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Recurrent prostate cancer following external beam radiotherapy: Follow-up strategies and management Charles Catton, MD, FRCPC*, Michael Milosevic, MD, FRCPC, Padraig Warde, MD, FRCPC, Andrew Bayley, MD, FRCPC, Juanita Crook, MD, FRCPC, Robert Bristow, MD, PhD, FRCPC, Department of Radiation Oncology, University of Toronto, Princess Margaret Hospital, 610 University Avenue, Patients with early-stage prostate cancer who are treated with radical radiotherapy (RT) have Because the prostate gland remains in situ after an excellent prognosis, and although long-term radical EBRT, the prostate-specific antigen (PSA) survival is expected, many patients fail and will does not fall to undetectable levels as is seen after require further interventions. The optimal follow- radical prostatectomy (RP). Rising PSA is the up strategies to detect treatment failure and the most common sign of recurrence after EBRT, but optimal timing of further treatment are the subject it may reflect local, regional, or distant failure, or of ongoing prospective trials. A well-designed a combination of the sites of failure. Digital rec- follow-up strategy is part of an optimal manage- tal examination (DRE) with PSA determination ment policy, and early detection of tumor recur- are employed in post-EBRT follow-up, although rence also may improve the chance of re-treatment Johnstone et al [2] determined that new informa- and salvage of a local or systemic relapse.
tion was provided by post-RT DRE in only 30% The availability and efficacy of additional of abnormal examinations, and in 75% of these treatment govern the timing, frequency, and sel- cases the findings were related to EBRT-induced ection of follow-up investigations. This requires rectal bleeding rather than to tumor recurrence.
an understanding of the natural history of treated The measurement of PSA levels following EBRT prostate cancer and the cost-effectiveness of is the most widely employed method of evaluating therapy. There is no benefit in an intensive post-EBRT outcome in patients with localized follow-up program if early intervention is not prostate cancer, but the sensitivity and specificity recommended and treatment is introduced only of the method for predicting a clinically relevant when recurrent disease is clinically apparent and outcome is less than perfect and is open to symptomatic [1]. This article reviews the informa- criticism [3,4]. Other follow-up tests, such as tion on the follow-up strategies including de- posttreatment biopsy of the prostate and func- tection and treatment of relapse of prostate cancer tional imaging, may be used to supplement DRE following radical external beam RT (EBRT) and PSA in determining post-RT disease status, The serum PSA level is correlated to total * Corresponding author.
E-mail address: tumor burden and the PSA level after treatment is a widely used surrogate endpoint of response 0094-0143/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved.
doi:10.1016/S0094-0143(03)00051-X C. Catton et al / Urol Clin N Am 30 (2003) 751–763 Fig. 1. (acrobat figure 030J). Follow-up flow chart for men treated with radical EBRT for prostate cancer.
in prostate cancer. The value of PSA response consensus panel published a consensus statement has been documented in a number of studies on the definition of PSA failure [10]. The [5–9], although the use of adjuvant hormone ASTRO consensus panel agreed on four guide- therapy makes the interpretation of PSA levels after RT unreliable because the PSA productionis under hormonal control and the value of PSA 1. Biochemical failure is not equivalent to may not reflect directly the presence or absence of tumor. The decline of PSA following RT is 2. Three consecutive increases in PSA is a rea- slow and normally takes 6 to 24 months or more, sonable definition of biochemical failure, with and the definition of response or failure based on the date of failure reported as the midpoint the PSA levels following treatment is referred to of the nadir PSA and the first of the three as ‘‘biochemical response or failure.’’ Biochemi- consecutive rises. Three consecutive rises were cal response may be defined as ‘‘PSA nadir’’ or adopted to prevent classification of patients ‘‘PSA failure.’’ In 1997, the American Society for with fluctuating PSA from being classified as Therapeutic Radiology and Oncology (ASTRO) Fig. 2. (acrobat figure 031J). Flow diagram for the management of clinical local failure or biochemical failure oflocalized prostate cancer following radical EBRT.
