- Email: [email protected]
Moving Toward Focal Therapy in Prostate Cancer: Dual-Isotope Permanent Seed Implants as a Possible Solution
Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 1, pp. 297–304, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter
doi:10.1016/j.ijrobp.2010.10.060
PHYSICS CONTRIBUTION
MOVING TOWARD FOCAL THERAPY IN PROSTATE CANCER: DUAL-ISOTOPE PERMANENT SEED IMPLANTS AS A POSSIBLE SOLUTION DORIN A. TODOR, PH.D.,* IGOR J. BARANI, M.D.,y PECK-SUN LIN, PH.D.,* AND MITCHELL S. ANSCHER, M.D.* *Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA; and yDepartment of Radiation Oncology, University of California-San Francisco, San Francisco, CA Purpose: To compare the ability of single- and dual-isotope prostate seed implants to escalate biologically effective dose (BED) to foci of disease while reducing prescription dose to the prostate. Methods and Materials: Nine plans, using 125I, 103Pd, and 131Cs alone and in combination were created retrospectively for 2 patients. Ultrasound and MRI/MRS datasets were used for treatment planning. Voxel-by-voxel BED was calculated for single- and dual-isotope plans. Equivalent uniform BED (EUBED) was used to compare plans. The MRS-positive planning target volumes (PTVi) were delineated along with PTV (prostate + 5 mm), rectum, and urethra. Single-isotope implants, prescribed to conventional doses, were generated to achieve good PTV coverage. The PTVi were prospectively used to generate implants using mixtures of isotopes. For mixed-radioisotope implants, we also explored the impact on EUBED of lowering prescription doses by 15%. Results: The EUBED of PTVi in the setting of primary 125I implant increased 20–66% when 103Pd and 131Cs were used compared with 125I boost. Decreasing prescription dose by 15% in mixed-isotope implants results in a potential 10% reduction in urethral EUBED with preservation of PTV coverage while still boosting PTVi (up to 80%). When radiobiologic parameters corresponding to more-aggressive disease are assigned to foci, faster-decaying isotopes used in mixed implants have the potential to preserve the equivalent biological effect of mono-isotope implants considering less-aggressive disease distributed in the entire prostate. Conclusions: This is a hypothesis-generating study proposing a treatment paradigm that could be the middle ground between whole-gland irradiation and focal-only treatment. The use of two isotopes concurrent with decreasing the minimal peripheral dose is shown to increase EUBED of selected subvolumes while preserving the therapeutic effect at the level of the gland. Ó 2011 Elsevier Inc. Prostate, Brachytherapy, Radiobiologic model, Focal therapy, Dual isotopes.
the gland has been proposed (8). This approach represents a major paradigm shift, similar to partial breast irradiation for early-stage breast cancer. Focal therapy potentially offers a parenchymal-sparing approach that selectively ablates known disease while minimizing toxicity and preserving existent function without compromising treatment outcome or quality of life. Currently, the multifocal nature of PC, coupled with the inability to reliably detect foci of disease within the prostate gland, are the main obstacles to a rational selection of patients for focal therapy. Conventional singleisotope permanent prostate implants achieve adequate tumor control with moderate rectal and urethral toxicities. Previous studies (9) demonstrated the feasibility of MRS-targeted dose escalation ($120%) of small prostate subvolumes while preserving the accepted dose–volume limits for the prostate and surrounding normal tissues. Recent reports suggest that metabolic data from MRSI (10) alone or in
INTRODUCTION Prostate cancer (PC) is the most common cancer among American men. Brachytherapy has long been an effective treatment option for low-risk, organ-confined disease, with extensive follow-up of a large number of patients. Like other forms of radiotherapy, brachytherapy has been used to treat the entire prostate gland. Recent studies (1) show that the introduction of prostate-specific antigen (PSA) screening programs resulted in an earlier detection of PC (2, 3), and both the volume and the number of malignant foci within the prostate have decreased significantly. The volume of cancer found in radical prostatectomy specimens has decreased from a mean of 4.7–6.1 mL in 1995–1999 (4, 5) to 2.1–2.6 mL in 2001–2005 (6, 7) and the mean number of foci from 7.3 in the pre-PSA era to less than 2.5 (7). In light of these findings, the concept of focal therapy for PC treatment of only malignant foci while sparing the rest of Reprint requests to: Dorin A. Todor, Ph.D., Department of Radiation Oncology, Virginia Commonwealth University, 401 College St., Box 980058, Richmond, VA 23298-0058. Tel: (804) 8287415; Fax: (804) 828-6042; E-mail: [email protected]
Conflicts of interest: none. Received Feb 22, 2010, and in revised form Oct 21, 2010. Accepted for publication Oct 31, 2010. 297
298
I. J. Radiation Oncology d Biology d Physics
combination with digital contrast-enhanced MRI could successfully detect, delineate, and grade intraprostatic disease (11). As the imaging modalities improve, partial-organ brachytherapy may become a reasonable treatment approach for qualified patients. Using the linear-quadratic formalism for continuous dose irradiation developed by Chen and Nath (12), we explored whether dual-isotope brachytherapy can meet the following therapeutic goals: (1) maintain a therapeutic biological equivalent dose of the cancer foci within the prostate gland; (2) reduce the whole-gland dose (MPD - the Minimum Peripheral Dose to target has been historically used for prescribing dose and planning purposes); (3) boost foci of PC within the gland; and (4) reduce dose to surrounding normal structures. This work represents a theoretical feasibility study of the dual-isotope brachytherapy approach in the treatment of localized PC. Although we have used MRI/MRSI to delineate disease foci within the prostate, the theoretical implications of this study can be generalized to other approaches for identifying subvolumes of disease within the gland.
