- Top of page
- PATIENTS AND METHODS
The staging evaluations for newly diagnosed prostate cancer traditionally include 99mTc-based bone scintigraphy, as the outcome profoundly influences management decisions. Moreover, bone scintigraphy remains the most sensitive method for detecting skeletal metastasis in prostate cancer [1–3]. Recently, the application of bone scintigraphy as a staging tool in newly diagnosed prostate cancer has been more refined and selective, mainly because of the increasing understanding that the serum PSA level is correlated with tumour volume and clinical stage, and that the likelihood of a positive bone scan can be, to some extent, predicted by PSA levels. Several series have questioned the need for bone scintigraphy as part of the initial staging investigation in newly diagnosed prostate cancer, especially if the pretreatment PSA level is low [4–9]. When it is < 20 ng/mL, the likelihood of a positive bone scan in asymptomatic patients was estimated to be only 0.8%. Thus, it has been suggested that the bone scan can be omitted when the pretreatment PSA is low. This would result in significant cost savings, and avoid unnecessary psychological and physical stress of the test for a significant proportion of men with newly diagnosed prostate cancer.
Currently, there is no consensus on how to monitor disease progression in patients with clinically localized prostate cancer (CLPC) opting for watchful observation. Bone scintigraphy is often used as one of the surveillance tools to assess disease progression. However, the predictive value of serial bone scans for detecting the development of new bone metastasis has never been evaluated prospectively in patients with CLPC managed with watchful observation alone. At our institution, a prospective single-arm study, ‘watchful observation with selective delayed intervention based on clinical, histological, and/or PSA progression’, has been underway since November 1995 for patients with CLPC and favourable clinical variables (clinical stage T1b-2bN0M0, Gleason score ≤ 7 and PSA ≤ 15 ng/mL). In this study, patients have a bone scan regularly in accordance with the predefined follow-up evaluation schedules, as long as they remain on watchful observation. Therefore, the cohort of this prospective study provided a unique opportunity to examine the value of serial bone scans in CLPC managed with watchful observation, and any correlation between the change in PSA levels and bone scan findings.
PATIENTS AND METHODS
- Top of page
- PATIENTS AND METHODS
A prospective, single-arm, cohort study has been in progress since November 1995 to assess the feasibility of an observation protocol with selective delayed intervention using clinical, histological and/or PSA progression as treatment indicators. In this study, a patient is managed conservatively with watchful observation alone if he does not meet the criteria of disease progression, empirically defined with three variables: a PSA doubling time of < 2 years, clinical progression and histological upgrading on a repeat prostate biopsy. When a patient meets any of the predefined criteria of disease progression during follow-up, he ceases watchful observation, and treatment is implemented according to his age, extent of disease, comorbidity and personal preference. Patients are closely monitored to enhance the likelihood of intervening within the therapeutic ‘window of curability’ in those identified as progressing. The interim analysis of this study, including the wide variability in PSA doubling time, was described in a previous report .
STUDY PATIENTS, EVALUATIONS AND FOLLOW-UP
Each patient was screened according to well-defined inclusion and exclusion criteria, and enrolled into the study if all of the following eligibility criteria were met: (i) a histological diagnosis of adenocarcinoma of prostate within the year before entry; (ii) no previous treatment for prostate carcinoma; (iii) clinical stage T1b-T2bN0M0 (1997 TNM classification); (iv) a PSA level of ≤ 15 ng/mL; (v) a Gleason score of ≤ 7; (vi) able to give informed consent.
As baseline, all patients had a histopathological review of the prostate biopsy specimen to confirm a low to intermediate grade of malignancy. They had a medical history taken, and a physical examination, chest X-ray, TRUS of the prostate and blood tests, measuring serum creatinine, PSA and prostate acid phosphatase. An initial staging investigation using radioisotope bone scintigraphy and CT of the abdomen and pelvis were optional, and applied individually. Patients were followed every 3 months for the first 2 years and every 6 months thereafter as long as they remained on the study.
