- Email: [email protected]
LDR vs. HDR brachytherapy for localized prostate cancer
Brachytherapy 1 (2002) 219–226
LDR vs. HDR brachytherapy for localized prostate cancer: the view from radiobiological models Christopher R. King Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
Abstract
Purpose: Permanent LDR brachytherapy and temporary HDR brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never be conducted comparing these two forms of brachytherapy, a comparative radiobiological modeling analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. Methods and Materials: Radiobiological models based upon the linear quadratic equations are presented for fractionated external beam, fractionated 192Ir HDR brachytherapy, and 125I and 103Pd LDR brachytherapy. These models incorporate the dose heterogeneities present in brachytherapy based upon patient-derived dose volume histograms (DVH) as well as tumor doubling times and repair kinetics. Radiobiological parameters are normalized to correspond to three accepted clinical risk factors based upon T-stage, PSA, and Gleason score to compare models with clinical series. Tumor control probabilities (TCP) for LDR and HDR brachytherapy (as monotherapy or combined with external beam) are compared with clinical bNED survival rates. Predictions are made for dose escalation with HDR brachytherapy regimens. Results: Model predictions for dose escalation with external beam agree with clinical data and validate the models and their underlying assumptions. Both LDR and HDR brachytherapy achieve superior tumor control when compared with external beam at conventional doses ( 70 Gy), but similar to results from dose escalation series. LDR brachytherapy as boost achieves superior tumor control than when used as monotherapy. Stage for stage, both LDR and current HDR regimens achieve similar tumor control rates, in agreement with current clinical data. HDR monotherapy with large-dose fraction sizes might achieve superior tumor control compared with LDR, especially if prostate cancer possesses a high sensitivity to dose fractionation (i.e., if the / ratio is low). Conclusions: Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy using current dose regimens. However, HDR brachytherapy dose escalation regimens might be able to achieve higher biologically effective doses of irradiation in comparison to LDR, and hence improved outcomes. This advantage over LDR would be amplified should prostate cancer possess a high sensitivity to dose fractionation (i.e., a low / ratio) as the current evidence suggests. © 2003 American Brachytherapy Society. All rights reserved.
Keywords:
Prostate cancer, Brachytherapy, LDR, HDR, Radiobiology
Introduction Although clinical evidence supports superior outcomes with dose escalation for localized prostate cancer, the means of delivReceived 5 July 2002; received in revised form 24 October 2002; accepted 28 October 2002. Presented at the 43rd annual meeting of ASTRO, San Francisco, CA, November 2001. Corresponding author. Stanford University School of Medicine, Department of Radiation Oncology, 300 Pasteur Drive, Stanford, CA 94305. Tel: 1-650-736-0698; fax: 1-650-498-6922. E-mail address: [email protected] (C.R. King).
ering optimally biological effective doses remains unclear. In this respect brachytherapy might allow for improved conformal dose escalation as compared with 3D external-beam techniques, in part because of the significant dose heterogeneity present with brachytherapy. Two competing modalities of brachytherapy exist: permanent low-dose rate (LDR) brachytherapy with either 125I or 103Pd, and temporary high-dose rate (HDR) brachytherapy with 192Ir. At present, the available clinical data with these two techniques suggests that they are equally effective, stage for stage, in providing high tumor control rates (1–6). Each of these techniques has attributes that has created advocates for one or the other. First, they represent the ex-
1538-4721/03/$ – see front matter © 2003 American Brachytherapy Society. All rights reserved. doi:10.1016/S1538-4721(02)00101-0
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King / Brachytherapy 1 (2002) 219–226
treme ends of the spectrum with respect to dose rate and fractionation and therefore have inherently different radiobiological properties. LDR brachytherapy has the great advantage of being practically a one-time procedure and enjoys a long-term follow-up database supporting its excellent outcomes and low morbidity (1, 3). It suffers, however, from limited capability for adequate dose coverage beyond the gland and from some anatomic restrictions such as pubic arch interference. On the other hand, HDR is a fairly invasive procedure requiring several sessions associated with a brief hospital stay. Although lacking in significant longterm data, it possesses the technical advantage of control over its postimplant dosimetry (by modulating the source dwell time and position), which is absent in LDR brachytherapy. This important difference in dosimetric control allows HDR doses to be escalated safely, a flexibility that does not exist for LDR brachytherapy. Although a randomized trial will likely never be conducted comparing these two forms of brachytherapy, a comparative radiobiological modeling analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. Radiobiological modeling allows for the clinical results to be understood apart from their potential patient selection bias effects. In this study we establish radiobiological models and use them to predict PSA outcomes after fractionated external-beam, permanent LDR, or temporary HDR brachytherapy that are closely compared with clinical series. Within the context of prostate cancer radiobiology there is increasingly convincing evidence that it might be highly sensitive to dose fractionation, that is, that it might possess a low / ratio similar to that of late-responding normal tissues (7–11). Although it is still unproven in the clinical sense, the evidence is nevertheless compelling and bears a direct relationship on the present study because HDR brachytherapy is well suited for the delivery of hypofractionated regimens.
Methods and materials An algorithm to calculate the surviving fraction of clonogens, and hence tumor control rates, is developed based upon the linear quadratic (LQ) equations for both fractionated and protracted irradiation. These models include potential tumor repopulation, sublethal damage repair kinetics, source decay and clinically derived dose volume histograms. The radiobiological parameters of the LQ equation, including clonogen numbers, are normalized from clinical data so that three risk groups can be established for comparison with clinical series: FAVORABLE— iPSA 10, bGS 6 and stage T2; INTERMEDIATE—one parameter increased; and UNFAVORABLE—two parameters increased (12). A similar algorithm was successfully presented previously (13) and further details can be found therein. The outline of these models and their underlying assumptions follows.
Fractionated irradiation For fractionated irradiation (i.e., external-beam or HDR brachytherapy) with n equal fractions of dose d, the Biological Equivalent Dose (BED) is given by: BED F = nd { 1 + d ⁄ ( α ⁄ β ) } – ( T ⁄ αT POT )1n ( 2 ) (1) where and / are the linear quadratic terms, T the treatment duration (in days) and TPOT the potential tumor doubling time. The second term of Eq. 1 accounts for tumor repopulation during the treatment course. Protracted irradiation For protracted irradiation (i.e., permanent LDR brachytherapy) with D as the minimum peripheral dose delivered to total decay, the BED is given by (14): BED LDR = D { 1 + 2 ( d 0 – λ ) ( β ⁄ α )κ ⁄ ( µ – λ ) } – ( T EFF ⁄ αT POT )1n ( 2 )
(2)
with the following term definitions: is the decay constant of the radioactive source ln(2)/ decay half-life d0 is the initial dose rate D is the sublethal damage repair constant ln(2)/repair half-life
1/(1- ){(1- 2)/ 2 [1 e Teff]/( )}
e Teff In the limit (with respect to treatment time) Eq. 2 will simplify to: BEDLDR D{1GD/(/)} (TEFF/TPOT)ln(2), where G (the so-called ‘Lea-Catcheside’ function) describes the temporal corrections resulting from the isotope decay and the repair kinetics of sublethal damage and can be written as: G /( ). Here TEFF is the ‘effective’ treatment time for LDR brachytherapy, when the decaying rate of cell kill has become equal to the repopulation rate. It is written as: TEFF (1/)ln[1.44d0TPOT] (14). Any dose beyond this time is ineffective. In the model calculations the complete form of Eq. 2 was used (but it should be noted that the simplified expression results in less than 5% difference). Cell survival Cell survival, in its generalized form, can be written as: S = exp ( – αBED )
(3)
The cell survival for fractionated external-beam (and fractionated HDR brachytherapy) or LDR brachytherapy are calculated with the above expression in Eq. 3, with BED as given by Eq. 1 or Eq. 2, respectively. When brachytherapy is combined with external beam then the resulting cell survival simply becomes: S SEBRT SBrachy.
