Bedside teaching in medical education; a literature review.
Digital version thesis Salvage for radiorecurrent prostate cancer, Max Peters
1. Salvageforradiorecurrentprostatecancer MaxPeters2016
Salvage for radiorecurrent
prostate cancer
Max Peters
Patients undergoing primary radiotherapy for prostate cancer are at risk of recurrent
disease. Recurrences are often confined to the prostate and therefore eligible for a
second curative ablation, known as salvage. Salvage modalities are usually directed
at the entire prostate volume, due to former difficulties in assessing localised
recurrences. Because of previous radiation damage to the prostate and surrounding
organs at risk (OAR), whole-gland salvage modalities are associated with significant
toxicity rates.
As a result of recent developments in assessing prostate cancer location using multi-
parametric MRI and different biopsy techniques, the attention has shifted to a focal
treatment approach in the salvage setting. This is known as focal salvage. With this
approach only the recurrent tumour area is targeted, which seems to maintain cancer
control, but decreases toxicity rates.
Focal salvage Iodine-125 brachytherapy appears to be able to provide durable disease
control, while minimising late severe genitourinary (GU) and gastrointestinal (GI)
toxicity. However, for salvage brachytherapy in general, dose constraints are necessary
for OAR to prevent late severe complications. In the primary setting, these are
available for both late GU and GI toxicity. These restrictions are probably inaccurate
for the salvage setting, since the repair capacity of OAR is compromised by previous
radiation damage. The dose restrictions for the rectum, urethra and bladder as found
in this thesis are lower than those used for primary brachytherapy.
Before implementation of these restrictions is possible, patients should be adequately
selected for salvage. Failure rates for whole-gland salvage are often significant,
indicating a role for prediction models assessing which patients are most eligible for
treatment. Whole-gland salvage brachytherapy patients can be adequately selected
using the disease free survival interval (DFSI) after primary therapy and their PSA-
doubling time (PSADT) before salvage.
Forfocalsalvage,therearenomultivariablemodelsavailablebecauseseriesareusually
limited. The model in this thesis for focal salvage high intensity focused ultrasound
(HIFU) shows that the DFSI after primary radiotherapy, the pre-treatment PSA,
PSADT, prostate volume and T-stage as assessed on MRI can adequately predict
biochemical disease free survival up to 3 years follow-up.
Lastly, it seems focal salvage brachytherapy is the most cost-effective option,
predominantly driven by the lower treatment costs and reduced toxicity rates for
which follow-up treatment is indicated.
5. Salvage for radiorecurrent
prostate cancer
Herbehandeling van prostaatkanker
recidieven na radiotherapie
(met een samenvatting in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor aan de Universiteit Utrecht
op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan,
ingevolge het besluit van het college voor promoties
in het openbaar te verdedigen
op donderdag 10 maart 2016 des middags te 2.30 uur
door
Max Peters
geboren op 17 mei 1989
te Utrecht
6. Promotor: Prof. dr. M. van Vulpen
Copromotoren: Dr. J.R.N. van der Voort van Zyp
Dr. Ir. M.A. Moerland
Dit proefschrift werd (mede) mogelijk gemaakt door financiële steun van
Varian Medical Systems, Elekta en de prostaatkankerstichting
7. “History repeats, but science reverberates.”
Siddhartha Mukherjee,
The Emperor of All Maladies: A Biography of Cancer
8. 33 Chapter 1
Patterns of outcome and toxicity after salvage
prostatectomy, salvage cryosurgery and salvage Iodine-125
brachytherapy for prostate cancer recurrences after
radiation therapy: a multi-centre experience and literature
comparison.
Contents
09 Introduction and outline of the thesis
49 Chapter 2
Focal salvage therapy for local prostate cancer recurrences
after primary radiotherapy – a comprehensive review.
67 Chapter 3
Focal salvage Iodine-125 brachytherapy for prostate cancer
recurrences after primary radiotherapy: a retrospective
study regarding toxicity, biochemical outcome and quality
of life.
89 Chapter 4
Urethral and bladder dosimetry of total and focal salvage
Iodine-125 prostate brachytherapy: Late toxicity and dose
constraints.
109 Chapter 5
Rectal dose constraints for salvage Iodine-125 prostate
brachytherapy.
9. 127 Chapter 6
Development and internal validation of a multivariable
prediction model for biochemical failure after whole-gland
salvage Iodine-125 prostate brachytherapy for recurrent
prostate cancer.
147 Chapter 7
Multivariable model development and internal validation
for prostate cancer specific survival and overall
survival after whole-gland salvage Iodine-125 prostate
brachytherapy.
167 Chapter 8
Development and internal validation of a multivariable
prediction model for biochemical failure after focal salvage
high intensity focused ultrasound for locally recurrent
prostate cancer: presentation of a risk score for individual
patient prognosis.
187 Chapter 9
Comparative cost-effectiveness of focal and total salvage
I-125 brachytherapy for recurrent prostate cancer after
primary radiotherapy.
203 Chapter 10
Discussion
Summary
233 Addenda
Samenvatting
Dankwoord
List of publications
Curriculum vitae
12. Introduction and outline
10
1. Epidemiology
In many countries, prostate cancer is the most commonly diagnosed male cancer
(excluding non-melanoma skin cancers), with an estimated 220,800 new cases and
an expected 27,540 prostate cancer related deaths in the United States in 20151
.
In the Netherlands, there were approximately 10.000 new cases in 2014. Since the
1990’s, the annual mortality rate is approximately stable at 2500 yearly2
. In 2012,
there were 1.1 million cases worldwide, with 307,000 attributable deaths3
. Prostate
cancer is often diagnosed in an early stage and these patients are usually eligible for
active surveillance or radical treatment. However, because of the high incidence,
in absolute terms it remains the cancer site with the second most cancer related
deaths in the United States (after lung cancer) and the fifth most common cause of
cancer-related death worldwide1,3
.
2. Stage migration
As opposed to many other types of cancer, there has been a dramatic rise in the
incidence of prostate cancer in the past decades, as can be seen in figure 1. Due to
several factors, a significant and increasing proportion of patients is diagnosed in
an early and often organ-confined stage. Most importantly, the dramatic rise in
incidence of localised disease is a direct consequence of the introduction of PSA-
testing in the 1990’s (figure 1)1
. Patients are screened using PSA at an earlier age
and more frequently, thereby increasing the possibility of finding indolent, organ-
confined tumours.
Figure 1: Time-trends in several tumour incidences.
Noticeable is the dramatic rise in prostate cancer
incidence1
Male
Prostate
Lung & bronchus
Colorectum
Urinary bladder
Thyroid Liver*Melanoma of the skin
Rateper100,000Population
0
25
50
75
100
125
150
175
200
225
250
1980 1985 1990 1995 2000 2005 2011
13. Introduction and outline
11
Localised disease is usually assessed using digital rectal examination (DRE) in
combination with transrectal ultrasound (TRUS)-guided biopsies. Technetium-99
scintigraphy (bone-scan) and/or CT are used to exclude metastases in high risk
localised disease (with a Gleason score ≥8 and/or PSA ≥20) or ≥cT3a tumours4
. In
addition,localiseddiseasecanbepartlypredictedbasedonnomogramsincorporating
clinical characteristics: for example Partin tables which use the clinical tumour(T)-
stage, histopathological Gleason score and the PSA-value5
.
In recent years, however, developments in diagnostic techniques have led to
increasing accuracy in assessing localised disease and partly in excluding lymph-
node or distant metastases. Multiparametric (mp) magnetic resonance imaging
(MRI) and 11C-Choline and 18F-Fluorocholine Positron-Emission Tomography in
combinationwithCT(PET-CT)havecontributedsignificantlytothisassessment4,6-14
.
