Purpose
Patients with organ-confined prostate cancer are the appropriate candidates for curative treatment. There are several modalities that can be performed in order to treat this kind of cancer, such as: external beam radiation therapy (EBRT), prostatectomy, cryotherapy or interstitial brachytherapy (BT). Brachytherapy is one of the oldest methods and means implantation of radioactive sources directly into the prostate.
Low-dose-rate brachytherapy
Low-dose-rate brachytherapy is one of the radiation methods that is known for almost 30 years in treatment of localized prostate cancer. The main idea of this method is to implant small radioactive seeds as a source of radiation, directly into the prostate gland. Low-dose-rate brachytherapy is applied as a monotherapy, and also used along with EBRT as a boost. It is used as a sole radical treatment modality, however, not as a palliative treatment. The application of permanent seeds implants is a curative treatment alternative in patients with organ-confined cancer, without extracapsular extension of the tumour [1-7]. Recommendations are based on risk groups which are confirmed by several societies (Tables 1 and 2) [1,4,8]. This technique is particular favorite in United States, Japan, Netherlands, Spain.
In Eastern European countries, however, high-dose rate brachytherapy method (HDR-BT) is still more popular in early staged prostate cancer treatment. As a monotherapy, LDR-BT seems to be a reliable choice for early stage prostate cancer, according to low morbidity rate good results and short hospitalization. It is curative alternative of radical prostatectomy or EBRT (i.e. 3D CRT, IMRT) with comparable long-term survival and biochemical control, and most favorable toxicity [9-14]. Low-dose-rate brachytherapy represents the most conformal radiation therapy, and the number of patients referred to this radical treatment has grown rapidly in last 15 years, especially in the United States. In 1995, brachytherapy has taken a part in prostate cancer treatment only in ~5% (surgery ~65% procedures). Development of new techniques with new computer planning systems caused raising popularity of brachytherapy to about 40% in 2006. There are several reasons why LDR-BT achieved such popularity. Better toxicity profile with higher dose applying to prostate gland are the main points for brachytherapy in comparison with EBRT. Comparing with radical prostatectomy, permanent seed’s implantation is a short, one day therapy with lower complication rate during and after the procedure (bleeding, urinary incontinence, impotence). Specific selection of radioactive isotopes and their correct localization, allows to deposit high dose into the prostate tumor with rapid fall off the dose outside the area of treatment, and – at the same time – allows to preserve organs at risk (OaRs). Low-dose-rate brachytherapy has been a gold standard for prostate brachytherapy in low risk patients for many years.
High-dose-rate brachytherapy
High-dose-rate brachytherapy is a temporary type of brachytherapy where the high-dose rate radioactive source (usually iridium 192 [192Ir] or cobalt 60 [60Co]) is placed in the gland during the applicator implantation procedure.
In Europe, since at least 30 years, HDR-BT has been developed parallel to LDR-BT [15-20], and in the last years with growing interest in the USA. High-dose-rate equipment is commonly available and the radioactive source used for treatment is the same as in the case of other neoplasms.
The dwell-time position of the source in the applicators may be freely programmed during the procedure. The dwell time may be adapted to the requirements of treatment. In the course of treatment and real-time planning, the possibility of imprecise indication of the applicators position in relation to the treated gland is minimal, which ensures high precision of the treatment.
Initially HDR-BT was introduced as a high-dose-rate supplement for EBRT, and proved to be an effective and safe method of treatment [21-25]. Treatment of patients from the low and intermediate risk groups with HDR-BT monotherapy was initiated at the end of the previous decade [15,26-32].