C. Catton et al / Urol Clin N Am 30 (2003) 751–763 3. No definition of PSA failure has been shown instrumentation [13]. A PSA bounce is not pre- unequivocally to be a surrogate for clinical dictive of future biochemical failure and should not be used as a sole indicator of relapse, although 4. Although nadir PSA is a useful factor, no the risk of relapse is higher in patients who exhibit absolute level is a valid cutoff point in multiple episodes of PSA fluctuation [14].
deciding successful or unsuccessful treatmentoutcome.
Although these criteria generally correlate well Crook et al [16] proposed that routine, system- with clinical outcome [8,11], they have many atic, transrectal, ultrasound-guided prostate bi- limitations. Taylor et al [12] reported that the opsies might be an effective way of determining specificity and sensitivity of a rising PSA to post-RT local tumor control. They observed that predict a clinically meaningful failure such as sequential positive biopsies often converted to a local recurrence, distant recurrence, or initiation negative over time, and recommended that the of unplanned hormone therapy or RP is related to optimal time to biopsy was 24 to 30 months post- the proportional magnitude of the PSA rise above RT [17]. Several other reports of EBRT for nadir levels and the steepness of the slope of the localized prostate cancer have included post-RT rise (the PSA doubling time [PSADT]). For biopsies with the outcome assessment [18–20].
example, proportionally small consecutive rises Despite the attractiveness of using post-RT bi- measured over a short interval may have a benign opsies to determine local control, and the demon- cause and be misclassified as biochemical disease strated interest in this procedure, experience has progression. In another scenario, any gradually shown that correctly identifying viable tumor in progressing tumor may have a slowly rising PSA biopsies of irradiated prostate is not straightfor- trend that is obscured by occasional decreases in ward. In addition to the problem of correctly PSA levels, thus resulting in a much-delayed timing the biopsies after treatment, the diagnosis of complete response is difficult, with 3% to 40%of post-RT biopsies remaining as indeterminate, even with expert evaluation [9,21,22]. Further- more, there is significant interobserver variability measured after RT. A PSA nadir predicts a sub- in reporting positive post-RT biopsies among sequent biochemical and clinical failure [7], but expert uropathologists, and poor agreement of the nadir level is not in itself an indicator of expert pathologists with nonexpert pathologists disease remission or relapse. Longer interval from [21]. Immunohistochemical tumor staining for treatment to PSA nadir positively correlates with PSA, high—molecular-weight keratin, and pro- freedom from metastatic disease [6,7], and PSA liferative cell nuclear antigen have been reported to progression immediately following RT is a strong improve the sensitivity and specificity of reporting indicator of the presence of systemic metastases, positive post-RT biopsies [23], as does correlation presumably because in this situation PSA pro- of biopsy status with the post-RT PSA nadir [24].
