Chris Atkinson

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.

PHENOTYPIC CHARACTERISATION OF THE DENDRITIC CELL INFILTRATE IN PROSTATE CANCER

PURPOSE To investigate whether dendritic cells (DC), which as professional antigen presenting cells have the capacity to stimulate immune responses against tumour associated antigens, are recruited into and activated within prostate cancer. MATERIALS AND METHODS Immunoenzyme and immunofluorescence labelling was used to identify leucocyte and DC subsets within 15 cases of prostate cancer. Cell numbers were compared with numbers in adjacent normal prostatic tissue. Total DC numbers were identified as CD45+ leucocytes not coexpressing any lineage specific markers. The Langerhans cell (LC) subset was detected using anti CD1a staining and activated DC were identified by their expression of either CD83, CD86 or CMRF44. RESULTS DC were found to represent a small subset of leucocytes present in both benign and malignant prostatic tissue. Statistically there were significantly less DC and LC in prostate cancer compared with normal prostatic tissue. While only a small subset of DC expressed markers of activation in prostate cancer, this was significantly more than the virtual absence of activated DC in normal prostatic tissue. CONCLUSIONS This is the first time that DC have been studied in prostate cancer using the relatively new DC specific monoclonal antibodies CD83 and CMRF-44. These findings suggest that there is no active recruitment of DC into prostate cancer and those DC present are only minimally activated.

Time to biochemical failure and prostate-specific antigen doubling time as surrogates for prostate cancer-specific mortality : evidence from the TROG 96.01 randomised controlled trial

BACKGROUND Surrogate endpoints for prostate cancer-specific mortality after curative primary treatment are not well established. We sought to assess time to biochemical failure (TTBF) and prostate-specific antigen doubling time (PSADT) after failure of curative treatment as candidates for this endpoint. METHODS PSA and survival data from the Trans-Tasman Radiation Oncology Group (TROG) 96.01 trial were used to assess surrogate candidates. Between June 28, 1996, and Feb 16, 2000, 802 eligible men with locally advanced prostate cancer were randomly allocated to prostatic irradiation alone, or to 3 or 6 months of maximum short-term androgen deprivation (STAD) before and during radiation. Successful surrogates were required to satisfy the Prentice criteria and to predict the trial finding. The TROG 96.01 trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000237482. FINDINGS 6 months of STAD was shown to significantly decrease prostate cancer-specific mortality compared with radiation alone, but 3 months of STAD did not result in a decrease. Relative to radiation alone, the hazard ratio of prostate cancer-specific mortality from randomisation was 0.95 (95% CI 0.63-1.41; p=0.79) in the 3-month STAD treatment arm and 0.56 (0.36-0.88; p=0.01) in the 6-month arm. PSADT predicted the trial finding and satisfied all four Prentice criteria at the cutpoints of less than 12 months and less than 15 months, with proportion of treatment effect ratios between 0.36 and 0.56. Time to biochemical failure was better than PSADT at predicting the trial finding and satisfying all four Prentice criteria at cutpoints of less than 1.5, less than 2, and less than 2.5 years, with proportion of treatment effect ratios between 0.45 and 0.64. INTERPRETATION This study provides proof of principle that TTBF and PSADT can be useful as surrogate endpoints for prostate cancer-specific mortality and offer potential to substantially reduce follow up in clinical trials. These endpoints now require assessment in multi-trial meta-analyses before use in clinical trials.

Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial.