King / Brachytherapy 1 (2002) 219–226
Brachytherapy dose inhomogeneity We incorporate the dose inhomogeneities that are inherently present in brachytherapy with average patient-derived dose volume histograms (DVH) for 125I and 103Pd (previously published in ref. 13) and 192Ir. These are shown in Figure 1. It is worth pointing out the degree of heterogeneity present, particularly in LDR brachytherapy. Less heterogeneity appears in HDR brachytherapy as would be expected because the dosime-
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try of HDR is optimized to some degree. The DVH describes the partial tumor volume vi receiving dose di. Cell survival S for the entire tumor is thus given by summing overall tumor volume elements: S = ΣV Si i
(4)
where Si exp( BEDi) is the survival of those clonogens within each partial tumor volume vi and BEDi is given by
Fig. 1. Differential dose volume histograms (dDVH) for 125I, 103Pd and 192Ir from average patient-derived data (13). Note that for the 192Ir HDR brachytherapy DVH, the dose scale is ‘percent dose’ because different dose fraction sizes can be prescribed. Note how heterogeneous and ‘hot’ these DVH are, particularly for 125I and 103Pd.
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Table 1 Radiobiological parameters and clonogen number (NC) normalization values for the three clinical risk groups as defined in the text Risk group 1
(Gy ) SF2* (/ 3) SF2 (/ 10) TCP† NC (/ 3) NC (/ 10)
Favorable
Intermediate
Unfavorable
0.3 0.37 0.48 80% 7.6 1013 5.5 109
0.2 0.51 0.61 50% 2.7 109 4.8 106
0.1 0.71 0.78 20% 7.7 104 3.2 103
TCP tumor control probability; bNED endpoint of biochemical survival. *SF2 exp( 2 4) is the survival fraction after a single 2Gy dose and measures radiosensitivity. † TCP equivalent to bNED after 68Gy external beam in 2Gy per fraction. Adapted from the MSKCC series in Zelefsky et al. (12).
either Eq. 1 or Eq. 2. The prescribed doses are as follows: for 125I and 103Pd brachytherapy, 144 Gy (TG-43) and 125Gy (NIST-1999) respectively for monotherapy, and 110 Gy and 100 Gy for boost doses after 45Gy external beam, respectively. For 192Ir HDR brachytherapy the prescribed dose varied according to the clinical series used for comparison (see tables). For these models to be compared with clinical series the prescribed doses were scaled to the D90 dose line (dose delivered to 90% of the target volume) to correspond with the actual doses delivered clinically. Tumor control probability Tumor control probability (TCP) can be represented by the surrogate endpoint of biochemical survival (bNED) as has been used by others (eg. 7). TCP is described by Poisson statistics in the usual fashion as: TCP = exp ( – N C S )
(5)
where NC is the number of clonogens and S is given by Eq. 4. Radiobiological parameters Because we wish to compare model predictions with clinical series we must “anchor,” or normalize, the models. This is easily accomplished by choosing well-known clini-
cal outcomes for a given dose regimen. We chose this to be bNED survival rates of 80%, 50%, and 20% respectively for the Favorable, Intermediate, and Unfavorable risk groups receiving conventional doses of external beam (rounded-off values from the Memorial Sloan-Kettering Cancer Center— MSKCC—series for EBRT doses of 68Gy, see ref. 12). From this we calculate the number of clonogens NC required to achieve a given TCP that will correspond to the clinical bNED for that risk group, dose regimen and the model’s LQ parameters by solving Eq. 5. Table 1 shows the radiobiological parameters adopted and the normalized clonogen numbers. To reflect the probable increased radio-resistance (increase in SF2) with increasing risk group, we chose decreasing values of with increasing risk. (The number of clonogens thus obtained should not be regarded as representing the true number of cells, but rather one of several equivalent means of normalizing these models). Because the / ratio for prostate cancer might be quite low, models with values of 3 as well as 10 are constructed. For our models we adopt a SLDR repair half-life of 1 hour (10) and a TPOT of 60 days (15). The validity of these assumptions is tested in the next section. Brachytherapy clinical series The representative clinical series chosen for comparison are those that have the longest follow-up and the largest patient numbers. These series have used the American Society for Therapeutic Radiology and Oncology (ASTRO) definition or a closely related definition to report bNED survival rates. For LDR brachytherapy such series are now reporting on 10-year outcomes for 125I and 103Pd, with or without external beam (1, 2, 3). For HDR brachytherapy there are considerably fewer series to quote due to the relative youth of this technique. The series with the longest follow-up (up to 10 years) represents a fairly homogenous dose regimen (50.4 Gy external beam 4 HDR fractions of 3–4 Gy each), but despite the long follow-up only has 104 patients (4). The other HDR brachytherapy series quoted (5, 6) suffers from short follow-up (minimum of 3 years), but offers several HDR dose-escalation regimens (from 5.5 Gy–10.5 Gy). These series are summarized in Table 2. For the time being, there are no adequate data for HDR as monotherapy.
Table 2 bNED survival rates for the three risk groups among the clinical series used to compare with models. The different LDR/HDR/EB dose regimens in these series are outlined Risk group 103
Pd 125 I EB (45 Gy) I/Pd EB (50.4 Gy) HDR 3–4 Gy 4 EB (46 Gy) HDR 5.5–6.5 Gy 3 or 8.5 9.5 Gy 2 EB (46 Gy) HDR 5.5–6.5 Gy 3 EB (46 Gy) HDR 8.25–10.5 Gy 2 na clinical data is not available.