duction continues unimpeded during and imme- However, in spite of the limitations, posttreat- ment biopsy remains a valuable tool for selectingpatients for local salvage therapy. In fact, re-treatment with a local ablative procedure should not be considered without a positive prostate re- A PSA bounce has been defined as an initial biopsy. A wider experience with the technique is posttreatment increase in PSA of greater than 0.4 required, and the criteria for the diagnosis of ng/mL or greater than or equal to 15% of the carcinoma in post-RT biopsies need to be refined previous value over a 6-month period within 60 further and applied uniformly before re-biopsy can months of therapy that subsequently decreases to be adopted as a routine method for assessing prebounce baseline levels [13–15] or lower. A PSA bounce has been identified in 12% to 33% ofpatients treated with EBRT [14,15], and the mean time to PSA bounce was found to be as long as 9months [15]. The cause has not been defined, but is Although the assessment of the response to speculated as possibly being due to ejaculation or treatment and early detection of recurrence in C. Catton et al / Urol Clin N Am 30 (2003) 751–763 prostate cancer are driven completely by serial imaging is not recommended as part of routine serum PSA measurements, the site of recurrence follow-up. For the investigation of a patient with cannot be determined by PSA and should be a rising PSA after EBRT, preliminary evidence assessed by clinical examination and imaging, suggests that the technique is more sensitive and recognizing that standard imaging is likely to be specific than is CT or MRI in identifying patients negative and should not be done unless the patient with nodal metastases. The very limited experi- has a Gleason score greater than 7 or a PSA ence with capromab pendetide imaging for re- staging patients treated with EBRT has shownit to be of value in making management decisions[32,33], but wider availability and more experi- ence with the technique will be required beforecapromab pendetide imaging can be consid- Skeletal imaging using 99mtechnetium-labeled ered as a substitute for these standard staging diphosphonate is the most widely used technique for the detection and surveillance of prostatecancer to the bones [27]. Because a PSA riseusually antedates the detection of bone metastases in patients with prostate cancer, routine bonescans are not recommended as part of follow-up [18F]fluorodeoxyglucose positron emission to- [28,29]. The bone scan should be used to help mography (FDG PET) is a common method for differentiate local recurrence from metastatic imaging the metabolic activity of cancer. FDG spread in patients with a rising PSA [27], although PET scanning is valuable for the identification of it has been demonstrated that for a PSA of less metastases in a variety of tumors, although the than 20 ng/mL and a Gleason score greater than low cellular uptake rate of FDG in prostate 7, or for a PSA of less than 50 ng/mL and cancer has limited the usefulness of the technique a Gleason score less than 8, a bone scan has less for staging and follow-up for adenocarcinoma of than 10% likelihood of being positive [26].
the prostate [34,35]. More effective radiotracers Because they are not useful, bone scans should such as [18F]flurocholine are under investigation not be performed in patients with very low PSA and may improve the ability of PET to detect prostate cancer metastases [34,36], but at presentPET scanning should not be used routinely forprostate cancer staging or follow-up.
Capromab pendetide (ProstaScint) is the con- jugated form of a murine immununoglobulin G1 monoclonal antibody directed against prostate-specific membrane antigen (PSMA). 111Indium Hormonal ablative therapy has a long history capromab pendetide is capable of identifying bone of effectiveness in the management of relapsed and soft tissue disease in patients with known prostate cancer and in a recent patterns of practice metastases [30], and it is approved only for report [37], 93% of patients who received second- imaging of soft-tissue disease. A recent compar- ison of capromab pendetide imaging to CT or hormonal ablative therapy. The numerous rea- MRI for the diagnostic assessment of prostate sons for the popularity of this approach include cancer in 51 surgically explored patients demon- the high response rate to therapy, the ease of strated that capromab pendetide had a sensitivity access to treatment, the relative lack of associated of 75% in detecting nodal involvement compared serious toxicity, and patient preference. In addi- with 20% for CT or MRI. Specificity and positive tion, clinical factors such as advanced patient age predictive value for capromab pendetide imaging at relapse and advanced disease extent at pre- was 86% and 79%, respectively, compared with sentation or at relapse may make other, more a specificity and positive predictive value of 68% aggressive approaches to salvage therapy less and 31% for CT or MRI imaging [31]. Imaging suitable. Clearly, there also is a role for curative with capromab pendetide is challenging tech- local salvage treatment in selected individuals, nically, and requires specific training to read the although this use remains controversial, due images [31], and routine capromab pendetide largely to many unresolved issues in the natural C. Catton et al / Urol Clin N Am 30 (2003) 751–763 history of disease progression in these patients, less than 6 months had an 8.5 fold increased odds and especially in accurately defining those patients of distant failure as opposed to local failure who have a high likelihood of having an isolated compared with patients with a doubling time of 6 to 12 months. Lee et al [41] reported on the Patients with locally recurrent disease may be pattern of failure after definitive RT in 459 candidates for RP, cryosurgery, and brachyther- patients with localized disease and found that apy, but these treatments are being used in- PSADT (<12 months) and a short interval from frequently and it is difficult to compare the the end of treatment to PSA elevation (<12 outcomes in these case series with the outcomes months) were significant independent predictors following conservative management. These series of distant metastases. Given the potential for tend to have carefully selected patients and include significant local side effects of re-treatment, local only a small proportion of men who relapse after salvage therapy should likely be considered only RT. Even so, only 35% to 50% of these patients for patients with a long life expectancy who would will have prolonged biochemical disease-free prefer the option of a potentially curative survival [38,39]. The curative potential of these treatment to the option of surveillance or long- salvage local therapies is poorly documented.
