Urologic Oncology: Seminars and Original Investigations 29 (2011) 676 – 681
Original article
Carboplatin plus paclitaxel therapy after docetaxel in men with metastatic castrate resistant prostate cancer Stephanie Jeske, M.D.a, Scott T. Tagawa, M.D.a, Olugbenga Olowokure, M.D.b, Jodi Selzer, F.N.P.a, Paraskevi Giannakakou, Ph.D.a, David M. Nanus, M.D.a,* a b
Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY 10065, USA Division of Hematology and Medical Oncology, Mount Sinai School of Medicine, New York, NY 10029, USA Received 3 September 2009; received in revised form 30 December 2009; accepted 31 December 2009
Abstract Objectives: Docetaxel is considered first-line chemotherapy for patients with metastatic castrate resistant prostate cancer (CRPC). Carboplatin and paclitaxel have demonstrated activity in CRPC but published data are limited regarding use after docetaxel. Methods: A retrospective, bi-institutional review was conducted of patients with advanced CRPC treated with carboplatin plus paclitaxel after docetaxel. Therapy was evaluated for tolerability, response, and survival. Endpoints used modified Prostate Cancer Working Group 2 criteria. Results: Twenty-five patients were identified from February 2000 to March 2008. Median pretreatment PSA was 130.2 ng/ml [range 0.1–2100]. Sites of metastases included bone (88%), lymph nodes (52%), pelvis (32%), lung (28%), and liver (20%). A median 4.5 cycles of docetaxel [range 1–22] were given with a median progression-free survival (PFS) of 12 weeks [range 2– 68]. Eighty-eight percent of patients (22/25) were docetaxel-refractory at the initiation of therapy with carboplatin (AUC 4 – 6) day 1 plus paclitaxel 60 – 80 mg/m2 days 1, 8, and 21 recycled every 28 days. Patients received a median of 3.5 cycles [range 1– 8] of carboplatin/paclitaxel with a median PFS of 12 weeks [range 2–35]. Sixty-four percent of patients (16/25) achieved ⱖ30% reduction in PSA with a median overall survival of 42 weeks [95% CI 30.6 –53.5 weeks]. Grade 3 or 4 adverse hematologic events occurred in 11/25 (44%) patients, with no neutropenic fever or grade 3/4 non-hematologic toxicity. Conclusion: Carboplatin/paclitaxel chemotherapy following docetaxel in metastatic CRPC is well tolerated with favorable PSA response rates and survival. This combination is a viable option after progression on docetaxel-based therapy. © 2011 Elsevier Inc. All rights reserved. Keywords: Prostate cancer; Docetaxel; Carboplatin; Paclitaxel; Metastatic; Castrate resistant; Chemotherapy
1. Introduction Prostate cancer is the most common non cutaneous malignancy and the second leading cause of cancer mortality in men in the U.S [1]. Most cancer-related deaths result from metastatic, castrate resistant disease. Widely thought to be chemoresistant, androgen suppression was historically the only effective therapy for patients who develop metastases. However, virtually all patients develop castrate resistance with a median response to androgen withdrawal between 12 and 24 months. In the 1990s, the FDA approved mitoxantrone and corticosteroids for use in prostate cancer after a demonstrated improvement in palliative benefit over ste* Corresponding author. Tel.: ⫹1-212-746-3152; fax: ⫹1-212-7466645. E-mail address:
[email protected] (D.M. Nanus). 1078-1439/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2009.12.023
roids alone [2,3]. Two landmark trials in 2004 established first-line therapy with docetaxel as the standard of care with a significant benefit in overall survival (OS) as well as patient-reported outcomes [4,5]. Unfortunately, the median survival benefit with docetaxel-based chemotherapy is only 2 to 3 months and there is currently no proven, effective second-line therapy for patients refractory to docetaxel. Early clinical trials suggested platinum analogues had modest antitumor activity in advanced prostate cancer with single agent response rates of 17% [6]. However, more recent studies have demonstrated clinical responses to platinum-based therapy in combination with other agents [7– 15]. The combination regimen of carboplatin, paclitaxel, and estramustine was developed based on the activity of microtubule targeting agents in prostate cancer, identified synergy of carboplatin with paclitaxel and platelet-sparing effect of weekly paclitaxel dosing [11]. Carboplatin in com-
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bination with a taxane with or without estramustine has demonstrated antitumor activity in the first- and second-line settings with objective response rates as high as 65% in soft tissue [11–14,16,17]. Nakabayashi et al. reported a retrospective analysis of 30 patients treated with docetaxel, carboplatin, plus estramustine. Eight-eight percent of previously untreated patients experienced a ⱖ50% PSA decline and a median OS of 17.7 months. Only twenty percent of previously treated patients receiving docetaxel and carboplatin (without estramustine) experienced a ⱖ50% decline in PSA with a median OS of 14.9 months [8]. Despite the morbidity and mortality of docetaxel-resistant metastatic castrate resistant prostate cancer (CRPC), there is limited data supporting effective second-line therapies. Preclinical data demonstrate resistance to docetaxel does not confer resistance to other taxanes [18]. Previous clinical trials demonstrate activity of carboplatin in combination with paclitaxel in this disease. Nevertheless, there is limited published literature to help guide clinicians in choosing therapy in patients who progress on or who are refractory to docetaxel therapy. We, therefore, conducted a bi-institutional retrospective review to investigate the efficacy and toxicity of carboplatin and paclitaxel after docetaxel-based therapy in CRPC.