Favorable
Intermediate
Unfavorable
Reference
94% 87% 87% 96–100% na na na
82% 79% 85% 72–85% 88% na na
65% na 62% 49% 51–62% 64–75% 87–95%
Blasko et al. (1) Grimm et al. (3) Blasko et al. (2) Eualu et al. (4) Martinez et al. (5, 6) Brenner et al. (8) Brenner et al. (8)
King / Brachytherapy 1 (2002) 219–226
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Caveats There are, of course, numerous limitations to studies of this nature. First, there is the ever-present issue of bNED definition when comparing clinical series. Rigorous adherence to the ASTRO definition of PSA failure, albeit an arbitrary one, is critically important when comparing clinical series. Small deviations from this can significantly affect the measured outcomes as has been demonstrated (16). Second, dose-escalated 3D conformal external-beam series and brachytherapy, especially HDR brachytherapy, are younger techniques and hence patients thus treated are from an era where follow-up will be inevitably shorter and stage migration toward earlier stages will be present. Both of these factors will favor recently treated patients (17). Third, the currently popular three-tier risk groups based upon clinical T-stage, initial PSA and biopsy Gleason score doesn’t take into account additional factors that have recently emerged as useful in risk stratification, such as the percent of positive cores and the length of positive segments (18). These are a sample of caveats to remember whenever one attempts a comparison between clinical series and the use of models to interpret them.
Results Model validation through comparison with external-beam dose-escalation series These models can be used to predict dose escalation results and compared with 3D conformal external-beam series. This is shown in Figure 2 where model TCP are compared with clinical bNED data for three dose-escalation series (12, 19, 20). The rather good agreement validates the assumptions made in these models and hence their predictive usefulness when extrapolated beyond their “anchor” point. Because there was no attempt to fit the radiobiological parameters to obtain the “best fit,” it is not surprising that the concordance isn’t perfect. Furthermore, it is worth remembering that models assume organ-confined disease. This is not always the case in clinical series even with early stage disease, and hence models will in general tend to slightly overestimate TCP. Predictions for LDR and HDR brachytherapy compared with clinical data Clinical bNED are compared with model TCP predictions in Tables 3 through 6. When such comparisons are made, we are not looking for an exact TCP/bNED match but for consistent trends, especially trends with increasing patient risk factors. For LDR brachytherapy monotherapy, the agreement with clinical series is very good (Table 3). For 45 Gy EB LDR brachytherapy boost, models generally predict higher TCP than the clinical bNED, perhaps reflecting the overall higher “true risk” among actual patients selected for this combined treatment. In general though, combined
Fig. 2. Predicted Tumor Control Probability (TCP) compared with clinical bNED results from several external-beam dose-escalation series (12, 20, 19) for Favorable, Intermediate and Unfavorable risk patients. Models are shown by solid lines (for tumor / 3) and dashed lines (for tumor / 10). Data are represented by symbols as identified within the figure legend. “Error bars” represent the range in doses and bNED survival rates from the clinical series.
external-beam LDR brachytherapy boost is suggested by the models to produce higher TCP than LDR monotherapy. Several fractionation regimens are in clinical usage for HDR brachytherapy boost. In Table 4 the HDR regimen is 50.4 Gy external beam 4 HDR fractions of 3–4 Gy each, according to the Seattle Prostate Institute series (4). The overall agreement between predicted TCP and bNED is good. This HDR regimen produces comparable long-term outcomes as with LDR brachytherapy. In Table 5 the HDR regimen is 46 Gy external beam with three HDR fractions of 5.5–6.5 Gy each or two HDR frac-
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Table 3 Clinical series bNED compared with model TCP for LDR brachytherapy Clinical series bNED 103
Pd monotherapy 125 I monotherapy EB (45 Gy) I/Pd
Favorable
Intermediate
Unfavorable
Reference
94% 87% 87%
82% 79% 85%
65% na 62%
Blasko et al. (1) Grimm et al. (3) Blasko et al. (2)
Favorable
Intermediate
Unfavorable
97% 96%
91% 90%
76% 75%
93% 97%
76% 89%
40% 67%
98/89% 99/99%
96/86% 99/99%
84/76% 95/92%
Model TCP 103
Pd monotherapy (/3) (/10) 125 I monotherapy (/3) (/10) EB (45 Gy) I/Pd boost (/3) (/10) 103
Pd dose is 125 Gy monotherapy, 100 Gy boost. 125I dose is 144 Gy monotherapy, 110 Gy boost. na clinical data is not available; bNED endpoint of biochemical survival; TCP tumor control probability; LDR low-dose rate.
tions of 8.25–10.5 Gy each, according to the William Beaumont series (5, 6, 8). The available clinical data here are comparatively sparse. The agreement between the models and clinical outcomes is once again fairly good. The range of TCP for a given range in dose fraction size is very dependent upon the / ratio, as expected. Although far from conclusive, the agreement between the models and clinical data seems more consistent for the models with the lower value of /.
Discussion and conclusions This radiobiological modeling study is but one aspect of the many differences between HDR and LDR prostate brachytherapy. Ultimately, only a prospective trial comparing the two techniques would truly discover clinically meaningful differences and optimal choices. Until data from such trials are available, if ever, one must make best use of the retrospective clinical data that are increasing in both quantity and quality. Although a simple comparison between clinical series suffers from patient selection bias effects, a radiobiological modelbased comparison bypasses these effects.
This study allows several general conclusions to be drawn which are supported by the available clinical data: 1) simple radiobiological models predict 3D dose-escalation outcomes that are in agreement with clinical series, 2) HDR and LDR brachytherapy delivered with current dose regimens achieve equivalent tumor control rates as compared with 3D dose-escalation external-beam series, and 3) LDR monotherapy achieves equivalent tumor control rates compared with EB/HDR boost regimens. Several interesting hypotheses are suggested by the models, but adequate supporting clinical data are not yet available: 1) LDR boost after EB might achieve improved tumor control rates compared with LDR monotherapy, 2) HDR monotherapy with current dose regimens might be equivalent to LDR monotherapy and 3D dose-escalation external-beam outcomes, and 3) HDR with dose escalated hypofractionated regimens might achieve maximal tumor control rates, especially for the Intermediate and Unfavorable risk patients. From a radiobiological perspective HDR brachytherapy has the flexibility of dose per fraction escalation and dose escalation, both of which are absent in LDR brachytherapy. This would be particularly significant should prostate cancer have a high sensitivity to dose fraction size (correspond-
Table 4 Clinical series bNED compared with model TCP for HDR brachytherapy regimen of 50.4 Gy EB 3–4 Gy 4 Clinical series bNED EB (50.4 Gy) HDR 3–4 Gy 4
Favorable
Intermediate
Unfavorable
Reference
96–100%
72–85%
49%
Eulau et al. (4)
Favorable
Intermediate
Unfavorable
95% 91%
88% 74%
64% 40%
Model TCP EB (50.4 Gy) HDR 4 Gy 4 (/3) (/10)
bNED endpoint of biochemical survival; TCP tumor control probability; HDR high-dose rate.
