Survival advantage for prostate cancer patients treated with high-dose three-dimensional conformal radiotherapy.

PURPOSE: The value of treating prostate cancer has been questioned, and some insist that a survival benefit is demonstrated to justify treatment. Prospective dose-escalation studies with three-dimensional conformal radiotherapy technique have demonstrated improvement in biochemical freedom from disease and local control. We report the outcomes of high-dose treatment with three-dimensional conformal radiotherapy compared with low-dose treatment for biochemical freedom from disease, freedom from distant metastasis, cause-specific survival, and overall survival. PATIENTS AND METHODS: The study design was retrospective, involving pairs matched on independent prognostic variables in which each patient treated with low-dose radiotherapy was matched with a patient treated with high-dose radiotherapy. Outcomes were compared for two groups of patients: Group I: Three-dimensional conformal radiotherapy treatment--296 patients treated with more than 74 Gy matched on stage, grade, and prostate-specific antigen level, to 296 patients treated with less than 74 Gy. Group II: Three-dimensional conformal radiotherapy treatment--357 patients treated with more than 74 Gy matched on stage and grade to 357 patients treated with less than 74 Gy. RESULTS: Univariate analysis showed that dose is a significant predictor of biochemical freedom from disease, freedom from distant metastasis, and cause-specific survival for group I and biochemical freedom from disease, freedom from distant metastasis, cause-specific survival, and overall survival for group II. Multivariate analysis showed that dose is a significant independent predictor in group I for biochemical freedom from disease and freedom from distant metastasis and for biochemical freedom from disease, freedom from distant metastasis, cause-specific survival, and overall survival in group II. DISCUSSION: These data provide strong support for the definitive treatment of prostate cancer with high-dose (> 74 Gy) three-dimensional conformal radiotherapy. These doses can be safely delivered with three-dimensional conformal radiotherapy techniques. Various institutions and industry must collaborate to expand the technology allowing the use of high-dose three-dimensional conformal radiotherapy in the national practice beyond centers of technological excellence.     

Long term tolerance of high dose three-dimensional conformal radiotherapy in patients with localized prostate carcinoma.

BACKGROUND: The current study was undertaken to evaluate the incidence and predictors of late toxicity in patients with localized prostate carcinoma treated with high dose three-dimensional conformal radiotherapy (3D-CRT). METHODS: A total of 743 patients with prostate carcinoma classified as T1c-T3 were treated with 3D-CRT that targeted the prostate and seminal vesicles. A minimum tumor dose of 64.8 gray (Gy) was given to 96 patients (13%), 70.2 Gy to 266 patients (365), 75.6 Gy to 320 patients (43%), and 81.0 Gy to 61 patients (8%). The median follow-up time was 42 months (range, 18-109 months). Late toxicity was graded according to the Radiation Therapy Oncology Group morbidity scoring scale. RESULTS: Late gastrointestinal (GI) and urinary (GU) toxicities were absent or minimal (Grade 0 or 1) in 90% of patients. The 5-year actuarial likelihood of the development of Grade 2 and 3 late GI toxicities was 11% and 0.75%, respectively. A multivariate analysis identified doses > or =75.6 Gy (P<0.001), history of diabetes mellitus (P = 0.01), and the presence of acute GI symptoms during treatment (P = 0.02) as independent predictors of Grade > or =2 late GI toxicity. The 5-year actuarial likelihood of the development of Grade 2 and 3 late GU toxicities was 10% and 3%, respectively. Doses > or =75.6 Gy (P = 0.008) and acute GU symptoms (P<0.001) were independent predictors of Grade > or =2 late GU toxicity. Among 544 patients who were potent before treatment (73% of all patients), 211 (39%) became impotent after 3D-CRT. The 5-year actuarial risk of potency loss was 60%. Doses > or =75.6 Gy (P<0.001) and the use of neoadjuvant androgen deprivation (P = 0.01) were independent predictors of posttreatment erectile dysfunction. CONCLUSIONS: The incidence of severe late complications after high dose 3D-CRT was minimal. Radiation doses > or =75.6 Gy and the presence of acute treatment-related symptoms during 3D-CRT correlated with a higher incidence of Grade > or =2 late GI and GU toxicities. In addition to higher doses, the use of androgen deprivation therapy increased the likelihood of permanent impotence in these patients. Intensity-modulated radiotherapy, which makes it possible to enhance the conformality of the dose distribution, has recently been implemented in an attempt to reduce the incidence of moderate grade toxicities in patients receiving high dose 3D-CRT.     

