified uniform loading was iteratively chosen to cover the prostate target with the prescription dose while ensuring that the urethra did not receive more than 50% of the prescription dose. Transperineal brachytherapy was performed cooperatively by a radiation oncologist and a urologist using preloaded needles. Four weeks following implant, patients returned for postimplant CT scan. CT scans were obtained using 1.5-mm slices through the prostate; prostate volumes were entered into CT-based treatment planning software. CT volumes were correlated with the ultrasound images obtained at the time of volume study and aligned manually at the rectal surface and the base of the prostate. This technique for alignment was chosen due to the relative consistency of these regions of the prostate across the different imaging modalities and because urethral-based registration was not possible due to lack of catheter-based urethral enhancement on the postimplant CT scans.27 Only the brachytherapy component of treatment was analyzed. Conventional DVHs were computed and standard dosimetric endpoints V100, V150, V200, HI (1⫺[V150/V100]), and D90 were obtained. Using the above reported transformations, dose grids were transformed to BED-early (␣/ ⫽ 10 Gy) and BED-late (␣/ ⫽ 3 Gy) grids, and the same dosimetric endpoints were obtained for analysis. Statistical analyses were performed for each BED-DVH dosimetric parameter (compared to its conventional-DVH counterpart) using the 2-sided paired student’s t-test. RESULTS The results of the analyses for the conventional DVHs BED-early DVHs, and BED-late DVHs are shown in Table 1 With regard to the conventional DVHs, for the reported cohort of patients, the average D90 was 119.5 ⫾ 18.7 Gy and the V100 was 0.896 ⫾ 0.045, corresponding well to published brachytherapy quality endpoints.9 –12 Toxicity endpoints V150 and V200 were 0.539 ⫾ 0.103 and 0.255 ⫾ 0.087, respectively, and the HI was 0.400 ⫾ 0.096; these values also correlate well with those reported in the published literature. As predicted in the methods section, and as seen in Table 1, there is good correlation of the common quality
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Table 1. Dosimetric quality endpoint summary and comparison
Conventional BED (early) p-value Mean diff BED (late) p-value Mean diff
V100
V150
V200
HI
D90 (Gy)
0.896 ⫾ 0.045 0.893 ⫾ 0.049 0.06 ⫺0.003 0.894 ⫾ 0.048 0.11 ⫺0.002
0.539 ⫾ 0.103 0.582 ⫾ 0.101 ⬍0.001 0.043 0.595 ⫾ 0.100 ⬍0.001 0.056
0.255 ⫾ 0.087 0.316 ⫾ 0.095 ⬍0.001 0.061 0.337 ⫾ 0.096 ⬍0.001 0.122
0.400 ⫾ 0.096 0.350 ⫾ 0.100 ⬍0.001 ⫺0.050 0.336 ⫾ 0.092 ⬍0.001 ⫺0.064
119.5 ⫾ 18.7 103.1 ⫾ 19.1 ⬍0.001 ⫺12.6 106.9 ⫾ 20.4 ⬍0.001 ⫺16.4
All non-italicized table entries are mean ⫾ standard deviation. p-values are results of the paired 2-way student’s t-test comparing a BED implant quality parameter with its counterpart conventional parameter. Mean diff ⫽ the difference in mean value of a BED implant quality parameter with its counterpart conventional parameter.