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Table 5 Clinical series bNED compared with model TCP for HDR brachytherapy regimens of 45 Gy EB 5.5–6.5 Gy 3 or 8.25–10.5 Gy 2 Clinical series bNED EB (46 Gy) HDR 5.5–6.5 Gy 3 or 8.25–9.5 Gy 2 EB (46 Gy) HDR 5.5–6.5 Gy 3 EB (46 Gy) HDR 8.25–10.5 Gy 2
Favorable
Intermediate
Unfavorable
Reference
na na na
88% na na
51–62% 64–75% 87–95%
Martinez et al. (5, 6) Brenner et al. (8) Brenner et al. (8)
Favorable
Intermediate
Unfavorable
76–98% 73–93%
76–96% 55–84%
64–89% 32–58%
98–99% 89–99%
96–99% 78–97%
89–99% 51–84%
Model TCP EB (45 Gy) HDR 5.5–6.5 Gy 3 (/ 3) (/ 10) EB (45 Gy) HDR 8.25–10.5 Gy 2 (/ 3) (/ 10)
na clinical data not available. bNED endpoint of biochemical survival; TCP tumor control probability; HDR high dose rate.
ing to a low / ratio). This has recently been the subject of lively debate (7–11) as the evidence in support of this accrues. Hypofractionated regimens are not new in prostate cancer and there are several clinical series that support the safety and efficacy of larger dose per fraction. First, an older British study using 6 Gy per fraction for a total of 36 Gy with conventional external beam produces long-term outcomes and morbidity that are as good as historical cohorts from the same era (21). More recently, a study using IMRT to deliver 70 Gy in 2.5 Gy per fraction has been reported with excellent acute and long-term morbidity (22). Much higher dose per fraction has been used with HDR brachytherapy as monotherapy and with excellent results so far (23). That series delivers 9.5 Gy per fraction with 4 fractions totaling 38 Gy using Ir-192 HDR brachytherapy. The acute toxicity seems to be within acceptable range whereas the long-term tumor control awaits maturation of the data, but is encouraging so far. Predictions for HDR monotherapy are made in Table 6, although no adequate clinical data are yet available. For models with a conventional tumor value of 10 for the / ratio, predicted TCP with this four-fraction regimen are the same as with LDR monotherapy. However, the advantage for this HDR regimen becomes dramatic should the tumor / ratio be as low as it is for late-reacting normal tissues. One has to be cautious to deliver so few large-dose fractions in a tumor that possesses regions of hypoxia, but there
Table 6 Model TCP predictions for HDR brachytherapy as monotherapy (38 Gy in four fractions) Model TCP HDR monotherapy 9.5 Gy 4 (/ 3) (/ 10)
Favorable
Intermediate
Unfavorable
98% 86%
97% 77%
96% 63%
HDR high dose rate; TCP tumor control probability.
might be an optimal number and schedule that would overcome the hypoxia challenge while simultaneously taking advantage of this radiobiological behavior. Although HDR brachytherapy is not the only technical means of delivering hypo-fractionated radiotherapy, it lends itself naturally to this. Other means currently contemplated include the use of IMRT in association with organ localization techniques and emerging technology such as the CyberKnife (a robotic arm–driven linac) which possesses some of the dosimetric attributes of IMRT but has built-in capabilities for real-time image-guided organ localization and position tracking (24). Acknowledgments The author thanks Drs. Charles Mayo and Ken Ulin for their help in acquiring the HDR dose volume histograms and for the many insights of Prof. Jack Fowler. References [1] Blasko JC, Grimm PD, Sylvester JE, et al. Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000;46: 839–850. [2] Blasko JC, et al. in 4th Annual advanced prostate brachytherapy conference, Seattle Prostate Institute, Seattle WA, 2001. [3] Grimm PD, Blasko JC, Sylvester JE, et al. 10-Year biochemical (PSA) control of prostate cancer with 125I brachytherapy. Int J Radiat Oncol Biol Phys 2001;51:31–40. [4] Eulau SM, Van Hollebeke L, Cavanagh W, et al. High dose rate 192Ir brachytherapy in localized prostate cancer: results and toxicity with maximum follow-up of 10 years. ASTRO 42nd Annual Meeting (abstract), Int J Radiat Oncol Biol Phys 2000;48:149. [5] Martinez AA, Kestin LL, Stromberg JS, et al. Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont phase II doseescalation trial. Int J Radiat Oncol Biol Phys 2000;47:343–352. [6] Martinez AA, et al. 4th Annual advanced prostate brachytherapy conference, Seattle Prostate Institute, Seattle WA, 2001. [7] Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999;43:1095– 1101. [8] Brenner DJ, Martinez AA, Edmundson GK, et al. Direct evidence
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King / Brachytherapy 1 (2002) 219–226 that prostate tumors show a high sensitivity to fractionation (low / ratio), similar to late-responding normal tissue. Int J Radiat Oncol Biol Phys 2002;52:6–13. King CR, Fowler JF. A simple analytic derivation suggests that prostate cancer / ratio is low. Int J Radiat Oncol Biol Phys 2001;51: 213–214. Fowler JF, Chappell R, Ritter M. Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001;50:1021–1031. King CR, Fowler JF. Yes, the prostate cancer / ratio is low, or, Methinks the lady doth protest too much ... about a low / ratio that is. Int J Radiat Oncol Biol Phys 2002;54:626–627. Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:491–500. King CR, DiPetrillo TA, Wazer DE. Optimal radiotherapy for prostate cancer: predictions for conventional external beam, IMRT, and brachytherapy from radiobiological models. Int J Radiat Oncol Biol Phys 2000;46:165–172. Dale RG. Radiobiological assessment of permanent implants using tumor repopulation factors in the linear-quadratic model. Br J Radiol 1989;62:241–244. Haustermans KMG, Hofland I, Van Poppel, et al. Measurements in prostate cancer. Int J Radiat Oncol Biol Phys 1997;37:1067–1070. Vicini FA, Kestin LL, Martinez AA. The correlation of serial prostate specific antigen measurements with clinical outcome after external beam radiation therapy of patients for prostate carcinoma. Cancer 2000;88:2305–2318.
[17] Kestin LL, Vicini FA, Martinez AA. Practical application of biochemical failure definitions: what to do and when to do it. Int J Radiat Oncol Biol Phys 2002;53:304 –315. [18] D’Amico AV, Desjardin A, Chung A, et al. Assessment of outcome prediction models for patients with localized prostate carcinoma managed with radical prostatectomy or external beam radiation therapy. Cancer 1998;82:1887–1896. [19] Pollack A, Zagars GK, Smith LG, et al. Preliminary results of a randomized radiotherapy dose-escalation study comparing 70Gy with 78Gy for prostate cancer. J Clin Oncol 2000;18;3904–3911. [20] Hanks GE, Hanlon AL, Pinover WH, et al. Dose selection for prostate cancer patients based on dose comparison and dose response studies. Int J Radiat Oncol Biol Phys 2000;46:823-–832. [21] Lloyd-Davis RW, Collins CD, Swan AV. Carcinoma of prostate treated by radical external beam radiotherapy using hypofractionation: 22 years experience (1962-1984). Urology 1990;36:107–111. [22] Kupelian PA, Reddy CA, Klein EA, et al. Short-course intensitymodulated radiotherapy (70Gy at 2.5Gy per fraction) for localized prostate cancer: preliminary results on late toxicity and quality of life. Int J Radiat Oncol Biol Phys 2001;51:988–993. [23] Martinez AA, Pataki I, Edmundson G, et al. Phase II prospective study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: a feasibility report. Int J Radiat Oncol Biol Phys 2001;49:61–69. [24] King CR, Lehmann J, Adler JA, et al. CyberKnife radiotherapy for prostate cancer: rationale and technical feasibility. Technol Cancer Res Treatm 2003. In press.
