RECOVERY
OF HORMONE SENSITIVITY AFTER SALVAGE BRACHYTHERAPY FOR HORMONE REFRACTORY
LOCALIZED PROSTATE CANCER
(
Download
pdf )
doi: 10.1590/S1677-55382010000300004
DAN SMITH, P. NICK PLOWMAN
Department of Radiotherapy (DS, PNP), St Bartholomew’s Hospital, West Smithfield, London and Department of Radiotherapy (PNP), The Cromwell Hospital, Cromwell Road, London
ABSTRACT
Purpose:
Recent work has demonstrated the return of hormone sensitivity after palliative
chemotherapy in androgen independent prostate cancer. We wished to establish
whether a similar phenomenon existed in patients with no exposure to chemotherapy.
Materials and Methods: A review of “hormone
resistant” patients who had received salvage brachytherapy for localized
prostate cancer after previous external beam radiotherapy was undertaken.
Three patients with subsequent biochemical relapse responded to the rechallenge
with hormonal treatment.
Results: The series of patients presented
here demonstrates this phenomenon occurs after salvage brachytherapy with
no exposure to chemotherapy. Recovery of sensitivity is demonstrated both
to androgen deprivation and to androgen receptor antagonism. The recovery
of hormone sensitivity was surprisingly durable, ranging from eight months
to over twenty-one months.
Conclusions: Hormone sensitivity may be
recovered after salvage brachytherapy. Potential mechanisms underlying
these observations are discussed and the likely central role of the activity
of the androgen receptor highlighted. The relevance of these findings
to the management of advanced prostate cancer is considered including
thoughts on the practice of intermittent anti-androgen therapy.
Key words: prostatic neoplasm; androgen antagonists;
brachytherapy; radiotherapy
Int Braz J Urol. 2010; 36: 283-91
INTRODUCTION
Prostate
cancer is unique amongst malignancies in that its initial growth is dependent
on the presence of intrinsic androgens. Whilst mutations in several tumor
suppressor genes have been described and are thought important in the
establishment of a clonal population of cells, development of clinically
significant cancer also requires an androgenic drive to cellular proliferation
(1).
This necessary androgenic drive provides therapeutic targets which may
be exploited to inhibit the growth of prostate cancer. Recurrent or metastatic
disease is typically first treated with hormonal manipulation: strategies
include testicular androgen deprivation by either bilateral orchidectomy
(2) or administration of a luteinizing hormone releasing hormone (LHRH)
agonist (3), and treatment with anti-androgens such as flutamide to compete
with testosterone for the androgen receptor binding site (4). Intrinsic
androgenic drive is thus abrogated, apoptosis of tumor cells occurs and
there is subsequent tumor regression with a fall in the plasma level of
prostate specific antigen (PSA).
Unfortunately, resistance to androgen suppression invariably develops:
cells accumulate further genetic abnormalities and proliferate despite
low testosterone levels at a median interval of 12-16 months after initiation
of endocrine treatment (5).
Subsequent lines of hormonal manipulation act through related pathways
and include the use of the synthetic estrogen diethylstilboestrol (6),
the reduction of adrenal androgen production by administration of adrenocorticotropic
hormone-suppressive glucocorticoids, e.g. hydrocortisone (7), and inhibition
of the androgen synthesizing hormones 17-alpha hydroxylase and C17,20
lyase by abiraterone (8).
Conventional wisdom is that the loss of hormone sensitivity is a fixed,
irreversible event, comparable to the loss of sensitivity to tamoxifen
or an individual chemotherapeutic agent in breast cancer. Once the range
of hormonal options is exhausted there is thought no benefit to restarting
hormonal treatments to which the cancer has previously exhibited resistance.
However, the recovery of sensitivity of prostate cancer to LHRH agonist
and to diethylstilboestrol has recently been reported following palliative
CL56 (chlorambucil/ lomustine) chemotherapy (9) despite prior acquired
resistance to both primary androgen suppression and estrogen therapy.