Acute toxicity of three-dimensional conformal radiotherapy in prostate cancer patients eligible for implant monotherapy

PURPOSE: To assess the acute toxicity of three-dimensional conformal radiotherapy (3D-CRT) in prostate cancer patients eligible for implant monotherapy. METHODS AND MATERIALS: Between December 1991 and June 1998, 198 prostate cancer patients were treated with 3D-CRT at the University of California Davis Medical Center. Fifty-two of these patients had a prostate-specific antigen (PSA) level /= Grade 3, e.g., hourly nocturia, gross hematuria, diarrhea requiring parenteral support, narcotics for pain control, or catheterization for acute urinary retention, was observed. CONCLUSION: Although relatively high doses of radiation are delivered to prostate cancers with 3D-CRT compared with conventional radiotherapy, 3D-CRT is surprisingly well-tolerated. No patients in the cohort eligible for implant monotherapy experienced acute toxicity >/= Grade 3.     

62例前列腺癌三维适形或调强放疗的临床研究

目的 分析前列腺癌适形调强放射治疗的临床疗效、副反应,分析前列腺癌特异性抗原(PSA)的变化水平和意义.方法 62例前列腺痛患者,60例采用调强放疗,2例采用三维适形放疗.56例放疗前接受内分泌治疗.前列腺+精囊95%计划靶体积的中位处方剂量为78 Gy,盆腔的为48 Gy.放疗前、后测量血液中PSA水平,观察PSA最低点值与预后关系.观察正常组织早、晚期副反应.结果 中位随访时间15.4个月.全组3年无远处转移生存率、无生化复发生存率、总生存率和肿瘤特异生存率分别为77%、87%、90%和92%,5年无远处转移生存率、无生化复发生存率和总生存率分别为55%、69%和83%.放疗后PSA最低点≤2 ng/ml与>2 ng/ml的3年总生存率和无远处转移生存率分别为94%、88%%与56%、11%(χ~2=16.39,P<0.01;χ~2=28.87,P<0.01).1、2级早期泌尿系统副反应发生率分别为32%、0%,1、2级早期直肠副反应发生率分别为19%、3%,1、2级嗍泌尿系统副反应发生率分别为10%、0%,1、2级晚期直肠副反应发生率分别为5%、3%.结论 前列腺癌适形调强放疗疗效好,早、晚期副反应小;放疗后PSA监测利于判断肿瘤预后.     

Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer.

PURPOSE: Several studies have defined risk groups for predicting the outcome after external-beam radiotherapy of localized prostate cancer. However, most models formed patient risk groups, and none of these models considers radiation dose as a predictor variable. The purpose of this study was to develop a nomogram to improve the accuracy of predicting outcome after three-dimensional conformal radiotherapy. MATERIALS AND METHODS: This study was a retrospective, nonrandomized analysis of patients treated at the Memorial Sloan-Kettering Cancer Center between 1988 and 1998. Clinical parameters of the 1,042 patients included stage, biopsy Gleason score, pretreatment serum prostate-specific antigen (PSA) level, whether neoadjuvant androgen deprivation therapy was administered, and the radiation dose delivered. Biochemical (PSA) treatment failure was scored when three consecutive rises of serum PSA occurred. A nomogram, which predicts the probability of remaining free from biochemical recurrence for 5 years, was validated internally on this data set using a bootstrapping method and externally using a cohort of patients treated at the Cleveland Clinic, Cleveland, OH. RESULTS: When predicting outcomes for patients in the validation data set from the Cleveland Clinic, the nomogram had a Somers' D rank correlation between predicted and observed failure times of 0.52. Predictions from this nomogram were more accurate (P<.0001) than the best of seven published risk stratification systems, which achieved a Somers' D coefficient of 0.47. CONCLUSION: The development process illustrated here produced a nomogram that seems to predict more accurately than other available systems and may be useful for treatment selection by both physicians and patients.     

