Accuracy of Dose Calibrators for 68Ga PET Imaging: Unexpected Findings in a Multicenter Clinical Pretrial Assessment.

We report the discovery of a systematic miscalibration during the work-up process for site validation of a multicenter clinical PET imaging trial using 68Ga, which manifested as a consistent and reproducible underestimation in the quantitative accuracy (assessed by SUV) of a range of PET systems from different manufacturers at several different facilities around Australia. Methods: Sites were asked to follow a strict preparation protocol to create a radioactive phantom with 68Ga to be imaged using a standard clinical protocol before commencing imaging in the trial. All sites had routinely used 68Ga for clinical PET imaging for many years. The reconstructed image data were transferred to an imaging core laboratory for analysis, along with information about ancillary equipment such as the radionuclide dose calibrator. Fourteen PET systems were assessed from 10 nuclear medicine facilities in Australia, with the aim for each PET system being to produce images within 5% of the true SUV. Results: At initial testing, 10 of the 14 PET systems underestimated the SUV by 15% on average (range, 13%-23%). Multiple PET systems at one site, from two different manufacturers, were all similarly affected, suggesting a common cause. We eventually identified an incorrect factory-shipped dose calibrator setting from a single manufacturer as being the cause. The calibrator setting for 68Ga was subsequently adjusted by the users so that the reconstructed images produced accurate values. Conclusion: PET imaging involves a chain of measurements and calibrations to produce accurate quantitative performance. Testing of the entire chain is simple, however, and should form part of any quality assurance program or prequalifying site assessment before commencing a quantitative imaging trial or clinical imaging.

Trans Tasman Radiation Oncology Group: Development of the Assessment of New Radiation Oncology Technology and Treatments (ANROTAT) Framework.

INTRODUCTION: The study aim was to develop a generic framework to derive the parameters to populate health-economic models for the rapid evaluation of new techniques and technologies in radiation oncology. METHODS: A draft framework was developed through horizon scanning for relevant technologies, literature review to identify framework models, and a workshop program with radiation oncology professionals, biostatisticians, health economists and consumers to establish the Framework's structure. It was tested using four clinical protocols, comparing intensity modulated with 3D conformal therapy (post-prostatectomy, anal canal and nasopharynx) and image-guided radiation therapy techniques with off-line review of portal imaging (in the intact prostate). RESULTS: The draft generic research framework consisted of five sequential stages, each with a number of components, and was assessed as to its suitability for deriving the evidence needed to populate the decision-analytic models required for the health-economic evaluations. A final Framework was established from this experience for use by future researchers to provide evidence of clinical efficacy and cost-utility for other novel techniques. The four clinical treatment sites tested during the project were considered suitable to use in future evaluations. CONCLUSIONS: Development of a generic research framework to predict early and long-term clinical outcomes, combined with health-economic data, produced a generally applicable method for the rapid evaluation of new techniques and technologies in radiation oncology. Its application to further health technology assessments in the radiation oncology sector will allow further refinement and support its generalisability.

Delayed rectal and urinary symptomatology in patients treated for prostate cancer by radiotherapy with or without short term neo-adjuvant androgen deprivation.

BACKGROUND AND PURPOSE: To identify contributing factors to delayed rectal and urinary symptoms in a randomised trial comparing different durations of maximal androgen deprivation (MAD), given prior to radiotherapy, for locally advanced prostate cancer. PATIENTS AND METHODS: Between 1996 and 2000, 818 patients with stages T2b,c, 3 and 4 prostate cancer were entered into a trial comparing 0, 3 and 6 months of MAD prior to and during radiotherapy. Their delayed normal tissue effects were recorded by their treating doctors using standardised scales and by the patients using a self-assessment questionnaire regularly. Time to occurrence and prevalence data were analysed. RESULTS: Rectal and urinary symptom levels were observed to vary markedly over time in at least 80% of patients, with some indicating lasting resolution of symptoms. Prevalence rates were found to be substantially lower than actuarial probability rates. Baseline symptom levels and greatest acute symptom levels were both very powerful predictors. Obstructive lower urinary tract symptoms were noted to improve during the first 4 years after radiotherapy in approximately 60% of cases in each treatment arm. However, the treatment arm itself was not shown to influence these improvements in other univariate or multivariate analyses. MAD was shown to reduce both time to occurrence and prevalence of delayed proctopathic symptoms, but this effect was confirmed statistically in the 3 month treatment arm only. Multivariate models indicated that higher levels of haemoglobin prior to any treatment may in some way protect against delayed proctopathic symptoms. CONCLUSIONS: Prevalence data provide more clinically meaningful estimates of risk of delayed effects in normal tissues where assessment relies substantially on reported symptom levels. In these tissues consideration of the impact of baseline symptom levels and pathologies, and greatest acute symptom levels in analyses of delayed effects appears mandatory. Obstructive lower urinary symptoms improve over several years in the majority of patients treated for locally advanced prostate cancer by radiotherapy. Future research could address whether rectal toxicity is affected by initial haemoglobin levels and declines in it due to MAD.

Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial.

BACKGROUND: Androgen deprivation is an established treatment regimen for disseminated prostate cancer; however, its role in patients with localised cancer is less clear. We did a large randomised controlled trial to determine whether 3 months or 6 months of androgen deprivation given before and during radiotherapy improves outcomes for patients with locally advanced prostate cancer. METHODS: 818 men with locally advanced prostate cancer were randomly assigned to: no androgen deprivation (ie, radiotherapy alone: 66 Gy in 33 fractions of 2 Gy per day over 6.5-7.0 weeks to the prostate and seminal vesicles); 3 months' androgen deprivation with 3.6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day starting 2 months before radiotherapy (same regimen as control group); or 6 months' androgen deprivation, with the same regimen, starting 5 months before radiotherapy (same regimen as control group). Primary endpoints were time to local failure and prostate-cancer-specific survival; secondary endpoints were distant failure, disease-free survival, and freedom from salvage treatment. Analyses were done by intention to treat. FINDINGS: 802 (98%) patients were eligible for analysis. Median follow-up was 5.9 years (range 0.1-8.5). Compared with patients assigned no androgen deprivation, those assigned 3 months' treatment had significantly improved local failure (hazard ratio [HR] 0.56 [95% CI 0.39-0.79], p=0.001), biochemical failure-free survival (0.70 [0.56-0.88], p=0.002), disease-free survival (0.65 [0.52-0.80], p=0.0001), and freedom from salvage treatment (0.73 [0.56-0.96], p=0.025). 6 months' androgen deprivation significantly improved local failure (0.42 [0.28-0.62], p<0.0001), biochemical failure-free survival (0.58 [0.46-0.74], p<0.0001), disease-free survival (0.56 [0.45-0.69], p<0.0001), freedom from salvage treatment (0.53 [0.40-0.71], p<0.0001), distant failure (0.67 [0.45-0.99], p=0.046) and prostate-cancer-specific survival (0.56 [0.32-0.98], p=0.04) compared with no androgen deprivation. INTERPRETATION: 6 months' androgen deprivation given before and during radiotherapy improves the outlook of patients with locally advanced prostate cancer. Further follow-up is needed to estimate precisely the size of survival benefits. Increased radiation doses and additional periods of androgen deprivation might lead to further benefit.

Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer.

PURPOSE: To determine the acceptability of short term neo-adjuvant maximal androgen deprivation (MAD) to patients treated with external beam radiation for locally advanced prostate cancer. METHODS: Between 1996 and 2000, 818 patients with locally advanced, but non-metastatic, prostate cancer were entered into a randomised clinical trial (TROG 96.01), which compared radiation treatment alone with the same radiation treatment and 3 or 6 months neo-adjuvant MAD with goserelin and flutamide. Relevant symptoms, and how troublesome they were to the patient, were scored using a self-assessment questionnaire. This was completed by the patient at registration, and at specified times during and after treatment. Patients taking flutamide had liver function tests checked at regular intervals. RESULTS: All patients have completed at least 12 months follow-up after treatment. Nearly all patients completed planned treatment with goserelin, but 27% of patients in the 6-month MAD treatment arm, and 20% in the 3-month arm, had to stop flutamide early. This was mainly due to altered liver function (up to 17% patients) and bowel side effects (up to 8% patients). However, although flutamide resulted in more bowel symptoms for patients on MAD, there was significant reduction in some urinary symptoms on this treatment. Acute bowel and urinary side effects at the end of radiation treatment were similar in all treatment arms. Side effect severity was unrelated to radiation target volume size, which was reduced by MAD, but symptomatology prior to any treatment was a powerful predictor. Of the 36% of patients who were sexually active before any treatment, the majority became inactive whilst on MAD. However, sexual activity at 12 months after radiation treatment was similar in all treatment arms, indicating that the effects of short term MAD on sexual function are reversible. CONCLUSION: Despite temporary effects on sexual activity, and compliance difficulties with flutamide, short-term neo-adjuvant MAD was not perceived by patients to be a major inconvenience. If neo-adjuvant MAD in the way tested can be demonstrated to lead to improved biochemical control and/or survival, then patients would view these therapeutic gains as worthwhile. Compliance with short-term goserelin was excellent, confirming that LH-RH analogues have a potential role in more long-term adjuvant treatment. However, for more protracted androgen deprivation, survival advantages and deleterious effects need to be assessed in parallel, in order to determine the optimal duration of treatment.