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High-dose-rate brachytherapy as monotherapy for prostate cancer

Open AccessPublished:July 30, 2014DOI:https://doi.org/10.1016/j.brachy.2014.03.002

      Abstract

      Purpose

      To review and analyze the published data on high-dose-rate brachytherapy as monotherapy in the treatment of prostate cancer.

      Methods

      A literature search and a systematic review of the high-dose-rate (HDR) brachytherapy (monotherapy) prostate literature were performed on PubMed using “high-dose-rate, brachytherapy, prostate, monotherapy” as search terms. More than 80 articles and abstracts published between 1990 and 2013 were identified. Data tables were generated and summary descriptions created. Commentary and opinion was formulated through discussion and consensus based on the critical review of the literature and the author's combined personal experience and knowledge.

      Results

      Thirteen articles reported clinical outcome and toxicity with followup ranging from 1.5 to 8.0 years. Results were available for all risk groups. A variety of dose and fractionation schedules were described. Prostate-specific antigen progression–free survival ranged from 79% to 100% and local control from 97% to 100%. The toxicity rates were low. Genitourinary toxicity, mainly frequency/urgency, was 0–16% (Grade 3). Gastrointestinal toxicity was 0–2% (Grade 3). Erectile function preservation was 67–89%. The radiobiological, clinical, and technical features of HDR brachytherapy were reviewed and discussed.

      Conclusions

      Consistently high local tumor control and low complications rates are reported with HDR monotherapy. It provides reproducible high-quality dosimetry, it has an advantage from a radiobiology perspective, and it has a good radiation safety profile. HDR brachytherapy is a safe and effective local treatment modality for prostate cancer.

      Keywords

      Introduction

      A literature search and systematic review of the high-dose-rate (HDR) brachytherapy (monotherapy) prostate literature was performed on PubMed using “high-dose-rate, brachytherapy, prostate, monotherapy” as search terms. More than 80 articles and abstracts published between 1990 and 2013 were identified. Data tables were generated and summary descriptions created. Historical information was derived from the literature and the author's combined personal experiences and knowledge. Commentary and opinion was formulated through discussion and consensus.
      HDR prostate brachytherapy began in 1986 at Kiel University in Germany and soon after in the United States, independently at the Seattle Prostate Institute in 1989 and in 1991 at the California Endocurietherapy Cancer Center (CET) in Oakland, California, and William Beaumont Hospital (WBH) in Royal Oak, Michigan (
      • Stromberg J.
      • Martinez A.
      • Gonzalez J.
      • et al.
      Ultrasound-guided high dose rate conformal brachytherapy boost in prostate cancer: Treatment description and preliminary results of a phase I/II clinical trial.
      ,
      • Kovacs G.
      • Galalae R.
      • Wirth B.
      • et al.
      Improvement of interstitial brachytherapy for localized prostate neoplasms with a new implantation technique.
      ,
      • Martinez A.
      • Gonzalez J.
      • Stromberg J.
      • et al.
      Conformal prostate brachytherapy: Initial experience of a phase I/II dose-escalating trial.
      ,
      • Mate T.P.
      • Gottesman J.E.
      • Hatton J.
      • et al.
      High dose-rate afterloading 192Iridium prostate brachytherapy: Feasibility report.
      ,
      • Kovacs G.
      • Galalae R.
      • Loch T.
      • et al.
      Prostate preservation by combined external beam and HDR brachytherapy in nodal negative prostate cancer.
      ,
      • Demanes D.J.
      • Rodriguez R.R.
      • Altieri G.A.
      High dose rate prostate brachytherapy: The California Endocurietherapy (CET) method.
      ). HDR was initially used only as a boost in conjunction with external beam radiation therapy (EBRT) because of concerns about the effect of large doses per fraction on normal tissues. Dose escalation studies by Martinez et al., however, established the safety and efficacy range for HDR in the context of combined EBRT and HDR (
      • Martinez A.A.
      • Gustafson G.
      • Gonzalez J.
      • et al.
      Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer.
      ,
      • Martinez A.A.
      • Kestin L.L.
      • Stromberg J.S.
      • et al.
      Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: The William Beaumont phase II dose-escalating trial.
      ,
      • Martinez A.A.
      • 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.
      ). During the 1990s, ultrasound image guidance and computer treatment planning technology evolved, clinical experience accumulated, and outcomes of HDR prostate brachytherapy began to be reported. The clinical rationale for HDR monotherapy for prostate cancer was derived from organ-specific treatments such as radical prostatectomy and permanent seed monotherapy. Recognition of the technical capabilities of HDR to reliably treat the prostate (and seminal vesicles) with a margin of surrounding tissue and to simultaneously control the dose to adjacent normal tissues led to the development of HDR prostate monotherapy clinical trials, which were initiated in the mid-1990s at WBH and CET for low- and intermediate-risk groups, and in Osaka, Japan for all risk groups (
      • Martinez A.A.
      • 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.
      ,
      • Rodriguez R.R.
      • Demanes D.J.
      • Altieri G.A.
      High dose rate brachytherapy in the treatment of prostate cancer.
      ,
      • Yoshioka Y.
      • Nose T.
      • Yoshida K.
      • et al.
      High-dose-rate interstitial brachytherapy as a monotherapy for localized prostate cancer: Treatment description and preliminary results of a phase I/II clinical trial.
      ).

      Why HDR?

      HDR brachytherapy and improvements in EBRT evolved simultaneously. Conformal EBRT and intensity modulated radiation therapy are two technologies, which allow physicians to deliver higher total doses and achieve better tumor control rates. However, three major drawbacks of conformal EBRT or intensity modulated radiation therapy are day-to-day variations in internal anatomy secondary to organ motion (interfraction motion), organ deformation and other variations in internal anatomy during radiation therapy delivery (intrafraction motion), and daily setup inaccuracies (setup errors). To overcome these limitations, HDR brachytherapy was identified as a potentially advantageous vehicle for dose-escalation.
      HDR technology combines a number of favorable qualities of brachytherapy with the sophisticated treatment planning developed for EBRT. HDR brachytherapy procedures are performed under general or spinal anesthesia, are usually done through a perineal template guide, and use ultrasound guidance similar to low-dose-rate (LDR) permanent seed implants. Organ motion and setup inaccuracies are not an issue with HDR either because they do not occur, or because they can be corrected with interactive online dosimetry during the procedure, or modified during simulation and treatment planning before dose delivery. There is no need to add treatment volume (margins) beyond the intended target to account for patient motion or variations in beam delivery.
      Common problems associated with permanent seeds implants such as discrepancy between planned and actual seeds distribution, inability to correct seeds position or to optimize the dose delivered once the seeds are in place, and operator dependency are relatively low in HDR brachytherapy, particularly with the introduction of intraoperative online HDR treatment planning and delivery (
      • Edmundson G.K.
      • Rizzo N.R.
      • Teahan M.
      • et al.
      Concurrent treatment planning for outpatient high dose rate prostate template implants.
      ,
      • Edmundson G.K.
      • Yan D.
      • Martinez A.A.
      Intraoperative optimization of needle placement and dwell times for conformal prostate brachytherapy.
      ).