LDR vs. HDR brachytherapy for localized prostate cancer: the view from radiobiological models Christopher R. King Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
Abstract
Purpose: Permanent LDR brachytherapy and temporary HDR brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never be conducted comparing these two forms of brachytherapy, a comparative radiobiological modeling analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. Methods and Materials: Radiobiological models based upon the linear quadratic equations are presented for fractionated external beam, fractionated 192Ir HDR brachytherapy, and 125I and 103Pd LDR brachytherapy. These models incorporate the dose heterogeneities present in brachytherapy based upon patient-derived dose volume histograms (DVH) as well as tumor doubling times and repair kinetics. Radiobiological parameters are normalized to correspond to three accepted clinical risk factors based upon T-stage, PSA, and Gleason score to compare models with clinical series. Tumor control probabilities (TCP) for LDR and HDR brachytherapy (as monotherapy or combined with external beam) are compared with clinical bNED survival rates. Predictions are made for dose escalation with HDR brachytherapy regimens. Results: Model predictions for dose escalation with external beam agree with clinical data and validate the models and their underlying assumptions. Both LDR and HDR brachytherapy achieve superior tumor control when compared with external beam at conventional doses ( 70 Gy), but similar to results from dose escalation series. LDR brachytherapy as boost achieves superior tumor control than when used as monotherapy. Stage for stage, both LDR and current HDR regimens achieve similar tumor control rates, in agreement with current clinical data. HDR monotherapy with large-dose fraction sizes might achieve superior tumor control compared with LDR, especially if prostate cancer possesses a high sensitivity to dose fractionation (i.e., if the / ratio is low). Conclusions: Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy using current dose regimens. However, HDR brachytherapy dose escalation regimens might be able to achieve higher biologically effective doses of irradiation in comparison to LDR, and hence improved outcomes. This advantage over LDR would be amplified should prostate cancer possess a high sensitivity to dose fractionation (i.e., a low / ratio) as the current evidence suggests. © 2003 American Brachytherapy Society. All rights reserved.
Keywords:
Prostate cancer, Brachytherapy, LDR, HDR, Radiobiology
Introduction Although clinical evidence supports superior outcomes with dose escalation for localized prostate cancer, the means of delivReceived 5 July 2002; received in revised form 24 October 2002; accepted 28 October 2002. Presented at the 43rd annual meeting of ASTRO, San Francisco, CA, November 2001. Corresponding author. Stanford University School of Medicine, Department of Radiation Oncology, 300 Pasteur Drive, Stanford, CA 94305. Tel: 1-650-736-0698; fax: 1-650-498-6922. E-mail address: [email protected] (C.R. King).
ering optimally biological effective doses remains unclear. In this respect brachytherapy might allow for improved conformal dose escalation as compared with 3D external-beam techniques, in part because of the significant dose heterogeneity present with brachytherapy. Two competing modalities of brachytherapy exist: permanent low-dose rate (LDR) brachytherapy with either 125I or 103Pd, and temporary high-dose rate (HDR) brachytherapy with 192Ir. At present, the available clinical data with these two techniques suggests that they are equally effective, stage for stage, in providing high tumor control rates (1–6). Each of these techniques has attributes that has created advocates for one or the other. First, they represent the ex-
1538-4721/03/$ – see front matter © 2003 American Brachytherapy Society. All rights reserved. doi:10.1016/S1538-4721(02)00101-0
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treme ends of the spectrum with respect to dose rate and fractionation and therefore have inherently different radiobiological properties. LDR brachytherapy has the great advantage of being practically a one-time procedure and enjoys a long-term follow-up database supporting its excellent outcomes and low morbidity (1, 3). It suffers, however, from limited capability for adequate dose coverage beyond the gland and from some anatomic restrictions such as pubic arch interference. On the other hand, HDR is a fairly invasive procedure requiring several sessions associated with a brief hospital stay. Although lacking in significant longterm data, it possesses the technical advantage of control over its postimplant dosimetry (by modulating the source dwell time and position), which is absent in LDR brachytherapy. This important difference in dosimetric control allows HDR doses to be escalated safely, a flexibility that does not exist for LDR brachytherapy. Although a randomized trial will likely never be conducted comparing these two forms of brachytherapy, a comparative radiobiological modeling analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. Radiobiological modeling allows for the clinical results to be understood apart from their potential patient selection bias effects. In this study we establish radiobiological models and use them to predict PSA outcomes after fractionated external-beam, permanent LDR, or temporary HDR brachytherapy that are closely compared with clinical series. Within the context of prostate cancer radiobiology there is increasingly convincing evidence that it might be highly sensitive to dose fractionation, that is, that it might possess a low / ratio similar to that of late-responding normal tissues (7–11). Although it is still unproven in the clinical sense, the evidence is nevertheless compelling and bears a direct relationship on the present study because HDR brachytherapy is well suited for the delivery of hypofractionated regimens.
Methods and materials An algorithm to calculate the surviving fraction of clonogens, and hence tumor control rates, is developed based upon the linear quadratic (LQ) equations for both fractionated and protracted irradiation. These models include potential tumor repopulation, sublethal damage repair kinetics, source decay and clinically derived dose volume histograms. The radiobiological parameters of the LQ equation, including clonogen numbers, are normalized from clinical data so that three risk groups can be established for comparison with clinical series: FAVORABLE— iPSA 10, bGS 6 and stage T2; INTERMEDIATE—one parameter increased; and UNFAVORABLE—two parameters increased (12). A similar algorithm was successfully presented previously (13) and further details can be found therein. The outline of these models and their underlying assumptions follows.
Fractionated irradiation For fractionated irradiation (i.e., external-beam or HDR brachytherapy) with n equal fractions of dose d, the Biological Equivalent Dose (BED) is given by: BED F = nd { 1 + d ⁄ ( α ⁄ β ) } – ( T ⁄ αT POT )1n ( 2 ) (1) where and / are the linear quadratic terms, T the treatment duration (in days) and TPOT the potential tumor doubling time. The second term of Eq. 1 accounts for tumor repopulation during the treatment course. Protracted irradiation For protracted irradiation (i.e., permanent LDR brachytherapy) with D as the minimum peripheral dose delivered to total decay, the BED is given by (14): BED LDR = D { 1 + 2 ( d 0 – λ ) ( β ⁄ α )κ ⁄ ( µ – λ ) } – ( T EFF ⁄ αT POT )1n ( 2 )
(2)
with the following term definitions: is the decay constant of the radioactive source ln(2)/ decay half-life d0 is the initial dose rate D is the sublethal damage repair constant ln(2)/repair half-life
1/(1- ){(1- 2)/ 2 [1 e Teff]/( )}
e Teff In the limit (with respect to treatment time) Eq. 2 will simplify to: BEDLDR D{1GD/(/)} (TEFF/TPOT)ln(2), where G (the so-called ‘Lea-Catcheside’ function) describes the temporal corrections resulting from the isotope decay and the repair kinetics of sublethal damage and can be written as: G /( ). Here TEFF is the ‘effective’ treatment time for LDR brachytherapy, when the decaying rate of cell kill has become equal to the repopulation rate. It is written as: TEFF (1/)ln[1.44d0TPOT] (14). Any dose beyond this time is ineffective. In the model calculations the complete form of Eq. 2 was used (but it should be noted that the simplified expression results in less than 5% difference). Cell survival Cell survival, in its generalized form, can be written as: S = exp ( – αBED )
(3)
The cell survival for fractionated external-beam (and fractionated HDR brachytherapy) or LDR brachytherapy are calculated with the above expression in Eq. 3, with BED as given by Eq. 1 or Eq. 2, respectively. When brachytherapy is combined with external beam then the resulting cell survival simply becomes: S SEBRT SBrachy.
