Stereotactic body radiotherapy for oligometastases.

The management of metastatic solid tumours has historically focused on systemic treatment given with palliative intent. However, radical surgical treatment of oligometastases is now common practice in some settings. The development of stereotactic body radiotherapy (SBRT), building on improvements in delivery achieved by intensity-modulated and image-guided radiotherapy, now allows delivery of ablative doses of radiation to extracranial sites. Many non-randomised studies have shown that SBRT for oligometastases is safe and effective, with local control rates of about 80%. Importantly, these studies also suggest that the natural history of the disease is changing, with 2-5 year progression-free survival of about 20%. Although complete cure might be possible in a few patients with oligometastases, the aim of SBRT in this setting is to achieve local control and delay progression, and thereby also postpone the need for further treatment. We review published work showing that SBRT offers durable local control and the potential for progression-free survival in non-liver, non-lung oligometastatic disease at a range of sites. However, to test whether SBRT really does improve progression-free survival, randomised trials will be essential.

Evaluating the efficacy of statins and ACE-inhibitors in reducing gastrointestinal toxicity in patients receiving radiotherapy for pelvic malignancies.

INTRODUCTION: 3-Hydroxy-methylglutaryl coenzyme-a reductase inhibitors (statins) improve survival following pelvic irradiation for cancer. Large studies suggest that patients with hypertension may have reduced gastrointestinal (GI) toxicity. Animal data suggest that statins and ACE inhibitors (ACEi) may protect against normal tissue injury. Their efficacy in humans has not been reported. AIMS/METHODS: To evaluate the impact of statins and ACEi on normal tissue toxicity during radical pelvic radiotherapy. GI symptomatology was recorded prospectively before radiotherapy, weekly during treatment and 1 year later using the inflammatory bowel disease questionnaire-bowel (IBDQ-B) subset. Cumulative acute toxicity (IBDQ-B AUC) and worst score were determined. Dose, brand and duration of statin and/or ACEi usage were obtained from General Practitioners. RESULTS: Of 308 patients recruited, 237 had evaluable acute drug and toxicity data and 164 had data at 1year. Acutely, 38 patients (16%) were taking statins, 39 patients (16.5%) were taking ACEi and 18 patients (7.6%) were taking statin+ACEi. Mean changes in acute scores were 7.3 points (non-statin users), 7.3 (non-ACEi users) and 7.0 (non-statin+ACEi users) compared to 4.8 points (statin users), 5.0 points (ACEi users) and 4.9 points (statin+ACEi users). Statin use (p=0.04) and combined statin+ACEi use (p=0.008) were associated with reduced acute IBDQ-B AUC after controlling for baseline scores (ANOVA). At 1 year, users maintained higher IBDQ-B scores than non-users in all user subgroups. CONCLUSION: Use of statin or statin+ACEi medication during radical pelvic radiotherapy significantly reduces acute gastrointestinal symptoms scores and also appears to provide longer-term sustained protection.

A risk prediction algorithm based on family history and common genetic variants: application to prostate cancer with potential clinical impact.

Genome wide association studies have identified several single nucleotide polymorphisms (SNPs) that are independently associated with small increments in risk of prostate cancer, opening up the possibility for using such variants in risk prediction. Using segregation analysis of population-based samples of 4,390 families of prostate cancer patients from the UK and Australia, and assuming all familial aggregation has genetic causes, we previously found that the best model for the genetic susceptibility to prostate cancer was a mixed model of inheritance that included both a recessive major gene component and a polygenic component (P) that represents the effect of a large number of genetic variants each of small effect, where . Based on published studies of 26 SNPs that are currently known to be associated with prostate cancer, we have extended our model to incorporate these SNPs by decomposing the polygenic component into two parts: a polygenic component due to the known susceptibility SNPs, , and the residual polygenic component due to the postulated but as yet unknown genetic variants, . The resulting algorithm can be used for predicting the probability of developing prostate cancer in the future based on both SNP profiles and explicit family history information. This approach can be applied to other diseases for which population-based family data and established risk variants exist.

Predicting late effects of pelvic radiotherapy: is there a better approach?