parameter V100 between conventional, early-BED, and late-BED DVHs. Quantitatively, there is no significant difference in the average V100 between conventional and BED-DVHs, either BED-early (p ⫽ 0.06) or BEDlate (p ⫽ 0.11) observed. This was predicted, as V100 is the volume receiving the prescribed dose—although the prescription dose changes with the transformation, the volume receiving this dose does not. When examining dose parameters that are known to correlate with toxicity, V150 and V200, the transformed DVHs reflect a higher delivered dose than the conventional DVHs both for BED-early (p ⬍ 0.001) and for BED-late (p ⬍ 0.001). Again, the increase in V150 after the BED transformation was predicted in the Methods section. Also, as demonstrated in the table, the mean difference in V200 is greater than the mean difference in V150. Furthermore, the mean differences in V150 and V200 are of greater magnitude, as predicted, for the BED-late transformation as compared with the BEDearly transformation. Because HI is arithmetically related to V150, it changes predictably, i.e., it is lower after the BED transformation, and is lower for the BED-late transformation than the BED-early transformation. The effects of the BED transformations on D90 are also shown in Table 1 As predicted in the Methods section, D90 is lower after the BED transformation is applied. Because the 90% dose line is close to the prescription (100%) dose, the absolute magnitude of decrease in D90 is similar between the BED-early and BED-late transformations. In summary, the dosimetric endpoints V100, V150, V200, HI, and D90 changed after the BED-early and BED-late transformations in a manner predicted by the models described in the Methods section. The potential clinical implications of these changes in the dosimetric endpoints are discussed below. DISCUSSION The construction of the BED-DVH was proposed herein to account for treatment delivery and tissue response parameters not reflected in the construction of the conventional DVH. Hence, the BED-DVH is more likely to correlate with clinical outcome and toxicity than the
conventional DVH. Because the BED-DVHs are nonlinear as a result of the transformation described in Eq. (1) and as demonstrated in (Figs. 1 and 2), BED dose values are lower than the conventional dose values in the dose range below the prescription dose, and higher than the conventional dose values in the dose range above the prescription dose. Also, although the prescription dose is itself transformed, the volume of tissue receiving the prescription dose should not change as a result of the transformation, and should allow for a uniform analysis of implant quality parameters. In other words, V100 is consistent between conventional-, early- and late-BEDDVHs, and reinforces the applicability of the transformation. In this context, the dosimetric parameters correlating best with toxicity, V150 and V200, are slightly (but highly significantly [p ⬍ 0.001]) higher (and, correspondingly, HI lower [p ⬍ 0.001]) for both the early- and late-BED-transformed DVHs as compared with the corresponding parameters obtained from the conventional DVHs. This implies that using the conventional-DVHbased parameters to evaluate the quality of a prostate brachytherapy treatment plan may result in a higher incidence of early and late toxicities than anticipated when using the corresponding BED-early and BED-late transformed parameters. The opposite result was found with respect to the implant parameter found best to correlate with treatment outcome, D90 (the dose delivered to at least 90% of the target volume, which correlates to the likelihood of a cure). Specifically, D90 is highly significantly [p ⬍ 0.001] lower for the BED-transformed DVHs as compared with the corresponding value obtained using conventional DVHs. This implies that using the conventional DVH to evaluate the quality of a prostate brachytherapy treatment plan may result in less than intended delivered dose, and potentially lower cure rate, than anticipated from using the corresponding BEDDVH. In this investigation, differences exist between the values of the parameters related to treatment toxicity (V150, V200, and HI) and the parameter relating to treatment outcome (D90) when comparing conventional
BED vs. conventional prostate brachy dose endpoints ● R. SINGH et al.
DVHs with their BED-early and BED-late counterparts. The central purpose of our analysis was to evaluate and quantitate the differences and make inferences about their potential role in improving prostate brachytherapy implant quality. We conclude that the BED-DVHs should be considered in addition to the conventional DVH when evaluating the quality of an implant, as there can be higher actual inhomogeneity (both with respect to higher than intended V150 and V200 [and corresponding lower HI], and with respect to lower than intended D90) than that predicted when using the conventional DVH alone. In this context, however, it should be noted that the authors are aware that the absolute magnitudes of the differences in dosimetric endpoints are relatively small. The true impact of these small differences in predicting outcome and toxicity cannot yet be stated with certainty and is beyond the scope of the current communication, which evaluated treatment plans from a strictly dosimetric standpoint. A separate, subsequent effort is currently underway to correlate the BED-DVH (as compared with conventional DVH) implant quality parameters with early and late toxicity and treatment outcome. REFERENCES 1. Sarma, A.V.; Schottenfeld, D. Prostate cancer incidence, mortality, and survival trends in the United States: 1981–2001. Semin. Urol. Oncol. 20:3–9; 2002. 2. Ragde, H.; Blasko, J.C.; Grimm, P.D.; et al. Interstitial I–125 radiation without adjuvant therapy in the treatment of clinically localized prostate cancer. Cancer 80:442–53; 1997. 3. Wallner, K.; Roy, J.; Harrison, L. Tumor control and morbidity following transperineal I-125 implantation for stage T1/T2 prostatic carcinoma. J. Clin. Oncol. 14:449 –453; 1996. 4. Blasko, J.C.; Wallner, K.; Grimm, P.D.; et al. Prostate specific antigen based disease control following ultrasound guided iodine125 implantation for stage T1/T2 prostatic carcinoma. J. Urol. 154:1096 –9; 1995. 5. Zelefsky, M.N.; Wallner, K.E.; Ling, C.; et al. Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for early-stage prostate cancer. J. Clin. Oncol. 17:517–22; 1999. 6. Grimm, P.D.; Blasko, J.C.; Sylvester, J.; et al. 10-year biochemical (prostate-specific antigen) control of prostate cancer with (125)I brachytherapy. Int. J. Radiat. Oncol. Biol. Phys. 51:31–40; 2001. 7. Blasko, J.C.; Grimm, P.D.; Cavanagh, W.; et al. Long term outcomes of external beam irradiation and I-125/Pd-103 brachytherapy boost for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 36:198 –203; 1996. 8. Sylvester, J.; Blasko, J.C.; Grimm, P.D.; et al. Short-course androgen ablation combined with external-beam radiation therapy and low-dose-rate permanent brachytherapy in early-stage prostate cancer: A matched subset analysis. Mol. Urol. 4:155–9; 2000.
