Technological advances in external-beam radiation therapy for the treatment of localized prostate cancer

The relative inability of conventional radiotherapy to control localized prostate cancer results from resistance of subpopulations of tumor clonogens to dose levels of 65 to 70 Gy, the maximum feasible with traditional two-dimensional (2D) treatment planning and delivery techniques. Several technological advances have enhanced the precision and improved the outcome of external-beam radiotherapy. The three-dimensional conformal radiotherapy (3D-CRT) approach has permitted significant increases in the tumor dose to levels beyond those feasible with conventional techniques. Intensity-modulated radiotherapy (IMRT), an advanced form of conformal radiotherapy, has resulted in reduced rectal toxicity, permitting tumor dose escalation to previously unattainable levels with a concomitant improvement in local tumor control and disease-free survival. The combination of androgen deprivation and conventional-dose radiotherapy, tested mainly in patients with locally advanced disease, has also produced significant outcome improvements. Whether androgen deprivation will preclude the need for dose escalation or whether high-dose radiotherapy will obviate the need for androgen deprivation remains unknown. In some patients, both approaches may be necessary to maximize the probability of cure. In view of the favorable benefit-risk ratio of high-dose IMRT, the design of clinical trials to resolve these critical questions is essential.     

Radiation dose escalation for localized prostate cancer

BACKGROUND:

In the current study, the effects of dose escalation for localized prostate cancer treatment with intensity‐modulated radiotherapy (IMRT) or permanent transperineal brachytherapy (BRT) in comparison with conventional dose 3‐dimensional conformal radiotherapy (3D‐CRT) were evaluated.

METHODS:

This study included 853 patients; 270 received conventional dose 3D‐CRT, 314 received high‐dose IMRT, 225 received BRT, and 44 received external beam radiotherapy (EBRT) + BRT boost. The median radiation doses were 68.4 grays (Gy) for 3D‐CRT and 75.6 Gy for IMRT. BRT patients received a prescribed dose of 144 Gy with iodine‐125 (I‐125) or 120 Gy with palladium‐103 (Pd‐103), respectively. Patients treated with EBRT + BRT received 45 Gy of EBRT plus a boost of 110 Gy with I‐125 or 90 Gy with Pd‐103. Risk group categories were low risk (T1‐T2 disease, prostate‐specific antigen level ≤10 ng/mL, and a Gleason score ≤6), intermediate risk (increase in value of 1 of the factors), and high risk (increase in value of ≥2 factors).

RESULTS:

With a median follow‐up of 58 months, the 5‐year biochemical control (bNED) rates were 74% for 3D‐CRT, 87% for IMRT, 94% for BRT, and 94% for EBRT + BRT (P <.0001). For the intermediate‐risk group, high‐dose IMRT, BRT, or EBRT + BRT achieved significantly better bNED rates than 3D‐CRT (P <.0001), whereas no improvement was noted for the low‐risk group (P = .22). There was no increase in gastrointestinal (GI) toxicity from high‐dose IMRT compared with conventional dose 3D‐CRT, although there was more grade 2 genitourinary (GU) toxicity (toxicities were graded at the time of each follow‐up visit using a modified Radiation Therapy Oncology Group [RTOG] scale). BRT caused more GU but less GI toxicity, whereas EBRT + BRT caused more late GU and GI toxicity than IMRT or 3D‐CRT.

CONCLUSIONS:

The data from the current study indicate that radiation dose escalation improved the bNED rate for the intermediate‐risk group. IMRT caused less acute and late GU toxicity than BRT or EBRT + BRT. Cancer 2009. © 2009 American Cancer Society.     

