To examine the prognosis after BCR with and without salvage therapy, including radiation and/or androgen deprivation.
The study population consisted of 431 patients, all of whom underwent radical prostatectomy and developed BCR (PSA > 0.2 ng/mL). According to the two risk factors [Gleason score ≥ 8 and PSA-doubling time (DT) < 6 months], we divided the patients into two groups. The high/intermediate-risk group consisted of patients with both or one risk factor. On the other hand, patients with neither factor were in the low-risk group. We set the starting point at the timing of BCR, and the endpoints were development to castration-resistant prostate cancer (CRPC) and cancer-specific death.
During the mean follow-up period of 8.3 years after BCR, CRPC was observed in 49 patients (11.4%), and 21 patients (4.9%) died due to prostate cancer. We first divided the 191 high/intermediate-risk patients according to the PSA level (PSA < 1.0 ng/mL, PSA 1.0–4.0, and PSA > 4.0 or no therapy) at the initiation of salvage therapy, including radiation and/or androgen deprivation. We found that delayed (PSA > 4.0 ng/mL) or no salvage therapy was significantly associated with CRPC and cancer-specific death. In the 240 low-risk patients, Kaplan–Meier curves demonstrated no significant difference in CRPC-free survival or cancer-specific survival within 10 years from the timing of BCR.
Observation after BCR without salvage therapy or delayed administration may be an option for low-risk patients with a Gleason score ≤ 7 and PSA-DT ≥ 6 months when their life expectancy is within 10 years.
Since the introduction of serum prostate-specific antigen (PSA) testing, the incidence of clinically localized prostate cancer has markedly increased and radical prostatectomy (RP) has become a mainstream of curative therapy . Following the routine use of PSA monitoring after RP, postoperative recurrence can be identified in the early phase. As the number of RP procedures increases, physicians are now frequently facing biochemical recurrence (BCR), which is generally defined as the asymptomatic increase in postoperative PSA to greater than 0.2 ng/mL . The options for BCR include local external beam radiotherapy to the prostatic bed [3, 4], systemic androgen deprivation therapy (ADT) [5, 6], and observation [7, 8].
We previously reported that salvage ADT for BCR should be started early, especially for patients with a Gleason score ≥ 8 and PSA-doubling time (DT) < 6 months, because there is a significant risk of the subsequent development of castration-resistant prostate cancer (CRPC) with delayed hormonal therapy . Conversely, observation after BCR without salvage therapy or delayed administration may be an option for low-risk disease. Due to the high sensitivity of PSA for early detection of disease recurrence, some patients have a long interval between BCR and the development of visible local recurrence or distant metastasis [7, 8]. Therefore, observation after BCR is often carried out, especially for elderly patients in clinical practice, although its safety has not been sufficiently elucidated.
In this study, we examined the prognosis after BCR with and without salvage therapy, including radiation and/or androgen deprivation. These data will assist in establishing indications for observation after BCR.
Patients and methods
After institutional review board approval, we retrospectively reviewed the medical records of patients who underwent RP during the period of 1991–2011 at three institutions, and identified 431 patients with BCR after the nadir PSA was less than 0.2 ng/mL. Patients with a history of adjuvant androgen deprivation and/or radiotherapy were excluded.
Follow-up and treatment
The starting point of this study was the timing of BCR, which was defined as a postoperative PSA level > 0.2 ng/mL . After BCR, the timing of salvage treatment was mainly depended on the physician and patient’s preference. The majority of patients whose recurrence was thought to be locally confined to the prostate bed (i.e., having a positive surgical margin, pT3 on the surgical specimen, and/or recurrent mass detected by MRI) were generally treated by salvage radiation therapy, whereas the others who were thought to have micrometastasis with rapid PSA increase were treated by salvage hormonal therapy. When visible distant metastasis was found on the images, salvage hormonal therapy was definitely selected. The first endpoint was development to castration-resistance prostate cancer (CRPC), which was defined as a 25% or greater increase and an absolute increase of 2.0 ng/mL or more from the nadir after combined antiandrogen blockade (CAB) . We set the second endpoint at the timing of cancer-specific death. The mean follow-up period after BCR was 8.3 years and that after RP was 10.7 years.
The Gleason scores of prostatectomy specimens were cited from medical records. Our study included 77 patients who received neoadjuvant ADT. For them, Gleason score of needle biopsy was assigned instead of prostatectomy Gleason score. PSA-DT after BCR was calculated, assuming the first-order kinetics as reported previously . Then, according to the two risk factors mentioned above (Gleason score ≥ 8 and PSA-DT < 6 months) , we sub-grouped the patients. The high/intermediate-risk group consisted of patients with both or one risk factor. On the other hand, patients with neither factor were in the low-risk group.
