Japanese Journal of Clinical Oncology Advance Access originally published online on May 10, 2005
Japanese Journal of Clinical Oncology 2005 35(5):256-259; doi:10.1093/jjco/hyi078
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© 2005 Foundation for Promotion of Cancer Research
Predictor of Response to Salvage Radiotherapy in Patients with PSA Recurrence after Radical Prostatectomy: the Usefulness of PSA Doubling Time
Department of Urology, Shikoku Cancer Center, Matuyama, Japan
For reprints and all correspondence: Kousaku Numata, Department of Urology, Shikoku Cancer Center, 13 Horinouchi, Matuyama, Japan. E-mail: knumata{at}shikoku-cc.go.jp
Received February 24, 2005; accepted March 21, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: We assessed predictors of response to salvage radiotherapy (sRT) in patients with prostate-specific antigen (PSA) recurrence after radical prostatectomy.
Methods: A total of 21 patients receiving sRT for PSA recurrence without systemic progression after radical prostatectomy had medical records available for retrospective review. We defined sRT as external beam radiotherapy for patients with a continuous increase in PSA level 
0.2 ng/ml after radical prostatectomy. Response was defined as achievement of a PSA nadir of 
0.1 ng/ml. Various pre-treatment parameters were evaluated retrospectively.
Results: The median follow-up period after sRT was 38 months. Of the 21 patients, 15 were good responders (71%). The only predictive factor was PSA doubling time (PSADT). Age and PSA level at diagnosis, Gleason score and surgical margin status were not significant predictors of response. The median PSADT in responders was 6.2 months versus 1.9 months in non-responders (P = 0.019). The patients with a PSADT of 5 months were all responders.
Conclusion: PSADT appears to be a good predictor of response to sRT. sRT was especially effective when PSADT was 5 months.
Key Words: prostate cancer • radical prostatectomy • salvage radiotherapy • PSA doubling time
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The widespread use of measurement of prostate-specific antigen (PSA) has increased the detection of early prostate cancer. Radical prostatectomy is widely used in the treatment of organ-confined disease. However,
10–30% of patients with clinically localized prostate cancer have recurrence of the disease after radical prostatectomy, as evidenced by post-operative elevation of serum PSA (1–3). Salvage radiotherapy (sRT) might be an option in attempts to cure recurrent disease, particularly in patients with a high probability of local recurrence. The reported success rates of sRT have ranged between 10 and 50% for unselected patients with PSA increasing (2). Rapid PSA doubling time (PSADT), high-grade disease and short disease-free interval after radical prostatectomy are associated with the development of metastasis (4). Although isolated local recurrence can potentially be cured by sRT, there is no proven cure for metastatic disease. Current imaging modalities lack the ability to detect occult metastatic lesions. It is very important to distinguish effective cases from ineffective ones. We therefore retrospectively evaluated the outcomes of sRT and variables which might predict the outcomes of sRT after radical prostatectomy for localized prostate cancer. |
PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Between January 1993 and December 2003, 249 patients with prostate cancer underwent radical prostatectomy at Shikoku Cancer Center. Of these patients, 40 had nodal metastasis and 65 underwent adjuvant therapy (hormonal treatment, radiation or both). Of the 65 patients, 45 were early cases and routinely received adjuvant therapy. Twenty did not achieve undetectable PSA levels. Of the 144 patients remaining after exclusion of the above patients, 29 experienced only PSA recurrence. Of these 29 patients, one died of other disease, one received hormone therapy, one received chemotherapy for bladder cancer, two patients are now receiving sRT and three patients are being observed without treatment. The remaining 21 patients underwent sRT. All 21 had medical records available for retrospective review. All PSA measurements were conducted with Architect kits.
PSA recurrence was defined as two consecutive increases above the level of 0.1 ng/ml. sRT was performed by external beam radiotherapy for patients with a PSA level of 0.2 ng/ml without systemic progression on radiological examination. Seven patients received treatment before the PSA level reached 0.2 ng/ml but had at least two consecutive PSA increases to levels of 0.1 ng/ml. Radiation was delivered to the prostatic fossa by a four-field technique, at a dose of 2 Gy five times per week (total dose, 60 Gy). A responder was defined as the achievement of a PSA nadir of <0.1 ng/ml, and a non-responder as lack of achievement of this. Progression was defined as a PSA level of 0.1 ng/ml above the post-radiotherapy PSA nadir confirmed by a second PSA measurement that was higher than the first by any amount. The PSADT was calculated from the slope of the regression line between the post-operative PSA nadir and pre-radiotherapy PSA level, as 0.693 divided by that slope (1). Three or more points were used to calculate the PSADT. Toxicities were graded using National Cancer Institution-Common Toxicity Criteria (NCI-CTC) version 2.
Differences in variables between responders and non-responders were tested by the Mann–Whitney U-test. The level of significance was P < 0.05.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The median age of patients at sRT was 67 years (range 55–73), the median interval from prostatectomy to sRT was 25 months (range 4–67) and the median follow-up after sRT was 38 months (range 8–68). Four patients received neoadjuvant hormone therapy. The median PSA level at diagnosis was 10.390 ng/ml (range 4.0–125.0), the median pre-radiotherapy PSA level was 0.243 ng/ml (range 0.148–0.520) and the median PSADT was 4.2 months (range 0.8–17.3) (Table 1).
