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A Phase 2 Clinical Trial Exploring 3-Dimensional Imaging of Androgen Deprivation Induced Osteoporosis, Radiotherapy Hypofractionation and the Prognostic Significance of Micrometastatic Disease in Men With Prostate Cancer

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Prostate Cancer

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Trial Information

A Phase 2 Clinical Trial Exploring 3-Dimensional Imaging of Androgen Deprivation Induced Osteoporosis, Radiotherapy Hypofractionation and the Prognostic Significance of Micrometastatic Disease in Men With Prostate Cancer

1. ADT induced Osteoporosis

Prostate cancer is a common malignancy in Australian men. In men with localized
disease at the time of diagnosis, baseline PSA level, tumour stage and Gleason grade
can be used to help stratify into risk categories. Men with high risk disease are
defined by an absence of metastatic disease using conventional imaging, and any one of
the following: a presenting PSA of >20, Gleason grade 8-10 disease on histology, or
stage T3-4 disease.[1] Such men are often treated with a combination of radiotherapy
to the prostate and pelvic lymph nodes, in conjunction with a course of adjuvant
androgen deprivation therapy (ADT) of between 18-36 months.[2] Recent literature
suggests that the greatest benefit from adjuvant ADT comes from the first 4-6 months of
treatment, and although there is measurable benefit from prolonging the course of ADT,
it follows the law of diminishing returns with progressively smaller benefit per unit
of increased treatment time.[3] This is important, in that if cumulative toxicities
are being inflicted by prolonging the treatment, there is likely to be a duration where
the harm of further treatment will start to outweigh the shrinking disease control

With greater clinical experience of the use of adjuvant ADT, there has become a better
awareness of the toxicities associated with this treatment. Accelerated loss of bone
mineral density has long been recognized as a complication of being hypogonadal. There
is now good evidence that this leads to an approximately 7% higher risk of fractures
for men with prostate cancer managed with ADT.[4] Osteoporotic fractures are
associated with increased morbidity and mortality, and a high proportion of patients
who suffer them never fully regain their pre-fracture level of functioning.

There are Australian guidelines for the management of osteopaenia / osteoporosis for
men managed with ADT.[5, 6] They recommend monitoring of bone mineral density (BMD)
using annual DEXA scanning, supplementary Vitamin D with Calcium, and the use of
bisphosphanate therapy for men with prevalent minimal trauma fracture or baseline BMD
T-Score <-2.0. One point high-lighted is that there is a wide spectrum in the rate of
bone mineral loss between patients and techniques of measurement, with figures as high
as 8% per year reported. This is far in excess of a normal rate of bone loss amongst
males of 0.5% per year.[7]

Although validated nomograms exist for the general population combining DEXA findings
with clinical parameters to predict long term fracture risks, no such tool exists for
men rendered hypogonadal with the use of ADT.[8] Guidelines for men on ADT are
empirical, and largely copy risk factors from the general population.[9]

Beyond baseline BMD, the only clinical factor shown to have any accuracy in predicting
bone loss for men on ADT is the change in serum P1NP (N-Terminal Pro-peptide of Type 1
Procollagen, a marker of bone formation).[10] One study showed that men in the highest
tertile for P1NP after 6 months of ADT, had the greatest loss in BMD at 12 months.
This finding has not been verified, and there remains a need to investigate the utility
of other clinical parameters either at baseline or early in ADT therapy to find
accurate predictors of which patients are at highest risk for accelerated BMD loss.

Osteoporosis Imaging

Currently, the only method to reliably determine which men are more rapid bone losers
is to perform serial DEXA imaging. Thus, by the time that rapid bone loss occurs, it
is too late to take measures to prevent it by interventions such as curtailing the
duration of adjuvant ADT. Furthermore, we have level 2 evidence from a randomized
clinical trial, that intervention with a bisphosphonate needs to be instigated at the
commencement of ADT and continued throughout the duration of ADT to maximize bone
density.[10] This study will aim to define a predictive tool combining baseline
imaging and clinical characteristics to help determine which patients are at higher
risk of accelerated bone loss prior to the initiation of ADT.

Osteoporosis is a complex condition characterized by loss of both cortical and
trabecular bone.[11] The structural basis of bone loss is poorly quantified by DEXA
scanning which combines cortical and trabecular bone density in its measurement.[12]
However, they can be separately and non-invasively quantified with the use of
ultrasound (US), computerized tomography (CT), peripheral high resolution quantitative
CT (pHR-QCT) or magnetic resonance imaging (MRI).[13] The last of these methods has
the advantages of not being operator dependent, not requiring exposure to ionizing
radiation and wide availability. A disadvantage is the relatively poor
characterization of cortical and trabecular bone at a field strength of 1.5 T.