It was postulated that the chemotherapy may have altered the subsequent
behavior of the disease, particularly as a large proportion of patients
with second response to estrogen therapy had been resistant to this hormone
treatment immediately before chemotherapy. Similar observations have been
reported after docetaxel and prednisolone therapy (10).
We describe three patients whose second response to hormone therapy occurred
in a very different clinical context to those above. There was no exposure
to chemotherapy as the relevant therapeutic intervention was salvage brachytherapy.
MATERIALS AND METHODS
The records
of patients at our institution receiving salvage brachytherapy for recurrent
localized androgen independent prostate cancer between 1999 and 2007 were
reviewed. Localized relapse was diagnosed with repeat prostate biopsy
after consistent PSA rise and no evidence of extraprostatic disease seen
on bone scan and pelvic magnetic resonance imaging (MRI).
Patients were eligible for inclusion in this review only if they had previously
been treated with conventionally fractionated external beam radiotherapy
(EBRT) to 68-72Gy (a dose considered radical at the time of first treatment),
had subsequently developed biochemical relapse and had initially responded
to hormonal treatment before developing androgen resistance.
As salvage brachytherapy is currently unproven, patients were treated
under an investigative protocol approved by the Hospital Ethics Committee
and all gave full written informed consent to treatment.
Eleven men aged 54-77 were treated within this protocol. Initial results
of efficacy and toxicity have been reported elsewhere (11). Nine patients
have subsequently developed a further biochemical relapse and, of these,
three were found to have disease which did respond to rechallenge with
hormone therapy; these three are reported in detail in this manuscript.
RESULTS
Patient 1
A 56 year
old man presented with Gleason 3+3 organ-confined prostate adenocarcinoma
and prostate-specific antigen (PSA) of 9.9 ng/mL. He was treated with
radical EBRT but achieved a PSA nadir of only 2.0 ng/mL and by 2.5 years,
the PSA had risen to 7.2 ng/mL.
Goserelin was started with a PSA fall to 0.3 ng/mL, maintained for four
years when the PSA rose to 1.4 ng/mL and to 3.0 ng/mL after a further
two years despite ongoing goserelin. Repeat biopsy found Gleason 4+3 disease
in both lobes but MRI indicated no extracapsular disease and a bone scan
showed no distant disease.
Goserelin was discontinued and the patient underwent salvage 125I seed
brachytherapy to a marginal dose of 60 Gy. The PSA fell to 0.8 ng/mL at
three months following treatment but rose to 1.2 ng/mL and 3.6 ng/mL at
nine and eighteen months respectively.
Goserelin was recommenced and the PSA became undetectable, remaining so
for twelve months after restarting the LHRH agonist. At that point, goserelin
was stopped and a policy of intermittent anti-androgen therapy instituted:
the PSA remained undetectable for another five months before rising to
the current level of 1.1 ng/mL after a further three months. Reintroduction
of goserelin again led to PSA falling to an undetectable level (Figure-1).
Patient 2
A 67 year
old man presented with a PSA of 11.9 ng/mL and was diagnosed with localized
Gleason 5+3 adenocarcinoma of the prostate. He received radical EBRT to
a dose of 70 Gy and achieved a PSA nadir of < 1 ng/mL at two years.
Repeat biopsy following a PSA rise to 4.5 ng/mL three years later yielded
recurrent adenocarcinoma of the same grade, and goserelin was instituted
with a PSA response to near undetectable levels. Two years later, despite
continued goserelin, the PSA rose to 1.1 ng/mL, with rises to 3.3 ng/mL
and 5.6 ng/mL after one and two further years respectively. The prostate
was palpably hard at the right side (the site of the positive biopsy)
but further staging investigations were negative for disease beyond the
prostate.
Goserelin was discontinued and salvage 125I seed brachytherapy was delivered
to a marginal dose of 60 Gy with subsequent PSA fall over six months to
2.3 ng/mL. Nine months later PSA started rising to a peak of 21.0 ng/mL
eighteen months after brachytherapy with inguinal and iliac lymphadenopathy
seen on MRI.
