- Email: [email protected]
A retrospective review of combination chemohormonal therapy as initial treatment for locally advanced or metastatic adenocarcinoma of the prostate
Urologic Oncology: Seminars and Original Investigations 27 (2009) 165–169
Original article
A retrospective review of combination chemohormonal therapy as initial treatment for locally advanced or metastatic adenocarcinoma of the prostate Robert J. Amato, D.O.a,b,1,*, Bin S. Teh, M.D.a,b, Haby Henary, M.D.a,b, Muhammad Khan, M.D.a,b, Somyata Saxena, B.S.a,b a
Genitourinary Oncology Program, The Methodist Hospital Research Institute, Houston, TX 77030, USA b Department of Radiation Oncology, The Methodist Hospital, Houston, TX 77030, USA Received 2 October 2007; received in revised form 11 December 2007; accepted 11 December 2007
Abstract Objective: Chemotherapy for hormone-refractory prostate cancer reduces PSA levels and enhances overall survival (OS), suggesting that administration in earlier disease stages may be beneficial. If expansion of an androgen-independent clone present during androgen deprivation mediates the transformation from an androgen-dependent to an androgen-independent phenotype, combination chemohormonal therapy would be effective initial treatment for locally advanced or metastatic prostate cancers. A retrospective review was conducted to evaluate results. Materials and methods: Chemohormonal therapy outcomes were retrospectively evaluated in men with locally advanced or metastatic prostate cancer seen at our institution between January 2001 and February 2003. Chemotherapy consisted of three 8-week cycles (once weekly intravenous doxorubicin 20 mg/m2 and thrice daily oral ketoconazole 400 mg in weeks 1, 3, and 5; once weekly intravenous docetaxel 35 mg/m2 and thrice daily oral estramustine 280 mg in weeks 2, 4, and 6; and no therapy in weeks 7 and 8). Hormone therapy consisted of hormonal ablation during and after antiandrogen therapy after chemotherapy. Results: Data for 31 men (median age, 63 years [range, 41–74 years]; white, 97% [30/31]) were reviewed. At 1 year, median PSA level had fallen 99.3% (range, 91.7%–99.9%) from a baseline value of 14.3 ng/ml (range, 1.9 – 497.9 ng/mL). Median time to progression was 34⫹ months (range, 14 – 68⫹ months). Median OS was 56⫹ months (range, 17–73⫹ months). Conclusions: Combination chemohormonal therapy for locally advanced or metastatic prostate cancer safely and effectively reduces PSA levels and increases OS. We are now testing this approach in a prospective, Phase II randomized clinical trial. © 2009 Elsevier Inc. All rights reserved. Keywords: Prostate cancer; Chemohormonal therapy; Retrospective review
1. Introduction Despite its essentially palliative and short-lasting effects, androgen deprivation therapy remains the most common therapy for localized prostate cancer. Estimated median time to treatment failure is relatively short (16 months to 2 years) [1]. Alternatives such as salvage radiation therapy
* Corresponding author. Tel.: ⫹1-832-325-7701; fax: ⫹1-713-5127140. E-mail address: [email protected] (R.J. Amato). 1 Present affiliation: University of Texas Health Science Center, Houston Medical School, Houston, TX 77030, USA. 1078-1439/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2007.12.004
(RT) after failed radical prostatectomy (RP) [2,3] and vice versa [4] have been considered but still fall short in terms of clinical benefit. Thus, the search continues for new therapeutic approaches. Elevated PSA levels at diagnosis correlate strongly with nonlocalized disease [5]. Rising or falling PSA levels correlate with clinical disease progression or improvement, respectively. However, the PSA value indicative of clinically significant improvement and the exact relationship between rising PSA levels and tumor burden remain undefined. Rising PSA levels often precede symptomatic progression by 6 months [6]. Even minimal elevations can predict clinical relapse in prostatectomized
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patients, and PSA doubling times after initial RP or RT may identify and stratify patients at high risk of prostate cancer-specific death [7–9]. Chemotherapy in hormone-refractory or androgen-independent disease with its frequent association with PSA reduction and prolonged survival implies some diseasemodifying potential. Meanwhile, few reports have addressed chemotherapy’s potential clinical benefit in early, hormone-responsive prostate cancer [10 –12]. Several combination regimens have produced PSA response rates of approximately 50%. Two of the most effective are ketoconazole plus weekly doxorubicin [13] and weekly vinblastine plus estramustine [14]. An approach taken is alternating administration of ketoconazole plus adriamycin, and estramustine plus vinblastine was reported as safe and may enhance survival [15]. Based on the established literature defining taxotere, as the most active chemotherapy agent in prostate cancer, we substituted taxotere for vinblastine [16,17]. Early application of chemohormonal therapy to localized, androgen-dependent prostate cancers seems rational, given that the tumor burden would be relatively well confined and any androgen-independent clones therein may have already started expanding and transforming the tumor into a more androgen-refractory phenotype. Therefore, we retrospectively analyzed the safety and efficacy of chemohormonal therapy as initial treatment for locally advanced or metastatic prostate cancers.