METHODS AND MATERIALS At present, three isotopes are available for prostate low-dose-rate brachytherapy, with a half-life of 59.4 days (125I), 17 days (103Pd), and 9.7 days (131Cs). In this study, we model the biological implications of combinations of these isotopes. In the evaluated scenarios, the MRS-positive subvolumes of disease are targeted with a faster-decaying isotope, on the basis of the theoretical assumption that increased dose rate will improve tumor control probability. For example, for 125I base implant, the boost to foci of disease is achieved with either 103Pd or 131Cs, whereas for a 103Pd base implant only a boost with 131Cs is considered. Currently, postimplant dosimetry is described by V100/V150/V200 parameters (where Vx is the volume of the target receiving x = 100%, 150%, or 200% of prescription dose) and D90 (minimum dose received by 90% of the target volume). It is interesting to note that for 125I a D90 $140 Gy (representing 96.5% of the standard prescription dose) seems adequate to achieve excellent local control rates (13); however, for 103Pd, a D90 of 100 Gy (80% of a typical 103Pd prescription dose) was reported to provide similar outcomes (14). These observations were used to justify a 103Pd dose de-escalation trial (15) in which the prescription dose was reduced from 125 Gy to 110 Gy for selected low-risk PC patients (PSA #10 ng/mL, Gleason score <6, and clinical stage T1b– T2b). In our study, we evaluate the possibility of reducing prescription dose by 15%. It has long been recognized that the conventional postimplant dose–volume parameters may be inadequate to measure the implant ‘‘quality’’ in the absence of spatial information (16). This is emphasized even more for mixtures of isotopes because spatial distribution of dose and differential dose-rate will exaggerate the disconnect between the physical and biological dose. A biologically effective dose (BED) model for a mixture of two isotopes was developed by Chen and Nath (12), extending the previously published models by Dale (17). The model incorporates the kinetic parameters of sublethal damage repair, described by a single repair half-life and the effect of cell proliferation during continuous irra-
Volume 81, Number 1, 2011
diation. Thus, for a mixture of two isotopes, the BED is described by: BED ¼
2 X ln2 D_ 0i 1 eli Teff RE Teff li aTp i¼1
(1)
where RE is b RE ¼ 1þ2 a
P P D_ 0i D_ 0j n 1 1 1eðli þlj ÞTeff 1eðmþlj ÞTeff mli li þlj mþlj i j P D_ 0i li Teff Þ ð1e li i
(2)
and Teff is 1 ln2 Teff ¼ ln l a,Tpot ,D_ 0
(3)
In these equations, D_ 0i represents the initial dose rate for isotope i, Teff is the effective time of the implant (the time at which the repopulation rate becomes larger than the cell-killing rate as a result of dose rate drop), Tpot is the tumor potential doubling time, l is the radioactive decay constant, and m is the time constant for cellular repair of sublethal damage. The derivation of radiobiologic parameters for the prostate was the object of numerous studies (18–21). Brenner and Hall (18) were the first to point out that a/b for prostate might be unusually low. Between the values reported by Wang et al. (22) for prostate (a/b = 3.1 Gy and a = 0.15 Gy1) and those reported by Fowler et al. (23) (a/b = 1.5 Gy and a = 0.039 Gy1), we choose to use a = 0.155 Gy1 (interval, 0.055–0.3), b = 0.052 Gy2, a/b = 2.98 Gy, and Tpot = 42 days. The radiobiologic parameters for the urethra were taken from in vitro measurements published by Marchese et al. (24): a = 0.458 Gy1, b = 0.020 Gy2, and a Tpot = 60 days was used for both the urethra and the rectum. The half-life for the sublethal damage repair process was considered 1 h for both organs. For each voxel of tissue the instantaneous dose rate is a sum of the dose rates of the two contributing isotopes: _ ! Dð r ; tÞ ¼
ni 2 X X i¼1
li t D_ 0i ! rj e
(4)
j¼1
where n ¼ n1 þ n2 ; the total number of sources from the two isotopes. To compare vastly different dose distributions, with significantly different dose rates associated with each voxel, we decided to use the formalism developed by Jones and Hoban (25), namely the equivalent uniform BED (EUBED): # " X 1 a,BEDi EUBED ¼ In ni e a i
(5)
Our study used ultrasound and MRI/MRS datasets of 2 patients who received permanent seed implants as the sole treatment modality for PC. Subvolumes of disease were delineated using the available MRS imaging, and the prostate, planning target volume (PTV) (prostate + 5 mm), rectum, and urethra were delineated with the help of MRI. Implants consisting of 125I, 103Pd, and 131Cs isotopes alone and in combination were planned using VariSeed V7.2 (Varian Medical Systems, Palo Alto, CA) software. Singleisotope implants were designed to achieve PTV coverage with D90 >95% of the prescription dose. Conventional isotope-specific prescription doses were used: 145 Gy for 125I, 124 Gy for 103Pd, and 115 Gy for 131Cs (26, 27).
Dual isotope prostate seed implants d D. A. TODOR et al.
The prostate sizes for Patients A and B were 19.5 cm3 and 23.9 cm3, respectively. Two MRS-positive volumes of 0.3 mL and 1.3 mL were outlined for Patient A and one of 0.58 mL for Patient B. Patient age, stage, initial PSA level, and Gleason score were not considered in this study because the objective was to explore the radiobiologic effect of a mixture of implanted isotopes. The boost of disease foci in the background of a base implant was achieved by either increasing the number of same-strength seeds of the base isotope or by implanting seeds of an isotope with a shorter half-life, and implicitly increased dose rate. The treatment plans were created by placing needles only in grid positions, so the number of needles going through the subvolumes to be boosted was limited to the number of available grid positions in the subvolume’s largest transversal cross-section. As in the actual implants, two adjacent seeds were allowed, but we avoided, whenever possible, three successive seeds. For each isotope the native prescription dose was preserved, and a V100 approximately equal to the volume of the disease foci was created. A nomogram method was used to derive an approximate number of seeds that would ‘‘cover’’ with prescription dose the volume of the disease foci. In total, nine plans were generated for each patient (Table 1). Magnetic resonance and ultrasounds images were rigidly coregistered under user guidance, matching previously segmented contours for the prostate and urethra. Because the current treatment planning system (TPS) can only generate plans for seeds of a single isotope, multiple plans had to be merged to create the desired dualisotope scenarios. The air-kerma strength of the seeds used in the single-isotope implants was 0.45 U for 125I, 2.4 U for 103Pd, and 2.0 U for 131Cs. The same seed strength was used for boosting. The boost plans were prescribed to the same standard prescription as the sole implants (example shown in Fig. 1), but given the significantly smaller volumes, the actual delivered dose to 90% of the PTVi was in the range of 120–160% of the minimum peripheral dose used as prescription dose. To illustrate the integration of doses for two isotopes, Fig. 2 shows that despite the rapid dose falloff, there is some dose cross-contribution between the boost implant and the base implant. In Fig. 3, one can see clearly the enhanced biological effect of higher dose rate delivered by the faster-decaying isotope. Dose matrices and structure contours were exported from the planning system as DICOM (Digital Imaging and Communications in Medicine) files. In-house software based on MATLAB (Math-
Table. Isotope composition of the nine plans generated for each patient
Plan no. 1 2 3 4 5 6 7 8 9
Base (whole-gland) implant isotope,PTV 125
I Pd 131 Cs 125 I 103 Pd 131 Cs 125 I 125 I 103 Pd 103
Abbreviation: PTV = planning target volume.
Boost volume implant isotope, PTVi — — — 125 I 103 Pd 131 Cs 103 Pd 131 Cs 131 Cs
299
works, Nattick, MA) was then used to read the dose matrices and anatomic and planning structures and to perform voxel BED calculations for each structure. Voxel BEDs were then ‘‘integrated’’ into a representative EUBED. For the mixed-radioisotope implants we also explored the impact on EUBED of lowering the prescription dose from 100% to 85%. The prescription was reduced to 85% by simply scaling down the already-exported dose matrix corresponding to the 100% prescription. With prescription doses reduced by 15%, the aim was to deliver at least the same EUBED to the prostate as the conventional base implant, while boosting the MRS-positive subvolumes and reducing the overall urethral dose.
RESULTS Using the standard set of radiobiologic parameters for prostate, urethra, and rectum, we compared the nine plans described above. In the setting of a primary 125I implant, EUBED of PTV1 and PTV2 increased by 20% and 60% when 103Pd and 131Cs were used for boost of disease subvolumes, respectively, compared with 125I alone. In this setting, reduction by 15% in the prescription dose of both the primary and boost implants preserved the EUBED for prostate, PTV, and urethra while simultaneously achieving a boost of the MRS-positive subvolumes. Similar results were noted in the setting of the primary 103Pd implant (Fig. 4). A 131Cs boost in the setting of primary 103Pd implant results in even greater biological dose to MRS-positive volumes, compared with primary 125I implant, while preserving EUBEDs of other structures. A 10% reduction of urethral EUBED is possible for a primary 103Pd implant with a concentrated 103 Pd boost of the MRS-positive regions. Rectal dose remained largely invariant in all permanent prostate implant scenarios examined. The dose to rectum, as outlined during the implantation from ultrasound images or from a single CT for postimplant evaluation, would be affected anyway by significant uncertainties due to, for example, peristaltic motion, changes in shape, and filling variations for the weeks or months of active implant dose delivery. Three separate sets of radiobiologic parameters were used for three PC risk groups as identified by King et al. (28): favorable (R1), intermediate (R2), and unfavorable (R3) risk group. The EUBED was then calculated for the prostate and PTVi using these three risk categories. For comparison, hypothetical uniform dose plans (at the standard prescription dose for each isotope) were calculated to asses the ‘‘enhancement’’ effect of the real, nonuniform dose distribution created by seed implants. For example, for an 125I implant, planned without a priori knowledge of disease subvolumes, prescribed at 145 Gy and D90 >110%, the EUBED for the prostate (when the radiobiologic parameters assigned to that risk category are considered the same for the whole gland) drops to an average of 90% for the R2 group and 60% for R3 when normalized to R1. This suggests a potential loss of biological effect of up to 40% for patients in the R3 risk category. The ratio of computed EUBED for nonuniform dose distribution to a hypothetical uniform dose distribution at the
300
I. J. Radiation Oncology d Biology d Physics
Volume 81, Number 1, 2011
Fig. 1. Transversal cross-section from the treatment planning system. The 125I implant (left) is shown planned for planning target volume minus the MRS-positive subvolume (in cyan). The 131Cs implant (right) are planned for the MRS-positive sub-volume.
same prescription dose for R1, R2, and R3 disease categories increases from 1.0 to 1.1 and to 1.45, respectively. This simply illustrates that the effect of the inherent dose inhomogeneity on EUBED becomes more important as the clinical risk group increases (or the disease becomes more aggressive). For an 125I implant on which the PTVi volumes were boosted with supplemental 125I, the drop in EUBED with in-
creased risk category is similar to the previous case but of lesser magnitude: 100% for R1, 90% for R2, and 63% for R3. The enhancement due to inhomogeneity reaches 1.10 for R2 and 1.53 for R3. If the same 125I implant is boosted with 103Pd, the EUBED exhibits a lesser drop, from 100% to 92% for R2 and 70% for R3. Similar results are obtained when 125I implant is boosted with 131Cs.