There has been some work using CT imaging to separately quantify both cortical and
trabecular BMD, as well as other parameters of trabecular bone quality. Much of this
work has used pHR-QCT, which has revealed detailed changes in the porosity of cortical
bone for men on ADT which is likely to weaken the bone, and as been termed
'trabecularization'.[14] Recent studies have compared this technique which has
relatively limited accessibility, with more widely available technologies such as
Quantitative CT (QCT) and Multidetector CT (MDCT).[15, 16] A very accurate correlation
for Trabecular BMD was found between all 3 CT modalities. This raises the possibility
that BMD can be estimated from the staging MDCT performed on all prostate cancer
patients, without needing to expose them to the extra radiation dose required to
perform a QCT.

An advantage of MRI is that it also allows the collection of additional information
regarding bone marrow (BM) including fat fraction and perfusions. These measures have
previously shown some correlation with BMD measured by DEXA imaging, however the
correlation is relatively poor, with a wide degree of unexplained variation.[17-19] BM
has intimate proximity with trabecular bone, and paracrine factors such as the
RANK-Ligand secreted from the BM plays a key role in recruiting bone resorbing
osteoclasts.[20] It might therefore be that some of the variation in BMD measured with
DEXA is due to baseline variation in BM quantity. There are also possible correlations
between BM fat (BMF), and subcutaneous adipose tissue (SAT), visceral adipose tissue
(VAT) and hepatic adipose tissue (HAT), all of which can be separately quantified by
MRI.[21] This, is turn, may be linked with the deranged insulin levels and response
linked with ADT administration, and posited as a cause of increased cardiovascular

Other evidence shows that ADT induces a drop of haemoglobin from an average baseline
value of 151 g/L down to 135 within 18 months of starting treatment.[23] No haemolytic
process is evident, and the circumstantial evidence points to bone marrow suppression
as being the mechanism for this. Such mild anaemia may also contribute to the
insidious fatigue often seen in men treated with ADT. There is also some evidence from
reanalysis of randomized trial data, that men who have the greatest drop in haemoglobin
in the 3 months following initiation of ADT have a poorer overall survival in the
setting of metastatic disease.[24] As such, measuring BM at baseline may help in
predicting which patients are at risk of both losing bone faster, becoming anaemic, and
suffering fatigue. It is therefore plausible that measurement of BM will add an
important dimension to our knowledge of the bone as a functional unit as well as better
explaining some of the toxicities associated with ADT.

2. Circulating Tumour Cells

For a cancer to metastasize from the primary site of origin to other parts of the body,
malignant cells must under a series of changes. One crucial step involves being able
to use blood vessels to transport tumour cells around the body. Assays are now
commercially available to measure these Circulating Tumour Cells (CTCs), including one
which has FDA approval with the brand-name 'CellSearch'.[25, 26] This has superceded
older approaches using reverse transcriptase polymerase chain reaction to detect CTC in
men with prostate cancer.[27]

Work over the last decade in patients with metastatic cancer has shown that the
presence of CTCs in men with PC are a bad prognostic factor, with higher levels of CTCs
correlating with poorer overall survival.[28] On the other side of the spectrum of
tumour burden, work looking at patients undergoing a radical prostatectomy has shown
only a very low incidence of CTCs (~20%) prior to surgery, which was no different to
that measured in a cohort of healthy controls.[29] One issue with this study is that
<5% of the patients involved would be predicted to eventually suffer metastatic
failure, hence the chance of finding CTCs was likely to be very low based on the mainly
low to intermediate risk patient cohort examined.

Men with high risk PC have a much higher chance of eventual metastatic failure, of the
order of 20-30%, or higher depending on their initial risk factors (PSA level, tumour
stage and Gleason grade). At the time of diagnosis these men may therefore exhibit CTC
levels intermediate between the metastatic and surgical cohorts previously considered.
It may be that high risk PC patients with CTCs detected represent a very high risk
group, and apart from providing important prognostic information for men, it could
therefore warrant treatment intensification with increased duration of adjuvant ADT, or
entry into clinical trials.

3. Prostate Radiotherapy Hypofractionation

Radiotherapy (RT) has been shown to independently improve overall survival for men with
high risk PC managed with ADT.[30] As such, standard of care for these men remains
bimodality treatment with both RT and ADT.[1]

RT has traditionally been given at doses of 1.8-2 Gy per day due to concerns about the
potential for larger fraction sizes to cause late toxicity. Over the last 10 years
multiple randomized controlled trials (RCTs) have shown that higher doses of RT (of the
order of 74-80 Gy) lead to better rates of no biochemical evidence of disease
(bNED).[31, 32] Due to the long natural history of PC, bNED is a validated surrogate
endpoint looking at PSA control,[33] however the trial with the longest follow-up is
now also beginning to show an improvement in Prostate Cancer Specific Survival
(PCSS).[31] The use of such regimens leads to treatment durations of 8-10 weeks, which
can be inconvenient for patients, consume a large proportion of the capacity of a RT
department, and consequently be a significant factor in the existence of waiting lists
for radiotherapy.