PURPOSE: Significant chronic symptoms following pelvic radiotherapy occur more frequently than commonly realized. Predictive factors for the development of late symptoms are poorly defined. Moderate sustained acute (cumulative) toxicity might predict severe late effects better than peak reaction. METHODS AND MATERIALS: To determine prospectively whether peak or cumulative gastrointestinal (GI) acute symptoms better predict late symptoms in patients receiving pelvic radiotherapy. Symptom scores were measured weekly from the start of radiotherapy, and at 1 year using the Modified Inflammatory Bowel Disease Questionnaire-Bowel subset. The possible prognostic impact of patient-related factors was explored. RESULTS: Three hundred and eight patients were recruited. 100 were excluded due to lack of follow-up data at one year resulting from death, too ill, stoma, relapsed, non-response or withdrawal. A further 15 were excluded for incomplete data, leaving 193 patients with evaluable data. Of these, 28 had GI, 101 urological, and 64 gynecological cancers. Patients' median age was 65 years (range, 23-82), and they were treated with median 60 Gy dose for a median of 6 weeks. Univariate analysis revealed a significant association between cumulative acute symptom scores and scores at 1 year (p < 0.001), which was dose-independent (p < 0.001). Acute peak and 1-year scores were not associated (p = 0.431). The correlation coefficient between cumulative acute symptoms and symptoms at 1 year was 0.367 and for peak acute symptoms was weaker at 0.057. Patients with an abnormal body mass index and current smokers were more likely to experience worse symptoms at 1 year. CONCLUSION: Cumulative acute symptoms are more predictive of late symptoms than peak acute changes in score. This association is independent of the radiotherapy dose delivered and is suggestive of a consequential late effect.

Prostate cancer segregation analyses using 4390 families from UK and Australian population-based studies.

Familial aggregation of prostate cancer is likely to be due to multiple susceptibility loci, perhaps acting in conjunction with shared lifestyle risk factors. Models that assume a single mode of inheritance may be unrealistic. We analyzed genetic models of susceptibility to prostate cancer using segregation analysis of occurrence in families ascertained through population-based series totaling 4390 incident cases. We investigated major gene models (dominant, recessive, general, X-linked), polygenic models, and mixed models of susceptibility using the pedigree analysis software MENDEL. The hypergeometric model was used to approximate polygenic inheritance. The best-fitting model for the familial aggregation of prostate cancer was the mixed recessive model. The frequency of the susceptibility allele in the population was estimated to be 0.15 (95% confidence interval (CI) 0.11-0.20), with a relative risk for homozygote carriers of 94 (95% CI 46-192), and a polygenic standard deviation of 2.01 (95% CI 1.72-2.34). These analyses suggest that one or more genes having a strong recessively inherited effect on risk, as well as a number of genes with variants having small multiplicative effects on risk, may account for the genetic susceptibility to prostate cancer. The recessive component would predict the observed higher familial risk for siblings of cases than for fathers, but this could also be due to other factors such as shared lifestyle by siblings, targeted screening effects, and/or non-additive effects of one or more genes.

Multiple loci on 8q24 associated with prostate cancer susceptibility.

Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility.

Assessment of bladder motion for clinical radiotherapy practice using cine-magnetic resonance imaging.

PURPOSE: Organ motion is recognized as the principal source of inaccuracy in bladder radiotherapy (RT), but there is currently little information on intrafraction bladder motion. METHODS AND MATERIALS: We used cine-magnetic resonance imaging (cine-MRI) to study bladder motion relevant to intrafraction RT delivery. On two occasions, a 28 minute cine-MRI sequence was acquired from 10 bladder cancer patients and 5 control participants immediately after bladder emptying, after abstinence from drinking for the preceding hour. From the resulting cine sequences, bladder motion was subjectively assessed. To quantify bladder motion, the bladder was contoured in imaging volume sets at 0, 14, and 28 min to measure changes to bladder volumes, wall displacements, and center of gravity (COG) over time. RESULTS: The dominant source of bladder motion during imaging was bladder filling (up to 101% volume increase); rectal and small bowel movements were transient, with minimal impact. Bladder volume changes were similar for all participants. However for bladder cancer patients, wall displacements were larger (up to 58 mm), less symmetrical, and more variable compared with nondiseased control bladders. CONCLUSIONS: Significant and individualized intrafraction bladder wall displacements may occur during bladder RT delivery. This important source of inaccuracy should be incorporated into treatment planning and verification.

Identification of new genetic risk factors for prostate cancer.

There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.