自动和逆向3DCRT与逆向IMRT计划剂量学比较

目的 比较自动3DCRT、逆向3DCRT、逆向IMRT计划的剂量学差异。方法 选取2014—2015年间单一靶区肺癌10例和颅内肿瘤10例,经网络传输至RayStation4.5TPS。采用自动3DCRT、逆向3DCRT和逆向IMRT方法分别对20例病例进行治疗计划设计,3种PTV和OAR剂量体积限制条件一致、射野数相同,比较3种计划的等剂量分布、靶区和OAR剂量参数。采用多相关变量和双相关变量分布分析。结果 肺癌病例中IMRT计划D_98%、D_50%、D_2%、CI和HI均优于逆向3DCRT和自动3DCRT计划(P=0.007、0.001、0.002、0.000、0.000);自动3DCRT计划的CI优于逆向3DCRT计划(P=0.000),3种计划中心脏D₃₃、脊髓D_max和D_{1 cm³}、双肺的各参数受量均相近(P=0.702、0.237、0.163、0.739、0.908、0.832、0.886、0.722、0.429、0.840、0.702);颅内肿瘤病例中逆向IMRT和自动3DCRT计划的CI优于逆向3DCRT计划(P=0.002、0.034),其他靶区参数相近(P=0.648、0.783、0.256、0.931),3种计划全脑受量各参数相近(P=0.446、0.755、0.772、0.0266、0.440、0.290、0.939)。结论 单一靶区肺癌和颅内肿瘤病例中,与逆向3DCRT技术相比,自动3DCRT技术可提高靶区CI;与逆向IMRT技术相比,对OAR保护相近,考虑到3DCRT的简便性和低成本,自动3DCRT技术可以作为一种新放疗技术进行推广。     

Influence of organ motion on conformal vs. intensity-modulated pelvic radiotherapy for prostate cancer

PURPOSE: To compare an intensity-modulated radiotherapy (IMRT) planning approach for prostate pelvic RT with a conformal RT (CRT) approach taking into account the influence of organ-at-risk (OAR) motion. METHODS AND MATERIALS: A total of 20 male patients, each with one planning computed tomography scan and five to eight treatment computed tomography scans, were used for simulation of IMRT and CRT for delivery of a prescribed dose of 50 Gy to the prostate, seminal vesicles, and pelvic lymph nodes. Planning was done in Eclipse without correcting for OAR motion. Evaluation was performed using the CRT and IMRT dose matrices and the planning and treatment OAR outlines. The generalized equivalent uniform dose (gEUD) was calculated for 894 OAR volumes using a volume-effect parameter of 4, 12, and 8 for bowel, rectum and bladder, respectively. For the bowel, the gEUD was normalized to a reference volume of 200 cm(3). For each patient and each OAR, an average of the treatment gEUDs (gEUD(treat)) was calculated for CRT and IMRT. The paired t test was used to compare IMRT with CRT and gEUD(treat) with gEUD(plan). RESULTS: The mean gEUD(treat) was reduced from 43 to 40 Gy, 47 to 46 Gy, and 48 to 45 Gy with IMRT for the bowel, rectum, and bladder, respectively (p < 0.001). Differences between the gEUD(plan) and gEUD(treat) were not significant (p > 0.05) for any OAR but was >6% for the bowel in 6 of 20 patients. CONCLUSION: Intensity-modulated RT reduced the bowel, rectum, and bladder gEUDs also under influence of OAR motion. Neither CRT nor IMRT was robust against bowel motion, but IMRT was not less robust than CRT.     

Dosimetric implications of changes in patient repositioning and organ motion in conformal radiotherapy for prostate cancer.