There is strong data for PC suggesting that hypofractionation (that is, daily fraction
sizes of >2 Gy) is particularly effective at maximizing tumour effect. Newer
technologies such as image guided RT (IGRT) which ensures more accurate delivery of the
RT, and intensity modulated RT (IMRT) which reduces unwanted radiation dose to adjacent
normal structures are now in clinical use in Australia. They both have been used in
phase 2 trials of Hypofractionated RT (HypoRT), with results for efficacy and late
toxicity comparable to those reported in the literature for conventionally fractionated
cohorts.[34, 35] There have been two small RCTs recently reported comparing HypoRT and
conventionally fractionated populations, both showing no increased toxicity with the
HypoRT, and better bNED.[36, 37] One of these focused mainly on high-risk men and
included ADT, similar to the patient population eligible for PROCITT.[36]

4. Radiotherapy Volume

When defining the RT treatment volume for a man with PC, traditional thinking has been
to treat the prostate alone. However, for a local treatment modality such as RT or
surgery, it is important to appreciate the natural patterns of spread of the disease.
For instance, there are good consensus guidelines for patients with head and neck
cancer to help radiation oncologists to know who are most likely to benefit from
elective treatment of their cervical neck lymph nodes. This is because, despite the
neck being negative at the time of diagnosis, surgical neck dissection series have
helped to inform decision aids regarding the chance of a clinically normal neck
harbouring sub-clinical disease.

Nomograms have been constructed from large surgical PC cohorts to help define the risk
of extracapsular extension, seminal vesicle involvement and lymph node involvement
based on initial clinical parameters. Trying to treat all patients with the
progressively larger treatment volumes required to include these areas would
potentially increase toxicity without a high chance of improving efficacy. However, if
a threshold risk level of 15-25% were required prior to including each elective target
volume, we would aim to apply such treatments to patients most likely to benefit. Such
concepts are already beginning to enter into consensus guidelines,[1, 38] and clearly
represent a promising avenue of investigation.

Of all of these expanded treatment volumes, only Whole Pelvic Radiotherapy (WPRT) has
been investigated in men with PC in RCT.[39] Neither RCT found a significant benefit
for the use of WPRT. However, many practice changing RCTs have used WPRT on all
patients.[2, 40-42] One of the reasons for this discrepancy is likely to be that entry
criteria for the largest WPRT RCT estimated a 15% risk of pelvic lymph node
involvement.[39] Later work has shown that this only corresponded to a 2% pathological
risk of nodal involvement. This emphasizes the need to use validated decision tools to
select appropriate treatments.

5. Duration of neoadjuvant ADT

Often adjuvant ADT is given prior to commencing RT. This is known as neoadjuvant hormonal
therapy (NHT). There is no clear guidance on what duration to give this for, although 3-6
months is a common approach. Results from an Australian randomized trial have shown 6
months of NAT to result in superior survival than 3 months.[43] Intuitively, it would seem
that some patients would benefit from a shorter duration of NHT than others depending on
their tumour response. There has been some preliminary work looking at an adaptive approach
for this, where RT is started once a maximal PSA response has been achieved.[44] This has
been shown to be feasible and effective in the phase 2 setting.

Inclusion Criteria

Inclusion Criteria

1. Patient capable of giving informed consent

2. Histological diagnosis of prostate cancer

3. High risk disease defined by any one of:

1. Baseline PSA>20

2. Gleason grade 8 disease

3. Clinical stage T3-T4

4. Negative conventional staging in the form of a:

1. T99m whole body bone scan

2. CT of the abdomen and pelvis

5. No previous pelvic radiotherapy

Exclusion Criteria

1. History of prior malignancy within the last 5 years with the exception of
non-melanomatous skin cancers.

2. ECOG performance status >1

3. Inability to have intraprostatic fiducials inserted.

4. Inability to be given an MRI due to:

1. Implanted magnetic metal eg intraocular metal

2. Pacemaker / Implantable defibrillator

3. Extreme claustrophobia

Type of Study:


Study Design:

Observational Model: Cohort, Time Perspective: Prospective

Outcome Measure:

Prediction of ADT induced bone mineral density loss

Outcome Description:

That baseline MR and CT imaging of lumbar spine cortical bone, trabecular bone, marrow and fat fraction combined with clinical factors predicts which men are at greater risk of accelerated Androgen Deprivation Therapy (ADT) induced bone mineral density loss than baseline DEXA scanning alone.

Outcome Time Frame:

6 years

Safety Issue:


Principal Investigator

Jarad M Martin, FRANZCR

Investigator Role:

Principal Investigator

Investigator Affiliation:

Radiation Oncology Queensland


Australia: Human Research Ethics Committee

Study ID:

IIS MET-10-0030



Start Date:

July 2011

Completion Date:

July 2017

Related Keywords:

  • Prostate Cancer
  • Prostatic Neoplasms