- Email: [email protected]
Phase II trial of estramustine phosphate and oral etoposide in patients with hormone-refractory prostate cancer
original article
Annals of Oncology 20: 498–502, 2009 doi:10.1093/annonc/mdn650 Published online 12 January 2009
Phase II trial of estramustine phosphate and oral etoposide in patients with hormone-refractory prostate cancer G. Spitaleri1* , D. V. Matei2 , G. Curigliano1, S. Detti2, F. Verweij2, S. Zambito2, E. Scardino2, B. Rocco2, F. Nole`1, L. Ariu1, T. De Pas1, F. de Braud1 & O. De Cobelli2 1
Division of Medical Oncology; 2Division of Urology, European Institute of Oncology, Milan, Italy
original article
Background: There is a need for active agents with a better safety profile than docetaxel, yet good activity, for patients with hormone-refractory prostate cancer (HRPC). We carried out a phase II trial to determine the activity and safety of estramustine plus oral etoposide in HRPC. Patients and methods: Patients were given estramustine (280 mg twice daily) and etoposide (100 mg/day, days 1– 21) in 28-day cycles until disease progression or unacceptable toxicity. Primary end points were overall response rate and safety, as determined by prostrate-specific antigen (PSA) levels and lesion assessment. Results: From November 2001 to February 2007, 75 patients were enrolled. All patients were assessable for safety; 17 (22.6%) had grade 3/4 toxicity. PSA response was assessable in 69, 14 of whom had a >50% reduction in PSA. Of 10 patients with one or more measurable lesions, two (20%) had partial response and two (20%) disease stabilization. Overall, median time to progression was 4.4 months (range 1 week–43 months); median survival was 23 months (range 3 weeks–64+ months). Conclusions: Estramustine plus etoposide is active and has a manageable safety profile in patients with HRPC. In asymptomatic patients with nonaggressive disease this combination could be useful to delay the start of more demanding treatments. Key words: estramustine phosphate, etoposide, hormone-refractory prostate cancer
introduction The standard care for hormone-refractory prostate cancer (HRPC) is considered docetaxel every 3 weeks in association with prednisone, which confers a modest survival advantage compared with mitoxantrone plus prednisone [1, 2]. However, the significant toxicity of docetaxel can worsen quality of life, so there is a need to find agents with better safety profile and good activity that can delay the need to administer docetaxel. Estramustine phosphate (EMP) is an estrogenic molecule attached to a nitrogen mustard moiety that inhibits microtubule dynamics and has shown activity alone and in combination with taxanes in HRPC [3–10]. Importantly, nontaxane-based EMP combinations have shown modest activity in feasibility studies [11–16]. A phase II study with EMP alone reported serum prostrate-specific antigen (PSA) decrease of 50% or more in 24% of 34 patients with HRPC and better survival in responders than nonresponders [17]. Oral *Correspondence to: Dr G. Spitaleri, Division of Medical Oncology, European Institute of Oncology, Ripamonti 435, 20141 Milan, Italy. Tel: +39-02-57489 482; Fax: +39-02-57489-581; E-mail: [email protected]
Both authors contributed equally to this work.
etoposide in association with oral cyclophosphamide or biweekly epidoxorubicin has also shown modest activity in HRPC [18, 19]. Finally, some small studies indicate that EMP plus etoposide is active orally in patients with HRPC [20–22]. We carried out a prospective phase II study to further investigate the activity and safety of EMP plus oral etoposide in a large series of patients with HRPC.
patients and methods patient selection Patients with histologically documented hormone-refractory metastatic prostate adenocarcinoma were enrolled. Enrollment criteria were two or more consecutive elevations of PSA titer not less than 14 days apart in surgically or chemically castrated patients; age 18 years or older; life expectancy at least 12 weeks; Eastern Cooperative Oncology Group (ECOG) performance status of zero to two; completion of chemotherapy at least 4 weeks previously (6 weeks previously for mitomycin C or a nitrosourea); discontinuation of nonsteroidal antiandrogens at least 4 weeks previously; adequate bone marrow function (hemoglobin 9 g/dl, absolute neutrophil count 1500/ll, platelet count 100 000/ll); adequate liver function (total bilirubin within our Institute’s upper limit of normal; serum aspartate and alanine transferases <1.5 times upper normal limit; alkaline phosphatase
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on May 24, 2015
Received 15 May 2008; revised 1 September 2008; accepted 2 September 2008
original article
Annals of Oncology <2.5 times upper normal limit); adequate renal function (serum creatinine <1.5 times upper normal limit); and no coexisting medical problems of sufficient severity (including thromboembolic disease, stroke, or myocardial infarction) to limit study compliance. The study was approved by our Institute’s review board and all patients gave written informed consent before treatment.
treatment
examinations Complete medical history, physical examination, and routine laboratory studies were carried out at screening, including the following: blood tests (complete blood count, differential white blood cell count, prothrombin and partial thromboplastin times, routine electrolytes and blood chemistry, total protein, and albumin) urinalysis, electrocardiogram, PSA, and radiological studies to assess all disease sites. The radiological evaluations were repeated every 2 months. PSA, physical examination, and routine laboratory tests were repeated monthly or before each new course.
statistical analyses This was an open-label, nonrandomized phase II study. The primary end point was overall response defined as >50% drop in PSA or as complete or partial response in patients with at least one lesion measurable in two dimensions. Fleming’s one-sample multiple testing procedure was used to assess therapeutic efficacy [25]. We considered a PSA response in 30% as clinically significant [1]. Supposing a PSA drop >50% in at least 10% of patients and a PSA drop >50% in 30% as clinically significant, then 78 patients need to be enrolled in the trial to have an 80% (1-b) power of demonstrating efficacy at a = 5%. Median time to progression and median overall survival were represented according Kaplan–Meier [26].
results From November 2001 to February 2007, 75 patients with HRPC were enrolled (Table 1). Median age was 67 years (range 28–84 years). Sixty-one (81%) patients had bone metastases. Eight (10%) patients were assessable only for PSA. Sixty-two (83%) patients received the treatment as first-line therapy after developing hormone-refractory disease. All except three patients who underwent surgical orchiectomy received concomitant leuprorelin.