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9. Willins, J.; Wallner, K. CT based dosimetry for transperineal I-125 prostate brachytherapy. Int. J. Radiat. Oncol. Biol. Phys. 39:347– 53; 1997. 10. Merrick, G.S.; Butler, W.M.; Dorsey, A.T.; et al. The dependence of prostate postimplant dosimetric quality on CT volume determination. Int. J. Radiat. Oncol. Biol. Phys. 44:1111–7; 1999. 11. Nag, S.; Beyer, D.; Friedland, J.; et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 44:789 –99; 1999. 12. Horwitz, E.M.; Mitra, R.K.; Das, I.J.; et al. Impact of target volume coverage with RTOG 98-05 guidelines for transrectal ultrasound guided permanent I-125 prostate implants. Radiother. Oncol. 55:68; 2000. 13. Hall, E.J. Radiobiology for the Radiobiologist. 5th ed. Philadelphia: JB Lippincott & Company; 2001: 211–29. 14. Dale, R.G.; Jones, B. The clinical radiobiology of brachytherapy. Br. J. Radiol. 71:465–83; 1998. 15. Dale, R.G. Radiobiological assessment of permanent implants using tumour repopulation factors in the linear-quadratic model. Br. J. Radiol. 62:241–4; 1989. 16. Dale, R.G.; Coles, I.P.; Deehan, C.; et al. Calculation of integrated biological response in brachytherapy. Int. J. Radiat. Oncol. Biol. Phys. 38:633–42; 1997. 17. Dale, R.G. Some theoretical derivations relating to the tissue dosimetry of brachytherapy nuclides, with particular reference to iodine-125. Med. Phys. 10:176 –83; 1983. 18. Ling, C.C. Permanent implants using Au-198, Pd-103, and I-125: Radiobiological considerations based on the linear quadratic model. Int. J. Radiat. Oncol. Biol. Phys. 23:81–87; 1991. 19. Jani A.B.; Hand C.M.; Pelizzari C.A.; et al. Biologically effective versus conventional dose volume histograms correlated with late gastrointestinal and genitourinary toxicity after external beam radiotherapy for prostate cancer. BMC Cancer 3: 2003. 20. Hand, C.M.; Lujan, A.E.; Roeske, J.C.; et al. The Use of Biological Effective Dose-Volume Histograms for Comparison of Prostate Cancer Treatment Plans. American Association of Physicists in Medicine Annual Meeting, Salt Lake City, Utah; July 2000. 21. Fowler, J.; Chappell, R.; Ritter, M. Is ␣/ for prostate tumors really low? Int. J. Radiat. Oncol. Biol. Phys. 50:1021–31; 2001. 22. Haustermans, K.M.G.; Hofland, I.; Van Poppel, H.; et al. Cell kinetic measurements in prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 37:1067–70; 1997. 23. King, C.R.; DiPetrillo, T.A.; Wazer, D.E. Optimal radiotherapy for prostate cancer: Predictions for conventional external beam, IMRT, and brachytherapy from radiobiologic models. Int. J. Radiat. Oncol. Biol. Phys. 46:165–72; 2000. 24. Ling, C.C.; Roy, J.; Sahoo, N.; et al. Quantifying the effect of dose inhomogeneity in brachytherapy: Application to permanent prostateic implant with 125I seeds. Int. J. Radiat. Oncol. Biol. Phys. 28:971–8; 1994. 25. Yaes, R.J. Late normal tissue injury from permanent interstitial implants. Int. J. Radiat. Oncol. Biol. Phys. 49:1163–9; 2001. 26. Fowler, J.F. Is repair of DNA strand break damage from ionizing radiation second-order rather than first-order? A simpler explanation of apparently multiexponential repair. Radiat. Res. 152:124 – 36; 1999. 27. Narayana, V.; Roberson, P.L.; Winfield, R.; et al. Impact of ultrasound and computed tomography prostate volume registration on evaluation of permanent prostate implants. Int. J. Radiat. Oncol. Biol. Phys. 39:341–6; 1997.