Together with developments in biopsy techniques such as transperineal template
prostate mapping (TTPM) and MRI-guided biopsies, there has been a further
increaseinclassifyinglocalisedandclinicallysignificantdiseaseoverDREandTRUS-
guided biopsies11,12,15-18
. This stage migration to organ-confined and increasingly low-
risk disease has some important consequences: most importantly the potential to
curatively treat disease and thereby excluding or postponing the use of androgen
deprivation therapy (ADT) in case of metastases.
3. To treat or not to treat?
3.1 Treatment versus observation
Whether these often low-volume, low-grade tumours need radical treatment is a
challenging question. Large randomised controlled trials (RCT’s) have provided
conflicting results regarding radical treatment for early-stage prostate cancer.
The Prostate Cancer Intervention versus Observation (PIVOT)-trial found no
evidence of a survival difference in patients with localised prostate cancer who
were randomised between radical prostatectomy and watchful waiting (hazard ratio
[HR] 0.88; 95% confidence interval [CI] 0.71-1.08; p=0.22; absolute risk reduction
2.9%19
). Contrary, the Scandinavian Prostate Cancer Group Study Number 4
(SPCG-4) did find a difference in both overall and prostate cancer specific mortality,
with a number needed to treat (NNT) of approximately 8 to prevent one death20
.
However, the PIVOT-study might have been exposed to the above mentioned stage
migration, since patients were recruited mostly in the PSA-era. This was primarily
visible in the incidence of 50% non-palpable T1c-tumours. The SPGC-4 study only
had 12% T1c tumours, because patients were assessed mostly before the PSA era.
This could suggest a possible delayed effect of radical prostatectomy in the PIVOT
trial which might become visible after longer follow-up.
14. Introduction and outline
12
3.2 Screening
This so-called ‘lead-time bias’ also seems to be present in large screening trials for
prostate cancer, in which the ‘number needed to screen (NNS)’ and ‘number needed
to treat (NNT)’ to prevent one death due to prostate cancer seem to be decreasing
with longer follow-up. This has been observed in the European Randomised Study
of Screening for Prostate Cancer (ERSPC), in which over the years the NNS and
NNT have decreased from 1410 and 48 to 781 and 27, respectively21-23
. However,
not all studies confirm these results, with the most important example being the
US Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial, which
showed no effect of annual PSA and DRE on survival. This study, however, suffered
from a significant contamination of the control group, in which 50% of the patients
underwent PSA-testing outside the study protocol24
.
A recent Cochrane meta-analysis did not show a pooled effect of PSA-screening
in five studies (including the ERSPC and PLCO) on prostate cancer specific and
overall mortality25,26
. This effect was also not present when pooling the results of
the ERSPC and PLCO separately. In addition, no effect on overall mortality has
been observed in any of the separate trials.
3.3 Side-effects of treatment
Assuming an effect of screening, the question remains whether the latest NNS of
781 and NNT of 27 from the ERSPC are worth the often severe side-effects of
primary radical treatment. Toxicity data from the PIVOT trial shows significant
incontinence rates after treatment: 17.1% in the radical prostatectomy group versus
6.3% in the observation group. Erectile dysfunction also considerably increased:
81.1% versus 44.1%. In addition, over 20% often severe 30-day surgical morbidity
was seen. Aggravation of toxicity after radical treatment is seen up to 15 years,
as assessed in a large cohort study comparing radiotherapy with prostatectomy
(n=1655). Both prostatectomy and radiotherapy showed an incontinence rate of
approximately 18% in this cohort and 90% erectile dysfunction. Radiotherapy
patients had some more bowel dysfunction at 15 years follow-up (16% versus
5.2%)27
. Whether these effects are actually related to surgery or radiotherapy will
possibly be answered by the awaited results of the ProtecT trial, an RCT evaluating
radiotherapy, radical prostatectomy and active surveillance for localised disease.
In addition, this trial is the first comparing these treatment modalities in a direct
manner. Active surveillance in the current era seems a safe option for low risk
patients, with long term excellent prostate cancer specific survival while preventing
side-effects from radical treatment28
. Especially with the increasing use of PSA as
15. Introduction and outline
13
a screening tool and therefore a large stage migration to low-risk disease, active
surveillance is appealing both in terms of quality of life as well as cost-effectiveness.
Whether treatment is necessary for all patients therefore remains a vital question.
4. Radiotherapy as primary treatment
When we choose to treat, there is little evidence from randomised controlled trials
that suggests how to treat. As the leading modalities for primary treatment, radical
prostatectomy and radiotherapy do not differ substantially in terms of cancer
control29
. This would make the side-effect profile essential, which might favour
radiotherapy.
There are several developments in the field of radiotherapy that make the treatment
appealing. Using external beam radiotherapy (EBRT), intensity modulated
radiotherapy (IMRT) offers a great advantage over the older 3D conformal
technique (3D-CRT) by increasing the dose delivered to the prostate while sparing
organs at risk (OAR)30,31
. The use of IMRT for treatment of patients with localised
prostate cancer has therefore increased from 0.15% in 2000 to 95.6% in 200832
. A
recent development is that proton therapy is increasingly being adopted, because
of its theoretical advantages in increasing conformality. All therapies show high
biochemical disease free survival (bDFS)29
. However, preliminary results seem
to favour IMRT over proton therapy in terms of treatment-related side-effects,
especially gastrointestinal32,33
.
Furthermore, combining EBRT with brachytherapy, it is possible to boost the
tumour,whichisadvantageousespeciallyforintermediateandhighriskpatients34,35
.
These improvements in accuracy of dose delivery resulted in over 40% of
prostate cancer patients older than 65 year nowadays being treated with EBRT,
brachytherapy or a combination36
.
Where EBRT is traditionally delivered fractionated, brachytherapy can be
delivered in a single procedure. In low and intermediate risk patients, low-dose-
rate (LDR) and high-dose-rate (HDR) brachytherapy can achieve bDFS rates that
are comparable to other primary treatment modalities29,35,37
. Brachytherapy offers a
steep dose decline and high conformality, limiting damage to surrounding organs
at risk and subsequently preventing toxicity. Also the single procedure in which it
can be performed has a great benefit over the many daily fractions with external
beam radiotherapy38
.This makes brachytherapy the most cost-effective primary
treatmentmodalityforprostatecancer39
.Arecentpropensityscoreadjustedanalysis
even indicated that brachytherapy leads to significantly increased bDFS compared
to EBRT for low and intermediate risk patients40
. Unfortunately, brachytherapy as
16. Introduction and outline
14
a primary treatment modality seems to be declining due to increasing popularity of
other primary (more expensive) treatments, among other factors38,41
.
Another advantage of brachytherapy that was developed in recent years, is a focal
approach to prostate cancer, both with LDR42
and HDR (Netherlands Trial register
number3790andNCT00913939),asopposedtotraditionalwhole-glandtreatment.
This was made possible by increased accuracy of tumour localisation using
multiparametric MRI and (image-guided or systematic) biopsy techniques8,10,16,43,44
.
Also applied with modalities like high intensity focused ultrasound (HIFU)45,46
and
cryotherapy47,48
, the focal approach appears to substantially decrease toxicity rates
while possibly maintaining acceptable cancer control49
. However, longer follow-
up and randomised trials are necessary to ascertain this, because proponents and
opponents considerably differ in their viewpoints49-51
.
Due to this large range of developments in primary radiotherapy and their effects
on prostate cancer management, radiotherapy is increasing as a primary treatment
modality.
5. Recurrent disease after primary radiotherapy
While whole-gland radiotherapy is an established and effective treatment option
for primary tumours, recurrences can still be common. Even in the era of dose
escalation, in which total treatment doses are above 78 Gray (Gy) in the majority
of patients, biochemical relapses occur frequently52-54
. The Kaplan-Meier curves
in figure 2 show the biochemical recurrence rates for the three National Cancer
Comprehensive Network (NCCN) risk groups. Estimated 8-year recurrence rates
of 9.7%, 22.7% and 43.9% for low, intermediate and high risk groups were observed,
respectively. All 2.694 patients were treated with IMRT with a total dose of ≥79.2
Gy, up to maximal 85.6 Gy53
.