The presence of both brachytherapy techniques in many countries is interesting to compare. The aim of this publication is to describe indications, similarities and differences of both brachytherapy techniques used in prostate cancer treatment.Indications for brachytherapy
The American Brachytherapy Society (ABS) and the Groupe Europeen de Curietherapie–European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) has formed recommendations on consensus panel through clinical experience of experts and their analysis of published data. According to their publications, the appropriate candidates for LDR and HDR monotherapy are patients with a high probability of organ-confined disease (Tables 1 and 3). It is a general agreement not to apply LDR-BT or HDR-BT alone on patients with significant risk of extra prostatic extension. Most of physicians defines this group by the presence of at least two main risk factors such as PSA level greater than 20 ng/ml, stage higher than T2b and/or Gleason score greater than 7. It is to note that inclusions for HDR-BT include selected T4 cases (in combined therapy). In general intermediate risk group (at least one of the risk factors mentioned above) is not an absolute contraindication of a single BT modality treatment. Good results published by several authors change the physicians preferences to monotherapy combined with androgen deprivation [34]. However, to confirm these prospective observations, comprehensive studies are inevitable. In Table 4 inclusions for LDR-BT and HDR-BT monotherapy and combined therapy are presented.Contraindications
ABS and GEC-ESTRO recommends LDR-BT and HDR-BT in patients with at least 5 years of expected survival rate, what seems to be rather relative contraindication [1,14,15]. It is not included in HDR-BT Task Group recommendations (Table 5) [26,33]. According to their publications, neoadjuvant androgen deprivation can decrease volume of the gland before brachytherapy [1]. No nodal involvement and absence of distant metastases are basic points in definition of organ-confined prostate cancer. Patients with disseminated disease can not be cured by radical treatment with both techniques, which is not clearly mentioned in Hsu I-C et al. recommendations [26]. Transurethral resection of the prostate (TURP) is another relative contraindication for brachytherapy, and is associated with higher rate (~50%) of urinary incontinence after procedure. Nevertheless, several publications did not confirmed these data and proved that risk of this kind of complication is less than 10% [35]. Pubic arch interference as a result of large prostate may preclude adequate placement of seeds, which is the reason why volume of prostate higher than 60 ml seems to be relative contraindication. Potential solution of this difficulty in most cases is hormonal ablation for 3 months before the procedure. Neoadjuvant hormone deprivation can also reduce significant preoperative obstructive symptom, which is again a possible serious contraindication for brachytherapy, which decreases the probability of postoperative acute urinary retention. Several authors reported that downsizing of the prostate gland by 25-40% enables BT procedure, and reduces the risk of obstructive complication in patients with large glands [36]. It is worth to note that contraindications are defined in different mode in LDR-BT Task Group and GEC-ESTRO recommendations (Table 5).Implantation techniques
Most of both brachytherapy technical steps are similar. Many centers has improved and introduced their own techniques. Preoperative workup before brachytherapy insertion includes mechanical bowel preparation, prophylactic intravenous antibiotics, continued per os for several days afterwards (in some centers). Before the procedure, patients with history of deep vein thrombosis are being given heparin subcutaneously to prevent any complications in connection with these blood condition. Because of significant risk of perineal hemorrhage, the rest of the procedure candidates are to stop receiving anticoagulants, including aspirin, nonsteroidal anti-inflammatory drugs or warfarin.
In the operating room, a patient is placed under general or spinal anesthesia in dorsal lithotomic position. After catheterization of contrast or air filled gel that are usually used to visualize the urethra, and to differentiate the bladder from the prostate. First step of the procedure is the necessity to determine the shape and size of the gland by initial trans-rectal ultrasound examination (TRUS) - before needles insertion. It can be done a few days before seeds (needles) insertion (preimplant treatment planning, preplanning) or can be performed on the day of the procedure (intraoperative treatment planning). A biplanar probe at 5, 6, or 7.5 MHz of frequency, gather ultrasound visualization of prostate localization at 0.5 cm intervals, compared with the one after needles insertion. Treatment plan should contain several information such as needle location, number and strength of seeds (or number and position of HDR needles), and shape and volume of the target. To achieve the exact dose inside the prostate it is essential to use nomograms (inadequate amount activity per volume) combined with real-time TRUS and treatment planning system [37]. Transrectal ultrasound equipment is combined with special template, and by guiding creates stepping unit. Before proper procedure it is important to measure the distance from bladder base to template. Only then two stabilizing needles are