Salvage Brachytherapy After External-Beam Irradiation for Prostate Cancer

February 1, 2004

Dr. Beyer provides an insightful and balanced approach tothe indications for salvageprostate brachytherapy after externalbeamradiotherapy failure. As hepoints out, the challenge for the cliniciancontemplating local salvage therapyto address biochemical failure isto determine whether the biochemicalrelapse represents local relapse onlyor systemic disease. Local salvagetreatment in a patient with micrometastaticdisease would have no appreciableimpact on disease-free survivaland is more likely to be associatedwith significant potential morbidity.Unfortunately, with the current lackof reliable molecular markers or sensitiveimaging modalities, it is impossibleto determine with certainty thesource of a biochemical relapse inmost settings.

Dr. Beyer provides an insightful and balanced approach tothe indications for salvageprostate brachytherapy after externalbeamradiotherapy failure. As hepoints out, the challenge for the cliniciancontemplating local salvage therapyto address biochemical failure isto determine whether the biochemicalrelapse represents local relapse onlyor systemic disease. Local salvagetreatment in a patient with micrometastaticdisease would have no appreciableimpact on disease-free survivaland is more likely to be associatedwith significant potential morbidity.Unfortunately, with the current lackof reliable molecular markers or sensitiveimaging modalities, it is impossibleto determine with certainty thesource of a biochemical relapse inmost settings.Identifying Patients With IsolatedLocal Relapsing Disease
Patients with tumor characteristicssuch as initial Gleason scores 8 to 10or initially high prostate-specific antigenlevels-consistent with an increasedlikelihood of extraprostaticdisease-are not the optimal candidatesfor salvage brachytherapy dueto expected poor outcomes in thesepatients. In addition to the fact thatthese patients have a greater risk ofextracapsular disease, they are alsoas likely to have a larger volume ofdisease, and brachytherapy alone isoften insufficient treatment.It is well known that higher radiationdoses are critical in the treatmentof patients with intermediate- and unfavorable-risk disease, so one wouldexpect that high radiation doses areas important for eradicating locally recurrentdisease. I have often wondered,therefore, why we should realisticallyexpect local tumor controlwith a salvage low-dose-rate implantdelivering a dose of only 120 Gy or144 Gy. On the other hand, higherdoses in the salvage setting cannot begiven without impunity when radiotherapyhas been previously given tothe same region.It may be conceptually appealingto deliver an escalated radiationdose with a combination interstitialimplant and a more modest dose ofexternal-beam radiotherapy in therecurrent setting, yet there is minimalinformation to support the safetyof such a salvage approach. The combinationof both therapies in thesetting of prior treatment could be aprescription for disaster and shouldonly be done in the hands of experiencedpractitioners. Even in experiencedhands, this form of doseescalation is essentially unproven asfar as toxicity is concerned and shouldonly be conducted in the context of aclinical trial.It is important to exercise cautionwhen considering salvage brachytherapy,because dose escalation withexternal-beam radiotherapy has becomecommon. The 1999 Patterns ofCare survey showed a significantincrease among radiation oncologistswho deliver doses > 72 Gy, comparedto the prior survey conducted in1993.[1] The published literatureincludes a report on a small cohort ofpatients with salvage brachytherapywho previously had been irradiated todose levels of 70 Gy or less. If previousdose levels ≥ 75 Gy were usedfor the patient being consideredfor salvage therapy, the expectedmorbidity of salvage brachytherapy after external-beam radiotherapyfailure remains to be determined. Wedon't know how well-tolerated asalvage implant will be for thesepatients.The Potential ofFunctional Imaging
Enhanced imaging techniques to localizeintraprostatic recurrent diseasehold great promise for improving thetherapeutic ratio of salvage brachytherapy.Magnetic resonance (MR)spectroscopy can localize disease withinthe prostate after failed external-beamradiotherapy and may allow cliniciansto dose-paint abnormal regions withinthe clinical target volume and escalatethe radiation doses to these areas, whilepotentially minimizing the dose to normaltissues previously irradiated.We and others have reported on usinginformation from MR imaging andMR spectroscopy with intraoperativelyplanned conformal brachytherapyto dose-escalate intraprostatictumor deposits to 150% of prescriptiondose (and higher) for patients withnonrecurrent prostate cancer as theirprimary therapy.[2,3] Ellis and coinvestigators[4] recently reported excellentresults in 80 patients treatedwith brachytherapy, where radioimmunoscintigraphywith indium-111was used to dose-escalate abnormal regionswithin the gland to 150% of theprescription dose.These approaches adapted in thesalvage setting may represent an attractiveapproach in the future to effectivelyminimize dose to the rectumand the urethra. Although relapsingdisease is likely be multifocal in natureand such patients may not be idealcandidates for such approaches, otherscenarios can be envisioned in whicha dominant abnormality in the prostatecould receive higher doses, allowingfor the opportunity to spare thepreviously irradiated rectum and urethra and to reduce the potential morbidityof therapy.Conclusions
Emerging technologies and improvementsin brachytherapy treatmentplanning will pave the way for salvagebrachytherapy to be delivered with potentiallyless toxicity and improved tumor-control rates. Selection of patientswith isolated local relapse disease willremain critical, and improved imagingmodalities and more precise molecularmarkers will be required to more accuratelydetermine the source of a biochemicalrelapse. In the meantime, itmay be prudent to offer salvagebrachytherapy to highly selected patientswith biopsy-proven local recurrence,a low likelihood of micrometastaticdisease, and no significant proctitisor urethritis after initial radiotherapy.I wouldn't be surprised if hundredsof patients actually have been treatedwith salvage radiotherapy by practitionersaround the country, but we canonly make statements about the efficacyand safety of salvage therapybased on the published results in fewerthan 100 patients. We need prospectiveclinical trials to clarify the efficacyand morbidity of this approach,so we may better advise our patientsabout the best intervention to treattheir relapsing disease and howit would impact upon their qualityof life.

Disclosures:

The author is a consultantfor ONCURA, a US corporation witha global presence in the treatment of prostatecancer.

References:

1.

Zelefsky MJ, Moughan J, Owen J, et al:Changing trends in the national practice forexternal beam radiotherapy for clinically localizedprostate cancer: The 1999 patterns ofcare survey for prostate cancer. Int J RadiatOncol Biol Phys 54(suppl):8, 2002.

2.

Zelefsky MJ, Cohen G, Zakian K, et al:Intraoperative conformal optimization fortransperineal prostate implantation using magneticresonance spectroscopic imaging. CancerJ 6:249-255, 2000.

3.

Dibiase SJ, Hosseinzadeh K, GullapalliRP, et al: Magnetic resonance spectroscopic imaging-guided brachytherapy for localized prostatecancer. Int J Radiat Oncol Biol Phys52:429-438, 2002.

4.

Ellis RJ, Vertocnik A, Kim E, et al: Fouryearbiochemical outcome after radioimmunoguidedtransperineal brachytherapy forpatients with prostate adenocarcinoma. Int