Richard A Cowan

Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial

BACKGROUND In men with localised prostate cancer, conformal radiotherapy (CFRT) could deliver higher doses of radiation than does standard-dose conventional radical external-beam radiotherapy, and could improve long-term efficacy, potentially at the cost of increased toxicity. We aimed to present the first analyses of effectiveness from the MRC RT01 randomised controlled trial. METHODS The MRC RT01 trial included 843 men with localised prostate cancer who were randomly assigned to standard-dose CFRT or escalated-dose CFRT, both administered with neoadjuvant androgen suppression. Primary endpoints were biochemical-progression-free survival (bPFS), freedom from local progression, metastases-free survival, overall survival, and late toxicity scores. The toxicity scores were measured with questionnaires for physicians and patients that included the Radiation Therapy Oncology Group (RTOG), the Late Effects on Normal Tissue: Subjective/Objective/Management (LENT/SOM) scales, and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI) scales. Analysis was done by intention to treat. This trial is registered at the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN47772397. FINDINGS Between January, 1998, and December, 2002, 843 men were randomly assigned to escalated-dose CFRT (n=422) or standard-dose CFRT (n=421). In the escalated group, the hazard ratio (HR) for bPFS was 0.67 (95% CI 0.53-0.85, p=0.0007). We noted 71% bPFS (108 cumulative events) and 60% bPFS (149 cumulative events) by 5 years in the escalated and standard groups, respectively. HR for clinical progression-free survival was 0.69 (0.47-1.02; p=0.064); local control was 0.65 (0.36-1.18; p=0.16); freedom from salvage androgen suppression was 0.78 (0.57-1.07; p=0.12); and metastases-free survival was 0.74 (0.47-1.18; p=0.21). HR for late bowel toxicity in the escalated group was 1.47 (1.12-1.92) according to the RTOG (grade >/=2) scale; 1.44 (1.16-1.80) according to the LENT/SOM (grade >/=2) scales; and 1.28 (1.03-1.60) according to the UCLA PCI (score >/=30) scale. 33% of the escalated and 24% of the standard group reported late bowel toxicity within 5 years of starting treatment. HR for late bladder toxicity according to the RTOG (grade >/=2) scale was 1.36 (0.90-2.06), but this finding was not supported by the LENT/SOM (grade >/=2) scales (HR 1.07 [0.90-1.29]), nor the UCLA PCI (score >/=30) scale (HR 1.05 [0.81-1.36]). INTERPRETATION Escalated-dose CFRT with neoadjuvant androgen suppression seems clinically worthwhile in terms of bPFS, progression-free survival, and decreased use of salvage androgen suppression. This additional efficacy is offset by an increased incidence of longer term adverse events.

Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial

Summary Background Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer. Methods Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65–69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633. Results Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4–8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70–78 vs 66%, 60–70; hazard ratio [HR] 0·77, 95% CI 0·61–0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups). Interpretation The benefits of combined modality treatment—ADT and RT—should be discussed with all patients with locally advanced prostate cancer. Funding Canadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council.

Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: Long-term results from the MRC RT01 randomised controlled trial

BACKGROUND The aim of this trial was to compare dose-escalated conformal radiotherapy with control-dose conformal radiotherapy in patients with localised prostate cancer. Preliminary findings reported after 5 years of follow-up showed that escalated-dose conformal radiotherapy improved biochemical progression-free survival. Based on the sample size calculation, we planned to analyse overall survival when 190 deaths occurred; this target has now been reached, after a median 10 years of follow-up. METHODS RT01 was a phase 3, open-label, international, randomised controlled trial enrolling men with histologically confirmed T1b-T3a, N0, M0 prostate cancer with prostate specific antigen of less than 50 ng/mL. Patients were randomly assigned centrally in a 1:1 ratio, using a computer-based minimisation algorithm stratifying by risk of seminal vesicle invasion and centre to either the control group (64 Gy in 32 fractions, the standard dose at the time the trial was designed) or the escalated-dose group (74 Gy in 37 fractions). Neither patients nor investigators were masked to assignment. All patients received neoadjuvant androgen deprivation therapy for 3-6 months before the start of conformal radiotherapy, which continued until the end of conformal radiotherapy. The coprimary outcome measures were biochemical progression-free survival and overall survival. All analyses were done on an intention-to-treat basis. Treatment-related side-effects have been reported previously. This trial is registered, number ISRCTN47772397. FINDINGS Between Jan 7, 1998, and Dec 20, 2001, 862 men were registered and 843 subsequently randomly assigned: 422 to the escalated-dose group and 421 to the control group. As of Aug 2, 2011, 236 deaths had occurred: 118 in each group. Median follow-up was 10·0 years (IQR 9·1-10·8). Overall survival at 10 years was 71% (95% CI 66-75) in each group (hazard ratio [HR] 0·99, 95% CI 0·77-1·28; p=0·96). Biochemical progression or progressive disease occurred in 391 patients (221 [57%] in the control group and 170 [43%] in the escalated-dose group). At 10 years, biochemical progression-free survival was 43% (95% CI 38-48) in the control group and 55% (50-61) in the escalated-dose group (HR 0·69, 95% CI 0·56-0·84; p=0·0003). INTERPRETATION At a median follow-up of 10 years, escalated-dose conformal radiotherapy with neoadjuvant androgen deprivation therapy showed an advantage in biochemical progression-free survival, but this advantage did not translate into an improvement in overall survival. These efficacy data for escalated-dose treatment must be weighed against the increase in acute and late toxicities associated with the escalated dose and emphasise the importance of use of appropriate modern radiotherapy methods to reduce side-effects. FUNDING UK Medical Research Council.