Goserelin was reintroduced; the PSA fell to 8.5 ng/mL after six months
but three months later rose to 21.8 ng/mL. Bicalutamide was added and
two months later PSA fell to 6.3 ng/mL. Four months later a further PSA
rise to 18.6 ng/mL occurred, bicalutamide was withdrawn with no beneficial
effect and the patient declined both glucocorticoids and estrogens in
favor of chemotherapy (Figure-1).
Patient 3
A 77 year old man was found to have Gleason 4+4 disease with a PSA of
40 ng/mL and extracapsular extension but no nodal or distant involvement.
He received three months of neoadjuvant bicalutamide (150 mg per day)
with a PSA fall to 7.4 ng/mL before radical EBRT to a dose of 70 Gy. With
adjuvant bicalutamide for one year the PSA fell further to 1.6 ng/mL and
the anti-androgen was discontinued.
At twelve months PSA rose to 10 ng/mL and goserelin was commenced with
a PSA fall to 7.4 ng/mL six months later. Further rises to 11.2 ng/mL
and 14.2 ng/mL after another six and nine months indicated progressive
disease. MRI and a bone scan showed no extra-prostatic disease and with
biopsy proof of Gleason 5+4 disease goserelin was stopped and brachytherapy
delivered to a marginal dose of 60 Gy.
There was no significant change to the PSA at six months (14.9 ng/mL)
but at one year it had risen sharply to 87.5 ng/mL with the subsequent
appearance of metastatic disease. Goserelin was restarted and six months
later the PSA had fallen to 23 ng/mL. A further fifteen months later the
level remains stable at 25 ng/mL (Figure-1).
COMMENTS
There are
limited treatment options once recurrent prostate cancer develops androgen
independence. Palliative chemotherapy with docetaxel has been shown to
improve survival (12) and is commonly instituted for metastatic disease
following failure of maximal androgen blockade but is not suitable for
all patients, particularly those with poor performance status.
Those patients with no discernible distant disease may receive local salvage
treatment such as brachytherapy or cryotherapy. Salvage brachytherapy
has been shown to deliver a biochemical response in patients with localized
disease (13). The dose for patients who have previously received EBRT
is necessarily lower than for those who have been treated without radiotherapy
and is the subject of debate: whilst many clinicians treat to a marginal
dose of 95-100 Gy our practice is to treat to 60 Gy using low dose rate
125I seeds as this has a similar biochemical effect with a lower risk
of late toxicity.
The apparent recovery of hormone sensitivity described in these three
patients after brachytherapy is an unexpected finding. PSA measurement
has long been accepted as a surrogate marker for disease activity as potentially
more direct measures such as circulating tumor cell assays remain experimental.
The phenomenon of PSA bounce (that is a transient PSA elevation following
therapy) is recognized but is unlikely to be relevant to these cases:
the phenomenon has not been recorded following salvage brachytherapy after
previous EBRT; neither the double response to hormones in case 1 nor the
response of metastatic disease in case 3 could be so explained. We believe
the data support tumor progression after brachytherapy, particularly given
the magnitude of PSA rise in each case. Moreover, there is the precedent
for the reacquisition of hormone sensitivity in the reports following
chemotherapy quoted above (9,10).
All three patients had convincing biochemical evidence of androgen independent
prostate cancer but after salvage brachytherapy and subsequent biochemical
failure were found to have reacquired hormone responsive disease. So good
was the response in one patient (Patient 1) that the practice of intermittent
endocrine therapy has been introduced. In another patient (Patient 2)
the response was complete but brief and in a third (Patient 3), although
the response was partial, it was remarkably durable.
Activity of the androgen receptor is key to regulation of prostate cancer
and may be critical to the explanation of this observation (14). Normally,
in the absence of ligand, the androgen receptor is held inactive in the
cytoplasm by heat shock protein 90. Testosterone enters the prostate cell
and is converted by the enzyme 5-alpha reductase to its derivative dihydrotestosterone
which binds to the androgen receptor causing dimerisation. The receptor
then enters the nucleus where binding at androgen responsive elements
within regulatory genes, modulated by co-activators and co-repressors,
causes increased transcription and cellular proliferation.
