Brachytherapy for prostate cancer: Present and future

Based on recent, important publications on the impact of brachytherapy in the management of prostate cancer, we analysed already validated indications and the “under investigations” use of brachytherapy. Published studies (MEDLINE), randomized trials and recommendations were reviewed, as well as Delphi consensus when available. While low-dose rate brachytherapy remains a standard of care for low-risk eligible patients, three randomized trials are now available to consider that combination of external beam radiation therapy with brachytherapy boost (low- or high-dose rate) appears as a recommended treatment for intermediate and high-risk patients. Other indications of prostate brachytherapy (monotherapy and salvage) remain under evaluation. For low-risk patients with good urinary status, low-dose rate brachytherapy alone should be offered. For low-intermediate risk prostate cancer, low-dose rate brachytherapy alone may be offered as monotherapy, while for high-intermediate risk prostate cancer, a combination of external beam radiation therapy (with or without androgen deprivation therapy) plus brachytherapy boost (low- or high-dose rate) should be offered to eligible patients. For patients with high-risk prostate cancer receiving external beam radiation therapy and androgen deprivation therapy, brachytherapy boost (low- or high-dose rate) should be offered to eligible patients. High-dose rate brachytherapy as monotherapy (single dose for low-risk/multifractionated for intermediate and high-risk) must be explored under clinical investigations, as well as salvage brachytherapy for local recurrence.     

Innovations thérapeutiques en radiothérapie du cancer de la prostate localisé

Intensity-modulated radiation therapy, image-guided radiation therapy with fiducial markers and prostate brachytherapy allow the delivery of dose escalation for localized prostate cancer with very low rates of long-term toxicity and sequelae. Nowadays, modern radiotherapy techniques make it possible to shorten treatment time with hypofractionation, to better protect surrounding healthy tissues and to escalate the dose even further. Advances in radiotherapy are closely linked to advances in magnetic resonance imaging (MRI) and/or PET imaging. Functional imaging makes it possible to deliver personalised pelvic nodal radiotherapy, targeting the nodal areas at higher risk of microscopic involvement. In patients with an index lesion at baseline or at failure, MR-based focal therapy or focal dose escalation with brachytherapy or stereotactic body radiation therapy is also currently investigated. MR-based adaptive radiotherapy, which makes it possible to track prostate shifts during radiation delivery, is another step forward in the integration of MR imaging in radiation delivery.     

Radiothérapie robotisée des cancers de prostate par CyberKnife™

After 3D conformal radiation therapy without and with modulated intensity, image-guided radiation therapy represents a new technological step. Should prostate cancer treatment using radiotherapy with the CyberKnife™ robotic system be considered as a new treatment and then investigated through classical clinical research procedure rather than a technical improvement of an already validated treatment? After a general presentation of the CyberKnife™, the authors focused on prostate cancer treatment assuming that, according to dosimetric and biological considerations, the treatment by robotic system appears comparable to high dose rate brachytherapy. For prostate cancer treatment are discussed: biological rational for hypofractionated treatment, high dose rate brachytherapy boost and interest of dose escalation. A comparison is presented between CyberKnife™ and other validated treatment for prostate cancer (radical prostatectomy, 3D conformal radiation therapy and low and high dose rate brachytherapy). In summary, CyberKnife™ treatment could be considered as a technical improvement of an already validated treatment in order to deliver a prostate boost after pelvic or peri-prostatic area irradiation. However, the clinical, biological and economical results must be precisely analyzed and could be assessed in the frame of a National Observatory based on shared therapeutic program.     

Association de radiothérapie externe et de curiethérapie pour les cancers de la prostate

Brachytherapy as sole treatment is standard of care for D’Amico classification low-risk prostate cancer. For intermediate and high-risk patients, brachytherapy can be associated to external beam radiation therapy to better take into account the risk of extracapsular effraction and/or seminal vesicle involvement. Three randomized studies have shown that this association increases freedom from relapse survival compared to exclusive external beam radiation therapy. This benefit is not shown for overall survival. The addition of a hormonal therapy to this association is most likely mandatory for high-risk patients, and needs to be confirmed for intermediate risk patients. Both high-dose rate and low-dose rate brachytherapy are suitable with similar biochemical disease free survival rates. High-dose rate brachytherapy seems to have a better genitourinary tolerance profile, while low-dose rate brachytherapy is an easier process and has a more widespread expertise.     