Volume 20 | No. 3 | March 2009
Characteristic
No.
ECOG 0/1 ECOG 2 Stage at diagnosis Early/locally advanced Advanced Biopsy Gleason score £4 5–7 ‡8 Not available Surgical Gleason score £4 5–7 ‡8 Not assessable Disease sites Lymph nodes Bone and lymph nodes Bone No identifiable lesions Local treatment RP RP plus pelvic external radiotherapy (ERT) RP plus ERT at PSA failure ERT ERT plus lymph node dissection ERT plus palliative surgery Palliative surgery Previous nonhormonal treatment None Docetaxel, vinorelbine Diestilbestrol IFN + thalidomide Gefitinib Samarium-153-EDTMP
19/41 15 39 36 5 15 15 40 0 3 4 14 6 9 52 8 13 4 4 11 1 4 8
62 1 1 2 6 3
ECOG, Eastern Cooperative Oncology Group; IFN, interferon-a; RP, radical prostatectomy; ERT, external radiotherapy; PSA, prostrate-specific antigen.
toxicity A total of 337 cycles were administered (median four cycles per patient, range 1–12). All patients were assessable for safety (Table 2). Four patients received only one cycle: three of whom stopped for toxicity (anemia, nausea, diarrhea), the other for early worsening of clinical condition. Nine patients received their last two cycles without etoposide, and five patients received reduced etoposide after the first cycle (75% reduction in one, 50% reduction in three, 25% reduction in one). Six patients delayed starting subsequent cycles by 1 week due the toxicity (anemia in three, high gamma-glutamyl transferase in one, asthenia in the other). The most frequent grade 1/2 adverse events (>20%) were asthenia, anemia, and nausea.
doi:10.1093/annonc/mdn650 | 499
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on May 24, 2015
Patients received EMP 280 mg twice daily and oral etoposide 100 mg daily for 21 of 28-day cycles until disease progression or unacceptable toxicity. Patients continued to receive the LHRH analogue leuprorelin (3.75 mg every 28 days) if already on it. For patients with at least one lesion evaluable in two dimensions, response evaluation criteria in solid tumors (RECIST) were used [23]. Complete response was stated as disappearance of all target lesions compared to baseline. Partial response was defined as at least a 30% decrease in the sum of the longest diameter of all target lesions compared to baseline. Otherwise PSA levels were followed. A PSA response was defined as a 50% decrease in PSA compared with pretreatment sustained for at least one course. Progressive disease was defined as a >50% increase in PSA from PSA nadir. Stable disease was defined as a <50% decrease or <50% increase in PSA level over pretreatment PSA levels for at least one course. The National Cancer Institute Common Toxicity Criteria (version 2) were used to assess toxicity [24]. A 25% reduction in EMP and etoposide dose was planned for persistent G1 nausea, vomiting or other gastrointestinal side-effects, and hematologic toxicity. For grade ‡2 non-hematological toxicity (except alopecia and adequately treated nausea/vomiting) and for grade ‡3 hematological toxicity, treatment was delayed until recovery (£grade 1). More marked reductions including continuation with one drug only were permitted at the treating physician’s discretion.
Table 1. Characteristics of 75 patients, median age 67 years (range 28-84 years) with hormone-refractory prostate cancer
original article
Annals of Oncology
Table 2. Adverse events according to National Cancer Institute Common Toxicity Criteria (version 2) Adverse event
G1, n (%)
G2, n (%)
G3, n (%)
G4, n (%)
15 (20) 1 (1) 0 4 (5) 0 2 (2.5) 1 (1) 1 (1) 21 (28) 6 (8) 1 (1) 2 (2.5) 1 (1) 10 (13) 0 10 (13) 6 (8) 2 (2.5) 1 (1) 20 (26.5) 3 (4) 1 (1) 7 (9)
10 1 2 1 1 1 0 0 1 1 0 2 0 0 2 0 1 0 1 10 1 0 3 0 4
5 (6) 4 (5) 3 (4) 0 0 0 0 0 0 0 0 0 0 0 0
0 1 (1) 1 (1) 0 0 0 0 0 0 0 0 0 0 0 0
a
a
0 0 0 0 0 0 0 3 (4)
a
0 0 0 0 0 0 0
a
a
a a
(13) (1) (2.5) (1) (1) (1)
(1) (1) (2.5)
(2.5) (1) (1) (13) (1) (4) (5)
Assessable patients PSA response >50% reduction in PSA <50% reduction in PSA RECIST responses in patients with one or more measurable lesions PR SD PD RECIST responses in patients with bone metastases only SD PD Not assessed
69 14 (20%) 26 (37.5%) 10 2 (20) 2 (20) 6 (60) 52 17 (32.5%) 20 (38.5%) 15 (29%)
PSA, prostrate-specific antigen; PR, partial response; SD, stable disease; PD, progressive disease.
a
National Cancer Institute—Common Toxicity Criteria grade nonexistent. GGT, gamma-glutamyl transferase; DVT, deep vein thrombosis.