doi:10.1016/j.meddos.2003.04.001
DOSIMETRIC QUALITY ENDPOINTS FOR LOW-DOSE-RATE PROSTATE BRACHYTHERAPY USING BIOLOGICAL EFFECTIVE DOSE (BED) VS. CONVENTIONAL DOSE RACHANA SINGH, M.D., HANIA AL-HALLAQ, PH.D., CHARLES A. PELIZZARI, PH.D., GREGORY P. ZAGAJA, M.D., ANDREW CHEN, M.D., and ASHESH B. JANI, M.D., M.S.E.E. Departments of Radiation and Cellular Oncology and Urology, University of Chicago Hospitals, Chicago, IL (Received 30 May 2002; accepted 15 April 2003)
Abstract—The purpose of this study was to compare conventional low-dose-rate prostate brachytherapy dosimetric quality parameters with their biological effective dose (BED) counterparts. To validate a model for transformation from conventional dose to BED, the postimplant plans of 31 prostate brachytherapy patients were evaluated using conventional dose-volume histogram (DVH) quality endpoints and analogous BED-DVH endpoints. Based on CT scans obtained 4 weeks after implantation, DVHs were computed and standard dosimetric endpoints V100 (volume receiving 100% of the prescribed dose), V150, V200, HI (1ⴚ[V150/V100]), and D90 (dose that 90% of the target volume received) were obtained for quality analysis. Using known and reported transformations, dose grids were transformed to BED-early (␣/ ⴝ 10 Gy) and BED-late (␣/ ⴝ 3 Gy) grids, and the same dosimetric endpoints were analyzed. For conventional, BED-early and BED-late DVHs, no differences in V100 were seen (0.896, 0.893, and 0.894, respectively). However, V150 and V200 were significantly higher for both BED-early (0.582 and 0.316) and BED-late (0.595 and 0.337), compared with the conventional (0.539 and 0.255) DVHs. D90 was significantly lower for the BED-early (103.1 Gy) and BED-late transformations (106.9 Gy) as compared with the conventional (119.5 Gy) DVHs. The conventional prescription parameter V100 is the same for the corresponding BED-early and BED-late transformed DVHs. The toxicity parameters V150 and V200 are slightly higher using the BED transformations, suggesting that the BED doses are somewhat higher than predicted using conventional DVHs. The prescription/quality parameter D90 is slightly lower, implying that target coverage is lower than predicted using conventional DVHs. This methodology can be applied to analyze BED dosimetric endpoints to improve clinical outcome and reduce complications of prostate brachytherapy. © 2003 American Association of Medical Dosimetrists. Key Words: Prostate cancer, Brachytherapy, Biological effective dose, Dose-volume histogram.