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Of the 21 patients, 15 (71%) were responders. Variables were compared between 15 responders and six non-responders, and included age, PSA level at diagnosis, pre-radiotherapy PSA level, interval from prostatectomy to sRT, PSADT, clinical stage, pathological stage, Gleason score and surgical margin status. The median PSADTs of responders and non-responders were 6.3 and 1.9 months, respectively, and PSADT was the only predictive variable that differed significantly between responders and non-responders (Table 2).
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Figure 1 shows plots of both PSADT and the pre-radiotherapy PSA level of 21 patients. The PSADTs of non-responders were all <5 months. Of the patients with PSADT <5 months, those with a lower pre-radiotherapy PSA level tended to exhibit a response.
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During follow-up, only one of the 15 responders had PSA progression, 42 months after sRT. His current PSA level is 0.143 ng/ml and he has received no additional therapy over 47 months after sRT without clinical failure. None of the responders exhibited clinical progression during follow-up. Of the four patients who received neoadjuvant hormone therapy, three patients were non-responders and one had PSA progression.
All non-responders received additional hormone therapy, and their PSADTs were <5 months. Three patients exhibited clinical progression. Two of them had pelvic nodal metastasis and one had bone metastasis. The patient with bone metastasis died 54 months after sRT. Two patients with clinical progression (one with bone metastasis and one with pelvic nodal metastasis) never had PSA decline after sRT.
Gastrointestinal toxicity was noted in 10 patients, and genitourinary adverse events occurred in four patients. All toxicities were grade I or II and treatment breaks were not needed.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Widespread screening with PSA has led to increased detection of prostate cancer at an early stage, when the tumor is confined to the prostate and therefore curable. However,
10–30% of patients with clinically localized prostate cancer have recurrence of disease after radical prostatectomy, as evidenced by post-operative elevation of serum PSA (1–3). The prognosis following radical prostatectomy depends strongly upon pathological characteristics, such as seminal vesicle invasion, nodal metastasis, margin status and the presence of extracapsular extension (5–7). If serum PSA never falls to undetectable levels, or is rapidly rising, systemic disease is assumed to be present (8,9). In contrast, if levels remain undetectable for 2–4 years and then gradually rise, the likelihood of a local recurrence is higher (1,9). However, these criteria do not supply information sufficient to distinguish local recurrence from distant metastasis. The clinical application of PSADT is based on the suggestion that the growth of prostate cancer is exponential, and that doubling time should therefore reflect biological activity (10). For example, PSADT is often calculated for patients who are not treated with a watchful waiting strategy (11). Some authors have reported that PSADT after radical prostatectomy is related to progression patterns. Pound et al. reported that a PSADT of 10 months identifies patients who are at higher risk of development of distant metastasis (1). D'Amico et al. reported, in the largest series published of 8669 men with clinical localized or locally advanced non-metastatic prostate cancer, that a PSADT of <3 months identified men who were 19.6-fold more likely to die of prostate cancer than those with a PSADT >3 months (12).
sRT after radical prostatectomy can provide long-term disease control if disease is localized within an encompassable field of radiation and a sufficient radiation dose can be delivered to eradicate recurrent cancer. The reported success rates of sRT range between 10 and 50% (1). Katz et al. reported a series of 115 men who received sRT. Negative margins, absence of extracapsular extension and presence of seminal vesicle invasion were independent predictors of PSA relapse after sRT (13). Leventis et al. reported a series of 95 men in which pre-radiotherapy PSA level and PSADT were independent predictors of PSA relapse after sRT (14). Egawa et al. reported a Japanese series of 38 patients undergoing sRT. In that study, they described that those with a lower PSADT might be better candidates for sRT (15). Stephenson et al. reported that in a series of 501 patients, predictors of progression after sRT were Gleason score of 8–10, pre-radiotherapy PSA level >2.0 ng/ml, negative surgical margins, PSADT of 10 months or less and seminal vesicle invasion (4). In that study, the authors concluded that these five parameters were related to progressive metastatic disease. Matsui et al. reported the impact of volume-weighted mean nuclear volume of biopsy specimens to predict the pre-treatment factor of sRT (16). It is very important but difficult to distinguish local recurrence from distant metastasis for patients with PSA elevation alone after radical prostatectomy. Bone scintigraphy is not sufficiently sensitive to rule out the presence of metastases because lesions usually are not detectable at serum PSA levels <10 ng/ml (17). The rates of pelvic nodal metastasis by CT diagnosis are only 30–80% (18). Half of patients with normal digital rectal examination (DRE) findings have positive biopsy findings in the prostatic fossa (19). The ProstaScint scan is expected to detect recurrent lesions, but its clinical utility is still being investigated (20). Therefore, candidates for sRT should be selected based on pathological and post-operative parameters.
In our study, PSADT was the factor most strongly predictive of response to sRT. PSADT can be calculated easily and, as described above, some authors have also reported that it is a good predictor of response to sRT. However, the present study had two limitations. First, the total number of patients was small. Secondly, this study used a retrospective design. As a consequence, selection bias may have existed in our study.
In conclusion, for patients with localized prostate cancer, radical prostatectomy is a curative treatment. However, some patients experience PSA failure. sRT has the possibility of curing recurrent disease. Although no study has shown that sRT improves survival and prevents development of distant metastasis, it is of great importance to recognize patterns of recurrence and select appropriate additional therapy. PSADT can, in addition to pathological characteristics, be a very important predictor of response to sRT.
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References |
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