G3/4 toxicity occurred in 17 (22.6%) patients. One patient experienced G4 neutropenia. Five patients developed G3 anemia, three of whom required blood transfusion. Three other patients required low molecular weight heparin for deep vein thrombosis.
activity Ten patients with one or more measurable lesions were evaluated by RECIST (Table 3): two had short-lasting partial remission of lymph node metastases (4 and 5 months); two had shortlasting stable disease (5 and 6 months); six had progressive disease. Six patients were not assessable for PSA: five stopped treatment before completion of two cycles for worsening performance status, and one did not have raised PSA levels. Of the 69 patients assessable for PSA, 14 (20%) had >50% PSA decrease of median duration 5 months (range 4–11); 26 (37.5%) had stable PSA with median time to progression 5 months (range 2–9); 29 had progressive disease. Of the 52 patients with nonmeasurable bone lesions, 15 were not assessable as they stopped treatment for PSA progression or unacceptable toxicity before CT could be carried out, and 17 (32.5%) had stable disease (Table 3). Overall, median time to progression was 4.4 months (range 1 week–43 months) (Figure 1) and median survival was 23 months (range 3 weeks–64 months at latest follow-up) (Figure 2). Twenty-seven patients (36%) were alive at latest follow-up and nine (12%) were lost to follow-up.
500 | Spitaleri et al.
Figure 1. Kaplan Myer representation of median time to progression.
Figure 2. Kaplan-Meier representation of median survival.
Volume 20 | No. 3 | March 2009
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on May 24, 2015
Anemia Leukopenia Neutropenia Thrombocytopenia Increase on GGT Stomatitis Dysguesia Sialorrhea Nausea Vomiting Constipation Diarrhea Meteorism Anorexia Pneumonitis Alopecia Weight loss Headache Fever Asthenia Articular pain Retrosternal pain Edema DVT Thrombophlebitis
Table 3. Activity of estramustine phosphate plus etoposide in patients with hormone-refractory prostate cancer
original article
Annals of Oncology
Table 4. Phase II trials of oral estramustine and oral etoposide in patients with HRPC Reference
Schedule
No. of patients
PSA response
RECIST
Pienta et al. [20]
Estramustine 15 mg/kg/day; etoposide 50 mg/m2/day for 21 of 28-day cycles Estramustine 140 mg t.i.d.; etoposide 50 mg/m2/day for 21 of 28-day cycles Estramustine 140 mg TID, etoposide 100 mg for 21 of 28-day versus lanreotide (30 mg i.m.) fortnightly plus dexamethasone (4 mg)
42: 18 for PSA and target lesions; 24 with nonmeasurable disease 56: 33 with target lesions; 52 with nonmeasurable disease
14/18 >50% PSA decrease
3/18 CR; 6/18 PR; 15/24 SD
30/33 >50% PSA decrease
5/33 CR; 10/33 PR; 34/52 SD
40: 14 versus 10 with target lesions; 17 versus 16 with nonmeasurable disease
14 versus 13 >50% PSA decrease
4/14 versus 2/10 PR; 4/14 versus 2/10 SD; 10/17 versus 7/16 with nonmeasurable disease
Dimopoulos et al. [21]
Dimopoulos et al. [22]
PSA, prostrate-specific antigen; RECIST, response evaluation criteria in solid tumors; CR, complete response; PR, partial response; SD, stable disease.
acknowledgement
With the aim of identifying active agents with a better safety profile than docetaxel or mitoxantrone, yet good activity, so as to delay the need to administer docetaxel, we carried out a prospective phase II trial with estramustine plus etoposide, both administered orally. Three small phase II trials (Table 4) [20–22] had indicated that this combination has activity: 80% experienced PSA reduction and 30%–40% of those with measurable lesions had clinical benefit, although doses and study designs differed. Our study, on 75 patients with HRPC, showed that the combination was capable of stabilizing PSA levels (partial response plus stable disease) in 57.5% of assessable patients and stabilizing lesion size in 40% of assessable patients, but only for a limited period (4–5 months). Benefit only occurred in patients with ECOG <2 and hence the combination does not appear appropriate for patients with ECOG 2. Although grade 3/4 toxicity at 22.6% was higher than expected, overall the treatment was manageable and less than encountered with docetaxel. [1] Three patients developed deep vein thrombosis, less than the four (6%) cases reported by Pienta et al. [20] and two (10%) cases reported by Dimopoulos et al. [22]. However, a metaanalysis of 23 studies involving 896 patients treated with estramustine concluded that the risk of thromboembolic events was low (0.07) and not dose related [27]. Two randomized trials investigated estramustine as add-on to docetaxel in HRPC finding no indication that estramustine could increase the benefit of docetaxel [28, 29]. No studies have been designed to determine whether specific subgroups of HRPC patients might benefit from EMP or oral etoposide as individual agents or in combination. A retrospective assessment of 78 patients with HRPC provided no evidence that prior estrogen response predicts response to EMP [30]. However, it seems reasonable that asymptomatic HRPC patients with low Gleason score and low PSA might benefit from the EMP–etoposide combination. To conclude, EMP plus etoposide has shown modest activity and acceptable safety in HRPC patients, suggesting that in asymptomatic patients with nonaggressive disease this combination could be useful to delay the start of more demanding treatments.
The authors thank Don Ward for help with the English.
