Docetaxel in Combination with Prednisolone for Hormone Refractory Prostate Cancer

Transcription

1 Original Article Japanese Journal of Clinical Oncology Advance Access published October 22, 2009 Jpn J Clin Oncol 2009 doi: /jjco/hyp126 Docetaxel in Combination with Prednisolone for Hormone Refractory Prostate Cancer Hiroki Ide 1, Eiji Kikuchi 1, Hidaka Kono 1, Hirohiko Nagata 1, Akira Miyajima 1, Ken Nakagawa 1, Takashi Ohigashi 2, Jun Nakashima 3 and Mototsugu Oya 1 1 Department of Urology, Keio University School of Medicine, 2 Department of Urology, International University of Health and Welfare Mita Hospital and 3 Department of Urology, Tokyo Medical University, Tokyo, Japan Received July 24, 2009; accepted August 24, 2009 Objective: The objective of this study was to evaluate the efficacy and toxicity of docetaxel in combination with prednisolone in Japanese patients with hormone refractory prostate cancer. Methods: Twenty patients with hormone refractory prostate cancer (HRPC) were administered a treatment regimen consisting of docetaxel 75 mg/m 2 once every 3 or 4 weeks and prednisolone 5 mg twice daily at our institution between 2006 and Results: The patients received a median of 5.5 cycles of treatment (range, 2 11 cycles). Nine of the 20 patients (45%) had a 50% decrease in serum prostate-specific antigen (PSA). The median duration of response was 4 months (range, 1 12 months). The number of cycles performed, the presence of bone metastasis and the extent of disease had statistically significant associations with the response. Three patients had a transient PSA rise among the patients who ultimately had a response. Grade 3/4 leukopenia and neutropenia occurred in 80.0% and 85.0% of the patients, respectively. Interstitial pneumonia occurred in only one patient; however, the patient recovered. Finally, no treatment-related deaths were seen during the observation period. Conclusions: The combination of docetaxel 75 mg/m 2 every 3 weeks and prednisolone 10 mg daily was effective and well tolerated in Japanese patients with HRPC. The results of this study suggest that a decision concerning discontinuation of this treatment should be carefully considered because a transient PSA rise was observed. Although interstitial pneumonia was rare, the potential risk of its development should be taken into consideration. Key words: prostate cancer chemotherapy docetaxel INTRODUCTION As prostate cancer initially grows in an androgen-dependent manner, androgen deprivation therapy is effective in 80% of the patients with metastatic prostate cancer (1). However, prostate cancer eventually becomes refractory to hormone treatment (HT). The prognosis for patients with hormone refractory prostate cancer (HRPC) remains poor, with a median survival of 12 months (2). There are some treatment options for patients with HRPC, such as chemotherapy. For reprints and all correspondence: Eiji Kikuchi, Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo , Japan. eiji-k@kb3.so-net.ne.jp Although chemotherapy for HRPC has been evaluated for many years, the results for most agents have been disappointing and they have been used as palliative therapy with no survival benefit. In the late 1990s, some trials demonstrated that the combination of mitoxantrone and corticosteroids could provide pain relief and decreases in prostate-specific antigen (PSA), with improved quality of life (QoL) compared with corticosteroid alone; however, there was no improvement in survival (1,3). Single agents such as docetaxel and steroid have shown similar results. Daily use of single-agent prednisone (10 mg/ day) produced a 22% PSA response rate (RR) and a 38% improvement in QoL measures in patients with HRPC. # The Author (2009). Published by Oxford University Press. All rights reserved.