At each visit a medical history, physical examination including a DRE and blood tests for PSA, prostatic acid phosphatase and serum creatinine were obtained. Patients underwent TRUS of the prostate every 6 months. TRUS-guided re-biopsies of the prostate were taken at 12–18 months after enrolment. Bone scans were taken every year for the first 2 years and then every 2 years if the patient remained on surveillance. When the PSA level was> 15 ng/mL a bone scan was taken every year.
Disease progression resulting in therapeutic intervention was empirically defined and consisted of three categories, i.e. clinical, histological and PSA progression. The patient was considered to have clinical progression when he developed one of the following conditions: (i) more than a doubling of the product of the maximum perpendicular diameters of the primary lesion, as measured digitally; (ii) symptoms requiring TURP; (iii) the development of ureteric obstruction; (iv) radiological and/or clinical evidence of distant metastasis. Patients who required TURP were conservatively scored as having progressed, although obstructive urinary symptoms could be caused by the progression of either malignancy or coexisting BPH. Furthermore, TURP prevented further PSA monitoring. Histological progression occurred when the Gleason score was upgraded to ≥ 8 in the re-biopsy of the prostate at 12–18 months after study enrolment. PSA progression was defined when all of the following three conditions were met: (i) PSA doubling time of < 2 years, based on at least three separate measurements over ≥ 6 months; (ii) a final PSA level of> 8 ng/mL; and (iii) P < 0.05 from a regression analysis of ln(PSA) on time.
All bone scintigraphy was undertaken using 99mTc-methylenediphosphonate, and reported by certified nuclear medicine physicians. Any equivocal findings in bone scans were correlated with a plain X-ray, CT or MRI, as advised by the radiologists. In the attempt to evaluate the value of serial bone scans the prospectively collected data were examined systematically, including bone scan reports. In addition, the distribution of the PSA levels corresponding to all the follow-up bone scans was examined.
Baseline characteristics (age, clinical stage, Gleason score and initial PSA) were tabulated, and the PSA doubling time calculated assuming that PSA changed over time in a simple exponential fashion. The approach applied for calculating PSA doubling time was discussed in detail in a previous report . All PSA measurements available since the date of enrolment were used for calculating the PSA doubling time. As all bone scans in the study were negative, the observed positive rate was zero, and an upper one-sided 95% CI (U) could be calculated as 1 –[0.05](1/n), where N is the number of scans. Assuming that the risk of a positive bone scan increases monotonically with increasing PSA, the PSA readings corresponding to all the bone scans were sorted, and the above equation used to calculate the upper confidence limit for any PSA threshold, using for N the number of negative scans obtained corresponding to PSA readings at or above the threshold. The results of these calculations were plotted as a graph.
- Top of page
- PATIENTS AND METHODS
The study was closed in September 2001 and accrued a total of 252 patients; eight patients were ineligible and excluded from analyses. The reasons for ineligibility were PSA> 15 ng/mL (three patients), clinical stage T3 (four) and a Gleason score of 8 (one). Thus 244 eligible patients were available for analysis (median age 71 years, range 49–84). The patient characteristics according to initial PSA level, Gleason score and clinical stage are summarized in Table 1; 162 and 82 patients had clinical stage T1 and T2 at enrolment, respectively. The initial Gleason score was Gx in two patients with microscopic foci of malignancy which could not be adequately graded, ≤ 5 in 50, 6 in 139 and 7 in 53; the initial PSA was < 5 ng/mL in 73, 5–9.9 in 128 and 10–14.9 in 43.