Fig. 2. Two-isotopes seed implant example. Same transversal cross-section as in Fig. 1 is shown (upper row) and a dose profile along the dotted line (lower row). An 125I implant (left) is prescribed to 145 Gy for prostate + 5 mm margin minus the MRS-positive volume. A 131Cs implant (center) is prescribed to 115 Gy for the MRS volume only. The two are added outside of the treatment planning system (right). The figure shows total physical dose, but one has to keep in mind that the two implants provide significantly different dose rates (and biological effects).
Dual isotope prostate seed implants d D. A. TODOR et al.
301
Fig. 3. Example of significant and focal biologically effective dose enhancement produced by the larger dose rate associated with the faster-decaying isotope. For comparison, physical dose profile is shown in blue.
However, the situation changes when 103Pd and 131Cs implants are boosted with the same isotope to disease subvolumes. For 103Pd, the drop in EUBED for the prostate with increasing risk category was minimal (R1: 100%; R2: 97%; R3: 93%). For 131Cs base implant, the decrease was commensurate (R1: 100%; R2: 96%; R3: 94%). In the above scenarios, the radiobiological parameters for different risk groups were applied uniformly to the whole prostate. We also explored three scenarios in which different radiobiologic parameters are assigned to the prostate and higher risk group parameters to the foci of disease: A: prostate (R1) + foci (R2); B: prostate (R1) + foci (R3); and C: prostate (R2) + foci (R3). For Scenario A, the use of 125I base implant and 103Pd disease-specific boost results in an EUBED decrease of 10% for disease foci, whereas for Scenario B the decrease was 25%. A 25% increase in the MPD for the foci of disease restores the EUBED to its value if low-risk (R1) disease would have been considered distributed uniformly. A 45% foci MPD increase for Scenario B and 25% increase for Scenario C would also restore EUBED to its value if lessaggressive disease would be the only one considered. Similarly, in the setting of a primary 103Pd implant and using 131 Cs to treat the foci of disease, Scenarios A and B need an increase in the MPD of 20% and 25%, respectively, whereas for Scenario C, an increase of 10–15% of the prescription dose for the 131Cs portion of the implant would suffice. DISCUSSION The first point of discussion is whether it is reasonable to assign faster-decaying isotopes to higher-grade tumors. There is no clinical evidence that, with the current prescrip-
tion doses and usage, 125I and 103Pd implants have different outcomes, but an important factor making the distinction more difficult might be the inherent heterogeneity of the individual foci of disease. Biopsy-detected foci of disease may not necessarily reflect the grade of other unbiopsied disease foci within the gland. This experience is supported by observations of upstaging after prostatectomy. Armpilia et al. (29) have used a linear-quadratic model suitable for the analysis of permanent brachytherapy implants to investigate the radionuclide half-lives that will maximize the BED delivered to tumors. Their conclusion is that ‘‘for a wide range of tumor types, shorter-lived radionuclides are more versatile for achieving reasonable clinical results.’’ A publication by Antipas et al. (30) states that ‘‘the biological dose uncertainties are found to be less with 103 Pd,’’ and the ‘‘TCPs [Tumor Control Probability] associated with this radionuclide are expected to be significant higher in the treatment of faster growing, more aggressive tumors’’ (one can perhaps argue that effective dose per cell cycle is greater for 103Pd than for 125I). ‘‘Using typically prescribed doses for 125I appears to be better for treating radiosensitive tumors with long doubling time. However, unless 125I doses are reduced this advantage may well be offset by the enhanced biological doses delivered to adjacent normal structures.’’ In a study aimed to determine the optimal dose, Stock et al. (13) reported that ‘‘125I implantation alone was limited to patients with PSA #10, stage #T2a and Gleason score < 7.. Patients with Gleason scores $7 were implanted with 103Pd seeds’’; and while no further explanation of the isotope choice is given, the choice is clearly aiming to treat the ‘‘more-aggressive’’ disease with faster-decaying isotopes and implicitly larger dose rates.
302
I. J. Radiation Oncology d Biology d Physics
Volume 81, Number 1, 2011
Fig. 4. Summary of equivalent uniform biologically effective dose (EUBED) values of various structures for plans as described in Table 1. (A) For an 125I base implant; (B) for a 103Pd base implant. ‘‘R’’ indicates that the prescription dose was reduced to 85%. PTV = planning target volume.
A second issue would be whether such implant would be possible to plan with today’s TPS. Given that MPD is historically the way dose is prescribed for permanent prostate seed implants, we have resorted to using the same metric in our study. However, given that the two implants are created separately, and each of them is optimized to its own set of structures, it is difficult or impossible to create a truly optimal dual-isotope implant with the current TPS. This work is not a study on optimizing dual-isotope implants but merely a study that points out that a dual-isotope approach could be the middle ground between whole-gland and focal-only treatment.
We have used VariSeed (Varian Medical Systems, Palo Alto, CA), which is designed to handle multiple seed strengths in one implant. Although we are confident that it can be easily modified to handle two different isotopes at two different airkerma strengths, the issue of plan optimization is more difficult because it involves BED rather than physical dose. The need to shift gears from physical dose to BED was also expressed recently by Stone et al. (31, 32), who have shown that a BED of 200 Gy is needed for excellent local control and low recurrence rates. In 2006 the same group (33) pointed out that ‘‘BED was the most significant predictor of biopsy
Dual isotope prostate seed implants d D. A. TODOR et al.
outcome in multivariate analysis.’’ A postimplant evaluation of a mixed implant would likely have to use either nonrigid registration between the preplan and the CT reconstructed implant or be based on an intraoperative approach in which seeds are identified as they are implanted. Boosting and dose escalation are well known strategies for increasing disease control, in both external-beam radiotherapy (EBRT) and brachytherapy. Kim and Tome (34, 35) have shown that selective boosting of high-risk subvolumes is a better choice than homogeneous dose escalation. In brachytherapy, Li et al. (36) have shown that the level of dose escalation currently achieved in EBRT can be matched in brachytherapy by modest increases of the MPD (5–10%) with ‘‘acceptable dose increases in the rectum and urethra.’’ Most studies used equivalent uniform dose to measure benefits of these strategies, but given the emphasis on BED relative to outcome in brachytherapy and the inherent spatially inhomogeneous, time varying at the voxel level, dose distributions, we felt compelled to use EUBED to compare various implants. Zaider et al. (9) described a biologically based method in which dose to MRSI subvolumes is increased with a minimum of 120%, but 125I-only implants were considered, and boosting was achieved only by increasing the number of 125I seeds in those subvolumes. The same
303
group recently published (10) evidence connecting Gleason scores with MRS findings, leading the way for MRS-based ‘‘biologically motivated focal treatment for which intensitymodulated radiotherapy and especially brachytherapy are ideally suited.’’ The location of the PTVi (MRI/MRSI) positive or otherwise identified foci of disease is likely to have some bearing on ones ability to biologically boost these volumes with no penalties to adjacent organs. Our study is not large enough to address this issue. This work is rather a proof of principle study, showing that a mixture of two isotopes could potentially be used to boost disease subvolumes by taking advantage of both dose and dose-rate increase as opposed to the classic dose-only escalation paradigm. CONCLUSION This is a hypothesis-generating study proposing a treatment paradigm that could be viewed as an intermediate solution between whole-gland irradiation and focal treatment. The use of two isotopes concurrent with decreasing the minimal peripheral dose is shown to increase EUBED of selected subvolumes while preserving the therapeutic effect at the level of the whole gland.