PURPOSE: To assess the influence of patient repositioning and organ motion on dose distribution within the prostate and the seminal vesicles (clinical target volume, (CTV)). MATERIAL AND METHODS: Nine patients were simulated and treated in the supine position, with an empty bladder, and without immobilization devices. While on treatment, patients underwent weekly pelvic computed tomography (CT) scans under conditions identical to those at simulation. Patients were aligned using lasers on anterior and lateral skin tattoos, onto which lead markers were placed. After each CT scan (n=53) the CTV was redefined by contouring, and a new isocenter was obtained. A six-field technique was used. The field margins around the CTV were 20 mm in the cranio-caudal axis, and 13 mm in the other axes, except in the lateral fields where a 10 mm posterior margin was used. Dose-volume histograms (DVHs) for each organ were compared with those determined at simulation, using the notion of the proportional change in the area under the CTV-DVH curve resulting from a change in treatment plan (cDVH). RESULTS: The reproducibility of the dose distribution was good for the prostate (%cDVH, mean+/-SD: -0.97+/-2.11%) and less than optimal for the seminal vesicles (%cDVH, mean+/-SD: -4.66+/-10.45%). When correlating prostate %cDVH variations with displacements of the isocenter in the Y axis (antero-posterior) the %cDVH exceeded (-)5% in only two dosimetries, both with an isocenter shift of >10 mm. For the seminal vesicles, however, ten out of 53 dosimetries showed a %cDVH exceeding (-) 5%. In nine of these ten dose distribution studies the posterior shift of the isocenter exceeded 8 mm. CONCLUSIONS: Precise targeting of prostate radiotherapy is primarily dependent on careful daily set-up and on random changes in rectal geometry. Margins no less than 10 mm around the prostate and at least 15 mm around the seminal vesicles are probably necessary to insure adequate target coverage with a six-field technique.     

Variation of clinical target volume definition in three-dimensional conformal radiation therapy for prostate cancer.

PURPOSE: Currently, three-dimensional conformal radiation therapy (3D-CRT) planning relies on the interpretation of computed tomography (CT) axial images for defining the clinical target volume (CTV). This study investigates the variation among multiple observers to define the CTV used in 3D-CRT for prostate cancer. METHODS AND MATERIALS: Seven observers independently delineated the CTVs (prostate +/- seminal vesicles [SV]) from the CT simulation data of 10 prostate cancer patients undergoing 3D-CRT. Six patients underwent CT simulation without the use of contrast material and serve as a control group. The other 4 had urethral and bladder opacification with contrast medium. To determine interobserver variation, we evaluated the derived volume, the maximum dimensions, and the isocenter for each examination of CTV. We assessed the reliability in the CTVs among the observers by correlating the variation for each class of measurements. This was estimated by intraclass correlation coefficient (ICC), with 1.00 defining absolute correlation. RESULTS: For the prostate volumes, the ICC was 0.80 (95% confidence interval [CI]: 0.56-0.96). This changed to 0.92 (95% CI: 0.75-0.99) with the use of contrast material. Similarly, the maximal prostatic dimensions were reliable and improved. There was poor agreement in defining the SV. For this structure, the ICC never exceeded 0.28. The reliability of the isocenter was excellent, with the ICC exceeding 0.83 and 0.90 for the prostate +/- SV, respectively. CONCLUSIONS: In 3D-CRT for prostate cancer, there was excellent agreement among multiple observers to define the prostate target volume but poor agreement to define the SV. The use of urethral and bladder contrast improved the reliability of localizing the prostate. For all CTVs, the isocenter was very reliable and should be used to compare the variation in 3D dosimetry among multiple observers.     

前列腺癌三维适形放疗中体位对靶区和正常组织体积及照射剂量的影响

目的对比研究仰、俯卧体位下前列腺癌三维适形放疗对靶区和周边重要器官体积改变和照射剂量变化。方法临床穿刺细胞学证实的分期为T1~T2N0M0期的前列腺癌8例,行对称六野三维适形放疗。定位前1 h排空膀胱,定位前1.0、0.5 h口服造影剂各400 ml,每例病例同一时间分别行前列腺癌仰、俯卧位CT定位扫描,定位后勾画靶区及盆腔重要器官结构,三维计划设计。分别评估CTV、PTV、直肠、膀胱、股骨头和盆腔小肠体积,CTV、PTV、直肠、膀胱、股骨头、盆腔小肠平均照射剂量,50 Gy膀胱、直肠和30 Gy股骨头受照体积及盆腔小肠最大照射剂量,对比仰、俯卧位各器官结构体积变化以及照射剂量差别。结果无论是仰卧位还是俯卧位,靶区均能得到均匀理想的剂量分布。直肠体积在不同体位下变化较大。仰、俯卧位各正常组织的平均体积分别为:膀胱(306±58)、(325±69)cm3,直肠(59±20)(、144±96)cm3,小肠(94±51)、(75±18)cm3。CTV、PTV、股骨头体积变化不明显。CTV、PTV、膀胱、股骨头、小肠平均照射剂量在不同治疗体位下差别不大。仰、俯卧位直肠平均照射剂量分别为(3364±995)(、2221±1176)cGy。DVH分析显示直肠在俯卧位保护最好,仰、俯卧位50 Gy直肠体积分别占总体积的39.5%±19.7%、19.8%±15.7%。俯、仰卧位小肠最大照射剂量分别为(234±143)(、275±220)cGy。结论前列腺癌俯卧位三维适形放疗使直肠体积明显增大,可因减少直肠照射而起一定保护作用。     