Table 1. Characteristics of the 244 eligible patients
|PSA (ng/mL)||Clinical stage T1b-T1c||Clinical stage T2a-T2b||Total|
|< 5||5–9.9||10–14.9||< 5||5–9.9||10–14.9|
|Gx*|| 0|| 0|| 0|| 1|| 1|| 0|| 2|
|3|| 0|| 0|| 1|| 0|| 0|| 0|| 1|
|4|| 3|| 3|| 2|| 0|| 0|| 0|| 8|
|5|| 8||17|| 4|| 5|| 7|| 0|| 41|
|7|| 4||17|| 7|| 7||12|| 6|| 53|
As of March 2002 the median (range) follow-up of the study cohort was 30 (3–71) months; 76 patients ceased the watchful observation protocol while 168 remained on active surveillance. The reasons for discontinuing were: clinical progression in 16, PSA progression in 15, histological progression in seven, the patient's wish in 27, protocol violation in six, intercurrent death in three, a second malignancy in two. Thirty-eight patients met the arbitrarily defined criteria for disease progression and subsequently received therapeutic intervention; 16, 15 and seven had clinical, PSA and histological progression, respectively. Six patients were scored as protocol violators, including four who had Gleason 7 with a primary Gleason grade 4 on their follow-up biopsy. Two remaining protocol violations were treated on the basis of PSA progression, although they did not strictly meet all three criteria for PSA progression. Twenty-seven patients chose to cease surveillance (median age 71 years, range 54–81); 20 of these proceeded with treatment while the remaining seven continued on watchful observation but off the protocol. Two patients had a second primary malignancy (both had lung cancer) and three had intercurrent death unrelated to prostate cancer.
The numbers of patients by ranges of PSA doubling time based on at least three separate measurements over ≥ 6 months were: 112 (48.9%) of> 10 years, 30 (13.1%) of 5.1–9.9 years, 63 (27.5%) of 2–5 years and 24 (10.5%) of < 2 years.
In all, 449 bone scans were taken, as of March 2002; 150 were at baseline and 299 were follow-up evaluation scans. Overall, 171 patients had at least one follow-up bone scan as part of surveillance evaluation. The distribution of the number of patients according to the number of follow-up bone scans is summarized in Table 2, and according to the PSA levels at the times they were taken. All follow-up bone scans were negative for bone metastasis. The observed positive bone scan rate of zero, based on 299 follow-up scans, has an exact upper one-sided 95% confidence limit of 1.0%. Of 38 men who met the predefined criteria of tumour progression, 27 had at least one follow-up bone scan either as part of the predefined follow-up schedule or at the time of disease progression; 16 had bone scans at or close to the time of disease progression, and all were negative for bone metastasis. Table 3 summarizes the upper confidence limit of the probability of a positive follow-up bone scan at different PSA thresholds; the graphical representation of this is shown in Fig. 1. At a PSA threshold of 10 ng/mL the true probability of a positive follow-up bone scan is 0–3.5%; at 15 ng/mL the probability is 0–11.7%.
Table 2. Distribution of the number of patients by the number of follow up bone scans
|Number of follow-up bone scans||N (%)||Total number of bone scans|
|1|| 89 (52.0)|| 89|
|2|| 53 (31.0)||106|
|3|| 17 (9.9)|| 51|
|4|| 8 (4.7)|| 32|
|5|| 3 (1.8)|| 15|
|6|| 1 (0.6)|| 6|
|PSA (ng/mL) at the time of scan|
|< 10|| ||214|
|10–14.9|| || 61|
|15–19.9|| || 18|
| ≥ 20 (21.3–24.9)|| || 6|
Table 3. Upper 95% confidence limits of probability of a positive bone scan by PSA threshold
|PSA threshold (ng/mL)||Upper confidence limit (%) for follow-up bone scans|
| 5.0|| 1.4|
| 7.5|| 1.9|
Figure 1. Graphical representation of the upper 95% confidence limit of the probability of a positive bone scan at different PSA thresholds.