The role of high-dose rate brachytherapy in locally advanced prostate cancer

Although the optimal management of patients with locally advanced prostate cancer remains undefined, sufficient clinical data have emerged showing that patients treated with radiation therapy (RT) have a significantly better outcome as the dose to the gland is escalated. What remains unresolved, however, is how to best deliver these higher tumoricidal doses of RT. Conformal high-dose rate brachytherapy (C-HDR BT) is an alternative means of precise dose escalation that offers similar tumoricidal effects as 3-dimensional (3D) conformal external beam radiotherapy (EBRT) with potential additional advantages. By placing HDR afterloading needles directly into the prostate gland under real-time ultrasound guidance, a steep dose gradient between the prostate and adjacent normal tissues can be generated that is unaffected by organ motion and edema or treatment setup uncertainties. The ability to control the amount of time the single radioactive source dwells at each position along the length of each brachytherapy catheter further enhances the conformity of the dose. In addition, recent radiobiologic data on prostate cancer treatment suggest that the alpha/beta ratio for tumor control is similar to (or possibly even smaller) than that for surrounding late-responding normal tissues. If true, hypofractionation (as practiced with C-HDR BT combined with EBRT) would be expected to produce tumor control and late sequelae that are at least as good as achieved with conventional fractionation, with the additional possibility that early sequelae might be reduced. Recent data from several groups performing C-HDR BT in patients with locally advanced disease have confirmed these assumptions. Combined with the physical advantages discussed earlier, C-HDR BT as a means of dose escalation should provide similar tumor control as 3D conformal EBRT with the added advantages of reduced treatment times, less acute toxicity, and no additional technological requirements to account and correct for treatment setup uncertainties and organ motion. The issues that remain unresolved with this technique (as with other methods of dose escalation) revolve around the amount of additional dose required to provide optimal tumor control, the role of androgen deprivation in the management of patients with locally advanced disease, and whether the regional lymphatics should be irradiated.     

Intensity-modulated Radiotherapy in the Treatment of Prostate Cancer

Three-dimensional conformal radiotherapy (3DCRT) as the primary treatment for prostate cancer has improved outcomes compared with conventional radiotherapy, but with an associated increase in toxicity due to radiation effects on the bladder and rectum. Intensity-modulated radiotherapy (IMRT) is a newer method of radiotherapy that uses intensity-modulated beams that can provide multiple intensity levels for any single beam direction and any single source position allowing concave dose distributions and dose gradients with narrower margins than those possible using conventional methods. IMRT is ideal for treating complex treatment volumes and avoiding close proximity organs at risk that may be dose limiting and provides increased tumour control through an escalated dose and reduces normal tissue complications through organ at risk sparing. Given the potential advantages of IMRT and the availability of IMRT-enabled treatment planning systems and linear accelerators, IMRT has been introduced in a number of disease sites, including prostate cancer. This systematic review examined the evidence for IMRT in the treatment of prostate cancer in order to quantify the potential benefits of this new technology and to make recommendations for radiation treatment programmes considering adopting this technique. The findings were in favour of recommending IMRT over 3DCRT in the radical treatment of localised prostate cancer where doses greater than 70 Gy are required, based on a review of 11 published reports including 4559 patients. There were insufficient data to recommend IMRT over 3DCRT in the postoperative setting. Future research should examine image-guided IMRT in the post-prostatectomy setting, with altered fractionation, and in combination with hormone and chemotherapy.     

3D conformal HDR brachytherapy and external beam irradiation combined with temporary androgen deprivation in the treatment of localized prostate cancer.