      Important features of HDR brachytherapy

      • 1.
        HDR catheters are relatively easy to visualize with transrectal ultrasound (TRUS), and they can be safely implanted outside the prostate capsule and into the seminal vesicles without the risk of seed migration.
      • 2.
        HDR avoids uncertainties in dosimetry (target dose) associated with prostate volume changes that occur with permanent seed brachytherapy. Immediate swelling and subsequent gland shrinkage due to fibrosis are irrelevant.
      • 3.
        Real-time dose modulation HDR planning software offers immediate feedback for the physician and physicist to achieve optimal implant catheter distributions.
      • 4.
        HDR planning provides multiparametric dose optimization through modulation of catheter geometry, dwell position, and dwell time. HDR dosimetry is “high density” because there are approximately twice as many HDR dwell positions as seeds in the typical permanent seed prostate (LDR) implant.
      • 5.
        The versatility of intratarget dose modulation inherent to brachytherapy can be controlled and directed with HDR to deliver high doses to gross disease (concomitant boost), or it can be used to selectively reduce the dose to parts of the prostate or organs-at-risk (OARs) as in partial prostate irradiation (focal therapy). This process is sometimes described as dose sculpting or dose painting.
      • 6.
        HDR dosimetry is prospective (known and approved before treatment delivery), and it consistently provides good target coverage and normal organ sparing (
        • White E.C.
        • Kamrava M.R.
        • Demarco J.
        • et al.
        High-dose-rate prostate brachytherapy consistently results in high quality dosimetry.
        ).
      • 7.
        The low alpha/beta ratio (estimated 1.2–4) means that the large fraction sizes used in HDR have a relatively high biological effectiveness for prostate cancer (
        • Brenner D.J.
        • Hall E.J.
        Fractionation and protraction for radiotherapy of prostate carcinoma.
        ,
        • Brenner D.J.
        • Martinez A.A.
        • Edmundson G.K.
        • et al.
        Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue.
        ,
        • Fowler J.F.
        The radiobiology of prostate cancer including new aspects of fractionated radiotherapy.
        ).
      • 8.
        HDR is applicable to a wide range of clinical circumstances in prostate cancer.
      • 9.
        A single radioactive source may deliver treatment to large numbers of patients and it can be used for many disease sites. The modality can be deployed in a cost-effective manner.
      • 10.
        HDR treatment courses are of short duration, and recovery from acute side effects is comparatively brief.
      • 11.
        HDR radiation safety is good because patients are not radioactive after the procedure. As such, patients do not need to follow special precautions such as limiting distance or duration of contact with other adults, children, or pregnant women. Likewise, there are no issues in handling radioactive sources by pharmacy or medical personnel.
      • 12.
        Because androgen deprivation therapy (ADT) has not been shown to enhance disease control with prostate HDR monotherapy, and as ADT is usually not required for downsizing of prostate volume with HDR brachytherapy, it can usually be omitted, at least in low- and intermediate-risk group cases.

      Patient and case selection

      Patients whose disease is confined to the prostate or immediate surrounding tissue are ideal candidates for locally directed treatments such as prostatectomy, EBRT, or brachytherapy alone. National Comprehensive Cancer Network defined low- and intermediate-risk cases are more likely to have disease confined to the prostate region and, therefore, are logically the best candidates for local treatment (National Comprehensive Cancer Network guidelines version 1.2014 at www.nccn.org/professionals/physician_gls/pdg/prostate.pdf).
      Nonetheless, some centers have elected to use HDR monotherapy in high-risk group patients based on the idea that it provides a treatment margin greater than radical prostatectomy and that there is no convincing evidence showing an improvement in outcome by treating the pelvic lymph nodes. The use of HDR monotherapy in high-risk group disease is being tested because it can reliably distribute dose around the prostate and into the seminal vesicles. It creates a dose margin without the risk of seed migration, and the dose to the bladder and rectum remain significantly lower than when treating with EBRT.
      HDR brachytherapy is technically feasible after transurethral resection of the prostate (TURP) because it uses a scaffolding of catheters rather than prostate tissue to hold the radiation source and the dose to the prostatic urethra can be controlled to limit toxicity (
      • Peddada A.V.
      • Jennings S.B.
      • Faricy P.O.
      • et al.
      Low morbidity following high dose rate brachytherapy in the setting of prior transurethral prostate resection.
      ). Careful urethral dosimetry (maximum dose not exceeding 110% of the prescribed dose) and waiting at least 3 months after TURP to allow wound healing are recommended. In the authors' experience, by following these measures, HDR brachytherapy can be safely administered after TURP.
      HDR brachytherapy enables treatment of prostates across a wide range of gland sizes for a variety of reasons including, among other things, the use of a catheter matrix, dwell time modification, and the relatively high energy of the source. It has been shown that prostate glands larger than 50 cm3 can be treated with HDR without the need of hormonal downsizing (
      • Monroe A.T.
      • Faricy P.O.
      • Jennings S.B.
      • et al.
      High-dose-rate brachytherapy for large prostate volumes (> or =50cc)—Uncompromised dosimetric coverage and acceptable toxicity.
      ,
      • Yamada Y.
      • Bhatia S.
      • Zaider M.
      • et al.
      Favorable clinical outcomes of three-dimensional computer-optimized high-dose-rate prostate brachytherapy in the management of localized prostate cancer.
      ). The authors have successfully treated prostate glands larger than 100 cm3. Although prostate size does not always correlate with symptom scores, highly symptomatic patients can be expected to have more urinary outflow issues after brachytherapy than patients who are not symptomatic. However, HDR appears to be less likely to cause prolonged exacerbation of urination symptoms than LDR or EBRT because even patients with International Prostate Symptom Score (IPSS) of 20 or higher tend to have a relatively rapid return to pretreatment baseline urinary function status (
      • Yamada Y.
      • Bhatia S.
      • Zaider M.
      • et al.
      Favorable clinical outcomes of three-dimensional computer-optimized high-dose-rate prostate brachytherapy in the management of localized prostate cancer.
      ).
      Prior pelvic radiation, inflammatory bowel disease, and prior pelvic surgery are not contraindications to prostate HDR brachytherapy, but the dosimetry must include carefully defined normal tissue constraints and there must be full disclosure to the patient of the additional potential risks. Normal tissue sparing is substantially better with HDR than with EBRT and the dose distribution more accurate and predictable than with LDR (
      • Hermesse J.
      • Biver S.
      • Jansen N.
      • et al.
      Dosimetric comparison of high-dose-rate brachytherapy and intensity-modulated radiation therapy as a boost to the prostate.
      ,
      • Holly R.
      • Myrehaug S.
      • Kamran A.
      • et al.
      High-dose-rate prostate brachytherapy in a patient with bilateral hip prostheses planned using megavoltage computed tomography images acquired with a helical tomotherapy unit.
      ,
      • Hsu I.C.
      • Pickett B.
      • Shinohara K.
      • et al.
      Normal tissue dosimetric comparison between HDR prostate implant boost and conformal external beam radiotherapy boost: Potential for dose escalation.
      ). Finally, HDR is one of the salvage treatment options for locally recurrent prostate cancer (
      • Jo Y.
      • Fujii T.
      • Hara R.
      • et al.
      Salvage high-dose-rate brachytherapy for local prostate cancer recurrence after radiotherapy—Preliminary results.
      ,
      • Lee B.
      • Shinohara K.
      • Weinberg V.
      • et al.
      Feasibility of high-dose-rate brachytherapy salvage for local prostate cancer recurrence after radiotherapy: The University of California-San Francisco experience.
      ,
      • Tharp M.
      • Hardacre M.
      • Bennett R.
      • et al.
      Prostate high-dose-rate brachytherapy as salvage treatment of local failure after previous external or permanent seed irradiation for prostate cancer.
      ,
      • De Cicco L.
      • Vavassori A.
      • Cattani F.
      • et al.
      Salvage high dose rate brachytherapy after primary external beam irradiation in localized prostate cancer: A case report.
      ,
      • Niehoff P.
      • Loch T.
      • Nurnberg N.
      • et al.
      Feasibility and preliminary outcome of salvage combined HDR brachytherapy and external beam radiotherapy (EBRT) for local recurrences after radical prostatectomy.
      ).

      HDR planning and dosimetry: CT or MRI scan vs. TRUS-based

      There are currently two common ways to perform dosimetry and treatment planning for prostate HDR brachytherapy, based on the image acquisition modality and its timing relative to the insertion of the brachytherapy catheters: CT-based and real-time TRUS based. Each method has advantages and disadvantages; choosing one or the other is a matter of departmental resources, site-specific logistics, experience, and personal preferences.

      CT scan–based simulation and dosimetry

      TRUS-guided HDR catheter insertion is the first of four steps using this method. The catheter insertion is performed under anesthesia in an operating or procedure room. After postoperative recovery, the patient is transferred to a CT scanner for Step 2 where simulation images are obtained and refinements of the catheter positions can be made. CT is most often used for this purpose because they are much more available and practical, although MRI scanners provide better anatomic detail of the prostate and surrounding anatomy. Once approved, the CT image data set is transferred to a treatment planning computer for Step 3 where contours of the target and OARs are generated. Implant catheter distributions are registered and dose calculations are made to produce isodose clouds, dose volume histograms, and virtual dosimetry images. After dosimetry is reviewed and approved by the physician, the plan is uploaded to the treatment console, which transfers the source delivery instructions to the robotic afterloader and where data about the final step, HDR treatment, are monitored.
      CT-based dosimetry offers excellent visualization of the brachytherapy catheters and OARs (rectum, urethra, and bladder) and it allows time for careful assessment of the dosimetry (Fig. 1). Although the prostate is more accurately contoured on TRUS, the CT scans can be fused with MRI to gather even more detailed information on key anatomic relationships. Except where dosimetry is performed in a room shielded for HDR brachytherapy, CT simulation in its current form often involves moving the patient. Therefore, the potential disadvantages of CT dosimetry are the need to move the patient and the time it takes to go from one location to another to perform serial functions.
      Figure thumbnail gr1
      Fig. 1CT-based dosimetry. Transverse, sagittal, coronal, and three-dimensional views.
      Moreover, changes in catheter positions that occur between simulation and treatment delivery must be identified and corrected.