Download figure to PowerPoint
- Top of page
- PATIENTS AND METHODS
Traditionally bone scintigraphy has been routinely scheduled as part of staging investigations for newly diagnosed prostate cancer. This is based on two main factors; first, prostate cancer metastasizes most commonly to the bone. Lehr et al. showed in vitro that prostate cancer cells adhere preferentially to the endothelial cells in the bone marrow. Second, a radionuclide bone scan is better at detecting skeletal metastasis in prostate cancer than a clinical evaluation, plain X-ray of the bone, serum alkaline and acid phosphatase levels [1–3].
During the last decade the widespread use of serum PSA for detecting prostate cancer has not only increased the incidence of prostate cancer but also significantly changed the profile of clinical stage at diagnosis. In the era before PSA up to a third of men diagnosed with prostate cancer presented with distant metastasis [13,14]. In contrast, the recent screening series using serum PSA and a DRE have suggested that 95% of patients are now diagnosed with clinically localized cancers, and only 5% had radiological evidence of bone metastasis at the time of diagnosis [15–17]. This significant change in the profile of clinical stage at diagnosis, and some correlation of serum PSA levels with tumour volume and clinical stage, have led physicians to re-examine the routine use of bone scans for staging in patients with newly diagnosed prostate cancer.
Several studies have examined the potential role of serum PSA levels in predicting bone scan findings in newly diagnosed prostate cancer [4–9]. These studies suggested that bone scans could be omitted in these men when the pretreatment PSA was < 10 ng/mL [4,7,9]. Some even suggested a PSA threshold of < 20 ng/mL [5,6,8], as the probability of positive yield from a routine bone scan in this range of PSA was very low, but others reported a higher rate of positive bone scans with this threshold, i.e. 18.9% and 13.2% respectively [7,18], at this threshold. Table 4 lists some of the studies in which the rate of positive bone scans was evaluated in men with a low pretreatment PSA.
Table 4. Previous studies evaluating the rate of positive bone scans with a low pretreatment PSA level
|Reference||No. of patients||N (%) of positive bone scans at PSA (ng/mL) |
|< 10||< 20|
| [ 5 ] ||852|| 3 (0.4)|| 7 (0.8)|
| [ 10 ] ||378|| 0|| 4 (1.1)|
| [ 9 ] ||316|| 0|| 1 (0.3)|
| [ 13 ] ||144||14 (9.7)||19 (13.2)|
| [ 8 ] || 37|| 0|| 7 (18.9)|
| [ 6 ] || 30|| 0|| 0|
The optimum frequency and extent of follow-up evaluation for patients with CLPC opting for watchful observation remain unclear. Bone scintigraphy is frequently used as a part of surveillance to detect skeletal metastasis in this group of patients. This is in part because a recent phase III study reported the benefit of early hormone therapy for patients with newly diagnosed, asymptomatic, bone metastasis, compared with hormone therapy delayed until the development of symptomatic bone metastasis . However, there are several unresolved questions about the use of bone scans in this clinical setting, because the predictive value of serial bone scans in detecting new bone metastasis remains unknown. How frequently should bone scan be taken in the follow-up of CLPC managed with watchful observation? Is there a PSA threshold below which follow-up bone scans can be omitted because of the very low probability of a positive bone scan? Is there any correlation between the probability of a positive bone scan and the rate of PSA change over time (i.e. PSA doubling time)? There has been no study addressing these questions. The present study represents, to the best of our knowledge, the first assessment of the value of serial bone scans prospectively in patients with CLPC and managed by watchful observation.