term hormonal ablation. Patients most likely torespond to re-treatment will have clinical stageT1/T2 at initial presentation and at relapse, PSADT of greater than 6 months, and an interval between primary treatment and relapse of greater The individual most likely to benefit from than 1 year. In addition, the serum PSA presalv- ablative local treatment after failure of radical RT age treatment should be less than 10 ng/mL and will have an anticipated life span of 10 years or the initial Gleason score should be 7 or less.
more, a proven local recurrence, and a lowprobability of harboring micrometastatic disease.
Because biochemical failure after RT can be dueto local recurrence, distant recurrence, or both, RP has not been accepted widely as salvage biopsy proof of a local recurrence is essential, and therapy for local recurrence after radiation restaging investigations looking for nodal or bone therapy because of the morbidity and high re- metastasis should be negative. The likelihood of currence rates. Reports from the pre-PSA era success for local salvage therapy is dependent on show a 40% to 50% incidence of postsurgery the same risk factors as is the success of RT. A incontinence, 100% impotence, and a substantial patient with a low pre-RT Gleason score, low incidence of serious bowel and rectal injury [43– PSA, and low initial clinical stage is least likely to 46]. In the modern era, with relapse being detected fail because of the low risk of micrometastases, earlier based on rising PSA, a number of series and therefore is most likely to benefit from reported more favorable outcomes. Pisters et al [47] reported on 13 patients treated with salvage In addition to the pre-RT risk factors, the RP between 1995 and 1999. All received a conti- timing of biochemical relapse after RT and nent catheterizable reconstruction to prevent PSADT both have been shown to be useful in urinary incontinence, and 9 of 13 remain dis- predicting the pattern of failure after RT [40–42].
ease-free 6 to 48 months after surgery. Gheiler Sartor et al [42] reported the outcome of 400 et al [48] reported results in 30 patients treated patients with localized prostate cancer treated with salvage RP between 1992 and 1997 at Wayne with radical RT between 1987 and 1994. With State University. With a mean follow-up of 36 a median follow-up of 3 years, 234 patients months, 15 patients (50%) had no evidence of (58.6%) had rising PSA values, 38 patients biochemical disease progression. Only 15 patients (9.7%) developed local failure, and 23 (5.8%) (50%) were continent; mild incontinence was developed distant failure. On multivariate analy- present in 8 patients (26%) and severe inconti- sis, rapid PSADT was found to predict for nence was seen in 7 patients (23%). Vaidya and metastatic rather than for local failure. Thirty- Soloway [49] reported the outcome of six patients seven patients had a PSADT of less than 6 months who underwent salvage RP at the University of and 17 (46%) of these patients developed distant Miami between 1995 and 2000. Androgen depri- metastasis as compared with only 4 (8%) who vation therapy was given preoperatively in five developed local relapse. Patients with a PSADT of of these patients. With a mean follow-up of C. Catton et al / Urol Clin N Am 30 (2003) 751–763 27 months, biochemical failure has occurred in a posttreatment America Urological Association only one patient. All six patients are impotent, five symptom score greater than 20. Overall satisfac- are continent, and one patient has mild stress tion with cryotherapy was reported by only 33% of Although these results may be encouraging, it Cryosurgery has been approved by the Centers is impossible to generalize them, given the degree for Medicare and Medicaid Services as the only of patient selection in these series. Patients treatment specifically approved for the indication choosing RP as salvage local therapy should be of recurrent local cancer after radiation. However, informed of the potential morbidity, particularly the significant complication rates after treatment the risk of clinically significant incontinence, and and the lack of proven efficacy have limited its use surgery optimally should be performed in a center that has experience with this approach.