Although rarely mutated in localized disease, most androgen insensitive
cell lines do show abnormalities of the gene coding for the androgen receptor
including gene amplification (15), increased sensitivity to ligand (16)
and inappropriate activation by other ligands (17). Thus, in a prostate
cancer cell with one or more of these mutations the drive to proliferation
persists despite an undetectable level of circulating testosterone.
Furthermore, mutations are known to accumulate during the life of a malignant
cell and may result in a particular treatment actually becoming a stimulus
for disease progression. For example it was observed that in approximately
one third of patients with progression on anti-androgens, withdrawal of
that treatment would lead to a PSA fall (18). Subsequently it was shown
that amino acid substitutions allowed the receptor to be activated by
cortisol, other steroids and even anti-androgens such as flutamide (19).
Hence, withdrawal of a previously active treatment may have a beneficial
effect.
The cases presented here and in previous reports indicate that the observed
clinical state of androgen independence is not necessarily permanent.
Whilst many of the mechanisms by which androgen dependence is lost are
understood, the mechanisms by which androgen dependence is restored are
uncertain.
One explanation could be that the androgen receptor itself has a degree
of plasticity and that hormone sensitivity is reinduced by a mechanism
perhaps triggered by a therapeutic insult. Chemotherapy has been proposed
as that therapeutic insult (9) but our data suggest radiation exposure
may similarly act to reverse androgen independence. Several mutations
have been outlined above and it is plausible that, were further mutations
to take place disabling the abnormal androgen receptor gene and hence
the mechanism by which androgen resistance had developed, hormone sensitivity
could be regained. This mutation may be induced by radiotherapy or potentially
even arise purely from the passage of time: certainly the pelvic side
wall metastases in case 2 did not receive brachytherapy.
Alternatively, androgen independent and dependent clones may coexist within
a clinical cancer. The measured PSA would reflect PSA production from
each clone, changes in PSA would reflect progression or response to treatment
of each clone and would be most influenced by the behavior of the dominant
clone. Chemotherapy and radiotherapy could act to more selectively deplete
androgen independent clones, allowing residual androgen sensitive clones
to become the more dominant producers of PSA, and hence the clinical cancer
phenotype would seem to return to a hormone sensitive state.
A further explanation may be found in changes to downstream survival pathways,
either induced by therapeutic interventions or occurring as de novo mutations.
Non-androgen receptor activation pathways have been described including
p53 (20) and bcl-2 (21) and disruption to these could affect tumor activity.
It is important that subsequent investigations probe whether interruption
to these pathways may be helpful.
Such studies may impact on the current trend towards intermittent androgen
blockade in the long term care of hormone responsive metastatic prostate
cancer. The rationale underlying this strategy is that continuous androgen
suppression may produce a natural selection pressure in favor of androgen
independent clones whereas intermittent suppression allows cytoreduction
during treatment but not to the extent that insensitive clones “outcompete”
sensitive clones when treatment ceases. Although clinically attractive,
not least owing to presumed reduction of side effects during periods off
treatment, there is not yet convincing evidence favoring the intermittent
strategy and a large international trial for patients with metastatic
disease is currently addressing this question following encouraging preliminary
results (22).
CONCLUSIONS
The data
presented here reconfirm that prostate cancer cells which have developed
resistance to androgen deprivation and androgen receptor antagonism may
later reacquire sensitivity to that same hormonal therapy. The data demonstrate
that this phenomenon is not peculiar to patients who have received cytotoxic
chemotherapy but may occur after brachytherapy, either causally related
to the brachytherapy or with the passage of time.
These findings suggest that important undetermined mechanisms underlie
androgen resistance and give hope that there may be therapeutic interventions
available to a large cohort of patients with recurrent prostate cancer
previously considered permanently androgen independent, and provoke thought
as to whether the policy of intermittent androgen therapy for metastatic
prostate cancer may have advantages not previously contemplated.
ACKNOWLEDGEMENTS
We thank Dr. Jonathan Shamash for reviewing this paper.
CONFLICT OF INTEREST
None declared.