2 Page 2 of 6 Docetaxel and steroid for prostate cancer However, this improvement lasted a median of only 1 month (4). Also, docetaxel (75 mg/m 2 every 3 weeks) produced a 46% PSA RR in patients with HRPC and responses were maintained for a median of 9 months (5). However, this treatment did not demonstrate a survival benefit in patients with HRPC. Recently, some studies examining combination treatment consisting of docetaxel and steroid have shown a survival benefit in patients with HRPC. In the TAX 327 Phase III randomized trial, the patients were divided into three groups (prednisone 5 mg twice daily plus either docetaxel 75 mg/m 2 every 3 weeks, docetaxel 30 mg/m 2 weeklyfor5outofevery 6 weeks or mitoxantrone 12 mg/m 2 every 3 weeks). The median overall survival with docetaxel 75 mg/m 2 every 3 weeks was statistically longer than that with mitoxantrone 12 mg/m 2 every 3 weeks (18.9 vs months, P ¼ 0.009) (1). Thus, the combination of docetaxel and steroid was found to be an effective treatment for HRPC in the USA. However, there have only been a few reports on this combination in Japan. In a Phase II study in Japanese patients with HRPC who received docetaxel 70 mg/m 2 every 3 weeks, the efficacy of docetaxel plus prednisolone (DP) was proven (6). However, to our knowledge, there has been no study conducted in Japan that examined the same dose of docetaxel as that used in the TAX 327 study (75 mg/m 2 every 3 weeks). In this study, we retrospectively reviewed patients who received docetaxel 75 mg/m 2 every 3 weeks and prednisolone 10 mg daily for HRPC in order to evaluate the efficacy and toxicity of the treatment. PATIENTS AND METHODS PATIENT CHARACTERISTICS A total of 20 patients received DP for HRPC at our institution between 2006 and The treatment regimen consisted of docetaxel 75 mg/m 2 once every 3 weeks and prednisolone 5 mg twice daily. These patients had received permission to undergo this novel treatment which had not yet been approved by the Ministry of Health, Labor and Welfare in Japan. We carefully explained the anticipated clinical response and possible side effects of the treatment. This regimen was approved by the Oncology Board of Keio University Hospital. This regimen was given if the patients met the following criteria: an Eastern Cooperative Oncology Group (ECOG) performance status of 0 2, adequate baseline bone marrow function (neutrophil count 2000/mm 3 and platelet count /mm 3 ), adequate hepatic function (total bilirubin level 1.5 mg/dl, aspartate aminotransferase and alanine aminotransferase levels 1.5 the upper limit of normal) and adequate renal function (1.5 the upper limit of normal). Exclusion criteria were no prior treatment with cytotoxic agents (except estramustine) or radioisotopes, no history of other cancer within the preceding 5 years, no symptomatic peripheral neuropathy corresponding to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) of Grade 2 and no other serious medical condition. There had to be at least 4 weeks between prior surgery or radiotherapy and this treatment. The characteristics of the 20 patients are shown in Table 1. They had histologically confirmed adenocarcinoma of the prostate and had had disease progression during HT. Chlormadinone acetate or flutamide must have been stopped at least 4 weeks before the last PSA evaluation, whereas bicalutamide had to have been stopped at least 6 weeks beforehand, so as to avoid the possibility of confounding results due to the response to anti-androgen withdrawal. Disease progression was defined as three consecutive increases in PSA according to the criteria of the 3rd edition of General Rules for Clinical and Pathological Studies on Prostate Cancer of the Japanese Urological Association and Japanese Society of Pathology (7). The tumor was staged and graded according to the criteria of the 3rd edition of General Rules for Clinical and Pathological Studies on Prostate Cancer of the Japanese Urological Association and Japanese Society of Pathology (7). CHEMOTHERAPY REGIMEN The regimen used in the present study was as follows. On day 1, all patients received docetaxel 75 mg/m 2,administered intravenously over a period of 1 h every 3 or 4 weeks and prednisolone 5 mg twice daily starting on day 1 and continuing throughout treatment. As premedications, we administered dexamethasone (16 mg intravenously) 30 min before Table 1. Patient characteristics Characteristic No. of patients Cases 20 Age, mean + SE PSA when DP treatment was started, mean + SE Gleason score Initial treatment Surgery 3 Radiation 4 Endocrine 13 Metastatic site at DP treatment Lymph node 8 Bone 16 Liver 2 Lung 1 Number of cycles, mean + SE SE, standard error; PSA, prostate-specific antigen; DP, docetaxel and prednisolone.

