Prostate Cancer Trials Group, University of Newcastle, New South Wales, Australia.
This review describes the present curative role of radiotherapy in men with localised prostate cancer, and the many technical innovations that have occurred over the last 20 years that have improved its accuracy and safety. These have resulted in today’s state of the art irradiation technique known as ‘imaged guided intensity modulated radiotherapy’. Emerging changes in practice for men with good prognosis tumours, which include radiation dose escalation, and major reductions in the duration of radiotherapy treatment courses are outlined. Finally, the role of adjuvant treatments for men with poor prognosis, high risk locally advanced tumours, and new approaches to these initiatives are summarised.
Until the turn of the century, radiotherapy techniques had serious limitations and adverse outcomes, including primary tumour progression and radiation-induced morbidity. Thanks to the technical innovations described below, external beam radiotherapy (EBRT) is now a curative option for all men with newly diagnosed localised prostate cancer, where CT scans of the abdomen and pelvis and whole body isotopic bone scans are negative for metastases. Fortunately, radical prostatectomy has also undergone important technical improvements. The decision the patient has to make is therefore more difficult and the information he and his partner need to receive is more comprehensive. The most obvious reason for this is that the curative options for prostate cancer, their side-effect profiles, and their accessibility and cost profiles are so different. One man can undergo radical surgery, another, a course of radiotherapy and a third can receive androgen suppression therapy (AST) prior to other treatments. A fourth who has a curable cancer can be offered monitoring without treatment (active surveillance). This option is particularly difficult to understand, because most newly diagnosed patients and their partners share the common expectation that all localised cancers ‘must’ be treated with the intention of cure. Perceptions of the experience, integrity and communication skills of the doctors that may be administering his treatment will usually also be important considerations when choosing treatment type.
For men with good prognosis tumours that fall into the ‘low risk category’ i.e. T stage 1c 2a, Gleason score (GS) less than or equal to 6 and prostate specific antigen (PSA) ≤10 where metastatic progression within their lifespans is unusual (i.e. <20%), there is little to choose between the oncological outcomes that follow radical prostatectomy, EBRT or brachytherapy and active surveillance. The patient’s decision hinges on the types of side-effects he is prepared to risk, knowing that most of them could be permanent (see table 1).
For men with intermediate risk cancers i.e. T stage 2b or GS of 7 or PSA 10 – ≤20, where the chances of cancerous progression within their lifespans are moderate (20-40%), the treatment options are restricted to radical prostatectomy and EBRT. Because there is little to choose between these two options from the oncological endpoint perspective, the patient will select treatment largely on the same considerations listed above.
For men with high risk, locally advanced cancers i.e. T stage ≥2c or GS 8-10 or PSA >20, the probability of metastatic cancerous progression within a 10 year period is high (i.e. ≥50%). Unless there are serious intercurrent medical disorders, radiotherapy with neo-adjuvant and/or adjuvant androgen suppression is usually recommended. Further discussion of this approach follows under ‘new developments’.
The most commonly used technique for delivering curative irradiation is ‘image guided intensity modulated radiation therapy,’ which employs several important computer driven technical innovations that have taken place in the last 20 years:
(a) Shows the extent of beam shaping achievable by linear acceleration prior to 2000. Although the banana shaped target volume is well covered, two-thirds of the oval shaped normal tissue structure receives exactly the same dose.
(b) Shows how the multiple small beams used in intensity modulated radiation therapy achieves much lower doses in the oval normal tissue volume, than the banana shaped target volume.
Figure 2: Shows how the radiotherapy beam can now be shaped to conformally cover the prostate and seminal vesicles using multi-leaf collimation.