REFERENCES 1. Mouraviev V, Mayes JM, Polascik TJ. Pathologic basis of focal therapy for early-stage prostate cancer. Nat Rev Urol 2009;6: 205–215. 2. Lim LS, Sherin K, ACPM Prevention Practice Committee. Screening for prostate cancer in U.S. men ACPM position statement on preventive practice. Am J Prev Med 2008;34: 164–170. 3. Etzioni R, Tsodikov A, Mariotto A, et al. Quantifying the role of PSA screening in the US prostate cancer mortality decline. Cancer Causes Control 2008;19:175–181. 4. Stamey TA, McNeal JE, Yemoto CM, et al. Biological determinants of cancer progression in men with prostate cancer. JAMA 1999;281:1395–1400. 5. Cupp MR, Bostwick DG, Myers RP, et al. The volume of prostate cancer in the biopsy specimen cannot reliably predict the quantity of cancer in the radical prostatectomy specimen on an individual basis. J Urol 1995;153:1543–1548. 6. Cheng L, Poulos CK, Pan CX, et al. Preoperative prediction of small volume cancer (less than 0.5 ml) in radical prostatectomy specimens. J Urol 2005;174:898–902. 7. Sebo TJ, Cheville JC, Riehle DL, et al. Predicting prostate carcinoma volume and stage at radical prostatectomy by assessing needle biopsy specimens for percent surface area and cores positive for carcinoma, perineural invasion, Gleason score, DNA ploidy and proliferation, and preoperative serum prostate specific antigen: A report of 454 cases. Cancer 2001;91:2196– 2204. 8. Onik G, Narayan P, Vaughan D, et al. Focal ‘‘nerve-sparing’’ cryosurgery for treatment of primary prostate cancer: A new approach to preserving potency. Urol 2002;60:109–114. 9. Zaider M, Zelefsky MJ, Lee EK, et al. Treatment planning for prostate implants using magnetic-resonance spectroscopy imaging. Int J Radiat Oncol Biol Phys 2000;47:1085–1096. 10. Carlani M, Mancino S, Bonanno E, et al. Combined morphological, [1H]-MR spectroscopic and contrast-enhanced imag-
11.
12.
13. 14.
15. 16.
17. 18. 19.
ing of human prostate cancer with a 3-Tesla scanner: Preliminary experience. Radiol Med 2008;113:670–688. Brame RS, Zaider M, Zakian KL, et al. Regarding the focal treatment of prostate cancer: Inference of the Gleason grade from magnetic resonance spectroscopic imaging. Int J Radiat Oncol Biol Phys 2009;74:110–114. Chen Z, Nath R. Biologically effective dose (BED) for interstitial seed implants containing a mixture of radionuclides with different half-lives. Int J Radiat Oncol Biol Phys 2003;55: 825–834. Stock RG, Stone NN, Tabert A, et al. A dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998;41: 101–108. Kollmeier MA, Stock RG, Stone N. Biochemical outcomes after prostate brachytherapy with 5-year minimal follow-up: Importance of patient selection and implant quality. Int J Radiat Oncol Biol Phys 2003;57:645–653. Gregory S, Merrick MD. Pd-103 dose de-escalation for early stage prostate cancer: A prospective randomized trial. Study NCT00247312. Wheeling, WV: Schiffler Cancer Center. D’Souza WD, Thames HD, Kuban DA. Dose-volume conundrum for response of prostate cancer to brachytherapy: Summary dosimetric measures and their relationship to tumor control probability. Int J Radiat Oncol Biol Phys 2004;58: 1540–1548. Dale RG. Radiobiological assessment of permanent implants using tumor repopulation factors in the linear-quadratic model. Br J Radiol 1989;62:241–244. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999;43:1095–1101. Fowler JF, Ritter MA, Fenwick JD, et al. How low is the a/b ratio for prostate cancer? In regard to Wang, et al. IJROBP 2003; 55:194–203 [letter]. Int J Radiat Oncol Biol Phys 2003;57: 593–595.
304
I. J. Radiation Oncology d Biology d Physics
20. Brenner DJ, Martinez AA, Edmundson GK, et al. Direct evidence that prostate tumors show high sensitivity to fractionation (low a/b ratio) comparable to late-responding normal tissue. Int J Radiat Oncol Biol Phys 2002;52:6–13. 21. Wang JZ, Guerrero M, Li XA. How low is the a/b ratio for prostate cancer? Int J Radiat Oncol Biol Phys 2003;55:194–203. 22. King CR, Fowler JF. A simple analytic derivation suggests that prostate cancer alpha/beta ratio is low. Int J Radiat Oncol Biol Phys 2001;51:213–214. 23. Fowler JF, Chappell RJ, Ritter MA. Is a/b for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001;50:1021–1031. 24. Marchese MJ, Hei TK, Zaider M, et al. Radiation repair in human endothelial cells. Int J Radiat Oncol Biol Phys 1987;13: 1857–1860. 25. Jones LC, Hoban PW. Treatment plan comparison using equivalent uniform biologically effective dose (EUBED). Phys Med Biol 2000;45:159–170. 26. Yue N, Heron DE, Komanduri K, et al. Prescription dose in permanent (131)Cs seed prostate implants. Med Phys 2005;32: 2496–2502. 27. Bice WS, Prestidge BR, Kurtzman SM, et al. Recommendations for permanent prostate brachytherapy with (131)Cs: A consensus report from the Cesium Advisory Group. Brachytherapy 2008;7:290–296. 28. King CR, DiPetrillo TA, Wazer DE. Optimal radiotherapy for prostate cancer: predictions for conventional external beam, IMRT, and brachytherapy from radiobiologic models. Int J Radiat Oncol Biol Phys 2000;46:165–172. 29. Armpilia CI, Dale RG, Coles IP, et al. The determination of radiobiologically optimized half-lives for radionuclides used in
Volume 81, Number 1, 2011
30.
31.
32.
33.
34.
35. 36.
permanent brachytherapy implants. Int J Radiat Oncol Biol Phys 2003;55:378–385. Antipas V, Dale RG, Coles IP. A theoretical investigation into the role of tumor radiosensitivity, clonogen repopulation, tumor shrinkage, and radionuclide RBE in permanent brachytherapy implants of 125I and 103Pd. Phys Med Biol 2001;46:2557–2569. Stone NN, Stock RG, Cesaretti JA, et al. Local control following permanent prostate brachytherapy: Effect of high biologically effective dose on biopsy results and oncologic outcomes. Int J Radiat Oncol Biol Phys 2010;76:355–360. Stone NN, Potters L, Davis BJ, et al. Multicenter analysis of effect of high biologic effective dose on biochemical failure and survival outcomes in patients with Gleason score 7-10 prostate cancer treated with permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2009;73:341–346. Stock RG, Stone NN, Cesaretti JA, et al. Biologically effective dose values for prostate brachytherapy: Effects on PSA failure and posttreatment biopsy results. Int J Radiat Oncol Biol Phys 2006;64:527–533. Kim Y, Tome WA. Is it beneficial to selectively boost high-risk tumor subvolumes? A comparison of selectively boosting highrisk tumor subvolumes versus homogeneous dose escalation of the entire tumor based on equivalent EUD plans. Acta Oncol 2008;47:906–916. Kim Y, Tome WA. Risk-adaptive optimization: Selective boosting of high-risk tumor subvolumes. Int J Radiat Oncol Biol Phys 2006;66:1528–1542. Li XA, Wang JZ, Stewart RD, et al. Dose escalation in permanent brachytherapy for prostate cancer: Dosimetric and biological considerations. Phys Med Biol 2003;48:2753–2765.