      TRUS-based dosimetry

      This method uses the ultrasound images and computer planning in “real-time” to simultaneously guide brachytherapy catheter placement and to perform the dosimetry calculations. It has the advantages that the ultrasound clearly delineates; the prostate capsule and treatment can be delivered immediately afterward without moving the patient, if the implant procedure is performed in a properly shielded venue (i.e., a shielded operating room or brachytherapy suite). TRUS-based planning, however, presents some technical challenges. The image distortions (“shadows”) produced by the posterior (dorsal) catheters can obscure the view of more anterior (ventral) catheters during treatment planning, and the catheters themselves can obscure the prostate contour especially near the apex. Schmid et al. (
      • Simnor T.
      • Li S.
      • Lowe G.
      • et al.
      Justification for inter-fraction correction of catheter movement in fractionated high dose-rate brachytherapy treatment of prostate cancer.
      ) compared needle reconstruction accuracy with ultrasound to CT using a phantom. The two main problems were spurious echoes on TRUS and difficulty with craniocaudal needle tip identification (up to 6 mm). In addition, definition of contours of the rectum and to a lesser extent the bladder may be less accurately rendered with real time TRUS planning than with CT-based planning. Newer 3D ultrasound probes will likely reduce some of these technical difficulties (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Ultrasound-based dosimetry. Coronal, transverse, sagittal, and 3D views with 100% isodose lines and 3D cloud (red). 3D = three-dimensional. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

      Patient motion and multifractioned HDR

      Monitoring and adjustment of catheters is not unique to CT dosimetry or TRUS, but rather it is a key element of multifraction HDR brachytherapy. Most of the catheter displacement studies are based on the CT dosimetry process, which involves moving the patient between simulation and treatment delivery. Kovalchuk et al. (
      • Schmid M.
      • Crook J.M.
      • Batchelar D.
      • et al.
      A phantom study to assess accuracy of needle identification in real-time planning of ultrasound-guided high-dose-rate prostate implants.
      ) at the Mayo Clinic did a dosimetry study of catheter displacement by comparing initial dosimetry with doses that would be delivered with displaced catheters. They noted a mean needle displacement of 3.5 mm between fractions. The D90 ≥ 95% was 100% vs. 82% (initial vs. displaced), V100 ≥ 95% was 87% vs. 53%, and urethra V115 ≤ 10% was 78% vs. 69%. Replanning improved the dosimetry. Huang et al. (
      • Kovalchuk N.
      • Furutani K.M.
      • Macdonald O.K.
      • et al.
      Dosimetric effect of interfractional needle displacement in prostate high-dose-rate brachytherapy.
      ) at Henry Ford Hospital performed CT scans before every HDR fraction in 13 patients and made catheter adjustments when there was >3 mm catheter displacement. Adjustments were made on 30% catheters by an average of 5.8 mm. Without adjustments, the D90 would have been 10–32% less than the originally planned and after making adjustments, the D90 was within 10% of the original plan. Holly et al. (
      • Huang Y.
      • Miller B.
      • Doemer A.
      • et al.
      Online correction of catheter movement using CT in high-dose-rate prostate brachytherapy.
      ) from Ontario Canada performed cone-beam CT to assess catheter displacement between planning and the first treatment in 20 consecutive patients and evaluated the ability to improve dosimetry by catheter readjustment. A mean catheter displacement of 11 mm was noted, and it would have resulted in a decrease in mean V100 from 98% to 77% (p < 0.001), mean D90 from 111% to 73% (p < 0.001), and an increase in urethra D10 from 118% to 125% (p = 0.0094) had it not been corrected. Catheter readjustments were helpful (V100 90%, D90 97%, and urethra D10 126%) but did not completely restore the original dosimetry. These and other studies demonstrate that catheter displacement can be a source of discrepancy between the calculated and delivered dose (
      • Holly R.
      • Morton G.C.
      • Sankreacha R.
      • et al.
      Use of cone-beam imaging to correct for catheter displacement in high dose-rate prostate brachytherapy.
      ,
      • Foster W.
      • Cunha J.A.
      • Hsu I.C.
      • et al.
      Dosimetric impact of interfraction catheter movement in high-dose rate prostate brachytherapy.
      ,
      • Kolkman-Deurloo I.K.
      • Roos M.A.
      • Aluwini S.
      HDR monotherapy for prostate cancer: A simulation study to determine the effect of catheter displacement on target coverage and normal tissue irradiation.
      ). The clinical significance of small (e.g., <3 mm) changes in catheter position has not been demonstrated.
      There are two TRUS treatment planning interfraction motion studies. Seppenwoolde et al. (
      • Seppenwoolde Y.
      • Kolkman-Deurloo I.K.
      • Sipkema D.
      • et al.
      HDR prostate monotherapy: dosimetric effects of implant deformation due to posture change between TRUS- and CT-imaging.
      ) in Holland studied dosimetry of 3 patients to determine if a TRUS ultrasound treatment plan (dwell positions and times) used for the first HDR fraction could be used for subsequent fractions based on CT images. They found that the changes in “posture” (i.e., leg position) resulted in significant decreases in planning target volume (PTV) coverage (6–28%) and increases in urethra dose. Martinez et al. (
      • Martinez A.A.
      • 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.
      ) at WBH studied their first 23 patients treated with TRUS-based (four fraction, one implant) HDR monotherapy. Serial TRUS prostate volume measurements were made before each treatment and CT was obtained before the first and after the last treatment. They observed an increase in mean prostate volume from pretreatment 31–37 cm3 by the first fraction. There was little additional change by the end of treatment (38 cm3). The corresponding dosimetry between fractions was stable (D90 104–100% and D10 urethra 122–132%). The main difference was that the leg position was maintained stable at WBH.
      All these studies that address applicator and patient position during the course of HDR treatment highlight the importance of applicator fixation, consistent positioning (or not moving the patient at all), and the need to check and, if necessary, adjust catheters before treatment. The method of catheter and template fixation is another important variable, which has not been addressed in these studies.
      Regardless of the technical differences, there is no outcome evidence that one treatment planning method (TRUS vs. CT) is more or less effective than the other. In an effort to improve patient comfort and work flow, the current trend is toward delivering fewer treatments with larger fractions. For example, one treatment per implant in 1–3 separate procedures eliminates interfraction displacement or need for replanning, reduces patient immobilization time, and eliminates an overnight hospital stay. In this regard, portable CT scanners have recently been developed that can be used to obtain the image data set necessary for HDR brachytherapy dosimetry. In terms of patient stability and motion avoidance, the portable CT process and workflow will be very similar to TRUS treatment planning. The real time dosimetry during needle placement will remain a distinct advantage of the TRUS approach and the image quality an advantage of the CT. It is interesting to speculate that technology development might lead to MRI-guided applicator insertion and dosimetry with the dual advantages of real time planning and high image quality.

      Target definition and normal tissue dosimetry

      Standardization of prostate target is complicated by differences in imaging techniques and variances in image interpretation. There is no consensus whether to contour the prostate at the capsule or with a margin. Although we include the proximal seminal vesicles in the target, it is not clear from the literature whether it is standard practice to do so or not. OAR contouring is similarly subject to variability; particularly because the distinction between the rectoprostate (Denonvillier's) fascia, and the bladder wall from the prostate can be difficult.
      HDR prostate monotherapy dose and fractionation schedules have in common a high biological effective dose (BED; 237–354 Gy range at alpha/beta ratio 1.5) and a 1.8–2.0 Gy equivalent dose of ∼100–120 Gy. As a general rule, the prostate target volume with or without the seminal vesicles should be covered by at least 95% of the prescription dose (i.e., V100 prostate >95%). Maintenance of dose constraints to OARs is equally important. The urethra maximum dose should be below 110% (ideally V100 urethra <90%). We recommend further reduction to 105% for patients who have had a TURP; and it is advisable to wait for wound healing at least 3 months between TURP and prostate brachytherapy. The rectal dose constraints should be 75–80% (e.g., V75 rectum <1%). Bladder dosimetry should be considered in terms of minimum and maximum so the dose to bladder wall (surrogate for the peripheral base of the prostate) does not receive <80% nor the bladder neck and trigone >80% (V80 bladder neck <1%). Updated European and American guidelines for HDR prostate brachytherapy that include normal tissue dose constraints have been recently published (
      • Hoskin P.J.
      • Colombo A.
      • Henry A.
      • et al.
      GEC/ESTRO recommendations on high dose rate afterloading brachytherapy for localised prostate cancer: An update.
      ,
      • Yamada Y.
      • Rogers L.
      • Demanes D.J.
      • et al.
      American Brachytherapy Society consensus guidelines for high-dose-rate prostate brachytherapy.
      ).

