Chris Wynne

Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial

BACKGROUND The TROG 96.01 trial assessed whether 3-month and 6-month short-term neoadjuvant androgen deprivation therapy (NADT) decreases clinical progression and mortality after radiotherapy for locally advanced prostate cancer. Here we report the 10-year results. METHODS Between June, 1996, and February, 2000, 818 men with T2b, T2c, T3, and T4 N0 M0 prostate cancers were randomly assigned to receive radiotherapy alone, 3 months of NADT plus radiotherapy, or 6 months of NADT plus radiotherapy. The radiotherapy dose for all groups was 66 Gy, delivered to the prostate and seminal vesicles (excluding pelvic nodes) in 33 fractions of 2 Gy per day (excluding weekends) over 6·5-7·0 weeks. NADT consisted of 3·6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day. NADT began 2 months before radiotherapy for the 3-month NADT group and 5 months before radiotherapy for the 6-month NADT group. Primary endpoints were prostate-cancer-specific mortality and all-cause mortality. Treatment allocation was open label and randomisation was done with a minimisation technique according to age, clinical stage, tumour grade, and initial prostate-specific antigen concentration (PSA). Analysis was by intention-to-treat. The trial has been closed to follow-up and all main endpoint analyses are completed. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000237482. FINDINGS 802 men were eligible for analysis (270 in the radiotherapy alone group, 265 in the 3-month NADT group, and 267 in the 6-month NADT group) after a median follow-up of 10·6 years (IQR 6·9-11·6). Compared with radiotherapy alone, 3 months of NADT decreased the cumulative incidence of PSA progression (adjusted hazard ratio 0·72, 95% CI 0·57-0·90; p=0·003) and local progression (0·49, 0·33-0·73; p=0·0005), and improved event-free survival (0·63, 0·52-0·77; p<0·0001). 6 months of NADT further reduced PSA progression (0·57, 0·46-0·72; p<0·0001) and local progression (0·45, 0·30-0·66; p=0·0001), and led to a greater improvement in event-free survival (0·51, 0·42-0·61, p<0·0001), compared with radiotherapy alone. 3-month NADT had no effect on distant progression (0·89, 0·60-1·31; p=0·550), prostate cancer-specific mortality (0·86, 0·60-1·23; p=0·398), or all-cause mortality (0·84, 0·65-1·08; p=0·180), compared with radiotherapy alone. By contrast, 6-month NADT decreased distant progression (0·49, 0·31-0·76; p=0·001), prostate cancer-specific mortality (0·49, 0·32-0·74; p=0·0008), and all-cause mortality (0·63, 0·48-0·83; p=0·0008), compared with radiotherapy alone. Treatment-related morbidity was not increased with NADT within the first 5 years after randomisation. INTERPRETATION 6 months of neoadjuvant androgen deprivation combined radiotherapy is an effective treatment option for locally advanced prostate cancer, particularly in men without nodal metastases or pre-existing metabolic comorbidities that could be exacerbated by prolonged androgen deprivation. FUNDING Australian Government National Health and Medical Research Council, Hunter Medical Research Institute, AstraZeneca, and Schering-Plough.

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.

Risk Stratification after Biochemical Failure following Curative Treatment of Locally Advanced Prostate Cancer: Data from the TROG 96.01 Trial

Purpose. Survival following biochemical failure is highly variable. Using a randomized trial dataset, we sought to define a risk stratification scheme in men with locally advanced prostate cancer (LAPC). Methods. The TROG 96.01 trial randomized 802 men with LAPC to radiation ± neoadjuvant androgen suppression therapy (AST) between 1996 and 2000. Ten-year follow-up data was used to develop three-tier post-biochemical failure risk stratification schemes based on cutpoints of time to biochemical failure (TTBF) and PSA doubling time (PSADT). Schemes were evaluated in univariable, competing risk models for prostate cancer-specific mortality. The performance was assessed by c-indices and internally validated by the simple bootstrap method. Performance rankings were compared in sensitivity analyses using multivariable models and variations in PSADT calculation. Results. 485 men developed biochemical failure. c-indices ranged between 0.630 and 0.730. The most discriminatory scheme had a high risk category defined by PSADT < 4 months or TTBF < 1 year and low risk category by PSADT > 9 months or TTBF > 3 years. Conclusion. TTBF and PSADT can be combined to define risk stratification schemes after biochemical failure in men with LAPC treated with short-term AST and radiotherapy. External validation, particularly in long-term AST and radiotherapy datasets, is necessary.