Volume 20 | No. 3 | March 2009
references 1. Tannock IF, de Wit R, Berry WR et al. TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15): 1502–1512. 2. Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351(15): 1513–1520. 3. Hudes GR, Nathan FE, Khater C et al. Paclitaxel plus estramustine in metastatic hormone-refractory prostrate cancer. Semin Oncol 1995; 22 (5 Supp. 12):41–45. 4. Hudes GR, Nathan F, Khater C et al. Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer. J Clin Oncol 1997; 15(9): 3156–3163. 5. Savarese DM, Halabi S, Hars V et al. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B. J Clin Oncol 2001; 19(9): 2509–2516. 6. Sitka Copur M, Ledakis P, Lynch J et al. Weekly docetaxel and estramustine in patients with hormone-refractory prostrate cancer. Semin Oncol 2001; 28 (4 Suppl 15):16–21. 7. Kuruma H, Fujita T, Shitara T et al. Weekly paclitaxel plus estramustine combination therapy in hormone-refractory prostate cancer: a pilot study. Int J Urol 2003; 10(9): 470–475. 8. Safarinejad MR. Combination chemotherapy with docetaxel, estramustine and suramin for hormone refractory prostate cancer. Urol Oncol 2005; 23(2): 93–101. 9. Segawa T, Kamoto T, Kinoshita H et al. Monthly paclitaxel and carboplatin with oral estramustine phosphate in patients with hormone-refractory prostrate cancer. Int J Clin Oncol 2005; 10(5): 333–337. 10. Kikuno N, Urakami S, Nakamura S et al. Phase-II study of docetaxel, estramustine phosphate, and carboplatin in patients with hormone-refractory prostate cancer. Eur Urol 2007; 51(5): 1252–1258. 11. Hudes G, Einhorn L, Ross E et al. Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: a Hoosier Oncology Group and Fox Chase Network phase III trial. J Clin Oncol 1999; 17(10): 3160–3166. 12. Bracarda S, Tonato M, Rosi P et al. Oral estramustine and cyclophosphamide in patients with metastatic hormone refractory prostate carcinoma: a phase II study. Cancer 2000; 88(6): 1438–1444. 13. Nishimura K, Nonomura N, Ono Y et al. Oral combination of cyclophosphamide, uracil plus tegafur and estramustine for hormone-refractory prostate cancer. Oncology 2001; 60(1): 49–54.
doi:10.1093/annonc/mdn650 | 501
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on May 24, 2015
discussion
original article
502 | Spitaleri et al.
23.
24. 25. 26. 27.
28.
29.
30.
refractory prostate cancer: a randomized phase II study. Urology 2004; 63(1): 120–125. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92(3): 205–216. CTC Version 2.0. http://www.pharmadhoc.com/NCI%20CTC.htm (3 May 2008, date last accessed). Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982; 38(1): 143–151. Kaplan EL, Meier P. Non-parametric estimation from incomplete observation. J Am Stat Assoc 1958; 53: 457–461. Lubiniecki GM, Berlin JA, Weinstein RB, Vaughn DJ. Thromboembolic events with estramustine phosphate-based chemotherapy in patients with hormonerefractory prostate carcinoma: results of a meta-analysis. Cancer 2004; 101(12): 2755–2759. Nelius T, Klatte T, Yap R et al. A randomized study of docetaxel and dexamethasone with low- or high-dose estramustine for patients with advanced hormone-refractory prostate cancer. BJU Int 2006; 98(3): 580–585. Eymard JC, Priou F, Zannetti A et al. Randomized phase II study of docetaxel plus estramustine and single-agent docetaxel in patients with metastatic hormonerefractory prostate cancer. Ann Oncol 2007; 18(6): 1064–1070. Garcia JA, Weinberg V, Small EJ. Prior estrogen therapy as a predictor of response to subsequent estramustine-based chemotherapy in patients with androgen-independent prostate cancer. Clin Prostate Cancer 2005; 4(2): 113–117.
Volume 20 | No. 3 | March 2009
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on May 24, 2015
14. Borrega P, Velasco A, Bolan˜os M et al. Phase II trial of vinorelbine and estramustine in the treatment of metastatic hormone-resistant prostate cancer. Urol Oncol 2004; 22(1): 32–35. 15. Kaku H, Saika T, Tsushima T et al. Combination chemotherapy with estramustine phosphate, ifosfamide and cisplatin for hormone-refractory prostate cancer. Acta Med Okayama 2006; 60(1): 43–49. 16. Nakabayashi M, Ling J, Xie W et al. Response to vinorelbine with or without estramustine as second-line chemotherapy in patients with hormone-refractory prostate cancer. Cancer J 2007; 13(2): 125–129. 17. Hirano D, Minei S, Kishimoto Y et al. Prospective study of estramustine phosphate for hormone refractory prostate cancer patients following androgen deprivation therapy. Urol Int 2005; 75(1): 43–49. 18. Maulard-Durdux C, Dufour B, Hennequin C et al. Phase II study of the oral cyclophosphamide and oral etoposide combination in hormone-refractory prostate carcinoma patients. Cancer 1996; 77(6): 1144–1148. 19. Odrazka K, Vaculikova M, Petera J et al. Bi-weekly epirubicin, etoposide and low dose dexamethasone for hormone-refractory prostrate cancer. Int J Urol 2003; 10(7): 387–391. 20. Pienta KJ, Redman B, Hussain M et al. Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. J Clin Oncol 1994; 12(10): 2005–2012. 21. Dimopoulos MA, Panopoulos C, Bamia C et al. Oral estramustine and oral etoposide for hormone-refractory prostrate cancer. Urology 1997; 50(5): 754–758. 22. Dimopoulos MA, Kiamouris C, Gika D et al. Combination of LHRH analog with somatostatin analog and dexamethasone versus chemotherapy in hormone-
Annals of Oncology
Annals of Oncology 20: 498–502, 2009 doi:10.1093/annonc/mdn650 Published online 12 January 2009
Phase II trial of estramustine phosphate and oral etoposide in patients with hormone-refractory prostate cancer G. Spitaleri1* , D. V. Matei2 , G. Curigliano1, S. Detti2, F. Verweij2, S. Zambito2, E. Scardino2, B. Rocco2, F. Nole`1, L. Ariu1, T. De Pas1, F. de Braud1 & O. De Cobelli2 1
Division of Medical Oncology; 2Division of Urology, European Institute of Oncology, Milan, Italy
original article