The development of biochemical failure is problematic, since it commonly precedes
the development of distant metastases by a median 5.4 years and prostate cancer
specific mortality by a median 10.5 years53
. Even though cancer control rates are
increasing with further dose-escalation, ADT-use and enhanced patient selection,
there will be an increase in absolute numbers of patients with biochemical recurrent
disease because more patients are primarily treated with radiotherapy for prostate
cancer. In addition, the previously discussed rise in PSA-screening will shift the
diagnosis of prostate cancer to an increasingly lower age, creating a group with a
longer life-expectancy after primary treatment and therefore possibly more risk of
developing biochemical failure. Basically, physicians will more often be faced with
biochemical recurrent disease in the future and management of these recurrences
will become an important issue.
17. Introduction and outline
15
6. The index lesion and the relation with recurrent disease
Biochemical recurrence in prostate cancer often seems to be the result of a localised
process. The data on the exact location of these recurrences is scarce, but in several
series it is suggested that the tumour often regrows at the site of the primary
dominant and usually largest lesion, also called the ‘index lesion’ (figure 3)55-59
.The
evidence is not straightforward, however, with some suggesting tumour regrowth
to occur more multifocal, although organ-confined and even unifocal disease is still
often observed60,61
. Furthermore, salvage radical prostatectomy is not always used
as the reference standard to assess the localised radiorecurrent tumours, thereby
possibly not giving a representable estimate of the exact recurrence location(s).
In addition, patients were often treated with lower doses of radiation than with
current dose-escalation schedules. This could mean that radiorecurrent disease
is currently shifting towards the index lesion because secondary tumour foci are
increasingly successfully treated55,57,58
.
This idea of the index lesion has originated in the primary setting, where it
represents the tumour driving the prognosis of the disease. While prostate cancer
is often a multifocal disease with multiple, often bilateral foci62
, the index lesion is
thought in most cases to make up the largest and most aggressive tumour63-65
.
Figure 2: Biochemical recurrence rates per NCCN risk group53
Low risk 590 547 471 363 263 129 58 19
Int Risk 1289 1129 880 566 354 200 86 24
High Risk 815 653 488 337 226 133 66 29
Low risk
Intermediate Risk
High Risk
PSARecurrenceFreeSurvival
Time (yr)
100%
80%
60%
40%
20%
0%
0 2 4 6 8 10 12 14
18. Introduction and outline
16
It has even been observed that prostate cancer metastases have a monoclonal
singular origin which could originate in the index lesion, although this is still being
(fiercely) debated66,67
. This idea of the index lesion is tempting, since targeting
therapy to only a focal region of the prostate might reduce toxicity associated
with whole-gland treatment45,46,49,68-71
. As discussed above, treatments in the
primary setting are increasingly targeting partial areas of the gland72,73
, or boosting
dominant intraprostatic lesions74
. Trials are even ongoing in which ‘insignificant’
tumour foci are left untreated45
. Significant developments in staging procedures
using multiparametric-MRI and sophisticated biopsy-techniques make such an
alteration in the way we think of and treat prostate cancer possible. Proponents of
the focal approach compare it to other tumour sites in which this is now common
practice, such as breast and kidney cancer75
. It has even been called a ‘male
lumpectomy’ in the cryotherapy setting48
, equivalent to breast cancer treatment.
For recurrent tumours, this idea of the index lesion and a focal treatment approach
is potentially even more appealing, since secondary tumour foci might have
been successfully treated by the primary radiation. In addition, the decrease in
treatment-related toxicity is potentially much larger in the recurrent treatment
setting. These ideas are gaining increasing international attention and will be
further explored here.
Figure 3: Recurrent prostate tumours. Depicted here as vertical lines (over the horizontal lines indicating
the primary lesion)55
19. Introduction and outline
17
7. Current treatment strategies for recurrent disease
This thesis will focus on the specific subgroup of patients who have locally failed
primary radiotherapy. In prostate cancer, treating localised radiorecurrent prostate
cancer with a curative second approach is referred to as salvage. There are quite
extensive series available in the literature, describing a variety of salvage procedures.
Mostly, these procedures are directed at the entire prostatic volume. The largest
series available to date are those of salvage radical prostatectomy (SRP)76-78
, salvage
cryosurgery (SCS)79-81
, salvage HIFU82,83
and salvage brachytherapy (SBT, both
LDR and HDR)84-87
. All series show decent cancer control rates, with 5-year bDFS
in the range of 50-60% for SRP, SCS and SBT and 40-50% after 3 years for salvage
HIFU88-91
. These techniques therefore have the potential to postpone, or even
prevent the use of ADT, which has been associated with significant cardiovascular,
endocrinologic and sexual toxicity and even mental decline92,93
.
However, a recent overview has shown that salvage therapies are not frequently
adopted, with approximately 98% of patients receiving ADT as subsequent
treatment for recurrent disease. Only 2% of patients were found to be treated with
a form of curatively intended salvage94
. This was also observed in an analysis of
the large (UCSF) Cancer of the Prostate Strategic Urological Research Endeavor
(CaPSURE) database95
.
A reason to refrain from salvage therapies is that they are mostly performed
on a whole-gland basis88,90,91,96
. Because of prior difficulties in the assessment of
recurrences, whole gland approaches were (and are still often) the only way to make
sure residual disease is fully targeted. The downside to a whole-gland approach is
the severe toxicity associated with these procedures. After primary radiotherapy,
the prostate becomes fibrotic and OAR surrounding the prostate such as the
rectal wall, bladder neck and urethra, show similar changes85,97
. These fibrotic
changes impair the normal repair capacities of these structures, making salvage
surgical approaches difficult and cumulative radiation from SBT hazardous. High
percentages of toxicity have been found with all salvage modalities, although with
a wide spread across series. Summarised, up to a third of patients can experience
a combination of severe (≥grade 3) genitourinary (GU) and gastro-intestinal (GI)
toxicity, requiring surgical intervention to resolve89,91,96,98
. Erectile dysfunction is
poorly reported and frequently pre-existent, but often found to be almost universal
after salvage procedures88,96,98
. These severe side-effects are likely to contribute
to the previously mentioned 2% of patients who are treated with some form of
salvage. Salvage has for these reasons remained a treatment generally offered only
in specialised, high volume centres.
20. Introduction and outline
18
8. Focal salvage
Due to the severe toxicity rates associated with whole-gland salvage in combination
with the developments in accurate staging and the attention on focally targeting
prostate cancer, the hypothesis of a focal approach in the salvage setting is being
developed. With the evidence that recurrences are often localised at the primary
index lesion and secondary tumour foci are successfully treated by the primary
radiation, the rationale for a focal approach might be even more potent in the
salvage than in the primary setting. A focal approach could theoretically spare
a substantial part of the prostate and with this, prevent damage to surrounding
OAR. However, this procedure is technically challenging and the work-up to assess
focal recurrences is intensive and requires a high level of specialised assessment99
.
Therefore, focal salvage series are limited in the literature and performed only
in specialised centres. A variety of techniques are now described in some pilot
series, most importantly cryotherapy (n=10-91)100-103
, HIFU (n=39-48)104,105
and Iodine-125 (LDR) brachytherapy (n=15-25)106-108
. Most of these series
adopt a multimodality approach in assessing recurrent disease. This consists of
multiparametric MRI: T2-weighted, dynamic contrast enhanced (DCE), diffusion
weighted imaging (DWI) and sometimes spectroscopy (MRSI). Furthermore,
tumour location is confirmed by either systematic transrectal ultrasound guided
biopsies, or template prostate mapping biopsies (TTPM) in one series104
. The
extent of ablation varies from completely focal with a specified margin to hemi or
zonal, which is also referred to as a ‘dog leg’ or ‘hockey stick’ ablation (Figure 4)73
.