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2.2. Treatment All patients were treated with carboplatin- and paclitaxelbased chemotherapy after treatment with docetaxel-based therapy. Carboplatin was administered at an AUC of 4 – 6 (day 1) with paclitaxel at 60 – 80 mg/m2 weekly (days 1, 8, and 15) on a 28-day cycle. Additional subsequent chemotherapeutic agents given at the discretion of the investigator were recorded. 2.3. Evaluation of response and toxicity PSA nadir was defined as the lowest PSA achieved while on active therapy. Percentage of PSA reduction was calculated using baseline PSA and nadir value. Progression was identified by either PSA or measurable disease progression, as defined by modified PCWG2 [19] with PSA progression defined as an increase in PSA to 25% above the nadir. Docetaxel resistance was defined as progression on or within 60 days of treatment with docetaxel [20,21]. Key clinical toxicities of docetaxel-based therapy were identified from patient records including hematologic toxicity, febrile neutropenia, fatigue, neuropathy, and edema. Grades were assigned according to the National Cancer Institute Common Toxicity Criteria (CTCAE) version 3.0 (http://ctep.cancer. gov/forms/CTCAEv3.pdf).
2. Materials and methods 2.4. Statistical analysis 2.1. Patients The Institutional Review Boards of the Weill Cornell and Mount Sinai Medical Centers approved this study. A retrospective chart review of patients with CRPC treated with carboplatin and paclitaxel after docetaxel therapy between February 2000 and March 2008 was performed. A primary reviewer collected data on approved data collection sheets, and a secondary reviewer confirmed clinical data. All patients had histologically-confirmed prostate cancer and progressive disease, as defined by the Prostate Cancer Working Group 2 (PCWG2), [19] despite adequate medical or surgical castration therapy. Any number of previous hormonal therapies was allowed. The patient’s previous disease characteristics, including age at diagnosis, ethnicity, Gleason’s score, local therapy received, duration of primary androgen deprivation therapy, secondary hormonal therapies received, time from diagnosis to development of metastatic disease, and sites of metastatic disease were recorded. All patients had received docetaxel-based therapy given either weekly or on an every 3-week schedule. Any additional anti-cancer therapy given in conjunction with docetaxel (on a clinical study) was noted. Baseline characteristics at initiation of therapy included Eastern Cooperative Oncology Group (ECOG) performance status (PS), PSA level, alkaline phosphatase, albumin, and lactate dehydrogenase. Toxicities, doses, and cycles of therapy were collected retrospectively.
All analyses were undertaken by treatment regimen. OS was defined as the time from starting carboplatin/paclitaxel chemotherapy to death or was censored at the date last known alive. The progression-free survival (PFS) was defined as the time from initiation of chemotherapy to PSA or measurable disease progression or death, as defined by the PCWG2. PFS was censored at the date of the last visit if alive or lost to follow-up with no disease progression. Kaplan-Meier estimates of the probability of OS and PFS distributions were conducted with the use of the SPSS software version 15.0 [22].