Predicting the probability of deferred radical treatment for localised prostate cancer managed by active surveillance.

OBJECTIVES: Outcome data from a prospective study of active surveillance of localised prostate cancer were analysed to identify factors, present at the time of diagnosis, that predict subsequent radical treatment. METHODS: Eligible patients had clinical stage T1-T2a, N0-Nx, M0-Mx adenocarcinoma of the prostate with serum PSA<15 ng/ml, Gleason score 1 ng/ml/yr) or histological progression (primary Gleason grade >or= 4, or %pbc > 50%). Multivariate Cox regression analysis of baseline variables was performed with respect to time to radical treatment. RESULTS: The 326 men recruited from 2002 to 2006 have been followed for a median of 22 mo. Median age was 67 yr, and median initial PSA (iPSA) 6.4 ng/ml. Sixty-five patients (20%) had deferred radical treatment, 16 (5%) changed to watchful waiting because of increasing comorbidity, 7 (2%) died of other causes, and 238 (73%) remain on surveillance. On multivariate Cox regression analysis, the free/total PSA ratio (p<0.001) and clinical T stage (p=0.006) were independent determinants of time to radical treatment. CONCLUSIONS: In addition to established prognostic factors, the free/total PSA ratio may predict time to radical treatment in patients with untreated, localised prostate cancer managed by active surveillance. This possibility warrants further study.

Multiple newly identified loci associated with prostate cancer susceptibility.

Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at

A comparison of the use of bony anatomy and internal markers for offline verification and an evaluation of the potential benefit of online and offline verification protocols for prostate radiotherapy.

PURPOSE: To evaluate the utility of intraprostatic markers in the treatment verification of prostate cancer radiotherapy. Specific aims were: to compare the effectiveness of offline correction protocols, either using gold markers or bony anatomy; to estimate the potential benefit of online correction protocol's using gold markers; to determine the presence and effect of intrafraction motion. METHODS AND MATERIALS: Thirty patients with three gold markers inserted had pretreatment and posttreatment images acquired and were treated using an offline correction protocol and gold markers. Retrospectively, an offline protocol was applied using bony anatomy and an online protocol using gold markers. RESULTS: The systematic errors were reduced from 1.3, 1.9, and 2.5 mm to 1.1, 1.1, and 1.5 mm in the right-left (RL), superoinferior (SI), and anteroposterior (AP) directions, respectively, using the offline correction protocol and gold markers instead of bony anatomy. The subsequent decrease in margins was 1.7, 3.3, and 4 mm in the RL, SI, and AP directions, respectively. An offline correction protocol combined with an online correction protocol in the first four fractions reduced random errors further to 0.9, 1.1, and 1.0 mm in the RL, SI, and AP directions, respectively. A daily online protocol reduced all errors to <1 mm. Intrafraction motion had greater impact on the effectiveness of the online protocol than the offline protocols. CONCLUSIONS: An offline protocol using gold markers is effective in reducing the systematic error. The value of online protocols is reduced by intrafraction motion.

Assessing intra-fractional bladder motion using cine-MRI as initial methodology for Predictive Organ Localization (POLO) in radiotherapy for bladder cancer.

AIM: To assess the feasibility of using cine-MR to study intra-fractional time-volume and volume-deformity patterns of the bladder during radiotherapy as initial methodology for Predictive Organ Localization (POLO). METHODS: Nine patients receiving radiotherapy for localized muscle invasive bladder cancer were prospectively studied. Each had an MR scan performed on an empty bladder using a T1 weighted cine sequence over a period of 20 min. Scans were taken prior to, and repeated towards the end of, radiotherapy treatment. Time-volume sequences were determined and compared before and during radiotherapy. Absolute bladder volumes were then correlated with changes in bladder wall position. RESULTS: The mean post void residual bladder volume prior to radiotherapy at time 0 was 113 cm(3) [SD 53] and this did not differ significantly during radiotherapy -106 cm [SD 40] (p=0.24, paired t-test analysis). A linear relationship was observed for the rate bladder filling over a 20 min period, which did not significantly change on the cine-MR during radiotherapy (regression coefficient 2.1 vs 1.6, respectively, p=0.51). Significant positive relationships were seen between volume and anterior (p=0.02), superior (p<0.001), and inferior (p=0.03) wall motion. These relationships were complex, though linearity was observed for volumes up to 150 cm(3). The 1.5 cm CTV-PTV margin was sufficient to account for expansion in the majority of cases with the only breach occurring on the anterior wall in one patient. CONCLUSIONS: This study confirms the feasibility of using cine-MR for POLO. The development of such predictive methodology may compensate for the need to use an isotropic CTV-PTV margin to simply cover bladder filling when using image-guided radiotherapy.