being inserted through the template just posterior to the urethra on either side of the midline. Because of movement of the prostate, during the procedure a pre-plan can be created in order to minimize the risk of positioning errors. The loading pattern indicate coordinates in the computer planning system in connection with the templates stepping unit. That gives the physicians exact points to insert each needle. In this step brachytherapy techniques differ one from other. When the pre-plan is done, 20 cm long needles are inserted, and after consulting two plans (before and after insertion), radioactive seeds (in case of LDR-BT) are placed into the prostate gland. Withdrawing each needle should be done very carefully to avoid source migration inside the gland (LDR-BT). LDR-BT: once the procedure has been completed, the position of seeds must be observed under fluoroscopy and ultrasonography. Usually there is no possibility of removing seeds after insertion and if a “cold spots” are observed, a few extra seeds can be added to cover them. Performing a final CT scan of the prostate and postimplant dosimetry ends up the whole procedure of LDR seeds implantation in prostate cancer treatment. The patient leaves the theatre catheterized, and after removing it, can be discharged home the next day. In LDR-BT there is another advanced technique of seeds implantation worth of mentioning. In stranded seeds technique, the point is to implant radioactive sources embedded in a polymer strand of glycolide, lactide and polydioxanone spaced from 5 mm to over 50 mm apart, and placed in 18-gauge needle. The main advantages of this technique is significant improvement in D90 parameter without increasing of toxicity rate and less number of seeds migration incidences.Doses
According to ABS recommendations, patients with organ-confined prostate cancer are to be treated with monotherapy, others – with combined treatment (EBRT in 40-50 Gy dose with BT boost of 110 Gy and 100 Gy depending on which EBRT dose was administered (LDR-BT) or different HDR-BT schemas. The HDR-BT procedure is performed once or repeated several times, depending on the fractionating schema assumed. The ABS proposes three fractionating schemas for HDR-BT monotherapy and four schemas for combined treatment [26], however, other schemas are also applied (Table 6). Depending on the mode of fractioning, the fractionated doses are administered in one session at time intervals (e.g. every 6 hours) or are repeated in the course of subsequent procedures. Some centres use the 3 x 10.5-11 Gy fractioning schema with a 1-2 week interval between fractions [15,16,21]. Many different fractionations schema make difficult to compare treatment results. Using radiobiological models we noted also different BEDs (biologically effective doses), comparing to LDR-BT nd HDR-BT – differences are sometimes significant [38].Treatment planning
Describing of planning target volume (PTV) for HDR-BT and LDR-BT was published by both Task Groups [26,33]. The definition of volumes is based on ICRU Report 58.
HDR Task Group recommendations are more specific and differs significantly from the recommendations of LDR Task Group (Table 7). There is a difference between recommended evaluated postoperative dosimetric parameters for HDR and LDR brachytherapy, according to ABS and GEC-ESTRO/ EAU/EORTC [4,15,26,33] (Table 8). Dosimetry after LDR-BT
Apart from dosimetric planning of the implant before or during seed insertion, ABS and GEC-ESTRO recommend postimplant dosimetry in all patients after LDR-BT for the best optimal care [1,4]. According to availability, cost and exact way to visualize a prostate with implanted seeds, CT-based dosimetry is in the world-wide use nowadays.
CT scanning has to be determined by each center at a consistent postoperative intervals to check the evaluation of implanted seeds position and this intervals should be reported [1,4,7]. On every digital examination, physicians with physicist should obtain isodoses overlapping the gland at 50%, 80%, 90%, 100%, 150% and 200% of the prescribed dose, and compared with dose-volume-histograms (DVH) on previous CT scans. Nevertheless, ABS recommends for all centers to perform DVH and report the D90 value (dose received by 90% of the target volume) and the V100 (volume received 100% of the prescribed dose). To prevent any serious complication of organs at risk (OaR), the rectal and the urethral doses should be reported and correlated with patient ailments during the interview. In addition to the treatment, post implant radiographs can be performed to verify the seeds location and their number. The dose is usually prescribed at the periphery of the target volume and for 125I, 103Pd - it equals to 145, 125 Gy, respectively. The prescribed dose in the centre of radiated volume should not be higher than 150%, what can be achieve by decreasing the number of seeds from potential “hot-spots” [3]. Oedema of the gland after implantation procedure is the last point worth of mention in this paragraph. Higher volume of prostate causes worse value of therapeutic dose cover. The use of treatment margin value (TM) in treatment planning should help to cover exact volume of the gland. Anyway, the role of treatment margin around the prostate is to cure possible microscopic disease spread outside the capsule. TM in most cases should be equal not less than 3-5 mm as seen in many publications [39]. The V100 indicator is used for assessment of the HDR-BT treatment plan for prostatic carcinoma – it provides a percentage value of the treated volume covered by the isodose of the fractionated dose. The American Brachytherapy Society recommends that the fractionated dose should cover > 90% of the planning target volume (PTV), i.e. V100 > 90%. In the urinary bladder and rectum, the volume which receives 75% of the reference dose should be less than 1 cm3 (V75 of the rectum and V75 of the urinary bladder < 1 cm3). The volume of the urethra covered by 125% of the reference dose should be smaller than 1 cm3 [1]. GEC/ESTRO-EUA-EORTC recommends the median target dose (MTD) in the urethra at a level of less than 120% per fraction, and below 50 Gy of the total dose on the bulb of the penis in combination therapy with EBRT + HDR-BT in order to reduce the risk of impotency [4]. The comparison of temporary and permanent implants