3. Results 3.1. Patients Between February 2000 and March 2008, a total of 25 patients at 2 institutions with metastatic CRPC were identified as having been treated with carboplatin- and paclitaxelbased therapy after treatment with docetaxel. Table 1 summarizes the patients’ baseline characteristics. The median age of the patients at diagnosis with prostate cancer was 60 years (range 45–76); 40% of patients had a Gleason’s score ⱖ 8. Ten patients had undergone radical prostatectomy and 10 radiation therapy; five patients were diagnosed with metastatic disease at presentation and received no local
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Table 1 Patient demographics and characteristics prior to chemotherapy
3.2. Clinical response
Number of patients Median age at diagnosis, years (range) Ethnicity, % White Black Asian Other Unknown Gleason’s score 6 7 8 9 10 Unknown Local therapy, n (%) Radiation therapy Radical prostatectomy None Unknown Additional salvage therapy Radiation therapy Radical prostatectomy Median duration of response to androgen deprivation therapy, months (range) Median time to metastatic disease, months (range) Secondary hormonal therapies*, n (%) Bicalutamide Nilutamide Ketoconazole PC-SPES Flutamide Estradiol Sites of metastatic disease, n (%) Bone Lymph node Pelvis Lung Liver
Table 3 describes patient response to therapy. Of 25 patients, 15 (60%) had a decline in PSA on docetaxel with a median decline of 27%. Eleven (44%) experienced a PSA decline ⱖ 30%. Of the 25 patients subsequently treated with carboplatin/paclitaxel, 19 (76%) had a decline in PSA with a median 43% decline. Sixteen patients (64%) experienced a ⱖ 30% decrease in PSA. Median PFS was 12 weeks [95% CI 9.2, 14.8] on therapy with docetaxel and 12 weeks [10.4, 13.6] on carboplatin/paclitaxel. Response to docetaxel did not correlate with response to carboplatin/paclitaxel. Of the 10 patients (40%) with a PSA decline ⱖ50% on docetaxel, only 6 (60%) experienced a PSA decline ⱖ50% on carboplatin/paclitaxel. Of the 10 patients (40%) with no PSA response to docetaxel, 7 (70%) demonstrated a decline in PSA on carboplatin/paclitaxel with 4 (40%) achieving a PSA decline ⱖ50%. Of the 3 patients removed from docetaxel due to side effects of therapy, 2 achieved a PSA decline with their maximum PSA reduction on carboplatin/paclitaxel being 0%, 59%, and 92% of pretreatment PSA. Median follow-up for all patients was 8.9 months (range 1.9 –27.4 months) after initiation of carboplatin/paclitaxel.
25 60 (45–76) 15 (60) 2 (8) 1 (4) 2 (8) 5 (20) 4 (16) 8 (32) 4 (16) 6 (24) 1 (4) 2 (8) 8 (32) 10 (40) 5 (20) 2 (8) 6 (24) 5 (20) 1 (4) 11 (0–79) 26 (0–228) 20 (80) 13 (52) 12 (48) 1 (4) 1 (4) 1 (4) 22 (88) 13 (52) 8 (32) 7 (28) 5 (20)
* As patients may have been treated with more than one hormonal therapy, these numbers exceed 100% of patients.
therapy. Median duration of primary anti-androgen therapy as well as time to metastatic disease is depicted in Table 1. The modal number of hormonal therapies in addition to LHRH agonist was 2 with a range 1– 4. All patients continued LHRH agonist throughout chemotherapy. Sites of metastatic disease involvement included: bone (88%), lymph nodes (52%), pelvis (32%), lung (28%), and liver (20%). Patient characteristics at the time of receiving docetaxel and then carboplatin/paclitaxel are listed in Table 2. Median age at start of treatment was 69 years for both regimens. Baseline PSA was 49.85 ng/dl (0.1–1066.9 ng/dl) for docetaxel therapy and 130.2 ng/dl (0.1–2100 ng/dl) for carboplatin/paclitaxel. Twenty-two patients (88%) were docetaxel-refractory at the time of carboplatin/paclitaxel. The remaining 3 patients (12%) were removed from therapy due to toxicities of treatment necessitating discontinuation. Two of these 3 had sustained PSA responses to docetaxel lasting 32 and 36 weeks despite stopping docetaxel.