Results from focal salvage series are preliminary, but seem favourable. Reported
focal salvage 1, 2, 3 and 5- year bDFS rates are 69%-100%, 49%-100%, 50%-72.4%
and 46.5%-54.4%, respectively101-108
. These are in line with bDFS-outcomes from
Targeted ablation Hemiablation Zonal ablation
Figure 4: Different focal ablation methods for the primary and salvage setting73
.
21. Introduction and outline
19
the whole-gland setting. However, a selection bias towards a more favourable focal
salvage patient group cannot be excluded based on these observational studies.
Randomised trials, or (less favourably) propensity-score adjusted observational
cohorts will have to assess whether there are differences in cancer control between
a whole-gland and focal salvage approach.
Nonetheless, even if cancer control rates are in favour of whole-gland salvage, the
decrease in toxicity with focal salvage could still be a reason to refrain from a whole-
gland approach. Toxicity results from focal salvage are favourable, with most studies
reporting side-effects which are self-limiting or treatable with medication (grade
1 and 2)101,103,106,107
. Some series report higher toxicity rates, which sometimes need
surgical intervention to resolve104,108
. The extent of treatment could have influenced
these results, with one study targeting the entire peripheral zone108
. If toxicity results
are favourable compared to whole-gland approaches, repeating focal salvage could
even be an option if patients initially fail retreatment. This has been successfully
done in one of the focal SBT series106
and focal salvage cryotherapy series100
.
9. Problems with current whole-gland and focal salvage I-125
brachytherapy
Brachytherapy is often adopted as a salvage modality, both in the whole-gland and
focal savage setting. To perform SBT in a safe and effective way, dose constraints
and selection criteria related to cancer control are of vital importance. However,
these are not available in the current literature.
Dose constraints are usually adopted from the primary setting. However, these
restrictions might be too lenient because of previous radiation damage to
surrounding organs at risk109-113
. It is vital that there are constraints found for SBT
below which toxicity is reduced to a minimum, in a way equivalent to the research
which is available for primary brachytherapy111,112,114
.
Selection criteria in relation to cancer control are available from multivariable
analyses performed in larger whole-gland salvage cohorts using SRP, SCS and
HIFU76,79,83
. For whole-gland SBT, these are less well defined, due to smaller series
with limited events to which prognostic determinants can be related85-87,115
.
Also, predictive factors are often categorised (leading to information loss), missing
data is not described and no prediction models are available to obtain adequate
individual prognoses. These problems are also observed in the other salvage
modalities. Furthermore, due to the limited focal salvage data so far, there has not
been any uni- or multivariable modelling done to identify factors related to cancer
control. For these reasons, selection of patients for whole-gland and especially focal
22. Introduction and outline
20
salvage is now often performed on the basis of determinants related to prognosis in
the primary setting or on expert opinion.
Conclusively, to this day there are no reliable dose constraints, selection criteria
and prediction models developed specifically for SBT. They are frequently adopted
from primary BT data and do not take into account issues such as previous
radiation damage to OAR or the clinical profile of patients.
10. Outline
This thesis will focus on cancer control and toxicity regarding whole-gland salvage
modalities and focal salvage Iodine-125 brachytherapy and HIFU.
Chapter 1 demonstrates that whole-gland salvage modalities adopted in the
Netherlands nowadays are associated with high failure rates, probably because of
insufficient assessment of localised disease and exclusion of metastases.
Also, significant toxicity rates are observed, which is probably due to targeting the
entire prostatic volume. To prevent the high toxicity rates of these whole-gland
approaches while maintaining cancer control, focal salvage might be a viable
solution. The literature provides us with small series assessing different focal
salvage modalities. Chapter 2 summarises literature results of focal and whole-
gland salvage and compares cancer control and toxicity.
A focal salvage approach using I-125 (LDR) brachytherapy has further been
evaluated at our department. Twenty patients with a biochemical recurrence after
primary radiotherapy (EBRT or I-125 brachytherapy) were treated. Cancer control,
toxicity and quality of life of this cohort are evaluated in chapter 3.
The whole-gland I-125 brachytherapy cohort from chapter 1 and the focal salvage
cohort from chapter 3 were further evaluated regarding dosimetry and toxicity
of both the genitourinary (GU) and gastro-intestinal (GI) system. With these
dosimetry differences it was possible to construct dose constraints to prevent late
severe GU and GI toxicity (chapters 4 and 5, respectively). Dose constraints for
salvage I-125 brachytherapy are important for future adoption of this technique,
since constraints for the primary setting might be too lenient in salvage patients
because of previous radiation damage to surrounding organs at risk.
Chapters 6, 7 and 8 are all related to prediction models to improve selection of
patients for both whole-gland and focal salvage. Selection is often performed based
on characteristics associated with failure in the primary setting. However, whether
these characteristics have the same predictive value in the salvage setting is mostly
unknown. No prediction models to quantify the exact effects of pre-treatment
characteristics are available for salvage. For the larger whole-gland salvage series,
23. Introduction and outline
21
there are some multivariable models assessing the effects of certain characteristics.
For SBT, these models are based on small datasets with often limited events,
categorisation of predictors, insufficient description of missing data and other
problems which lead to an inaccurate assessment of the effect of prognostic factors.
To overcome these problems, chapters 6 and 7 use the most recent methodological
guidelines to quantify the effect of prognostic factors on both biochemical failure
(chapter 6) and mortality (chapter 7, both prostate cancer specific and overall
mortality). With these prediction models, a more accurate selection of whole-
gland SBT patients is possible.
Nevertheless, these predictors are assessed for whole-gland SBT and might have
a different relation with the outcome in focal salvage. The focal SBT cohort from
chapter 3 was too limited to create a prediction model. Therefore, in cooperation
with the University College London Hospitals (UCLH) Department of Urology,
a prediction model was created based on their focal salvage HIFU cohort after
EBRT-failure. This prediction model was based on a substantially larger cohort and
therefore the creation of a clinically useful risk score was possible. These results are
described in chapter 8.
Lastly, if focal salvage leads to equivalent cancer control rates and less toxicity
than whole-gland salvage, cost-effectiveness is an important aspect which needs to
be assessed. Chapter 9 compares the results of the whole-gland and focal salvage
I-125 brachytherapy cohorts in terms of cost-effectiveness. The limitations of the
described research and future perspectives with regard to salvage are discussed
after these chapters in the general discussion.
24. Introduction and outline
22
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100. Bomers JG, Yakar D, Overduin CG, et al. MR imaging-guided focal cryoablation in patients with
recurrent prostate cancer. Radiology. 2013;268(2):451-460. doi: 10.1148/radiol.13121291 [doi].
101. de Castro Abreu AL, Bahn D, Leslie S, et al. Salvage focal and salvage total cryoablation for locally
recurrent prostate cancer after primary radiation therapy. BJU Int. 2013;112(3):298-307. doi:
10.1111/bju.12151 [doi].
102. Eisenberg ML, Shinohara K. Partial salvage cryoablation of the prostate for recurrent
prostate cancer after radiotherapy failure. Urology. 2008;72(6):1315-1318. doi: 10.1016/j.
urology.2008.03.040 [doi].
103. Li YH, Elshafei A, Agarwal G, Ruckle H, Powsang J, Jones JS. Salvage focal prostate cryoablation
for locally recurrent prostate cancer after radiotherapy: Initial results from the cryo on-line data
registry. Prostate. 2015;75(1):1-7. doi: 10.1002/pros.22881 [doi].
104. Ahmed HU, Cathcart P, McCartan N, et al. Focal salvage therapy for localised prostate cancer
recurrence after external beam radiotherapy: A pilot study. Cancer. 2012;118(17):4148-4155. doi:
10.1002/cncr.27394 [doi].
105. Baco E, Gelet A, Crouzet S, et al. Hemi salvage high-intensity focused ultrasound (HIFU)
in unilateral radiorecurrent prostate cancer: A prospective two-centre study. BJU Int.
2014;114(4):532-540. doi: 10.1111/bju.12545 [doi].