Two brachytherapy treatment modalities (LDR-BT and HDR-BT) can be only compared in monotherapy in patients with low risk tumors. In most cases, LDR-BT is administrated as a monotherapy in early detected prostate cancer. HDR-BT is usually applied along with external beam irradiation to patients with prostate tumors non qualified by strict stage terms. HDR-BT is relatively new as a monotherapy, and at the moment there are limited data about the results and the complication rates in longer follow-up [16,21,38,40]. In some publications HDR as a radiation modality has ability to deposit higher dose to the tumor and lower dose to organs at risk [38]. It produces more inhomogeneous dose distribution in the target (higher V150 and V200 parameters), but due to flexibility of planning, inhomogeneity can be used to keep the dose of organs at risk low while increase the dose on the periphery of the gland. Inhomogeneity is a cost of preserving conformality, and differs in both HDR-BT and LD-BT techniques. Figure 1 presents differential dose volume histograms for 125I, 103Pd and 192Ir from average patient-derived data. We observed heterogeneous and ‘hot’ DVH, particularly for 125I and 103Pd [38] (Fig. 1). Because of impossibility to remove or adjust permanent seeds, there is no way to compensate isodose by computer planning system after implantation. Moreover, it is advisable to use high-dose rate brachytherapy in prostate cancer, suspected of extracapsular spread, in order to achieve better coverage of this area, if compared with gland only targeted seeds therapy, since the seed migration can be significant problem in this case. Apart from the dosimetry, the larger dose per fraction seems to respond better in local control of prostate cancer treatment. According to radiobiological considerations, the use of HDR-BT in these kind of tumors is far more practical. After temporary HDR-BT there are no restrictions about patients radioactivity, and possibility of seeds migration through the bloodstream outside the gland. Oedema’s therapeutic dose coverage trouble does not exist in temporary implantation procedure, because of real time planning and short treatment time.
There are also some positive aspects about using LDR-BT in radiation oncology. Patients with cancers at early stage are able to attend one day procedure in surgery with all cost profits, according to this fact. In United States, single LDR-BT costs much less than EBRT along with HDR-BT. The comparison of time duration in these two modality treatments is another serious plus point of using seeds therapy (one day versus 4-5 weeks). This technique has yet another strong argument - many cancer centers has a lot of experience in performing permanent implants, usually about 5 years longer than modern HDR-BT. Wide availability of this treatment and its frequent performing, give rise to increased number of publishing data with generally good results in treatment of organ confined prostate cancer. Seeds implants therapy, performed by experienced brachytherapist, gives almost the same quality of glands dose coverage as the temporary implants technique. One of the earliest summarized comparison of both brachytherapy techniques was presented at
ASTRO Meeting in Phoenix, 1998 (Table 9).Conclusions
For the radiation treatment of prostate cancer high dose should be delivered for optimal biochemical control. Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy using current dose regimens. At present, the available clinical data with these two techniques suggests that they are equally effective, stage for stage, in providing high tumor control rates. Several hundred of thousands of patients have been treated with LDT-BT, with experience over 15 years and more in major centers in the US and Europe. Results are mature and well established, and mainly related to the risk group of the patient. LDR-BT has been a gold standard for prostate brachytherapy in low risk patients for many years in a lot of countries. It is a convenient technique for a patient. On the other hand HDR-BT is more cost effective with reimbursement in Eastern Europe and results for HDR monotherapy are very promising.
Concluding, brachytherapy is a high, effective method of radiation dose, with higher concentration of the dose within the prostate, which affects the reduction in the risk of complications in OaRs and reduction in the frequency of complications such as impotence (5-15%) and urinary incontinence (< 5%). It is also the most cost-sparing technique of all prostate cancer treatment counting all costs including diagnostic, treatment and social costs after treatment.References
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