PURPOSE: To evaluate treatment outcome of 3D conformal high dose rate (HDR) brachytherapy and external beam irradiation (EBRT) combined with temporary androgen deprivation for patients with localized prostate cancer. PATIENTS AND METHODS: Between January 1997 and September 1999 we treated 102 patients with stage T1-3 N0 M0 prostate cancer. Stage T1-2 was found in 71, T3 in 31 patients. Median pretreatment PSA level was 15.3 ng/ml. After ultrasound-guided transrectal implantation of four afterloading needles, CT based 3D brachytherapy planning was performed. All patients received four HDR implants using a reference dose per implant of 5 or 7Gy. Time between each implant was 14 days. After brachytherapy EBRT followed up to 39.6 or 45.0 Gy. All patients received temporary androgen deprivation, starting 2-19 months before brachytherapy, ending 3 months after EBRT. RESULTS: Median follow-up was 2.6 years (range 2.0-4.1 years). Actuarial biochemical control rate was 87% at 2 years and 82% at 3 years. In 14 patients we noted biochemical failure, in five patients clinical failure. Overall survival was 90%, disease specific survival 98.0% at 3 years. Acute grade 3 toxicity occurred in 4%, late grade 3 toxicity in 5%. One patient developed a prostatourethral-rectal fistula as late grade 4 toxicity. The conformal quality of 300 HDR implants was analyzed using dose volume histograms. CONCLUSIONS: 3D conformal HDR brachytherapy and EBRT combined with temporary androgen deprivation is an effective treatment modality for prostate cancer with minimal associated toxicity and encouraging biochemical control rates after a median follow-up of 2.6 years.     

Adjuvant androgen deprivation impacts late rectal toxicity after conformal radiotherapy of prostate carcinoma

To evaluate whether androgen deprivation impacts late rectal toxicity in patients with localised prostate carcinoma treated with three-dimensional conformal radiotherapy. One hundred and eighty-two consecutive patients treated with 3DCRT between 1995 and 1999 at our Institution and with at least 12 months follow-up were analysed. three-dimensional conformal radiotherapy consisted in 70-76 Gy delivered with a conformal 3-field arrangement to the prostate+/-seminal vesicles. As part of treatment, 117 patients (64%) received neo-adjuvant and concomitant androgen deprivation while 88 (48.4%) patients were continued on androgen deprivation at the end of three-dimensional conformal radiotherapy as well. Late rectal toxicity was graded according to the RTOG morbidity scoring scale. Median follow up is 25.8 (range: 12-70.2 months). The 2-year actuarial likelihood of grade 2-4 rectal toxicity was 21.8+/-3.2%. A multivariate analysis identified the use of adjuvant androgen deprivation (P=0.0196) along with the dose to the posterior wall of the rectum on the central axis (P=0.0055) and the grade of acute rectal toxicity (P=0.0172) as independent predictors of grade 2-4 late rectal toxicity. The 2-year estimates of grade 2-4 late rectal toxicity for patients receiving or not adjuvant hormonal treatment were 30.3+/-5.2% and 14.1+/-3.8%, respectively. Rectal tolerance is reduced in presence of adjuvant androgen deprivation.     

Optimal treatment of intermediate-risk prostate carcinoma with radiotherapy: clinical and translational issues

The clinical heterogeneity of intermediate-risk prostate carcinoma presents a challenge to urologic oncology in terms of prognosis and management. There is controversy regarding whether patients with intermediate-risk prostate carcinoma should be treated with dose-escalated external beam radiotherapy (EBRT) (e.g., doses > 74 gray [Gy]), or conventional-dose EBRT (e.g., doses < 74 Gy) combined with androgen deprivation (AD). Data for this review were identified through searches for articles in MEDLINE and in conference proceedings, indexed from 1966 to 2004. Currently, the intermediate-risk prostate carcinoma grouping is defined on the basis of prostate-specific antigen (PSA), tumor classification (T classification), and Gleason score. Emerging evidence suggests that additional prognostic information may be derived from the percentage of positive core needle biopsies at the time of diagnosis and/or from the pretreatment PSA doubling time. Novel prognostic biomarkers include protein expression relating to cell cycle control, cell death, DNA repair, and intracellular signal transduction. Preclinical data support dose escalation or combined AD with radiation as a means to increase prostate carcinoma cell kill. There is Level I evidence that patients with intermediate-risk prostate carcinoma benefit from dose-escalated EBRT or AD plus conventional-dose EBRT. However, clinical evidence is lacking to support the uniform use of AD plus dose-escalated EBRT. Patients in the intermediate-risk group should be entered into well designed, randomized clinical trials of dose-escalated EBRT and AD with sufficient power to address biochemical failure and cause-specific survival endpoints. These studies should be stratified by novel prognostic markers and accompanied by strong translational endpoints to address clinical heterogeneity and to allow for individualized treatment.     