doi:10.1016/j.ijrobp.2010.10.060
PHYSICS CONTRIBUTION
MOVING TOWARD FOCAL THERAPY IN PROSTATE CANCER: DUAL-ISOTOPE PERMANENT SEED IMPLANTS AS A POSSIBLE SOLUTION DORIN A. TODOR, PH.D.,* IGOR J. BARANI, M.D.,y PECK-SUN LIN, PH.D.,* AND MITCHELL S. ANSCHER, M.D.* *Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA; and yDepartment of Radiation Oncology, University of California-San Francisco, San Francisco, CA Purpose: To compare the ability of single- and dual-isotope prostate seed implants to escalate biologically effective dose (BED) to foci of disease while reducing prescription dose to the prostate. Methods and Materials: Nine plans, using 125I, 103Pd, and 131Cs alone and in combination were created retrospectively for 2 patients. Ultrasound and MRI/MRS datasets were used for treatment planning. Voxel-by-voxel BED was calculated for single- and dual-isotope plans. Equivalent uniform BED (EUBED) was used to compare plans. The MRS-positive planning target volumes (PTVi) were delineated along with PTV (prostate + 5 mm), rectum, and urethra. Single-isotope implants, prescribed to conventional doses, were generated to achieve good PTV coverage. The PTVi were prospectively used to generate implants using mixtures of isotopes. For mixed-radioisotope implants, we also explored the impact on EUBED of lowering prescription doses by 15%. Results: The EUBED of PTVi in the setting of primary 125I implant increased 20–66% when 103Pd and 131Cs were used compared with 125I boost. Decreasing prescription dose by 15% in mixed-isotope implants results in a potential 10% reduction in urethral EUBED with preservation of PTV coverage while still boosting PTVi (up to 80%). When radiobiologic parameters corresponding to more-aggressive disease are assigned to foci, faster-decaying isotopes used in mixed implants have the potential to preserve the equivalent biological effect of mono-isotope implants considering less-aggressive disease distributed in the entire prostate. Conclusions: This is a hypothesis-generating study proposing a treatment paradigm that could be the middle ground between whole-gland irradiation and focal-only treatment. The use of two isotopes concurrent with decreasing the minimal peripheral dose is shown to increase EUBED of selected subvolumes while preserving the therapeutic effect at the level of the gland. Ó 2011 Elsevier Inc. Prostate, Brachytherapy, Radiobiologic model, Focal therapy, Dual isotopes.
the gland has been proposed (8). This approach represents a major paradigm shift, similar to partial breast irradiation for early-stage breast cancer. Focal therapy potentially offers a parenchymal-sparing approach that selectively ablates known disease while minimizing toxicity and preserving existent function without compromising treatment outcome or quality of life. Currently, the multifocal nature of PC, coupled with the inability to reliably detect foci of disease within the prostate gland, are the main obstacles to a rational selection of patients for focal therapy. Conventional singleisotope permanent prostate implants achieve adequate tumor control with moderate rectal and urethral toxicities. Previous studies (9) demonstrated the feasibility of MRS-targeted dose escalation ($120%) of small prostate subvolumes while preserving the accepted dose–volume limits for the prostate and surrounding normal tissues. Recent reports suggest that metabolic data from MRSI (10) alone or in
INTRODUCTION Prostate cancer (PC) is the most common cancer among American men. Brachytherapy has long been an effective treatment option for low-risk, organ-confined disease, with extensive follow-up of a large number of patients. Like other forms of radiotherapy, brachytherapy has been used to treat the entire prostate gland. Recent studies (1) show that the introduction of prostate-specific antigen (PSA) screening programs resulted in an earlier detection of PC (2, 3), and both the volume and the number of malignant foci within the prostate have decreased significantly. The volume of cancer found in radical prostatectomy specimens has decreased from a mean of 4.7–6.1 mL in 1995–1999 (4, 5) to 2.1–2.6 mL in 2001–2005 (6, 7) and the mean number of foci from 7.3 in the pre-PSA era to less than 2.5 (7). In light of these findings, the concept of focal therapy for PC treatment of only malignant foci while sparing the rest of Reprint requests to: Dorin A. Todor, Ph.D., Department of Radiation Oncology, Virginia Commonwealth University, 401 College St., Box 980058, Richmond, VA 23298-0058. Tel: (804) 8287415; Fax: (804) 828-6042; E-mail: [email protected]
Conflicts of interest: none. Received Feb 22, 2010, and in revised form Oct 21, 2010. Accepted for publication Oct 31, 2010. 297
298
I. J. Radiation Oncology d Biology d Physics
combination with digital contrast-enhanced MRI could successfully detect, delineate, and grade intraprostatic disease (11). As the imaging modalities improve, partial-organ brachytherapy may become a reasonable treatment approach for qualified patients. Using the linear-quadratic formalism for continuous dose irradiation developed by Chen and Nath (12), we explored whether dual-isotope brachytherapy can meet the following therapeutic goals: (1) maintain a therapeutic biological equivalent dose of the cancer foci within the prostate gland; (2) reduce the whole-gland dose (MPD - the Minimum Peripheral Dose to target has been historically used for prescribing dose and planning purposes); (3) boost foci of PC within the gland; and (4) reduce dose to surrounding normal structures. This work represents a theoretical feasibility study of the dual-isotope brachytherapy approach in the treatment of localized PC. Although we have used MRI/MRSI to delineate disease foci within the prostate, the theoretical implications of this study can be generalized to other approaches for identifying subvolumes of disease within the gland.
METHODS AND MATERIALS At present, three isotopes are available for prostate low-dose-rate brachytherapy, with a half-life of 59.4 days (125I), 17 days (103Pd), and 9.7 days (131Cs). In this study, we model the biological implications of combinations of these isotopes. In the evaluated scenarios, the MRS-positive subvolumes of disease are targeted with a faster-decaying isotope, on the basis of the theoretical assumption that increased dose rate will improve tumor control probability. For example, for 125I base implant, the boost to foci of disease is achieved with either 103Pd or 131Cs, whereas for a 103Pd base implant only a boost with 131Cs is considered. Currently, postimplant dosimetry is described by V100/V150/V200 parameters (where Vx is the volume of the target receiving x = 100%, 150%, or 200% of prescription dose) and D90 (minimum dose received by 90% of the target volume). It is interesting to note that for 125I a D90 $140 Gy (representing 96.5% of the standard prescription dose) seems adequate to achieve excellent local control rates (13); however, for 103Pd, a D90 of 100 Gy (80% of a typical 103Pd prescription dose) was reported to provide similar outcomes (14). These observations were used to justify a 103Pd dose de-escalation trial (15) in which the prescription dose was reduced from 125 Gy to 110 Gy for selected low-risk PC patients (PSA #10 ng/mL, Gleason score <6, and clinical stage T1b– T2b). In our study, we evaluate the possibility of reducing prescription dose by 15%. It has long been recognized that the conventional postimplant dose–volume parameters may be inadequate to measure the implant ‘‘quality’’ in the absence of spatial information (16). This is emphasized even more for mixtures of isotopes because spatial distribution of dose and differential dose-rate will exaggerate the disconnect between the physical and biological dose. A biologically effective dose (BED) model for a mixture of two isotopes was developed by Chen and Nath (12), extending the previously published models by Dale (17). The model incorporates the kinetic parameters of sublethal damage repair, described by a single repair half-life and the effect of cell proliferation during continuous irra-
Volume 81, Number 1, 2011
diation. Thus, for a mixture of two isotopes, the BED is described by: BED ¼
2 X ln2 D_ 0i 1 eli Teff RE Teff li aTp i¼1
(1)
where RE is b RE ¼ 1þ2 a
P P D_ 0i D_ 0j n 1 1 1eðli þlj ÞTeff 1eðmþlj ÞTeff mli li þlj mþlj i j P D_ 0i li Teff Þ ð1e li i
(2)
and Teff is 1 ln2 Teff ¼ ln l a,Tpot ,D_ 0
(3)