The significance of residual mediastinal abnormality on the chest radiograph following treatment for Hodgkin's disease.

The chest radiographs (CXRs) of 110 patients with mediastinal Hodgkins disease (HD) were reviewed to determine the incidence, degree, and significance of mediastinal abnormalities following treatment. Residual mediastinal abnormalities were defined as either minimal or measurable, and occurred in 64% of all patients at the completion of treatment, but were more common in those with bulky mediastinal disease at presentation (40 of 48, 83%). Fifty-one patients with a mediastinal abnormality at the end of treatment had follow-up films available. Partial or complete regression of the abnormality occurred by 1 year in 30 of these patients (59%). Over a median follow-up of 80.5 months, there were more relapses (13 of 70, 19%) in patients with residual abnormalities following treatment than in those where the mediastinum was considered normal (four of 40, 10%). Measurable abnormality was associated with a higher relapse rate (six of 25, 24%) than minimal abnormality (seven of 45, 16%), but none of these differences were statistically significant. the subsequent relapse rate for patients with persisting abnormality at 1 year was 14%, compared with 17% for patients in whom regression had occurred and 14% in whom the mediastinum had always been considered normal. Considering the whole group, the presence of a mediastinal abnormality following treatment did not predict for relapse, but for the 34 patients treated by chemotherapy (CTR) alone, a residual abnormality was associated with a significantly higher relapse rate (P = .029). We conclude that following mediastinal radiotherapy (XRT) administered either alone or combined with CTR, residual mediastinal abnormalities do not indicate the need for further treatment. However, following CTR alone, such abnormalities may signify persisting disease and we recommend that XRT be considered for these patients.

Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer

Purpose We have previously reported that radiotherapy (RT) added to androgen-deprivation therapy (ADT) improves survival in men with locally advanced prostate cancer. Here, we report the prespecified final analysis of this randomized trial. Patients and Methods NCIC Clinical Trials Group PR.3/Medical Research Council PR07/Intergroup T94-0110 was a randomized controlled trial of patients with locally advanced prostate cancer. Patients with T3-4, N0/Nx, M0 prostate cancer or T1-2 disease with either prostate-specific antigen (PSA) of more than 40 μg/L or PSA of 20 to 40 μg/L plus Gleason score of 8 to 10 were randomly assigned to lifelong ADT alone or to ADT+RT. The RT dose was 64 to 69 Gy in 35 to 39 fractions to the prostate and pelvis or prostate alone. Overall survival was compared using a log-rank test stratified for prespecified variables. Results One thousand two hundred five patients were randomly assigned between 1995 and 2005, 602 to ADT alone and 603 to ADT+RT. At a median follow-up time of 8 years, 465 patients had died, including 199 patients from prostate cancer. Overall survival was significantly improved in the patients allocated to ADT+RT (hazard ratio [HR], 0.70; 95% CI, 0.57 to 0.85; P < .001). Deaths from prostate cancer were significantly reduced by the addition of RT to ADT (HR, 0.46; 95% CI, 0.34 to 0.61; P < .001). Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity, but only two of 589 patients had grade 3 or greater diarrhea at 24 months after RT. Conclusion This analysis demonstrates that the previously reported benefit in survival is maintained at a median follow-up of 8 years and firmly establishes the role of RT in the treatment of men with locally advanced prostate cancer.

A Comparison of the Radiosensitivity of Lymphocytes from Normal Donors, Cancer Patients, Individuals with Ataxia-telangiectasia (A-T) and A-T Heterozygotes

The aim was to determine whether peripheral blood lymphocytes can be used retrospectively to detect hypersensitivity to radiation in breast cancer patients who had exhibited severe reactions to radiotherapy. Blood samples were obtained from patients who developed both acute and late complications. For comparison, samples were also taken from a group of normal individuals, ataxia-telangiectasia (A-T) patients, A-T gene carriers and breast cancer patients previously treated with radiotherapy who failed to develop treatment-related complications. Radiosensitivity was assessed using a limiting dilution clonogenic assay following both high (HDR) and low (LDR) dose-rate irradiation. Following HDR irradiation, only lymphocytes from individuals with A-T were significantly more radiosensitive than those from normal donors. In contrast, at LDR, lymphocytes from A-T heterozygotes and breast cancer over reactors were also, on average, more sensitive than those from normal donors. Lymphocytes from breast cancer patients treated with radiotherapy without developing complications showed no significant differences in radiosensitivity compared with normals. This work has shown that peripheral blood lymphocytes from cancer patients who suffered severe reaction to radiotherapy are, on average, more radiosensitive than those from normal donors, and suggests that lymphocytes may be useful in the future for the development of rapid predictive assays for normal tissue tolerance to radiotherapy.