REFERENCES
- Berger R, Febbo PG, Majumder PK, Zhao JJ, Mukherjee S, Signoretti S, et al.: Androgen-induced differentiation and tumorigenicity of human prostate epithelial cells. Cancer Res. 2004; 64: 8867-75.
- Huggins C: Effect of orchiectomy and irradiation on cancer of the prostate. Ann Surg. 1942; 115: 1192-200.
- Allen JM, O’Shea JP, Mashiter K, Williams G, Bloom SR: Advanced carcinoma of the prostate: treatment with a gonadotrophin releasing hormone agonist. Br Med J. (Clin Res Ed). 1983; 286: 1607-9.
- Sogani PC, Whitmore WF Jr: Experience with flutamide in previously untreated patients with advanced prostatic cancer. J Urol. 1979; 122: 640-3.
- Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al.: A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989; 321: 419-24. Erratum in: N Engl J Med. 1989; 321: 1420.
- Huggins C, Hodges CV: Studies on prostatic cancer, effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941; 1: 293-7.
- Plowman PN, Perry LA, Chard T: Androgen suppression by hydrocortisone without aminoglutethimide in orchiectomised men with prostatic cancer. Br J Urol. 1987; 59: 255-7.
- Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, et al.: Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008; 26: 4563-71.
- Shamash J, Davies A, Ansell W, Mcfaul S, Wilson P, Oliver T, et al.: A phase II study investigating the re-induction of endocrine sensitivity following chemotherapy in androgen-independent prostate cancer. Br J Cancer. 2008; 98: 22-4.
- Cox RA, Sundar S: Re-induction of hormone sensitivity to diethylstilboestrol in androgen refractory prostate cancer patients following chemotherapy. Br J Cancer. 2008; 98: 238-9.
- Smith D, Maclean J, Plowman PN. Salvage Iodine-125 Brachytherapy for Locally Recurrent Prostate Cancer after External Beam Radiotherapy. Clin Onc (RCR). 2009; 21: 249. Abstract # 24.
- Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004; 351: 1502-12.
- Grado GL, Collins JM, Kriegshauser JS, Balch CS, Grado MM, Swanson GP, et al.: Salvage brachytherapy for localized prostate cancer after radiotherapy failure. Urology. 1999; 53: 2-10.
- Debes JD, Tindall DJ: Mechanisms of androgen-refractory prostate cancer. N Engl J Med. 2004; 351: 1488-90.
- Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J, et al.: Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 1997; 57: 314-9.
- Gregory CW, Johnson RT Jr, Mohler JL, French FS, Wilson EM: Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001; 61: 2892-8.
- Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, et al.: Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995; 332: 1393-8.
- Kelly WK, Scher HI: Prostate specific antigen decline after antiandrogen withdrawal: the flutamide withdrawal syndrome. J Urol. 1993; 149: 607-9.
- Monge A, Jagla M, Lapouge G, Sasorith S, Cruchant M, Wurtz JM, et al.: Unfaithfulness and promiscuity of a mutant androgen receptor in a hormone-refractory prostate cancer. Cell Mol Life Sci. 2006; 63: 487-97.
- Bookstein R, MacGrogan D, Hilsenbeck SG, Sharkey F, Allred DC: p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Res. 1993; 53: 3369-73.
- Colombel M, Symmans F, Gil S, O’Toole KM, Chopin D, Benson M, et al.: Detection of the apoptosis-suppressing oncoprotein bc1-2 in hormone-refractory human prostate cancers. Am J Pathol. 1993; 143: 390-400.
- Albrecht W, Collette L, Fava C, Kariakine OB, Whelan P, Studer UE, et al.: Intermittent maximal androgen blockade in patients with metastatic prostate cancer: an EORTC feasibility study. Eur Urol. 2003; 44: 505-11.
____________________
Accepted after revision:
December 2, 2009
_______________________
Correspondence address:
Dr. P. Nick Plowman
Department of Radiotherapy
St Bartholomew’s Hospital
West Smithfield, London, EC1A-7BE
Fax: + 44 20 7601-8364
E-mail: nick.plowman@bartsandthelondon.nhs.uk