Point: Cesium-131: Ready for prime time

Point: Cesium-131: Ready for prime time

Brachytherapy 8 (2009) 1e3 Point/Counterpoint: Cesium-131: Ready for Prime Time? Point: Cesium-131: Ready for prime time William S. Bice* Foundation...

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Brachytherapy 8 (2009) 1e3

Point/Counterpoint: Cesium-131: Ready for Prime Time?

Point: Cesium-131: Ready for prime time William S. Bice* Foundation for Medical Physics Research, San Antonio, TX

The first permanent prostate implants with 131Cs were performed in late 2004. In less than 4 years, the brachytherapy community has performed almost 3000 implants at more than 50 sites (1). Still, and appropriately so, the question lingers: do we know enough about permanent prostate brachytherapy (PPB) with 131Cs that it may safely be used by all brachytherapists who routinely perform PPB for early-stage disease? Or should the use of 131Cs be limited to only a handful of the most experienced practitioners? The decision to use any particular treatment modality clearly lies in the joined hands of the practitioner and the patient. But inherent in the practitioner’s offer of treatment is the subjective belief that the outcome will be a positive one, the treatment intent will be met within an acceptable level of risk for either failure or unacceptable treatment complications. Based on these criteria, I will present arguments that support the general use of 131Cs for permanent prostate brachytherapy. These arguments will outline our present level of knowledge about 131Cs brachytherapyd radiobiologic, radiologic and clinical; and characterize this knowledge in terms of historical perspective. Radiobiologic knowledge Although a large part of the radiation-using community would suspect that the expression ‘‘radiobiologic knowledge’’ constitutes an oxymoron, there are still sound radiobiologic arguments for choosing an isotope to treat prostate cancer that delivers its punch quickly (2). Such arguments center on the increased therapeutic ratio that is calculated using the linear-quadratic model for permanent prostate brachytherapy with cesium as compared with iodine or palladium. The enhanced therapeutic ratio depends on recent, well-supported data that indicate that the alpha-beta ratio for prostate cancer is low, 1.5e2.0 Gy, as compared with that of normal tissues, specifically with regard to causation of long-term complications (3e6). Such an argument is not new, at one time providing an impetus for the introduction of palladium to replace iodine (7). * Corresponding author. Foundation for Medical Physics Research, 3307 Falling Creek, San Antonio, TX 78216, USA. Tel.: þ1-210-8601774; fax: þ1-210-538-5457. E-mail address: [email protected] (W.S. Bice).

Radiologic knowledge 131

Cs is not listed in the American Association of Physicists in Medicine/Radiological Physics Center (AAPM/ RPC) registry of ‘‘approved’’ sources, those that have met the AAPM dosimetric requirements. Such a listing requires that the manufacturer meet three primary requirements: (1) a full set of dosimetric data that describes the one- and twodimensional dose distribution from the source in accordance with the latest published formalism (TG43U1) (8, 9), (2) a National Institute of Standards and Technology (NIST) standard has been established for the source and transferred to the Accredited Dosimetry Calibration Laboratory (ADCL) and (3) the vendor has a program to periodically compare the manufacturer’s calibration and the ADCL standards with the NIST standard (10). The radiologic characteristics of 131Cs have been studied by multiple authors. These studies include both empiric and calculation (Monte Carlo) techniques (11e14). The deposition of radiation from Cs sources has been described in accordance with TG43U1. After an initial misstep with regard to the dose constant, the published values for performing a dose calculation with cesium agree within the uncertainties seen by similar studies that have characterized the radiologic parameters of iodine and palladium. The other two requirements for AAPM ‘‘approval’’ cannot be met. There is no 131Cs standard established at NIST for the IsoRay source. Clinical knowledge Although radiobiology and proper characterization of the radiation distribution of the sources are important in deciding whether or not a radionuclide is appropriate for general use, the only true test for the brachytherapist is how well it performs clinically. For the interested practitioner, there are multiple sources of information pertaining to the use of this radionuclide. The first clinical trial with cesium opened in 2004. This multi-institutional monotherapy trial for early-stage, lowrisk disease accrued 100 patients before closing in early 2007. It has been the topic of several reports. A single institutional trial comparing iodine and cesium monotherapy recently closed in May of this year. Cesium combined as