前列腺癌三维放疗疗效的Meta分析

目的 Meta分析三维放疗对前列腺癌疗效。方法 在2名独立研究员制定相关文献的检索策略以及纳入、剔除标准后,通过检索PubMed、荷兰医学文献数据库、中国知网、万方数据库中有关三维放疗前列腺癌有关研究。检索时间为开始建库至2017年2月,限定语种为英文与中文。采用RevMan 5.3软件对相关文献资料进行数据处理与分析。结果 根据严格的检索策略及纳入、排除标准共纳入15篇相关临床研究,均为回顾性队列研究。相关患者4608例,其中IMRT组2229例,3DCRT组2379例。IMRT与3DCRT组在泌尿系早晚期损伤上相近(OR=0.77,95%CI为0.43~1.40,P=0.390;OR=0.75,95%CI为0.55~1.04,P=0.080);肠道早、晚期损伤IMRT比3DCRT组少(OR=0.47,95%CI为0.27~0.82,P=0.008;OR=0.52,95%CI为0.35~0.78,P=0.001);无生化复发生存率IMRT比3DCRT组高(OR=1.87,95%CI:1.51~2.32,P=0.000)。结论 IMRT相比3DCRT在治疗前列腺癌过程中对肠道损伤的保护作用最为明显,同时无生化复发生存率也相对较高。     

Potency preservation after three-dimensional conformal radiotherapy for prostate cancer: preliminary results

We sought to assess potency preservation after three-dimensional conformal radiotherapy (3D-CRT) in prostate cancer patients eligible for radical prostatectomy, conventional radiotherapy, 3D-CRT, or transperineal prostate implantation. Patients with more advanced disease are commonly treated with hormonal therapy, which can cause impotence, and were consequently excluded from the analysis. Between December 1991 and June 1998, 198 prostate cancer patients were treated with 3D-CRT at the University of California, Davis Medical Center. Fifty-two of these patients had a pretreatment prostate-specific antigen (PSA) level of 10.0 ng/ml or less, a Gleason score of 6 or less, and a 1997 AJCC clinical stage T1bN0M0 to T2bN0M0. One patient was not evaluable. None of the 51 evaluable patients had diabetes mellitus. In 40 patients, the prostate gland only was irradiated to a total dose of 66 to 79.2 Gy by using daily 1.8-Gy fractions. In 11 patients, the prostate and seminal vesicles were treated to 44 to 55.8 Gy. Lymph nodes were not included in the clinical target volume. The median age was 68 years, and the median length of follow-up was 15 months. Potency in this study is defined as an erection sufficient for vaginal penetration. Kaplan-Meier analysis was used to describe potency as a function of time after 3D-CRT. Of the 51 evaluable patients, 35 (69%) were potent, 15 were impotent, and 1 was sexually inactive before 3D-CRT. Kaplan-Meier estimates of the potency preservation rates 1, 2, and 3 years after 3D-CRT are 100%, 83%, and 63%, respectively. On multivariate analysis, age, total radiation dose, and a history of transurethral resection of the prostate did not significantly affect potency preservation rates. Three (43%) of 7 patients who became impotent after 3D-CRT and used sildenafil were subsequently able to achieve erections sufficient for vaginal penetration. The preliminary results reported herein suggest that approximately two thirds of prostate cancer patients will retain their potency 3 years after 3D-CRT. Further follow-up is necessary to assess long-term potency after 3D-CRT. Sildenafil should be considered in patients who develop radiation-induced impotence.     