2. Patients and methods 2.1. Patient eligibility Men presenting to our institution with histologically confirmed, unresectable or metastatic adenocarcinoma of the prostate were eligible. Inclusion criteria were a PSA failure with or without metastatic disease, and had prior definitive therapy either radical prostatectomy, radiation therapy, or both. In addition, those men who were not candidates for local therapy at initial presentation. Other inclusion criteria were no serious comorbidity, ejection fraction ⱖ45% for patients with diabetes or an abnormal ECG, life expectancy ⱖ3 years, and adequate physiologic reserves. Excluded were patients with other histologic tumor subtypes (e.g., pure ductal) or tumors exhibiting small-cell carcinoma components. Other exclusion criteria were history of central nervous system disease, second malignancy (unless confident of previous curative therapy), or HIV infection; recent history of transient ischemic attack, regular antianginal therapy, or activity-limiting claudication, history of deep venous thrombosis (DVT) or pulmonary embolism, cardiac valve replacement requiring aggressive anticoagulation, regular antacid use, active peptic ulcer disease, use of H2 blockers, terfenadine, astemizole, omeprazole, or cisapride, or active or predicted achlorhydria.
Tumors of potentially variant histology (e.g., visceral but not high-volume bone metastasis, especially with modestly elevated PSA levels) were biopsied to rule out nonprostate tumors, except when clinical characteristics of advanced prostate cancer were apparent. 2.2. Intervention Patients received three 8-week cycles of chemotherapy (6 weeks of chemotherapy followed by 2 weeks of rest) in combination with androgen deprivation. In weeks 1, 3, and 5, patients received doxorubicin (20 mg/m2 as a 24-hour intravenous infusion on day 1 of each applicable week) and ketoconazole (400 mg orally 3 times daily for 7 days); in weeks 2, 4, and 6, docetaxel (35 mg/m2 intravenously on day 1 of each applicable week) and estramustine (280 mg orally 3 times daily for 7 days). Androgen deprivation began within 3 months of chemotherapy initiation. Oral antiandrogen therapy (casodex 50 mg daily) was started at week 25. This timing avoided exacerbation of any cumulative chemotherapy-induced hepatic toxicity. Three-cycle chemotherapy was chosen because of (1) its favorable toxicity profile in a previous Phase II trial and (2) its ability to deliver a cumulative doxorubicin dose (180 mg/m2) well within acceptable safety limits [15]. Our decision to combine estramustine with docetaxel and not vinblastine was based on recent trials demonstrating the first combination’s relatively superior efficacy. Maintenance hydrocortisone (20 mg morning and 10 mg afternoon) was administered daily throughout chemotherapy to counteract potential ketoconazole-induced adrenal complications. Coumadin 1 mg was given during chemotherapy as prophylaxis against thrombosis due to indwelling intravenous infusion catheters. 2.3. Objectives Clinical outcomes of combination chemohormonal therapy were measured and evaluated in terms of time to progression (TTP) and overall survival (OS). An ancillary objective was to evaluate PSA’s clinical utility in predicting disease progression, and to document the interval between PSA relapse and symptomatically or radiographically established disease progression. 2.4. Assessments 2.4.1. Measures For this review, primary and secondary efficacy endpoints were median TTP and median OS. Treatment responses were defined as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). CR was defined as normalization of PSA levels to ⱕ0.1 ng/ml and radiographically documented disease resolution, as defined by response evaluation criteria in solid tumors (RECIST) guidelines [18], for at least 8 weeks. PR
R.J. Amato et al. / Urologic Oncology: Seminars and Original Investigations 27 (2009) 165–169
167
Cancer Institute common toxicity criteria for adverse events (NCI CTCAE), version 3.
