Annals of Oncology Advance Access published online on March 19, 2008
Annals of Oncology, doi:10.1093/annonc/mdn062
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The postchemotherapy PSA surge syndrome
1 Department of Medicine
2 Department of Radiotherapy and
3 Department of Translational Research/BU Prostate, Institut Gustave Roussy, Villejuif, France
* Correspondence to: Dr Karim Fizazi, Department of Medicine, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94800 Villejuif, France. Tel: +33-1-42-11-62-64; Fax: +33-1-42-11-52-30; E-mail: fizazi{at}igr.fr Presented in part at the 29th European Society for Medical Oncology congress, Vienna 2004.
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Background: Chemotherapy has emerged as a standard treatment in patients with castration-refractory prostate cancer (CRPC). Consensus criteria are available to define response in CRPC as at least a 50% decline in serum prostate-specific antigen (PSA) confirmed 4 weeks later. The objective of this work was to study early serum PSA changes in patients under chemotherapy and to correlate these changes with subsequent response assessment.
Patients and methods: Serum PSA levels were monitored every 3 weeks in 79 patients with CRPC treated with chemotherapy and a time course of serum PSA levels was obtained. Correlation with response was studied.
Results: According to consensus criteria, 21 (40%) and 20 (38%) patients achieved a PSA response and stabilization, respectively, after first-line chemotherapy. Among patients who achieved either a response or a stabilization, 8 of 41 (20%) had a serum PSA rise during the first 8 weeks of chemotherapy, followed by a subsequent decline in serum PSA. The same observation was made in patients receiving second-line chemotherapy: 6 of 20 patients achieving a response or stabilization had an initial serum PSA rise. The postchemotherapy increase in serum PSA could reach more than twice the baseline value. The duration of the PSA surge ranged from 1 to 8 weeks. When considering responders only, 6 of 30 (20%) had a postchemotherapy serum PSA surge, followed by a drop.
Conclusion: Postchemotherapy PSA surges occur not infrequently in patients with CRPC who respond to chemotherapy. Physicians should be aware of this effect to avoid inadequate early discontinuation of chemotherapy.
castration-refractory prostate cancer, chemotherapy, prostate-specific antigen
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introduction |
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Castration-refractory prostate cancer (CRPC) is the lethal form of the disease and it is responsible for significant morbidity, including pain and other bone metastasis-related events. During the last decade, chemotherapy has emerged as standard treatment for patients with CRPC, with a benefit in terms of palliation [1, 2] and, more recently, survival improvement [3–5]. For a long time, one of the obstacles to developing chemotherapy in prostate cancer was the lack of criteria to assess tumor response, with most patients exhibiting nonmeasurable, bone-only disease. Although a debate persists as to whether a decline in serum prostate-specific antigen (PSA) is a surrogate for overall survival in metastatic prostate cancer [6, 7], a PSA decline of at least 50%, confirmed 4 weeks later, was consensually regarded as a criterion of response to chemotherapy [8]. Most oncologists currently use PSA monitoring to assess the efficacy of chemotherapy in individual patients. However, little information is available about the kinetics of serum PSA during the first weeks following the initiation of chemotherapy [9, 10]. This prompted us to study the time course of serum PSA in a database of patients with CRPC receiving chemotherapy. We discovered an important phenomenon: a high proportion of responders to chemotherapy initially experience a rise in serum PSA.
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eligibility criteria and treatment plan
Since March 1999, data concerning patients with CRPC treated at the Institut Gustave Roussy, Villejuif, France, have been recorded in a computed database. Patients deemed eligible for the present study had histologically confirmed adenocarcinoma of the prostate, evidence of metastases, and progressive disease while on medical castration using a gonadotropin-releasing hormone (GNRH) agonist or after surgical castration. An antiandrogen withdrawal syndrome [11] was also eliminated in all 10 patients who were on complete androgen blockade. The baseline serum PSA value exceeded 5 ng/ml in all cases. All nonsurgically castrated patients were maintained on a GNRH agonist after they had reached the castration-refractory status. All patients had cancer-related symptoms, most often pain related to bone metastases. Baseline serum PSA was typically measured within the week before starting chemotherapy.
Before each cycle of chemotherapy, a physical examination, a complete blood count, biochemistry tests including liver and renal assessment, and a serum PSA test were obtained. Chemotherapy was administered until progression or toxicity or until a total of six cycles.
response criteria
Consensus criteria were used to define response, stabilization, and progression following chemotherapy [8]. Response to chemotherapy was defined as a serum PSA decline of at least 50%, confirmed by a second PSA test at least 4 weeks later.
Progression-free survival (PFS) was calculated from the start of chemotherapy to the first date of documented progression, death, or the last follow-up. Survival curves were estimated by the Kaplan–Meier method.
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results |
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From March 1999 to October 2003, a total of 79 patients with CRPC received first-line (n = 52) or second-line (n = 27) chemotherapy (Table 1). Chemotherapy regimens consisted mainly of docetaxel (with or without estramustine) [3, 4], mitoxantrone–prednisone [1], doxorubicin–estramustine [11, 12], and irofulven [13].