In these equations, D_ 0i represents the initial dose rate for isotope i, Teff is the effective time of the implant (the time at which the repopulation rate becomes larger than the cell-killing rate as a result of dose rate drop), Tpot is the tumor potential doubling time, l is the radioactive decay constant, and m is the time constant for cellular repair of sublethal damage. The derivation of radiobiologic parameters for the prostate was the object of numerous studies (18–21). Brenner and Hall (18) were the first to point out that a/b for prostate might be unusually low. Between the values reported by Wang et al. (22) for prostate (a/b = 3.1 Gy and a = 0.15 Gy1) and those reported by Fowler et al. (23) (a/b = 1.5 Gy and a = 0.039 Gy1), we choose to use a = 0.155 Gy1 (interval, 0.055–0.3), b = 0.052 Gy2, a/b = 2.98 Gy, and Tpot = 42 days. The radiobiologic parameters for the urethra were taken from in vitro measurements published by Marchese et al. (24): a = 0.458 Gy1, b = 0.020 Gy2, and a Tpot = 60 days was used for both the urethra and the rectum. The half-life for the sublethal damage repair process was considered 1 h for both organs. For each voxel of tissue the instantaneous dose rate is a sum of the dose rates of the two contributing isotopes: _ ! Dð r ; tÞ ¼
ni 2 X X i¼1
li t D_ 0i ! rj e
(4)
j¼1
where n ¼ n1 þ n2 ; the total number of sources from the two isotopes. To compare vastly different dose distributions, with significantly different dose rates associated with each voxel, we decided to use the formalism developed by Jones and Hoban (25), namely the equivalent uniform BED (EUBED): # " X 1 a,BEDi EUBED ¼ In ni e a i
(5)
Our study used ultrasound and MRI/MRS datasets of 2 patients who received permanent seed implants as the sole treatment modality for PC. Subvolumes of disease were delineated using the available MRS imaging, and the prostate, planning target volume (PTV) (prostate + 5 mm), rectum, and urethra were delineated with the help of MRI. Implants consisting of 125I, 103Pd, and 131Cs isotopes alone and in combination were planned using VariSeed V7.2 (Varian Medical Systems, Palo Alto, CA) software. Singleisotope implants were designed to achieve PTV coverage with D90 >95% of the prescription dose. Conventional isotope-specific prescription doses were used: 145 Gy for 125I, 124 Gy for 103Pd, and 115 Gy for 131Cs (26, 27).
Dual isotope prostate seed implants d D. A. TODOR et al.
The prostate sizes for Patients A and B were 19.5 cm3 and 23.9 cm3, respectively. Two MRS-positive volumes of 0.3 mL and 1.3 mL were outlined for Patient A and one of 0.58 mL for Patient B. Patient age, stage, initial PSA level, and Gleason score were not considered in this study because the objective was to explore the radiobiologic effect of a mixture of implanted isotopes. The boost of disease foci in the background of a base implant was achieved by either increasing the number of same-strength seeds of the base isotope or by implanting seeds of an isotope with a shorter half-life, and implicitly increased dose rate. The treatment plans were created by placing needles only in grid positions, so the number of needles going through the subvolumes to be boosted was limited to the number of available grid positions in the subvolume’s largest transversal cross-section. As in the actual implants, two adjacent seeds were allowed, but we avoided, whenever possible, three successive seeds. For each isotope the native prescription dose was preserved, and a V100 approximately equal to the volume of the disease foci was created. A nomogram method was used to derive an approximate number of seeds that would ‘‘cover’’ with prescription dose the volume of the disease foci. In total, nine plans were generated for each patient (Table 1). Magnetic resonance and ultrasounds images were rigidly coregistered under user guidance, matching previously segmented contours for the prostate and urethra. Because the current treatment planning system (TPS) can only generate plans for seeds of a single isotope, multiple plans had to be merged to create the desired dualisotope scenarios. The air-kerma strength of the seeds used in the single-isotope implants was 0.45 U for 125I, 2.4 U for 103Pd, and 2.0 U for 131Cs. The same seed strength was used for boosting. The boost plans were prescribed to the same standard prescription as the sole implants (example shown in Fig. 1), but given the significantly smaller volumes, the actual delivered dose to 90% of the PTVi was in the range of 120–160% of the minimum peripheral dose used as prescription dose. To illustrate the integration of doses for two isotopes, Fig. 2 shows that despite the rapid dose falloff, there is some dose cross-contribution between the boost implant and the base implant. In Fig. 3, one can see clearly the enhanced biological effect of higher dose rate delivered by the faster-decaying isotope. Dose matrices and structure contours were exported from the planning system as DICOM (Digital Imaging and Communications in Medicine) files. In-house software based on MATLAB (Math-
Table. Isotope composition of the nine plans generated for each patient
Plan no. 1 2 3 4 5 6 7 8 9
Base (whole-gland) implant isotope,PTV 125
I Pd 131 Cs 125 I 103 Pd 131 Cs 125 I 125 I 103 Pd 103
Abbreviation: PTV = planning target volume.
Boost volume implant isotope, PTVi — — — 125 I 103 Pd 131 Cs 103 Pd 131 Cs 131 Cs
299
works, Nattick, MA) was then used to read the dose matrices and anatomic and planning structures and to perform voxel BED calculations for each structure. Voxel BEDs were then ‘‘integrated’’ into a representative EUBED. For the mixed-radioisotope implants we also explored the impact on EUBED of lowering the prescription dose from 100% to 85%. The prescription was reduced to 85% by simply scaling down the already-exported dose matrix corresponding to the 100% prescription. With prescription doses reduced by 15%, the aim was to deliver at least the same EUBED to the prostate as the conventional base implant, while boosting the MRS-positive subvolumes and reducing the overall urethral dose.
RESULTS Using the standard set of radiobiologic parameters for prostate, urethra, and rectum, we compared the nine plans described above. In the setting of a primary 125I implant, EUBED of PTV1 and PTV2 increased by 20% and 60% when 103Pd and 131Cs were used for boost of disease subvolumes, respectively, compared with 125I alone. In this setting, reduction by 15% in the prescription dose of both the primary and boost implants preserved the EUBED for prostate, PTV, and urethra while simultaneously achieving a boost of the MRS-positive subvolumes. Similar results were noted in the setting of the primary 103Pd implant (Fig. 4). A 131Cs boost in the setting of primary 103Pd implant results in even greater biological dose to MRS-positive volumes, compared with primary 125I implant, while preserving EUBEDs of other structures. A 10% reduction of urethral EUBED is possible for a primary 103Pd implant with a concentrated 103 Pd boost of the MRS-positive regions. Rectal dose remained largely invariant in all permanent prostate implant scenarios examined. The dose to rectum, as outlined during the implantation from ultrasound images or from a single CT for postimplant evaluation, would be affected anyway by significant uncertainties due to, for example, peristaltic motion, changes in shape, and filling variations for the weeks or months of active implant dose delivery. Three separate sets of radiobiologic parameters were used for three PC risk groups as identified by King et al. (28): favorable (R1), intermediate (R2), and unfavorable (R3) risk group. The EUBED was then calculated for the prostate and PTVi using these three risk categories. For comparison, hypothetical uniform dose plans (at the standard prescription dose for each isotope) were calculated to asses the ‘‘enhancement’’ effect of the real, nonuniform dose distribution created by seed implants. For example, for an 125I implant, planned without a priori knowledge of disease subvolumes, prescribed at 145 Gy and D90 >110%, the EUBED for the prostate (when the radiobiologic parameters assigned to that risk category are considered the same for the whole gland) drops to an average of 90% for the R2 group and 60% for R3 when normalized to R1. This suggests a potential loss of biological effect of up to 40% for patients in the R3 risk category. The ratio of computed EUBED for nonuniform dose distribution to a hypothetical uniform dose distribution at the
300
I. J. Radiation Oncology d Biology d Physics
Volume 81, Number 1, 2011
Fig. 1. Transversal cross-section from the treatment planning system. The 125I implant (left) is shown planned for planning target volume minus the MRS-positive subvolume (in cyan). The 131Cs implant (right) are planned for the MRS-positive sub-volume.
same prescription dose for R1, R2, and R3 disease categories increases from 1.0 to 1.1 and to 1.45, respectively. This simply illustrates that the effect of the inherent dose inhomogeneity on EUBED becomes more important as the clinical risk group increases (or the disease becomes more aggressive). For an 125I implant on which the PTVi volumes were boosted with supplemental 125I, the drop in EUBED with in-
creased risk category is similar to the previous case but of lesser magnitude: 100% for R1, 90% for R2, and 63% for R3. The enhancement due to inhomogeneity reaches 1.10 for R2 and 1.53 for R3. If the same 125I implant is boosted with 103Pd, the EUBED exhibits a lesser drop, from 100% to 92% for R2 and 70% for R3. Similar results are obtained when 125I implant is boosted with 131Cs.