3. Results 3.1. Patient characteristics
Fig. 1. Kaplan-Meier estimates of median time to progression, as an indicator of progression-free survival (n ⫽ 31); 23 subjects experienced progressive disease; the remaining 8 subjects remain disease free.
was defined as a decrease of ⱖ50% in PSA level ⱖ30% in radiographically measurable lesions (i.e., longest diameter in centimeters) [18], for at least 8 weeks. SD was defined as no change in radiographically measurable lesions qualifying as CR, PR, or PD and no evidence of new lesions. PD was defined as either (1) two consecutive increases in PSA to ⬎25% above nadir measured at least 2 weeks apart or (2) a ⱖ20% increase in radiographically measurable disease, progression of existing nontarget lesions, and/or appearance of an unequivocally new lesion as defined by RECIST criteria [18]. TTP was defined as time from commencement of combination chemohormonal therapy to disease progression. 2.4.2. Pretreatment evaluations The pretreatment (baseline) evaluation included patient history, physical examination, chest X-ray, whole-body bone scan, measurement of cancerous lesions along longest diameters (in centimeters), and PSA levels (ng/ml), cardiac profile including electrocardiography, assessment of Zubrod performance status, hematologic, coagulation, biochemical profiles, urinalysis, and determination of Gleason scores. 2.4.3. Treatment assessments Efficacy was assessed regularly during and after chemotherapy. Each assessment included patient history, physical examination, measurement of PSA levels, assessment of Zubrod performance status, hematologic, coagulation, and biochemical profiles, and urinalysis. PSA levels were measured every 8 weeks during chemotherapy and every 12 weeks during subsequent androgen deprivation. Patients with radiographic evidence of disease at baseline underwent tumor restaging at 16 weeks, 32 weeks, and then every 12 weeks until the maximal radiographic benefit was documented. Radiographic reassessments were not performed until PSA progression was documented. Safety was assessed by grading adverse events and laboratory abnormalities for severity according to the National
Retrospective data from 31 patients seen consecutively between January 2001 and February 2003 were reviewed and evaluated. This population was predominantly late middle-aged (median age [range], 63 [41–74] years) and white (97% [30/31]). Most (65% [20/31]) had undergone previous RP, RT, or RP ⫹ RT; the rest (35% [11/31]) had tumors not amenable to local therapy. The median baseline PSA level was 14.3 ng/ml (range, 1.9 – 497.9 ng/ml). Metastasis at baseline was documented radiographically in 74% (23/31) and biochemically (by PSA level) in 26% (8/31). Most (94% [29/31]) had Gleason scores ⱖ7. 3.2. Efficacy After completing chemotherapy, all patients experienced tumor regression, as evidenced by a median reduction in PSA level of ⬎90%. Two years after chemohormonal therapy initiation, more than half (61.3% [19/31]) had PSA levels ⱕ0.1 ng/ml; at 3 years, approximately half did (48.4% [15/31]). Median TTP, as measured by PSA relapse, was 34⫹ months (range, 14 – 68⫹ months) (Fig. 1). All 23 patients who had radiographically documented metastasis at baseline also experienced CRs. Eight complete responders in this study still have no detectable PSA or radiographic evidence of disease after a median follow-up of 51⫹ months (range, 40 – 68⫹ months). Six of them continue taking hormones and 2 continue demonstrating testosterone recovery after hormone discontinuation. For all 31 patients, median OS was 56⫹ months (range, 17–73⫹ months) (Fig. 2).
Fig. 2. Kaplan-Meier estimates of median overall survival (n ⫽ 31); 6 subjects died during the study; the remaining 25 subjects remain alive.
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Table 1 Toxicities occurring during chemotherapy (n ⫽ 31) Toxicity
Gradea 1
Hematologic Neutropenia Anemia Liver enzyme elevation Hyponatremia Infection Nonhematologic Alopecia Peripheral edema Fatigue Deep venous thrombosis Hyperlacrimation Nausea/vomiting Diarrhea
2
3
4
4 7 0 0 2
0 0 1 0 0
0 0 0 1 0
0 0 2 0 0
0 5 13 0 0 0 0
20 7 0 0 1 4 3
0 0 0 8 0 0 0
0 0 0 0 0 0 0
a
National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE), version 3.
Two patients who had not undergone local therapy before PSA relapse and who showed no radiographic evidence of systemic disease after chemohormonal therapy underwent repeat prostate biopsies that revealed focal, viable, PSA-positive disease. Both patients received additional RT, were placed on a continuing hormonal therapy regimen, and remain alive with no detectable PSA. 3.3. Safety Chemotherapy-associated toxicities were no more frequent than expected (Table 1). Serious (grade 3/4) nonhematologic and hematologic toxicities were relatively infrequent. The most frequent nonhematologic adverse event was Grade 3 DVT (26% [8/31]). Hematologic adverse events included Grade 4 liver enzyme elevations necessitating ketoconazole and docetaxel dose reductions (6% [2/31]) and Grade 3 hyponatremia (3% [1/31]). Two patients (6%) experienced infectious complications not requiring hospitalization.