      Clinical experience with HDR monotherapy

      A summary of the clinical experience with HDR monotherapy can be found in Table 1 (the treatment protocols), Table 2 (late toxicity), and Table 3 (clinical outcomes).
      Table 1High-dose-rate monotherapy published dose, fractionation, and dosimetry
      Author (reference)YearNRisk groupDose × fractionsTotal dose (Gy)Implant numberImplant interval (wk)Dosimetry
      Barkati et al.
      • Barkati M.
      • Williams S.G.
      • Foroudi F.
      • et al.
      High-dose-rate brachytherapy as a monotherapy for favorable-risk prostate cancer: A phase II trial.
      201279Low–interm.10–11.5 Gy × 330–34.51n/aCT
      Demanes et al.
      • Demanes D.J.
      • Martinez A.A.
      • Ghilezan M.
      • et al.
      High-dose-rate monotherapy: Safe and effective brachytherapy for patients with localized prostate cancer.
      2011157Low–interm.7 Gy × 64221X-ray/CT
      Ghadjar et al.
      • Ghadjar P.
      • Keller T.
      • Rentsch C.A.
      • et al.
      Toxicity and early treatment outcomes in low- and intermediate-risk prostate cancer managed by high-dose-rate brachytherapy as a monotherapy.
      200936Low–interm.9.5 Gy × 4381n/aCT
      Ghilezan et al.
      • Ghilezan M.
      • Martinez A.
      • Gustason G.
      • et al.
      High-dose-rate brachytherapy as monotherapy delivered in two fractions within one day for favorable/intermediate-risk prostate cancer: Preliminary toxicity data.
      201250Low–interm.12 Gy × 2241n/aTRUS
      4413.5 Gy × 2271
      Hoskins et al.
      • Hoskin P.
      • Rojas A.
      • Lowe G.
      • et al.
      High-dose-rate brachytherapy alone for localized prostate cancer in patients at moderate or high risk of biochemical recurrence.
      201255Interm.–high8.5–9 Gy × 434–361n/aCT
      109
      10.5 Gy × 331.51
      33
      13 Gy × 2261
      Komiya et al.
      • Komiya A.
      • Fujiuchi Y.
      • Ito T.
      • et al.
      Early quality of life outcomes in patients with prostate cancer managed by high-dose-rate brachytherapy as monotherapy.
      201351Low–high6.5 Gy × 745.51n/a
      Mark et al.
      • Mark R.J.
      • Anderson P.J.
      • Akins R.S.
      • et al.
      Interstitial high-dose-rate brachytherapy as monotherapy for early stage prostate cancer; median 8-year results in 301 patients.
      2010317Low–high7.5 Gy × 64524CT
      Martinez et al.
      • Martinez A.A.
      • Demanes J.
      • Vargas C.
      • et al.
      High-dose-rate prostate brachytherapy: An excellent accelerated-hypofractionated treatment for favorable prostate cancer.
      2010141Low–interm.9.5 Gy × 4381n/aTRUS
      Prada et al.
      • Prada P.J.
      • Jimenez I.
      • Gonzalez-Suarez H.
      • et al.
      High-dose-rate interstitial brachytherapy as monotherapy in one fraction and transperineal hyaluronic acid injection into the perirectal fat for the treatment of favorable stage prostate cancer: Treatment description and preliminary results.
      201240Low–interm.19 Gy × 1191n/aTRUS
      Rogers et al.
      • Rogers C.L.
      • Alder S.C.
      • Rogers R.L.
      • et al.
      High dose brachytherapy as monotherapy for intermediate risk prostate cancer.
      2012284Interm.6.5 Gy × 63921–5CT
      Yoshioka et al.
      • Yoshioka Y.
      • Konishi K.
      • Sumida I.
      • et al.
      Monotherapeutic high-dose-rate brachytherapy for prostate cancer: Five-year results of an extreme hypofractionation regimen with 54 Gy in nine fractions.
      2011111Interm.–high6 Gy × 9541n/aX-ray/CT
      6.5 Gy × 745.51
      Zamboglou et al.
      • Zamboglou N.
      • Tselis N.
      • Baltas D.
      • et al.
      High-dose-rate interstitial brachytherapy as monotherapy for clinically localized prostate cancer: Treatment evolution and mature results.
      2013141Low–high9.5 Gy × 4381n/aCT
      3519.5 Gy × 43822TRUS
      22511.5 Gy × 33833TRUS
      Interm. = intermediate; n/a = not applicable; TRUS = transrectal ultrasound.
      Table 2Late toxicity
      Author (reference)YearNRisk groupsGU Grade 2 (%)GU Grade 3 (%)GI Grade 2 (%)GI Grade 3 (%)ED (%)
      Barkati et al.
      • Barkati M.
      • Williams S.G.
      • Foroudi F.
      • et al.
      High-dose-rate brachytherapy as a monotherapy for favorable-risk prostate cancer: A phase II trial.
      201279Low–interm.2–62–40–3043
      Demanes et al.
      • Demanes D.J.
      • Martinez A.A.
      • Ghilezan M.
      • et al.
      High-dose-rate monotherapy: Safe and effective brachytherapy for patients with localized prostate cancer.
      2011157Low–interm.10310n/a
      Ghadjar et al.
      • Ghadjar P.
      • Keller T.
      • Rentsch C.A.
      • et al.
      Toxicity and early treatment outcomes in low- and intermediate-risk prostate cancer managed by high-dose-rate brachytherapy as a monotherapy.
      200936Low–interm.25116025
      Ghilezan et al.
      • Ghilezan M.
      • Martinez A.
      • Gustason G.
      • et al.
      High-dose-rate brachytherapy as monotherapy delivered in two fractions within one day for favorable/intermediate-risk prostate cancer: Preliminary toxicity data.
      201250

      44
      Low–interm.16111n/a
      Hoskins et al.
      • Hoskin P.
      • Rojas A.
      • Lowe G.
      • et al.
      High-dose-rate brachytherapy alone for localized prostate cancer in patients at moderate or high risk of biochemical recurrence.
      201255Interm.–high33–40
      RTOG toxicity scale.
      3–16,
      RTOG toxicity scale.


      3–6 strictures
      4–13
      RTOG toxicity scale.
      0–1
      RTOG toxicity scale.
      n/a
      109
      33
      Komiya et al.
      • Komiya A.
      • Fujiuchi Y.
      • Ito T.
      • et al.
      Early quality of life outcomes in patients with prostate cancer managed by high-dose-rate brachytherapy as monotherapy.
      201351Low–highQoL (IPSS, FACT-P & IIEF) at baseline after 12 wk
      Mark et al.
      • Mark R.J.
      • Anderson P.J.
      • Akins R.S.
      • et al.
      Interstitial high-dose-rate brachytherapy as monotherapy for early stage prostate cancer; median 8-year results in 301 patients.
      2010317Low–high3.201.31%