Fig. 2. Two-isotopes seed implant example. Same transversal cross-section as in Fig. 1 is shown (upper row) and a dose profile along the dotted line (lower row). An 125I implant (left) is prescribed to 145 Gy for prostate + 5 mm margin minus the MRS-positive volume. A 131Cs implant (center) is prescribed to 115 Gy for the MRS volume only. The two are added outside of the treatment planning system (right). The figure shows total physical dose, but one has to keep in mind that the two implants provide significantly different dose rates (and biological effects).
Dual isotope prostate seed implants d D. A. TODOR et al.
301
Fig. 3. Example of significant and focal biologically effective dose enhancement produced by the larger dose rate associated with the faster-decaying isotope. For comparison, physical dose profile is shown in blue.
However, the situation changes when 103Pd and 131Cs implants are boosted with the same isotope to disease subvolumes. For 103Pd, the drop in EUBED for the prostate with increasing risk category was minimal (R1: 100%; R2: 97%; R3: 93%). For 131Cs base implant, the decrease was commensurate (R1: 100%; R2: 96%; R3: 94%). In the above scenarios, the radiobiological parameters for different risk groups were applied uniformly to the whole prostate. We also explored three scenarios in which different radiobiologic parameters are assigned to the prostate and higher risk group parameters to the foci of disease: A: prostate (R1) + foci (R2); B: prostate (R1) + foci (R3); and C: prostate (R2) + foci (R3). For Scenario A, the use of 125I base implant and 103Pd disease-specific boost results in an EUBED decrease of 10% for disease foci, whereas for Scenario B the decrease was 25%. A 25% increase in the MPD for the foci of disease restores the EUBED to its value if low-risk (R1) disease would have been considered distributed uniformly. A 45% foci MPD increase for Scenario B and 25% increase for Scenario C would also restore EUBED to its value if lessaggressive disease would be the only one considered. Similarly, in the setting of a primary 103Pd implant and using 131 Cs to treat the foci of disease, Scenarios A and B need an increase in the MPD of 20% and 25%, respectively, whereas for Scenario C, an increase of 10–15% of the prescription dose for the 131Cs portion of the implant would suffice. DISCUSSION The first point of discussion is whether it is reasonable to assign faster-decaying isotopes to higher-grade tumors. There is no clinical evidence that, with the current prescrip-
tion doses and usage, 125I and 103Pd implants have different outcomes, but an important factor making the distinction more difficult might be the inherent heterogeneity of the individual foci of disease. Biopsy-detected foci of disease may not necessarily reflect the grade of other unbiopsied disease foci within the gland. This experience is supported by observations of upstaging after prostatectomy. Armpilia et al. (29) have used a linear-quadratic model suitable for the analysis of permanent brachytherapy implants to investigate the radionuclide half-lives that will maximize the BED delivered to tumors. Their conclusion is that ‘‘for a wide range of tumor types, shorter-lived radionuclides are more versatile for achieving reasonable clinical results.’’ A publication by Antipas et al. (30) states that ‘‘the biological dose uncertainties are found to be less with 103 Pd,’’ and the ‘‘TCPs [Tumor Control Probability] associated with this radionuclide are expected to be significant higher in the treatment of faster growing, more aggressive tumors’’ (one can perhaps argue that effective dose per cell cycle is greater for 103Pd than for 125I). ‘‘Using typically prescribed doses for 125I appears to be better for treating radiosensitive tumors with long doubling time. However, unless 125I doses are reduced this advantage may well be offset by the enhanced biological doses delivered to adjacent normal structures.’’ In a study aimed to determine the optimal dose, Stock et al. (13) reported that ‘‘125I implantation alone was limited to patients with PSA #10, stage #T2a and Gleason score < 7.. Patients with Gleason scores $7 were implanted with 103Pd seeds’’; and while no further explanation of the isotope choice is given, the choice is clearly aiming to treat the ‘‘more-aggressive’’ disease with faster-decaying isotopes and implicitly larger dose rates.
302
I. J. Radiation Oncology d Biology d Physics
Volume 81, Number 1, 2011
Fig. 4. Summary of equivalent uniform biologically effective dose (EUBED) values of various structures for plans as described in Table 1. (A) For an 125I base implant; (B) for a 103Pd base implant. ‘‘R’’ indicates that the prescription dose was reduced to 85%. PTV = planning target volume.
A second issue would be whether such implant would be possible to plan with today’s TPS. Given that MPD is historically the way dose is prescribed for permanent prostate seed implants, we have resorted to using the same metric in our study. However, given that the two implants are created separately, and each of them is optimized to its own set of structures, it is difficult or impossible to create a truly optimal dual-isotope implant with the current TPS. This work is not a study on optimizing dual-isotope implants but merely a study that points out that a dual-isotope approach could be the middle ground between whole-gland and focal-only treatment.
We have used VariSeed (Varian Medical Systems, Palo Alto, CA), which is designed to handle multiple seed strengths in one implant. Although we are confident that it can be easily modified to handle two different isotopes at two different airkerma strengths, the issue of plan optimization is more difficult because it involves BED rather than physical dose. The need to shift gears from physical dose to BED was also expressed recently by Stone et al. (31, 32), who have shown that a BED of 200 Gy is needed for excellent local control and low recurrence rates. In 2006 the same group (33) pointed out that ‘‘BED was the most significant predictor of biopsy
Dual isotope prostate seed implants d D. A. TODOR et al.
outcome in multivariate analysis.’’ A postimplant evaluation of a mixed implant would likely have to use either nonrigid registration between the preplan and the CT reconstructed implant or be based on an intraoperative approach in which seeds are identified as they are implanted. Boosting and dose escalation are well known strategies for increasing disease control, in both external-beam radiotherapy (EBRT) and brachytherapy. Kim and Tome (34, 35) have shown that selective boosting of high-risk subvolumes is a better choice than homogeneous dose escalation. In brachytherapy, Li et al. (36) have shown that the level of dose escalation currently achieved in EBRT can be matched in brachytherapy by modest increases of the MPD (5–10%) with ‘‘acceptable dose increases in the rectum and urethra.’’ Most studies used equivalent uniform dose to measure benefits of these strategies, but given the emphasis on BED relative to outcome in brachytherapy and the inherent spatially inhomogeneous, time varying at the voxel level, dose distributions, we felt compelled to use EUBED to compare various implants. Zaider et al. (9) described a biologically based method in which dose to MRSI subvolumes is increased with a minimum of 120%, but 125I-only implants were considered, and boosting was achieved only by increasing the number of 125I seeds in those subvolumes. The same
303
group recently published (10) evidence connecting Gleason scores with MRS findings, leading the way for MRS-based ‘‘biologically motivated focal treatment for which intensitymodulated radiotherapy and especially brachytherapy are ideally suited.’’ The location of the PTVi (MRI/MRSI) positive or otherwise identified foci of disease is likely to have some bearing on ones ability to biologically boost these volumes with no penalties to adjacent organs. Our study is not large enough to address this issue. This work is rather a proof of principle study, showing that a mixture of two isotopes could potentially be used to boost disease subvolumes by taking advantage of both dose and dose-rate increase as opposed to the classic dose-only escalation paradigm. CONCLUSION This is a hypothesis-generating study proposing a treatment paradigm that could be viewed as an intermediate solution between whole-gland irradiation and focal treatment. The use of two isotopes concurrent with decreasing the minimal peripheral dose is shown to increase EUBED of selected subvolumes while preserving the therapeutic effect at the level of the whole gland.