Grado [56] and Grado et al [57] reported on Initial results of cryotherapy as salvage therapy a series of 49 men treated with salvage brachy- after failure of RT were disappointing. Control therapy, using either iodine 125 or palladium 103 rates were less than 25% and significant in- for full-dose permanent transperineal seed im- continence was seen in more than 40% of patients plants. Median follow-up was 64 months. Initial [50]. Advances in cryosurgical technique have RT dose was 66 Gy (range 20–70 Gy) completed improved these results with long-term inconti- at a median interval of 41.7 months previously.
nence rates now being reported as less than 10% Patients were not rigorously selected for having [51–53]. Biochemical disease-free survival rates are a high chance of successful local salvage. Seventy- in the 30% to 40% range, with better results seen one percent had presented with an initial stage B2- in patients with low-grade T1/T2 disease and PSA C tumor. Moderately differentiated tumors had less than 10 ng/mL before treatment [51,54] Chin been documented in 53% and poorly differenti- et al [51] reported results in 118 patients treated ated tumors had been documented in 34%. Only between 1994 and 1999. With a median follow-up half had baseline PSA levels available from the of 19 months, the biochemical no evidence of time of initial diagnosis; the median value was disease rate at 4 years was 34%. Severe incon- 26.4 ng/mL. Despite the high-risk profile of the tinence was noted in eight patients (6.7%) and population, the actuarial, biochemical, disease- rectourethral fistula occurred in four patients free survival at 3 and 5 years following salvage (3.3%). In a recent update of the MD Anderson brachytherapy was 48% and 34%, respectively.
data, Izawa et al [54] reported a 5-year disease-free More importantly, the results of these studies survival of 40% in 131 patients treated between [56,57] demonstrate the feasibility of salvage 1992 and 1995 (median follow-up = 4.8 years).
brachytherapy in terms of toxicity. Posttreatment As in other series, patients with a precryotherapy irritative and obstructive urinary symptoms were Gleason score greater than 9, PSA greater than 10 self-limited and managed with alpha-blockers.
ng/mL, and advanced clinical stage did poorly. In Transurethral resection of the prostate (TURP) addition, patients with androgen-independent was performed in 14%, 4% experienced persistent local progression did worse compared with those gross hematuria, 6% experienced penile dysuria, with androgen-dependent disease [54].
and 4% had rectal ulcers. One of these latter Quality of life is compromised after cryother- patients required colostomy after aggressive rectal apy in a substantial number of patients. In a biopsies. Incontinence (at least one pad per day patient-based questionnaire administered to 150 pa- more than 6 months after the procedure) was tients (112 questionnaires returned, 74%) at MD documented in 6%, all of who had a postbrachy- Anderson Cancer Center, 72% of patients reported therapy TURP. Only one patient who previously some degree of dribbling or leakage when asked to was potent reported diminished sexual function.
describe bladder control [55]. Forty-four percent of The authors [56,57] now recommend avoidance of patients reported problems with perineal pain, and TURP and management of irritative and obstruc- pain interfered with normal daily activity in 38% tive urinary symptoms with alpha-blockers and of patients. Treatment without an effective urethral intermittent self-catheterization. Beyer [58] re- warming catheter was associated with urinary ported on 17 patients treated with salvage incontinence, perineal pain, tissue sloughing, and permanent seed prostate brachytherapy. Those C. Catton et al / Urol Clin N Am 30 (2003) 751–763 patients with a low-grade tumor at the time of Surgical or medical castration produces a high salvage had 83% freedom from second relapse as likelihood of prolonged PSA control in the compared with 30% for those patients with high- majority of men. The combination of a nonsteroi- grade tumors. Salvage brachytherapy compares dal antiandrogen and castration to produce ‘‘total favorably with other potentially curative salvage androgen blockade’’ [60] yields only minimal options for locally recurrent prostate cancer after improvement in survival compared with castra- conventional-dose RT. There is no experience tion alone [61–63]. Furthermore, increased cost, with its use after modern external RT techniques more frequent and bothersome side effects, and that employ prostate doses greater than 70 Gy a general reduction in quality of life may over- [57], and the potential for increased rectal and shadow the small benefit. Short-course neoadju- urinary toxicity exists with re-treatment following vant androgen suppression, which is commonly high-dose EBRT. The ideal patient for retreat- prescribed before RT, does not compromise the ment with brachytherapy should have presented response to subsequent salvage hormonal treat- originally with a tumor likely to be confined to the ment administered for disease progression [64].