Background: There is a need for active agents with a better safety profile than docetaxel, yet good activity, for patients with hormone-refractory prostate cancer (HRPC). We carried out a phase II trial to determine the activity and safety of estramustine plus oral etoposide in HRPC. Patients and methods: Patients were given estramustine (280 mg twice daily) and etoposide (100 mg/day, days 1– 21) in 28-day cycles until disease progression or unacceptable toxicity. Primary end points were overall response rate and safety, as determined by prostrate-specific antigen (PSA) levels and lesion assessment. Results: From November 2001 to February 2007, 75 patients were enrolled. All patients were assessable for safety; 17 (22.6%) had grade 3/4 toxicity. PSA response was assessable in 69, 14 of whom had a >50% reduction in PSA. Of 10 patients with one or more measurable lesions, two (20%) had partial response and two (20%) disease stabilization. Overall, median time to progression was 4.4 months (range 1 week–43 months); median survival was 23 months (range 3 weeks–64+ months). Conclusions: Estramustine plus etoposide is active and has a manageable safety profile in patients with HRPC. In asymptomatic patients with nonaggressive disease this combination could be useful to delay the start of more demanding treatments. Key words: estramustine phosphate, etoposide, hormone-refractory prostate cancer
introduction The standard care for hormone-refractory prostate cancer (HRPC) is considered docetaxel every 3 weeks in association with prednisone, which confers a modest survival advantage compared with mitoxantrone plus prednisone [1, 2]. However, the significant toxicity of docetaxel can worsen quality of life, so there is a need to find agents with better safety profile and good activity that can delay the need to administer docetaxel. Estramustine phosphate (EMP) is an estrogenic molecule attached to a nitrogen mustard moiety that inhibits microtubule dynamics and has shown activity alone and in combination with taxanes in HRPC [3–10]. Importantly, nontaxane-based EMP combinations have shown modest activity in feasibility studies [11–16]. A phase II study with EMP alone reported serum prostrate-specific antigen (PSA) decrease of 50% or more in 24% of 34 patients with HRPC and better survival in responders than nonresponders [17]. Oral *Correspondence to: Dr G. Spitaleri, Division of Medical Oncology, European Institute of Oncology, Ripamonti 435, 20141 Milan, Italy. Tel: +39-02-57489 482; Fax: +39-02-57489-581; E-mail: [email protected]
Both authors contributed equally to this work.
etoposide in association with oral cyclophosphamide or biweekly epidoxorubicin has also shown modest activity in HRPC [18, 19]. Finally, some small studies indicate that EMP plus etoposide is active orally in patients with HRPC [20–22]. We carried out a prospective phase II study to further investigate the activity and safety of EMP plus oral etoposide in a large series of patients with HRPC.
patients and methods patient selection Patients with histologically documented hormone-refractory metastatic prostate adenocarcinoma were enrolled. Enrollment criteria were two or more consecutive elevations of PSA titer not less than 14 days apart in surgically or chemically castrated patients; age 18 years or older; life expectancy at least 12 weeks; Eastern Cooperative Oncology Group (ECOG) performance status of zero to two; completion of chemotherapy at least 4 weeks previously (6 weeks previously for mitomycin C or a nitrosourea); discontinuation of nonsteroidal antiandrogens at least 4 weeks previously; adequate bone marrow function (hemoglobin 9 g/dl, absolute neutrophil count 1500/ll, platelet count 100 000/ll); adequate liver function (total bilirubin within our Institute’s upper limit of normal; serum aspartate and alanine transferases <1.5 times upper normal limit; alkaline phosphatase
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on May 24, 2015
Received 15 May 2008; revised 1 September 2008; accepted 2 September 2008
original article
Annals of Oncology <2.5 times upper normal limit); adequate renal function (serum creatinine <1.5 times upper normal limit); and no coexisting medical problems of sufficient severity (including thromboembolic disease, stroke, or myocardial infarction) to limit study compliance. The study was approved by our Institute’s review board and all patients gave written informed consent before treatment.
treatment
examinations Complete medical history, physical examination, and routine laboratory studies were carried out at screening, including the following: blood tests (complete blood count, differential white blood cell count, prothrombin and partial thromboplastin times, routine electrolytes and blood chemistry, total protein, and albumin) urinalysis, electrocardiogram, PSA, and radiological studies to assess all disease sites. The radiological evaluations were repeated every 2 months. PSA, physical examination, and routine laboratory tests were repeated monthly or before each new course.
statistical analyses This was an open-label, nonrandomized phase II study. The primary end point was overall response defined as >50% drop in PSA or as complete or partial response in patients with at least one lesion measurable in two dimensions. Fleming’s one-sample multiple testing procedure was used to assess therapeutic efficacy [25]. We considered a PSA response in 30% as clinically significant [1]. Supposing a PSA drop >50% in at least 10% of patients and a PSA drop >50% in 30% as clinically significant, then 78 patients need to be enrolled in the trial to have an 80% (1-b) power of demonstrating efficacy at a = 5%. Median time to progression and median overall survival were represented according Kaplan–Meier [26].
results From November 2001 to February 2007, 75 patients with HRPC were enrolled (Table 1). Median age was 67 years (range 28–84 years). Sixty-one (81%) patients had bone metastases. Eight (10%) patients were assessable only for PSA. Sixty-two (83%) patients received the treatment as first-line therapy after developing hormone-refractory disease. All except three patients who underwent surgical orchiectomy received concomitant leuprorelin.