3 Jpn J Clin Oncol 2009 Page 3 of 6 docetaxel administration. Before each cycle of chemotherapy, laboratory tests were conducted to determine the presence of any hematological, hepatic and renal toxicities. If a neutrophil count of,2000/mm 3 and/or a platelet count of, /mm 3 or inadequate hepatic or renal function was observed, treatment was delayed for several days until the laboratory test values had recovered. The dose of docetaxel was reduced by 10 mg/m 2 in subsequent treatment cycles if any of the following criteria were met: hemorrhage with Grade 3/4 thrombocytopenia or Grade 3/4 non-hematological toxicity that required dose reduction according to the investigator s judgment. If toxicities persisted after the dose of docetaxel was reduced by 20 mg/m 2, patients were withdrawn from this study. Also, dose reduction or cessation of prednisolone administration was considered in cases of gastric ulcer, posterior subcapsular cataract, glaucoma, infection or for any other toxicities judged by the investigator. The patients were, in principal, admitted to our hospital at the time of the initial course of the treatment; however, if a patient had no or minor side effects, then we administered the treatment at an outpatient clinic. RESPONSE CRITERIA AND TOXICITY ASSESSMENT Tumor response was assessed according to the criteria of the 3rd edition of General Rules for Clinical and Pathological Studies on Prostate Cancer of the Japanese Urological Association and Japanese Society of Pathology (7). Complete response (CR) required a reduction from the normal value in the serum PSA level (4.0 ng/ml). Partial response (PR) required at least a 50% reduction in serum PSA. No change (NC) was defined as a,50% reduction or a,25% increase in serum PSA. Progressive disease (PD) was defined as at least a 25% increase in serum PSA or an increase from a normal value to an abnormal value. Toxicity was graded according to the NCI-CTC. STATISTICAL ANALYSIS The associations of responses to this treatment according to clinical and pathological features were assessed with the Wilcoxon rank sum test or the x 2 test for trends. Clinical and pathological factors assessed were age, Gleason score, PSA when DP treatment was started, the number of cycles performed, initial treatment, time to HRPC, prior estramustine, response to estramustine, the extent of disease and the presence of bone metastasis. A P value,0.05 was considered to indicate statistical significance. These analyses were performed using an SPSS w, version 11.0, statistical software package. RESULTS RESPONSE The patient received a median of 5.5 cycles of DP treatment (range, 2 11 cycles). Nine of the 20 patients (45%) had a major response (CR þ PR) to treatment. These patients achieved a PR at a median of 2 cycles (range, 1 8 cycles). Three (15%) of these 20 patients achieved a CR at a median of 1 cycle (range, 1 5 cycles). In one patient, PSA decreased from to 2.72 after the first cycle was completed and the nadir was 0.28 after four cycles were completed. In another patient,psadecreasedfrom12.7to3.72afterfivecycles were completed and the nadir was 0.92 after nine cycles. In the other patient, PSA decreased from 14.7 to 3.27 after the first cycle and the nadir was 1.71 after seven cycles were completed. The median duration of the response was 4 months (range, 1 12 months). In patients with CR, the median duration of the response was 7 months, whereas in those with PR, the median duration of the response was 2 months. In addition, seven patients (35%) had NC and two patients (10%) had PD. We defined the patients who achieved a CR or PR as responders and analyzed the differences in clinical and pathological characteristics, including age, Gleason score, PSA when DP treatment was started, the number of cycles performed, initial treatment, time to HRPC, prior estramustine, response to estramustine, the extent of disease and the presence of bone metastasis between responders and nonresponders. According to Table 2, the number of cycles performed, the presence of bone metastasis and the extent of disease had a statistically significant association with the DP response. Fifty-five percent of responders had bone metastases, compared with 100% of non-responders (P ¼ 0.026). Also, the proportions of responders with soft tissue (lymph node, lung and liver) metastasis only, bone metastasis only and both soft tissue and bone metastasis were 44.4%, 44.4% and 11.1%, respectively, whereas those of non-responders were 0%, 45.5% and 54.5%, respectively (P ¼ 0.023). Thus, the proportion of patients with soft tissue metastasis only in responders was larger than that in non-responders. Also, the proportion of patients with concurrent soft tissue and bone metastasis in non-responders was larger than that in responders. Figure 1 shows that three patients had a transient PSA rise followed by a subsequent decline in serum PSA. Table 3 shows the PSA kinetics in these three patients. Two of the patients had an increase in PSA during the first 2 months following the initiation of DP treatment, whereas the other patient had an increase from 3 to 5 months following the initiation of DP treatment, followed later by a drop in serum PSA until finally the criteria for PR were reached. TOXICITY Hematological and non-hematological Grade 3/4 toxicities are summarized in Table 4. Myelosuppression was the most frequent toxicity. NCI-CTC Grade 3 4 neutropenia occurred in 17 patients (85%) and Grade 3 4 leukopenia occurred in 16 patients (80%); however, Grade 3 4 thrombocytopenia