The use of simulator and CT information in the planning of radiotherapy for non-small cell lung cancer: An Australasian patterns of practice study

Abstract In a patterns of practice study 14 Australasian radiation oncologists were invited to define tumour and target volumes in 12 sample cases of non-small cell carcinoma of the lung (NSCCL) firstly using orthogonal simulator AP and lateral radiographic views, then using computed tomography (CT) slices obtained in the treatment position. In addition, they were asked to complete questionnaires addressing their criteria for determining treatment policy and their reasons for choosing specific tumour and target volume boundaries in individual cases. Significant variations in choice of size and position of both tumour and target volume were apparent between clinicians. These variations, however were no greater for simulator planned volumes than for CT planned volumes, except in cases selected for palliative treatment, were CT planned volumes were significantly larger. Failure to include tumour extensions, the mistaken inclusion of normal structures as tumour, and major differences in allowance for microscopic tumour spread were identified as the most significant cause for variation in the size and positioning of target volumes between clinicians. Differences over margins to allow for factors such as variation in day-to-day set-up, patient movement, equipment-related factors, etc, were also apparent. CT and simulator planned target volumes were equally successful in adequate tumour coverage; 79162 (49%), and 80162 (49%) respectively. Gross miss of tumour was more common in simulator planned target volumes than CT planned target volumes; 70162 (43%) and 55162 (34%), respectively. This study supports the integration of diagnostic expertise into the planning process for simulator and CT planning, but suggests that substantial practice variation would still exist in planning for radiotherapy in NSCCL.

Paradoxical metastatic progression following 3 months of neo-adjuvant androgen suppression in the TROG 96.01 trial for men with locally advanced prostate cancer

PURPOSE In the TROG 96.01 trial 6 month neo-adjuvant androgen suppression (NAS) and radiotherapy (RT) for locally advanced prostate cancer prevented distant progressions (DPs) when compared to RT alone, but 3 months did not. We ask why? METHODS Between 1996 and 2000, 802 men with T2-4 N0 M0 prostate cancers received RT alone (0 month NAS) to 66 Gy, 3 months or 6 months NAS before RT. Interval hazards and cumulative incidences of DP were compared using competing risks methodology. RESULTS In the first 4 follow-up years 39, 40 and 26 DPs were diagnosed in subjects treated with 0, 3 and 6 month NAS, respectively. Compared with 0 month, significant reductions in PSA doubling time in subjects with DP occurred following 3 month NAS (p=0.01), but a significant reduction (p=0.01) and a near significant delay in DPs (p=0.06) occurred after 6 month NAS. Subsequently 25, 20 and 11 DPs occurred in the three trial arms. After early secondary therapy for PSA or local progression 34, 19 and 12 DPs were diagnosed after median delays of almost 4 years. CONCLUSIONS The data are consistent with the failure of 3 month NAS to prevent the progression of sub-clinical metastatic deposits already present before treatment.

Radiation Myelopathy after 36 Gy in 12 Fractions Palliative Chest Radiotherapy for Squamous Cell Cancer of the Lung: Case Report and Review of Published Studies

A 55 year old man was treated with 36 Gy in 12 fractions palliative chest irradiation for squamous cell carcinoma of the lung. This was followed by 3 cycles of cisplatin and gemcitabine. Five months later he developed clinical and imaging findings consistent with radiation myelopathy. The maximum spinal cord dose was 38.9 Gy. The possible contributions of portal imaging and gemcitabine are discussed and the literature reviewed.