      0.6% (Grade 4)
      n/a
      Martinez et al.
      • Martinez A.A.
      • Demanes J.
      • Vargas C.
      • et al.
      High-dose-rate prostate brachytherapy: An excellent accelerated-hypofractionated treatment for favorable prostate cancer.
      2010141Low–interm.Grade 1–3, 15–4306.5020
      Prada et al.
      • Prada P.J.
      • Jimenez I.
      • Gonzalez-Suarez H.
      • et al.
      High-dose-rate interstitial brachytherapy as monotherapy in one fraction and transperineal hyaluronic acid injection into the perirectal fat for the treatment of favorable stage prostate cancer: Treatment description and preliminary results.
      201240Low–interm.0000NR
      Rogers et al.
      • Rogers C.L.
      • Alder S.C.
      • Rogers R.L.
      • et al.
      High dose brachytherapy as monotherapy for intermediate risk prostate cancer.
      2012284Interm.1.50.60017.4
      Yoshioka et al.
      • Yoshioka Y.
      • Konishi K.
      • Sumida I.
      • et al.
      Monotherapeutic high-dose-rate brachytherapy for prostate cancer: Five-year results of an extreme hypofractionation regimen with 54 Gy in nine fractions.
      2011112Low–high7162NR
      Zamboglou

      et al.
      • Zamboglou N.
      • Tselis N.
      • Baltas D.
      • et al.
      High-dose-rate interstitial brachytherapy as monotherapy for clinically localized prostate cancer: Treatment evolution and mature results.
      2013141Low–high15.69.200.711.1
      35116.54.81.70
      22517.63.83.50
      GU = genitourinary; GI = gastrointestinal; ED = erectile dysfunction; interm. = intermediate; n/a = not applicable; RTOG = Radiation Therapy Oncology Group; QoL = quality of life; IPSS = International Prostate Symptom score; FACT-P = Functional Assessment of Cancer Therapy-Prostate; IIEF = International Index of Erectile Function; NR = not reported.
      * RTOG toxicity scale.
      Table 3High-dose-rate monotherapy disease control
      First authorYearNDose × fractionsYears median fuLocal control (%)PSA-PFS low (%)PSA-PFS interm. (%)PSA-PFS high (%)DMFS (%)CSS (%)OS (%)
      Barkati20127910–11.5 Gy × 33.39988n/an/an/an/a
      Demanes20101577 Gy × 65.29997n/a999995
      Ghadjar2009369.5 Gy × 43n/a100100n/an/an/an/a
      Hoskins2012558.5–9 Gy × 4

      10.5 Gy × 3
      4.5n/an/a9587n/an/an/a
      1093
      Komiya2013516.5 Gy × 71.5n/a96n/an/an/a
      Mark20103177.5 Gy × 68n/a88n/an/an/a
      Martinez20101419.5 Gy × 45.29997n/a999995
      Prada20124019 Gy × 11.610010088n/a989898
      Rogers20122846 Gy × 63100n/a94n/a9910098
      Yoshioka20111116 Gy × 95.497859379n/a8796
      Zamboglou20134929.5 Gy × 4

      11.5 Gy × 3
      4.4n/a959393n/an/a97.5
      225
      fu = followup; PSA = prostate-specific antigen; PSA-PFS = PSA progression-free survival, biochemical control (ASTRO or nadir +2); interm. = intermediate; n/a = not applicable; DMFS = distant metastases-free survival; CSS = cause-specific survival; OS = overall survival.
      In May 1995, the first trial of prostate cancer HDR brachytherapy as monotherapy was opened at the University of Osaka, Japan and reported by Yoshioka et al. in 2000 (
      • Yoshioka Y.
      • Nose T.
      • Yoshida K.
      • et al.
      High-dose-rate interstitial brachytherapy as a monotherapy for localized prostate cancer: Treatment description and preliminary results of a phase I/II clinical trial.
      ). The original treatment regimen was 48 Gy in eight fractions and five consecutive days delivered with a single implant. In November 1996, the radiation dose was increased to 54 Gy in nine fractions over 5 days. The treatments were delivered twice daily with an interfraction time of 6 h. Interestingly, 19/22 patients had high-risk features, either T3–4 disease or prostate-specific antigen (PSA) >20 ng/mL, and they received hormonal therapy.
      They reported their results in 112 patients (68 high-risk) in 2011 (
      • Yoshioka Y.
      • Konishi K.
      • Sumida I.
      • et al.
      Monotherapeutic high-dose-rate brachytherapy for prostate cancer: Five-year results of an extreme hypofractionation regimen with 54 Gy in nine fractions.
      ). Intermediate-risk patients and those patients with prostate volumes >40 cm3 received 6–12 months of neoadjuvant ADT, and high-risk patients were treated adjuvant ADT for 3 years to life. The 5-year PSA disease–free survival was 83% (low 85%, intermediate 93%, and high 79%), local control 97%, disease–free survival 87%, and overall survival 96%. Initial PSA and younger age were the only significant prognostic variables. Most toxicity was genitourinary (GU). Acute Grade 3 “Common Toxicity Criteria for Adverse Events” (CTCAE) toxicity was observed in 6 patients. There were thirteen Grade 2 and three Grade 3 toxicities reported.
      A detailed dosimetry analysis of late toxicity in 83 patients treated with 54 Gy in nine fractions (median followup 3 years) was reported in 2009 (
      • Konishi K.
      • Yoshioka Y.
      • Isohashi F.
      • et al.
      Correlation between dosimetric parameters and late rectal and urinary toxicities in patients treated with high-dose-rate brachytherapy used as monotherapy for prostate cancer.
      ). Toxicity correlations with dose volume histogram parameters revealed greatest difference for rectal toxicity were the V40 (volume of rectum that receives 40% of the prescription dose) and the D5 (the dose to 5 cm3 of the rectum). Rectal toxicity (V40 ≥ 8 cm3 vs. V40 < 8 cm3) was 42% vs. 8%, respectively; p < 0.001 and (D5cc ≥ 27 Gy vs. D5cc < 27 Gy) was 50% vs. 11%, respectively; p < 0.001. Dosimetry parameters of the urethra of 15 patients with late urinary toxicity were not significantly different from the 68 patients without toxicity. This higher dose regimen was changed to 45.5 Gy in seven fractions over 4 days and it is now the one widely used in Japan.
      Komyia et al. (
      • Komiya A.
      • Fujiuchi Y.
      • Ito T.
      • et al.
      Early quality of life outcomes in patients with prostate cancer managed by high-dose-rate brachytherapy as monotherapy.
      ) evaluated the quality of life 51 patients in various risk groups who were treated with a single implant of 45.5 Gy in seven fractions. Long term adjuvant ADT was used for high-risk cases. Quality of life outcomes were measured with the IPSS, the Functional Assessment of Cancer Therapy-Prostate—FACT-P, and the International Index of Erectile Function questionnaire. The FACT-P scores decreased for several months after HDR but subsequently recovered to baseline. In the physical and well-being domain, the score recovered baseline status by 12 weeks. In the social/family well-being domain, baseline status was achieved by 1 year. The total and components of IPSS increased and sexual function decreased at 2 weeks after treatment, but returned to baseline after 12 weeks. There were few severe complications.
      Demanes et al. (
      • Demanes D.J.
      • Rodriguez R.R.
      • Altieri G.A.
      High dose rate prostate brachytherapy: The California Endocurietherapy (CET) method.
      ) at CET in the United States began treating low- and intermediate-risk group patients with HDR monotherapy in 1996 with 7 Gy × 6 fractions in two implants, 1 week apart. In 1997, Martinez et al. (
      • Martinez A.A.
      • 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.
      ) at WBH initiated an even more hypofractionated program of 9.5 Gy × 4 fractions in one implant over 2 days using a TRUS real time planning system. Given the similarity of the selection criteria, dosimetry, and radiobiology used at CET and WBH, the two centers reported their results in 298 (CET 157 and WBH 141) patients together in 2011 (
      • Demanes D.J.
      • Martinez A.A.
      • Ghilezan M.
      • et al.
      High-dose-rate monotherapy: Safe and effective brachytherapy for patients with localized prostate cancer.
      ). Eligibility criteria were T1c–T2a, Gleason ≤7 (3 + 4, no perineural invasion), and pretreatment PSA <15 ng/mL. Most of the patients had low- or intermediate-risk prostate cancer. The median followup was 5.2 years during which a mean of 10 PSA tests were performed. Twenty-four percent of patients received a median of 4 months ADT for downsizing the gland volume or other reasons by referring physicians. The dosimetry parameters are shown in Table 4. The 5-year (n = 158) and 8-year (n = 39) results were 99% local control, 97% biochemical disease–free survival at 5 years (nadir +2), 99% distant metastasis–free survival, 99% cause-specific survival, and 95% overall survival. GU toxicity was 10% transient Grade 2 urinary frequency or urgency and 3% Grade 3 urinary retention. Gastrointestinal (GI) toxicity was <1%. The low morbidity rates were not demonstrably different between protocols. There was no demonstrable impact from the short course of ADT.
      Table 4High-dose-rate monotherapy prescription doses and normal tissue doses
      InstitutionDose (Gy × fx)BED (α/β 1.8)EBRT (1.8 Gy/fx)Bladder (%)Rectum (%)Urethra (%)D90 (%)V100 (%)
      CET7 Gy × 6205 Gy103 Gy8080110>100>97
      WBH9.5 Gy × 4239 Gy119 Gy8075120>100>96
      fx = fraction; BED = biological effective dose; EBRT = external beam radiation therapy; CET = California Endocurietherapy Cancer Center; WBH = William Beaumont Hospital.
      Maximum normal tissue doses (as percent of prescription).
      During these early years of HDR monotherapy, there were concerns about normal tissues toxicities and long-term complications that might be associated with large doses per fraction. However, the rationale for proceeding with HDR monotherapy was the precision dosimetry and ability of HDR to reliably partition the dose between the prostate target and adjacent normal organs, and ultimately in retrospect, the low alpha/beta ratio of prostate that makes large fraction radiobiologically advantageous. Assuming a prostate alpha/beta ratio of 1.5, these programs provided BED in the range of 237–354 Gy, considerably higher than the BED of 178 Gy achieved with EBRT to a total dose of 81 Gy in 1.8 Gy/fraction (
      • Bossi A.
      Quelle modalite pour la curietherapie du cancer de prostate.
      ).
      As a result of these favorable initial clinical experience with HDR monotherapy, several radiation oncologists around the world started HDR monotherapy programs of their own (Table 1, Table 2, Table 3). Most of the centers providing HDR monotherapy follow, or started by following, programs similar to the Osaka, CET, or WBH.