Apports de la radiothérapie avec modulation d’intensité guidée par l’image dans les cancers prostatiques

External beam radiotherapy (RT) is used to treat all stages of localized prostate cancer. Using a 3D conformal RT (3DCRT) without any androgen deprivation, a clear dose–effect relationship has been shown in terms of both biochemical control and also unfortunately of rectal and urinary toxicity. Compared to a “standard” 3DCRT, intensity modulated RT (IMRT) improves the dose distribution by mainly providing concave dose distribution and tight dose gradients. Based on large clinical experiences for at least one decade, IMRT is widely used to increase the dose in the prostate and therefore local control, without increasing toxicity. Indeed, toxicity rates observed after high dose delivered in the prostate (80 Gy) with IMRT appear no different than those observed after a standard dose (70 Gy) delivered by a standard 3DCRT. Arc IMRT appears a new promising IMRT modality, decreasing dramatically treatment duration. However, this IMRT-based dosimetric benefit may not be translated into a full clinical benefit, if intra-pelvic prostate motion is not taken in account. Image-guided radiotherapy (IGRT) should be therefore associated with IMRT for a maximal clinical benefit. This article is a literature review showing the interest of both combined approaches.     

Optimal radiotherapy for prostate cancer: predictions for conventional external beam, IMRT, and brachytherapy from radiobiologic models

PURPOSE: To determine, on the basis of radiobiological models, optimal modalities of radiotherapy for localized prostate cancer, and to provide a rational basis for therapeutic decisions. METHODS AND MATERIALS: An algorithm based on extensions to the linear-quadratic (LQ) cell survival model is constructed for fractionated and protracted irradiation. These radiobiological models include prostate tumor cell line-derived LQ parameters, clonogen repopulation, repair of sublethal damage, hypoxia, and radioisotope decay. In addition, dose inhomogeneities for both IMRT and brachytherapy (125I and 103Pd) from patient-derived Dose Volume Histograms (DVH), as well as dose escalation, are incorporated. Three risk groups are defined in terms of sets of biologic parameters tailored to correspond to clinical risk groups as follows: Favorable-iPSA <10 and bGS < or =6 and stage T2; Intermediate-one parameter increased; and Unfavorable-two or more parameters increased. Tumor control probabilities (TCP) are predicted for conventional external beam radiotherapy (EBRT, including 3D-CRT), intensity modulated radiotherapy (IMRT), and permanent brachytherapy. RESULTS: Brachytherapy is less susceptible to variations in alpha/beta than EBRT and more susceptible to variations in clonogen potential doubling time (Tp). Our models predict TCP consistent with the bNED results from recent dose escalation trials and long-term outcomes from brachytherapy. TCP from IMRT are systematically superior to those from conventional fractionated RT, and suggests its possible use in dose escalation without additional dose to surrounding normal tissues. For potentially rapidly dividing tumors (Tp < 30 days) 103Pd yields superior cell kill compared with 125I, but for very slowly proliferating tumors the converse is suggested. Brachytherapy predicts equivalent or superior TCP to dose escalated EBRT. For unfavorable risk tumors, combined 45 Gy EBRT+brachytherapy boost predicts superior TCP than with either modality alone. CONCLUSIONS: The radiobiological models presented suggest a rational basis for choosing among several radiotherapeutic modalities based on biologic risk factors. In addition, they suggest that IMRT may potentially be superior to 3D-CRT in allowing dose escalation without increased morbidity, and that brachytherapy, as monotherapy or as boost, may achieve superior tumor control compared with dose escalation 3D-CRT. The latter conclusion is supported by clinical data.     

