Medical Research Council RT01 Research Articles

Older Age, Early Symptoms and Physical Function are Associated with the Severity of Late Symptom Clusters for Men Undergoing Radiotherapy for Prostate Cancer

AimsTo identify symptom clusters and predisposing factors associated with long-term symptoms and health-related quality of life after radiotherapy in men with prostate cancer. Materials and methodsPatient-reported outcomes (PROs) data from the Medical Research Council RT01 radiotherapy with neoadjuvant androgen deprivation therapy trial of 843 patients were used. PROs were collected over 5 years with the University of California, Los Angeles Prostate Cancer Index (UCLA-PCI) and the 36 item Short-Form Health Survey (SF-36). Symptom clusters were explored using hierarchical cluster analysis. The association of treatment dose, baseline patient characteristics and early symptom clusters with the change in severity of PROs over 3 years was investigated with multivariate linear mixed effects models. ResultsSeven symptom clusters of three or more symptoms were identified. The clusters were stable over time. The longitudinal profiles of symptom clusters showed the onset of acute symptoms during treatment for all symptom clusters and significant recovery by 6 months. Some clusters, such as physical health and sexual function, were adversely affected more than others by androgen deprivation therapy, and were less likely to return to pretreatment levels over time. Older age was significantly associated with decreased long-term physical function, physical health and sexual function (P < 0.001). Both baseline and acute symptom clusters were significant antecedents for impaired function and health-related quality of life at 3 years. ConclusionsMen with poorer physical function and health before or during treatment were more likely to report poorer PROs at year 3. Early assessment using PROs and lifestyle interventions should be used to identify those with higher needs and provide targeted rehabilitation and symptom management.

Symptom clusters for revising scale membership in the analysis of prostate cancer patient reported outcome measures: a secondary data analysis of the Medical Research Council RT01 trial (ISCRTN47772397)

PurposeTo investigate the role of symptom clusters in the analysis and utilisation of patient reported outcome measures (PROMs) for data modelling and clinical practice. To compare symptom clusters with scales, and to explore their value in PROMs interpretation and symptom management.MethodsA dataset called RT01 (ISCRTN47772397) of 843 prostate cancer patients was used. PROMs were reported with the University of California, Los Angeles Prostate Cancer Index (UCLA-PCI). Symptom clusters were explored with hierarchical cluster analysis (HCA) and average linkage method (correlation > 0.6). The reliability of the Urinary Function Scale was evaluated with Cronbach’s Alpha. The strength of the relationship between the items was investigated with Spearman’s correlation. Predictive accuracy of the clusters was compared to the scales by receiver operating characteristic (ROC) analysis. Presence of urinary symptoms at 3 years measured with the late effects on normal tissue: subjective, objective, management tool (LENT/SOM) was an endpoint.ResultsTwo symptom clusters were identified (urinary cluster and sexual cluster). The grouping of symptom clusters was different than UCLA-PCI Scales. Two items of the urinary function scales (“number of pads” and “urinary leak interfering with sex”) were excluded from the urinary cluster. The correlation with the other items in the scale ranged from 0.20 to 0.21 and 0.31 to 0.39, respectively. Cronbach’s Alpha showed low correlation of those items with the Urinary Function Scale (0.14–0.36 and 0.33–0.44, respectively). All urinary function scale items were subject to a ceiling effect. Clusters had better predictive accuracy, AUC = 0.70 –0.65, while scales AUC = 0.67–0.61.ConclusionThis study adds to the knowledge on how cluster analysis can be applied for the interpretation and utilisation of PROMs. We conclude that multiple-item scales should be evaluated and that symptom clusters provide a study-specific approach for modelling and interpretation of PROMs.

The Impact of Clinical Factors on the Development of Late Radiation Toxicity: Results from the Medical Research Council RT01 Trial (ISRCTN47772397)