BACKGROUND We investigated whether 18 months of androgen suppression plus radiotherapy, with or without 18 months of zoledronic acid, is more effective than 6 months of neoadjuvant androgen suppression plus radiotherapy with or without zoledronic acid. METHODS We did an open-label, randomised, 2 × 2 factorial trial in men with locally advanced prostate cancer (either T2a N0 M0 prostatic adenocarcinomas with prostate-specific antigen [PSA] ≥10 μg/L and a Gleason score of ≥7, or T2b-4 N0 M0 tumours regardless of PSA and Gleason score). We randomly allocated patients by computer-generated minimisation--stratified by centre, baseline PSA, tumour stage, Gleason score, and use of a brachytherapy boost--to one of four groups in a 1:1:1:1 ratio. Patients in the control group were treated with neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) for 6 months (short-term) and radiotherapy alone (designated STAS); this procedure was either followed by another 12 months of androgen suppression with leuprorelin (intermediate-term; ITAS) or accompanied by 18 months of zoledronic acid (4 mg every 3 months for 18 months, intravenously; STAS plus zoledronic acid) or by both (ITAS plus zoledronic acid). The primary endpoint was prostate cancer-specific mortality. This analysis represents the first, preplanned assessment of oncological endpoints, 5 years after treatment. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00193856. FINDINGS Between Oct 20, 2003, and Aug 15, 2007, 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 7·4 years (IQR 6·5-8·4). Cumulative incidences of prostate cancer-specific mortality were 4·1% (95% CI 2·2-7·0) in the STAS group, 7·8% (4·9-11·5) in the STAS plus zoledronic acid group, 7·4% (4·6-11·0) in the ITAS group, and 4·3% (2·3-7·3) in the ITAS plus zoledronic acid group. Cumulative incidence of all-cause mortality was 17·0% (13·0-22·1), 18·9% (14·6-24·2), 19·4% (15·0-24·7), and 13·9% (10·3-18·8), respectively. Neither prostate cancer-specific mortality nor all-cause mortality differed between control and experimental groups. Cumulative incidence of PSA progression was 34·2% (28·6-39·9) in the STAS group, 39·6% (33·6-45·5) in the STAS plus zoledronic acid group, 29·2% (23·8-34·8) in the ITAS group, and 26·0% (20·8-31·4) in the ITAS plus zoledronic acid group. Compared with STAS, no difference was noted in PSA progression with ITAS or STAS plus zoledronic acid; however, ITAS plus zoledronic acid reduced PSA progression (sub-hazard ratio [SHR] 0·71, 95% CI 0·53-0·95; p=0·021). Cumulative incidence of local progression was 4·1% (2·2-7·0) in the STAS group, 6·1% (3·7-9·5) in the STAS plus zoledronic acid group, 1·5% (0·5-3·7) in the ITAS group, and 3·4% (1·7-6·1) in the ITAS plus zoledronic acid group; no differences were noted between groups. Cumulative incidences of bone progression were 7·5% (4·8-11·1), 14·6% (10·6-19·2), 8·4% (5·5-12·2), and 7·6% (4·8-11·2), respectively. Compared with STAS, STAS plus zoledronic acid increased the risk of bone progression (SHR 1·90, 95% CI 1·14-3·17; p=0·012), but no differences were noted with the other two groups. Cumulative incidence of distant progression was 14·7% (10·7-19·2) in the STAS group, 17·3% (13·0-22·1) in the STAS plus zoledronic acid group, 14·2% (10·3-18·7) in the ITAS group, and 11·1% (7·6-15·2) in the ITAS plus zoledronic acid group; no differences were recorded between groups. Cumulative incidence of secondary therapeutic intervention was 25·6% (20·5-30·9), 28·9% (23·5-34·5), 20·7% (16·1-25·9), and 15·3% (11·3-20·0), respectively. Compared with STAS, ITAS plus zoledronic acid reduced the need for secondary therapeutic intervention (SHR 0·67, 95% CI 0·48-0·95; p=0·024); no differences were noted with the other two groups. An interaction between trial factors was recorded for Gleason score; therefore, we did pairwise comparisons between all groups. Post-hoc analyses suggested that the reductions in PSA progression and decreased need for secondary therapeutic intervention with ITAS plus zoledronic acid were restricted to tumours with a Gleason score of 8-10, and that ITAS was better than STAS in tumours with a Gleason score of 7 or lower. Long-term morbidity and quality-of-life scores were not affected adversely by 18 months of androgen suppression or zoledronic acid. INTERPRETATION Compared with STAS, ITAS plus zoledronic acid was more effective for treatment of prostate cancers with a Gleason score of 8-10, and ITAS alone was effective for tumours with a Gleason score of 7 or lower. Nevertheless, these findings are based on secondary endpoint data and post-hoc analyses and must be regarded cautiously. Long- term follow-up is necessary, as is external validation of the interaction between zoledronic acid and Gleason score. STAS plus zoledronic acid can be ruled out as a potential therapeutic option. FUNDING National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Calvary Health Care (Calvary Mater Newcastle Radiation Oncology Fund), Hunter Medical Research Institute, Maitland Cancer Appeal, Cancer Standards Institute New Zealand.