A Randomized Phase II Trial of Prostate Boost Irradiation With Stereotactic Body Radiotherapy (SBRT) or Conventional Fractionation (CF) External Beam Radiotherapy (EBRT) in Locally Advanced Prostate Cancer: The PBS Trial (NCT03380806)

Standard therapy for high-risk (HR) prostate cancer (PrCa) involves androgen deprivation therapy (ADT) and pelvic conventional fractionation (CF) external beam radiotherapy (EBRT) followed by boost CF-EBRT treatment to prostate for a total of 78 to 80 Gy in 39 to 40 fractions. This is a long and inconvenient treatment for patients. Brachytherapy boost treatment studies indicate that escalation of biological dose of radiotherapy (RT) can improve outcomes in HR-PrCa. However, brachytherapy is an invasive treatment associated with increased toxicity and requires specialized resources. Stereotactic body radiotherapy (SBRT) is a promising, non-invasive alternative to brachytherapy. However, its impact on patient quality of life (QoL) and RT-associated toxicity has not been investigated in a randomized setting. In this study, we investigate SBRT as a boost treatment, following pelvic CF-EBRT, in patients with HR-PrCa treated with ADT. One hundred patients with locally advanced PrCa will be randomized to receive daily CF-EBRT of 45 to 46 Gy in 23 to 25 fractions followed by either daily CF-EBRT of 32 to 33 Gy in 15 to 16 fractions (control arm) or SBRT boost treatment of 19.5 to 21 Gy in 3 fractions (1 fraction per week) (experimental arm). The primary objective of the PBS trial is early bowel and urinary QoL (expanded prostate index composite [EPIC], up to 6 months after RT). This phase II randomized study (PBS) provides an appropriate setting to investigate effectively the impact of SBRT boost on QoL and toxicity in patients with HR-PrCa, before this modality can be compared against the current standard of care in larger phase III protocols.     

Comparison of dose contribution to normal pelvic tissues among conventional, conformal and intensity-modulated radiotherapy techniques in prostate cancer

High-energy external radiotherapy has become one of the most common treatment in localized prostate cancer. We compared the difference of dose distribution, mainly at the 5-30 Gy dose level, in the irradiated pelvic volume among three modalities of radiotherapy for patients with prostate cancer: conventional, conformal and intensity-modulated radiotherapy (IMRT). We selected six patients with prostate cancer treated by conformal radiotherapy at the doses of 46 Gy to PTVN (prostate and seminal vesicles), and 70 Gy to PTV-T (prostate). The conventional technique": an 8-field arrangement was used; the conformal technique 4 fields with a boost through 6 fields. For IMRT, a five-beam arrangement was used. Dose-volume histograms (DVH) were analyzed and compared among the three techniques. The IMRT technique significantly increased the pelvic volume covered by the isodose surfaces below 15 Gy as compared with the conventional and conformal techniques. The mean absolute increase for the pelvic volume included between 5-30 Gy for the IMRT technique, was about 2 900 ml as compared with the conventional technique. However, IMRT significantly reduced the irradiated volume of the rectum in the dose range of 5 to 40 Gy, also significantly reduced the irradiated volume of bladder and femoral heads, and obtained a similar or improved isodose distribution in the PTVs. In addition, the use of IMRT slightly increased the relative dose delivered to the body volume outside the pelvis, as estimated by the use of specific software. A long-term follow-up will be needed to evaluate potential late treatment complications related to the use of IMRT and the low or moderate irradiation dose level obtained in the pelvis and in the whole body.     

Intensity-modulated radiotherapy in nasopharyngeal carcinoma: dosimetric advantage over conventional plans and feasibility of dose escalation