4. Discussion Treating locally advanced or metastatic cancers with alternating weekly dual-chemotherapy regimens is clinically beneficial. The regimen used here was partly based on that used in an M. D. Anderson, Phase II trial in which 45 patients with advanced, androgen-independent disease received alternating weekly injections of doxorubicin and vinblastine [15]. During doxorubicin weeks, they took oral ketoconazole; during vinblastine weeks, oral estramustine. In that trial, 8-week treatment cycles produced the best response rates observed to date in this patient population: PSA reductions of ⱖ50% in 31 patients (69%) and ⱖ80% in 26 (58%), and a median OS (18.1
months) [9] that compares favorably with that in other Phase II trials of nonalternating regimens in similar populations (range, 10.1–15.5 months) [13,19 –22]. As described here, combination chemohormonal therapy for locally advanced or metastatic prostate cancer delayed disease progression and enhanced OS. Biochemically, it elicited a nearly 100% reduction in median PSA at 1 year. Clinically, it extended both median TTP (to 34⫹ months) and median OS (to 56⫹ months). These findings compare favorably with results from previous trials and support a prospective trial now underway at our institution in patients hormone naïve with locally advanced or metastatic prostate cancer. These results also correlate well with those from previous relevant trials. In a nonrandomized trial involving highrisk prostatectomized patients, combination of mitomycin C, adriamycin, and vinblastine markedly reduced the PSA relapse rate in treated vs. control patients (7% [2/27] vs. 80% [8/10]) [10]. Several randomized trials compared the efficacy of androgen deprivation therapy alone vs. combination chemohormonal therapy. A Southwest Oncology Group (SWOG) trial found no difference in survival or TTP between patients treated chemohormonally (i.e., fifteen 21day courses of low-dose doxorubicin [20 mg/m2] and cyclophosphamide [500 mg/m2] and either orchiectomy or diethylstilbestrol) and control patients treated hormonally [11]. That trial, however, was limited in (1) antedating PSA’s availability as a clinical indicator, (2) defining survival and TTP by clinically apparent disease relapse and thus likely accruing a patient population with much more advanced tumors than ours, (3) having a lower-than-expected response rate among control patients with treatmentnaïve but minimally metastatic disease, and (4) using a 21-day chemotherapy cycle potentially less active against advanced, androgen-independent prostate cancers than current weekly regimens. A randomized trial reported by Goodin et al. found that mitoxantrone treatment of hormone-naïve, progressive prostate tumors led to reduced PSA levels but could not prevent eventual biochemical relapse [12]. More recently, in a small feasibility trial in prostate cancer patients who experienced biochemical relapse after initial local therapy, sequential chemohormonal therapy (i.e., up to six 3-week cycles of docetaxel 70 mg/m2 followed by 12 to 20 months of androgen deprivation) achieved short-lived disease control by reducing PSA levels by ⱖ50% in almost half of evaluable patients [17]. Despite its limitations as a retrospective review, our study has shown that a chemohormonal approach warrants further clinical study. Together, our results demonstrate the clinical benefit of attacking locally advanced (residual) and metastatic (recurrent) prostate cancers earlier, when they are still sensitive to both cytotoxic drugs and hormones, and warrant continued prospective randomized clinical trials of this double-barreled approach.
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Acknowledgments The authors thank Rose Salazar and Laura Riojas for preparation of the manuscript. References [1] Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989;321:419. [2] Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004; 291:1325–32. [3] Pacholke HD, Wajsman Z, Algood CB, et al. Postoperative adjuvant and salvage radiotherapy for prostate cancer: Impact on freedom from biochemical relapse and survival. Urology 2004;64:982– 6. [4] Stephenson AJ, Eastham JA. Role of salvage radical prostatectomy for recurrent prostate cancer after radiation therapy. J Clin Oncol 2005;23:8198 –203. [5] Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostatespecific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991;324:1156. [6] Miller JI, Ahmann FR, Drach GW, et al. The clinical usefulness of serum prostate specific antigen after hormonal therapy of metastatic prostate cancer. J Urol 1992;147:956 – 61. [7] Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591–7. [8] Zhou P, Chen MH, McLeod D, et al. Predictors of prostate cancerspecific mortality after radical prostatectomy or radiation therapy. J Clin Oncol 2005;23:6992– 8. [9] Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 2005;294:433–9. [10] Bagley C, Lane R, Blasko J, et al. Adjuvant chemotherapy and hormonal therapy of high risk prostate cancer. Proc Am Soc Clin Oncol 1995;14:230 [Abstract].