Volume 20 | No. 3 | March 2009
Characteristic
No.
ECOG 0/1 ECOG 2 Stage at diagnosis Early/locally advanced Advanced Biopsy Gleason score £4 5–7 ‡8 Not available Surgical Gleason score £4 5–7 ‡8 Not assessable Disease sites Lymph nodes Bone and lymph nodes Bone No identifiable lesions Local treatment RP RP plus pelvic external radiotherapy (ERT) RP plus ERT at PSA failure ERT ERT plus lymph node dissection ERT plus palliative surgery Palliative surgery Previous nonhormonal treatment None Docetaxel, vinorelbine Diestilbestrol IFN + thalidomide Gefitinib Samarium-153-EDTMP
19/41 15 39 36 5 15 15 40 0 3 4 14 6 9 52 8 13 4 4 11 1 4 8
62 1 1 2 6 3
ECOG, Eastern Cooperative Oncology Group; IFN, interferon-a; RP, radical prostatectomy; ERT, external radiotherapy; PSA, prostrate-specific antigen.
toxicity A total of 337 cycles were administered (median four cycles per patient, range 1–12). All patients were assessable for safety (Table 2). Four patients received only one cycle: three of whom stopped for toxicity (anemia, nausea, diarrhea), the other for early worsening of clinical condition. Nine patients received their last two cycles without etoposide, and five patients received reduced etoposide after the first cycle (75% reduction in one, 50% reduction in three, 25% reduction in one). Six patients delayed starting subsequent cycles by 1 week due the toxicity (anemia in three, high gamma-glutamyl transferase in one, asthenia in the other). The most frequent grade 1/2 adverse events (>20%) were asthenia, anemia, and nausea.
doi:10.1093/annonc/mdn650 | 499
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on May 24, 2015
Patients received EMP 280 mg twice daily and oral etoposide 100 mg daily for 21 of 28-day cycles until disease progression or unacceptable toxicity. Patients continued to receive the LHRH analogue leuprorelin (3.75 mg every 28 days) if already on it. For patients with at least one lesion evaluable in two dimensions, response evaluation criteria in solid tumors (RECIST) were used [23]. Complete response was stated as disappearance of all target lesions compared to baseline. Partial response was defined as at least a 30% decrease in the sum of the longest diameter of all target lesions compared to baseline. Otherwise PSA levels were followed. A PSA response was defined as a 50% decrease in PSA compared with pretreatment sustained for at least one course. Progressive disease was defined as a >50% increase in PSA from PSA nadir. Stable disease was defined as a <50% decrease or <50% increase in PSA level over pretreatment PSA levels for at least one course. The National Cancer Institute Common Toxicity Criteria (version 2) were used to assess toxicity [24]. A 25% reduction in EMP and etoposide dose was planned for persistent G1 nausea, vomiting or other gastrointestinal side-effects, and hematologic toxicity. For grade ‡2 non-hematological toxicity (except alopecia and adequately treated nausea/vomiting) and for grade ‡3 hematological toxicity, treatment was delayed until recovery (£grade 1). More marked reductions including continuation with one drug only were permitted at the treating physician’s discretion.
Table 1. Characteristics of 75 patients, median age 67 years (range 28-84 years) with hormone-refractory prostate cancer
original article
Annals of Oncology
Table 2. Adverse events according to National Cancer Institute Common Toxicity Criteria (version 2) Adverse event
G1, n (%)
G2, n (%)
G3, n (%)
G4, n (%)
15 (20) 1 (1) 0 4 (5) 0 2 (2.5) 1 (1) 1 (1) 21 (28) 6 (8) 1 (1) 2 (2.5) 1 (1) 10 (13) 0 10 (13) 6 (8) 2 (2.5) 1 (1) 20 (26.5) 3 (4) 1 (1) 7 (9)
10 1 2 1 1 1 0 0 1 1 0 2 0 0 2 0 1 0 1 10 1 0 3 0 4
5 (6) 4 (5) 3 (4) 0 0 0 0 0 0 0 0 0 0 0 0
0 1 (1) 1 (1) 0 0 0 0 0 0 0 0 0 0 0 0
a
a
0 0 0 0 0 0 0 3 (4)
a
0 0 0 0 0 0 0
a
a
a a
(13) (1) (2.5) (1) (1) (1)
(1) (1) (2.5)
(2.5) (1) (1) (13) (1) (4) (5)
Assessable patients PSA response >50% reduction in PSA <50% reduction in PSA RECIST responses in patients with one or more measurable lesions PR SD PD RECIST responses in patients with bone metastases only SD PD Not assessed
69 14 (20%) 26 (37.5%) 10 2 (20) 2 (20) 6 (60) 52 17 (32.5%) 20 (38.5%) 15 (29%)
PSA, prostrate-specific antigen; PR, partial response; SD, stable disease; PD, progressive disease.
a
National Cancer Institute—Common Toxicity Criteria grade nonexistent. GGT, gamma-glutamyl transferase; DVT, deep vein thrombosis.