A potential role of heat shock proteins and nicotinamide N-methyl transferase in predicting response to radiation in bladder cancer

The use of definitive radiotherapy for treatment of invasive bladder cancer has the advantage of preserving bladder function, but tumour regression is only achieved in approximately 40–50% of patients. Knowledge of the molecular basis of sensitivity to ionizing radiation and identification of potential molecular predictors will provide useful information regarding patient response and thus help clinicians to individualize treatment. The recent application of cDNA expression array technology provides a useful tool to investigate hundreds or even thousands of genes in a single experiment. In our study, we have used the Atlas human stress cDNA array™ to investigate the expression profile of stress‐related and DNA repair genes in a radioresistant bladder carcinoma cell line (MGH‐U1) and its radiosensitive subclone (S40b). This provides an ideal situation to study genes related to radiation because the genotypes of both cell lines are basically similar and differential changes detected are likely to be related to the different radiosensitivity phenotype. Of 234 genes blotted on the array, 3 genes (Heat shock protein 90, Heat shock protein 27 and Nicotinamide N‐methyl transferase) showed consistent downregulation in the radiosensitive clone in 2 independent experiments. These results were further confirmed for HSP27 and NNMT using Sybr Green I‐based real‐time QRT‐PCR. The role of heat shock proteins (HSPs) in response to radiation remains to be determined; however, the results of our present work suggest a possible role of HSP27 in determining radiosensitivity. Our study also opens avenues for the investigation of genes, such as NNMT, which has not previously been linked to response to radiation.

Phase II Study of Conformal Hypofractionated Radiotherapy With Concurrent Gemcitabine in Muscle-Invasive Bladder Cancer

PURPOSE The aim of this prospective, phase II trial was to determine the response of muscle-invasive bladder cancer (MIBC) to concurrent chemoradiotherapy of weekly gemcitabine with 4 weeks of radiotherapy (RT; GemX). PATIENTS AND METHODS Fifty patients with transitional cell carcinoma, stage T2-3, N0, M0 after transurethral resection and magnetic resonance imaging, were recruited. Gemcitabine was given intravenously at 100 mg/m(2) on days 1, 8, 15, and 22 of a 28-day RT schedule that delivered 52.5 Gy in 20 fractions. Chemotherapy was stopped for Radiation Therapy Oncology Group (RTOG) grade 3 bladder or bowel toxicity. The primary end points were tumor response, toxicity, and survival. RESULTS All patients completed RT; 46 tolerated all four cycles of gemcitabine. Two patients stopped after two cycles, and two stopped after three cycles, because of bowel toxicity. Forty-seven patients had a post-treatment cystoscopy; 44 (88%) achieved a complete endoscopic response. At a median follow-up of 36 months (range, 15 to 62 months), 36 patients were alive, and 32 of these had a functional and intact bladder. Fourteen patients died; seven died as a result of metastatic MIBC, five died as a result of intercurrent disease, and two died as a result of treatment-associated deaths. Four patients underwent cystectomy; three because of recurrent disease and one because of toxicity. One patient required a bowel resection for late toxicity. By using Kaplan-Meier analyses, 3-year cancer-specific survival was 82%, and overall survival was 75%. CONCLUSION Concurrent gemcitabine-based chemoradiotherapy (ie, GemX) produces a high response rate in MIBC and has durable local control and acceptable toxicity, which allows patients to preserve their own bladder. This treatment modality warrants additional investigation in a phase III setting.

Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model

PURPOSE Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. PATIENTS AND METHODS Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). RESULTS Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). CONCLUSION To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.

The value of bone marrow examination in the staging of Hodgkin's lymphoma: a review of 955 cases seen in a regional cancer centre

Summary. Bone marrow aspirates (BMA) and trephine biopsies (BMT) are commonly performed in the staging of patients with newly diagnosed Hodgkins lymphoma (HL) but the value of these procedures is controversial. The purpose of this study was to evaluate the predictive value of the blood count and erythrocyte sedimentation rate (ESR) for bone marrow involvement (BMI) and the influence of BMI on stage and prognostic score. A retrospective analysis of 955 patients with newly diagnosed HL entered into clinical trials in a regional cancer centre between 1975 and 1999 was performed. BMI was identified by BMT in 50 patients (5·2%) but in only five of these by BMA. The negative predictive values of a normal full blood count (FBC) and ESR for absence of BMI were 98·8% and 97·3%, respectively, and the positive predictive value of an abnormal FBC and ESR for presence of BMI were both 6·7%. BMT did not alter initial patient management in a single case but provided valuable prognostic information in certain subgroups of patients. BMA gave no additional staging information over BMT and abnormalities of blood count and ESR were poor predictors of infiltration. We conclude that BMA should be abandoned for staging purposes in HL and BMT restricted to patients with stage IIB or III disease, for whom valuable prognostic information may be obtained.