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[11] Osborne CK, Blumenstein B, Crawford ED, et al. Combined vs. sequential chemo-endocrine therapy in advanced prostate cancer: Final results of a randomized Southwest Oncology Group study. J Clin Oncol 1990;8:1675– 82. [12] Goodin S, Medina P, Capanna T, et al. Effect of docetaxel in patients with hormone-dependent prostate-specific antigen progression after local therapy for prostate cancer. J Clin Oncol 2005;23:3352–7. [13] Sella A, Kilbourn R, Amato R, et al. Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen-independent prostate cancer. J Clin Oncol 1994;12:683. [14] Amato RJ, Ellerhorst J, Bui C, et al. Estramustine and vinblastine for patients with progressive androgen-independent adenocarcinoma of the prostate. Urol Oncol 199;1:168 –72. [15] Ellerhorst J, Tu SM, Amato RJ, et al. Phase II trial of alternating weekly chemotherapy for patients with androgen-independent prostate cancer. Clin Cancer Res 1997;3:2371– 6. [16] Petrylak DP, Tangen CM, Hussain MHA, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–20. [17] Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:15. [18] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–16. [19] Hussain A, Dawson N, Amin P, et al. Docetaxel followed by hormone therapy in men experiencing increasing prostate-specific antigen after primary local treatments for prostate cancer. J Clin Oncol 2005;23: 2789 –96. [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;12:2005–12. [21] Maulard-Durdux C, Dufour B, Hennequin C, et al. Phase II study of the oral cyclophosphamide and oral etoposide combination in hormonerefractory prostate carcinoma patients. Cancer 1996;77:1144 – 8. [22] Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative end points. J Clin Oncol 1996;14:1756 – 64.
Original article
A retrospective review of combination chemohormonal therapy as initial treatment for locally advanced or metastatic adenocarcinoma of the prostate Robert J. Amato, D.O.a,b,1,*, Bin S. Teh, M.D.a,b, Haby Henary, M.D.a,b, Muhammad Khan, M.D.a,b, Somyata Saxena, B.S.a,b a
Genitourinary Oncology Program, The Methodist Hospital Research Institute, Houston, TX 77030, USA b Department of Radiation Oncology, The Methodist Hospital, Houston, TX 77030, USA Received 2 October 2007; received in revised form 11 December 2007; accepted 11 December 2007
Abstract Objective: Chemotherapy for hormone-refractory prostate cancer reduces PSA levels and enhances overall survival (OS), suggesting that administration in earlier disease stages may be beneficial. If expansion of an androgen-independent clone present during androgen deprivation mediates the transformation from an androgen-dependent to an androgen-independent phenotype, combination chemohormonal therapy would be effective initial treatment for locally advanced or metastatic prostate cancers. A retrospective review was conducted to evaluate results. Materials and methods: Chemohormonal therapy outcomes were retrospectively evaluated in men with locally advanced or metastatic prostate cancer seen at our institution between January 2001 and February 2003. Chemotherapy consisted of three 8-week cycles (once weekly intravenous doxorubicin 20 mg/m2 and thrice daily oral ketoconazole 400 mg in weeks 1, 3, and 5; once weekly intravenous docetaxel 35 mg/m2 and thrice daily oral estramustine 280 mg in weeks 2, 4, and 6; and no therapy in weeks 7 and 8). Hormone therapy consisted of hormonal ablation during and after antiandrogen therapy after chemotherapy. Results: Data for 31 men (median age, 63 years [range, 41–74 years]; white, 97% [30/31]) were reviewed. At 1 year, median PSA level had fallen 99.3% (range, 91.7%–99.9%) from a baseline value of 14.3 ng/ml (range, 1.9 – 497.9 ng/mL). Median time to progression was 34⫹ months (range, 14 – 68⫹ months). Median OS was 56⫹ months (range, 17–73⫹ months). Conclusions: Combination chemohormonal therapy for locally advanced or metastatic prostate cancer safely and effectively reduces PSA levels and increases OS. We are now testing this approach in a prospective, Phase II randomized clinical trial. © 2009 Elsevier Inc. All rights reserved. Keywords: Prostate cancer; Chemohormonal therapy; Retrospective review
1. Introduction Despite its essentially palliative and short-lasting effects, androgen deprivation therapy remains the most common therapy for localized prostate cancer. Estimated median time to treatment failure is relatively short (16 months to 2 years) [1]. Alternatives such as salvage radiation therapy
* Corresponding author. Tel.: ⫹1-832-325-7701; fax: ⫹1-713-5127140. E-mail address: [email protected] (R.J. Amato). 1 Present affiliation: University of Texas Health Science Center, Houston Medical School, Houston, TX 77030, USA. 1078-1439/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2007.12.004
(RT) after failed radical prostatectomy (RP) [2,3] and vice versa [4] have been considered but still fall short in terms of clinical benefit. Thus, the search continues for new therapeutic approaches. Elevated PSA levels at diagnosis correlate strongly with nonlocalized disease [5]. Rising or falling PSA levels correlate with clinical disease progression or improvement, respectively. However, the PSA value indicative of clinically significant improvement and the exact relationship between rising PSA levels and tumor burden remain undefined. Rising PSA levels often precede symptomatic progression by 6 months [6]. Even minimal elevations can predict clinical relapse in prostatectomized
166