2(a) from the lateral projection;
2(b) from the antero-posterior projection.
a) Radiation dose escalation
The technical improvements described above enable higher tumour radiation doses to be delivered without increasing doses to adjacent healthy normal structures. One of the benefits to emerge is an improvement in the curative potential of radiotherapy for localised prostate cancer. This has been demonstrated in a series of randomised ‘radiation dose escalation trials’ conducted on both sides of the Atlantic.5-11 The higher doses used in these trials have led to significant reductions in PSA progression. To date, however, only one has demonstrated reductions in metastases and mortality.12
As several authors have pointed out, the question arises whether adjuvant androgen suppression is necessary now that higher radiation doses are readily achievable.13,14 Probably both are necessary for optimal outcomes. However, this conclusion awaits confirmation by the RTOG 0815 trial which is expected to report in late 2015. In the meantime, 2015 results from the analysis of the structured radiation dose escalation program built into the stratification scheme of the ‘RADAR’ trial run in 23 centres across Australia and New Zealand, are now in press.4 In this program, EBRT doses used were 66, 70 and 74Gy in 2Gy incremental fractional doses. In centres equipped with HDRB apparatus, it was also permissible to use the option of escalating dose to >80Gy, using 46Gy in 2Gy incremental fractions using EBRT, followed by a HDRB boost in three divided doses over 24 hours.
However, improvements are usually bought at a cost. In the RADAR trial there was an increase in dysuria and stream weakness in subjects receiving HDRB boosts. Formal evaluation of these reports indicate that the use of HDRB boosts was associated with urethral strictures.
b) Shortening radiotherapy courses
The realisation that two incremental fractions of 2Gy would kill less prostate cancer cells than a single dose of 4Gy lead to the interesting possibility that a commonly used conventionally fractionated course of 74Gy, using 37 fractions of 2Gy over 7.4 weeks, would not necessarily be more effective than a shorter course of 60Gy using 20 fractions of 3Gy over four weeks, or a very short course of 34Gy using 5 fractions of 6.8Gy over one week.15 However, these interesting possibilities would not be considered exciting unless these shorter courses were shown to cause similar or lower levels of long-term side-effects.
Sufficient studies using brachytherapy and/or EBRT have follow-up data indicating that this approach is worth pursuing. Randomised trials are now underway to determine what the optimal options will ultimately be. Unfortunately, it could be a decade or more before this initiative translates to the clinic.
c) The use of adjuvant treatment regimens
The veterans trials of adjuvant treatment regimens following prostatectomy in the 1960s showed that the majority of men dying from prostate cancer did so as a result of metastatic spread.16 However, the development of successful adjuvant regimens did not develop momentum until the advent of luteinising hormone-releasing hormone analogs and anti-androgens in the 1980s provided a means of delivering temporary AST. It quickly became evident that men with high stage, high grade, apparently localised cancers, commonly dubbed ‘high risk’ or ‘locally advanced prostate cancers’ (LAPC), had the most to gain from adjuvant regimens in associated curative EBRT.
Over the next 20 years, Radiation Therapy Oncology Group (RTOG), European Organisation for Research into the Treatment of Cancer (EORTC), Trans Tasman Radiation Oncology Group (TROG) and other trials groups were to demonstrate that various durations of AST could more than halve prostate cancer specific mortality (PCSM) and produce clinically relevant improvements in overall survival in men with ‘high risk’ (localised) cancers. The reduction in metastatic spread was identified as the major contributor to survival improvements. Space precludes description of all of these trials, but table 2 provides their prostate cancer specific mortality and overall survival outcomes.
It is important to note that the absolute reductions in mortality, which range between 6% and 20.1%, in trials comparing EBRT alone with EBRT plus AST, are not as impressive as the relative reductions achieved (table 2a and 2b). They are even less impressive in the trials comparing short- and long-term adjuvant AST (i.e. 1.5% at five years and 4.8% at 10 years, in table 2c). These smaller margins of benefit increase the importance of knowing what adverse sequelae occurred in these trials.