stage patients,2– 8 brachytherapy is an established treatment option in varied stages of prostate cancer. While the multiple uses of brachytherapy in prostate cancer are well established, they all rely on optimal and uniform dosimetric coverage of the target volume. The assessment of dosimetric quality of an implant relies on postimplant dose-volume histogram (DVH) analysis, most commonly using CI images,9,10 and involves correlation with the CT with the preplan ultrasound prostate volume. The common endpoints of postimplant analysis include D90 (the dose delivered to 90% of the target volume), V100 (the volume receiving 100% of the prescribed dose), and, similarly, V150 and V200. The homogeneity index (HI) (defined as [1 ⫺ (V150/V100)]) is also commonly assessed. These dosimetric endpoints are used ubiquitously in evaluating the quality of the implant, and quantifying the delivery of physical dose to the target.11,12 Biological effective dose (BED) is defined by both physical and radiobiologic factors, and reflects the amount of lethal damage sustained by accounting for the dose received by a given tissue over time and its biological response.13,14 As a result, using BED-DVH-based
INTRODUCTION Prostate cancer is the most common malignancy for which health care intervention is sought in the United States.1 Widespread screening efforts, using the combination of digital rectal exam (DRE) and prostate-specific antigen (PSA) have allowed prostate cancer to be diagnosed earlier in its natural history and, in turn, has allowed a number of treatment options to become available for early-stage prostate cancer. Transperineal prostate brachytherapy has become widely accepted as a form of curative therapy for selected early-stage patients, with clinical and biochemical results comparable to modern external beam and prostatectomy series in similar patients.2–7 With recent reports demonstrating similar biochemical outcomes between external beam radiation therapy and brachytherapy in well-selected early-stage patients and others demonstrating outcome improvement with dose escalation with external beam radiotherapy with or without hormone therapy in unfavorable laterReprint requests to: Ashesh B. Jani, M.D., M.S.E.E., University of Chicago Hospitals, Department of Radiation and Cellular Oncology, 5758 S. Maryland Avenue, MC 9006, Chicago, IL 60637. E-mail: [email protected] 255
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endpoints as an alternative to conventional-DVH-based endpoints may yield a more realistic and precise quality analysis of prostate brachytherapy. BED-based analysis may better correlate with toxicity and outcome data by accounting more accurately for responses based on the ␣/-based responses of various tissues and changes in dose rate secondary to constant falloff of the implanted sources.15–18 In a previous investigation from our institution,19 BED-DVHs correlated better than conventional DVHs of external beam radiation in predicting late gastrointestinal (GI) and genitourinary (GU) toxicities. In a separate investigation, BED-DVHs have allowed for the successful quantitative merging of external beam and brachytherapy treatment plans.20 This investigation concentrates on exploring the relationship between BED-DVH quality endpoints and their conventional DVH counterparts and examining whether BED-DVHs can accurately be used in assessing brachytherapy quality in the clinic. We report our preliminary experience with the application of BED transformation of conventional implant quality endpoints obtained from postimplant CT scans. METHODS The model used for transformation from conventional to BED dose in described below. For interstitial brachytherapy, BED incorporates, among other factors, initial dose rate, isotope half-life, tissue type, and repopulation terms.13–18 Although the model can be expanded to include any of many different isotopes, the current investigation was limited to Iodine-125 (125I). Analytically,
再
冉 冊冎 冉
BED ⫽ D 1⫹2(d 0*)(/␣)ⴱ
⫺
⫺
冊
0.693*T ␣ ⴱTp
with ⫽
冉 冊 再冉 1 ⴱ 1⫺
冊 冋
册冎
1 ⫺ 2 1 ⫺ 共ⴱe ⫺Teff) ⫺ 2* ⫹
and 1 Teff ⫽ ⴱln关共1.44*d0兲*共 ␣ *Tp兲兴
(1)
where: D ⫽ total conventional (prescription) dose in Gy do ⫽ initial dose rate in Gy/h ⫽ 0.693/t1/2 ⬇ 0.01166/day [t1/2 ⫽ half-life of 125 I ⫽ 60 days] ⫽ 0.693/t1/2 (repair) ⬇ 11.09/day [t1/2 (repair) ⫽ 1.5 h] ⬇ 45.10/day ␣/ ⫽ 10 Gy (early toxicity or tumor control) or 3 Gy (late toxicity) ␣ ⫽ 0.3/Gy ⫽ e⫺Teff ⫽ 0.0541
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Fig. 1. BED and scaled conventional dose vs. conventional dose for early effects (␣/ ⫽ 10). Plotted dose (BED-early dose [solid line] and scaled conventional dose [dashed line]) against conventional dose. The scaled conventional dose was chosen to intersect at the prescription dose (in this case, 100 Gy).
Tp ⫽ potential doubling time ⫽ 34 days T ⫽ Teff ⬇ 250.2 days* For this investigation, D ⫽ 144, 110, or 108 Gy, and the corresponding do ⫽ 1.69 Gy/day (for D ⫽ 144 Gy), 1.29 Gy/day (for D ⫽ 110 Gy), and 1.27 Gy/day (for D ⫽ 108 Gy). For the above BED model, there is considerable controversy as to the actual values to be used above for many of the parameters,21–25 and, furthermore, there are many different BED models in existence;26 however, the robustness of the model is not central to the goals of the current investigation. Because Eq. (1) is highly nonlinear, it is a formidable task to predict intuitively what effects the BED transformations would have on the chosen dosimetric quality endpoints (V100, V150, V200, HI, and D90). To facilitate the predictions, the authors found it useful to plot the conventional dose vs. the transformed dose. These plots are shown in Fig. 1 (BED-early vs. conventional dose) and Fig. 2 (BED-late vs. conventional dose). As shown in Fig. 1, the scaled conventional dose was chosen to intersect at the prescription dose (in this case chosen as 100 Gy). The underlying assumption is that V100 should not change as a function of BED transformation. Intuitively, this implies that the prescribed dose, when transformed, is still the prescribed dose after the BED transformation; therefore the volume receiving this prescribed dose should not change. Figure 1 can also be used to predict changes in V150 because the BED dose increases faster than conventional dose at values of dose above the prescribed dose (i.e., the solid line is above the dashed line for values above 100% of the prescribed dose). Intuitively, this implies that the volume receiving 150% of the prescribed dose will be higher after the BED transformation than for the conventional dose, and thus V150 would be expected to be higher after the BED-early transformation than on the
BED vs. conventional prostate brachy dose endpoints ● R. SINGH et al.