Ameloblastoma of the jaw. A reappraisal of the role of megavoltage irradiation

Ten patients with ameloblastoma of the jaw were treated with megavoltage irradiation between 1958 and 1982. Seven cases were treated with radiation alone and six responded initially. One patient subsequently recurred and was successfully salvaged surgically. Three patients were treated with combined radiation therapy and surgery. Carefully applied megavoltage irradiation has a useful role in the management of ameloblastoma, particularly in large maxillary tumors with associated destruction of the infrastructure of the maxillary antrum. It is apparent from this series, and from the literature, that the ameloblastoma is not an inherently radioresistant tumor.

Carboplatin is ototoxic

SummaryFor assessment of the ototoxic potential of carboplatin [cis-diammine-1,1-cyclobutane dicarboxylate platinum(II); CBDCA], pure-tone audiograms were evaluated in 27 patients receiving a total of 119 doses of carboplatin in the range of 300–400 mg/m2. Pure-tone audiometry (PTA) was done immediately prior to and 4 weeks after the administration of 80 doses (67%). Defining carboplatin ototoxicity as an increase of ⩾ 30 dB in auditory thresholds that was unexplainable by other causes, we identified 5 examples (19%). Hearing loss tended to be cumulative with increasing dose and was always maximal at 8,000 Hz. Two patients had an increase in auditory thresholds at 1,000 Hz, but this only amounted to 10 dB in each case. Patients developing ototoxicity tended to be older. Sex, the pre-treatment creatinine clearance, the pretreatment audiogram, the number of doses, and the cumulative dose did not emerge as being reliable predictors of subsequent ototoxicity. We conclude that although carboplatin is ototoxic, clinically significant deafness does not occur with conventional dosing and routine audiometric monitoring is therefore unnecessary. However, we suggest that caution should be exercised when carboplatin is given either at higher doses or for longer periods when there is concomitant use of other potentially ototoxic agents or when there is significant pre-existing auditory impairment.

CD1A DENDRITIC CELLS PREDOMINATE IN TRANSITIONAL CELL CARCINOMA OF BLADDER AND KIDNEY BUT ARE MINIMALLY ACTIVATED

PURPOSE In this study, we employed similar techniques to detail dendritic cell subsets within bladder transitional cell carcinoma and kidney transitional cell carcinoma. MATERIALS AND METHODS To identify both the CD1a+ and CD1a- antigen-expressing dendritic cell populations we employed a double labeling technique to identify non-lineage-expressing leukocytes similar to that employed to isolate blood dendritic cells. RESULTS Dendritic cells were found in significant numbers within both bladder and kidney derived transitional cell carcinoma. Almost all the dendritic cells among the tumor cells belonged to the CD1a+ subset of epithelial dendritic cells. Similar numbers of dendritic cells were observed in the lamina propria adjacent to the tumor. These dendritic cells belonged predominantly to the CD1a- subset. These differences appear to reflect the different dendritic cell phenotypes reported for the epidermis and dermis. CONCLUSIONS The number of dendritic cells increased as the grade of the tumor increased, reflecting an overall higher leukocyte density in higher grade tumors. However, a possible trend for less dendritic cell activation in higher grade cancers was noted, raising the intriguing possibility that this might be a relevant prognostic factor, to be confirmed in a larger study.

Quality of life in men with locally advanced prostate cancer treated with leuprorelin and radiotherapy with or without zoledronic acid (TROG 03.04 RADAR): secondary endpoints from a randomised phase 3 factorial trial