prostate (T1c/T2a, Gleason  6, PSA<10 ng/mL), The type and severity of the side effects from and should have biopsy evidence of residual low- androgen suppressive therapy vary depending on grade prostate carcinoma with minimal radiation the specific treatment and its mechanism of effect [24]. Because early biochemical failure is action, but commonly include vasomotor hot likely to be associated with a distant component, flashes, loss of libido, erectile dysfunction, breast a disease-free interval of at least 12 months and pain and gynecomastia, mood swings and anxiety, preferably 24 months is more likely to be as- anemia, osteoporosis that predisposes to frac- sociated with purely local recurrence [6]. Finally, tures, loss of muscle mass, and altered glucose absence of rectal or urinary toxicity is advisable.
and impaired sexual performance affect a largeproportion of men treated with a luteinizinghormone-releasing hormone (LHRH) agonist.
Hormonal therapy for progression following RT Nonsteroidal antiandrogens—particularly bicalu- It has been known for many years that prostate tamide—may preserve erectile function at the cancer is a hormonally responsive disease and expense of a higher incidence of breast symptoms that withdrawal of testosterone leads to rapid [65]. The implications of long-term androgen regression of disease [59]. The mechanisms un- ablation on bone, lipid, and glucose metabolism, derlying the dramatic response to androgen withdrawal that frequently is seen clinically are metastatic disease in which survival is limited, complex and interrelated, and include increased are potentially much greater in otherwise healthy apoptosis, inhibition of angiogenesis, and altered expression of hormonally responsive genes. Most following RT and are expected to live for many men who recur following RT for prostate cancer will, at some point in their disease, requiretreatment with androgen suppression. Histori- cally, the diagnosis of recurrence was most likelyto be made on the basis of new urinary symptoms, Men who develop clinical local progression or due to progressive local disease or musculoskeletal metastases following RT for prostate cancer re- pain from bone metastases. However, rising PSA quire immediate androgen suppression by or- in the absence of symptoms now provides an early chiectomy or with an LHRH agonist. In the case sign of recurrence following RT and precedes of the latter, pretreatment with an antiandrogen is clinical evidence of failure by many years. Many required to prevent tumor flare and worsening of men at the time of PSA progression are not symptoms. However, this is now a rarely seen candidates for potentially curative salvage treat- presentation of relapse. The majority of patients ments, but may nevertheless live long, productive is followed with serial PSA measurements and lives with slowly progressive disease. Therefore, develops PSA failure with no evidence of clinical management recommendations at the time of disease. The optimal time to begin hormonal recurrence must focus on extending the symp- therapy in an asymptomatic man with PSA failure tom-free interval and improving survival, while alone is not know, but, in practice, most men in North America opt for earlier rather than later C. Catton et al / Urol Clin N Am 30 (2003) 751–763 treatment. The choice may differ from individual the attendant side effects and potential reduction to individual depending on how each weighs the potential benefits versus the side effects. Some men The definition of ‘‘early treatment’’ in the or their families experience considerable anxiety context of modern medical practice, where pro- and emotional distress knowing that a rising PSA gression after RT most commonly is diagnosed on represents progressive cancer and demand active the basis of serial rises in PSA, is ill defined. It is treatment immediately upon diagnosis of recur- likely that men participating in the MRC study had rence. Others prefer to defer treatment and a broad spectrum of locally advanced and occult exposure to possible side effects for as long as metastatic disease and, extrapolating from more recent experience, a correspondingly broad range There is increasing evidence from clinical of PSAs ranging from minimally abnormal to very studies that ‘‘early’’ intervention with hormonal high values that would now be viewed as a clear therapy is beneficial, compared with later treat- indication for immediate treatment. In contrast, ment at the time of symptom development. This is men with progression following RT frequently likely due to an effect of hormonal treatment on have normal or minimally elevated PSAs that gene expression in prostate cancer, with delayed increase very slowly over time. It is not known emergence of clinically aggressive and metastatic whether beginning hormonal treatment immedi- phenotypes. Messing et al [66] demonstrated a ately at PSA progression offers any advantage survival advantage to immediate medical or compared with careful follow-up and later initia- surgical castration in men with node-positive tion of treatment at some ‘‘trigger’’ point before the prostate cancer identified at the time of radical development of symptoms. This is particularly prostatectomy compared with initial observation.