PURPOSE: To compare intensity-modulated radiotherapy (IMRT) with two-dimensional RT (2D-RT) and three-dimensional conformal radiotherapy (3D-CRT) treatment plans in different stages of nasopharyngeal carcinoma and to explore the feasibility of dose escalation in locally advanced disease. MATERIALS AND METHODS: Three patients with different stages (T1N0M0, T2bN2M0 with retrostyloid extension, and T4N2M0) were selected, and 2D-RT, 3D-CRT, and IMRT treatment plans (66 Gy) were made for each of them and compared with respect to target coverage, normal tissue sparing, and tumor control probability/normal tissue complication probability values. In the Stage T2b and T4 patients, the IMRT 66-Gy plan was combined with a 3D-CRT 14-Gy boost plan using a 3-mm micromultileaf collimator, and the dose-volume histograms of the summed plans were compared with their corresponding 66-Gy 2D-RT plans. RESULTS: In the dosimetric comparison of 2D-RT, 3D-CRT, and IMRT treatment plans, the T1N0M0 patient had better sparing of the parotid glands and temporomandibular joints with IMRT (dose to 50% parotid volume, 57 Gy, 50 Gy, and 31 Gy, respectively). In the T2bN2M0 patient, the dose to 95% volume of the planning target volume improved from 57.5 Gy in 2D-RT to 64.8 Gy in 3D-CRT and 68 Gy in IMRT. In the T4N2M0 patient, improvement in both target coverage and brainstem/temporal lobe sparing was seen with IMRT planning. In the dose-escalation study for locally advanced disease, IMRT 66 Gy plus 14 Gy 3D-CRT boost achieved an improvement in the therapeutic ratio by delivering a higher dose to the target while keeping the normal organs below the maximal tolerance dose. CONCLUSIONS: IMRT is useful in treating all stages of nonmetastatic nasopharyngeal carcinoma because of its dosimetric advantages. In early-stage disease, it provides better parotid gland sparing. In locally advanced disease, IMRT offers better tumor coverage and normal organ sparing and allows room for dose escalation.     

Prospective evaluation of urinary and intestinal side effects after BeamCath stereotactic dose-escalated radiotherapy of prostate cancer.

BACKGROUND: New data suggest that a higher radiation dose will improve outcome in treatment of localized prostate cancer. External beam radiotherapy (EBRT) may on the other hand induce disturbances in the patient's urinary and intestinal function. Since 1997, 195 patients have been treated with a stereotactic boost of 4-8 Gy added to conventional 70 Gy EBRT. Late side effects were prospectively evaluated 3 years after dose-escalated EBRT. METHODS: Urinary and intestinal problems were prospectively evaluated with a validated self-assessment questionnaire, the Prostate Cancer Symptom Scale (PCSS). Two hundred and eighty-seven patients completed the questionnaire at the 1 year follow-up, and 153 at 3 years after treatment. Pre-treatment mean age was 66 years. One hundred and sixty-eight patients were treated with the conformal technique and 195 were treated with the dose-escalated stereotactic BeamCath technique. Mean total dose in the conformal group (< or =70 Gy) was 66 Gy (60.8-70.4 Gy). The dose-escalated group consists of three dose levels, 74 Gy (n = 68), 76 Gy (n = 74), and 78 Gy (n = 53). RESULTS: Analyzing the whole population 3 years after treatment, urgency and starting problems decreased in comparison to pre-treatment. A minor increase in urinary incontinence was reported 3 years after treatment in comparison to pre-treatment. No increases in other urinary symptoms were reported. Intestinal symptoms were slightly increased during the follow-up period in comparison to pre-treatment. Dose escalation with stereotactic EBRT (74-78 Gy) did not increase gastrointestinal or genitourinary late side effects at 1 year or 3 years in comparison to doses < or =70 Gy. CONCLUSIONS: The stereotactic BeamCath EBRT technique facilitates safe dose escalation of patients with prostate cancer.     

