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The introduction of PSA screening in the mid-1980s has led to a rapid rise in prostate cancer detection. Although prostate cancer is found predominantly in older men, this rise is particularly pronounced in younger men, as demonstrated by a recognized tripling of the incidence of prostate cancer in men aged 50–59 years within the last 10–20 years . Overdiagnosis remains a significant concern for all age groups, but because of the potential for disease progression beyond 15 years, younger patients are preferentially offered definitive therapy rather than active surveillance strategies . Contemporary series examining radical prostatectomy, external beam radiation therapy (EBRT) and brachytherapy (BT) indicate excellent cancer-specific outcomes among younger patients suggesting that the disease is not necessarily more aggressive in younger patients [3-7]. Despite evidence that radiotherapeutic approaches are appropriate for young patients, there remains a tendency to favour radical surgery for this patient population .
Given the high cure rates for the majority of patients with prostate cancer, the emphasis has shifted to improving the morbidity of definitive therapy. A major advantage of BT-based treatment is the ability to escalate intraprostatic doses above those of EBRT with minimal dose to normal surrounding tissue. Improved dose conformality will result in a reduction of normal tissue radiation exposure and holds the potential for reduced late toxicity and improved quality-of-life outcomes for patients. Young men with longer life expectancies, therefore, are the population most likely to benefit from reduced normal tissue toxicity, particularly erectile preservation.
We report the acute and long-term genitourinary (GU), gastrointestinal (GI) and erectile outcomes in addition to PSA relapse-free (RFS), prostate-cancer-specific and overall survival of patients aged ≤ 60 years who were treated with BT-based regimens at Memorial Sloan-Kettering Cancer Center.
Materials and Methods
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- Materials and Methods
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Of 1655 patients treated at our institution between January 1998 and May 2008 with BT-based regimens for clinically localized prostate cancer, 236 patients with National Comprehensive Cancer Network (NCCN) low- (n = 178) or intermediate-risk (n = 58) were aged ≤ 60 years and had a minimum 3-year follow-up. The median (range) patient age was 56 (42–60) years. The median (range) follow-up was 83 (36–158) months. Prostate BT was performed using either low-dose-rate (LDR) BT (iodine-125 [I-125]) as monotherapy (n = 167) or LDR (I-125 or palladium-103 [Pd-103]; n = 38) or high-dose-rate (HDR) BT (n = 31) followed 4–8 weeks later by EBRT (median dose = 50.4 Gy). In general, monotherapy was reserved for patients with NCCN low-risk disease and selected patients with intermediate-risk disease, whereas combined BT (I-125, Pd-103, or iridium-192 [Ir-192]) and EBRT was used for the majority of patients with intermediate-risk disease. Patients with pre-implantation prostate volumes >50 gm were pre-treated for 3 months with short-term neoadjuvant androgen deprivation therapy (ADT) for cytoreductive purposes. In these patients, ADT was continued until the completion of EBRT. Patient characteristics are shown in Table 1.
Table 1. Patient characteristics (n = 236).
|T stage, n (%)|| |
|Gleason score, n (%)|| |
|Pretreatment PSA, n (%)|| |
|≤10 ng/mL||217 (92)|
|10.1–20 ng/mL||19 (8.1)|
|NCCN risk group, n (%)|| |
|Neoadjuvant hormone therapy, n (%)|| |
|Implant type, n (%)|| |
|Median (range) IPSS at baseline||4 (0–2)|
|Pretreatment potency, n (%)|| |
|Not active||11 (4.7)|
|Erectile dysfunction||50 (21.2)|
|Not available||25 (11)|
|ED medication use at baseline, n (%)|| |
Our techniques of LDR and HDR BT have been reported previously [9-11]. All BT procedures were performed using real-time TRUS-guidance in the dorsal lithotomy position under general anaesthesia. For LDR BT, an intra-operative planning system that incorporates a genetic optimization algorithm was used to achieve the optimum seed-loading pattern for delivery of the prescription dose of 144 Gy for monotherapy or 110 Gy using I-125 or 100 Gy using Pd-103 for combined treatment regimens. A Day 0 postimplant CT was performed for postimplant dosimetry analysis. For HDR BT, all patients were treated with Ir-192 using a Gammamed® 12i delivery unit (Varian Medical Systems, Inc., Palo Alto, CA, USA) with dosimetric evaluation performed using an in-house CT-based treatment planning system incorporating genetic optimization. Patients were treated with three fractions delivered 4–6 h apart during an overnight hospital stay. The dose per fraction was escalated over the study years (5.5–7 Gy) such that the total dose delivered was 16.5 Gy (n = 10), 18 Gy (n = 7), 19.5 Gy (n = 6), and 21 Gy (n = 8). Postimplant dosimetry patient information is shown in Table 2. To equilibrate the dose from LDR and HDR treatment regimens, biologically effective doses (BEDs) were calculated using the method reported by Stock et al. . The BED values for regimens involving BT and EBRT were calculated by adding the BEDs computed for each treatment. An α/β of 2 for the prostate was assumed for all BED calculations.