      HDR toxicity and comparisons with LDR (permanent seed) brachytherapy

      Grills et al. (
      • Grills I.S.
      • Martinez A.A.
      • Hollander M.
      • et al.
      High dose rate brachytherapy as prostate cancer monotherapy reduces toxicity compared to low dose rate palladium seeds.
      ) in the United States were the first to report the toxicity profile of HDR monotherapy. They assessed comparably match HDR and permanent seed implant, mostly low risk group, followed a median of 35 months (65 patients HDR 9.5 Gy × 4 vs. 84 patients Palladium103 120 Gy). ASTRO definition PSA control disease–free survival was equally high for both treatments (97% and 98%). The majority of toxicities were Grade 1. Acute side effects were significantly lower with HDR (dysuria 36% vs. 67%, frequency/urgency 54% vs. 92%, and rectal pain 6% vs. 20%). Chronic frequency/urgency was also less with HDR 32% vs. 56%. Urethral stricture rates were not statistically different (8% vs. 3% p = 0.17). Potency preservation was better for HDR 83% vs. 55%.
      WBH and CET did a comprehensive toxicity comparison between 248 HDR monotherapy patients and 206 103Pd permanent seeds patients (
      • Martinez A.A.
      • Demanes J.
      • Vargas C.
      • et al.
      High-dose-rate prostate brachytherapy: An excellent accelerated-hypofractionated treatment for favorable prostate cancer.
      ). A short course (<6 months) of neoadjuvant ADT was used in 30% of patients. The 5-year actuarial biochemical control for monotherapy was 88% for HDR and 89% for seeds. There was no difference in cancer mortality or overall survival.

      Acute toxicity

      HDR brachytherapy was associated with statistically significant reductions in acute rates of dysuria (seeds 60% vs. HDR 39%) and urgency/frequency (seeds 91% vs. HDR 58%). HDR was also associated with lower rates of rectal pain (seeds 17% vs. HDR 7%). Chronic toxicity: HDR brachytherapy was associated with significantly less Grade 1–2 chronic dysuria (seeds 22% vs. HDR 15%) and urinary frequency and urgency (seeds 54% vs. HDR 43%). The occurrence of hematuria was slightly greater for HDR than seeds (11% vs. 7%). The rate of urethral stricture was equal (seeds 2.5% seeds vs. HDR 3%) with the median time to diagnosis of 17 months. Chronic Grade 3 GU toxicity was low in both groups. Approximately 75% of the HDR toxicities were self-limited and required little or no intervention (Grade 1), 23% responded to therapy (Grade 2), and about 2% had more prolong or more severe (Grade 3) symptoms (mostly urinary frequency/urgency). No HDR patient had Grade 4 toxicity. Erectile dysfunction data were available for study in 58% of the cases. The 5-year potency preservation rate was 80% for HDR of 80% and 70% for seeds (p = 0.23).

      Toxicity and outcome of other CET/Osaka-like regimens (6–7 fractions, 1–2 implants)

      Mark et al. (
      • Mark R.J.
      • Anderson P.J.
      • Akins R.S.
      • et al.
      Interstitial high-dose-rate brachytherapy as monotherapy for early stage prostate cancer; median 8-year results in 301 patients.
      ) reported in abstract form the results of 301 patients with T1–2, Gleason 4–10, median PSA 9.3 (2.7–39.8) treated with HDR monotherapy. They administered 7.5 Gy in six fractions in two implants performed 1 month apart. Urethral dose points (
      • Edmundson G.K.
      • Rizzo N.R.
      • Teahan M.
      • et al.
      Concurrent treatment planning for outpatient high dose rate prostate template implants.
      ,
      • Edmundson G.K.
      • Yan D.
      • Martinez A.A.
      Intraoperative optimization of needle placement and dwell times for conformal prostate brachytherapy.
      ,
      • White E.C.
      • Kamrava M.R.
      • Demarco J.
      • et al.
      High-dose-rate prostate brachytherapy consistently results in high quality dosimetry.
      ,
      • Brenner D.J.
      • Hall E.J.
      Fractionation and protraction for radiotherapy of prostate carcinoma.
      ,
      • Brenner D.J.
      • Martinez A.A.
      • Edmundson G.K.
      • et al.
      Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue.
      ) limited to <105% of the prescription dose. Acute urinary retention occurred in 5%. Late Radiation Therapy Oncology Group (RTOG) urinary toxicity was 3% Grade 2 and Grade 3–4 (urethral stricture requiring dilation 6%). Late RTOG rectal toxicity was Grade 1–2 (2.3%) and Grade 3–4 (0.3%). The PSA progression–free survival was 88% at 8 years.
      Rogers et al. (
      • Rogers C.L.
      • Alder S.C.
      • Rogers R.L.
      • et al.
      High dose brachytherapy as monotherapy for intermediate risk prostate cancer.
      ) reported their experience on 284 patients with intermediate-risk group patients treated with two HDR implants to deliver six fractions of 6.5 Gy. The 5-year actuarial biochemical survival was 94.4%, local control and cause-specific survival 100%, and distant metastasis–free survival 99%. Percent of core positive over 75% and Stage T2c predicted for worse biochemical control. Patients without these adverse risk factors had a 5-year biochemical control of 97.5%. The incidence of side effects was low. Unlike other reports, there were no urethral strictures. Transient Grade 1 incontinence was found in 7.7% of cases after treatment, but exclusive of patients with prior transurethral resection or neurologic illness it was 2.5%. Grade 1 RTOG rectal toxicity occurred in 4.2%. Potency was maintained in 83% of patients 2 years after therapy.

      Toxicity and outcome of WBH-like regimens (four fractions, single implant)