Evaluating the relationship between erectile dysfunction and dose received by the penile bulb: using data from a randomised controlled trial of conformal radiotherapy in prostate cancer (MRC RT01, ISRCTN47772397).

AIM: To evaluate the relationship between erectile function and the radiation dose to the penile bulb and other proximal penile structures in men receiving conformal radiotherapy (CFRT) for prostate cancer (PCa). METHODS: The Medical Research Council (MRC) RT01 trial randomised 843 men who had localised PCa to receive either 64 or 74 Gy after 3 - 6 months neoadjuvant hormonal treatment. Fifty-one men were selected who were potent prior to hormonal treatment, having completed both pre-hormone and 2-year post-CFRT Quality of Life assessments, and on whom dose volume data were available for analysis. The men were divided into three groups according to 2-year follow-up: potent, reduced potency, and impotent. The bulb of the penis together with the crura, were outlined on restored treatment plans. Dose - volume histograms were generated and compared between the three groups. An ordered logistic regression model was used to calculate the odds ratio of a range of dose - volume parameters to the penile bulb and effect on erectile dysfunction. The dose to the penile bulb was correlated to the dose received by the crura. RESULTS: Of the 51 patients, 12 remained potent, 22 had reduced potency, and 17 were impotent at 2 years. No differences were seen in mean dose to the penile bulb by allocated treatment (t test = 1.61, p = 0.11). The mean doses to the penile bulb received by the potent, reduced potency, and impotent groups were 45.5 Gy (SD 17.1), 48 Gy (SD 16.1), and 59.2 Gy (SD 13.8), respectively. There was a strong correlation between the mean dose received by the penile bulb and dose to the crura (r = 0.82, p < 0.0001). 83.3% of impotent patients received a D90 > or = 50 Gy to the penile bulb compared with 29.4% of patients who maintained potency at 2 years (p = 0.006). CONCLUSION: There is evidence from this study to suggest a dose volume effect on the penile bulb and erectile dysfunction. A D90 > or = 50 Gy is associated with a significant risk of erectile dysfunction and this should form a basis for selecting dose constraints in future dose escalation studies.

A modified inflammatory bowel disease questionnaire and the Vaizey Incontinence questionnaire are more sensitive measures of acute gastrointestinal toxicity during pelvic radiotherapy than RTOG grading.

PURPOSE: Simple scales with greater sensitivity than Radiation Therapy Oncology Group (RTOG) grading to detect acute gastrointestinal toxicity during pelvic radiotherapy, could be clinically useful. METHODS AND MATERIALS: Do questionnaires used in benign gastrointestinal diseases detect toxicity in patients undergoing radiotherapy? The patient-completed Inflammatory Bowel Disease (IBDQ) and Vaizey Incontinence questionnaires were compared prospectively at baseline and at Week 5 to physician-completed RTOG grading. RESULTS: A total of 107 patients, median age 63 years, were recruited. After 5 weeks of treatment, patients with gynecologic and gastrointestinal cancer were more symptomatic than urologic patients (p = 0.012; p = 0.014). Overall, 94% had altered bowel habits, 80% loose stool, 74% frequency, 65% difficult gas, 60% pain, >48% distress, 44% tenesmus, >40% restrictions in daily activity, 39% urgency, 37% fecal incontinence, and 40% required antidiarrheal medication. The median RTOG score was 1 (range, 0-2), median IBDQ score 204.5 (range, 74-224), and median Vaizey score 5 (range, 0-20). Chemotherapy preceding radiotherapy increased fecal incontinence (p = 0.002). RTOG scores stabilized after 3 weeks, IBDQ scores peaked at Week 4, and Vaizey scores worsened throughout treatment. IBDQ and Vaizey scores distinguished between groups with different RTOG scores. CONCLUSION: The IBDQ and Vaizey questionnaires are reliable and sensitive, offering greater insight into the severity and range of symptoms compared with RTOG grading.

X-ray volumetric imaging in image-guided radiotherapy: the new standard in on-treatment imaging.