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Brachytherapy dose inhomogeneity We incorporate the dose inhomogeneities that are inherently present in brachytherapy with average patient-derived dose volume histograms (DVH) for 125I and 103Pd (previously published in ref. 13) and 192Ir. These are shown in Figure 1. It is worth pointing out the degree of heterogeneity present, particularly in LDR brachytherapy. Less heterogeneity appears in HDR brachytherapy as would be expected because the dosime-
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try of HDR is optimized to some degree. The DVH describes the partial tumor volume vi receiving dose di. Cell survival S for the entire tumor is thus given by summing overall tumor volume elements: S = ΣV Si i
(4)
where Si exp( BEDi) is the survival of those clonogens within each partial tumor volume vi and BEDi is given by
Fig. 1. Differential dose volume histograms (dDVH) for 125I, 103Pd and 192Ir from average patient-derived data (13). Note that for the 192Ir HDR brachytherapy DVH, the dose scale is ‘percent dose’ because different dose fraction sizes can be prescribed. Note how heterogeneous and ‘hot’ these DVH are, particularly for 125I and 103Pd.
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Table 1 Radiobiological parameters and clonogen number (NC) normalization values for the three clinical risk groups as defined in the text Risk group 1
(Gy ) SF2* (/ 3) SF2 (/ 10) TCP† NC (/ 3) NC (/ 10)
Favorable
Intermediate
Unfavorable
0.3 0.37 0.48 80% 7.6 1013 5.5 109
0.2 0.51 0.61 50% 2.7 109 4.8 106
0.1 0.71 0.78 20% 7.7 104 3.2 103
TCP tumor control probability; bNED endpoint of biochemical survival. *SF2 exp( 2 4) is the survival fraction after a single 2Gy dose and measures radiosensitivity. † TCP equivalent to bNED after 68Gy external beam in 2Gy per fraction. Adapted from the MSKCC series in Zelefsky et al. (12).
either Eq. 1 or Eq. 2. The prescribed doses are as follows: for 125I and 103Pd brachytherapy, 144 Gy (TG-43) and 125Gy (NIST-1999) respectively for monotherapy, and 110 Gy and 100 Gy for boost doses after 45Gy external beam, respectively. For 192Ir HDR brachytherapy the prescribed dose varied according to the clinical series used for comparison (see tables). For these models to be compared with clinical series the prescribed doses were scaled to the D90 dose line (dose delivered to 90% of the target volume) to correspond with the actual doses delivered clinically. Tumor control probability Tumor control probability (TCP) can be represented by the surrogate endpoint of biochemical survival (bNED) as has been used by others (eg. 7). TCP is described by Poisson statistics in the usual fashion as: TCP = exp ( – N C S )
(5)
where NC is the number of clonogens and S is given by Eq. 4. Radiobiological parameters Because we wish to compare model predictions with clinical series we must “anchor,” or normalize, the models. This is easily accomplished by choosing well-known clini-
cal outcomes for a given dose regimen. We chose this to be bNED survival rates of 80%, 50%, and 20% respectively for the Favorable, Intermediate, and Unfavorable risk groups receiving conventional doses of external beam (rounded-off values from the Memorial Sloan-Kettering Cancer Center— MSKCC—series for EBRT doses of 68Gy, see ref. 12). From this we calculate the number of clonogens NC required to achieve a given TCP that will correspond to the clinical bNED for that risk group, dose regimen and the model’s LQ parameters by solving Eq. 5. Table 1 shows the radiobiological parameters adopted and the normalized clonogen numbers. To reflect the probable increased radio-resistance (increase in SF2) with increasing risk group, we chose decreasing values of with increasing risk. (The number of clonogens thus obtained should not be regarded as representing the true number of cells, but rather one of several equivalent means of normalizing these models). Because the / ratio for prostate cancer might be quite low, models with values of 3 as well as 10 are constructed. For our models we adopt a SLDR repair half-life of 1 hour (10) and a TPOT of 60 days (15). The validity of these assumptions is tested in the next section. Brachytherapy clinical series The representative clinical series chosen for comparison are those that have the longest follow-up and the largest patient numbers. These series have used the American Society for Therapeutic Radiology and Oncology (ASTRO) definition or a closely related definition to report bNED survival rates. For LDR brachytherapy such series are now reporting on 10-year outcomes for 125I and 103Pd, with or without external beam (1, 2, 3). For HDR brachytherapy there are considerably fewer series to quote due to the relative youth of this technique. The series with the longest follow-up (up to 10 years) represents a fairly homogenous dose regimen (50.4 Gy external beam 4 HDR fractions of 3–4 Gy each), but despite the long follow-up only has 104 patients (4). The other HDR brachytherapy series quoted (5, 6) suffers from short follow-up (minimum of 3 years), but offers several HDR dose-escalation regimens (from 5.5 Gy–10.5 Gy). These series are summarized in Table 2. For the time being, there are no adequate data for HDR as monotherapy.
Table 2 bNED survival rates for the three risk groups among the clinical series used to compare with models. The different LDR/HDR/EB dose regimens in these series are outlined Risk group 103
Pd 125 I EB (45 Gy) I/Pd EB (50.4 Gy) HDR 3–4 Gy 4 EB (46 Gy) HDR 5.5–6.5 Gy 3 or 8.5 9.5 Gy 2 EB (46 Gy) HDR 5.5–6.5 Gy 3 EB (46 Gy) HDR 8.25–10.5 Gy 2 na clinical data is not available.
Favorable
Intermediate
Unfavorable
Reference
94% 87% 87% 96–100% na na na
82% 79% 85% 72–85% 88% na na
65% na 62% 49% 51–62% 64–75% 87–95%
Blasko et al. (1) Grimm et al. (3) Blasko et al. (2) Eualu et al. (4) Martinez et al. (5, 6) Brenner et al. (8) Brenner et al. (8)
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Caveats There are, of course, numerous limitations to studies of this nature. First, there is the ever-present issue of bNED definition when comparing clinical series. Rigorous adherence to the ASTRO definition of PSA failure, albeit an arbitrary one, is critically important when comparing clinical series. Small deviations from this can significantly affect the measured outcomes as has been demonstrated (16). Second, dose-escalated 3D conformal external-beam series and brachytherapy, especially HDR brachytherapy, are younger techniques and hence patients thus treated are from an era where follow-up will be inevitably shorter and stage migration toward earlier stages will be present. Both of these factors will favor recently treated patients (17). Third, the currently popular three-tier risk groups based upon clinical T-stage, initial PSA and biopsy Gleason score doesn’t take into account additional factors that have recently emerged as useful in risk stratification, such as the percent of positive cores and the length of positive segments (18). These are a sample of caveats to remember whenever one attempts a comparison between clinical series and the use of models to interpret them.