Time requirements in conformal radiotherapy treatment planning.

To investigate the influence of implementing three-dimensional treatment planning on staffing needs, valid questionnaire responses from 22 radiotherapy institutions have been evaluated. Average time requirements per plan rise from 213 to 439 min upon implementation, but with experience decrease to 317 min. No institution reports additional staff positions according to estimated requirements.     

Normalization of serum testosterone levels in patients treated with neoadjuvant hormonal therapy and three-dimensional conformal radiotherapy for prostate cancer

PURPOSE: To determine the expected time to serum testosterone normalization after short-course neoadjuvant androgen deprivation therapy (NAAD) and three-dimensional conformal radiotherapy for patients with localized prostate cancer and to identify pretreatment predictors that correlated with the time to testosterone normalization. METHODS: Between 1993 and 1999, 88 patients with localized prostate cancer, treated with NAAD and external beam radiotherapy, were prospectively monitored after treatment with sequential testosterone levels. NAAD was administered before and during the entire course of radiotherapy and discontinued at the end of treatment. The median duration of NAAD was 6 months. The actuarial rate of serum testosterone normalization from the end of treatment was evaluated, and the presence or absence of androgen deprivation-related symptoms was correlated with serum testosterone levels. Symptoms assessed included weight gain, loss of libido, breast tenderness, breast enlargement, hot flashes, and fatigue. RESULTS: Serum testosterone levels returned to the normal range in 57 (65%) of the 88 patients and failed to normalize in 31 patients (35%). The median time to normalization was 18.3 months. The actuarial rate of normalization at 3, 6, 12, and 24 months was 10%, 26%, 38%, and 59%, respectively. In a multivariate analysis, a pretreatment testosterone level in the lower range of normal was the only variable that predicted for delayed testosterone normalization after NAAD (p = 0.00047). Among 45 patients with information concerning androgen deprivation-related symptoms recorded 1 year after cessation of NAAD, 24 (53%) had normalized testosterone levels, but in 21 patients (47%), the levels had not yet returned to normal. At 1 year, only 1 (4%) of 24 patients whose testosterone level had returned to normal experienced NAAD-related symptoms compared with 14 (67%) of 21 patients who did not have normal testosterone levels (p <0.001). CONCLUSION: Testosterone levels often remain depressed for extended periods after cessation of short-course NAAD. Lower baseline testosterone levels predict for a delay in testosterone normalization, and the persistence of symptoms related to androgen deprivation correlates with low testosterone levels.     

Incidence of late rectal and urinary toxicities after three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for localized prostate cancer

PURPOSE: To report the incidence and predictors of treatment-related toxicity at 10 years after three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) for localized prostate cancer. METHODS AND MATERIALS: Between 1988 and 2000, 1571 patients with stages T1-T3 prostate cancer were treated with 3D-CRT/IMRT with doses ranging from 66 to 81 Gy. The median follow-up was 10 years. Posttreatment toxicities were all graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events. RESULTS: The actuarial likelihood at 10 years for the development of Grade>or=2 GI toxicities was 9%. The use of IMRT significantly reduced the risk of gastrointestinal (GI) toxicities compared with patients treated with conventional 3D-CRT (13% to 5%; p<0.001). Among patients who experienced acute symptoms the 10-year incidence of late toxicity was 42%, compared with 9% for those who did not experience acute symptoms (p<0.0001). The 10-year incidence of late Grade>or=2 genitourinary (GU) toxicity was 15%. Patients treated with 81 Gy (IMRT) had a 20% incidence of GU symptoms at 10 years, compared with a 12% for patient treated to lower doses (p=0.01). Among patients who had developed acute symptoms during treatment, the incidence of late toxicity at 10 years was 35%, compared with 12% (p<0.001). The incidence of Grade 3 GI and GU toxicities was 1% and 3%, respectively. CONCLUSIONS: Serious late toxicity was unusual despite the delivery of high radiation dose levels in these patients. Higher doses were associated with increased GI and GU Grade 2 toxicities, but the risk of proctitis was significantly reduced with IMRT. Acute symptoms were a precursor of late toxicities in these patients.