Aims A variety of dosimetric parameters have been shown to influence the incidence of late radiation toxicity. The effect of other treatment- and patient-related factors is less well established. The aim of this study was to elucidate the influence of such factors in the development of late symptoms after radical radiotherapy to the prostate. Materials and methods Patient- and treatment-related factors that are thought to influence the development of late toxicity were analysed in 788 patients who had received radical radiotherapy to the prostate in the Medical Research Council RT01 trial. Late toxicity data were recorded using the Radiation Therapy Oncology Group, Late Effects of Normal Tissues/Subjective, Objective, Management, Analytic, Royal Marsden Hospital and the University of California, Los Angeles, Prostate Cancer Index. Acute toxicity was measured using the Radiation Therapy Oncology Group grading system. Results On multivariate analysis, acute bowel toxicity was statistically significantly associated with increased proctitis (hazard ratio = 1.63, 95% confidence interval 1.18, 2.24; P = 0.003) and increased stool frequency (hazard ratio = 1.77, 95% confidence interval 1.27, 2.46; P = 0.001). Hypertension was strongly associated with a decreased risk of poor urinary stream (hazard ratio = 0.25, 95% confidence interval 0.09, 0.71; P = 0.009). There was an increased risk of rectal bleeding with increased age (hazard ratio = 1.04 per year of age, 95% confidence interval 1.01, 1.08; P = 0.009). As expected, a higher prescribed dose increased the risk of several late toxicity end points. Although acute bladder toxicity was associated with the presence of bladder symptoms at 5 years, the effect disappeared for all symptoms except increased urinary frequency and haematuria when a change in bladder function from baseline was calculated. Patients with any pretreatment bladder symptoms were more likely to report increased urinary frequency (hazard ratio = 2.09, 95% confidence interval 1.48, 2.95; P < 0.0005), increased urinary incontinence (hazard ratio = 4.22, 95% confidence interval 2.13, 8.35; P < 0.0005) and decreased stream (hazard ratio = 2.64, 95% confidence interval 1.62, 4.31; P < 0.0005), after treatment and before the most recent follow-up assessment. Conclusions In this study, increased acute gastrointestinal and bladder symptoms and prescribed dose were associated with increased late radiation toxicity. The presence of hypertension seemed to be protective for the development of late effects. Baseline symptoms should be taken into account when radiation toxicity is analysed.

Late Gastrointestinal Toxicity After Dose-Escalated Conformal Radiotherapy for Early Prostate Cancer: Results From the UK Medical Research Council RT01 Trial (ISRCTN47772397)

PurposeIn men with localized prostate cancer, dose-escalated conformal radiotherapy (CFRT) improves efficacy outcomes at the cost of increased toxicity. We present a detailed analysis to provide further information about the incidence and prevalence of late gastrointestinal side effects.Methods and MaterialsThe UK Medical Research Council RT01 trial included 843 men with localized prostate cancer, who were treated for 6 months with neoadjuvant radiotherapy and were randomly assigned to either 64-Gy or 74-Gy CFRT. Toxicity was evaluated before CFRT and during long-term follow-up using Radiation Therapy Oncology Group (RTOG) grading, the Late Effects on Normal Tissue: Subjective, Objective, Management (LENT/SOM) scale, and Royal Marsden Hospital assessment scores. Patients regularly completed Functional Assessment of Cancer Therapy--Prostate (FACT-P) and University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) questionnaires.ResultsIn the dose-escalated group, the hazard ratio (HR) for rectal bleeding (LENT/SOM grade ≥2) was 1.55 (95% CI, 1.17–2.04); for diarrhea (LENT/SOM grade ≥2), the HR was 1.79 (95% CI, 1.10–2.94); and for proctitis (RTOG grade ≥2), the HR was 1.64 (95% CI, 1.20–2.25). Compared to baseline scores, the prevalence of moderate and severe toxicities generally increased up to 3 years and than lessened. At 5 years, the cumulative incidence of patient-reported severe bowel problems was 6% vs. 8% (standard vs. escalated, respectively) and severe distress was 4% vs. 5%, respectively.ConclusionsThere is a statistically significant increased risk of various adverse gastrointestinal events with dose-escalated CFRT. This remains at clinically acceptable levels, and overall prevalence ultimately decreases with duration of follow-up.

A Comparison of Treatment Planning Techniques Used in Two Randomised UK External Beam Radiotherapy Trials for Localised Prostate Cancer

Aims To compare the radiotherapy planning techniques from two multicentre randomised external beam radiotherapy trials in the UK of conformal radiotherapy vs intensity-modulated radiotherapy (IMRT). Materials and methods Sixteen sequential patients with histologically confirmed localised prostate cancer treated in the conventional or hypofractionated IMRT trial (CHHiP) were planned using both the CHHiP and Medical Research Council RT-01 planning protocols to 74 Gy in 37 daily fractions. The CHHiP plan used a single phase simple forward planned three-field IMRT plan for easy multicentre adoption. The RT-01 plan used two phases: three-field conformal radiotherapy plan to 64 Gy followed by a six-field boost of 10 Gy. After coverage of the planning target volumes according to the respective trial protocols, the dose to the rectum and bladder was assessed for the two planning techniques. Results There was acceptable planning target volume coverage by both the CHHiP and RT-01 plans. All CHHiP plans produced lower mean irradiated rectal volumes at all measured dose levels compared with the RT-01 plans, particularly for irradiated rectal volumes at 50 and 70 Gy ( P < 0.05). In the cases when a CHHiP plan failed to meet its own trial dose constraints, the volumes of irradiated rectum were less than if an RT-01 planning technique had been used. The CHHiP plans gave lower mean irradiated bladder volumes at both 50 and 60 Gy, but higher volumes at 74 Gy. These differences in irradiated bladder volumes were significant at the 60 and 74 Gy dose levels ( P < 0.05) in favour of the CHHiP and RT-01 plans, respectively. Conclusion The forward planned CHHiP IMRT planning solution gives more favourable rectal sparing than the RT-01 plan. This is important to limit any potential increase in late rectal toxicity for prostate cancer patients treated with high-dose conventional or hypofractionated schedules.