Present and future in brachytherapy--from the discovery of radium to the 21st century]

Brachytherapy can deliver high doses of radiation to a tumor with only low doses to the normal tissue. Brachytherapy can be classified as intracavitary, intraluminar and interstitial radiotherapy. It can be also divided into three groups according to dose rate: low (LDR), medium (MDR) and high (HDR) dose rates. In recent years, HDR remotely controlled afterloading systems are widespread in Japan. HDR brachytherapy has solved the problem of radiation exposure for medical staff, and patients need not be isolated in highly sealed rooms. Local control rates of T1 and T2 tongue cancer treated with LDR interstitial radiation using 226Ra and 192Ir were 80% and 67%. A phase III trial of HDR versus LDR interstitial brachytherapy for early tongue cancer revealed the same local control rates between the two groups. For uterine cervix cancer, the cause-specific survival rates of patients treated with HDR intracavitary brachytherapy were almost the same as those treated with LDR. HDR brachytherapy can be applied against recurrent tumors. Almost half of recurrent tumors can be controlled with HDR treatment. Brachytherapy is widely used for prostate cancer in the USA. LDR brachytherapy using 125I seeds is used for prostate cancer. In Japan, 125I seeds can not be used because of the regulation of radioisotopes, so we treat prostate cancer patients with HDR brachytherapy. The two-year biochemical NED rate is 83%. Brachytherapy has a long history of nearly 100 years. In recent years, the development of an HDR remotely controlled afterloading system and treatment planning system allows us to make a precise treatment plan and a uniform dose distribution. In the next century, HDR-brachytherapy will continue to play an important role in the field of radiotherapy.     

Management of local relapse after prostate cancer radiotherapy: Surgery or radiotherapy?

Isolated local relapse after prostate cancer radiotherapy corresponds to 40% of biochemical failure. The management of these relapses is not well defined. Several strategies are available including surgery, high-intensity focused ultrasounds (HIFU), cryotherapy and reirradiation. Radical prostatectomy is the historical approach; biochemical control is obtained in 50 to 80% at 5 year. However, morbidity is higher after irradiation than as a first line treatment. Some limited series of HIFU and cryotherapy have been published with interesting results, but again the risk of urinary and rectal toxicity is high. However, new generation technologies could decrease the complication rate. Reirradiation could be performed with brachytherapy and more recently with stereotactic radiation therapy. The results of salvage low-dose-rate brachytherapy have been reported in some series with a 5-year biochemical control rate of 34 to 88%. High-dose rate brachytherapy seems to be better tolerated, but the number of patients treated and reported is too low to draw firm conclusions. This is the same for stereotactic radiation therapy salvage treatment. A prospective trial of salvage brachytherapy (CAPRICUR) is now open in France and inclusion in this trial is recommended.     

Treatment of localized prostate cancer using a combination of high dose rate Iridium‐192 brachytherapy and external beam irradiation: Initial Australian experience

Combination high dose rate brachytherapy (HDRB) and external beam radiation therapy is technically and clinically feasible as definitive treatment for localized prostate cancer. We report the first large Australian experience using this technique of radiation dose escalation in 82 patients with intermediate‐ and high‐risk disease. With a median follow up of 3 years (156 weeks), complications were low and overall prostate‐specific antigen progression‐free survival was 91% using the American Society for Therapeutic Radiology and Oncology consensus definition. The delivery of hypofractionated radiation through the HDRB component shortens overall treatment time and is both biologically and logistically advantageous. As a radiation boost strategy, HDRB is easy to learn and could be introduced into most facilities with brachytherapy capability.     

Salvage brachytherapy as a modern reirradiation technique for local cancer failure: The Phoenix is reborn from its ashes

The treatment of local recurrence of a previously irradiated cancer or a second cancer arising in-field remains challenging. Ultimately, the objective of salvage therapy is to control disease while ensuring minimal collateral damage, thereby optimizing both cancer and toxicity outcomes. Reirradiation has historically been associated with unacceptable toxicity and a limited benefit. Brachytherapy offers the best dose distribution and a high radiation dose to the target volume while better protecting surrounding previously irradiated healthy tissues. The management of local cancer recurrence in irradiated areas should be planned through multidisciplinary discussions and patients should be selected carefully. This overview of the literature describes brachytherapy as a reirradiation treatment in local recurrences of previously irradiated prostate, breast, head and neck and rectal cancers, or second primary cancers occurring in-field. For these cancers, the prognosis and therapeutic challenges are quite different and depend on the type of primary cancer. However, current data confirm that brachytherapy reirradiation is feasible and has acceptable toxicity.     