      Ghadjar et al. (
      • Ghadjar P.
      • Keller T.
      • Rentsch C.A.
      • et al.
      Toxicity and early treatment outcomes in low- and intermediate-risk prostate cancer managed by high-dose-rate brachytherapy as a monotherapy.
      ) reported on 36 patients with low- (28) and intermediate- (8) risk prostate cancer treated with HDR monotherapy in a single implant and four fractions of 9.5 Gy over 2 days. Acute Grade 3 GU toxicity rate was 3% and late GU toxicity 11%. There was no Grade 3 GI toxicity. The 3-year PSA progression–free survival rate was 100%. The sexual preservation rate in patients without ADT was 75%. Late Grade 3 GU toxicity was associated with higher PTV doses as represented by the V100 (percent target coverage by 100% isodose) and D90 (dose to 90% of the PTV), and the urethral V120 (volume urethra receiving ≥120% of the prescription dose).
      Hoskin et al. (
      • Hoskin P.
      • Rojas A.
      • Lowe G.
      • et al.
      High-dose-rate brachytherapy alone for localized prostate cancer in patients at moderate or high risk of biochemical recurrence.
      ), in the United Kingdom, conducted a dose escalation trial for mostly intermediate- (52%) and high-risk (44%) patients. A total of 197 patients were treated with 34 Gy in four fractions, 36 Gy in four fractions, 31.5 Gy in three fractions, or 26 Gy in two fractions. Median followup times were 60, 54, 36, and 6 months. Incidence of early Grade ≥3 GU morbidity was 3–7%, and Grade 4 0–4%. Grade 3 or 4 early GI morbidity was not observed. Late GU toxicity (3 year actuarial) Grade 3 was 3–16%. The 4-year stricture (requiring surgery) rate was 3–7%. Late GI toxicity Grade 3 was 1%. There was no late Grade 4 GI or GU toxicity. At 3 years, 99% of patients with intermediate-risk and 91% with high-risk disease were free of biochemical relapse (p = 0.02).
      Researchers at Peter McCallum Cancer Center in Australia reported the results of a Phase II prospective dose escalation study of 79 low- and intermediate-risk prostate cancer patients (
      • Barkati M.
      • Williams S.G.
      • Foroudi F.
      • et al.
      High-dose-rate brachytherapy as a monotherapy for favorable-risk prostate cancer: A phase II trial.
      ). Half of the patients had T2 and half had Gleason 7 prostate cancer. They administered HDR in a single implant over 2 days in three fractions; four different dose schedules were evaluated (10, 10.5, 11, or 11.5 Gy). The 3- and 5-year biochemical control rates (nadir + 2) were 88% and 85%. There were no differences in toxicity between doses. Acute rectal toxicity was nearly all Grade 1 and acute Grade 3 urinary toxicity occurred in only 1 patient. Chronic Grade 3 urinary toxicity was <10% and no Grade 4 toxicities were recorded.
      The group from Offenbach Germany, lead by Zamboglou and Baltas, obtained excellent results in 718 patients using intraoperative TRUS treatment planning. The dose and fractionation schedule evolved over time (
      • Zamboglou N.
      • Tselis N.
      • Baltas D.
      • et al.
      High-dose-rate interstitial brachytherapy as monotherapy for clinically localized prostate cancer: Treatment evolution and mature results.
      ). Protocol A (9.5 Gy × 4 in one implant), protocol B (9.5 Gy × 4 in two implants), and finally the current protocol C (11.5 Gy × 3 in three implants). The authors progressively included higher risk group cases so that for protocol C 57% of cases were intermediate- or high-risk compared with 27% in protocol A and 44% in protocol B. The median followup by protocol was 7.7 years for 141 patients (protocol A), 4.9 years for 351 patients (protocol B), and 2.1 years for 226 patients (protocol C). The 3-year biochemical control for all patients was 95% and distant metastasis–free survival was 98%. The 5-year results were available for protocols A and B (9.5 Gy × 4). Biochemical control was 97% and 94%. There were no significant differences correlated with T score, PSA, Gleason score, or risk group. Late Grade 3 GU and GI toxicities were 3.5% and 1.6%. Urinary strictures that required urethrotomy (Grade 3 GU toxicity) occurred in 1.8% and 2 patients required urinary diversion to manage urinary incontinence (Grade 4 GU toxicity). Although the followup is significantly less in protocol C, there were no apparent differences in tumor control or morbidity between the three protocols.

      Toxicity and outcome of ultra-hypofractionation (1–2 fractions)

      Ghilezan et al. (
      • Ghilezan M.
      • Martinez A.
      • Gustason G.
      • et al.
      High-dose-rate brachytherapy as monotherapy delivered in two fractions within one day for favorable/intermediate-risk prostate cancer: Preliminary toxicity data.
      ) reported on an ultra-hypofractionated HDR monotherapy trial for low- and intermediate-risk prostate cancer that accrued 100 patients. The total dose was 24 Gy for the first 50 patients (one implant, two fractions, and 6 h interfraction interval) and 27 Gy in the next 50 patients. The median followup was 17 months. There were no differences in acute or chronic toxicities between the two doses. The maximum chronic GU and GI toxicities Grade 2 or higher were ≤5% with the exception of urinary frequency/urgency, which was 16%. These symptoms resolved by 6 months in most cases (0% for the 24 Gy and 4.8% for the 27 Gy). The program was changed to two implants 2–3 weeks apart to increase the time for normal tissue repair and to shorten the time of the procedure per day by removing the same day waiting between fractions. It also eliminated the need for epidural anesthesia and also improved patient tolerance and satisfaction. Encouraged by this favorable tolerance and toxicity profile, a new protocol of 19 Gy in one fraction was implemented. There has been no Grade 3 or 4 GI or GU toxicity with this protocol, during the first 3 months followup. Patients ineligible for single fraction HDR received the two fraction protocol. Patients with T1c disease, PSA <10 ng/mL, Gleason score 6, up to 3/12 cores positive, none >50% tumor involvement, and patients' age of 65 years or older, are offered 12 Gy × 2 fractions. All other cases are treated with 13.5 Gy × 2 fractions.
      Prada et al. (
      • Prada P.J.
      • Jimenez I.
      • Gonzalez-Suarez H.
      • et al.
      High-dose-rate interstitial brachytherapy as monotherapy in one fraction and transperineal hyaluronic acid injection into the perirectal fat for the treatment of favorable stage prostate cancer: Treatment description and preliminary results.
      ) from Spain published preliminary outcomes in 29 low-risk and 11 intermediate-risk group patients treated with one fraction of 19 Gy. Hyaluronic acid was injected in the rectoprostatic fascia to displace the rectum posterior and away from the prostate. Although the incidence of rectal complications with HDR monotherapy is low with fractionated HDR brachytherapy, the authors were concerned about the effect on the rectum of giving treatment as a single large HDR dose. The hyaluronic acid is injected after catheter placement so it does not interfere with TRUS imaging and then is slowly absorbed by the body over many weeks to months. The median followup was 19 (8–32) months. Thirty-five percent of patients received ADT before brachytherapy. Actuarial biochemical control at 32 months was 100% in low-risk and 88% in intermediate-risk group patients. The CTCAE Version 4 was used, which, parenthetically, is a system that grades outlet obstruction requiring a catheter as Grade 1. The procedures were well tolerated (one case of postoperative urinary outlet obstruction) and the all the reported acute and chronic toxicity was ≤ Grade 1.
      Hoskin et al. (
      • Hoskin P.
      • Rojas A.
      • Ostler P.
      • et al.
      High-dose-rate brachytherapy alone given as two or one fraction to patients for locally advanced prostate cancer: Acute toxicity.
      ) compared acute GU and GI morbidity in patients with intermediate- and high-risk prostate cancer. They compared 13 Gy × 2 (n = 115), 19 Gy × 1 (n = 24), and 20 Gy × 1 (n = 20) using the RTOG scoring system and IPSS at 2, 4, and 12 weeks. The early (2 week) effect on IPSS was greater for 20 Gy × 1 fraction, but by 12 weeks “all groups were at pretreatment levels or less”. Grade 3 GU toxicity was noted in 9% at 20 Gy × 1, 2% for 13 Gy × 2 fractions, and 0% for 19 Gy × 1 fraction. The numbers of patients were too small to demonstrate statistical significance. There were no Grade 4 complications. The single fraction programs were associated with a significant increase in the need for urinary catheters (19 Gy 21% and 20 Gy 29% compared with 13 Gy × 2 7%). The authors suggest that tolerance to single fraction HDR monotherapy may have been reached at 20 Gy × 1.
      A randomized Phase II trial sponsored by Sunnybrook Health Science Center in Toronto (principal investigator Dr. Gerard Morton) was opened in 2013 in Canada (ClinicalTrials.gov identifier NCT01890096). Low- and intermediate-risk prostate cancer patients with a gland size up to 60 cm3 are randomized to either two fractions of 13.5 Gy delivered in two separate implants 7–13 days apart or a single implant with one fraction of 19 Gy. CT and TRUS-based dosimetry are allowed. The primary end point is patient-reported toxicity and health-related quality of life at 1 year.

      Focal prostate brachytherapy and organ at risk dose de-escalation

      At the University of California Los Angeles research efforts have been directed toward focal prostate brachytherapy using HDR. Kamrava et al. (
      • Kamrava M.
      • Chung M.P.
      • Kayode O.
      • et al.
      Focal high-dose-rate brachytherapy: A dosimetric comparison of hemigland vs. conventional whole-gland treatment.
      ) published a dosimetric analysis assessing the impact on target coverage and dose to OARs with hemi-gland compared with whole-gland treatment. As expected, the dose to OARs was significantly lower with hemi-gland treatments. Focal HDR treatment planning using interactive multimodality image combination such as multiparametric MRI and spectroscopy along with sophisticated image registration alogorithms are currently being investigated (
      • Reed G.
      • Cunha J.A.
      • Noworolski S.
      • et al.
      Interactive, multi-modality image registrations for combined MRI/MRSI-planned HDR prostate brachytherapy.
      ).

