Endocrine-Related Cancer (2005) 12 109–117 Independent prognostic role of circulating chromogranin A in prostate cancer patients with hormone-refractory disease A Berruti1, A Mosca1, M Tucci1, C Terrone2, M Torta1, R Tarabuzzi2, L Russo1, C Cracco2, E Bollito3, R M Scarpa2, A Angeli4 and L Dogliotti1 Dipartimento di Scienze Cliniche e Biologiche, Universita` di Torino, Italy Prostate cancer unit: Oncologia Medica1, Urologia2, Anatomica Patologica3, Medicina Interna4, Azienda Ospedaliera San Luigi, Orbassano, Italy (Requests for offprints should be addressed to L Dogliotti; Email: [email protected]) Abstract The presence of neuroendocrine (NE) differentiation in the context of predominantly exocrine prostate cancer may play a key role in androgen-independent tumor growth. The prognostic signifi- cance of plasma chromogranin A (CgA) was assessed in a series of consecutive prostate cancer patients with hormone-refractory disease. One hundred and eight patients with newly diagnosed hormone-refractory prostate cancer entered the study. Plasma CgA levels and other biochemical parameters, such as serum prostate specific antigen, serum alkaline phosphatase, serum lactate dehydrogenase, serum albumin and hemoglobin concentration, were measured at baseline (i.e. when hormone refractoriness occurred) and their prognostic role was evaluated together with patient performance status, Gleason score (at diagnosis of prostate cancer) and the presence of visceral metastases. Furthermore, plasma CgA was prospectively evaluated in 50 patients undergoing chemotherapy. At baseline, 45 patients (43.3%) showed elevated CgA values. Plasma CgA negatively correlated with survival, either in univariate analysis (P=0.008) or in multivariate analysis, after adjusting for previously mentioned prognostic parameters (P<0.05). In the patient subset undergoing chemo- therapy, median CgA (range) values were 13.3 (3.0–141.0) U/l at baseline, 19.1 (3.0–486.0) U/l after 3 months, 20.8 (3.0–702.0) U/l after 6 months and 39.4 (3.0–414.0) U/l after 9 months (P<0.01). The corresponding supranormal rates were 17/50 (34%), 23/50 (46%), 26/50 (52%) and 34/50 (68%) respectively (P<0.005). Elevated plasma CgA levels are frequently observed in prostate cancer patients with hormone- refractory disease and correlate with poor prognosis. NE differentiation in hormone-refractory patients is a time-dependent phenomenon and is not influenced by conventional antineoplastic treatments. Endocrine-Related Cancer (2005) 12 109–117 Introduction is dismal and the overall survival is about 15–16 months (Smaletz et al. 2002, Halabi et al. 2003). Treat- Prostate cancer is frequent in the aging male popu- ment options for hormone-refractory disease include lation (De Angelis et al. 1997). Androgen suppression intensive supportive care, radiotherapy, bisphospho- by either orchiectomy or administration of luteinizing nates, second-line hormonal manipulations, cytotoxic hormone-releasing hormone analogs (LHRH-As) is chemotherapy and investigational agents (Sandler et al. the mainstay of treatment for patients with advanced 2003). Chemotherapeutic agents, such as docetaxel, disease. Although this therapy frequently results in have recently yielded improved response rates and tumor shrinkage and improvement of symptoms, it is survival in two randomized independent clinical trials not curative and the majority of patients eventually (Petrylak et al. 2004, Tannock et al. 2004). Docetaxel develop hormone-refractory disease. Once disease be- represents therefore the new standard treatment. comes refractory to hormonal manipulation, prognosis The survival benefit obtained with this drug in Endocrine-Related Cancer (2005) 12 109–117 DOI:10.1677/erc.1.00876 1351-0088/05/012–109 g 2005 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/27/2021 04:52:24PM via free access hormone-refractory patients, however, is modest. The biological and clinical significance of NE Understanding mechanisms underlying the develop- differentiation in prostate cancer patients who become ment of hormone refractoriness is the basis for devel- hormone-refractory is still to be elucidated. oping new treatment strategies for the disease at this CgA appears to be the most sensitive marker and is stage. most frequently used for detecting NE differentiation The majority of conventional prostate cancers dis- either at the tissue level or in the general circulation play at diagnosis focal neuroendocrine (NE) differ- (Berruti et al. 2001). The availability of such a specific entiation, usually revealed by immunohistochemistry circulating marker for the NE component could allow as scattered individual cells or nests of cells in the con- us to easily detect and monitor NE differentiation in text of predominantly exocrine tumors (Abrahamsson prostate cancer patients. 