Place of modern imaging in brachytherapy planning

Imaging has probably been the most important driving force for the development of brachytherapy treatments the last 20 years. Due to implementation of three-dimensional imaging, brachytherapy is nowadays a highly accurate and reliable treatment option for many cancer patients. To be able to optimize the dose distribution in brachytherapy the anatomy and the applicator(s) or sources should be correctly localised in the images. For computed tomography (CT) the later criteria is easily fulfilled for most brachytherapy sites. However, for many sites, like cervix and prostate, CT is not optimal for delineation since soft tissue is not adequately visualized and the tumor is not well discriminated. For cervical cancer treatment planning based on magnetic resonance imaging (MRI) is recommended. Some centres also use MRI for postimplant dosimetry of permanent prostate seed implant and high dose rate prostate brachytherapy. Moreover, in so called focal brachytherapy where only a part of the prostate is treated, multiparametric MRI is an excellent tool that can assist in defining the target volume. Applicator or source localization is challenging using MRI, but tolls exist to assist this process. Also, geometrical distortions should be corrected or accounted for. Transrectal ultrasound is considered to be the gold standard for high dose rate prostate brachytherapy and transrectal ultrasound -based brachytherapy procedure offers a method for interactive treatment planning. Reconstruction of the needles is sometimes challenging, especially to identify the needle tip. The accuracy of the reconstruction could be improved by measuring the residuals needle length and by using a bi-planar transducer. The last decade several groups worldwide have explored the use of transrectal and transabdominal ultrasound for cervical cancer brachytherapy. Since ultrasonography is widely available, offers fast image acquisition and is a rather inexpensive modality such development is interesting. However, more work is needed to establish this as an adequate alternative for all phases of the treatment planning process. Studies using positron emission tomography imaging in combination with brachytherapy treatment planning are limited. However, development of new tracers may offer new treatment approaches for brachytherapy in the future. Combination of several image modalities will be the optimal solution in many situations, either during the same session or for different fractions. When several image modalities are combined so called image registration procedures are used and it is important to understand the principles and limitations of such procedures.     

Curiethérapie de la prostate : évolutions des indications et des techniques

Prostate brachytherapy has been for a long time one of the standard treatments for low risk prostate cancer, with high rates of biochemical control and low levels of urinary and sexual late toxicity compared to other available techniques, namely external beam radiotherapy and radical prostatectomy. The aim of this article is to review the recent innovations of prostate brachytherapy, which suggest a bright future for the technique. We will discuss the extension of indications of permanent implant brachytherapy to favorable intermediate-risk patients, the use of novel isotopes such as Palladium 103 and Cesium 131, and the benefit of brachytherapy as a boost following external beam radiotherapy for intermediate and high-risk patients. We will also discuss the rise of high dose rate brachytherapy, as a boost or monotherapy, the increasing use of MRI for patient selection and treatment planning, as well as the development of brachytherapy as a means of focal therapy.     

The use of magnetic resonance imaging for image-guided brachytherapy

Progress has been made in the delivery of brachytherapy, from low-dose rate (LDR) to high-dose rate (HDR) treatments, allowing for dose optimisation, conformal treatments, improved radiation protection, and improved accuracy and efficiency. Image-guided brachytherapy, incorporating spatial and temporal changes, is now possible with advanced imaging and treatment technology. This report reviews the evidence for the benefits of image-guided brachytherapy using magnetic resonance imaging (MRI), mainly for cervix and prostate cancer, but also possibilities for other tumour sites. It also emphasises the need for a dedicated MRI unit for brachytherapy.     