1538-4721/09/$ e see front matter Ó 2009 Published by Elsevier Inc on behalf of American Brachytherapy Society. doi:10.1016/j.brachy.2008.11.002


W.S. Bice / Brachytherapy 8 (2009) 1e3

a boost for external beam radiotherapy is being studied in multi-institutional trial, which opened early this year. It is worthwhile to note that despite the initial uncertainty associated with the dose constant, the concomitant change in the prescription dose has ensured that all of the patients treated with cesium have been treated with the same dose. Although clinical information from the first two trials is presently available in abstract and poster form, the first published manuscript regarding these trials is not expected until 2009. Realizing this, a group of brachytherapists and physicists which, combined, have performed more than 1200 cesium monotherapy implants, was formulated in late 2007 to form and promulgate a set of consensus recommendations pertaining to use of the radionuclide for PPB. The published information includes recommendations with regard to prescription dose and dose constant, radiation safety concerns, and postimplant imaging and quantifier target values. The group’s report emphasizes the differences between optimal cesium implants and those performed with iodine and palladium (15). A brief summary of the published trial results indicates that 131Cs performs as one would expect from its decay and energy characteristics. Postimplant complications can be likened to the pain associated with pulling an adhesive bandage. Cesium, with its short half life, has urinary and rectal complications that may be somewhat more intense but seem to resolve more quickly than those experienced with iodine and palladium. The higher average energy contributes to better uniformity of the dose distribution, but can push unwanted dose into the rectum if the brachytherapy team does not allow and plan for this. With a maximum followup of just over 3 years and median followup of 23 months, the drop in prostate-specific antigen levels from cesium appears equivalent to that from the other isotopes. Historical perspective As stated previously, the decision as to whether there is sufficient physical and clinical information to use cesium is subjective, a matter for each practitioner to determine. The gamut of information that goes into making such a decision is not limited to this information and varies among brachytherapists. Patient preference, logistical and fiscal concerns, the local political environment, time and staff issues, and the opinion of trusted colleagues can all play a role in such a decision. In the end, though, it is the radiation oncologist who decides when and if to pull the trigger. The necessary levels of comfort are undoubtedly as numerous as the number of brachytherapistsdeveryone is different. For our purposes we may turn to an analogous historical example that characterizes the medical community’s willingness to accept a new radionuclide to treat prostate cancer with a permanent implant. A Yale study of complication rates from two radiation ‘‘seed’’ implant therapies shows that the newer therapy

. has fewer long-term side effects than Iodine-125, an older, more commonly prescribed therapy (16). Patients treated with . recovered from their radiation induced prostatitis sooner than I-125 patients (17). The overall conclusion that the biochemical control rates are similar is sound. [Author’s note: median followup was 34 months] (18) These quotations were not written for 131Cs, but for Pd. When palladium was introduced in the early 1990s as an alternative to iodine for prostate brachytherapy, the same radiobiologic arguments were made then for palladium as are currently made for cesium. Today, however, the alpha-beta ratio for prostate cancer appears to be even lower than when palladium was introduced, implying the need for an even more aggressive, shorter-half-life isotope (2e6, 19, 20). Tribulations and uncertainties resulted from the change in the dose constant for cesium. However, these tribulations and uncertainties pale pathetically compared with the tremors created in the brachytherapy community over palladium (21). The axis of evil in the prostate implant world was not North Korea, Iran, and Iraq, but the fearsome trio of calibrationdcalculationdprescription. Four years after the first cesium implant, even without an NIST calibration standard, brachytherapy physicists are much more certain about the dose from cesium than even 10 years after the introduction of palladium. Just as importantly, as a community, we are much more adept at understanding and making the required changes as the inevitable improvements arise. What about the required level of clinical knowledge? The first clinical trials describing the complication rate from palladium prostate implants were not published until 1999 (22), cure rates were not described in the literature until 1998e2000 (23e26). Publication of the results of multiinstitutional trials came along in 2003 (17, 27). Recent studies are still investigating the proper dose to deliver from 103 Pd (28). Did the brachytherapy community wait until these results were published before adoption of the 103Pd for clinical use? Of course not! By the year 2000dthe first year of long-term published biochemical disease-free survival results, palladium had captured almost 40% of the implant market, with more than 15,000 palladium implants performed each year (29, 30). 103