1999a,b, di Sant’Agnese 2001). NE mechanisms are Plasma CgA levels were measured in a series of pros- emerging as important factors in the evolution, pro- tate cancer patients with hormone-refractory disease. gression and overall prognosis of prostate cancer The primary study aim was to determine the prog- (di Sant’Agnese 2001). They appear to be especially nostic role of elevated levels. A secondary aim was important in facilitating prostate cancer progression to evaluate the changes of this marker over time in a to androgen-deprivation therapy (Abrahamsson 1999b, subgroup of patients undergoing chemotherapy. di Sant’Agnese 2001). Several mechanisms have been identified: NE cells are androgen receptor negative, therefore they survive to androgen deprivation (Bonk- Patients and methods hoff 1998); NE cells produce peptides, hormones and growth factors (Bonkhoff, Abrahamsson 1999b) that Patients could stimulate the proliferation of exocrine prostate From January 1998 to January 2003, 108 consecutive cancer cells and increase their aggressiveness through patients with newly diagnosed hormone-refractory apoptosis inhibition (Xing et al. 2001) and neoangio- prostate cancer were enrolled in the present study. genesis stimulation (Mazzucchelli et al. 2000). Eligible patients were required to have histologically Some authors, including our group, have found that proven adenocarcinoma of the prostate that pro- NE cell numbers in prostate cancer correlate with stage gressed to LHRH-A administration, in the presence and Gleason score (Deftos et al. 1996, Ahlegren et al. of castrate levels of testosterone. From 1998 to 2000, 2000, Bollito et al. 2001). These findings notwith- castrate testosterone levels were defined as less than standing, the relationship with survival is still con- 50 ng/dl; from 2000 onwards it was reassessed as less troversial, since some studies demonstrated a negative than 20 ng/ml. The time from the diagnosis of hor- prognostic role (Weinstein et al. 1996, McWilliam mone refractoriness to the enrolment in the study et al. 1997, Theodorescu et al. 1997), while others should have been not greater than 2 months. Disease did not (Noordzij et al. 1995, Bubendorf et al. 1997, progression was defined by rising prostate specific Abrahamsson et al. 1998, Ahlegren et al. 2000, Bost- antigen (PSA) levels on two consecutive measurements wick et al. 2002). All these studies involved hormone- at least 2 weeks apart, in addition to a new lesion on a naive patients. bone scan and/or an increase in the size of a measur- It has recently pointed out that NE differentiation able lesion on a computed tomographic scan of the is not a static phenomenon. The NE compartment, abdomen/pelvis or chest. All patients previously treated in fact, increases after androgen deprivation and in with antiandrogen in addition to LHRH-A (total refractory disease (Abrahamsson 1999a, di Sant’Agnese androgen ablation) were required to undergo antian- 2001). The direct stimulation of NE differentiation by drogen withdrawal. Patients were required to be off all androgen-deprivation therapy was first demonstrated antiandrogens for at least 4 weeks with further evi- in an elegant preclinical study by Jongsma et al. (2002). dence of disease progression after cessation of the These authors demonstrated in xenograft models that antiandrogen. Further inclusion criteria included an castration results in a dramatic increase in the number Eastern Cooperative Oncology Group (ECOG) per- of cells expressing NE markers. These data have been formance status (PS) of 0-3 and normal renal and confirmed in humans by Sciarra et al. (2003), showing hepatic function. Patients were excluded from the a significant increase in circulating chromogranin A study for severe uncontrolled co-morbidity, second (CgA) levels after LHRH-A administration. Interest- malignancies, brain metastases and concomitant treat- ingly, this increase was lower during intermittent ment with proton pump inhibitors. All patients were therapy than after traditional continuous androgen required to give written informed consent before ablation. registration. 110 Downloadedwww.endocrinology-journals.org from Bioscientifica.com at 09/27/2021 04:52:24PM via free access Endocrine-Related Cancer (2005) 12 109–117 Biochemical measurements Table 1 Patient characteristics Plasma levels of CgA and serum values of PSA were No. 108 evaluated at baseline condition in all patients. Both Median age (range) 74 (58–86) markers were also prospectively measured after 3, 6 Gleason score at diagnosis and 9 months in 50 patients submitted to chemo- 5 5 (4.6%) therapy. 6 10 (9.2%)