Timing of salvage treatment
Next, we divided the patients with each risk level into “early treatment”, “delayed treatment”, and “late or no treatment” according to the PSA level (PSA < 1.0 ng/mL, PSA 1.0–4.0, and PSA > 4.0 or no therapy) at the initiation of salvage therapy, including radiation and/or androgen deprivation. The “early treatment” group included patients who received salvage treatment before PSA exceeded 1.0 ng/mL or whose PSA had not reached 1.0 ng/mL at the last follow-up visit. The “delayed treatment” group consisted of patients for whom salvage treatment was initiated when their PSA was 1.0–4.0 ng/mL or whose PSA had not reached 4.0 ng/mL. The “late or no treatment” group comprised patients who had not received any salvage treatment until or after their PSA reached 4.0 ng/mL.
Differences in continuous variables between two groups were analyzed using the Mann–Whitney U test. The Chi-squared test was used to analyze the difference in the number of patients between two groups. Kaplan–Meier curves were drawn to examine postoperative CRPC-free survival and cancer-specific survival (CSS). Hazard ratios for CRPC and cancer-specific death were calculated applying Cox’s proportional hazards model. Patients without these events were censored at the last follow-up visit. Differences among the groups were analyzed using the log-rank test. In all analyses, p < 0.05 was considered significant. All analyses were performed using R software (version 3.0.2).
Clinicopathologic characteristics of entire cohort
During the mean follow-up period, development to CRPC was observed in 49 patients (11.4%), and 21 patients (4.9%) died due to prostate cancer. The clinicopathologic differences between the high/intermediate-risk and low-risk patients are summarized in Table 1. High/intermediate-risk patients had a significantly higher Gleason score and faster PSA-DT.
We first divided the 191 high/intermediate-risk patients into “early”, “delayed”, and “late or no treatment” groups according to the timing of salvage therapy. The clinicopathologic differences among them are summarized in Table 2. We found that “late or no treatment” was significantly associated with CRPC (Fig. 1a) and CSS (Fig. 1b). The 10-year CRPC-free survival rates were 89%, 77%, and 34%, respectively. The 10-year CSS rates were 93%, 90%, and 84%, respectively. Supplemental Fig. 1 demonstrates the Kaplan–Meier curves, discriminating the salvage ADT and radiation therapy. Supplemental Fig. 2 demonstrates the CRPC-free survival and CSS rates, excluding 39 patients who received neoadjuvant ADT. The hazard ratio for CRPC in patients with “late or no treatment” was 6.81 (p < 0.001) and that for cancer-specific death was 4.08 (p = 0.002) as compared with patients with “early treatment” (Table 3).
For the 240 low-risk patients, the clinicopathologic differences among the “early”, “delayed”, and “late or no treatment” groups are summarized in Table 4. Kaplan–Meier curves demonstrated no significant difference in CRPC-free survival (Fig. 2a) or CSS (Fig. 2b) within 10 years from the timing of BCR. The 10-year CRPC-free survival rates were 97%, 93%, and 92%, respectively. The 10-year CSS rates were 100%, 100%, and 95%, respectively. Supplemental Fig. 3 demonstrates the Kaplan–Meier curves, discriminating the salvage ADT and radiation therapy. Supplemental Fig. 4 demonstrates the CRPC-free survival and CSS rates, excluding 38 patients who received neoadjuvant ADT. The hazard ratio for CRPC in patients with “late or no treatment” was 1.54 as compared with patients with “early treatment”, but there was no significant difference (p = 0.568). Regarding cancer-specific death, the hazard ratio was incalculable due to the limited number of events (Table 3). In the “late or no treatment” group, the mean PSA level at the initiation of salvage therapy was 9.5 ng/mL (range 4.5–37.6 ng/mL). This group included six patients who had not received salvage treatment, and their mean PSA level at the last follow-up was 5.5 ng/mL (range 4.3–8.6). Two patients in this group died of prostate cancer, one of whom received salvage CAB 2.5 years after BCR when his PSA was 4.8 ng/mL. Subsequently, his PSA re-increased under CAB, and he died 9.9 years after BCR. Another patient received salvage CAB 6.8 years after BCR when his PSA was 25.6 ng/mL. Later, the disease developed to CRPC, and he died 13.3 years after BCR.
RP is the standard treatment for clinically localized prostate cancer, but residual cancer or micrometastases after surgery may be diagnosed by detecting asymptomatic elevation of PSA. The sensitivity of PSA monitoring after RP is extremely high, because all patients who develop late local recurrence or distant metastasis inevitably develop BCR in advance. Therefore, measurement of PSA is essential for surveillance after RP to identify patients who may need salvage treatment beforehand. On the other hand, the natural history of BCR without salvage treatment may not necessarily lead to clinically significant metastasis or mortality. Therefore, physicians often have difficulty in deciding whether to initiate early salvage treatment or avoid overtreatment.