Table 2 Baseline patient characteristics Docetaxel Median age, years (range) ECOG Performance Status, n (%) 0 1 2 3 Unknown Median baseline labs (range) PSA, ng/ml Albumin, g/dl Alkaline phosphatase, g/dl Hemoglobin, g/dl Presence of visceral metastatic disease, n (%) Median number of cycles administered (range) Schedule of docetaxel administration, n (%) Every 3 weeks Weekly Unknown Median dose of carboplatin, AUC (range) Additional therapy received, n (%) Docetaxel refractory, n (%)
69 (50–80)
69 (50–80)
8 (32) 11 (44) 2 (8) 0 (0) 4 (16)
1 (4) 17 (68) 5 (20) 1 (4) 1 (4)
49.5 (0.1–1066.9) 3.8 (1.8–4.4) 169 (51–1786) 11.65 (10–13.8) 12 (48) 4.5 (1–22)
19 (76) 4 (16) 2 (8) n/a 16* (64) n/a
Carboplatinpaclitaxel
130.2 (0.1–2100) 3.5 (2.6–4.3) 177 (58–2608) 11.0 (7.8–14.5) 12 (48) 3.5 (1–8)
n/a n/a n/a 4 (2–6) 6** (24) 22 (88)
* Additional therapies with docetaxel: estramustine (11/16), atrasentan (3/16), bevacizumab (1/16), calcitriol (1/16). ** Additional therapies with carboplatin-paclitaxel: estramustine (5/6), imatinib (1/6).
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Table 3 Clinical Outcome Response to therapy
Docetaxel
Carboplatin/paclitaxel
Any PSA decline, n (%) Median decline, % (range) ⱖ30% decline, n (%) ⱖ50% decline, n (%) Median PFS, weeks (range) Median overall survival, weeks (range)
15 (60) 27 (0–98) 11 (44) 10 (40) 12 (2–68) n/a
19 (76) 48 (0–93) 16 (64) 12 (48) 12 (2–35) 42 (8–117)
Therapy toxicities
Clinical toxicities, n (%) Fatigue Alopecia Neuropathy Edema Hematologic toxicities, n (%) Anemia Leukopenia Neutropenia Neutropenic fever Thrombocytopenia
CTCAE grade
CTCAE grade
1
2
3
4
1
2
3
4
7 (28) — 3 (12) 4 (16)
5 (20) — 0 5 (20)
0 — 0 0
0 — 0 0
9 (36) 4 (16) 11 (40) —
7 (28) 0 3 (12) —
0 0 0 —
0 0 0 —
3 (12) 1 (4) 0 (0) — 3 (12)
6 (24) 3 (12) 4 (16) — 1 (4)
2 (8) 8 (32) 6 (24) 1 (4) 1 (4)
2 (8) 4 (16) 7 (28) 0 0
1 (4) 1 (4) 5 (20) — 8 (32)
13 (52) 8 (32) 10 (36) — 6 (24)
4 (16) 6 (24) 2 (8) 0 2 (8)
2 (8) 1 (4) 2 (8) 0 2 (8)
A Kaplan-Meier curve of OS is demonstrated in Fig. 1. Median OS with carboplatin/paclitaxel was 42 weeks [95% CI 30.6, 53.5]. Individual patient PSA responses to both docetaxel and carboplatin/paclitaxel therapy are shown with waterfall plots in Fig. 1. 3.3. Toxicity Table 3 describes toxicities of both docetaxel and carboplatin/paclitaxel-based therapies. Six patients (24%) were removed from therapy due to toxicity, primarily fatigue, edema, and bone marrow suppression. No grade 3 or 4 non hematologic toxicities were observed with carboplatin/paclitaxel-based therapy.