Fig. 2. BED and scaled conventional dose vs. conventional dose for late effects (␣/ ⫽ 3). Plotted dose (BED-late dose [solid line] and scaled conventional dose [dashed line]) against conventional dose. The scaled conventional dose was chosen to intersect at the prescription dose (in this case, 100 Gy).
conventional DVH. This argument can be logically extended for V200 —as the difference between the solid and dashed curves increases with increasing dose, the increase in V200 after the BED transformation would be expected to be even greater than the increase for V150. With regard to HI, because it is arithmetically related to V150 and V100 (i.e., HI ⫽ (1 ⫺ [V150/V100])), if V100 remains the same and V150 increases after the BED transformation, the HI would be expected to be lower. Figure 1 can also be used to predict the effect of the BED transformation on D90. Because the BED transformation shows a lower dose at the 90% level than conventional dose (i.e., the solid curve is below the dashed curve for values below the prescription dose), D90 would be expected to be lower after the BED transformation than it was on the conventional DVH. Figure 2 shows the identical analysis for BED-late transformation. This figure predicts that V100 would also be the same after the BED-late transformation. Using the difference in the solid and dashed curves, the effects on V150, V200, D90, and HI would be similar to that for BED-early transformation described above, but would be of a slightly greater magnitude (as the difference between the solid and dashed curves are in the same direction as seen on Fig. 1 but are amplified; that is, for Fig. 2, the solid curve is higher than the dashed curve in Fig. 1 for values above the prescription dose, and the solid curve is lower than the dashed curve in Fig. 1 for values below the prescription dose). This model was applied to 31 patients who had undergone permanent transperineal prostate brachytherapy at our institution from 2000 to 2001 for whom postimplant CT scan was available for dosimetric analysis. Reflecting the diverse applications of brachytherapy in prostate cancer, all patients had T1c-T2b disease, with PSA values ranging from 4.5 to 20, and Gleason scores of 5 to 7. Patients received external beam radiation
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therapy (EBRT) or neoadjuvant hormonal therapy (NAHT) prior to brachytherapy, based on the disease and anatomical characteristics of the individual, at the discretion of the attending radiation oncologist. Brachytherapy doses ranged from 108 to 110 Gy for boost doses (n ⫽ 20) following EBRT to 144 Gy for implant monotherapy (n ⫽ 11). Permanent NycomedAmersham Iodine-125 (125I) seeds were used for 24 implants while Imagyn Isostar 125I seeds were used for the remaining 7 implants. Uniform seed activities ranging from 0.27 mCi (brachytherapy following external beam radiation therapy) to 0.355 mCi (brachytherapy monotherapy) were used to plan the implant. Modified uniform loading was iteratively chosen to cover the prostate target with the prescription dose while ensuring that the urethra did not receive more than 50% of the prescription dose. Transperineal brachytherapy was performed cooperatively by a radiation oncologist and a urologist using preloaded needles. Four weeks following implant, patients returned for postimplant CT scan. CT scans were obtained using 1.5-mm slices through the prostate; prostate volumes were entered into CT-based treatment planning software. CT volumes were correlated with the ultrasound images obtained at the time of volume study and aligned manually at the rectal surface and the base of the prostate. This technique for alignment was chosen due to the relative consistency of these regions of the prostate across the different imaging modalities and because urethral-based registration was not possible due to lack of catheter-based urethral enhancement on the postimplant CT scans.27 Only the brachytherapy component of treatment was analyzed. Conventional DVHs were computed and standard dosimetric endpoints V100, V150, V200, HI (1⫺[V150/V100]), and D90 were obtained. Using the above reported transformations, dose grids were transformed to BED-early (␣/ ⫽ 10 Gy) and BED-late (␣/ ⫽ 3 Gy) grids, and the same dosimetric endpoints were obtained for analysis. Statistical analyses were performed for each BED-DVH dosimetric