R.J. Amato et al. / Urologic Oncology: Seminars and Original Investigations 27 (2009) 165–169
patients, and PSA doubling times after initial RP or RT may identify and stratify patients at high risk of prostate cancer-specific death [7–9]. Chemotherapy in hormone-refractory or androgen-independent disease with its frequent association with PSA reduction and prolonged survival implies some diseasemodifying potential. Meanwhile, few reports have addressed chemotherapy’s potential clinical benefit in early, hormone-responsive prostate cancer [10 –12]. Several combination regimens have produced PSA response rates of approximately 50%. Two of the most effective are ketoconazole plus weekly doxorubicin [13] and weekly vinblastine plus estramustine [14]. An approach taken is alternating administration of ketoconazole plus adriamycin, and estramustine plus vinblastine was reported as safe and may enhance survival [15]. Based on the established literature defining taxotere, as the most active chemotherapy agent in prostate cancer, we substituted taxotere for vinblastine [16,17]. Early application of chemohormonal therapy to localized, androgen-dependent prostate cancers seems rational, given that the tumor burden would be relatively well confined and any androgen-independent clones therein may have already started expanding and transforming the tumor into a more androgen-refractory phenotype. Therefore, we retrospectively analyzed the safety and efficacy of chemohormonal therapy as initial treatment for locally advanced or metastatic prostate cancers.
2. Patients and methods 2.1. Patient eligibility Men presenting to our institution with histologically confirmed, unresectable or metastatic adenocarcinoma of the prostate were eligible. Inclusion criteria were a PSA failure with or without metastatic disease, and had prior definitive therapy either radical prostatectomy, radiation therapy, or both. In addition, those men who were not candidates for local therapy at initial presentation. Other inclusion criteria were no serious comorbidity, ejection fraction ⱖ45% for patients with diabetes or an abnormal ECG, life expectancy ⱖ3 years, and adequate physiologic reserves. Excluded were patients with other histologic tumor subtypes (e.g., pure ductal) or tumors exhibiting small-cell carcinoma components. Other exclusion criteria were history of central nervous system disease, second malignancy (unless confident of previous curative therapy), or HIV infection; recent history of transient ischemic attack, regular antianginal therapy, or activity-limiting claudication, history of deep venous thrombosis (DVT) or pulmonary embolism, cardiac valve replacement requiring aggressive anticoagulation, regular antacid use, active peptic ulcer disease, use of H2 blockers, terfenadine, astemizole, omeprazole, or cisapride, or active or predicted achlorhydria.
Tumors of potentially variant histology (e.g., visceral but not high-volume bone metastasis, especially with modestly elevated PSA levels) were biopsied to rule out nonprostate tumors, except when clinical characteristics of advanced prostate cancer were apparent. 2.2. Intervention Patients received three 8-week cycles of chemotherapy (6 weeks of chemotherapy followed by 2 weeks of rest) in combination with androgen deprivation. In weeks 1, 3, and 5, patients received doxorubicin (20 mg/m2 as a 24-hour intravenous infusion on day 1 of each applicable week) and ketoconazole (400 mg orally 3 times daily for 7 days); in weeks 2, 4, and 6, docetaxel (35 mg/m2 intravenously on day 1 of each applicable week) and estramustine (280 mg orally 3 times daily for 7 days). Androgen deprivation began within 3 months of chemotherapy initiation. Oral antiandrogen therapy (casodex 50 mg daily) was started at week 25. This timing avoided exacerbation of any cumulative chemotherapy-induced hepatic toxicity. Three-cycle chemotherapy was chosen because of (1) its favorable toxicity profile in a previous Phase II trial and (2) its ability to deliver a cumulative doxorubicin dose (180 mg/m2) well within acceptable safety limits [15]. Our decision to combine estramustine with docetaxel and not vinblastine was based on recent trials demonstrating the first combination’s relatively superior efficacy. Maintenance hydrocortisone (20 mg morning and 10 mg afternoon) was administered daily throughout chemotherapy to counteract potential ketoconazole-induced adrenal complications. Coumadin 1 mg was given during chemotherapy as prophylaxis against thrombosis due to indwelling intravenous infusion catheters. 2.3. Objectives Clinical outcomes of combination chemohormonal therapy were measured and evaluated in terms of time to progression (TTP) and overall survival (OS). An ancillary objective was to evaluate PSA’s clinical utility in predicting disease progression, and to document the interval between PSA relapse and symptomatically or radiographically established disease progression. 2.4. Assessments 2.4.1. Measures For this review, primary and secondary efficacy endpoints were median TTP and median OS. Treatment responses were defined as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). CR was defined as normalization of PSA levels to ⱕ0.1 ng/ml and radiographically documented disease resolution, as defined by response evaluation criteria in solid tumors (RECIST) guidelines [18], for at least 8 weeks. PR
R.J. Amato et al. / Urologic Oncology: Seminars and Original Investigations 27 (2009) 165–169
167
Cancer Institute common toxicity criteria for adverse events (NCI CTCAE), version 3.