REFERENCES 1. Mouraviev V, Mayes JM, Polascik TJ. Pathologic basis of focal therapy for early-stage prostate cancer. Nat Rev Urol 2009;6: 205–215. 2. Lim LS, Sherin K, ACPM Prevention Practice Committee. Screening for prostate cancer in U.S. men ACPM position statement on preventive practice. Am J Prev Med 2008;34: 164–170. 3. Etzioni R, Tsodikov A, Mariotto A, et al. Quantifying the role of PSA screening in the US prostate cancer mortality decline. Cancer Causes Control 2008;19:175–181. 4. Stamey TA, McNeal JE, Yemoto CM, et al. Biological determinants of cancer progression in men with prostate cancer. JAMA 1999;281:1395–1400. 5. Cupp MR, Bostwick DG, Myers RP, et al. The volume of prostate cancer in the biopsy specimen cannot reliably predict the quantity of cancer in the radical prostatectomy specimen on an individual basis. J Urol 1995;153:1543–1548. 6. Cheng L, Poulos CK, Pan CX, et al. Preoperative prediction of small volume cancer (less than 0.5 ml) in radical prostatectomy specimens. J Urol 2005;174:898–902. 7. Sebo TJ, Cheville JC, Riehle DL, et al. Predicting prostate carcinoma volume and stage at radical prostatectomy by assessing needle biopsy specimens for percent surface area and cores positive for carcinoma, perineural invasion, Gleason score, DNA ploidy and proliferation, and preoperative serum prostate specific antigen: A report of 454 cases. Cancer 2001;91:2196– 2204. 8. Onik G, Narayan P, Vaughan D, et al. Focal ‘‘nerve-sparing’’ cryosurgery for treatment of primary prostate cancer: A new approach to preserving potency. Urol 2002;60:109–114. 9. Zaider M, Zelefsky MJ, Lee EK, et al. Treatment planning for prostate implants using magnetic-resonance spectroscopy imaging. Int J Radiat Oncol Biol Phys 2000;47:1085–1096. 10. Carlani M, Mancino S, Bonanno E, et al. Combined morphological, [1H]-MR spectroscopic and contrast-enhanced imag-
11.
12.
13. 14.
15. 16.
17. 18. 19.
ing of human prostate cancer with a 3-Tesla scanner: Preliminary experience. Radiol Med 2008;113:670–688. Brame RS, Zaider M, Zakian KL, et al. Regarding the focal treatment of prostate cancer: Inference of the Gleason grade from magnetic resonance spectroscopic imaging. Int J Radiat Oncol Biol Phys 2009;74:110–114. Chen Z, Nath R. Biologically effective dose (BED) for interstitial seed implants containing a mixture of radionuclides with different half-lives. Int J Radiat Oncol Biol Phys 2003;55: 825–834. Stock RG, Stone NN, Tabert A, et al. A dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998;41: 101–108. Kollmeier MA, Stock RG, Stone N. Biochemical outcomes after prostate brachytherapy with 5-year minimal follow-up: Importance of patient selection and implant quality. Int J Radiat Oncol Biol Phys 2003;57:645–653. Gregory S, Merrick MD. Pd-103 dose de-escalation for early stage prostate cancer: A prospective randomized trial. Study NCT00247312. Wheeling, WV: Schiffler Cancer Center. D’Souza WD, Thames HD, Kuban DA. Dose-volume conundrum for response of prostate cancer to brachytherapy: Summary dosimetric measures and their relationship to tumor control probability. Int J Radiat Oncol Biol Phys 2004;58: 1540–1548. Dale RG. Radiobiological assessment of permanent implants using tumor repopulation factors in the linear-quadratic model. Br J Radiol 1989;62:241–244. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999;43:1095–1101. Fowler JF, Ritter MA, Fenwick JD, et al. How low is the a/b ratio for prostate cancer? In regard to Wang, et al. IJROBP 2003; 55:194–203 [letter]. Int J Radiat Oncol Biol Phys 2003;57: 593–595.
304
I. J. Radiation Oncology d Biology d Physics
20. Brenner DJ, Martinez AA, Edmundson GK, et al. Direct evidence that prostate tumors show high sensitivity to fractionation (low a/b ratio) comparable to late-responding normal tissue. Int J Radiat Oncol Biol Phys 2002;52:6–13. 21. Wang JZ, Guerrero M, Li XA. How low is the a/b ratio for prostate cancer? Int J Radiat Oncol Biol Phys 2003;55:194–203. 22. King CR, Fowler JF. A simple analytic derivation suggests that prostate cancer alpha/beta ratio is low. Int J Radiat Oncol Biol Phys 2001;51:213–214. 23. Fowler JF, Chappell RJ, Ritter MA. Is a/b for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001;50:1021–1031. 24. Marchese MJ, Hei TK, Zaider M, et al. Radiation repair in human endothelial cells. Int J Radiat Oncol Biol Phys 1987;13: 1857–1860. 25. Jones LC, Hoban PW. Treatment plan comparison using equivalent uniform biologically effective dose (EUBED). Phys Med Biol 2000;45:159–170. 26. Yue N, Heron DE, Komanduri K, et al. Prescription dose in permanent (131)Cs seed prostate implants. Med Phys 2005;32: 2496–2502. 27. Bice WS, Prestidge BR, Kurtzman SM, et al. Recommendations for permanent prostate brachytherapy with (131)Cs: A consensus report from the Cesium Advisory Group. Brachytherapy 2008;7:290–296. 28. King CR, DiPetrillo TA, Wazer DE. Optimal radiotherapy for prostate cancer: predictions for conventional external beam, IMRT, and brachytherapy from radiobiologic models. Int J Radiat Oncol Biol Phys 2000;46:165–172. 29. Armpilia CI, Dale RG, Coles IP, et al. The determination of radiobiologically optimized half-lives for radionuclides used in
Volume 81, Number 1, 2011
30.
31.
32.
33.
34.
35. 36.
permanent brachytherapy implants. Int J Radiat Oncol Biol Phys 2003;55:378–385. Antipas V, Dale RG, Coles IP. A theoretical investigation into the role of tumor radiosensitivity, clonogen repopulation, tumor shrinkage, and radionuclide RBE in permanent brachytherapy implants of 125I and 103Pd. Phys Med Biol 2001;46:2557–2569. Stone NN, Stock RG, Cesaretti JA, et al. Local control following permanent prostate brachytherapy: Effect of high biologically effective dose on biopsy results and oncologic outcomes. Int J Radiat Oncol Biol Phys 2010;76:355–360. Stone NN, Potters L, Davis BJ, et al. Multicenter analysis of effect of high biologic effective dose on biochemical failure and survival outcomes in patients with Gleason score 7-10 prostate cancer treated with permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2009;73:341–346. Stock RG, Stone NN, Cesaretti JA, et al. Biologically effective dose values for prostate brachytherapy: Effects on PSA failure and posttreatment biopsy results. Int J Radiat Oncol Biol Phys 2006;64:527–533. Kim Y, Tome WA. Is it beneficial to selectively boost high-risk tumor subvolumes? A comparison of selectively boosting highrisk tumor subvolumes versus homogeneous dose escalation of the entire tumor based on equivalent EUD plans. Acta Oncol 2008;47:906–916. Kim Y, Tome WA. Risk-adaptive optimization: Selective boosting of high-risk tumor subvolumes. Int J Radiat Oncol Biol Phys 2006;66:1528–1542. Li XA, Wang JZ, Stewart RD, et al. Dose escalation in permanent brachytherapy for prostate cancer: Dosimetric and biological considerations. Phys Med Biol 2003;48:2753–2765.