Results Model validation through comparison with external-beam dose-escalation series These models can be used to predict dose escalation results and compared with 3D conformal external-beam series. This is shown in Figure 2 where model TCP are compared with clinical bNED data for three dose-escalation series (12, 19, 20). The rather good agreement validates the assumptions made in these models and hence their predictive usefulness when extrapolated beyond their “anchor” point. Because there was no attempt to fit the radiobiological parameters to obtain the “best fit,” it is not surprising that the concordance isn’t perfect. Furthermore, it is worth remembering that models assume organ-confined disease. This is not always the case in clinical series even with early stage disease, and hence models will in general tend to slightly overestimate TCP. Predictions for LDR and HDR brachytherapy compared with clinical data Clinical bNED are compared with model TCP predictions in Tables 3 through 6. When such comparisons are made, we are not looking for an exact TCP/bNED match but for consistent trends, especially trends with increasing patient risk factors. For LDR brachytherapy monotherapy, the agreement with clinical series is very good (Table 3). For 45 Gy EB LDR brachytherapy boost, models generally predict higher TCP than the clinical bNED, perhaps reflecting the overall higher “true risk” among actual patients selected for this combined treatment. In general though, combined
Fig. 2. Predicted Tumor Control Probability (TCP) compared with clinical bNED results from several external-beam dose-escalation series (12, 20, 19) for Favorable, Intermediate and Unfavorable risk patients. Models are shown by solid lines (for tumor / 3) and dashed lines (for tumor / 10). Data are represented by symbols as identified within the figure legend. “Error bars” represent the range in doses and bNED survival rates from the clinical series.
external-beam LDR brachytherapy boost is suggested by the models to produce higher TCP than LDR monotherapy. Several fractionation regimens are in clinical usage for HDR brachytherapy boost. In Table 4 the HDR regimen is 50.4 Gy external beam 4 HDR fractions of 3–4 Gy each, according to the Seattle Prostate Institute series (4). The overall agreement between predicted TCP and bNED is good. This HDR regimen produces comparable long-term outcomes as with LDR brachytherapy. In Table 5 the HDR regimen is 46 Gy external beam with three HDR fractions of 5.5–6.5 Gy each or two HDR frac-
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Table 3 Clinical series bNED compared with model TCP for LDR brachytherapy Clinical series bNED 103
Pd monotherapy 125 I monotherapy EB (45 Gy) I/Pd
Favorable
Intermediate
Unfavorable
Reference
94% 87% 87%
82% 79% 85%
65% na 62%
Blasko et al. (1) Grimm et al. (3) Blasko et al. (2)
Favorable
Intermediate
Unfavorable
97% 96%
91% 90%
76% 75%
93% 97%
76% 89%
40% 67%
98/89% 99/99%
96/86% 99/99%
84/76% 95/92%
Model TCP 103
Pd monotherapy (/3) (/10) 125 I monotherapy (/3) (/10) EB (45 Gy) I/Pd boost (/3) (/10) 103
Pd dose is 125 Gy monotherapy, 100 Gy boost. 125I dose is 144 Gy monotherapy, 110 Gy boost. na clinical data is not available; bNED endpoint of biochemical survival; TCP tumor control probability; LDR low-dose rate.
tions of 8.25–10.5 Gy each, according to the William Beaumont series (5, 6, 8). The available clinical data here are comparatively sparse. The agreement between the models and clinical outcomes is once again fairly good. The range of TCP for a given range in dose fraction size is very dependent upon the / ratio, as expected. Although far from conclusive, the agreement between the models and clinical data seems more consistent for the models with the lower value of /.
Discussion and conclusions This radiobiological modeling study is but one aspect of the many differences between HDR and LDR prostate brachytherapy. Ultimately, only a prospective trial comparing the two techniques would truly discover clinically meaningful differences and optimal choices. Until data from such trials are available, if ever, one must make best use of the retrospective clinical data that are increasing in both quantity and quality. Although a simple comparison between clinical series suffers from patient selection bias effects, a radiobiological modelbased comparison bypasses these effects.
This study allows several general conclusions to be drawn which are supported by the available clinical data: 1) simple radiobiological models predict 3D dose-escalation outcomes that are in agreement with clinical series, 2) HDR and LDR brachytherapy delivered with current dose regimens achieve equivalent tumor control rates as compared with 3D dose-escalation external-beam series, and 3) LDR monotherapy achieves equivalent tumor control rates compared with EB/HDR boost regimens. Several interesting hypotheses are suggested by the models, but adequate supporting clinical data are not yet available: 1) LDR boost after EB might achieve improved tumor control rates compared with LDR monotherapy, 2) HDR monotherapy with current dose regimens might be equivalent to LDR monotherapy and 3D dose-escalation external-beam outcomes, and 3) HDR with dose escalated hypofractionated regimens might achieve maximal tumor control rates, especially for the Intermediate and Unfavorable risk patients. From a radiobiological perspective HDR brachytherapy has the flexibility of dose per fraction escalation and dose escalation, both of which are absent in LDR brachytherapy. This would be particularly significant should prostate cancer have a high sensitivity to dose fraction size (correspond-
Table 4 Clinical series bNED compared with model TCP for HDR brachytherapy regimen of 50.4 Gy EB 3–4 Gy 4 Clinical series bNED EB (50.4 Gy) HDR 3–4 Gy 4
Favorable
Intermediate
Unfavorable
Reference
96–100%
72–85%
49%
Eulau et al. (4)
Favorable
Intermediate
Unfavorable
95% 91%
88% 74%
64% 40%
Model TCP EB (50.4 Gy) HDR 4 Gy 4 (/3) (/10)
bNED endpoint of biochemical survival; TCP tumor control probability; HDR high-dose rate.