3. Results 3.1. Patient characteristics
Fig. 1. Kaplan-Meier estimates of median time to progression, as an indicator of progression-free survival (n ⫽ 31); 23 subjects experienced progressive disease; the remaining 8 subjects remain disease free.
was defined as a decrease of ⱖ50% in PSA level ⱖ30% in radiographically measurable lesions (i.e., longest diameter in centimeters) [18], for at least 8 weeks. SD was defined as no change in radiographically measurable lesions qualifying as CR, PR, or PD and no evidence of new lesions. PD was defined as either (1) two consecutive increases in PSA to ⬎25% above nadir measured at least 2 weeks apart or (2) a ⱖ20% increase in radiographically measurable disease, progression of existing nontarget lesions, and/or appearance of an unequivocally new lesion as defined by RECIST criteria [18]. TTP was defined as time from commencement of combination chemohormonal therapy to disease progression. 2.4.2. Pretreatment evaluations The pretreatment (baseline) evaluation included patient history, physical examination, chest X-ray, whole-body bone scan, measurement of cancerous lesions along longest diameters (in centimeters), and PSA levels (ng/ml), cardiac profile including electrocardiography, assessment of Zubrod performance status, hematologic, coagulation, biochemical profiles, urinalysis, and determination of Gleason scores. 2.4.3. Treatment assessments Efficacy was assessed regularly during and after chemotherapy. Each assessment included patient history, physical examination, measurement of PSA levels, assessment of Zubrod performance status, hematologic, coagulation, and biochemical profiles, and urinalysis. PSA levels were measured every 8 weeks during chemotherapy and every 12 weeks during subsequent androgen deprivation. Patients with radiographic evidence of disease at baseline underwent tumor restaging at 16 weeks, 32 weeks, and then every 12 weeks until the maximal radiographic benefit was documented. Radiographic reassessments were not performed until PSA progression was documented. Safety was assessed by grading adverse events and laboratory abnormalities for severity according to the National
Retrospective data from 31 patients seen consecutively between January 2001 and February 2003 were reviewed and evaluated. This population was predominantly late middle-aged (median age [range], 63 [41–74] years) and white (97% [30/31]). Most (65% [20/31]) had undergone previous RP, RT, or RP ⫹ RT; the rest (35% [11/31]) had tumors not amenable to local therapy. The median baseline PSA level was 14.3 ng/ml (range, 1.9 – 497.9 ng/ml). Metastasis at baseline was documented radiographically in 74% (23/31) and biochemically (by PSA level) in 26% (8/31). Most (94% [29/31]) had Gleason scores ⱖ7. 3.2. Efficacy After completing chemotherapy, all patients experienced tumor regression, as evidenced by a median reduction in PSA level of ⬎90%. Two years after chemohormonal therapy initiation, more than half (61.3% [19/31]) had PSA levels ⱕ0.1 ng/ml; at 3 years, approximately half did (48.4% [15/31]). Median TTP, as measured by PSA relapse, was 34⫹ months (range, 14 – 68⫹ months) (Fig. 1). All 23 patients who had radiographically documented metastasis at baseline also experienced CRs. Eight complete responders in this study still have no detectable PSA or radiographic evidence of disease after a median follow-up of 51⫹ months (range, 40 – 68⫹ months). Six of them continue taking hormones and 2 continue demonstrating testosterone recovery after hormone discontinuation. For all 31 patients, median OS was 56⫹ months (range, 17–73⫹ months) (Fig. 2).
Fig. 2. Kaplan-Meier estimates of median overall survival (n ⫽ 31); 6 subjects died during the study; the remaining 25 subjects remain alive.