Table 2. Postimplant dosimetry.
| ||LDR monotherapy, median (range)||LDR + EBRT, median (range)||HDR + EBRT, median (range)|
|Target volume, gm||30 (12–74)||24.9 (8–52.4)||52 (28–110)|
|D90, Gy||156.3 (76.9–216)||114.7 (71.4–155.1)|| |
|BED total, Gy2||164.8 (79–232.1)||215.1 (169–259.21)||167.8 (147–190.3)|
|V100, %||94 (62–10)||93.5 (61.3–100)|| |
|V150, %||54.7 (13–90)||47.6 (28.4–84.8)|| |
|UrD5, %||119.1 (88.2–160.5)||130.1 (100.5–183.8)||116.4* (75–201)|
|UrD20, %||111.3 (84.7–150.4)||119.8 (89.3–168.5)||6.5† (4.4–7.8)|
|R2mL, %||52.0 (0–112.5)||58.9 (36.5–89.8)||106.9* (62.9–121.8)|
|RV100, mL||0.08 (0–3)||0.21 (0–1.5)|| |
In general, post-treatment follow-up was performed every 6 months for the first 3 years and annually thereafter. All patients had a minimum 3-year follow-up (median: 83 months). At each visit, patients were monitored for GU and GI toxicity using the CTCAE v 3 and IPSS questionnaires. Erectile function was assessed using the International Index of Erectile Function (IIEF)-6 questionnaire and/or physician assessment. Potency was defined as an IIEF-6 score ≥ 22 or the ability to obtain erections suitable for intercourse. The use of erectile medication was recorded at each visit. Potential comorbid conditions of potent patients which may contribute to erectile dysfunction (ED) were recorded and are shown in Table 3. PSA relapse was defined using the Phoenix (‘nadir+2’) definition.
Table 3. Comorbid conditions in patients (n = 150) identified as potent before therapy.
|Diabetes mellitus|| |
|Tobacco history|| |
|Statin medication|| |
The Kaplan–Meier method was used to calculate PSA RFS and overall survival rates. A competing risks analysis method was used to calculate the cumulative prostate-cancer-specific mortality rate. Logistic regression was used to examine whether any clinical variables (age < 65 vs ≥65 years), prostate volume (<50 vs ≥50 cc), baseline IPSS (<15 v ≥15), hypertension (yes/no), diabetes (yes/no), tobacco use (yes/no), statin use (yes/no), BED <200 vs ≥200 Gy2, <300 vs ≥300 Gy2), ADT (yes/no), EBRT (yes/no), isotope (LDR v HDR) and postimplant dosimetric variables [Table 3]) were associated with GU, GI and erectile toxicity outcomes. P values and 95% CIs were two-sided. A P value <0.05 was considered to indicate statistical significance. SAS 9.1.3 (SAS institute Inc., Cary, NC, USA) was used for statistical analysis.