The impact of dose escalation on secondary cancer risk after radiotherapy of prostate cancer

PURPOSE: To estimate secondary cancer risk due to dose escalation in patients treated for prostatic carcinoma with three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated RT (IMRT), and spot-scanned proton RT. METHODS AND MATERIALS: The organ equivalent dose (OED) concept with a linear-exponential, a plateau, and a linear dose-response curve was applied to dose distributions of 23 patients who received RT of prostate cancer. Conformal RT was used in 7 patients, 8 patients received IMRT with 6- and 15-MV photons, and 8 patients were treated with spot-scanned protons. We applied target doses ranging from 70 Gy to 100 Gy. Cancer risk was estimated as a function of target dose and tumor control probability. RESULTS: At a 100-Gy target dose the secondary cancer risk relative to the 3D treatment plan at 70 Gy was +18.4% (15.0% for a plateau model, 22.3% for a linear model) for the 6-MV IMRT plan, +25.3% (17.0%, 14.1%) for the 15-MV IMRT plan, and -40.7% (-41.3%, -40.0%) for the spot-scanned protons. The increasing risk of developing a radiation-associated malignancy after RT with increasing dose was balanced by the enhanced cure rates at a larger dose. CONCLUSIONS: Cancer risk after dose escalation for prostate RT is expected to be equal to or lower than for conventional 3D treatment at 70 Gy, independent of treatment modality or dose-response model. Spot-scanned protons are the treatment of choice for dose escalation because this therapy can halve the risk of secondary cancers.     

Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime

PURPOSE: High-dose radiotherapy, delivered in an accelerated hypofractionated course, was utilized to treat prostate cancer. Therapy consisted of external beam radiotherapy (EBRT) and transrectal ultrasound (TRUS)-guided conformally modulated high-dose rate (HDR) brachytherapy. The purpose of this report is (1) to assess long-term comparative outcomes from three trials using similar accelerated hypofractionated regimes; and (2) to examine the long-term survival impact of a short course of < or =6 months adjuvant/concurrent androgen deprivation when a very high radiation dose was delivered. METHODS AND MATERIALS: Between 1986 and 2000, 1,260 patients were treated at three institutions with pelvic EBRT (36-50 Gy) integrated with HDR prostate brachytherapy. The total dose including brachytherapy was given over 5 weeks. The biologic equivalent EBRT dose ranged between 90 and 123 Gy (median, 102 Gy) using an alpha /beta of 1.2. Patient eligibility criteria included a pretreatment prostate-specific antigen > or =10, Gleason score > or =7, or clinical stage > or =T2b. A total of 1,260 patients were treated, and 934 meet the criteria. Kiel University Hospital treated 198 patients; William Beaumont Hospital, 315; and California Endocurietherapy Cancer Center, 459 patients. Brachytherapy dose regimes were somewhat different between centers and the dose was escalated from 5.5 x 3 to 15 Gy x 2 Gy. Patients were divided for analysis between the 406 who received up to 6 months of androgen deprivation therapy and the 528 patients who did not. All patients had a minimum follow-up of 18 months (3 times the exposure to androgen deprivation therapy). The American Society for Therapeutic Radiology and Oncology biochemical failure definition was used. RESULTS: Mean age was 69 years. Median follow-up time was 4.4 years (range, 1.5-14.5); 4 years for androgen deprivation therapy patients and 4.9 for radiation alone. There was no difference at 5 and 8 years in overall survival, cause-specific survival, or biochemical control among the three institutions. The corresponding 8-year rates with and without androgen deprivation therapy were biochemical control 85% and 81%; overall survival 83% and 78%; cause-specific survival 89% and 94%; and metastatic rates of 16.6% and 7.3%. A multivariate analysis revealed androgen deprivation therapy did not predict for biochemical failure for either the entire group or the subset of 177 patients harboring all three poor prognostic factors. Moreover, adding androgen deprivation therapy strongly correlated with higher rates of both metastasis (p = 0.09; hazard ratio, 2.08) and cancer-related deaths (p = 0.02, hazard ratio 3.25). These negative results for the most unfavorable group led us to question if androgen deprivation therapy might have a deleterious impact through delay in delivery of the potentially curative radiation or whether there may be a biologic basis by fixing the cycling cells in G0. CONCLUSIONS: Accelerated hypofractionated pelvic EBRT integrated with TRUS-guided conformally modulated HDR administered to 1,260 patients in three institutions was an excellent method of delivering very high radiation dose to the prostate in 5 weeks. Similar high overall, cause-specific, and biochemical no evidence of disease survival rates achieved show that prostate HDR can be successfully delivered in academic and community settings. At 8 years, the addition of a course of < or =6 months of neoadjuvant/concurrent androgen deprivation therapy to a very high radiation dose did not confer a therapeutic advantage but added side effects and cost. Furthermore, for the most unfavorable group, there was a higher rate of distant metastasis and more prostate cancer-related deaths. We question the value of a short course of androgen deprivation therapy when used with high-dose radiation.     