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Among patients receiving first-line chemotherapy, 21 (40%) and 20 (38%) achieved a PSA response and stabilization, respectively, according to consensus criteria [8] (Table 2). Among these 41 patients who achieved either a response or stabilization, eight (20%) had a PSA rise during the first 8 weeks of chemotherapy subsequently followed by a PSA decline, therefore reaching criteria for PSA response or stabilization. Their PSA time course is described in Figure 1. This phenomenon was observed in patients with a large range of baseline serum PSA values and there was no apparent association between the baseline value and the likelihood of observing it (Table 3).
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Although the number of patients precluded formal statistical comparison, there was no suggestion that the postchemotherapy PSA surge phenomenon negatively impacts PFS: the median PFS duration after the initiation of chemotherapy was 6, 3.7, and 1.3 months in patients with an initial PSA surge followed by a PSA response or stabilization, those with a response or stabilization but no PSA surge, and those with progression, respectively.
The same observation of a postchemotherapy PSA surge was made in patients receiving second-line chemotherapy: 6 of 20 patients who achieved a response or stabilization had an initial PSA rise (Table 2).
Overall, 8 of 14 patients (57%) who had an initial PSA surge phenomenon followed by a response or a stabilization (either after first-line or second-line chemotherapy) would had been considered as having a progressive disease by PSA working group criteria [8].
When considering only patients who achieved a response (either after first-line or second-line chemotherapy), not including those with a stabilization, 6 of 30 (20%) responders had an initial PSA surge phenomenon, followed by a subsequent PSA drop.
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Serum PSA is commonly used in prostate cancer patients to assess response to definitive local therapy, including radical prostatectomy [14] and radiotherapy [15], to detect relapse after definitive treatment in localized disease [16] and to monitor response and progression during androgen deprivation therapy and chemotherapy in advanced disease [8]. The initial PSA value [17] and PSA velocity before treatment [18] have an independent prognostic value in patients with localized disease. Moreover, a dramatic drop in serum PSA measured 3 months after initiating treatment independently correlates with metastasis-free survival in patients treated with androgen deprivation therapy and radiotherapy for high-risk localized disease [19]. Finally, a rapid PSA doubling time and a short interval from radical prostatectomy to the first detectable PSA level are strong and independent prognostic factors in patients with a rising PSA level after local treatment [19].
In this report, we provide evidence that a significant proportion of patients with CRPC have an initial rise in serum PSA during the first 8 weeks following the start of chemotherapy, followed later by a drop in serum PSA, finally reaching the criteria for response or stabilization according to consensus guidelines [8]. This ‘postchemotherapy PSA surge syndrome’ was observed both in patients receiving first-line and second-line chemotherapy and with various chemotherapy agents including docetaxel. Overall, among the 30 patients who achieved a PSA response according to consensus criteria, six (20%) initially had a serum PSA rise before experiencing a drop. Moreover, there was no suggestion that these patients with a postchemotherapy PSA surge syndrome later by a response or stabilization were at higher risk of early progression, when compared with those who immediately achieved a response or stabilization.
An early and transient rise in serum tumor markers (human chorionic gonadotrophin and 
-fetoprotein) followed by a drop is a well-known phenomenon which occurs in 
25% of patients receiving chemotherapy for disseminated germ-cell tumors [21, 22]. The explanation most usually proposed is that tumor markers are released in the blood due to acute cell lysis in this extremely chemosensitive disease. The prognostic value of this phenomenon is uncertain, although a negative impact on survival has been reported [22]. In contrast to CRPC where the PSA rise may continue up to 8 weeks before a drop occurs, the serum tumor marker rise is usually short lived in germ-cell tumors. The kinetics of tumor marker decline in the latter can therefore be measured as early as 3 weeks after the start of chemotherapy and it was shown to have an independent prognostic value in high-risk disease [23]. A brief and transitory increase in neuron-specific enolase followed by a drop has also been reported in patients with small-cell lung cancer during initial chemotherapy [24, 25], although only a normal value after 4 weeks of chemotherapy was shown to be of independent prognostic relevance [26]. In prostate cancer, such a serum PSA rise followed by a PSA drop was previously reported to be a very common occurrence in patients with CRPC receiving consolidation docetaxel–samarium after a response or stabilization following induction chemotherapy [27]. A PSA rise (without cancer progression) during the first year following brachytherapy is also a well-identified feature in patients with localized prostate cancer and is interpreted as PSA secretion due to local inflammation [28]. A PSA rise during the first weeks following cryosurgery followed by a subsequent decline has also been reported [29]. After radical prostatectomy, the half-life of PSA is short, being in the 2.5-day range [30, 31]. Interpreting the postchemotherapy PSA surge syndrome described in the present report is difficult and caution should be exercised. It may be hypothesized that this phenomenon corresponds to increased cancer cell destruction, but there is no firm evidence to support this postulate. Alternative hypothesis may include an increased differentiation of prostate cancer stem precursors or an enhanced PSA transcriptional efficiency induced by chemotherapy.
We believe that physicians should be aware of this postchemotherapy PSA surge syndrome during the first weeks following chemotherapy for CRPC, to preclude inadequate early discontinuation of chemotherapy, assuming that progression has occurred. As patients are usually aware of their PSA results, they should also be informed of this frequent phenomenon to avoid any undue stress if ever it occurs.
Received for publication November 24, 2007. Revision received February 11, 2008. Accepted for publication February 13, 2008.
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