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The 8-year PSA RFS for the entire cohort was 96% (Fig. 1). For patients with low- and intermediate-risk disease, the 8-year PSA RFS rates were 97 and 94%, respectively (P = 0.34). There was no significant difference in PSA RFS between patients who were treated with BT alone and those treated with combined therapy (P = 0.17). On univariate analysis, only Gleason score (<7 vs 7; P = 0.02) and pretreatment PSA (≤10 vs >10 ng/mL; P = 0.01) were significant predictors of PSA relapse; however these were no longer significant on multivariate analysis (P = 0.11) and (P = 0.09), respectively. For those patients without PSA relapse (n = 228), the mean (range) and median PSA level at last follow-up was 0.29 (<0.05–3.31) and 0.1 ng/mL, respectively, while 84% (199/236) had a PSA level at last follow-up of ≤0.5 ng/mL and 212/236 (90%) had a PSA <1.0 ng/mL. The 8-year prostate-cancer-specific and overall survival rates were 99 and 96%, respectively.
The overall rate of late grade 2 or higher GU toxicity was 14%. Four patients developed late urethral stricture at a median time of 50 months, all of which were managed successfully with urethral dilatation. The median IPSS at last follow-up was 6 for all patients and 11 for those with grade ≥2 toxicity. Urethral dose to 5% of urethra, urethral dose to 20% of urethra, isotope type, use of supplemental EBRT or hormone therapy, prostate volume or a baseline IPSS ≥10 were not associated with the development of grade 2 or higher GU toxicity.
The rate of grade 2 or higher GI toxicity was 2.5%. There were no late grade 3 GI toxicities. One of six patients with grade 2 rectal bleeding received combined BT and EBRT. None received hormone therapy. Rectal dose to 1cc of rectal wall, prostate volume, isotope type, diabetes, tobacco use, or statin use were not associated with the development of late grade 2 GI toxicity on univariate analysis.
Erectile function was assessed at baseline and 150 patients were identified as potent without the use of ED medication. Of these patients, 76 (51%) were identified as potent at last follow-up. Of patients who were potent after BT, 50 (66%) were potent without ED medication use and 26 (34%) were using ED medication at last follow-up. There was no significant difference in post-BT potency between patients treated with monotherapy and those who received supplemental EBRT (P = 0.74). Age, use of supplemental hormone therapy, diabetes, tobacco use, statin use and hypertension were not associated with post-BT potency on univariate analysis.
Secondary cancer diagnoses were identified in 11 patients (4.4%) and these data are shown in Table 4. Two patients developed cancers that were proximate to the prostate including one benign rectal polyp and one superficial bladder cancer. One patient was diagnosed with a precancerous distal rectal polyp 13 months after his BT implant for which he underwent a transanal excision and is without evidence of disease. Notably, he was also found to have a synchronous colonic polyps in the ascending and transverse colon. One patient with a history of tobacco use who worked in a chemical factory was diagnosed with a non-invasive urothelial carcinoma 54.5 months after I-125 monotherapy. He was treated with transurethral resection followed by intravesical BCG and is without evidence of bladder recurrence 6.4 years after his bladder cancer diagnosis (11 years after prostate BT).
Table 4. Secondary malignancies.
|Second malignancy||n||Location||Interval from Radiation Therapy to 2nd malignancy, months||Status at last followup|
|Skin cancer|| || || || |
|Head/neck||2||Out of field||61, 10||Alive|
|Forearm||1||Out of field||72||Alive|
|GI|| || || || |
|Gastric||1||Out of field||91||Dead|
|Colon||2||Out of field||12, 47||Alive|
|Rectal||1||In/close to field||13||Alive|
|GU|| || || || |
|Bladder||1||In/close to field||55||Alive|
|Thyroid||1||Out of field||15||Alive|
|CNS|| || || || |
|Meningioma||1||Out of field||77||Alive|
|Lung||1||Out of field||45||Dead|
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The present series represents one of the largest cohorts of young patients aged ≤ 60 years, treated with prostate BT with the longest follow-up reported. We demonstrate that young men treated with BT-based regimens for clinically localized prostate cancer have excellent disease and treatment-related outcomes. With a median follow-up of 6.75 years, the 8-year PSA RFS was 96%. These results compare favourably with contemporary series of radical prostatectomy and EBRT approaches in this age group [7, 13-15].