important in light of the young age of many patients Bolla et al [67,68] described improved survival in undergoing RT, their long anticipated survival, patients with locally advanced or high-grade and the side effects of hormonal treatment. The prostate cancer treated with RT and hormonal European Organization for Research and Treat- ablation for 3 years, compared with RT initially ment of Cancer (EORTC) 30943 study, which is and hormonal treatment at the time of disease randomizing men with a rising PSA to immediate versus delayed hormonal treatment, should help to answer this question. Currently, the most frequent Cancer Working Party Investigators Group [69] indication for beginning hormonal treatment in studied 934 asymptomatic men with previously men who fail RT is the rate of PSA rise. Short untreated locally advanced or metastatic prostate PSADTs predict metastatic disease and a shorter cancer, and randomized them to receive either interval to the development of symptoms [70,71].
immediate surgical or medical castration or initial Sylvester et al [60] surveyed urologists and radia- observation and the same treatment at the time tion oncologists who treat prostate cancer and of symptomatic progression. Men who received found that 65% to 70% used a short PSADT as the immediate treatment had a significantly lower main indication for hormonal therapy follow- risk of developing urethral obstruction, metastatic ing RT. Most used a threshold doubling time of disease, pain due to bone metastases, pathologic 6 months or less, although almost 25% recom- fracture, or spinal cord compression. There also mended treatment at a threshold doubling time was an advantage of immediate treatment with of 12 months or less. The remaining 30% to 35% respect to both overall and disease-specific sur- relied on either the absolute PSA value, or used vival, especially in men without metastases. This the ASTRO definition of failure to recommend study has been criticized because PSA follow-up was not available (given that the study was initiated in 1985 before the routine use of PSA),clinical follow-up of patients was erratic, and The development of hormone-refractory dis- a small proportion of patients on the delayed- ease remains a major problem in the management treatment arm died of progressive prostate cancer of men with prostate cancer. Although the rate of without receiving hormonal treatment. Neverthe- response to initial hormone treatment is high, most less, it provides strong support for early hormonal men develop progressive disease despite continued treatment in men with recurrent prostate cancer antiandrogen therapy at a median interval of after RT who are anxious to obtain the maximal about 2 years from the start of treatment [62,63].
benefit of this treatment, and are not bothered by The duration of hormone responsiveness may be C. Catton et al / Urol Clin N Am 30 (2003) 751–763 longer in men who have small-bulk disease when with the predictable steady-state of continuous treatment is initiated. Once hormone refractory treatment. The National Cancer Institute of disease becomes clinically evident on the basis of Canada with the collaboration of Intergroup is a rising PSA or the development of new symptoms, conducting a phase 3 randomized trial of in- the management options for patients are limited.
termittent versus continuous androgen ablation Changes in the type of hormone treatment may for asymptomatic men with a rising PSA follow- produce secondary responses, but the duration of ing RT and no clinical or radiographic evidence of response usually is short lived. Therefore, treat- metastatic disease that will provide answers to ment strategies that prolong the interval of hormone dependence have the potential also toprolong survival and improve quality of life.