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Table 1 Toxicities occurring during chemotherapy (n ⫽ 31) Toxicity
Gradea 1
Hematologic Neutropenia Anemia Liver enzyme elevation Hyponatremia Infection Nonhematologic Alopecia Peripheral edema Fatigue Deep venous thrombosis Hyperlacrimation Nausea/vomiting Diarrhea
2
3
4
4 7 0 0 2
0 0 1 0 0
0 0 0 1 0
0 0 2 0 0
0 5 13 0 0 0 0
20 7 0 0 1 4 3
0 0 0 8 0 0 0
0 0 0 0 0 0 0
a
National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE), version 3.
Two patients who had not undergone local therapy before PSA relapse and who showed no radiographic evidence of systemic disease after chemohormonal therapy underwent repeat prostate biopsies that revealed focal, viable, PSA-positive disease. Both patients received additional RT, were placed on a continuing hormonal therapy regimen, and remain alive with no detectable PSA. 3.3. Safety Chemotherapy-associated toxicities were no more frequent than expected (Table 1). Serious (grade 3/4) nonhematologic and hematologic toxicities were relatively infrequent. The most frequent nonhematologic adverse event was Grade 3 DVT (26% [8/31]). Hematologic adverse events included Grade 4 liver enzyme elevations necessitating ketoconazole and docetaxel dose reductions (6% [2/31]) and Grade 3 hyponatremia (3% [1/31]). Two patients (6%) experienced infectious complications not requiring hospitalization.
4. Discussion Treating locally advanced or metastatic cancers with alternating weekly dual-chemotherapy regimens is clinically beneficial. The regimen used here was partly based on that used in an M. D. Anderson, Phase II trial in which 45 patients with advanced, androgen-independent disease received alternating weekly injections of doxorubicin and vinblastine [15]. During doxorubicin weeks, they took oral ketoconazole; during vinblastine weeks, oral estramustine. In that trial, 8-week treatment cycles produced the best response rates observed to date in this patient population: PSA reductions of ⱖ50% in 31 patients (69%) and ⱖ80% in 26 (58%), and a median OS (18.1
months) [9] that compares favorably with that in other Phase II trials of nonalternating regimens in similar populations (range, 10.1–15.5 months) [13,19 –22]. As described here, combination chemohormonal therapy for locally advanced or metastatic prostate cancer delayed disease progression and enhanced OS. Biochemically, it elicited a nearly 100% reduction in median PSA at 1 year. Clinically, it extended both median TTP (to 34⫹ months) and median OS (to 56⫹ months). These findings compare favorably with results from previous trials and support a prospective trial now underway at our institution in patients hormone naïve with locally advanced or metastatic prostate cancer. These results also correlate well with those from previous relevant trials. In a nonrandomized trial involving highrisk prostatectomized patients, combination of mitomycin C, adriamycin, and vinblastine markedly reduced the PSA relapse rate in treated vs. control patients (7% [2/27] vs. 80% [8/10]) [10]. Several randomized trials compared the efficacy of androgen deprivation therapy alone vs. combination chemohormonal therapy. A Southwest Oncology Group (SWOG) trial found no difference in survival or TTP between patients treated chemohormonally (i.e., fifteen 21day courses of low-dose doxorubicin [20 mg/m2] and cyclophosphamide [500 mg/m2] and either orchiectomy or diethylstilbestrol) and control patients treated hormonally [11]. That trial, however, was limited in (1) antedating PSA’s availability as a clinical indicator, (2) defining survival and TTP by clinically apparent disease relapse and thus likely accruing a patient population with much more advanced tumors than ours, (3) having a lower-than-expected response rate among control patients with treatmentnaïve but minimally metastatic disease, and (4) using a 21-day chemotherapy cycle potentially less active against advanced, androgen-independent prostate cancers than current weekly regimens. A randomized trial reported by Goodin et al. found that mitoxantrone treatment of hormone-naïve, progressive prostate tumors led to reduced PSA levels but could not prevent eventual biochemical relapse [12]. More recently, in a small feasibility trial in prostate cancer patients who experienced biochemical relapse after initial local therapy, sequential chemohormonal therapy (i.e., up to six 3-week cycles of docetaxel 70 mg/m2 followed by 12 to 20 months of androgen deprivation) achieved short-lived disease control by reducing PSA levels by ⱖ50% in almost half of evaluable patients [17]. Despite its limitations as a retrospective review, our study has shown that a chemohormonal approach warrants further clinical study. Together, our results demonstrate the clinical benefit of attacking locally advanced (residual) and metastatic (recurrent) prostate cancers earlier, when they are still sensitive to both cytotoxic drugs and hormones, and warrant continued prospective randomized clinical trials of this double-barreled approach.
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