      HDR monotherapy as salvage treatment

      HDR monotherapy has been used for treatment of recurrent prostate cancer. Lee et al. (
      • Lee B.
      • Shinohara K.
      • Weinberg V.
      • et al.
      Feasibility of high-dose-rate brachytherapy salvage for local prostate cancer recurrence after radiotherapy: The University of California-San Francisco experience.
      ) at the University of California San Francisco reviewed 21 cases they treated with 6 Gy × 6 fractions HDR monotherapy using TRUS-guided and CT treatment–planned HDR brachytherapy. Approximately half of the cases received neoadjuvant ADT. The median followup was 19 (6–84) months. CTCAE Version 3 Grade 1 or 2 GU morbidity was reported in 18 patients by 3 months after HDR salvage. Three patients developed Grade 3 GU toxicity. Three patients had transient (<3 months) Grade 1 or 2 GI toxicity. The 2-year biochemical control was 89%. Failure to achieve a PSA nadir of ≤1.0 ng/mL was associated with biochemical recurrence and the development of distant metastasis.
      Tharp et al. (
      • Tharp M.
      • Hardacre M.
      • Bennett R.
      • et al.
      Prostate high-dose-rate brachytherapy as salvage treatment of local failure after previous external or permanent seed irradiation for prostate cancer.
      ) reported the 5-year results on 7 patients treated with HDR salvage after either external beam radiation (n = 5) or permanent seed implant (n = 2). Median followup was 58 (27–63) months. The disease-free survival was 71% (median not reached). Two patients died of metastatic disease but there were no local failures. One patient developed Grade 2 rectal bleeding attributed to radiation therapy. Although disease control was good and GI toxicity was low, the GU morbidity rate was high. Five patients (71%) developed symptomatic urethral strictures; 2 of these patients had prior TURP and 2 of them (prior seed brachytherapy) required artificial sphincters.
      Yamada et al. (
      • Yamada Y.
      • Kollmeier M.A.
      • Pey X.
      • et al.
      A phase II study of salvage high-dose-rate brachytherapy for the treatment of locally recurrent prostate cancer after definitive external beam radiotherapy.
      ) reported the results of a Phase II study of 40 patients treated with HDR brachytherapy (8 Gy × 4 in one implant) after prior EBRT (range 68.4–86.4 Gy). The median pretreatment PSA was 3.45 ng/mL. Twelve patients had neoadjuvant ADT. The median followup was 38 months and time from EBRT to recurrence was 73 months. PSA (nadir + 2) 5 year disease-free survival was 70% and cause-specific survival was 94%. Three patients developed distant metastasis. IPSS returned to baseline in 65% cases by 4.5 months. Patients with higher levels of GU symptoms at baseline were more likely to have Grade 2 urinary morbidity (but not so for Grade 3). Approximately 20% of cases had Grade 2 GI morbidity.

      Discussion

      HDR monotherapy is the logical extension of HDR used with EBRT as dose escalation and it builds on the large worldwide experience of permanent seed implants without EBRT. There is good evidence in the literature that HDR monotherapy is a safe and effective treatment for prostate cancer. The large doses per fraction take advantage of the radiobiology (low alpha/beta ratio) to potentially render HDR the most efficient and convenient form of radiation therapy. Although patients with early- and intermediate-risk groups are optimal candidates, patients with high-risk group disease also have reported excellent outcomes with HDR monotherapy when compared with other treatment methods. HDR delivers a therapeutic margin of safety for patients with periprostatic or seminal vesicle extension. Prostate HDR brachytherapy is versatile; it can be used as monotherapy, monotherapy salvage, combined with EBRT, or it can be used as an adjunct to systemic treatment to reduce disease burden to improve remission rates.
      HDR dosimetry is prospective (done before source delivery), consistent, and reliable because it is not impacted by setup errors, interfraction and intrafraction organ motion, prostate swelling, or shrinkage during treatment delivery. Furthermore, target coverage is verifiable through pretreatment image guidance designed to avoid unrecognized “dwell position displacement”. Dose modulation of the stepping source can compensate for catheter spacing and volume discrepancies by using “optimization” programs so that dose painting and dose sculpting can be done for dose adjustments within the target boundaries. Such capacities make HDR an excellent choice for monotherapy or for EBRT boost; and in properly selected cases, it can be used to reduce or eliminate radiation to parts of the prostate (focal therapy or dose de-escalation). These measures may enhance the therapeutic index by delivery of dose in proportion to the extent and severity of the disease, and it can reduce morbidity by limiting dose to normal structures.
      The excellent results of HDR prostate brachytherapy coupled with the radiobiological advantage of higher doses per fraction especially in tumors with low alpha/beta have prompted clinical trials of stereotactic body radiation therapy (SBRT) to deliver the full course of external beam therapy in 4–6 fractions like HDR (
      • Katz A.J.
      • Santoro M.
      • Ashley R.
      • et al.
      Stereotactic body radiotherapy for organ-confined prostate cancer.
      ,
      • Martin A.
      • Gaya A.
      Stereotactic body radiotherapy: A review.
      ,
      • Lo S.S.
      • Fakiris A.J.
      • Chang E.L.
      • et al.
      Stereotactic body radiation therapy: A novel treatment modality.
      ,
      • Friedland J.L.
      • Freeman D.E.
      • Masterson-McGary M.E.
      • et al.
      Stereotactic body radiotherapy: An emerging treatment approach for localized prostate cancer.
      ,
      • Abdel-Wahab M.
      • Pollack A.
      Radiotherapy: Encouraging early data for SBRT in prostate cancer.
      ,
      • Hossain S.
      • Xia P.
      • Chuang C.
      • et al.
      Simulated real time image guided intrafraction tracking-delivery for hypofractionated prostate IMRT.
      ,
      • King C.R.
      • Brooks J.D.
      • Gill H.
      • et al.
      Stereotactic body radiotherapy for localized prostate cancer: Interim results of a prospective phase II clinical trial.
      ,
      • Teh B.S.
      • Ishiyama H.
      • Mathews T.
      • et al.
      Stereotactic body radiation therapy (SBRT) for genitourinary malignancies.
      ). Fuller et al. (
      • Fuller D.B.
      • Naitoh J.
      • Lee C.
      • et al.
      Virtual HDR CyberKnife treatment for localized prostatic carcinoma: Dosimetry comparison with HDR brachytherapy and preliminary clinical observations.
      ) performed an analysis to determine if SBRT could reproduce the dosimetry achieved with HDR brachytherapy in what was termed “virtual HDR”. The real stereotactic plans were compared with “simulated” HDR plans in which the theoretical brachytherapy trajectories were inserted on the same contours used for SBRT planning. Although the V125 and V150 were significantly higher with HDR, the urethral doses were lower with the SBRT plans suggesting to the authors that SBRT may limit urethra doses more effectively than HDR. Although such plan comparisons are valuable, they are highly dependent on the treatment planning process. In a more recent dosimetric analysis comparing virtual SBRT with actual HDR monotherapy plans from treated patients have demonstrated HDR achieves significantly higher intraprostatic doses while achieving similar urethral dose and lower maximum rectal dose compared with virtual SBRT treatment planning (
      • Spratt D.E.
      • Scala L.M.
      • Folkert M.
      • et al.
      A comparative dosimetric analysis of virtual stereotactic body radiotherapy to high-dose-rate monotherapy for intermediate-risk prostate cancer.
      ). There are no direct clinical comparison outcome studies of HDR, permanent seeds, or SBRT.
      Because ADT has not been shown to enhance disease control with HDR prostate brachytherapy and ADT is usually not required for downsizing of prostate volume with HDR brachytherapy, it can usually be omitted for favorable risk group cases.

      Conclusions

      Most centers in the United States have used HDR monotherapy to treat low- and intermediate-risk group disease whereas those in Asia and Europe treat patients in all risk groups. HDR brachytherapy can be used to deliver the dose to a definable margin around the prostate and into the seminal vesicles; thus it effectively treats patients with local extension beyond the prostate. Whether higher risk group patients should have HDR monotherapy or HDR combined therapy with EBRT remains to be determined. There is no consensus on the optimal dose and fractionation schedule for HDR brachytherapy. The longest followup for outcomes is with moderate-hypofractionation (4–9 fractions), but excellent results are being reported with ultra-hypofractionation (1–3 fractions). The emergence of ultra-hypofractionation with only 1–2 treatments makes HDR logistically comparable to seed implant and adds a high degree of dosimetry control and accuracy in brachytherapy. There are two simulation and dosimetry methods (TRUS and CT). The advantages of TRUS are its use of real-time imaging and interactive dosimetry whereas CT dosimetry provides the clearest images of catheters and the relationship of the implant to adjacent organs. The TRUS approach is most time efficient. Regardless of the imaging modality and treatment planning system, HDR monotherapy is an excellent treatment modality for the management of prostate cancer.

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