PURPOSE: X-ray volumetric imaging (XVI) for the first time allows for the on-treatment acquisition of three-dimensional (3D) kV cone beam computed tomography (CT) images. Clinical imaging using the Synergy System (Elekta, Crawley, UK) commenced in July 2003. This study evaluated image quality and dose delivered and assessed clinical utility for treatment verification at a range of anatomic sites. METHODS AND MATERIALS: Single XVIs were acquired from 30 patients undergoing radiotherapy for tumors at 10 different anatomic sites. Patients were imaged in their setup position. Radiation doses received were measured using TLDs on the skin surface. The utility of XVI in verifying target volume coverage was qualitatively assessed by experienced clinicians. RESULTS: X-ray volumetric imaging acquisition was completed in the treatment position at all anatomic sites. At sites where a full gantry rotation was not possible, XVIs were reconstructed from projection images acquired from partial rotations. Soft-tissue definition of organ boundaries allowed direct assessment of 3D target volume coverage at all sites. Individual image quality depended on both imaging parameters and patient characteristics. Radiation dose ranged from 0.003 Gy in the head to 0.03 Gy in the pelvis. CONCLUSIONS: On-treatment XVI provided 3D verification images with soft-tissue definition at all anatomic sites at acceptably low radiation doses. This technology sets a new standard in treatment verification and will facilitate novel adaptive radiotherapy techniques.

X-ray volume imaging in bladder radiotherapy verification.

PURPOSE: To assess the clinical utility of X-ray volume imaging (XVI) for verification of bladder radiotherapy and to quantify geometric error in bladder radiotherapy delivery. METHODS AND MATERIALS: Twenty subjects undergoing conformal bladder radiotherapy were recruited. X-ray volume images and electronic portal images (EPIs) were acquired for the first 5 fractions and then once weekly. X-ray volume images were co-registered with the planning computed tomography scan and clinical target volume coverage assessed in three dimensions (3D). Interfraction bladder volume change was described by quantifying changes in bladder volume with time. Bony setup errors were compared from both XVI and EPI. RESULTS: The bladder boundary was clearly visible on coronal XVI views in nearly all images, allowing accurate 3D treatment verification. In 93.5% of imaged fractions, the clinical target volume was within the planning target volume. Most subjects displayed consistent bladder volumes, but 25% displayed changes that could be predicted from the first three XVIs. Bony setup errors were similar whether calculated from XVI or EPI. CONCLUSIONS: Coronal XVI can be used to verify 3D bladder radiotherapy delivery. Image-guided interventions to reduce geographic miss and normal tissue toxicity are feasible with this technology.

Treatment planning evaluation of non-coplanar techniques for conformal radiotherapy of the prostate.

BACKGROUND AND PURPOSE: To evaluate the benefit of using non-coplanar treatment plans for irradiation of two different clinical treatment volumes: prostate only (PO) and the prostate plus seminal vesicles (PSV). MATERIAL AND METHODS: An inverse planning algorithm was used to produce three-field, four-field, five-field and six-field non-coplanar treatment plans without intensity-modulation in ten patients. These were compared against a three-field coplanar plan. A dose of 74 Gy was prescribed to the isocentre. Plans were compared using the minimum dose to the planning target volume (PTV), maximum dose to the small bowel, and irradiated volumes of rectum, bladder and femoral head. Biological indices were also evaluated. RESULTS: For the PO group, volume of rectum irradiated to 60 Gy (V(60)) was 22.5+/-3.7% for the coplanar plan, and 21.5+/-5.3% for the five-field non-coplanar plan, which was the most beneficial (p=0.3). For the PSV group, the five-field non-coplanar plan was again the most beneficial. Rectal V(60) was in this case reduced from 41.5+/-10.4% for the coplanar plan to 35.2+/-9.3% for the non-coplanar plan (p=0.02). CONCLUSIONS: The use of non-coplanar beams in conformal prostate radiotherapy provides a small increase in rectal sparing, more significantly with PSV volumes than for PO volumes.

Technological advances in radiotherapy for the treatment of localised prostate cancer.