Brachytherapy: Current Status and Future Strategies — Can High Dose Rate Replace Low Dose Rate and External Beam Radiotherapy?

Brachytherapy delivers the most conformal high dose radiotherapy possible to the prostate, using either a low dose rate (LDR) or high dose rate (HDR) technique. It may be used either alone as monotherapy or in combination with external beam radiotherapy (EBRT) as a local boost. Comparative efficacy studies, including one randomised controlled trial, consistently show higher cancer control rates when brachytherapy is used compared with EBRT alone, with even some evidence of improvement in survival. There are now extensive mature data supporting the use of LDR as monotherapy for patients with low-risk and selected intermediate-risk disease, with most series reporting long-term disease control rates of over 90% after high-quality implants. HDR is most commonly combined with EBRT to treat intermediate- and high-risk disease, with disease control rates of over 90% reported. The low alpha/beta ratio of prostate cancer combined and the ability to optimally sculpt dose distribution provides the biological and dosimetric rationale for HDR. HDR enables more consistent implant quality than LDR, with evidence of lower acute and late toxicity. Many dose and fractionation schedules of HDR in combination with EBRT have been investigated, but a single fraction of 10–15 Gy is commonly combined with EBRT to a dose of 40–50 Gy to treat intermediate- and high-risk disease. High disease control rates are also reported with HDR as monotherapy, particularly in patients with low- and intermediate-risk disease. Although older series have delivered four to six fractions of HDR, there is growing evidence to support the delivery of HDR in three or even two fractions. Single-fraction HDR monotherapy is now being investigated and if early data are confirmed with longer follow-up, may well become the treatment of choice for many men with localised prostate cancer.     

Robotic Stereotactic Retreatment for Biochemical Control in Previously Irradiated Patients Affected by Recurrent Prostate Cancer

AimsRobotic stereotactic body radiotherapy (rSBRT) to local recurrences emerged as a valuable option for exclusive local failure after prior external beam radiation therapy (EBRT) for localised prostate cancer. The aim of this study was to assess the efficacy and safety of rSBRT in patients experiencing locally recurrent prostate cancer after prior definitive or postoperative radiotherapy using the Cyberknife.Materials and methodsData from 50 patients were retrospectively reviewed. Local recurrence was assessed by 18F-choline positron emission tomography and pelvic magnetic resonance imaging; a dose of 30 Gy was delivered in five fractions. Prostate-specific antigen (PSA) was assessed at 2 months, 6 months and every 4 months thereafter. Toxicity was assessed according to CTCAE v.4.03.ResultsAll patients received prior EBRT. The median EQD2 total dose was 74 Gy (60–80 Gy). Eleven patients were receiving androgen deprivation after prior biochemical failure. At 6 months, 41 patients showed a median PSA decline of –77.1% (14.3–99.3%), whereas nine patients experienced a median PSA elevation of +58.7% (0–2300.0%). Biochemical relapse-free survival (BRFS) was 80.0%. Impaired BRFS was correlated with the high-risk category at diagnosis (P = 0.014, hazard ratio 5.61) and ongoing androgen deprivation (P = 0.025, hazard ratio 2.98). Neither clinical variables nor dosimetric parameters were found to be predictive for toxicity.ConclusionFocal rSBRT can achieve durable remission in locally relapsing patients and systemic treatment can be postponed with acceptable toxicity. Accurate patient selection is mandatory to maximise disease control.