In this cohort, all 299 follow-up bone scans were negative regardless of initial clinical stage, Gleason score, PSA level and PSA doubling time. There are several possible reasons for this finding. First, a significant proportion of the study cohort may indeed have biologically indolent malignancy. This is reflected in that 62% of patients had a PSA doubling time of> 5 years. Moreover, the study had very strict eligibility criteria that excluded anyone with adverse clinical or pathological features. This selection process would probably lead to the inclusion of only patients with more indolent malignancy. Second, the very low observed rate of positive follow-up bone scans may result from relatively short follow-up in this cohort relative to the very long natural history of CLPC. Chodak et al. estimated in their pooled data of watchful observation series that the probabilities of developing bone metastasis at 10 years were 19% and 42% for WHO grade 1 and 2 malignancy, respectively. Thus, a much longer follow-up may be needed before the manifestation of clinically evident bone metastasis. Third, some patients ceased the surveillance protocol as they met the empirically defined disease progression definition based on PSA doubling time, clinical local progression or histological upgrade on follow-up prostate biopsy. As these patients received a therapeutic intervention they were not subjected to serial follow-up bone scans that would have been taken if left untreated. Thus, there is a possibility that the study may underestimate the probability of a positive follow-up bone scan through pre-emptive intervention. Last, most follow-up bone scans were taken when the PSA levels were < 15 ng/mL; therefore it is not unexpected that the probability of a positive follow-up bone scan would be low.
In the present study, 214 follow-up bone scans were taken in men with a PSA of < 10 ng/mL; all were negative for metastasis. This is consistent with published reports suggesting that a PSA of < 10 ng/mL is a strong predictor of a negative bone scan at the initial diagnosis of prostate cancer. Sixty-one follow-up scans were taken in men with a PSA of 10–14.9 ng/mL and again were all negative. This suggests that the yield of a positive follow-up bone scan is also low when the PSA is < 15 ng/mL. There were only 18 and six, respectively, follow-up bone scans at PSA values of 15–19.9 and ≥ 20 ng/mL, and hence no definitive conclusion could be drawn for this group of patients, as more would be needed to estimate a probability of positive follow-up bone scan. In this series, when a PSA threshold of 10 ng/mL was used, the probability of a positive follow-up bone scan was very low (0–3.5%); even with a threshold of 15 ng/mL there was still an 88–100% chance of a negative follow-up bone scan. The confidence limit of the probability of positive follow-up bone scan increases when a higher PSA threshold is applied (Fig. 1) because few scans were taken at higher PSA levels in this cohort. From this we suggest that serial follow-up bone scans can be omitted as long as the serum PSA remains < 15 ng/mL for patients with CLPC opting for watchful observation. In those with a follow-up PSA of> 15 ng/mL, the role and frequency of serial bone scans remain undefined, and further study with a larger sample is needed. This suggestion applies only to patients with clinically localized, low to intermediate grade, prostate cancer. For those with locally advanced disease (i.e. clinical stage T3) or poorly differentiated malignancy (i.e. Gleason ≥ 8) and opting for watchful observation, even though this would not be the standard of care, the optimal frequency and predictive value of serial bone scans remains unknown and needs to be investigated further.
We previously reported that PSA doubling time might be a useful tool to enable a clinician to evaluate the dynamic change in tumour kinetics over time, and to have a better understanding of the risk of disease progression inherent in watchful observation. This can, in turn, help a clinician to develop a strategy for optimizing the timing of therapeutic intervention, should there be disease progression in a patient opting for watchful observation alone . In the present cohort, 15 patients with a PSA doubling time of < 2 years were declared to have PSA progression and yet the bone scans at the time were negative in 11, while the other four had no bone scan at that time. This suggests that our empirically defined criteria of PSA progression for invoking treatment permit the introduction of therapeutic intervention at least before the development of clinically evident bone metastasis and possibly within the therapeutic window of curability.
The guideline about follow-up bone scans in patients with CLPC and opting for watchful observation can lead to significant savings in cost. It may also reduce the unnecessary psychological and physical distress of the test, thus improving quality of life. These goals can be achieved without compromising patient outcome, by careful patient selection. Osterling  estimated that if bone scans were omitted as part of the initial staging investigation in men with prostate cancer when the pretreatment PSA level was < 10 ng/mL, the overall net savings to the USA healthcare system would be $50 million. Similarly, significant costs could be saved among patients managed with active surveillance alone, if follow-up bone scans are taken only in those with a higher probability of positive finding.