Radiation is radiation The earlier discussion is not meant as an indictment of our overwillingness to adopt new modalities. On the contrary, like most medical communities, brachytherapists are typically very conservative, suspicious of the sales pitch and adopting new treatments only after they have proved their worth. But with regard to the adoption of cesium, as one brachytherapist has pointed out, radiation is radiation.

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There are no surprises here. Yes, cesium has a higher energy than either iodine or palladium, and the dose is delivered more quickly than with either. But such differences are common, and exploited, throughout the field of radiation oncology. The introduction of cesium is a tweak, not a revolution. Of course the brachytherapist must pay attention to where the dose is deposited; of course the brachytherapist must consider the dose rate effect; and of course the brachytherapist must pay attention to the results of clinical trials and panel recommendations. Nevertheless, 4 years out, we are much further along with 131Cs than we were with 103 Pd which, by the mid-1990s, was readily accepted as a viable treatment for early-stage prostate cancer. As for the general application of 131Cs in permanent prostate brachytherapy, I cannot see that any practitioner would not be able to plan and deliver an adequate implant with this isotope. Misapplication of the source array can just as well happen with iodine or palladium. The higher average energy of 131Cs may make it less forgiving in terms of rectal dose, but this also makes it more forgiving in terms of glandular coverage. The increased dose rate may make the patient more susceptible to early complications, but doesn’t this also mean less susceptible to late ones? Although neither of these last two statements has been demonstrated in a clinical trial, we, as a community, are well on the way. What has been shown is that the relative radiobiologic change in using cesium ‘‘goes the right way’’ and that there are no monsters lurking out there. References [1] Lauer L. Personal communication, 2008. Richland, WA. [2] Armpilia CI, Dale RG, Coles IP, Merrick G, True L, et al. The determination of radiobiologically optimized half-lives for radionuclides used in permanent brachytherapy implants. Int J Radiat Oncol Biol Phys 2003;55:378e385. [3] Brenner DJ, Martinez AA, Edmundson GR, et al. Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue. Int J Radiat Oncol Biol Phys 2002;52:6e13. [4] D’Souza WD, Thames HD. Is the alpha/beta ratio for prostate cancer low? Int J Radiat Oncol Biol Phys 2001;51:1e3. [5] Duchesne GM, Peters LJ. What is the alpha/beta ratio for prostate cancer? Rationale for hypofractionated high-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys 1999;44:747e748. [6] King CR, Fowler JF. A simple analytic derivation suggests that prostate cancer alpha/beta ratio is low. Int J Radiat Oncol Biol Phys 2001; 51:213e214. [7] Yaes RJ. Late normal tissue injury from permanent interstitial implants. Int J Radiat Oncol Biol Phys 2001;49:1163e1169. [8] Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. American Association of Physicists in Medicine. Med Phys 1995;22:209e234. [9] Rivard MJ, Butler WM, DeWerd LA, et al. Supplement to the 2004 update of the AAPM Task Group No. 43 Report. Med Phys 2007;34: 2187e2205. [10] Williamson J, Coursey BM, DeWerd LA, et al. Dosimetric prerequisites for routine clinical use of new low energy photon interstitial brachytherapy sources. Recommendations of the American Association of Physicists in Medicine Radiation Therapy Committee. Ad Hoc



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