4. Discussion No standard strategy exists for the treatment of CRPC following first-line chemotherapy with docetaxel. Satraplatin, the first orally administered platinum chemotherapeutic agent, has been investigated as a second-line therapy for patients with docetaxel-resistant metastatic prostate cancer. A randomized phase III trial of 950 patients treated with satraplatin plus prednisone vs. prednisone alone in this clinical setting demonstrated fewer composite progressionfree survival events (HR 0.69, P ⬍ 0.00001), superior PSA response (25% vs. 12%, P ⫽ 0.00007), and increased objective tumor response (7% vs. 1%, P ⬍ 0.002). However, no statistically significant difference in overall survival was identified (61.3 vs. 61.4 weeks, P ⫽ 0.80) [7,23]. Mitoxantrone, which was FDA approved for first-line chemother-
apy, remains the de facto second line agent for many oncologists. In this study, we report on the experience of carboplatin/ paclitaxel after docetaxel-based chemotherapy in 2 institutions. The objective of this study was to evaluate the tolerability and efficacy of this chemotherapy regimen. We chose the combination of carboplatin and paclitaxel as it has demonstrated clinical activity in patients with CRPC, is generally well tolerated, and studies in breast cancer have shown that resistance to docetaxel does not confer crossresistance to all taxane-based therapies [24 –26]. Moreover, preclinical studies have shown that cancer cell lines that are resistant to paclitaxel due to acquired -tubulin mutations at the taxane-binding site retain sensitivity to docetaxel or other microtubule-stabilizing drugs that bind tubulin at the same site, such as the epothilones [27–29]. This is attributed to the distinct binding modes of paclitaxel, docetaxel, or the epothilones in the same binding site in -tubulin so that single point mutations may affect one taxane but not the other even though the binding site is shared [30]. Carboplatin, paclitaxel, and estramustine were first reported to have antitumor activity in prostate cancer patients by Kelly et al. Of 56 patients treated, 67% experienced PSA decline ⱖ50%, and 2 patients experienced a complete response [11]. Additional trials of this combination have demonstrated similar activity [14,31]. However, because of gastrointestinal toxicities and frequent thromboembolic events with limited added efficacy [32], the use of estramustine is controversial and frequently not used. All patients in our study received carboplatin and paclitaxel without estramustine therapy. The primary toxicities were hematologic, especially anemia, and leukopenia. Eight percent of patients
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S. Jeske et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 676 – 681
Fig. 1. (A) Overall survival for carboplatin/paclitaxel. (B) Best individual PSA responses to docetaxel. (C) Best individual PSA responses to carboplatin/paclitaxel.
suffered from grade 4 anemia, neutropenia, and thrombocytopenia. No grade 3 or 4 nonhematologic toxicities were seen. Fatigue and neuropathy were the most common documented clinical toxicities with reported rates of grade 2 toxicities of 28% and 12%, respectively. Platinum-based therapy has previously been reported to recover docetaxel sensitivity in patients with CRPC. Ross et al. conducted a prospective phase 2 trial of carboplatin plus docetaxel as second-line therapy in 34 docetaxel-refractory patients with metastatic CRPC. PSA declines ⱖ50% were achieved in 18% of patients with a median duration of response of 5.7 months. An additional 9% of patients
achieved stable disease. The median PFS was 3 months and the median OS was 12.4 months [15]. In the current retrospective study, treatment with carboplatin/paclitaxel demonstrated good clinical activity with 76% of the patients demonstrating PSA decline and 48% experiencing at least a 50% decline. This response rate was seen despite prior therapy with docetaxel in all patients and 22 of 25 patients (88%) demonstrating docetaxel resistance. This is higher than a previous trial of carboplatin and paclitaxel compared with mitoxantrone in first line therapy, where PSA declines ⱖ 50% were seen in 40% of patients receiving carboplatin and paclitaxel compared to 10% in patients receiving mitoxantrone (P ⫽ 0.031), respectively. A tendency toward improved measurable response rates and overall survival was also identified [10]. However, response rates similarly robust to our results were seen with the use of carboplatin, paclitaxel, and estramustine by Kelly et al. [11] and Urakami et al. [17]. In our study, the median PFS on docetaxel therapy was 12 weeks, compared with the expected 25 weeks seen in prior prospective studies [4]. Although the reason for this is uncertain, it may speak to a significant burden of disease (48% with visceral involvement) in this patient population, or variability in dosing schedule (20% received weekly administration of docetaxel). The PFS of 12 weeks on carboplatin/paclitaxel is intriguing, as it appears similar to docetaxel in the same patient population and at least comparable to that seen in other second-line trials using other regimens [20,21]. This study is limited by its retrospective nature and the small sample size. In addition, the absence of frozen tumor material from these patients precluded us from testing for the presence of -tubulin mutations that could potentially explain why 88% of these patients were refractory to docetaxel, and subsequently responded to treatment with paclitaxel. Recent studies of abiraterone acetate, which inhibits the enzymatic activity of steroid 17␣-monooxygenase in patients following docetaxel chemotherapy, suggest significant antitumor activity with PSA declines ⱖ50% in 40%– 52% of patients, as well as partial responses in soft tissue disease [33,34]. An ongoing prospective randomized trial comparing abiraterone acetate with placebo will determine if there is an improvement in survival following docetaxel.
5. Conclusion These data serve to validate the potential benefit of using the combination of carboplatin and paclitaxel in metastatic CRPC. It is also the first published use of this regimen after docetaxel therapy. Despite demonstrated docetaxel-resistance in 88% of patients, 64% of patients achieved significant PSA decline. Treatment was well tolerated with no grade 3– 4 nonhematologic toxicities. These results suggest that this combination may be worth investigation in com-
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