The quality of life of men with locally advanced prostate cancer during neoadjuvant hormone therapy: data from the Medical Research Council RT01 trial (ISRCTN 47772397)

The quality of life of men with locally advanced prostate cancer during neoadjuvant hormone therapy: data from the Medical Research Council RT01 trial (ISRCTN 47772397)

The quality of life of men with locally advanced prostate cancer during neoadjuvant hormone therapy: data from the Medical Research Council RT01 trial (ISRCTN 47772397)

To explore patients' quality of life (QoL) during neoadjuvant hormone therapy (HT) using data from the Medical Research Council RT01 trial of standard- (64 Gy/32-fraction) and high- (74 Gy/37-fraction) dose radiotherapy (RT, both given conformally). Of the 843 patients randomized to the RT01 trial, 316 completed the Functional Assessment Of Cancer Therapy core questionnaire with its additional prostate subscale, and the Short Form-36 Health Survey questionnaire with the University of California-Los Angeles Prostate Cancer Index before HT and again before starting RT. Three predefined QoL hypotheses were generated to focus the analyses. For the three primary QoL analyses there was evidence that sexual functioning deteriorated, urinary function did not change, and there was a slight decline in physical well-being after > or = 3 months of HT. Sensitivity analyses confirmed these findings. Exploratory analyses also suggested that role functioning deteriorated, sleep was more disturbed, and there was an increase in fatigue. However, overall QoL was not reported to be affected and patients indicated an improvement in attitude and satisfaction with treatment. In this group of men, many of whom reported reduced sexual functioning before treatment, the additional decline during HT seemed to be generally accepted as the price to pay for an appropriate cancer treatment. Nevertheless, these changes need to be discussed with patients before HT is commenced.

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)

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). 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. 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). 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.

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

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. 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. 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. 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.

Implementing the UK Medical Research Council (MRC) RT01 trial (ISRCTN 47772397): methods and practicalities of a randomised controlled trial of conformal radiotherapy in men with localised prostate cancer

Background and purpose Radiotherapy is the most frequently used treatment for men with localised prostate cancer. Conformal radiotherapy (CFRT) is a relatively new development. MRC RT01 was set-up to explore optimum CFRT dose. Patients and methods RT01 was an international multi-centre randomised controlled trial for men with T1b-T3a, N0, M0 prostate cancer that evolved from a single-centre pilot trial of similar design. All men received at least 3 months of pre-radiotherapy hormone treatment, before randomisation to standard (64 Gy) or high dose (74 Gy) radical CFRT. Accrual was completed in December 2001 with 843 men randomised from 25 centres in less than 4 years. RT01 has been a catalyst for implementing CFRT across UK. In addition to the Trial Management Group, independent Data Monitoring and Ethics Committee and independent Trial Steering Committee, a Quality of Life and Health Economics (QL/HE) group, a radiotherapy Quality Assurance (QA) Group and a Radiography Trial Implementation Group were set up. The QL/HE group ensured implementation, compliance, analysis and interpretation of the QL and HE data in the trial. The inauguration of QA and Radiography groups facilitated inter-centre collaboration. The QA Group ensured procedures were in place before and during trial participation, and monitored quality and consistency with systems including a physics questionnaire, a clinical examples exercise, a standard operating procedure document, designing and building a phantom, and convening a complications modelling subgroup. The Radiography group agreed and implemented technique improvements. Results More centres participated than initially predicted, enabling recruitment better than scheduled. The trial expedited the implementation of CFRT in many UK radiotherapy centres. Additionally, the QA and Radiography groups helped ensure smooth initiation and established consistency in planning, dosimetry and delivery of prostate CFRT services at participating UK centres. Considerable data has been collected; a series of papers will be produced, although mature clinical trial results are not anticipated until 2006–2008.