106. Hsu CC, Hsu H, Pickett B, et al. Feasibility of MR imaging/MR spectroscopy-planned focal partial
salvage permanent prostate implant (PPI) for localised recurrence after initial PPI for prostate
cancer. Int J Radiat Oncol Biol Phys. 2013;85(2):370-377. doi: 10.1016/j.ijrobp.2012.04.028 [doi].
107. Peters M, Maenhout M, van der Voort van Zyp JRN, et al. Focal salvage iodine-125 brachytherapy
for prostate cancer recurrences after primary radiotherapy: A retrospective study regarding
toxicity, biochemical outcome and quality of life. Radiother Oncol. 2014;112(1):77-82. doi:
10.1016/j.radonc.2014.06.013 [doi].
108. Nguyen PL, Chen MH, D'Amico AV, et al. Magnetic resonance image-guided salvage brachytherapy
after radiation in select men who initially presented with favorable-risk prostate cancer: A
prospective phase 2 study. Cancer. 2007;110(7):1485-1492. doi: 10.1002/cncr.22934 [doi].
32. Introduction and outline
30
109. Crook JM, Potters L, Stock RG, Zelefsky MJ. Critical organ dosimetry in permanent seed prostate
brachytherapy: Defining the organs at risk. Brachytherapy. 2005;4(3):186-194. doi: S1538-
4721(05)00108-X [pii].
110. Davis BJ, Horwitz EM, Lee WR, et al. American brachytherapy society consensus guidelines for
transrectal ultrasound-guided permanent prostate brachytherapy. Brachytherapy. 2012;11(1):6-
19. doi: 10.1016/j.brachy.2011.07.005 [doi].
111. Price JG, Stone NN, Stock RG. Predictive factors and management of rectal bleeding side effects
following prostate cancer brachytherapy. Int J Radiat Oncol Biol Phys. 2013;86(5):842-847. doi:
10.1016/j.ijrobp.2013.04.033 [doi].
112. Hathout L, Folkert MR, Kollmeier MA, Yamada Y, Cohen GN, Zelefsky MJ. Dose to the bladder
neck is the most important predictor for acute and late toxicity after low-dose-rate prostate
brachytherapy: Implications for establishing new dose constraints for treatment planning. Int J
Radiat Oncol Biol Phys. 2014;90(2):312-319. doi: 10.1016/j.ijrobp.2014.06.031 [doi].
113. Salembier C, Lavagnini P, Nickers P, et al. Tumour and target volumes in permanent prostate
brachytherapy: A supplement to the ESTRO/EAU/EORTC recommendations on prostate
brachytherapy. Radiother Oncol. 2007;83(1):3-10. doi: S0167-8140(07)00028-X [pii].
114. Snyder KM, Stock RG, Hong SM, Lo YC, Stone NN. Defining the risk of developing grade 2
proctitis following 125I prostate brachytherapy using a rectal dose-volume histogram analysis. Int
J Radiat Oncol Biol Phys. 2001;50(2):335-341. doi: S0360-3016(01)01442-0 [pii].
115. Henriquez I, Sancho G, Hervas A, et al. Salvage brachytherapy in prostate local recurrence after
radiation therapy: Predicting factors for control and toxicity. Radiat Oncol. 2014;9:102-717X-9-
102. doi: 10.1186/1748-717X-9-102 [doi].
33.
34. Max Peters1
Maaike R. Moman1
Henk G. van der Poel2
Henk Vergunst3
Igle Jan de Jong4
Peter L.M. Vijverberg5
Jan J. Battermann1
Simon Horenblas2
Marco van Vulpen1
1 Department of Radiation Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands
2 Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands
3 Department of Urology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands
4 Department of Urology, University Medical Centre Groningen, Groningen, The Netherlands
5 Department of Urology, St. Antonius Hospital, Nieuwegein, The Netherlands
This work was published previously in: World Journal of Urology (2013) 31:403–409.
DOI 10.1007/s00345-012-0928-8
35. Patterns of outcome and toxicity after salvage
prostatectomy, salvage cryosurgery and salvage
Iodine-125 brachytherapy for prostate cancer
recurrences after radiation therapy:
a multi-centre experience and
literature comparison
Chapter 1
36. Chapter1
Chapter 1
34
Abstract
Purpose
Current salvage treatments for recurrent prostate cancer after primary radiation
therapy include radical prostatectomy, cryosurgery and brachytherapy. Because
toxicity and failure rates are considerable, salvage treatments are not commonly
performed. As most centres perform only one preferred salvage technique, the
literature only describes single-centre outcomes from a particular salvage technique
with a limited number of patients. In this overview, five high-volume Dutch centres
describe their toxicity and outcome data using different salvage techniques: salvage
radical prostatectomy, salvage Iodine-125 (I-125) brachytherapy and salvage
cryosurgery. This provides insight on how salvage is performed in clinical practice
in the Netherlands.
Methods
A total of 129 patients from five different centres in the Netherlands were
retrospectively analysed. Biochemical failure (BF) was defined as PSA >0.1 ng/ml
for the salvage prostatectomy group (n=44) and PSA nadir + 2.0 ng/ml (Phoenix
definition) for the salvage cryosurgery (n=54) and salvage I-125 brachytherapy
group (n=31). Toxicity was scored according to the Common Terminology Criteria
for Adverse events (CTCAE v3.0).
Results
BF occurred in 25 (81%) patients in the brachytherapy group after mean follow-up
of 29 (SD 24) months, in 29 patients (66%) patients in the prostatectomy group
after mean follow-up of 22 (SD 25) months and in 33 patients (61%) patients in the
cryosurgery group after mean follow-up of 14 (SD 11) months. Severe (≥grade 3)
genitourinary and gastrointestinal toxicity was observed in up to 30% of patients
in all three cohorts.
Conclusion
This overview shows clinical practice of prostate cancer salvage in the Netherlands.
Significant failure and toxicity rates are observed, regardless of salvage technique.
Patients should be selected with great care before offering these salvage treatment
strategies.
37. Chapter1
Outcomes of whole-gland salvage in the Netherlands
35
Introduction
Asignificantproportionofprostatecancerpatientstreatedwithprimaryradiotherapy
develops a recurrence. Estimations of risks exceeding 50% have been presented for
the highest risk groups1-4
. The recurrence risk is dependent on various risk factors
such as initial PSA level (iPSA), PSA doubling time (PSADT), Gleason score and PSA
nadir after initial treatment5
. A significant number of patients are thought to harbour
organ-confined disease6,7
. It seems local recurrences are particularly situated at the
position of the originally largest tumour, or index lesion8
. The currently dominantly
applied curative salvage treatments for these recurrences are salvage brachytherapy,
prostatectomyandcryosurgery.Unfortunately,thesesalvagetreatmentsareassociated
with high failure and severe toxicity rates9,10
. As most centres perform one preferred
salvage technique, the literature only describes single-centre outcomes with a limited
number of patients. In this overview, five high-volume Dutch centres describe their
outcomes using different salvage techniques. This provides a view on how salvage is
performed in clinical practice in the Netherlands.
Methods and materials
Treatment outcome and toxicity were recorded retrospectively for the salvage
treatments given: salvage radical prostatectomy (SRP), salvage cryosurgery (SCS)
and salvage Iodine-125 (I-125) implantation/brachytherapy (SBT). Primary
treatments were external beam radiation therapy or I-125 implantation. All men
showed PSA failure afterward, and recurrences were confirmed by transrectal
ultrasound (TRUS) guided biopsies. Furthermore, a bone scan and CT-scan were
made to exclude any possible distant or lymph node metastases. A PET-CT scan
was done in the more recent patients, but this imaging modality is not general
practice in the Netherlands. Patients were selected for salvage treatment based on a
life expectancy of at least 10 years, and all were counselled with respect to expected
toxicity and cancer control based on the experience of the institute.