Radiotherapy or ADT is performed as salvage treatment for BCR. In general, radiotherapy is performed with curative intent for patients whose disease is expected to be localized to the prostatic bed, whereas ADT is initiated as systemic therapy and the treatment target includes micrometastases. Physicians apply either treatment depending on the clinicopathologic parameters. Regarding salvage radiotherapy, previous studies reported that early initiation may lead to a cure for patients with BCR. A PSA value of ≤ 0.5 ng/mL at the timing of salvage radiotherapy was confirmed to be a predictive factor, and demonstrated to be associated with a higher biochemical progression-free survival [3, 4]. Furthermore, two randomized clinical trials demonstrated that adding ADT to salvage radiation therapy improves the prognosis for patients with poor prognostic factors as compared with salvage radiation therapy alone [12, 13]. Trock et al. reported that salvage radiation therapy after BCR was advantageous for CSS, especially in patients with a Gleason score ≥ 8 and/or PSA-DT < 6 months, which was consistent with our study, although the timing of salvage treatment in their study cohort varied (PSA ranged from 0.2 to 33.0 ng/mL) . Regarding the role of ADT for patients with BCR, we previously examined 138 patients who developed BCR after the nadir PSA of 0.2 ng/mL and all of them received ADT. We found that early ADT (before the PSA level exceeds 1.0 ng/mL) is beneficial for high-risk patients with a Gleason score ≥ 8 and PSA-DT < 6 months . Van den Bergh et al. performed a systematic review of previous reports on the effectiveness of ADT for patients with BCR. They concluded that early ADT should be reserved for patients with a short PSA-DT (< 6–12 months) or high Gleason score (≥ 8) and a long life expectancy . In summary, several previous studies including both radiotherapy and ADT suggested that early initiation of salvage treatment is associated with an improved prognosis for patients with clinical poor prognostic factors.
On the other hand, studies on observation or delayed salvage treatment for BCR are limited, even though it may be a viable option in clinical practice for elderly patients or those with low-risk factors. Pound et al. performed a retrospective single-arm study on 304 BCR patients with comparatively homogeneous clinical backgrounds, all of whom had not received salvage treatment until metastasis was noted. They reported that the median time to metastasis was 8 years from BCR, and that a Gleason score ≥ 8, BCR within 2 years after RP, and PSA-DT ≤ 10 months were risk factors for subsequent metastasis . Boorjian et al. similarly performed a retrospective single-arm study on 2426 patients with BCR, and found that age, Gleason score, pathological stage, and PSA-DT were associated with CSS, although their study included 580 patients who received some salvage treatment before systemic progression .
In the present study, we extracted patients for whom we were able to observe or delay the salvage treatment with limited risk of later CRPC or cancer-specific death. As a result, we found that observation or delayed treatment for BCR in low-risk patients with a Gleason score ≤ 7 and PSA-DT ≥ 6 months does not have a negative impact on later CRPC or cancer-specific mortality for at least 10 years in comparison with patients who received early salvage treatment. The significance of these two prognostic factors (high Gleason score and fast PSA-DT) for BCR was previously confirmed in several studies, as mentioned above, and these may be applied to as indicators of observation or delayed treatment. This simple risk stratification will be useful for counseling patients during the decision-making process for the treatment procedure.
The limitations of our study include its retrospective design and that the timing of salvage treatment after BCR was mainly at the physician’s discretion, which may have resulted in differences in the background among the groups. A previous report indicated that salvage radiation therapy was superior to ADT regarding the progression-free survival after BCR, although it was retrospective analysis . However, in this study “salvage treatment” included radiation therapy and ADT, and we were unable to perform further detailed analyses comparing the types of salvage treatment due to the limited number of patients. Conversely, its strengths were the comparatively long follow-up period and limited number of drop-outs despite enrolling consecutive patients. Our study included patients who received neoadjuvant ADT. We confirmed similar results after excluding these patients (Supplemental Figs. 2 and 4), but it could be one of the limitations. Our cohort did not include any patients treated by robotic radical prostatectomy, which is the current standard procedure . Although the influence of robotic surgery on oncological outcomes is unknown, it may be a limitation. We were unable to perform analyses regarding distant metastasis due to the lack of data, although they will be helpful for understanding the biological behavior of prostate cancer without salvage treatment. In the future, external validation with an independent data set containing a sufficient number of patients will be needed to confirm the safety of observation after BCR.
Our study suggested that observation after BCR without salvage therapy or delayed administration is a viable option for low-risk patients with a Gleason score ≤ 7 and PSA-DT ≥ 6 months, especially when their life expectancy is within 10 years. However, for other patients, early salvage therapy against BCR may be advantageous for both CRPC-free and CSS.
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Matsumoto, K., Niwa, N., Hagiwara, M. et al. Type of patients in whom biochemical recurrence after radical prostatectomy can be observed without salvage therapy. World J Urol 38, 1749–1756 (2020). https://doi.org/10.1007/s00345-019-02970-w
- Radical prostatectomy
- Biochemical recurrence
- PSA-doubling time
- Castration-resistant prostate cancer
- Gleason score