parameter (compared to its conventional-DVH counterpart) using the 2-sided paired student’s t-test. RESULTS The results of the analyses for the conventional DVHs BED-early DVHs, and BED-late DVHs are shown in Table 1 With regard to the conventional DVHs, for the reported cohort of patients, the average D90 was 119.5 ⫾ 18.7 Gy and the V100 was 0.896 ⫾ 0.045, corresponding well to published brachytherapy quality endpoints.9 –12 Toxicity endpoints V150 and V200 were 0.539 ⫾ 0.103 and 0.255 ⫾ 0.087, respectively, and the HI was 0.400 ⫾ 0.096; these values also correlate well with those reported in the published literature. As predicted in the methods section, and as seen in Table 1, there is good correlation of the common quality
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Table 1. Dosimetric quality endpoint summary and comparison
Conventional BED (early) p-value Mean diff BED (late) p-value Mean diff
V100
V150
V200
HI
D90 (Gy)
0.896 ⫾ 0.045 0.893 ⫾ 0.049 0.06 ⫺0.003 0.894 ⫾ 0.048 0.11 ⫺0.002
0.539 ⫾ 0.103 0.582 ⫾ 0.101 ⬍0.001 0.043 0.595 ⫾ 0.100 ⬍0.001 0.056
0.255 ⫾ 0.087 0.316 ⫾ 0.095 ⬍0.001 0.061 0.337 ⫾ 0.096 ⬍0.001 0.122
0.400 ⫾ 0.096 0.350 ⫾ 0.100 ⬍0.001 ⫺0.050 0.336 ⫾ 0.092 ⬍0.001 ⫺0.064
119.5 ⫾ 18.7 103.1 ⫾ 19.1 ⬍0.001 ⫺12.6 106.9 ⫾ 20.4 ⬍0.001 ⫺16.4
All non-italicized table entries are mean ⫾ standard deviation. p-values are results of the paired 2-way student’s t-test comparing a BED implant quality parameter with its counterpart conventional parameter. Mean diff ⫽ the difference in mean value of a BED implant quality parameter with its counterpart conventional parameter.
parameter V100 between conventional, early-BED, and late-BED DVHs. Quantitatively, there is no significant difference in the average V100 between conventional and BED-DVHs, either BED-early (p ⫽ 0.06) or BEDlate (p ⫽ 0.11) observed. This was predicted, as V100 is the volume receiving the prescribed dose—although the prescription dose changes with the transformation, the volume receiving this dose does not. When examining dose parameters that are known to correlate with toxicity, V150 and V200, the transformed DVHs reflect a higher delivered dose than the conventional DVHs both for BED-early (p ⬍ 0.001) and for BED-late (p ⬍ 0.001). Again, the increase in V150 after the BED transformation was predicted in the Methods section. Also, as demonstrated in the table, the mean difference in V200 is greater than the mean difference in V150. Furthermore, the mean differences in V150 and V200 are of greater magnitude, as predicted, for the BED-late transformation as compared with the BEDearly transformation. Because HI is arithmetically related to V150, it changes predictably, i.e., it is lower after the BED transformation, and is lower for the BED-late transformation than the BED-early transformation. The effects of the BED transformations on D90 are also shown in Table 1 As predicted in the Methods section, D90 is lower after the BED transformation is applied. Because the 90% dose line is close to the prescription (100%) dose, the absolute magnitude of decrease in D90 is similar between the BED-early and BED-late transformations. In summary, the dosimetric endpoints V100, V150, V200, HI, and D90 changed after the BED-early and BED-late transformations in a manner predicted by the models described in the Methods section. The potential clinical implications of these changes in the dosimetric endpoints are discussed below. DISCUSSION The construction of the BED-DVH was proposed herein to account for treatment delivery and tissue response parameters not reflected in the construction of the conventional DVH. Hence, the BED-DVH is more likely to correlate with clinical outcome and toxicity than the
conventional DVH. Because the BED-DVHs are nonlinear as a result of the transformation described in Eq. (1) and as demonstrated in (Figs. 1 and 2), BED dose values are lower than the conventional dose values in the dose range below the prescription dose, and higher than the conventional dose values in the dose range above the prescription dose. Also, although the prescription dose is itself transformed, the volume of tissue receiving the prescription dose should not change as a result of the transformation, and should allow for a uniform analysis of implant quality parameters. In other words, V100 is consistent between conventional-, early- and late-BEDDVHs, and reinforces