d) New adjuvant strategies
Two lines of clinical evidence have influenced the debate concerning the optimal duration of AST and the need for new adjuvant strategies for the treatment of LAPC. First, over the past 15 years, a large number of reports in the international literature have described the prolonged harmful consequences of long-term AST. Aside from the well-known unwanted side-effects,17 which include loss of libido, erectile dysfunction, gynecomastia and hot flushes, most men also experience some degree of anemia,18 sarcopenia (muscle loss),19 and loss of bone mineral density (with increased fracture risk).20,21 Other commonly occurring phenomena include permanent hypogonadism,22 some degree of cognitive dysfunction,23 mood disturbances and depression.24 Less common problems are exacerbation of ‘the metabolic syndrome,’25 (which includes hypertension, diabetes, hypercholesterolemia, weight gain and increased risk of myocardial infarction.)26,27
Second, evidence from two large-scale randomised control trials have shown that indefinite durations of AST by itself achieve limited outcome benefits in LAPC. One was conducted by the Scandinavian Prostate Cancer Group Study and the Swedish Association for Urological Oncology 3,28 and the other by the National Cancer Institute of Canada-Clinical Trials Group.29 Both identified limited, but significant improvements in survival by the addition of radiotherapy to long-term AST. This suggests that new therapeutic agents with different modes of action need to be incorporated into adjuvant treatment strategies to achieve better results.
Since most of the longer term complications occur following AST durations greater than two years, two trials have tested the value of 18 months AST plus radiotherapy. The Canadian trial run by Nabid et al compared 18 months with the 36 months AST regimen used by the EORTC (in tables 2b and 2c).30 Preliminary data indicated that quality of life measures were superior in the 18 month arm, but produced similar oncological outcomes to 36 months. The TROG 03.04 RADAR trial compared 18 months with six months AST in a 2×2 factorial trial, where the second factor was 18 months of zoledronate. Preliminary data indicated that after three years of follow-up, quality of life measures were no different in the six and 18 month AST trial arms.31 Oncologic endpoints were somewhat better in the 18 months AST trial arm. The influence of zoledronate was unexpected and is described below.
The emergence of drugs with activity against ‘castrate resistant’ prostate cancer, i.e. prostate cancer that is no longer responsive to androgen suppression therapy, has led to hopes that these agents will improve outcomes in men receiving radiotherapu/AST combinations with curative intent.32 The bisphosphonates have been the most common class of drugs to be tested in this setting. Clodronate was integrated into British Medical Research Council Prostate 4 and Prostate 5 trials.32,33 It was found to improve survival in men with metastatic, but not localised prostate cancer and provided strong encouragement for continued evaluation of the more ‘oncologically’ potent aminobisphosphonates. One of these, zoledronate, was found to have a wide range of anticancer activities in preclinical studies and significant clinical benefits in men experiencing ‘skeletal related events’ due to prostate cancer.34,35 Since then, three international trials have gone on to assess the value of zoledronate as an adjuvant treatment and include subjects with LAPC. The TROG 03.04 RADAR trial completed enrolment of 1071 subjects in 2007 and reported preliminary oncological outcomes in 2014. Unexpectedly, evidence of an interaction between the use of zoledronate and the GS of the primary tumour emerged. Of greater interest was the beneficial effect of zoledronate on distant progression outcomes in men with GS 8-10 tumours,31 which are well known to be the most refractory tumours to AST strategies. A final report is projected to be released in late 2017. The multi-centre European ZEUS trial addressed the effectiveness of four years of three monthly zoledronate for the prevention of bone metastases in high risk prostate cancer patients. It completed recruitment of 1300 patients in 2008 and reported in 2014 that zoledronate did not prevent the development of bone metastases.36 This finding was regardless of the GS of the primary tumour (personal communication from Prof. Wim Witges 2014). Enrolment to the STAMPEDE (Systemic Therapy for Advancing or Metastatic Prostate Cancer) trial is ongoing, and the number of men with LAPC who will receive the planned 26 months of zoledronate is yet to be reported.
More recently, interest has focused on the cytotoxic agent docetaxel, which has improved survival in heavily pretreated men with advanced castrate resistant prostate cancer.37,38 The RTOG is evaluating its use in combination with long-term AST, by determining whether its addition to the 28-month AST/RT protocol, successful in the RTOG 92.02 trial,39 will further improve outcomes. A multi-centre trial run from the Dana Farber Institute, which includes centres from Australia and New Zealand, is determining whether its use will improve on outcomes achieved by six months of AST and radiotheraly.40 It is unclear when these two trials will report their oncological outcomes.
In summary, the outlook for men with newly diagnosed high-risk LAPC is highly encouraging. Ten-year prostate cancer specific mortality rates near 10% are now being achieved using current best practices. It is highly likely that the next generation of trials will bring these rates down to <5%.