There is preliminary evidence that intermittent androgen suppression—which involves sequential periods of androgen suppression followed by with- suppression for prostate cancer undergo either drawal of treatment and androgen recovery— surgical or medical castration as a component has the potential to delay the molecular and of their treatment, there is interest in exploring genetic changes that lead to hormone resistance, alternate treatments that produce a more accept- extend the duration of response to hormone able side-effect profile and therefore greater long- therapy, and reduce side effects. Several, small, term tolerance and compliance. Treatment with phase 2 clinical studies now have been reported, a nonsteroidal antiandrogen alone, particularly most of which used PSA as the indication for bicalutamide, has the potential to maintain po- starting and stopping treatment with an LHRH tency at the expense of an increased likelihood agonist [72–74] Treatment and off-treatment of gynecomastia and breast pain [65,75–77], a intervals in these studies have been approximately trade-off that many men would accept. There equal, typically ranging from 6 to 9 months in also is increasing clinical evidence to indicate that duration [72–74]. Testosterone recovery occurred bicalutamide alone may preserve bone density in the majority of men while off treatment, and relative to castration [78,79]. However, antian- was associated with improved libido and sexual drogens may yield inferior long-term disease capacity in those who were potent before begin- control in some circumstances relative to castra- ning treatment, as well as an overall improvement tion because of secondary elevation of serum in quality of life. There was a suggestion of testosterone levels that overcomes the competitive delayed development of hormone resistance rela- tive to continuous androgen suppression. How- Several randomized clinical studies [75–77] ever, the results in this regard are very difficult have evaluated treatment with bicalutamide alone to interpret, given differences in patient selection as a single agent relative to castration. A bicalu- and the multitude of factors that can affect the tamide dose of 150 mg daily was used in many of duration of hormonal response, including the the studies. In general, the results have shown the extent of disease at the time that treatment is survival of men with metastatic disease to be inferior with bicalutamide compared with castra- tion. However, the results in men with locally particularly well suited to men with PSA pro- advanced, nonmetastatic disease have been equiv- gression alone following EBRT, who may survive alent. The pooled results of three, large, ran- 10 years or more with slowly progressive disease.
domized studies of bicalutamide 150 mg daily It has the potential to extend the clinical pro- comprising over 8000 patients showed that 80% gression-free interval with minimal side effects and to 90% of men developed breast toxicity within cost. However, there is insufficient evidence at 6 months of beginning bicalutamide, and that 15% present to recommend intermittent therapy as of men abandoned treatment because of intolera- routine treatment. Prolonged hormone respon- ble breast symptoms. Breast pain resolved within siveness has not been documented rigorously in 1 year in the majority of men stopping bicalutamide.
the clinical domain, and the effect on survival is However, resolution of gynecomastia was less not known. Furthermore, intermittent hormone predictable and inversely influenced by the dura- therapy may lead to repeated swings in symptoms, tion of prior treatment. There was a low incidence libido, sexual capacity, and general quality of life of impotency compared with controls, and a low that some men may find intolerable compared incidence of vasomotor symptoms [65].
C. Catton et al / Urol Clin N Am 30 (2003) 751–763 intermediate risk factors who wishes to consider all studies of single-agent bicalutamide in men with salvage options should he relapse, or for the high- a rising PSA following RT for prostate cancer.
risk individual in situations in which the proba- Nevertheless, the available evidence suggests that bility of systemic relapse is of major concern.
this may be appropriate treatment in those who Young patients with very adverse risk factors may wish to maintain potency and can tolerate the benefit from even closer follow-up in the early years after EBRT and the elderly or frail mayrequire only occasional visits to record or treattreatment toxicity and to ensure clinical non- All patients who undergo curative therapy for prostate cancer should be followed for a prolongedperiod of time to determine tumor control and treatment toxicity for quality assurance purposes.
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