Salvage procedures
All SRP procedures were performed at the Netherlands Cancer Institute-Antoni
van Leeuwenhoek Hospital (NKI-AVL), Amsterdam, via a perineal approach. Since
2003, 44 patients underwent SRP. A pelvic lymph node dissection was performed
before SRP in all patients, to exclude metastases. A median of 13 lymph nodes were
analysed.Theprocedureisdescribedelsewhereinmoredetail11
.Nonervesparingwas
attempted. Five patients received hormonal treatment ≤3 months prior to surgery.
SBT was performed by I-125 seed implantation at the University Medical Centre
38. Chapter1
Chapter 1
36
Utrecht (UMCU). Since 1993, 31 patients have been treated with permanent I-125
seed implants, via a transperineal route under ultrasound guidance. The standard
target dose was ≥145 Gy12
. The technique has been described previously13
. Only
patients with a prostate volume ≤50 cc were eligible for implantation. A total
of five patients received hormonal treatment three months prior to salvage in
order to decrease the prostatic volume. For the implants and the doses received
by the surrounding structures (rectum, bladder, urethra), the following criteria
were used: the prostatic V100 (the volume of the prostate that receives 100%
of the prescribed dose) ≥95%, the prostatic D90
(minimal dose to 90% of the
prostatic volume) ≥145 Gy, the rectal D2cc (the minimal dose received by the
maximally irradiated 2cc of the structure) ≤145 Gy and the D10 (the minimal
dose to 10% of the structure) of the prostatic urethra ≤150% of 145 Gy12,14
.
Cryosurgery was performed at the Canisius-Wilhelmina Hospital (CWH),
Nijmegen, the University Medical Centre Groningen (UMCG) and the Sint
Antonius Hospital (St.AH), Nieuwegein. Since 2007, 54 patients underwent salvage
cryosurgery. Cryosurgery was performed with Seednet (prostate <35 cc) and
Icerod needles (prostate >35 cc) inserted transperineally through a brachytherapy
template. The 17 Gauge needles were placed 1 cm apart with TRUS visualisation. A
transurethral warming catheter was inserted to protect the urethra. A suprapubic
catheter was left in situ for two weeks, in combination with antibiotic prophylaxis.
Patients were treated with two cycles of freezing and thawing. Thermosensors in the
midportion of the prostate gland ensured that the required temperature of -40 0C
was reached for effective cell killing.
Biochemical failure and toxicity
BF for patients after SRP was defined as a serum PSA level >0.1 ng/ml. For SBT
and SCS, failure according to the Phoenix and ASTRO definition was assessed:
PSA nadir + 2 ng/ml (Phoenix) and three consecutive rises in PSA with backdating
of the moment of failure to midway between the nadir after treatment and the
first rise (ASTRO)15,16
. Toxicity was scored from file records based on structured
interviewsatdifferenttimeintervalsaftersalvagetreatment.Toimproveuniformity,
the toxicity from each clinic was retrospectively converted to a grade using the
Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE v3.0)17
.
No subdivision into acute and late toxicity was made for this analysis.
Statistical analysis
Descriptive statistics and Kaplan–Meier survival analyses for freedom from
biochemical failure (FFF) were performed with the Statistical Package for the
39. Chapter1
Outcomes of whole-gland salvage in the Netherlands
37
Social Sciences, version 17.0 (SPSS, Chicago, IL, USA). Differences in Kaplan-
Meier FFF estimates were tested with the log-rank test, with statistical significance
set at p ≤0.05. Toxicity is presented as the proportion of patients suffering from
genitourinary (GU) or gastrointestinal (GI) morbidity and erectile dysfunction
(ED).
Results
A total of 129 patients were included. Various baseline characteristics differed
betweenthegroups,inparticularage,iPSA,clinicaltumourstageandfollow-uptime
(Table 1). SBT and SCS patients were older at the time of salvage than SRP patients
(69 and 70 years vs. 65 years). The iPSA was higher than 20 ng/ml in 35% of the SBT
group and 30% of the SCS group, versus 5% in the SRP group. Primary cT3 tumours
were19%inSBTpatients,32%inSRPpatientsand39%inSCSpatients.Meanfollow-
up in the SCS group was 3 years, in comparison with 5 and 9 years for SRP and SBT,
respectively.Resultsregardingbiochemicalresponse,mortalityandsevere(grade3)
toxicity are presented in table 2. Figure 1 shows the Kaplan–Meier curve for the FFF.
In the SRP group, 29 (66%) patients suffered from BF after mean 22 months (SD
25 months). Grade 1 or 2 GU toxicity occurred in 24 (55%) patients, and grade 3
toxicity occurred in 10 (23%) patients. Grade 1 or 2 GI toxicity occurred in three
(7%) patients, and grade 3 (fistulas) occurred in four (9%) patients. Until now, five
(11%)patientshavediedduetoprostatecancer.EDwasobservedin86%ofpatients.
After I-125 implantation, 25 (81%) patients suffered from BF after mean 29 months
(SD 24 months). Grade 1 or 2 GU toxicity occurred in 17 (55%) patients, and grade
3 occurred in seven (23%) patients, predominantly urinary incontinence and
obstruction due to swelling of the prostate. Grade 1 and 2 GI toxicity occurred
in 16 (52%) patients, and grade 3 occurred in two (6%) patients. Twelve (39%)
patients have died due to prostate cancer. ED was present in 45% of patients.
After a mean 14 months after SCS, 33 (61%) patients suffered from BF after mean 14
months (SD 11 months). Grade 1 and 2 GU toxicity occurred in 30 (56%) patients,
and grade 3 occurred in 12 (22%) patients. Urinary incontinence, obstruction
and urinary tract infection were frequent complications. Perineal pain was also a
common complaint. Grade 1 and 2 GI toxicity occurred in seven (13%) patients,
and grade 3 occurred in four (7%) patients (predominantly fistula formation
between the rectum and urethra). ED was observed in 50 (93%) patients. Twenty-
four (44%) patients had pre-existent ED. No patients have died due to prostate
cancer–related events.
41. Chapter1
Outcomes of whole-gland salvage in the Netherlands
39
Table 2: Biochemical failure, mortality and toxicity rates after salvage, per salvage treatment group
Prostatectomy I-125 Cryosurgery
N 44 31 54
Mean (SD) FU after salvage, years 5 (4) 9 (3) 3 (0,3)
Mean (SD) PSA nadir, ng/ml 0.2 (0.8) 4.7 (6.6) 2 (3)
Mean (SD) time to nadir, months 1.5 10 (9) 2 (2)
Patients with biochemical failure†
Phoenix
ASTRO
PSA >0.1 ng/ml
NA
NA
29 (66%)
25 (81%)
17 (55%)
NA
33 (61%)
32 (59%)
NA
Mean (SD) time to failure, months
Phoenix
ASTRO
PSA >0.1 ng/ml
NA
NA
22 (25)
29 (24)
41 (25)
NA
14 (11)
16 (9)
NA
Patients (%) with severe GU toxicity, CTCAE
Grade 3 10 (23%) 7 (23%) 12 (22%)
Patients (%) with severe GI toxicity, CTCAE
Grade 3 4 (9%) 2 (6%) 4 (7%)
Death
Yes, PCa-specific
Yes, other cause
5 (11%)
7 (16%)
12 (39%)
2 (6%)
0 (0%)
5 (9%)
Abbreviations: I-125=Iodine-125; FU=follow up; SD=standard deviation; ASTRO=American
Society for Therapeutic Radiology and Oncology; GU=genitourinary; GI=gastrointestinal;
PCa=prostate cancer; CTCAE=Common Terminology Criteria for Adverse Events v3.0; NA=Not
applicable.
†
Proportion of patients with biochemical failure, as defined by 2 different criteria. Definitions of
biochemical failure: Phoenix=PSA nadir plus 2 ng/ml, ASTRO=3 consecutive rises in PSA backdating
the moment of failure to midway between the nadir after treatment and the first rise.
42. Chapter1
Chapter 1
40
Discussion
This paper shows how salvage for radiorecurrent prostate cancer is performed in
the Netherland and reports on the current cancer control outcomes and toxicity.