4 Page 4 of 6 Docetaxel and steroid for prostate cancer Table 2. Clinicopathological characteristics of responders or non-responders Responders a Non-responders b P value No. of patients Age PSA when DP treatment was started (ng/ml) PSA-DT before DP treatment (months) ECOG performance status , Gleason score Initial treatment Surgery Radiation HT Time from HT initiation to HRPC (months) Estramustine performed Yes No 3 2 Response to estramustine Yes No 8 9 Extent of disease Soft tissue only Bone only 4 5 Bone þ soft tissue 1 6 Bone metastasis No. of cycles PSA-DT, prostate-specific antigen doubling time; HT, hormonal therapy; HRPC, hormone refractory prostate cancer. a Patients who achieved a complete response or a partial response. b All others. Figure 1. PSA kinetics in patients who had a transient PSA rise followed by a subsequent decline in serum PSA. PSA, prostate-specific antigen. Table 3. PSA kinetics in patients who had a transient PSA rise followed by a subsequent decline in serum PSA Patient no. PSA at baseline (ng/ml) Table 4. Grade 3/4 toxicities observed with docetaxel and prednisolone treatment Toxicity Grade 3 (%) Grade 4 (%) Hematological Leukopenia Neutropenia Febrile neutropenia Anemia Non-hematological Hypotension Anorexia Constipation Dehydration Rash/desquamation Interstitial pneumonia did not occur. Granulocyte colony-stimulating factor was given to 15 patients (75%); however, transfusion was not required. One patient (5%) had interstitial pneumonia, possibly attributable to docetaxel. However, there were no severe non-hematological adverse events (Grade 4) or treatmentrelated deaths. Docetaxel dose reduction was required in two patients because non-hematological Grade 3 toxicity (diarrhea) was observed in both. However, prednisolone dose reduction was not required in any patients. DISCUSSION PSA at peak (ng/ml) Peak time after chemotherapy (months) Nadir (ng/ml) Recently, in both basic and clinical research, some evidence demonstrating the efficacy of docetaxel in combination with steroids for the treatment of HRPC has been presented. Basic research has shown that steroids enhanced the cytotoxicity of docetaxel against HRPC in in vitro and in vivo experiments. Furthermore, it was suggested that the mechanism of this combination treatment for HRPC might be associated with potentiation of the antiangiogenic activity of docetaxel by steroids (8). In the clinical research, some reports have examined docetaxel-based chemotherapy as a treatment for HRPC. The TAX 327 Phase III randomized trial used three groups: prednisone daily in combination with docetaxel administered

5 Jpn J Clin Oncol 2009 Page 5 of 6 every 3 weeks, with weekly docetaxel and with mitoxantrone administered every 3 weeks. The authors reported that the median overall survival with docetaxel given every 3 weeks was statistically longer than that with mitoxantrone given every 3 weeks (18.9 vs months, P ¼ 0.009) (1). In the SWOG trial, the patients were divided into two groups (docetaxel 60 mg/m 2 every 3 weeks in combination with estramustine 280 mg orally three times daily on days 1 5 vs. mitoxantrone 12 mg/m 2 in combination with prednisone 10 mg daily). Median overall survival with docetaxel and estramustine was significantly longer than that with mitoxantrone and prednisone (17.5 vs months, P ¼ 0.02). However, the addition of estramustine to docetaxel was associated with additional toxicity, including cardiovascular events such as deep vein thrombosis. When compared with the group given mitoxantrone and prednisone, the group given docetaxel and estramustine had significantly higher rates of Grade 3 or 4 cardiovascular events (15% vs. 7%, P ¼ 0.001) (9). Therefore, we hypothesized that docetaxel in combination with steroid might be appropriate for patients with HRPC on the basis of the promising efficacy results, relatively low toxicity profile and global evidence for improved survival. Recently, a study examining the effects of docetaxel in combination with steroid in patients with HRPC was conducted in Japan (8). The efficacy of DP has been proven in a Phase II study in Japanese patients with HRPC; however, the dose of docetaxel used was 70 mg/m 2 