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Table 5 Clinical series bNED compared with model TCP for HDR brachytherapy regimens of 45 Gy EB 5.5–6.5 Gy 3 or 8.25–10.5 Gy 2 Clinical series bNED EB (46 Gy) HDR 5.5–6.5 Gy 3 or 8.25–9.5 Gy 2 EB (46 Gy) HDR 5.5–6.5 Gy 3 EB (46 Gy) HDR 8.25–10.5 Gy 2
Favorable
Intermediate
Unfavorable
Reference
na na na
88% na na
51–62% 64–75% 87–95%
Martinez et al. (5, 6) Brenner et al. (8) Brenner et al. (8)
Favorable
Intermediate
Unfavorable
76–98% 73–93%
76–96% 55–84%
64–89% 32–58%
98–99% 89–99%
96–99% 78–97%
89–99% 51–84%
Model TCP EB (45 Gy) HDR 5.5–6.5 Gy 3 (/ 3) (/ 10) EB (45 Gy) HDR 8.25–10.5 Gy 2 (/ 3) (/ 10)
na clinical data not available. bNED endpoint of biochemical survival; TCP tumor control probability; HDR high dose rate.
ing to a low / ratio). This has recently been the subject of lively debate (7–11) as the evidence in support of this accrues. Hypofractionated regimens are not new in prostate cancer and there are several clinical series that support the safety and efficacy of larger dose per fraction. First, an older British study using 6 Gy per fraction for a total of 36 Gy with conventional external beam produces long-term outcomes and morbidity that are as good as historical cohorts from the same era (21). More recently, a study using IMRT to deliver 70 Gy in 2.5 Gy per fraction has been reported with excellent acute and long-term morbidity (22). Much higher dose per fraction has been used with HDR brachytherapy as monotherapy and with excellent results so far (23). That series delivers 9.5 Gy per fraction with 4 fractions totaling 38 Gy using Ir-192 HDR brachytherapy. The acute toxicity seems to be within acceptable range whereas the long-term tumor control awaits maturation of the data, but is encouraging so far. Predictions for HDR monotherapy are made in Table 6, although no adequate clinical data are yet available. For models with a conventional tumor value of 10 for the / ratio, predicted TCP with this four-fraction regimen are the same as with LDR monotherapy. However, the advantage for this HDR regimen becomes dramatic should the tumor / ratio be as low as it is for late-reacting normal tissues. One has to be cautious to deliver so few large-dose fractions in a tumor that possesses regions of hypoxia, but there
Table 6 Model TCP predictions for HDR brachytherapy as monotherapy (38 Gy in four fractions) Model TCP HDR monotherapy 9.5 Gy 4 (/ 3) (/ 10)
Favorable
Intermediate
Unfavorable
98% 86%
97% 77%
96% 63%
HDR high dose rate; TCP tumor control probability.
might be an optimal number and schedule that would overcome the hypoxia challenge while simultaneously taking advantage of this radiobiological behavior. Although HDR brachytherapy is not the only technical means of delivering hypo-fractionated radiotherapy, it lends itself naturally to this. Other means currently contemplated include the use of IMRT in association with organ localization techniques and emerging technology such as the CyberKnife (a robotic arm–driven linac) which possesses some of the dosimetric attributes of IMRT but has built-in capabilities for real-time image-guided organ localization and position tracking (24). Acknowledgments The author thanks Drs. Charles Mayo and Ken Ulin for their help in acquiring the HDR dose volume histograms and for the many insights of Prof. Jack Fowler. References [1] Blasko JC, Grimm PD, Sylvester JE, et al. Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000;46: 839–850. [2] Blasko JC, et al. in 4th Annual advanced prostate brachytherapy conference, Seattle Prostate Institute, Seattle WA, 2001. [3] Grimm PD, Blasko JC, Sylvester JE, et al. 10-Year biochemical (PSA) control of prostate cancer with 125I brachytherapy. Int J Radiat Oncol Biol Phys 2001;51:31–40. [4] Eulau SM, Van Hollebeke L, Cavanagh W, et al. High dose rate 192Ir brachytherapy in localized prostate cancer: results and toxicity with maximum follow-up of 10 years. ASTRO 42nd Annual Meeting (abstract), Int J Radiat Oncol Biol Phys 2000;48:149. [5] Martinez AA, Kestin LL, Stromberg JS, et al. Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont phase II doseescalation trial. Int J Radiat Oncol Biol Phys 2000;47:343–352. [6] Martinez AA, et al. 4th Annual advanced prostate brachytherapy conference, Seattle Prostate Institute, Seattle WA, 2001. [7] Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999;43:1095– 1101. [8] Brenner DJ, Martinez AA, Edmundson GK, et al. Direct evidence
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King / Brachytherapy 1 (2002) 219–226 that prostate tumors show a high sensitivity to fractionation (low / ratio), similar to late-responding normal tissue. Int J Radiat Oncol Biol Phys 2002;52:6–13. King CR, Fowler JF. A simple analytic derivation suggests that prostate cancer / ratio is low. Int J Radiat Oncol Biol Phys 2001;51: 213–214. Fowler JF, Chappell R, Ritter M. Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001;50:1021–1031. King CR, Fowler JF. Yes, the prostate cancer / ratio is low, or, Methinks the lady doth protest too much ... about a low / ratio that is. Int J Radiat Oncol Biol Phys 2002;54:626–627. Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:491–500. King CR, DiPetrillo TA, Wazer DE. Optimal radiotherapy for prostate cancer: predictions for conventional external beam, IMRT, and brachytherapy from radiobiological models. Int J Radiat Oncol Biol Phys 2000;46:165–172. Dale RG. Radiobiological assessment of permanent implants using tumor repopulation factors in the linear-quadratic model. Br J Radiol 1989;62:241–244. Haustermans KMG, Hofland I, Van Poppel, et al. Measurements in prostate cancer. Int J Radiat Oncol Biol Phys 1997;37:1067–1070. Vicini FA, Kestin LL, Martinez AA. The correlation of serial prostate specific antigen measurements with clinical outcome after external beam radiation therapy of patients for prostate carcinoma. Cancer 2000;88:2305–2318.
[17] Kestin LL, Vicini FA, Martinez AA. Practical application of biochemical failure definitions: what to do and when to do it. Int J Radiat Oncol Biol Phys 2002;53:304 –315. [18] D’Amico AV, Desjardin A, Chung A, et al. Assessment of outcome prediction models for patients with localized prostate carcinoma managed with radical prostatectomy or external beam radiation therapy. Cancer 1998;82:1887–1896. [19] Pollack A, Zagars GK, Smith LG, et al. Preliminary results of a randomized radiotherapy dose-escalation study comparing 70Gy with 78Gy for prostate cancer. J Clin Oncol 2000;18;3904–3911. [20] Hanks GE, Hanlon AL, Pinover WH, et al. Dose selection for prostate cancer patients based on dose comparison and dose response studies. Int J Radiat Oncol Biol Phys 2000;46:823-–832. [21] Lloyd-Davis RW, Collins CD, Swan AV. Carcinoma of prostate treated by radical external beam radiotherapy using hypofractionation: 22 years experience (1962-1984). Urology 1990;36:107–111. [22] Kupelian PA, Reddy CA, Klein EA, et al. Short-course intensitymodulated radiotherapy (70Gy at 2.5Gy per fraction) for localized prostate cancer: preliminary results on late toxicity and quality of life. Int J Radiat Oncol Biol Phys 2001;51:988–993. [23] Martinez AA, Pataki I, Edmundson G, et al. Phase II prospective study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: a feasibility report. Int J Radiat Oncol Biol Phys 2001;49:61–69. [24] King CR, Lehmann J, Adler JA, et al. CyberKnife radiotherapy for prostate cancer: rationale and technical feasibility. Technol Cancer Res Treatm 2003. In press.