Biochemical failure occurs often, with an estimated FFF of maximally 27% after
5years.Toxicitywasalsofrequent,withapproximately30%ofpatientsexperiencing
a grade 3 or higher complication of the genitourinary and gastrointestinal tract
combined.Intheliterature,awidevariationofpapersdescribestreatmentoutcomes
and toxicity after different salvage modalities, preceded by different primary
radiation therapy modalities and schedules. To our knowledge, no previous article
has presented outcomes of three different salvage treatment modalities from one
population. A comparison with the literature is summarised in table 3 (FFF) and
table 4 (toxicity).
Figure 1: Kaplan-Meier curve showing the freedom from biochemical failure following salvage radical
prostatectomy, salvage Iodine-125 implantation and salvage cryotherapy (Log rank: p=0.42). The
numbers at risk at 5 years were 7 for salvage radical prostatectomy, 5 for Iodine-125 brachytherapy and
6 (at three years) for salvage cryosurgery.
43. Chapter1
Outcomes of whole-gland salvage in the Netherlands
41
Table 3: Comparison with results from the literature – freedom from biochemical failure.
Salvage procedure No. studies
[References]
N Follow up FFF
(%)
Follow up
present study
FFF present
study (%)
Radical prostatectomy 4[10,11,19,27,28]
337 5 years 31 – 71 5 years 27
I-125 implantation 2[10,21,29]
66 5 years 34 – 53 5 years 19
Cryosurgery 3[10,22,24,30]
597 5 years 40 – 55 3 years 19
Abbreviations: FFF=freedom from biochemical failure; I-125=Iodine-125.
Table 4: Comparison with results from the literature – toxicity
Salvage procedure Radical prostatectomy I-125 implantation Cryosurgery
Literature
No. studies
[References]
4[10,11,19,27,31]
2[10,21,29]
2[10,23,30]
N 335 66 397
% GU toxicity 20-68% incontinence
22-41% bladder neck
stricture
0-47% grade 3-4 4-83% incontinence
7-55% bladder neck
stricture / retention
% GI toxicity 2-7% rectal injury 0-24% grade 3-4 6-37% perineal pain
1-11% fistula
Erectile dysfunction 72 %—Nearly uniform NA 72–86 %
Present study
% GU toxicity 23% grade 3 23% grade 3 22% grade 3
% GI toxicity 9% grade 3 6% grade 3 7% grade 3
Erectile dysfunction 86% 45% 93%*
Abbreviations: I-125=Iodine-125; GU=genitourinary; GI=gastrointestinal. NA=Not available
* 44% of patients had pre-existent erectile dysfunction.
However,thiscomparisonishamperedbythesmallanddivergentstudypopulations
and the different definitions for BF. Although the current study population is not
equivalent regarding patient and tumour characteristics and follow-up, it might be
possible to make a crude comparison regarding toxicity. Grade 3 GU and GI toxicity
occurredin32%ofSRPpatients,29%ofSBTpatientsand30%ofSCSpatients.These
toxicity rates are approximately equivalent to results as found in the literature9,10
.
The5-yearFFFwas27%followingSRPand19%followingSBT(Phoenixdefinition).
After 36 months, the FFF following cryosurgery was 19%. These figures are lower
44. Chapter1
Chapter 1
42
compared to those found in the literature (Table 3 & 4 and figure 1). This could be
due to incomplete salvage procedures, but dissemination before salvage is more
likely. Especially the cryosurgery group contained high risk cases with cT3 and
Gleason8–10tumours.Theliteratureshowsthatthepre-salvagePSAconcentration,
PSADT after primary radiation treatment and the tumour stage and grade are
important in predicting biochemical recurrences after salvage procedures9-11,18
. In
one SRP study, patients with a pre-salvage PSA <2 ng/ml and PSADT >12 months
showed better biochemical disease free survival (bDFS) rates than patient with
PSA >2 ng/ml and PSADT <12 months: >80% bDFS after 80 months in the most
favourable risk group compared with 0% bDFS after 20 months in the group with
the highest risk factors11
. Other SRP data indicate more favourable results for
primary T2 tumours in comparison with T3 tumours (100% bDFS after 5 years
in T2 tumours compared to 35% in T3 and 0% in N+ tumours)19
. In addition, the
tumour stage (T3/T4) was found to be an independent predictor of cancer specific
survival in a large series of SRP patients after multivariable analysis (n=199)18
.
In SBT, patients with pre-salvage Gleason scores ≥7 and PSADT <10 months show
poorer biochemical control rates in multivariable analysis10,20
. Possibly, a pre-
salvage PSA >10 ng/ml also leads to poorer cancer control outcomes21
. For the SCS
group, these risk factors for salvage treatment failure have also been recognised.
Patients with a pre-salvage PSA >10 ng/ml, Gleason scores ≥8 before primary
treatment and clinical T3/T4 tumours show decreased biochemical control rates
in comparison with patients without these risk factors9,10,22-24
. For an accurate
selection of patients likely to benefit from salvage therapy, these risk factors have to
be incorporated in salvage protocols. The general absence of these selection criteria
in these cohorts has probably contributed to the fairly low cancer control rates
observed. These pre-salvage characteristics would need to be researched with the
use of adequate prediction modelling to aid patient selection in the future.
The retrospective nature of this analysis yields several additional limitations.
First, the study populations are different at baseline, and therefore especially the
results regarding cancer control are difficult to compare between the three salvage
modalities. Also, the FFF rates depend on the criteria used to define BF. For SBT and
SCS, the Phoenix definition was used, because the ASTRO definition is more prone
to bias because of variable follow-up intervals. The ASTRO definition furthermore
has a false-positive rate of approximately 20% after the use of hormonal therapy,
versus5%associatedwiththePhoenixdefinition15,16
.Further,becausethegroupsare
limited, analysis of risk factors in a multivariable model was not perfomed. Finally,
the use of hormonal treatment was not standardised as well, further hampering
45. Chapter1
Outcomes of whole-gland salvage in the Netherlands
43
comparisons between groups. The primary objective of this study, however, was not
to provide an exhaustive comparison regarding different salvage modalities, but to
show the current clinical practice in the Netherlands. This can provide an indication
of what aspects need to be considered when offering salvage. Patients should be
intensely counselled regarding the high toxicity rates. These numbers might even
be underestimated due to the retrospective nature of the analysis, creating the
possibilitythatsalvagecanbeevenmoredetrimentalthanobservedinthesecohorts.
In addition, cancer control outcomes are suboptimal, which is possibly related to
inaccurate patient selection. In the SBT group, treatment goes back as far as 1993.
The patients selected in this period often had high-risk characteristics that would
exclude them from salvage treatment today. It is possible that especially this lack of
proper patient selection has negatively influenced the FFF. For future research, it is
important to pay further attention to patient selection. The most important aspect is
clearly defining local or distant disease at the time of BF after primary radiotherapy.
The PSA value is one of the most important diagnostic and follow-up measurement
available today, but is insufficient to assess disease progression. A rising PSA level
after primary radiotherapy can have several possible origins, including lymph-node
or distant metastases. Furthermore, the currently applied Phoenix definition has
a false positive rate of 5%16
. Better imaging techniques could contribute to a better
selection of patients with a local (organ-confined) recurrence and exclude patients
with systemic disease25,26
. Prediction models taking into account several pre-salvage
characteristicscouldfurtheraidpatientselection.Thesemodelsincombinationwith
accurate diagnostic modalities should be able to lead to a better patient selection
for salvage treatment in the future, thereby improving cancer control outcomes.
Lastly, with better assessment of localised disease, focal salvage directed only at
the recurrent tumour area might be able to decrease the often high toxicity rates
associated with a whole-gland approach by reducing cumulative damage to
previously irradiated surrounding organs at risk.
Conclusion
Both biochemical failure and toxicity rates are considerable after salvage radical
prostatectomy, Iodine-125 brachytherapy and cryosurgery. Improvements in
patient selection using pre-salvage characteristics and other diagnostic modalities
can possibly contribute to better outcomes in the future.