every 3 weeks. In the present study, we administered 75 mg/m 2 of docetaxel every 3 weeks and observed an RR of 45%, which was identical to that reported in the TAX 327 study (RR of 45%) and very similar to that in a Japanese Phase II study (RR of 44%). With regard to toxicity, the incidences of Grade 3/4 neutropenia and leukopenia were 85% and 80%, respectively, in the present study, compared with 81.4% and 93.0%, respectively, in the Phase II study in Japanese patients with HRPC who were administered a reduced dose of docetaxel (70 mg/ m 2 every 3 weeks). In addition, the incidence of febrile neutropenia was 10.0%, compared with 16.3% in the Japanese Phase II study with a reduced dose of docetaxel, and there were no significant differences in the incidences of other side effects (6). Therefore, it is believed that there is no significant difference between the incidence of toxicity in patients who received 70 mg/m 2 of docetaxel every 3 weeks and those administered 75 mg/m 2. Although our present study was evaluated in a limited number of patients, our results indicated that 75 mg/m 2 docetaxel every 3 weeks might be tolerable in Japanese patients with HRPC. In the present study, interstitial pneumonia was observed in one patient. The incidence of interstitial pneumonia in previous reports was only 0.2% and although it appears to be a rare complication of docetaxel treatment, it might be lifethreatening. It was also reported that a high cumulative dosage of docetaxel and a past history of lung disease were risk factors of severe interstitial pneumonia (10,11). In the present case, interstitial pneumonia occurred after only two cycles were completed and he did not have a past history of lung disease. The patient recovered after discontinuation of the treatment and the administration of steroid pulse therapy. Thus, the potential risk of interstitial pneumonia in patients who undergo DP treatment should be taken into consideration, particularly in patients administered a high cumulative dosage of docetaxel or who have a past history of lung disease. Furthermore, we recommend that pulmonary function tests are conducted in all patients prior to DP treatment. In the present study, the associations of the response to DP treatment according to clinical and pathological features were analyzed. As shown in Table 2, the number of cycles performed, the presence of bone metastasis and the extent of disease had statistically significant associations with the DP response. It is thought that this result is natural with respect to the number of cycles performed because patients who respond to DP continue to receive DP treatment. In terms of the presence of bone metastasis, we obtained the same result as that of a previous report (12). A higher sensitivity of soft tissue disease to docetaxel compared with mitoxantrone has also been reported (1). The prognostic significance of the extent of metastatic disease has also been shown by previous investigators and it seems that this parameter is applicable to patients treated with docetaxel (13 16). Bamias et al. (12) found that simultaneous bone and extraosseous disease predicted poor survival. Our result is in agreement with their finding. Figure 1 shows that three patients had a transient PSA rise among patients who had CR, PR or NC. Among these three patients, two had a PSA rise during the first 2 months following the initiation of DP treatment. In a previous report, it was shown that a significant proportion of patients with HRPC had an initial rise in serum PSA during the first 2 months following the start of chemotherapy, followed later by a drop in serum PSA, before finally reaching the criteria for CR, PR or NC. This post-chemotherapy PSA surge syndrome was observed in 6 (20%) among 30 patients who exhibited a PSA response to chemotherapy in the report (17). The prognostic value of this phenomenon is uncertain. Although it was reported that patients with a postchemotherapy PSA surge syndrome were at higher risk of early progression than those without, Thuret et al. (17) reported that there was no significant difference in progression-free survival between those with and without this phenomenon (18). The mechanism of postchemotherapy PSA surge syndrome may involve increased cancer cell destruction, although presently there is no firm evidence to support this hypothesis (18). In one of the three patients who exhibited a transient rise in PSA in this study, the increase in PSA occurred from 3 to 5 months following the initiation of DP treatment, followed later by a drop in serum PSA, until finally reaching the criteria for PR. A similar finding was also reported in a previous study, and the authors indicated that this phenomenon was PSA secretion due to local inflammation (16). However, to the best of our knowledge, no report has ever attempted to explain this phenomenon.