the applicability of the transformation. In this context, the dosimetric parameters correlating best with toxicity, V150 and V200, are slightly (but highly significantly [p ⬍ 0.001]) higher (and, correspondingly, HI lower [p ⬍ 0.001]) for both the early- and late-BED-transformed DVHs as compared with the corresponding parameters obtained from the conventional DVHs. This implies that using the conventional-DVHbased parameters to evaluate the quality of a prostate brachytherapy treatment plan may result in a higher incidence of early and late toxicities than anticipated when using the corresponding BED-early and BED-late transformed parameters. The opposite result was found with respect to the implant parameter found best to correlate with treatment outcome, D90 (the dose delivered to at least 90% of the target volume, which correlates to the likelihood of a cure). Specifically, D90 is highly significantly [p ⬍ 0.001] lower for the BED-transformed DVHs as compared with the corresponding value obtained using conventional DVHs. This implies that using the conventional DVH to evaluate the quality of a prostate brachytherapy treatment plan may result in less than intended delivered dose, and potentially lower cure rate, than anticipated from using the corresponding BEDDVH. In this investigation, differences exist between the values of the parameters related to treatment toxicity (V150, V200, and HI) and the parameter relating to treatment outcome (D90) when comparing conventional
BED vs. conventional prostate brachy dose endpoints ● R. SINGH et al.
DVHs with their BED-early and BED-late counterparts. The central purpose of our analysis was to evaluate and quantitate the differences and make inferences about their potential role in improving prostate brachytherapy implant quality. We conclude that the BED-DVHs should be considered in addition to the conventional DVH when evaluating the quality of an implant, as there can be higher actual inhomogeneity (both with respect to higher than intended V150 and V200 [and corresponding lower HI], and with respect to lower than intended D90) than that predicted when using the conventional DVH alone. In this context, however, it should be noted that the authors are aware that the absolute magnitudes of the differences in dosimetric endpoints are relatively small. The true impact of these small differences in predicting outcome and toxicity cannot yet be stated with certainty and is beyond the scope of the current communication, which evaluated treatment plans from a strictly dosimetric standpoint. A separate, subsequent effort is currently underway to correlate the BED-DVH (as compared with conventional DVH) implant quality parameters with early and late toxicity and treatment outcome. REFERENCES 1. Sarma, A.V.; Schottenfeld, D. Prostate cancer incidence, mortality, and survival trends in the United States: 1981–2001. Semin. Urol. Oncol. 20:3–9; 2002. 2. Ragde, H.; Blasko, J.C.; Grimm, P.D.; et al. Interstitial I–125 radiation without adjuvant therapy in the treatment of clinically localized prostate cancer. Cancer 80:442–53; 1997. 3. Wallner, K.; Roy, J.; Harrison, L. Tumor control and morbidity following transperineal I-125 implantation for stage T1/T2 prostatic carcinoma. J. Clin. Oncol. 14:449 –453; 1996. 4. Blasko, J.C.; Wallner, K.; Grimm, P.D.; et al. Prostate specific antigen based disease control following ultrasound guided iodine125 implantation for stage T1/T2 prostatic carcinoma. J. Urol. 154:1096 –9; 1995. 5. Zelefsky, M.N.; Wallner, K.E.; Ling, C.; et al. Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for early-stage prostate cancer. J. Clin. Oncol. 17:517–22; 1999. 6. Grimm, P.D.; Blasko, J.C.; Sylvester, J.; et al. 10-year biochemical (prostate-specific antigen) control of prostate cancer with (125)I brachytherapy. Int. J. Radiat. Oncol. Biol. Phys. 51:31–40; 2001. 7. Blasko, J.C.; Grimm, P.D.; Cavanagh, W.; et al. Long term outcomes of external beam irradiation and I-125/Pd-103 brachytherapy boost for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 36:198 –203; 1996. 8. Sylvester, J.; Blasko, J.C.; Grimm, P.D.; et al. Short-course androgen ablation combined with external-beam radiation therapy and low-dose-rate permanent brachytherapy in early-stage prostate cancer: A matched subset analysis. Mol. Urol. 4:155–9; 2000.
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