46. Chapter1
Chapter 1
44
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brachytherapy. Radiother Oncol. 2007;83(1):3-10. doi: S0167-8140(07)00028-X [pii].
15. RoachM,3rd,HanksG,ThamesH,Jr,etal.Definingbiochemicalfailurefollowingradiotherapywith
or without hormonal therapy in men with clinically localised prostate cancer: Recommendations
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974. doi: 10.1016/j.ijrobp.2006.04.029.
16. Buyyounouski MK, Hanlon AL, Eisenberg DF, et al. Defining biochemical failure after
radiotherapy with and without androgen deprivation for prostate cancer. Int J Radiat Oncol Biol
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10.1016/S1053-4296(03)00031-6.
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19. Sanderson KM, Penson DF, Cai J, et al. Salvage radical prostatectomy: Quality of life outcomes
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discussion 2031-2. doi: S0022-5347(06)01767-8 [pii].
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49.
50. p
Daniël A. Smit Duijzentkunst*1
Max Peters*1
Jochem R.N. van der Voort van Zyp1
Marinus A. Moerland1
Marco van Vulpen1
1 Department of Radiation Oncology, University Medical Centre Utrecht, The Netherlands
* Both authors contributed equally to this research
This chapter requires revisions for: World Journal of Urology
51. Chapter 2
Focal salvage therapy for
local prostate cancer recurrences
after primary radiotherapy:
a comprehensive review
52. Chapter2
Chapter 2
50
Abstract
Background/Aim
Patients with locally recurrent prostate cancer after primary radiotherapy can be
eligible for salvage treatment. Whole-gland salvage techniques carry a high risk
of toxicity. A focal salvage approach might reduce the risk of adverse events while
maintaining cancer control in carefully selected patients. The aim of this review is
to evaluate current literature to assess whether focal salvage leads to a comparable
or favourable recurrence rate and less toxicity compared to whole-gland salvage.
Methods
A literature search was performed using PubMed, Embase and the Cochrane
Library. 3015 Articles were screened and assessed for quality. Eight papers (on
focal cryoablation (n=3), brachytherapy (n=3) and HIFU (n=2)) were used to
report outcomes.
Results
1, 2, 3 and 5 year biochemical disease free survival (BDFS) ranges for focal salvage
are respectively 69%-100%, 49%-100%, 50%-91% and 46.5%-54.5%. Severe
genitourinary, gastrointestinal and sexual function toxicity rates are 0%-33.3%.
One study directly compares focal to whole-gland salvage cryotherapy, showing
5-year BDFS of respectively 54.4% and 86.5% with lower toxicity rates for focal
salvage patients.
Conclusion
Provisional data suggest that BDFS rates of focal salvage are in line with those of
whole-gland approaches. There is evidence that focal salvage could decrease severe
toxicity and preserve erectile function.
53. Focal salvage for radiorecurrent prostate cancer – a review
Chapter2
51
Introduction
Prostate cancer (PCa) patients primarily treated with external beam radiotherapy
(EBRT) or brachytherapy (BT) are at risk of a recurrence, depending on their
pre-treatment characteristics. The intermediate and high risk groups can
suffer from a biochemical recurrence in over 50% of the cases after 10 years
follow-up1,2
. Subsequently, these biochemical recurrences give rise to a risk
of developing metastases and (PCa specific) mortality3
. Up to 98% of patients
receive (palliative) androgen deprivation therapy (ADT) as treatment after a
biochemical recurrence4
. However, a substantial amount of patients harbour
organ-confined disease, for which a curative salvage procedure can provide
durable disease control5,6
, without exposing patients to the often severe side-
effects of ADT7
. Salvage nowadays is usually performed using a whole-gland
approach, which is accompanied by a high chance of severe gastro-intestinal (GI),
genitourinary (GU) and erectile toxicity due to previous radiation damage to
surrounding organs at risk5,6
. Given the evidence from pathology studies that
recurrences are frequently localised at the site of the primary largest (index)
tumour8,9
, a focal salvage approach, directed solely at the area containing
recurrent tumour, might be a viable treatment option for patients with unifocal
PCa recurrences without metastatic disease. This way, the serious adverse events
associated with whole-gland salvage might be prevented, while cancer control is
maintained. The current literature regarding survival and functional outcomes of
focal salvage techniques for prostate cancer recurrences after primary radiotherapy
is evaluated here.
Materials and methods
Literature search
On 19-08-2015 a systematic literature search was performed in the Pubmed,
Embase and Cochrane Library databases. In order to create a sensitive search, the
search syntax was build based on domain and determinant (Table 1). After removal
of duplicates, 3015 papers were screened, selecting 55 articles with matching
domain and determinant. Exclusion criteria are listed in the flowchart (Figure 1).
An additional reference search was performed, resulting in 12 studies for this
review.
Study selection
Studies were subjected to a critical appraisal based on an adaptation of the Dutch
Cochrane Centre recommendations (ACROBAT-NRSI risk of bias assessment
54. Chapter2
Chapter 2
52
Table 1: Search Syntax
All search terms (title/abstract) for Pubmed, (ab,ti) for Embase, (ti,ab,kw) for Cochrane
1 Salvage 14 Local
2 Therapy 15 Focal
3 Treatment 16 Prostate
4 Rescue 17 Prostatic
5 Cryoablation 18 Cancer
6 Cryosurgery 19 Carcinoma
7 Cryotherapy 20 Adenocarcinoma
8 Ablation 21 Neoplasma
9 Brachytherapy 22 Recurrence
10 HIFU 23 Recurrences
11 "high intensity focused ultrasound" 24 Recurrent
12 Hemi 25 Relapse
13 Partial 26 Radiorecurrent
27 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11
28 12 or 13 or 14 or 15
29 27 and 28
30 16 or 17 #34 Search Results
31 18 or 19 or 20 or 21 Pubmed: 1719
32 22 or 23 or 24 or 25 or 26 Embase: 2811
33 30 and 31 and 32 Cochrane: 199
34 29 and 33 Total: 4729
tool)10
. Studies were graded (+), (+) or (-) on relevance (domain, determinant,
outcome) and validity (selection, study population characteristics, exposure,
primary outcome, secondary outcomes, follow-up and number of patients) (Table
A1 (supplementary file)).
All studies were observational cohorts or case series with either prospective or
retrospective data acquisition. In that aspect, no study could be considered of high
quality. In none of the studies blinding was applied. However, the primary outcome
(BDFS) is unlikely to be influenced by information bias, due to the objectivity of
the failure definition (Phoenix, i.e. PSA-nadir + 2.0 ng/ml). On the contrary, the
secondary outcome is subjective to information bias and is graded in that way.
Confounding was not graded, since all studies except one were single-arm
55. Focal salvage for radiorecurrent prostate cancer – a review
Chapter2
53
4729
3015
55
11
12
Embase
2811
Pubmed
1719
Removal
of duplicates
Inclusion criteria
Domain = locally
recurrent PCa after
primary radiotherapy
Determinant = focal
salvage treatment
Exclusion criteria
No full text = 6
Review = 10
Conference abstract/
poster = 19
Comment/opinion/
reply = 2
Study protocol = 1
Guideline = 1
Technical report = 2
Reprinted article = 3
Screening
title/abstract
Full text
evaluation
Related
articles
Cochrane
199
Figure 1. Flowchart
observational cohorts. The study by De Castro et al.11
describes a two-armed cohort.
Here, possible confounding factors are adequately described, but not corrected for
in multivariable analysis. Four studies describe case series with 10 patients or less.
These were valued as low quality of evidence and therefore excluded.
Results
Search results
A total of 8 studies were eligible for data extraction, describing focal salvage
treatment with cryoablation (CA) (n=3), low-dose-rate brachytherapy (LDR-
BT) (n=3) and high intensity focused ultrasound (HIFU) (n=2) in a total of 278