Advancement of treatment for prostate cancer

The number of prostate cancer patients is rapidly increasing in Japan, as aging people are more common and the lifestyle is more westernized. Another reason is that prostate specific antigen (PSA) is prevalent and PSA test can detect organ-confined prostate cancer in the early stage. In the past, endocrine therapy was the main treatment modality since many prostate cancer patients were diagnosed in the advanced stage. However, endocrine therapy is not suitable for young patients with organ-confined prostate cancer. Surgery and radiation therapy are becoming standard therapy for these patients. Although retropubic radical prostatectomy is widely performed,urinary incontinence and sexual dysfunction are still problems. Other approaches such as laparoscopic prostatectomy, portless endoscopic prostatectomy and perineal prostatectomy are also performed. Radiation therapy is commonly used for organ-confined prostate cancer in Europe and the U.S.A. The advancement in computer technology has made it possible to accumulate enough radiation dose to target without damaging the surrounding organs (3 D conformal, intensity-modulated radiotherapy). Heavy ion particle radiotherapy is also attempted in some institutes. Moreover, brachytherapy can be another choice in radiation therapy. In Japan, only high-dose brachytherapy with (192)Ir has been performed. In July 2003, permanent seed brachytherapy with (121)I was legally approved in Japan, and more organ-confined prostate cancer patients are expected to undergo this treatment. There are several treatment modalities for organ-confined prostate cancer patients these days. Therefore, not only tumor grade and stage, but also patients'lifestyle and thought should be considered in determining treatment.     

High dose rate brachytherapy in the treatment of prostate cancer.

Because the HDR brachytherapy treatments are delivered within minutes and on an outpatient basis, HDR brachytherapy is very well tolerated by patients and offers complete radiation safety. Published studies2, 11, 12, 13, 16, 17, 18, 22, 24, 25 have shown high local clinical and biochemical control rates. Chronic complications have been acceptably low. Very low rates of urinary incontinence and high sexual potency rates have been reported. Gastrointestinal morbidity has been minimal. The development of Ir-192 HDR afterloading brachytherapy and refinements in the dosimetry have ushered in a new era in prostate brachytherapy. The control of the radiation dose and the ability to shape the radiation treatment envelope using a stepping source have allowed a giant step forward in radiation oncology technology. It is now possible to deliver tumoricidal doses of radiation conformally to the prostate while minimizing the dose to the bladder, urethra, and rectum. At present, HDR afterloaded brachytherapy is the optimal whole-organ and tumor-specific conformal radiation therapy for prostate cancer.     

Role of high dose rate brachytherapy in the treatment of prostate cancer

High dose rate (HDR) brachytherapy in intermediate and high-risk prostate cancer patients has started in the late eighties in Europe and the United States, as a boost combined with external beam radiation therapy, as an attractive method for dose escalation. The results of the first dose-escalation study performed at William Beaumont Hospital has established the safety and efficacy of this combined treatment approach. Likewise, this landmark study enabled a paradigm shift in the radiobiology of prostate cancer, demonstrating that the alpha/beta of prostate cancer was much lower than previously believed to be and therefore the sensitivity of this tumor model to higher-than-conventional doses per fraction led to a dramatic increase of hypofractionated treatment regimens, the object of significant clinical research efforts, currently under way. The excellent toxicity profile and clinical outcome of HDR boost combined treatment prompted investigators to expand HDR brachytherapy indications to low/intermediate prostate cancer patients as the sole treatment modality. The results, toxicity and a brief review of the literature for both HDR boost and HDR monotherapy will be presented.     

高剂量率近距离治疗前列腺癌进展北大核心CSCD

近距离放射治疗在局限期前列腺癌治疗中发挥重要作用。高剂量率近距离放疗经过几十年发展,作为单纯治疗或结合外照射增量治疗,与其他治疗相比,具有众多优势:精确提升靶区剂量,降低危及器官受量等。前列腺癌α/β值较小,单次高剂量HDR会诱导肿瘤基因的转录,提高放射敏感性。本文从HDR近距离放疗发展历史、患者选择、技术应用、疗效及不良反应等方面展开综述。     

Fractionation and protraction for radiotherapy of prostate carcinoma

Purpose: To investigate whether current fractionation and brachytherapy protraction schemes for the treatment of prostatic cancer with radiation are optimal, or could be improved.

Methods and Materials: We analyzed two mature data sets on radiotherapeutic tumor control for prostate cancer, one using EBRT and the other permanent seed implants, to extract the sensitivity to changes in fractionation of prostatic tumors. The standard linear-quadratic model was used for the analysis.

Results: Prostatic cancers appear significantly more sensitive to changes in fractionation than most other cancers. The estimated /β value is 1.5 Gy [0.8, 2.2]. This result is not too surprising as there is a documented relationship between cellular proliferative status and sensitivity to changes in fractionation, and prostatic tumors contain exceptionally low proportions of proliferating cells.