BACKGROUND Adjuvant androgen suppression and bisphosphonates with escalating doses of radiotherapy might improve efficacy outcomes in men with locally advanced prostate cancer. In this study, we investigated whether these treatments had a detrimental effect on patient-reported-outcome (PRO) scores. METHODS We undertook a phase 3 trial with a 2×2 factorial design in 23 centres in Australia and New Zealand in men with non-metastatic adenocarcinoma of the prostate (stage T2b-4 or T2a, Gleason score ≥7, and baseline prostate-specific antigen concentration [PSA] ≥10 μg/L), and without previous lymph node or systemic metastases or comorbidities that could reduce life expectancy to less than 5 years. The men were randomly assigned in a 1:1:1:1 ratio to 6 months of neoadjuvant (short-term) androgen suppression (STAS) with leuprorelin (22·5 mg every 3 months, intramuscularly) or an additional 12 months (intermediate-term androgen suppression [ITAS]) of leuprorelin with or without 18 months of zoledronic acid (4 mg every 3 months, intravenously). Study drug administration commenced at randomisation after which radiotherapy started within the fifth month in all groups. Treatment allocation was open-label, and computer-generated randomisation, stratified by centre, baseline concentrations of PSA, clinical stage of the tumour, Gleason score, and use of a brachytherapy boost, was done by use of the minimisation technique. PRO scores were calculated from European Organization for Research and Treatment of Cancer quality-of-life and prostate-specific quality-of-life module questionnaires and compared with multiple regression models at baseline, and end of radiotherapy, and 18 months and 36 months according to group and radiation dose. The trial is ongoing and the primary endpoint, prostate-cancer-specific mortality, will be reported in 2014. This study is the final report of PRO scores (a secondary endpoint). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00193856. FINDINGS 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). At the end of radiotherapy, significant detrimental changes in PRO scores (p<0·01) occurred in all groups. There were no significant differences in global health status between groups at any timepoint. At 18 months, PROs that were significantly worse in the ITAS groups when compared with STAS were hormone-treatment-related symptoms (HTRS; STAS, 10·20 [95% CI 8·66-11·75]; ITAS, 17·36 [13·63-21·08], p<0·01; and ITAS plus zoledronic acid, 19·14 [15·43-22·85], p<0·01), sexual activity (STAS, 26·38 [23·50-29·27]; ITAS, 14·40 [7·44-21·36], p<0·01; and ITAS plus zoledronic acid, 16·34 [9·39-23·28], p<0·01), social function (STAS, 90·31 [87·89-92·73]; ITAS, 87·35 [81·52-93·18], p=0·09; and ITAS plus zoledronic acid, 83·66 [77·85-89·48], p<0·01), fatigue (STAS, 17·05 [14·58-19·51]; ITAS 24·52 [18·58-30·46], p<0·01; and ITAS plus zoledronic acid, 24·26 [18·33-30·18], p<0·01), and financial problems (STAS, 3·39 [1·29-5·48]; ITAS, 8·97 [3·92-14·02], p<0·01; and ITAS plus zoledronic acid, 8·92 [3·89-13·96], p<0·01). With the exception of HTRS, in which marginal differences remained, persisting significant differences disappeared by 36 months. Other factors associated with significant detrimental changes in PRO scores were a brachytherapy boost, incomplete testosterone and haemoglobin recoveries, age, and smoking. INTERPRETATION Compared with 6 months of androgen suppression, 18 months of androgen suppression causes additional detrimental changes at the 18 month follow-up in some PRO scores but not in global quality-of-life scores. However, with the exception of HTRS, these differences resolved by 36 months. The use of zoledronic acid every 3 months over 18 months does not result in additional detrimental changes, but the use of a brachytherapy boost to achieve radiation dose escalation in the prostate can adversely affect emotional function and financial problems. FUNDING National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Radiation Oncology Fund, and Maitland Cancer Appeal.

Gleason scoring: a comparison of classical and modified (international society of urological pathology) criteria using nadir PSA as a clinical end point.

Aim: To compare the distribution and predictive performance of Gleason grade and scores derived using classical and modified (International Society of Urological Pathology) criteria. Methods: Classical and modified Gleason grades and scores were assigned to cases of prostate carcinoma accessioned by the Trans‐Tasman Radiation Oncology Group RADAR trial. Separate scores were derived for each grading system based on the percentage of each Gleason grade per case (area‐based score) and the score of the highest scoring core. The predictive performance of each of the four Gleason scores assigned to each case was evaluated using nadir prostate specific antigen (nPSA) as a clinical end point. Results: Modified Gleason scoring resulted in an upward shift of scores, primarily resulting from the reclassification of classical pattern 3 to modified pattern 4. On re‐grading classical Gleason score 7 cores, there was a 64% decrease in the number of cores with < 25% Gleason pattern 4 tumour, while the number of cores with 75–100% Gleason pattern 4 tumour increased by 96%. All four scoring models performed reasonably well as predictors of nPSA; however, on comparison of the prognostic gradients of the grade groupings, classical Gleason scoring outperformed modified Gleason scoring. Conclusion: The overlap of the predictive performance of Gleason pattern 3 with Gleason pattern 4, suggests that review of the defining features of modified pattern 4 may improve the prognostic prediction of modified Gleason scoring.

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.