G3/4 toxicity occurred in 17 (22.6%) patients. One patient experienced G4 neutropenia. Five patients developed G3 anemia, three of whom required blood transfusion. Three other patients required low molecular weight heparin for deep vein thrombosis.
activity Ten patients with one or more measurable lesions were evaluated by RECIST (Table 3): two had short-lasting partial remission of lymph node metastases (4 and 5 months); two had shortlasting stable disease (5 and 6 months); six had progressive disease. Six patients were not assessable for PSA: five stopped treatment before completion of two cycles for worsening performance status, and one did not have raised PSA levels. Of the 69 patients assessable for PSA, 14 (20%) had >50% PSA decrease of median duration 5 months (range 4–11); 26 (37.5%) had stable PSA with median time to progression 5 months (range 2–9); 29 had progressive disease. Of the 52 patients with nonmeasurable bone lesions, 15 were not assessable as they stopped treatment for PSA progression or unacceptable toxicity before CT could be carried out, and 17 (32.5%) had stable disease (Table 3). Overall, median time to progression was 4.4 months (range 1 week–43 months) (Figure 1) and median survival was 23 months (range 3 weeks–64 months at latest follow-up) (Figure 2). Twenty-seven patients (36%) were alive at latest follow-up and nine (12%) were lost to follow-up.
500 | Spitaleri et al.
Figure 1. Kaplan Myer representation of median time to progression.
Figure 2. Kaplan-Meier representation of median survival.
Volume 20 | No. 3 | March 2009
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on May 24, 2015
Anemia Leukopenia Neutropenia Thrombocytopenia Increase on GGT Stomatitis Dysguesia Sialorrhea Nausea Vomiting Constipation Diarrhea Meteorism Anorexia Pneumonitis Alopecia Weight loss Headache Fever Asthenia Articular pain Retrosternal pain Edema DVT Thrombophlebitis
Table 3. Activity of estramustine phosphate plus etoposide in patients with hormone-refractory prostate cancer
original article
Annals of Oncology
Table 4. Phase II trials of oral estramustine and oral etoposide in patients with HRPC Reference
Schedule
No. of patients
PSA response
RECIST
Pienta et al. [20]
Estramustine 15 mg/kg/day; etoposide 50 mg/m2/day for 21 of 28-day cycles Estramustine 140 mg t.i.d.; etoposide 50 mg/m2/day for 21 of 28-day cycles Estramustine 140 mg TID, etoposide 100 mg for 21 of 28-day versus lanreotide (30 mg i.m.) fortnightly plus dexamethasone (4 mg)
42: 18 for PSA and target lesions; 24 with nonmeasurable disease 56: 33 with target lesions; 52 with nonmeasurable disease
14/18 >50% PSA decrease
3/18 CR; 6/18 PR; 15/24 SD
30/33 >50% PSA decrease
5/33 CR; 10/33 PR; 34/52 SD
40: 14 versus 10 with target lesions; 17 versus 16 with nonmeasurable disease
14 versus 13 >50% PSA decrease
4/14 versus 2/10 PR; 4/14 versus 2/10 SD; 10/17 versus 7/16 with nonmeasurable disease
Dimopoulos et al. [21]
Dimopoulos et al. [22]
PSA, prostrate-specific antigen; RECIST, response evaluation criteria in solid tumors; CR, complete response; PR, partial response; SD, stable disease.
acknowledgement
With the aim of identifying active agents with a better safety profile than docetaxel or mitoxantrone, yet good activity, so as to delay the need to administer docetaxel, we carried out a prospective phase II trial with estramustine plus etoposide, both administered orally. Three small phase II trials (Table 4) [20–22] had indicated that this combination has activity: 80% experienced PSA reduction and 30%–40% of those with measurable lesions had clinical benefit, although doses and study designs differed. Our study, on 75 patients with HRPC, showed that the combination was capable of stabilizing PSA levels (partial response plus stable disease) in 57.5% of assessable patients and stabilizing lesion size in 40% of assessable patients, but only for a limited period (4–5 months). Benefit only occurred in patients with ECOG <2 and hence the combination does not appear appropriate for patients with ECOG 2. Although grade 3/4 toxicity at 22.6% was higher than expected, overall the treatment was manageable and less than encountered with docetaxel. [1] Three patients developed deep vein thrombosis, less than the four (6%) cases reported by Pienta et al. [20] and two (10%) cases reported by Dimopoulos et al. [22]. However, a metaanalysis of 23 studies involving 896 patients treated with estramustine concluded that the risk of thromboembolic events was low (0.07) and not dose related [27]. Two randomized trials investigated estramustine as add-on to docetaxel in HRPC finding no indication that estramustine could increase the benefit of docetaxel [28, 29]. No studies have been designed to determine whether specific subgroups of HRPC patients might benefit from EMP or oral etoposide as individual agents or in combination. A retrospective assessment of 78 patients with HRPC provided no evidence that prior estrogen response predicts response to EMP [30]. However, it seems reasonable that asymptomatic HRPC patients with low Gleason score and low PSA might benefit from the EMP–etoposide combination. To conclude, EMP plus etoposide has shown modest activity and acceptable safety in HRPC patients, suggesting that in asymptomatic patients with nonaggressive disease this combination could be useful to delay the start of more demanding treatments.
The authors thank Don Ward for help with the English.