Conclusions: High dose rate (HDR) brachytherapy would be a highly appropriate modality for treating prostate cancer. Appropriately designed HDR brachytherapy regimens would be expected to be as efficacious as low dose rate, but with added advantages of logistic convenience and more reliable dose distributions. Similarly, external beam treatments for prostate cancer can be designed using larger doses per fraction; appropriately designed hypofractionation schemes would be expected to maintain current levels of tumor control and late sequelae, but with reduced acute morbidity, together with the logistic and financial advantages of fewer numbers of fractions.     

Salvage reirradiation for locoregional failure after radiation therapy for prostate cancer: Who,when, where and how?

Even in the current era of dose-escalated radiotherapy for prostate cancer, biochemical recurrence is not uncommon. Furthermore, biochemical failure is not specific to the site of recurrence. One of the major challenges in the management of prostate cancer patients with biochemical failure after radiotherapy is the early discrimination between those with locoregional recurrence only and those with metastatic disease. While the latter are generally considered incurable, patients with locoregional disease may benefit from emerging treatment options. Ultimately, the objective of salvage therapy is to control disease while ensuring minimal collateral damage, thereby optimizing both cancer and toxicity outcomes. Advances in functional imaging, including multiparametric prostate MRI, abdominopelvic lymphangio-MRI, sentinel node SPECT-CT and/or whole-body PET/CT have paved the way for salvage radiotherapy in patients with local recurrence, microscopic nodal disease limited to the pelvis or oligometastatic disease. These patients may be considered for salvage reirradiation using different techniques: prostate low-dose or high-dose rate brachytherapy, pelvic and/or lomboaortic image-guided radiotherapy with elective nodal irradiation, focal nodal or bone stereotactic body radiation therapy (SBRT). An individualized approach is recommended. The decision about which treatment, if any, to use will be based on the initial characteristics of the disease, relapse patterns and the natural history of the rising prostate specific antigen (PSA). Preliminary results suggest that more than 50% of patients who have undergone salvage reirradiation are biochemically relapse-free with very low rates of severe toxicity. Large prospective studies with a longer follow-up are needed to confirm the promising benefit/risk ratio observed with salvage brachytherapy and or salvage nodal radiotherapy and/or bone oligometastatic SBRT when compared with life-long palliative hormones.     

L’évolution de la curiethérapie du cancer de prostate

Curietherapy, more commonly named brachytherapy, is one of the oldest irradiation techniques used for prostate cancer. Prostate brachytherapy evolved according to the scientific and technological progress. After a historical reminder of the evolution of prostate brachytherapy, different technical aspects are discussed: low-dose rate brachytherapy using permanent or temporary implants, high-dose rate brachytherapy as well as new imaging modalities. Prostate brachytherapy indications are listed regarding to the evidence-based medicine data for low, intermediate and high risks prostate cancers. Potential indications and new research programs (focal therapy, high-dose rate, single-dose brachytherapy) are also presented.     

How to select the treatment options in prostate cancer

Radiation therapy (RT) for prostate cancer has been developing dramatically during the past 10 years in Japan as well as in USA. There are several ways to treat prostate cancer by RT. As for external-beam RT (EBRT), a more sophisticated technique beyond 3-dimensional conformal RT called intensity modulated RT was developed and has been in use in many Japanese RT centers. It can raise the total radiation dose and is expected to increase the biochemical control rate. As for brachytherapy, a low-dose-rate seed implant using iodine-125 was initiated in 2003 and has become widespread throughout Japan in only a few years. High-dose-rate brachytherapy using iridium-19 2 has also been used in more advanced cases combined with EBRT. Brachytherapy offers an ideal RT dose concentration and can avoid rectal complications. As for particle therapy, we have carbon and proton in several institutions in Japan. Particles have the merit of good dose distributions and for carbons, relative biological effectiveness. Furthermore, some centers are considering the stereotactic hypofractionated RT due to the relatively low alfa-beta ratio of prostate cancer. Recent reports showed that after a certain period of followup, the biochemical control rate was similar either with external beam high-quality RT, brachytherapy, heavy ion RT and surgery. Therefore, the choice of treatment should depend on the adverse effects, quality of life, medical costs, and the lifestyle of the patient. The merits and demerits of each treatment modality were discussed. Longer follow-up is still necessary and informed consent is mandatory when choosing a treatment modality.