There is good evidence that radiation dose escalation in localised prostate cancer is associated with increased cell kill. The traditional two-dimensional (2D) technique of treatment planning and delivery is limited by normal tissue toxicity, such that the dose that can be safely delivered to the prostate by external beam radiotherapy is 65-70 Gy. Several technological advances over the last 20 years have enhanced the precision of external beam radiotherapy (EBRT), and have resulted in improved outcomes. The three-dimensional conformal radiotherapy (3D-CRT) approach reduces the dose-limiting late side-effect of proctitis and has allowed for dose escalation to the whole prostate to 78 Gy. More recently, intensity modulated radiotherapy (IMRT), an advanced form of conformal therapy, has resulted in reduced rectal toxicity when using doses greater than 80 Gy. In addition, IMRT can potentially escalate the dose to specific parts of the prostate where there are resistant subpopulations of tumour clonogens, or can be used to extend the high-dose region to pelvic lymph nodes. The addition of androgen deprivation to conventional radiotherapy has an impact on survival and local control. Initial hormone therapy causes cytoreduction of the prostate cancer allowing for a reduction in radiotherapy volume as well as an additive effect on cell kill. Long-term adjuvant androgen deprivation has been shown to improve overall survival in more advanced tumours. Prostate brachytherapy is now a recognised treatment for those with low-risk disease. It achieves similar long-term outcome to other treatment modalities. Brachytherapy can be used as monotherapy for localised disease, or as boost treatment following conventional EBRT for locally advanced disease. New techniques are available to improve the precision of both target definition and treatment verification. This so-called image-guided radiotherapy will help to enhance the accuracy of dose delivery by correcting both for inter-fraction positional variation and for intra-fraction movement of the prostate in real-time and will allow for tighter tumour margins and avoidance of normal tissues, thereby enhancing the safety of treatment.

Do differences in target volume definition in prostate cancer lead to clinically relevant differences in normal tissue toxicity?

PURPOSE: Many studies have described the quantitated differences between clinicians in target volume definition in prostate cancer. However, few studies have looked at the clinical effects of this. We aimed to assess the relevance and sequelae of such differences. METHODS AND MATERIALS: Five experienced radiation oncologists were given the clinical details of 5 patients with early-stage prostate cancer and asked to define the clinical target volume, consisting of the prostate and seminal vesicles (CTV1) and the prostate alone (CTV2), on specified planning CT scans of the pelvis. Planning target volumes (PTV1) were generated by automatic expansion of the CTV1 by a 1-cm margin. The PTV2 was defined as the CTV2. The rectum and bladder were defined by a single experienced clinician for each plan without knowledge of the involved clinician marking the CTVs. The Pinnacle planning system was used to generate the plans, using four-field conformal radiotherapy, to deliver 64 Gy in 32 fractions to the PTV1 followed by a boost of 10 Gy to the PTV2 (Medical Research Council RT01 trial protocol). Dose-volume histograms were generated for the whole bladder and rectum for each plan and the volume receiving a specific percentage of the dose (e.g., V(90)) calculated for 74 Gy, followed by estimates of normal tissue complication probabilities (NTCPs) for the bladder and rectum. RESULTS: Statistically significant differences were found in the CTV1 and CTV2 and, consequently, the PTV1 among the 5 clinicians (p < 0.0005). Most of the discrepancies occurred at the delineation of the prostatic apex and seminal vesicles, with the smallest variance noted at the rectum-prostate and bladder-prostate interfaces. No statistically significant differences were found among clinicians for the rectal V(90), V(85), V(80), V(70), or V(50) or for the bladder V(85), V(80), V(70), or V(50). A difference was noted among consultants for the bladder V(90) (p = 0.015), although no correlation was found between the bladder V(90) and the size of the outlined volumes. No statistically significant differences were found between the estimates of bladder (p = 0.1) and rectal (p = 0.09) NTCPs. CONCLUSION: The statistically significant difference in outlined volumes of the CTV1, CTV2, and PTV1 among the 5 clinicians is in keeping with the findings of previous studies. However, the interclinician variability did not result in clinically relevant outcomes with respect to the irradiated volume of rectum and bladder or NTCP. This may have been because the outlined areas in which interclinician differences were smallest (the rectal-prostate and prostate-bladder interfaces) are the areas that have the greatest effect on normal tissue toxicity. For the areas in which the interclinician correlation was lowest (the prostatic apex and distal seminal vesicles), the effects on normal tissue toxicity are smallest. The results of this study suggest that interclinician outlining differences in prostate cancer may have less clinical relevance than was previously thought.