There are several other BT series reporting favourable biochemical outcomes in younger patient populations [1, 6, 17, 18]. Merrick et al.  studied 119 men aged ≤ 62 years treated with BT, with or without EBRT, with a median of 5.4 years’ follow-up. They reported a 7-year biochemical progression-free survival rate of 98.3%. More recently Shapiro et al.  reported outcomes of 237 patients aged ≤ 60 years treated with BT-based regimens and followed for a median of 44 months. In their series, the 5- and 10-year freedom from biochemical progression rates were 90.1 and 85.6%, respectively, and did not significantly differ from those of older patients (P = 0.46). Similarly, Burri et al.  reported BT outcomes of 378 patients aged ≤ 60 years, followed for a median of 68 months. The 5- and 8-year freedom from biochemical failure for these patients was 95 and 92%, respectively. Importantly, when compared with an older cohort there was no significant difference (P = 0.07). Our results confirm the durability of these favourable biochemical outcomes in young patients with longer follow-up.
Brachytherapy is well-tolerated in the vast majority of properly selected patients with prostate cancer. Given the long survival expected for young patients with localized prostate cancer, long-term toxicity is an important aspect of decision-making for these patients. We found a low risk of grade 2 or higher GU (14%) and GI (2.5%) toxicity in this young cohort followed for a minimum of 3 years. Gomez-Iturriaga Pina et al. [4, 18] found similar results in 96 hormone-naïve LDR monotherapy patients who were aged ≤ 55 years with last grade 2 and 3 GU toxicity of 11.7%, respectively. Additionally in this series, late grade 2 GI toxicity was also low at 2.2% with no patient having grade 3 proctitis.
In the present series, approximately half of potent patients maintained erectile function, the majority of whom (66%) did not require aids. Variability in erectile function reporting tools makes comparison of the present cohort with others difficult. The IIEF questionnaire is a patient-administered, validated instrument used to assess erectile function; however the definition of potency using this instrument varies. Merrick et al.  reported potency preservation rates of 75.6% in a cohort of BT patients aged ≤ 50 years, but the definition of potency in their series was an IIEF-6 > 13 without aids. Stock et al.  reported actuarial erectile preservation rates of 58% at 6 years using a 4-point grading system in men aged ≤ 65 years. Erectile aid usage in potent patients in their study was not reported. We used a stricter definition of potency as IIEF-6 score of ≥22 as suggested by Cappelleri et al.  which may be more sensitive for detecting mild-to-moderate ED in the present patient cohort. All current erectile function measures are limited in their ability to account for influence of confounders such as comorbidities, medications affecting erectile function, sexual activity or interest and partner availability/interest. These probably contribute to the rate of erectile dysfunction in men aged 60–69 years of 4.6% per year in the normal male population according to the Massachusetts Male Aging Study . Another IIEF limitation is that function is measured over the preceding 4 weeks, therefore, less active but potent men scores may be low.
Secondary malignancies are potential late sequelae of radiotherapy. In our series with long post-treatment follow-up, we identified a very low rate of secondary cancers overall and, most importantly, in the tissues adjacent to the prostate. This addresses an important concern for younger patients who have a potentially long life expectancy and thus may be particularly concerned regarding secondary cancer risk. Although reassuring, additional follow-up would help identify cancers occurring in the very late post-treatment period.
The present retrospective series has several limitations. The patients included had low- and intermediate-risk disease, and for these patients long-term follow-up is critical given the long natural history of the disease. Although this series represents the longest to date, continued follow-up will further clarify late recurrence patterns over time. Owing to small patient numbers, we were not able to distinguish differences in toxicity outcomes between patients who had LDR and those who had HDR treatment. Also, our available dosimetric information may be inadequate to accurately identify predictors of GU, GI or erectile toxicity. A more comprehensive review of dosimetric information may improve the ability to detect predictors of toxicity, particularly dose to erectile structures. Additional studies are planned to evaluate these dosimetric variables .
In conclusion, young men with low- and intermediate-risk prostate cancer have excellent disease and treatment-related outcomes after BT-based regimens. The vast majority of patients have minimal long-term GU and GI sequelae. In our experience, erectile function is maintained in >50% of patients aged ≤ 60 years who were fully potent before treatment, of whom the majority do not require erectile aids. Given these favourable outcomes, we strongly believe that young men should be offered BT as a treatment choice for clinically localized prostate cancer.