Volume 20 | No. 3 | March 2009
references 1. Tannock IF, de Wit R, Berry WR et al. TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15): 1502–1512. 2. Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351(15): 1513–1520. 3. Hudes GR, Nathan FE, Khater C et al. Paclitaxel plus estramustine in metastatic hormone-refractory prostrate cancer. Semin Oncol 1995; 22 (5 Supp. 12):41–45. 4. Hudes GR, Nathan F, Khater C et al. Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer. J Clin Oncol 1997; 15(9): 3156–3163. 5. Savarese DM, Halabi S, Hars V et al. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B. J Clin Oncol 2001; 19(9): 2509–2516. 6. Sitka Copur M, Ledakis P, Lynch J et al. Weekly docetaxel and estramustine in patients with hormone-refractory prostrate cancer. Semin Oncol 2001; 28 (4 Suppl 15):16–21. 7. Kuruma H, Fujita T, Shitara T et al. Weekly paclitaxel plus estramustine combination therapy in hormone-refractory prostate cancer: a pilot study. Int J Urol 2003; 10(9): 470–475. 8. Safarinejad MR. Combination chemotherapy with docetaxel, estramustine and suramin for hormone refractory prostate cancer. Urol Oncol 2005; 23(2): 93–101. 9. Segawa T, Kamoto T, Kinoshita H et al. Monthly paclitaxel and carboplatin with oral estramustine phosphate in patients with hormone-refractory prostrate cancer. Int J Clin Oncol 2005; 10(5): 333–337. 10. Kikuno N, Urakami S, Nakamura S et al. Phase-II study of docetaxel, estramustine phosphate, and carboplatin in patients with hormone-refractory prostate cancer. Eur Urol 2007; 51(5): 1252–1258. 11. Hudes G, Einhorn L, Ross E et al. Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: a Hoosier Oncology Group and Fox Chase Network phase III trial. J Clin Oncol 1999; 17(10): 3160–3166. 12. Bracarda S, Tonato M, Rosi P et al. Oral estramustine and cyclophosphamide in patients with metastatic hormone refractory prostate carcinoma: a phase II study. Cancer 2000; 88(6): 1438–1444. 13. Nishimura K, Nonomura N, Ono Y et al. Oral combination of cyclophosphamide, uracil plus tegafur and estramustine for hormone-refractory prostate cancer. Oncology 2001; 60(1): 49–54.
doi:10.1093/annonc/mdn650 | 501
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on May 24, 2015
discussion
original article
502 | Spitaleri et al.
23.
24. 25. 26. 27.
28.
29.
30.
refractory prostate cancer: a randomized phase II study. Urology 2004; 63(1): 120–125. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92(3): 205–216. CTC Version 2.0. http://www.pharmadhoc.com/NCI%20CTC.htm (3 May 2008, date last accessed). Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982; 38(1): 143–151. Kaplan EL, Meier P. Non-parametric estimation from incomplete observation. J Am Stat Assoc 1958; 53: 457–461. Lubiniecki GM, Berlin JA, Weinstein RB, Vaughn DJ. Thromboembolic events with estramustine phosphate-based chemotherapy in patients with hormonerefractory prostate carcinoma: results of a meta-analysis. Cancer 2004; 101(12): 2755–2759. Nelius T, Klatte T, Yap R et al. A randomized study of docetaxel and dexamethasone with low- or high-dose estramustine for patients with advanced hormone-refractory prostate cancer. BJU Int 2006; 98(3): 580–585. Eymard JC, Priou F, Zannetti A et al. Randomized phase II study of docetaxel plus estramustine and single-agent docetaxel in patients with metastatic hormonerefractory prostate cancer. Ann Oncol 2007; 18(6): 1064–1070. Garcia JA, Weinberg V, Small EJ. Prior estrogen therapy as a predictor of response to subsequent estramustine-based chemotherapy in patients with androgen-independent prostate cancer. Clin Prostate Cancer 2005; 4(2): 113–117.
Volume 20 | No. 3 | March 2009
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on May 24, 2015
14. Borrega P, Velasco A, Bolan˜os M et al. Phase II trial of vinorelbine and estramustine in the treatment of metastatic hormone-resistant prostate cancer. Urol Oncol 2004; 22(1): 32–35. 15. Kaku H, Saika T, Tsushima T et al. Combination chemotherapy with estramustine phosphate, ifosfamide and cisplatin for hormone-refractory prostate cancer. Acta Med Okayama 2006; 60(1): 43–49. 16. Nakabayashi M, Ling J, Xie W et al. Response to vinorelbine with or without estramustine as second-line chemotherapy in patients with hormone-refractory prostate cancer. Cancer J 2007; 13(2): 125–129. 17. Hirano D, Minei S, Kishimoto Y et al. Prospective study of estramustine phosphate for hormone refractory prostate cancer patients following androgen deprivation therapy. Urol Int 2005; 75(1): 43–49. 18. Maulard-Durdux C, Dufour B, Hennequin C et al. Phase II study of the oral cyclophosphamide and oral etoposide combination in hormone-refractory prostate carcinoma patients. Cancer 1996; 77(6): 1144–1148. 19. Odrazka K, Vaculikova M, Petera J et al. Bi-weekly epirubicin, etoposide and low dose dexamethasone for hormone-refractory prostrate cancer. Int J Urol 2003; 10(7): 387–391. 20. Pienta KJ, Redman B, Hussain M et al. Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. J Clin Oncol 1994; 12(10): 2005–2012. 21. Dimopoulos MA, Panopoulos C, Bamia C et al. Oral estramustine and oral etoposide for hormone-refractory prostrate cancer. Urology 1997; 50(5): 754–758. 22. Dimopoulos MA, Kiamouris C, Gika D et al. Combination of LHRH analog with somatostatin analog and dexamethasone versus chemotherapy in hormone-
Annals of Oncology