6 Page 6 of 6 Docetaxel and steroid for prostate cancer Since most transient PSA rises during chemotherapy were found within the first 2 months following the start of chemotherapy in previous reports and our study, perhaps at least three cycles should be performed if severe side effects do not develop. Furthermore, the results of the present study indicate that an immediate decision concerning discontinuation of DP treatment should not be made if an increase in PSA is observed in a patient who initially had a PSA response. The combination of docetaxel 75 mg/m 2 every 3 weeks and prednisolone 10 mg daily might be effective and tolerable in Japanese patients with HRPC. Thus, this regimen may be appropriate for patients with HRPC not only in the USA but also in Japan. CONCLUSION In our population of 20 patients with HRPC administered docetaxel 75 mg/m 2 every 3 weeks and prednisolone 10 mg daily, a 50% reduction in PSA was observed in 45% of the patients. In addition, the side effects were tolerable and no treatment-related deaths were seen during the observation period. Therefore, the combination of docetaxel 75 mg/m 2 every 3 weeks and prednisolone 10 mg daily might be effective and tolerable in Japanese patients with HRPC. However, the potential risk of interstitial pneumonia, especially in patients who receive a high cumulative dosage of docetaxel or have a past history of lung disease, should be taken into consideration as it may be a life-threatening adverse effect. Conflict of interest statement None declared. References 1. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351: Yagoda A, Petrylak D. Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer. Cancer 1993;71: Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999;17: Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol 1989;7: Picus J, Schultz M. Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 1999;26: Naito S, Tsukamoto T, Koga H, Harabayashi T, Sumiyoshi Y, Hoshi S. Docetaxel plus prednisolone for the treatment of metastatic hormone-refractory prostate cancer: a multicenter Phase II trial in Japan. Jpn J Clin Oncol 2008;38: Japanese Urological Association, Japanese Society of Pathology. General Rules for Clinical and Pathological Studies on Prostate Cancer. 3rd edn. Tokyo: Kanehara 2001 (in Japanese). 8. Wilson C, Scullin P, Worthington J, Seaton A, Maxwell P, O Rourke D, et al. Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer. Br J Cancer 2008;99: Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351: Wang GS, Yang KY, Perng RP. Life-threatening hypersensitivity pneumonitis induced by docetaxel (taxotere). Br J Cancer 2001;85: Read WL, Mortimer JE, Picus J. Severe interstitial pneumonitis associated with docetaxel administration. Cancer 2002;94: Bamias A, Bozas G, Antoniou N, Poulias I, Katsifotis H, Skolarikos A, et al. Prognostic and predictive factors in patients with androgen-independent prostate cancer treated with docetaxel and estramustine: a single institution experience. Eur Urol 2008;53: Halabi S, Small EJ, Kantoff PW, Kattan MW, Kaplan EB, Dawson NA, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 2003;21: Sabbatini P, Larson SM, Kremer A, Zhang ZF, Sun M, Yeung H, et al. Prognostic significance of extent of disease in bone in patients with androgen-independent prostate cancer. J Clin Oncol 1999;17: Shulman MJ, Benaim EA. Prognostic model of event-free survival for patients with androgen-independent prostate carcinoma. Cancer 2005;103: Wyatt RB, Sanchez-Ortiz RF, Wood CG, Ramirez E, Logothetis C, Pettaway CA. Prognostic factors for survival among Caucasian, African-American and Hispanic men with androgen-independent prostate cancer. J Natl Med Assoc 2004;96: Thuret R, Massard C, Gross-Goupil M, Escudier B, Di Palma M, Bossi A, et al. The postchemotherapy PSA surge syndrome. Ann Oncol 2008;19: de Wit R, Collette L, Sylvester R, de Mulder PH, Sleijfer DT, ten Bokkel Huinink WW, et al. Serum alpha-fetoprotein surge after the initiation of chemotherapy for non-seminomatous testicular cancer has an adverse prognostic significance. Br J Cancer 1998;78: