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Carboplatin in Hormone-Refractory Prostate Cancer
Original Contribution
A Phase II Study of Weekly Paclitaxel/Estramustine/Carboplatin in Hormone-Refractory Prostate Cancer William Berry1,2 David Friedland1 John Fleagle1,3 Don Jackson1,4 Des Ilegbodu1 Kristi A. Boehm1 Lina Asmar1 1US Oncology, Inc, Houston, TX 2Cancer Centers of North Carolina, Cary 3Rocky Mountain Cancer Centers, Boulder, CO 4Asheville Hematology & Oncology Associates PA,
Abstract
NC
Clinical Genitourinary Cancer, Vol. 5, No. 2, 131-137, 2006 Key words: Adenocarcinoma, Metastasis, Multicenter studies, Progressive disease Submitted: Apr 4, 2006; Revised: Jul 19, 2006; Accepted: Jul 28, 2006 Address for correspondence: William Berry, MD Cancer Centers of North Carolina 218 Asheville Ave, Suite 20 Cary, NC 27511 Fax: 919-852-0321 E-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1558-7673, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Purpose: The objective of this phase II study was to determine the response rate in patients with hormone-refractory prostate cancer given paclitaxel/estramustine/carboplatin for weeks 1, 2, and 3 of a 4-week cycle. Patients and Methods: Eighty-four patients were registered into the trial. Paclitaxel 80 mg/m2 and carboplatin area under the curve of 2 were administered intravenously on days 2, 9, and 16, and oral estramustine 280 mg 3 times daily was given on days 1-3, 8-10, and 15-17 for 6 cycles. Eastern Cooperative Oncology Group performance status 0, 1, and 2 was 46%, 41%, and 13%, respectively, and median age was 70 years (range, 53-82 years), with 58 patients (69%) aged > 65 years. The majority of patients (83%) were white. Fifteen patients (18%) had received previous chemotherapy, 61 patients (73%) had undergone previous surgery, and 51 patients (61%) had received previous external-beam radiation therapy. Results: Intent-to-treat analysis revealed a * 50% prostate-specific antigen decrease rate of 61%. Median survival was 15.3 months. The most frequent grade * 3 toxicities included fatigue (11%), nausea (10%), neutropenia (9%), anemia (6%), and vomiting (6%). Conclusion: Paclitaxel/estramustine/ carboplatin administered in a weekly regimen is highly effective in the treatment of hormone-refractory prostate cancer and can be administered with reasonable safety in an outpatient setting.
Introduction Prostate cancer remains the most common cancer diagnosis and the second leading cause of cancer-related death in men in the United States. Androgen-deprivation therapy by means of orchiectomy, luteinizing hormone-releasing hormone (LHRH) agonist therapy, or estrogen therapy has been the primary means of initial systemic therapy for this disease. The vast majority of men with disseminated disease respond initially to this hormonal therapy, but virtually all of these cancers become resistant and progress after initial hormonal therapy. Patients who die of prostate cancer do so with hormone-refractory disease. Altering the natural history of hormone-refractory prostate cancer (HRPC) with systemic therapies has proven difficult. Treatments with second-line hormonal therapies can provide some palliative benefit and prostate-specific antigen (PSA) decreases in some patients, but responses are transient. Systemic chemotherapy gained a Food and Drug Administration indication for HRPC based on the palliative benefit of mitoxantrone/prednisone demonstrated by 2 phase III studies in the mid-1990s.1,2 More recently, in 2 large phase III trials, docetaxel in combination with estramustine or prednisone has been shown to produce an improvement in survival compared with the previous standard of mitoxantrone/prednisone in metastatic HRPC.3,4
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Weekly PEC in Hormone-Refractory Prostate Cancer The current trial was initiated before the demonstration of a survival benefit for a docetaxel-containing regimen in HRPC. This study had a phase II design using the 3-drug combination of carboplatin/paclitaxel/estramustine (PEC) administered on a weekly schedule for 3 of 4 weeks. We had performed a randomized phase II trial (previously reported) of weekly paclitaxel/estramustine versus weekly paclitaxel.5 In that trial, paclitaxel/estramustine had a PSA response rate of 48% versus 28% for paclitaxel and a strong trend toward improved survival for paclitaxel/estramustine (P = 0.049). The hypothesis for the present trial was that the addition of weekly carboplatin to the regimen of weekly paclitaxel/estramustine might improve the rate and duration of response with manageable toxicity.
Patients and Methods Study Design This was a single-arm phase II study conducted at 61 community-based cancer centers in the US Oncology Network of Research Physicians. The protocol was approved by a central institutional review board with jurisdiction over specific sites that registered patients on study, and all patients were required to sign an informed consent form before being admitted onto the study.
Patients Men with pathologically confirmed adenocarcinoma of the prostate with progressive metastatic disease or those with locally progressive disease after orchiectomy or LHRH agonist therapy (leuprolide or goserelin) were enrolled on this protocol; progression was objective (25% increase of measurable disease or obvious increase in the number of bone lesions) or based on increasing PSA. Testosterone levels were required to be at castrate level (< 30 ng/mL). Other inclusion criteria included PSA level > 4 ng/mL for patients who had not undergone prostatectomy, imaging evidence of metastatic disease other than an increasing PSA level, no regression of disease with * 4 weeks since flutamide or * 6 weeks since bicalutamide withdrawal, progression despite * 8 weeks on a maintenance dose of corticosteroids, Eastern Cooperative Oncology Group performance status ) 2, and normal lab values (neutrophil count > 1500/μL, platelet count * 100,000/μL, serum creatinine level ) 2 × the upper limit of normal [ULN], bilirubin ) 1.5 × ULN, and alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ) 2 × ULN). Patients may have received 1 previous regimen of chemotherapy that did not include carboplatin, paclitaxel, or estramustine. At least 4 weeks must have elapsed since any previous radiation therapy or 3 weeks since any surgery; patients must have recovered fully from any previous treatment. Patients on warfarin therapy were permitted to enroll if the study investigator thought that the potential benefit outweighed any risks. Patients were excluded from treatment if they had a recent history (5 years) of a malignancy that could have affected the treatment or diagnosis of HRPC. Other exclusion criteria included active thrombophlebitis or a thromboembolic disorder (not limited to cerebral vascular or coronary artery disease); parenchymal brain metastases that did not respond to treatment; peripheral neuropathy grade * 2; any serious intercurrent illness; * 1 previ-
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ous chemotherapy regimen; any previous immunotherapy; or any previous estramustine, platinum analogue, or taxane.
Treatment Oral estramustine 280 mg 3 times daily was taken on days 1-3, 8-10, and 15-17 of each 28-day cycle. Carboplatin area under the curve of 2 and paclitaxel 80 mg/m2 were infused on days 2, 9, and 16 of each 28-day cycle; no study drugs were administered in week 4. Dose reductions of 50% for carboplatin and paclitaxel occurred for neutrophil counts between 1000-1499/μL and for platelet counts between 75,000-99,000/μL. Carboplatin and paclitaxel were withheld if neutrophil counts were < 1000/μL or platelet counts were < 75,000/μL. Six 28-day cycles were planned; however, after the completion of 6 cycles, patients were permitted to continue treatment, discontinue, or switch to a new treatment at the discretion of the attending physician. Patients were premedicated before the paclitaxel infusion to minimize hypersensitivity reactions. A typical premedication regimen consisted of dexamethasone 10-20 mg intravenously (I.V.), diphenhydramine 50 mg I.V., and cimetidine 300 mg I.V. (or ranitidine 50 mg I.V.) given 30-60 minutes before the paclitaxel dose. Modifications of this regimen were at the discretion of the treating physician with the approval of the principal investigator. All patients who had not had orchiectomy continued LHRH agonist therapy for the duration of the trial.
Assessments Screening evaluations consisted of medical history, physical examination, Eastern Cooperative Oncology Group performance status, bone scans, clinical and radiologic tumor assessment, PSA and testosterone levels, complete blood cell count with differential and platelet counts, bilirubin, AST, ALT, creatinine, prothrombin time, completion of a Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire and a McGill Pain Assessment form, and history of analgesic use. These assessments were repeated at every cycle (with the exception of testosterone level); additional assessments at each cycle included toxicity and evaluation of symptomatic response. Radiologic tumor assessments were done every other cycle. At the completion of therapy, these assessments were repeated (with the exception of testosterone, complete blood cell count, bilirubin, AST, ALT, creatinine, and prothrombin time). During the posttreatment follow-up, PSA and survival data were obtained. If a patient discontinued prematurely because of toxicity, PSA levels were obtained every 4 weeks for * 12 weeks after discontinuation of protocol therapy.
Study Endpoints The primary endpoint was response rate, which was defined as the percentage of patients with a * 50% decrease in PSA (PSA response confirmed by 2 measurements * 4 weeks later).6 Secondary endpoints were overall survival, time to disease progression, and assessment of adverse events.
Statistical Analysis This study was designed to obtain the response rate in patients with HRPC treated with weekly PEC. A Simon 2-stage optimum
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Table 2 Best Response After Treatment and Reasons
Table 1 Patient Characteristics at Baseline Characteristic Number of Patients Enrolled
Characteristic
84
Ethnicity White
70 (83.3)
Black
10 (11.9)
Hispanic
3 (3.6)
Asian
1 (1.2)
Median Age, Years (Range)
for Nonevaluability and Study Discontinuation
Number of Patients (%)
Patients Enrolled
84
Patients Treated
82
Patients Evaluable
76
Best Response
69.7 (53.2-81.9)
ECOG Performance Status 0
39 (46.4)
1
34 (40.5)
2
11 (13.1) 5 (6)
II
17 (20.2)
III
17 (20.2)
IV
38 (45.2)
20
PD
6
Not evaluable*
6
Received ) 1 cycle
7 (8.3)
Histology Unknown
50
SD
6
Reason for Discontinuation (n=79)
I
Adenocarcinoma
PR
Reason for Nonevaluability
Stage at Diagnosis
Unknown
Number of Patients (%)
83 (98.8)
Previous Therapy 61 (72.6)
Radiation therapy
51 (60.7)
Chemotherapy
15 (17.9)
56 (71)
Toxicity
12 (15)
Refused treatment
1 (1)
Death
4 (5)
Intercurrent illness
2 (3)
Other
4 (5)
Patient Status
1 (1.2)
Surgery
PD
Alive
32 (38.1)
Dead
52 (61.9)
Causes of Death PD
Abbreviation: ECOG = Eastern Cooperative Oncology Group
design was used, with the sample size of the first stage being 28 patients and an additional 56 patients accrued in the second stage. The statistical parameters used were a PSA response, P0 = 0.5 and alternative hypothesis of P1 = 0.65, a significance level of P = 0.05, and a power of 80%. The intent-to-treat population included all registered patients. Time to disease progression and survival were analyzed using the Kaplan-Meier method.7 The incidence and types of grade 3/4 adverse events were tabulated and summarized based on all patients who received * 1 dose of treatment drug. Quality of life (QOL) was assessed using the FACT-P questionnaire. The QOL analysis calculated changes in median scores for each category from baseline through the cycles using the Wilcoxon signed rank test. All analyses were performed using the SAS system for Windows software, version 8.0. Survival was defined as the interval from the start of treatment to the date of last contact or death from any cause.
*Two
42 (80.77)
Congestive heart failure
2 (3.85)
Pneumonia
2 (3.85)
Pulmonary embolism
1(1.92)
Multiple organ failure
1 (1.92)
Hepatic failure
1 (1.92)
Complications after pathologic fracture
1 (1.92)
Complications after gallbladder surgery
1 (1.92)
Undetermined
1 (1.92)
patients did not receive treatment.
Eight patients were not evaluable for disease response: 6 patients completed ) 1 cycle of treatment (1 each: death from multiple organ failure, complications of pathologic fracture, new treatment, transient ischemic attack, pneumonia, and anxiety), and 2 patients never were treated (1 patient had a preexisting bladder condition and bacteremia, and the other patient required surgery before treatment). Patient demographics are provided in Table 1.
Treatment Outcomes
Results Patient Characteristics A total of 84 men with HRPC were enrolled on this community-based trial; 82 patients received * 1 dose of study drug.
Among the 82 patients who received * 1 dose of study drug, the overall rate of patients who achieved a * 50% decrease in PSA was 61%, and 20 patients (24%) experienced stable disease. Median time to response was 1 month (range, 1-3.4 months),
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Weekly PEC in Hormone-Refractory Prostate Cancer
Table 3 Quality of Life Scores Cycle
Subscales (Median Score)
Number of Patients
FACT-P
PCS
FACT-G
EWB
TOI
Baseline
78
98.5
25
74
18
59
1
70
102
28*
76
19*
63 64
2
65
104
27†
76
19*
3
58
105
28†
76
19.5†
64.3
4
48
106
28†
75
20†
62.2
5
42
103
27†
73.8
19*
61.5
103
28*
73
14*
62
6
42
*P
< 0.05. < 0.01. Abbreviations: EWB = Emotional Well Being; PCS = Prostate Cancer subscale; TOI = Trial Outcome Index
†P
and median duration of response was 8.1 months (range, 2.226.7 months). Median survival was 15.3 months (range, < 1-28.4 months), with estimated survival times at 1 and 2 years of 63% and 37%, respectively (Figure 1). Median progression-free survival was 7.9 months (range, < 1-27.5 months; Figure 2). Responses, defined as a combination of decreased PSA and measurable tumor (for measurable disease only); reasons for nonevaluability; and discontinuation are summarized in Table 2.
Table 4 Treatment-Related Grade * 3 Adverse Events Adverse Event
Number of Patients
Quality of Life Patients completed a QOL questionnaire (FACT-P) on the first day of every cycle from baseline through cycle 6. The median composite scores are summarized in Table 3. The number of respondents completing all parts of the questionnaire decreased at each cycle because of patients going off study; no further questionnaires were completed by these patients. The FACT-P median scores increased slightly up to cycle 4 but were not significantly different from baseline. The median prostate cancer subscale of the FACT-P score was significantly higher at every cycle after the baseline. The FACT-General median scores across the 6 cycles were not significantly different from baseline, although they increased from cycle 2 and returned to near baseline values at cycle 6. The Emotional Well Being component peaked at cycle 4 and showed significant differences from baseline at every cycle. Scores on the Trial Outcome Index showed no significant differences from baseline.
Grade 3
Grade 4
Total (%)
Anemia
5
0
5 (6.1)
Lymphocytopenia
2
0
2 (2.4)
Neutropenia
5
2
7 (8.5)
Drug Delivery
Thrombocytopenia
4
0
4 (4.9)
Deep vein thrombosis
3
0
3 (3.7)
Embolism
2
0
2 (2.4)
The median number of cycles completed was 6 (range, 1-8 cycles). The percentage of patients who had doses delayed was 12%; these delays were largely attributed to toxicity, specifically gastrointestinal bleeding, renal insufficiency, and deep vein thrombosis. Two patients were registered but were never treated.
Fatigue
8
1
9 (11)
Toxicity
Weakness
4
0
4 (4.9)
Anorexia
3
0
3 (3.7)
Diarrhea
2
0
2 (2.4)
Nausea
8
0
8 (9.8)
Vomiting
5
0
5 (6.1)
2
0
2 (2.4)
1
1
2 (2.4)
Several patients went off of study treatment because of toxicities, including hematuria, transient ischemic attack, anxiety, fatigue, and paresthesia. Fatigue, reported by 11% of patients, was the most frequently reported adverse event (grade * 3) that was related to this combination regimen. Grade 3/4 neutropenia occurred in 8.5% of patients. Six patients developed grade * 3 treatment-related thromboembolic events, which occurred despite prophylactic anticoagulation with warfarin. One pulmonary embolism was fatal. Several grade 3 treatment-related events were limited to 1 occurrence each, including allergic reaction, hearing loss, congestive heart failure, edema, increased prothrombin time, dehydration, rash, hematuria, increased ALT, infection, hypokalemia,
Blood/Bone Marrow
Cardiovascular (General)
Constitutional Symptoms
Gastrointestinal
Neurology Dizziness Pulmonary Dyspnea
A total of 37 patients were enrolled and 36 were treated.
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Table 5 Carboplatin in Combination Therapy for Hormone-Refractory Prostate Cancer12-14 Study
Treatment
PSA Response > 50% (%)
Clinical Response (%)
TTP/PFS (Months)
OS (Months)
67
45
5.2
19.9
59
22
5.3
16.6
100
61
11.1
21.9
61
50
7.9
15.3
Paclitaxel 60-100 mg/m2 weekly Estramustine 10 mg/m2 per day orally
Kelly et al12
Carboplatin AUC of 6 every 4 weeks Paclitaxel 100 mg/m2 weekly Estramustine 500-1500 mg/m2 I.V. weekly
Solit et al13
Carboplatin AUC of 6 every 4 weeks Paclitaxel 100 mg/m2 weekly Estramustine 10 mg/m2 daily
Urakami et al14
Carboplatin AUC of 6 every 4 weeks Paclitaxel 80 mg/m2 days 2, 9, and 16 Estramustine 280 mg 3 times per day orally on days 1-3, 8-10, and 15-17
Current Study
Carboplatin AUC of 2 days 2, 9, and 16 every 4 weeks Abbreviations: AUC = area under the curve; PFS = progression-free survival; TTP = time to progression
hypomagnesemia, neuropathy, paresthesia, stroke, syncope, pain, and hypoxia. All other grade 3/4 treatment-related adverse events are summarized in Table 4. The primary cause of death during the treatment period and follow-up was progressive metastatic prostate cancer (42 of 52 patients; 81%). There were no deaths caused by hematologic toxicity.
Discussion Until 2004, there had never been a large phase III trial in HRPC that demonstrated a survival benefit for any cytotoxic chemotherapy regimen. Two large phase III trials were reported that year, TAX 327 and Southwest Oncology Group 9916, which demonstrated a statistically significant survival benefit
for a docetaxel regimen administered every 3 weeks versus the then standard of care regimen of mitoxantrone/prednisone.3,4 The TAX 327 study combined prednisone with docetaxel, and the Southwest Oncology Group 9916 study combined estramustine with docetaxel. Before the publication of these 2 trials, 2 other small randomized trials had demonstrated a borderline survival benefit for the combination of estramustine plus another microtubule inhibitor: vinblastine in the Hoosier Oncology Group/Fox Chase Cancer Center trial8,9; and paclitaxel in a previous US Oncology trial.5 We had interest in adding a third agent, in this case carboplatin, to our regimen of paclitaxel/estramustine to see whether the response rate would be improved with manageable toxicity.
Figure 2 Estimated Progression-Free Survival
Figure 1 Estimated Overall Survival 100
100
Progression-Free Survival (%)
Survival (%)
80 60 40 20
0
84 N 52 Deaths 63% 1 Year 37% 2 Years 15.3 Months Median Range < 1-28.4 Months
3
6
9
12
15
Months
18
21
24
27
84 N 80 Deaths 21% 1 Year 5% 2 Years 7.9 Months Median Range < 1-27.5 Months
80 60 40 20
0
3
6
9
12
15
18
21
24
27
Months
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Weekly PEC in Hormone-Refractory Prostate Cancer There was previous experience suggesting activity of platinum analogues in HRPC. Yagoda et al reported a 12% partial remission rate and a 24% stable disease rate with cisplatin in the prePSA era.10 Miglietta et al treated 35 patients with carboplatin in a weekly schedule and demonstrated a * 50% PSA decrease rate of 28%.11 Carboplatin has been used in combination therapy in HRPC as well. Table 5 summarizes several of these trials12-14; these authors concluded that each regimen was safe and effective, and toxicities were manageable. Carboplatin has also been used in combination with docetaxel. Oh et al have performed phase I15 and II16 studies of DEC (docetaxel/estramustine/carboplatin). In their phase II trial, 68% of the 40 enrolled patients had * 50% decrease in PSA, and there was a 52% response rate in those with measurable disease. Median time to progression was 8.1 months, and overall median survival was 19 months. Toxicity was acceptable with use of granulocyte colony-stimulating factor support. In another report, Oh et al describe responses in HRPC with the addition of carboplatin to docetaxel after progression on docetaxel alone.17 The results of the current trial are comparable with the results of the other trials of PEC, though the drug administration schedules are slightly different. The * 50% PSA decrease rate of 61% and median survival of 15.3 months were achieved in this multicenter community-based trial despite having 8 of 84 patients who were not evaluated (6 of these patients received only 1 dose) or died before assessment of response. The percentage of patients with a * 50% PSA decrease appears to be higher in this trial and others when adding carboplatin to a taxane and estramustine compared with trials using just a taxane plus estramustine. A * 50% PSA decrease rate has not been universally accepted as a surrogate for survival in trials of HRPC but, nevertheless, has been extremely useful in the evaluation of treatment regimens in phase II trials. Without the use of a PSA decrease rate as a phase II measure of antineoplastic activity for treatment in HRPC, it is unlikely that many of the drugs we commonly use to treat this disease today would have been deemed useful.6,18
References
Conclusion Should carboplatin be included in future definitive phase III trials in HRPC? Verbel et al19 have concluded that the 1-year Kaplan-Meier estimate of survival of 89.5% in their trial of PEC in HRPC12 was greater than a historical population and enough to warrant taking the PEC regimen into a phase III trial. It is our opinion, based on this trial and the others discussed previously, that the addition of carboplatin to a taxane-containing regimen (such as PEC or DEC) might lead to increased response rates in the treatment of HRPC. Further studies using carboplatin in combination therapy in HRPC are warranted.
Acknowledgements We thank the patients who shared their experiences with US Oncology physicians; site coordinators in the field; project manager Mae Mirabel; and data reviewer Leonard Bush, who assured the accuracy and integrity of the data. Research support was provided by Bristol-Myers Squibb, Princeton, NJ.
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The following medical oncologists from the US Oncology Network also participated in this study: Stephan Anthony, Spokane, WA; Larry J. Barker, Sherman, TX; Michael Bowen, Ardmore, OK; Reginald J. Brooker, Greenville, SC; David M. Loesch, Indianapolis, IN; Jairo Olivares, Garland, TX; Aleda A. Toma, Oklahoma City, OK; Yousif Abubakr, Jacksonville Beach, FL; James Arseneau, Amsterdam, NY; David Barrera, Fort Worth, TX; Coralia Bonatsos, Albany, NY; Charles E. Bowers, Greenville, SC, and Spartenburg, SC; Marcus P. Braun, Vancouver, WA; Ernest W. Cochran, Paris, TX; James A. Corwin, Midland, TX; Dennis Costa, Lewisville, TX; Shaker R. Dakhil, Wichita, KS; Mark E. Ellis, Williamsburg, VA; Carlos Encarnacion, Waco, TX; Chirantan Ghosh, Cedar Rapids, IA; Thomas L. Goodman, Schenectady, NY; David H. Gordon, San Antonio, TX; Andrew R. Greenspan, Indianapolis, IN; Gregory J. Guzley, San Antonio, TX; David Hakimian, Niles, IL; James W. Hathorn, Durham, NC; Lewis J. Hellerstein, Houston, TX; Vincinio Hernandez, Orlando, FL; William J. Hyman, Tyler, TX; John W. Jaski, Rexford, NY; Michael Kasper, Austin, TX; Michael Kolodziej, Troy, NY; Alan D. Kritz, Raleigh, NC; Paul R. Landry, Bradenton, FL; Deborah L. Lindquist, Sedona, AZ; Keith W. Logie, Fishers, IN, and Indianapolis, IN; Jose A. Lopez, Fredericksburg, TX; Scott A. McKenney, Beaumont, TX; Jose Melo, Plantation, FL; Suzan R. Merten, Roanoke, VA; Marcus Neubauer, Overland Park, KS; Mark A. O’Rourke, Greenville, SC; Gregory A. Parker, Oklahoma City, OK; Devahnad Paul, Denver, CO; Robert E. Pluenneke, Lee’s Summit, MO; Christina W. Prillaman, Williamsburg, VA; James B. Puckett, Asheville, NC; Ahmad I. Qadri, Schenectady, NY; Regina Resta, Amsterdam, NY; Gerald Robbins, New Port Richey, FL; Robert L. Ruxer, Jr, Fort Worth, TX; David Schrier, Englewood, CO; Kenneth M. Simon, Altamonte Springs, FL; Michael Spivey, Denton, TX; Jack J. Sternberg, Little Rock, AR; Joel A. Stone, Jacksonville, FL; Claudia Tellez, Chicago, IL; Hugh J. Wallace, Winston-Salem, NC; Jeffery C. Ward, Edmonds, WA; and Isreal Wiznitzer, Highland Park, IL.
1. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-refractory prostate cancer: a Canadian randomized trial with palliative care endpoints. J Clin Oncol 1996; 14:1756-1764. 2. Kantoff PW, Halabi S, Sonaway M, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol 1999; 17:2506-2513. 3. 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; 351:1502-1512. 4. 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; 351:1513-1520. 5. Berry WR, Hathorn JW, Dakhil SR, et al. Phase II randomized trial of weekly paclitaxel with or without estramustine phosphate in metastatic hormone-refractory prostate cancer. Clin Prostate Cancer 2004; 3:104-111. 6. Bubley GI, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-specific Antigen Working Group. J Clin Oncol 1999; 17:3461-3467. 7. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Soc Assoc 1958; 53:457-481. 8. 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; 17:3160-3166. 9. Hudes G, Ross E, Roth B, et al. Improved survival for patients with hormone-refractory prostate cancer receiving estramustine-based antimicrotubule therapy: final report of a Hoosier Oncology Group and Fox-Chase Network phase III trial comparing
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10. 11. 12. 13. 14.
vinblastine and vinbalstine plus oral estramustine phosphate. Proc Am Soc Clin Oncol 2002; 21:177a (Abstract #704). Yagoda A, Watson RC, Natale RB, et al. A critical analysis of response criteria in patients with prostatic cancer treated with cis-diaminedichloride platinum II. Cancer 1979; 44:1553-1562. Miglietta L, Canobio L, Boccardo F. Assessment of response to carboplatin in patients with hormone-refractory prostate cancer: a critical analysis of drug activity. Anticancer Res 1995; 15:2825-2828. Kelly WK, Curley T, Slovin S, et al. Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer. J Clin Oncol 2001; 19:44-53. Solit DB, Morris M, Slovin S, et al. Clinical experience with intravenous estramustine phosphate, paclitaxel, and carboplatin in patients with castrate, metastatic prostate adenocarcinoma. Cancer 2003; 98:1842-1848. Urakami S, Igawa M, Kikuno N, et al. Combination chemotherapy with paclitaxel, estramustine and carboplatin for hormone refractory prostate cancer. J Urol 2002; 168:2444-2450.
15. Oh WK, Hagmann E, Manola J, et al. A phase I study of estramustine, weekly docetaxel, and carboplatin chemotherapy in patients with hormone-refractory prostate cancer. Clin Cancer Res 2005; 11:284-289. 16. Oh WK, Halabi S, Kelly WK, et al. A phase II study of estramustine, docetaxel, and carboplatin with granulocyte-colony-stimulating factor support in patients with hormone-refractory prostate cancer: Cancer and Leukemia Group B 99813. Cancer 2003; 98:2592-2598. 17. Oh WK, George DJ, Tay MH. Response to docetaxel/carboplatin in patients with hormone-refractory prostate cancer not responding to taxane-based chemotherapy. Clin Prostate Cancer 2005; 4:61-64. 18. Kelly WK, Scher HI, Mazumdar M, et al. Prostate-specific antigen as a measure of disease outcome in metastatic hormone-refractory prostate cancer. J Clin Oncol 1993; 11:607-615. 19. Verbel DA, Kelly WK, Smaletz O, et al. Estimating survival benefit in castrate metastatic prostate cancer: decision making in proceeding to a definitive phase III trial. Urology 2003; 61:142-144.
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A Phase II Study of Weekly Paclitaxel/Estramustine/Carboplatin in Hormone-Refractory Prostate Cancer William Berry1,2 David Friedland1 John Fleagle1,3 Don Jackson1,4 Des Ilegbodu1 Kristi A. Boehm1 Lina Asmar1 1US Oncology, Inc, Houston, TX 2Cancer Centers of North Carolina, Cary 3Rocky Mountain Cancer Centers, Boulder, CO 4Asheville Hematology & Oncology Associates PA,
Abstract
NC
Clinical Genitourinary Cancer, Vol. 5, No. 2, 131-137, 2006 Key words: Adenocarcinoma, Metastasis, Multicenter studies, Progressive disease Submitted: Apr 4, 2006; Revised: Jul 19, 2006; Accepted: Jul 28, 2006 Address for correspondence: William Berry, MD Cancer Centers of North Carolina 218 Asheville Ave, Suite 20 Cary, NC 27511 Fax: 919-852-0321 E-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1558-7673, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Purpose: The objective of this phase II study was to determine the response rate in patients with hormone-refractory prostate cancer given paclitaxel/estramustine/carboplatin for weeks 1, 2, and 3 of a 4-week cycle. Patients and Methods: Eighty-four patients were registered into the trial. Paclitaxel 80 mg/m2 and carboplatin area under the curve of 2 were administered intravenously on days 2, 9, and 16, and oral estramustine 280 mg 3 times daily was given on days 1-3, 8-10, and 15-17 for 6 cycles. Eastern Cooperative Oncology Group performance status 0, 1, and 2 was 46%, 41%, and 13%, respectively, and median age was 70 years (range, 53-82 years), with 58 patients (69%) aged > 65 years. The majority of patients (83%) were white. Fifteen patients (18%) had received previous chemotherapy, 61 patients (73%) had undergone previous surgery, and 51 patients (61%) had received previous external-beam radiation therapy. Results: Intent-to-treat analysis revealed a * 50% prostate-specific antigen decrease rate of 61%. Median survival was 15.3 months. The most frequent grade * 3 toxicities included fatigue (11%), nausea (10%), neutropenia (9%), anemia (6%), and vomiting (6%). Conclusion: Paclitaxel/estramustine/ carboplatin administered in a weekly regimen is highly effective in the treatment of hormone-refractory prostate cancer and can be administered with reasonable safety in an outpatient setting.
Introduction Prostate cancer remains the most common cancer diagnosis and the second leading cause of cancer-related death in men in the United States. Androgen-deprivation therapy by means of orchiectomy, luteinizing hormone-releasing hormone (LHRH) agonist therapy, or estrogen therapy has been the primary means of initial systemic therapy for this disease. The vast majority of men with disseminated disease respond initially to this hormonal therapy, but virtually all of these cancers become resistant and progress after initial hormonal therapy. Patients who die of prostate cancer do so with hormone-refractory disease. Altering the natural history of hormone-refractory prostate cancer (HRPC) with systemic therapies has proven difficult. Treatments with second-line hormonal therapies can provide some palliative benefit and prostate-specific antigen (PSA) decreases in some patients, but responses are transient. Systemic chemotherapy gained a Food and Drug Administration indication for HRPC based on the palliative benefit of mitoxantrone/prednisone demonstrated by 2 phase III studies in the mid-1990s.1,2 More recently, in 2 large phase III trials, docetaxel in combination with estramustine or prednisone has been shown to produce an improvement in survival compared with the previous standard of mitoxantrone/prednisone in metastatic HRPC.3,4
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Weekly PEC in Hormone-Refractory Prostate Cancer The current trial was initiated before the demonstration of a survival benefit for a docetaxel-containing regimen in HRPC. This study had a phase II design using the 3-drug combination of carboplatin/paclitaxel/estramustine (PEC) administered on a weekly schedule for 3 of 4 weeks. We had performed a randomized phase II trial (previously reported) of weekly paclitaxel/estramustine versus weekly paclitaxel.5 In that trial, paclitaxel/estramustine had a PSA response rate of 48% versus 28% for paclitaxel and a strong trend toward improved survival for paclitaxel/estramustine (P = 0.049). The hypothesis for the present trial was that the addition of weekly carboplatin to the regimen of weekly paclitaxel/estramustine might improve the rate and duration of response with manageable toxicity.
Patients and Methods Study Design This was a single-arm phase II study conducted at 61 community-based cancer centers in the US Oncology Network of Research Physicians. The protocol was approved by a central institutional review board with jurisdiction over specific sites that registered patients on study, and all patients were required to sign an informed consent form before being admitted onto the study.
Patients Men with pathologically confirmed adenocarcinoma of the prostate with progressive metastatic disease or those with locally progressive disease after orchiectomy or LHRH agonist therapy (leuprolide or goserelin) were enrolled on this protocol; progression was objective (25% increase of measurable disease or obvious increase in the number of bone lesions) or based on increasing PSA. Testosterone levels were required to be at castrate level (< 30 ng/mL). Other inclusion criteria included PSA level > 4 ng/mL for patients who had not undergone prostatectomy, imaging evidence of metastatic disease other than an increasing PSA level, no regression of disease with * 4 weeks since flutamide or * 6 weeks since bicalutamide withdrawal, progression despite * 8 weeks on a maintenance dose of corticosteroids, Eastern Cooperative Oncology Group performance status ) 2, and normal lab values (neutrophil count > 1500/μL, platelet count * 100,000/μL, serum creatinine level ) 2 × the upper limit of normal [ULN], bilirubin ) 1.5 × ULN, and alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ) 2 × ULN). Patients may have received 1 previous regimen of chemotherapy that did not include carboplatin, paclitaxel, or estramustine. At least 4 weeks must have elapsed since any previous radiation therapy or 3 weeks since any surgery; patients must have recovered fully from any previous treatment. Patients on warfarin therapy were permitted to enroll if the study investigator thought that the potential benefit outweighed any risks. Patients were excluded from treatment if they had a recent history (5 years) of a malignancy that could have affected the treatment or diagnosis of HRPC. Other exclusion criteria included active thrombophlebitis or a thromboembolic disorder (not limited to cerebral vascular or coronary artery disease); parenchymal brain metastases that did not respond to treatment; peripheral neuropathy grade * 2; any serious intercurrent illness; * 1 previ-
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ous chemotherapy regimen; any previous immunotherapy; or any previous estramustine, platinum analogue, or taxane.
Treatment Oral estramustine 280 mg 3 times daily was taken on days 1-3, 8-10, and 15-17 of each 28-day cycle. Carboplatin area under the curve of 2 and paclitaxel 80 mg/m2 were infused on days 2, 9, and 16 of each 28-day cycle; no study drugs were administered in week 4. Dose reductions of 50% for carboplatin and paclitaxel occurred for neutrophil counts between 1000-1499/μL and for platelet counts between 75,000-99,000/μL. Carboplatin and paclitaxel were withheld if neutrophil counts were < 1000/μL or platelet counts were < 75,000/μL. Six 28-day cycles were planned; however, after the completion of 6 cycles, patients were permitted to continue treatment, discontinue, or switch to a new treatment at the discretion of the attending physician. Patients were premedicated before the paclitaxel infusion to minimize hypersensitivity reactions. A typical premedication regimen consisted of dexamethasone 10-20 mg intravenously (I.V.), diphenhydramine 50 mg I.V., and cimetidine 300 mg I.V. (or ranitidine 50 mg I.V.) given 30-60 minutes before the paclitaxel dose. Modifications of this regimen were at the discretion of the treating physician with the approval of the principal investigator. All patients who had not had orchiectomy continued LHRH agonist therapy for the duration of the trial.
Assessments Screening evaluations consisted of medical history, physical examination, Eastern Cooperative Oncology Group performance status, bone scans, clinical and radiologic tumor assessment, PSA and testosterone levels, complete blood cell count with differential and platelet counts, bilirubin, AST, ALT, creatinine, prothrombin time, completion of a Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire and a McGill Pain Assessment form, and history of analgesic use. These assessments were repeated at every cycle (with the exception of testosterone level); additional assessments at each cycle included toxicity and evaluation of symptomatic response. Radiologic tumor assessments were done every other cycle. At the completion of therapy, these assessments were repeated (with the exception of testosterone, complete blood cell count, bilirubin, AST, ALT, creatinine, and prothrombin time). During the posttreatment follow-up, PSA and survival data were obtained. If a patient discontinued prematurely because of toxicity, PSA levels were obtained every 4 weeks for * 12 weeks after discontinuation of protocol therapy.
Study Endpoints The primary endpoint was response rate, which was defined as the percentage of patients with a * 50% decrease in PSA (PSA response confirmed by 2 measurements * 4 weeks later).6 Secondary endpoints were overall survival, time to disease progression, and assessment of adverse events.
Statistical Analysis This study was designed to obtain the response rate in patients with HRPC treated with weekly PEC. A Simon 2-stage optimum
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Table 2 Best Response After Treatment and Reasons
Table 1 Patient Characteristics at Baseline Characteristic Number of Patients Enrolled
Characteristic
84
Ethnicity White
70 (83.3)
Black
10 (11.9)
Hispanic
3 (3.6)
Asian
1 (1.2)
Median Age, Years (Range)
for Nonevaluability and Study Discontinuation
Number of Patients (%)
Patients Enrolled
84
Patients Treated
82
Patients Evaluable
76
Best Response
69.7 (53.2-81.9)
ECOG Performance Status 0
39 (46.4)
1
34 (40.5)
2
11 (13.1) 5 (6)
II
17 (20.2)
III
17 (20.2)
IV
38 (45.2)
20
PD
6
Not evaluable*
6
Received ) 1 cycle
7 (8.3)
Histology Unknown
50
SD
6
Reason for Discontinuation (n=79)
I
Adenocarcinoma
PR
Reason for Nonevaluability
Stage at Diagnosis
Unknown
Number of Patients (%)
83 (98.8)
Previous Therapy 61 (72.6)
Radiation therapy
51 (60.7)
Chemotherapy
15 (17.9)
56 (71)
Toxicity
12 (15)
Refused treatment
1 (1)
Death
4 (5)
Intercurrent illness
2 (3)
Other
4 (5)
Patient Status
1 (1.2)
Surgery
PD
Alive
32 (38.1)
Dead
52 (61.9)
Causes of Death PD
Abbreviation: ECOG = Eastern Cooperative Oncology Group
design was used, with the sample size of the first stage being 28 patients and an additional 56 patients accrued in the second stage. The statistical parameters used were a PSA response, P0 = 0.5 and alternative hypothesis of P1 = 0.65, a significance level of P = 0.05, and a power of 80%. The intent-to-treat population included all registered patients. Time to disease progression and survival were analyzed using the Kaplan-Meier method.7 The incidence and types of grade 3/4 adverse events were tabulated and summarized based on all patients who received * 1 dose of treatment drug. Quality of life (QOL) was assessed using the FACT-P questionnaire. The QOL analysis calculated changes in median scores for each category from baseline through the cycles using the Wilcoxon signed rank test. All analyses were performed using the SAS system for Windows software, version 8.0. Survival was defined as the interval from the start of treatment to the date of last contact or death from any cause.
*Two
42 (80.77)
Congestive heart failure
2 (3.85)
Pneumonia
2 (3.85)
Pulmonary embolism
1(1.92)
Multiple organ failure
1 (1.92)
Hepatic failure
1 (1.92)
Complications after pathologic fracture
1 (1.92)
Complications after gallbladder surgery
1 (1.92)
Undetermined
1 (1.92)
patients did not receive treatment.
Eight patients were not evaluable for disease response: 6 patients completed ) 1 cycle of treatment (1 each: death from multiple organ failure, complications of pathologic fracture, new treatment, transient ischemic attack, pneumonia, and anxiety), and 2 patients never were treated (1 patient had a preexisting bladder condition and bacteremia, and the other patient required surgery before treatment). Patient demographics are provided in Table 1.
Treatment Outcomes
Results Patient Characteristics A total of 84 men with HRPC were enrolled on this community-based trial; 82 patients received * 1 dose of study drug.
Among the 82 patients who received * 1 dose of study drug, the overall rate of patients who achieved a * 50% decrease in PSA was 61%, and 20 patients (24%) experienced stable disease. Median time to response was 1 month (range, 1-3.4 months),
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Weekly PEC in Hormone-Refractory Prostate Cancer
Table 3 Quality of Life Scores Cycle
Subscales (Median Score)
Number of Patients
FACT-P
PCS
FACT-G
EWB
TOI
Baseline
78
98.5
25
74
18
59
1
70
102
28*
76
19*
63 64
2
65
104
27†
76
19*
3
58
105
28†
76
19.5†
64.3
4
48
106
28†
75
20†
62.2
5
42
103
27†
73.8
19*
61.5
103
28*
73
14*
62
6
42
*P
< 0.05. < 0.01. Abbreviations: EWB = Emotional Well Being; PCS = Prostate Cancer subscale; TOI = Trial Outcome Index
†P
and median duration of response was 8.1 months (range, 2.226.7 months). Median survival was 15.3 months (range, < 1-28.4 months), with estimated survival times at 1 and 2 years of 63% and 37%, respectively (Figure 1). Median progression-free survival was 7.9 months (range, < 1-27.5 months; Figure 2). Responses, defined as a combination of decreased PSA and measurable tumor (for measurable disease only); reasons for nonevaluability; and discontinuation are summarized in Table 2.
Table 4 Treatment-Related Grade * 3 Adverse Events Adverse Event
Number of Patients
Quality of Life Patients completed a QOL questionnaire (FACT-P) on the first day of every cycle from baseline through cycle 6. The median composite scores are summarized in Table 3. The number of respondents completing all parts of the questionnaire decreased at each cycle because of patients going off study; no further questionnaires were completed by these patients. The FACT-P median scores increased slightly up to cycle 4 but were not significantly different from baseline. The median prostate cancer subscale of the FACT-P score was significantly higher at every cycle after the baseline. The FACT-General median scores across the 6 cycles were not significantly different from baseline, although they increased from cycle 2 and returned to near baseline values at cycle 6. The Emotional Well Being component peaked at cycle 4 and showed significant differences from baseline at every cycle. Scores on the Trial Outcome Index showed no significant differences from baseline.
Grade 3
Grade 4
Total (%)
Anemia
5
0
5 (6.1)
Lymphocytopenia
2
0
2 (2.4)
Neutropenia
5
2
7 (8.5)
Drug Delivery
Thrombocytopenia
4
0
4 (4.9)
Deep vein thrombosis
3
0
3 (3.7)
Embolism
2
0
2 (2.4)
The median number of cycles completed was 6 (range, 1-8 cycles). The percentage of patients who had doses delayed was 12%; these delays were largely attributed to toxicity, specifically gastrointestinal bleeding, renal insufficiency, and deep vein thrombosis. Two patients were registered but were never treated.
Fatigue
8
1
9 (11)
Toxicity
Weakness
4
0
4 (4.9)
Anorexia
3
0
3 (3.7)
Diarrhea
2
0
2 (2.4)
Nausea
8
0
8 (9.8)
Vomiting
5
0
5 (6.1)
2
0
2 (2.4)
1
1
2 (2.4)
Several patients went off of study treatment because of toxicities, including hematuria, transient ischemic attack, anxiety, fatigue, and paresthesia. Fatigue, reported by 11% of patients, was the most frequently reported adverse event (grade * 3) that was related to this combination regimen. Grade 3/4 neutropenia occurred in 8.5% of patients. Six patients developed grade * 3 treatment-related thromboembolic events, which occurred despite prophylactic anticoagulation with warfarin. One pulmonary embolism was fatal. Several grade 3 treatment-related events were limited to 1 occurrence each, including allergic reaction, hearing loss, congestive heart failure, edema, increased prothrombin time, dehydration, rash, hematuria, increased ALT, infection, hypokalemia,
Blood/Bone Marrow
Cardiovascular (General)
Constitutional Symptoms
Gastrointestinal
Neurology Dizziness Pulmonary Dyspnea
A total of 37 patients were enrolled and 36 were treated.
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Table 5 Carboplatin in Combination Therapy for Hormone-Refractory Prostate Cancer12-14 Study
Treatment
PSA Response > 50% (%)
Clinical Response (%)
TTP/PFS (Months)
OS (Months)
67
45
5.2
19.9
59
22
5.3
16.6
100
61
11.1
21.9
61
50
7.9
15.3
Paclitaxel 60-100 mg/m2 weekly Estramustine 10 mg/m2 per day orally
Kelly et al12
Carboplatin AUC of 6 every 4 weeks Paclitaxel 100 mg/m2 weekly Estramustine 500-1500 mg/m2 I.V. weekly
Solit et al13
Carboplatin AUC of 6 every 4 weeks Paclitaxel 100 mg/m2 weekly Estramustine 10 mg/m2 daily
Urakami et al14
Carboplatin AUC of 6 every 4 weeks Paclitaxel 80 mg/m2 days 2, 9, and 16 Estramustine 280 mg 3 times per day orally on days 1-3, 8-10, and 15-17
Current Study
Carboplatin AUC of 2 days 2, 9, and 16 every 4 weeks Abbreviations: AUC = area under the curve; PFS = progression-free survival; TTP = time to progression
hypomagnesemia, neuropathy, paresthesia, stroke, syncope, pain, and hypoxia. All other grade 3/4 treatment-related adverse events are summarized in Table 4. The primary cause of death during the treatment period and follow-up was progressive metastatic prostate cancer (42 of 52 patients; 81%). There were no deaths caused by hematologic toxicity.
Discussion Until 2004, there had never been a large phase III trial in HRPC that demonstrated a survival benefit for any cytotoxic chemotherapy regimen. Two large phase III trials were reported that year, TAX 327 and Southwest Oncology Group 9916, which demonstrated a statistically significant survival benefit
for a docetaxel regimen administered every 3 weeks versus the then standard of care regimen of mitoxantrone/prednisone.3,4 The TAX 327 study combined prednisone with docetaxel, and the Southwest Oncology Group 9916 study combined estramustine with docetaxel. Before the publication of these 2 trials, 2 other small randomized trials had demonstrated a borderline survival benefit for the combination of estramustine plus another microtubule inhibitor: vinblastine in the Hoosier Oncology Group/Fox Chase Cancer Center trial8,9; and paclitaxel in a previous US Oncology trial.5 We had interest in adding a third agent, in this case carboplatin, to our regimen of paclitaxel/estramustine to see whether the response rate would be improved with manageable toxicity.
Figure 2 Estimated Progression-Free Survival
Figure 1 Estimated Overall Survival 100
100
Progression-Free Survival (%)
Survival (%)
80 60 40 20
0
84 N 52 Deaths 63% 1 Year 37% 2 Years 15.3 Months Median Range < 1-28.4 Months
3
6
9
12
15
Months
18
21
24
27
84 N 80 Deaths 21% 1 Year 5% 2 Years 7.9 Months Median Range < 1-27.5 Months
80 60 40 20
0
3
6
9
12
15
18
21
24
27
Months
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Weekly PEC in Hormone-Refractory Prostate Cancer There was previous experience suggesting activity of platinum analogues in HRPC. Yagoda et al reported a 12% partial remission rate and a 24% stable disease rate with cisplatin in the prePSA era.10 Miglietta et al treated 35 patients with carboplatin in a weekly schedule and demonstrated a * 50% PSA decrease rate of 28%.11 Carboplatin has been used in combination therapy in HRPC as well. Table 5 summarizes several of these trials12-14; these authors concluded that each regimen was safe and effective, and toxicities were manageable. Carboplatin has also been used in combination with docetaxel. Oh et al have performed phase I15 and II16 studies of DEC (docetaxel/estramustine/carboplatin). In their phase II trial, 68% of the 40 enrolled patients had * 50% decrease in PSA, and there was a 52% response rate in those with measurable disease. Median time to progression was 8.1 months, and overall median survival was 19 months. Toxicity was acceptable with use of granulocyte colony-stimulating factor support. In another report, Oh et al describe responses in HRPC with the addition of carboplatin to docetaxel after progression on docetaxel alone.17 The results of the current trial are comparable with the results of the other trials of PEC, though the drug administration schedules are slightly different. The * 50% PSA decrease rate of 61% and median survival of 15.3 months were achieved in this multicenter community-based trial despite having 8 of 84 patients who were not evaluated (6 of these patients received only 1 dose) or died before assessment of response. The percentage of patients with a * 50% PSA decrease appears to be higher in this trial and others when adding carboplatin to a taxane and estramustine compared with trials using just a taxane plus estramustine. A * 50% PSA decrease rate has not been universally accepted as a surrogate for survival in trials of HRPC but, nevertheless, has been extremely useful in the evaluation of treatment regimens in phase II trials. Without the use of a PSA decrease rate as a phase II measure of antineoplastic activity for treatment in HRPC, it is unlikely that many of the drugs we commonly use to treat this disease today would have been deemed useful.6,18
References
Conclusion Should carboplatin be included in future definitive phase III trials in HRPC? Verbel et al19 have concluded that the 1-year Kaplan-Meier estimate of survival of 89.5% in their trial of PEC in HRPC12 was greater than a historical population and enough to warrant taking the PEC regimen into a phase III trial. It is our opinion, based on this trial and the others discussed previously, that the addition of carboplatin to a taxane-containing regimen (such as PEC or DEC) might lead to increased response rates in the treatment of HRPC. Further studies using carboplatin in combination therapy in HRPC are warranted.
Acknowledgements We thank the patients who shared their experiences with US Oncology physicians; site coordinators in the field; project manager Mae Mirabel; and data reviewer Leonard Bush, who assured the accuracy and integrity of the data. Research support was provided by Bristol-Myers Squibb, Princeton, NJ.
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The following medical oncologists from the US Oncology Network also participated in this study: Stephan Anthony, Spokane, WA; Larry J. Barker, Sherman, TX; Michael Bowen, Ardmore, OK; Reginald J. Brooker, Greenville, SC; David M. Loesch, Indianapolis, IN; Jairo Olivares, Garland, TX; Aleda A. Toma, Oklahoma City, OK; Yousif Abubakr, Jacksonville Beach, FL; James Arseneau, Amsterdam, NY; David Barrera, Fort Worth, TX; Coralia Bonatsos, Albany, NY; Charles E. Bowers, Greenville, SC, and Spartenburg, SC; Marcus P. Braun, Vancouver, WA; Ernest W. Cochran, Paris, TX; James A. Corwin, Midland, TX; Dennis Costa, Lewisville, TX; Shaker R. Dakhil, Wichita, KS; Mark E. Ellis, Williamsburg, VA; Carlos Encarnacion, Waco, TX; Chirantan Ghosh, Cedar Rapids, IA; Thomas L. Goodman, Schenectady, NY; David H. Gordon, San Antonio, TX; Andrew R. Greenspan, Indianapolis, IN; Gregory J. Guzley, San Antonio, TX; David Hakimian, Niles, IL; James W. Hathorn, Durham, NC; Lewis J. Hellerstein, Houston, TX; Vincinio Hernandez, Orlando, FL; William J. Hyman, Tyler, TX; John W. Jaski, Rexford, NY; Michael Kasper, Austin, TX; Michael Kolodziej, Troy, NY; Alan D. Kritz, Raleigh, NC; Paul R. Landry, Bradenton, FL; Deborah L. Lindquist, Sedona, AZ; Keith W. Logie, Fishers, IN, and Indianapolis, IN; Jose A. Lopez, Fredericksburg, TX; Scott A. McKenney, Beaumont, TX; Jose Melo, Plantation, FL; Suzan R. Merten, Roanoke, VA; Marcus Neubauer, Overland Park, KS; Mark A. O’Rourke, Greenville, SC; Gregory A. Parker, Oklahoma City, OK; Devahnad Paul, Denver, CO; Robert E. Pluenneke, Lee’s Summit, MO; Christina W. Prillaman, Williamsburg, VA; James B. Puckett, Asheville, NC; Ahmad I. Qadri, Schenectady, NY; Regina Resta, Amsterdam, NY; Gerald Robbins, New Port Richey, FL; Robert L. Ruxer, Jr, Fort Worth, TX; David Schrier, Englewood, CO; Kenneth M. Simon, Altamonte Springs, FL; Michael Spivey, Denton, TX; Jack J. Sternberg, Little Rock, AR; Joel A. Stone, Jacksonville, FL; Claudia Tellez, Chicago, IL; Hugh J. Wallace, Winston-Salem, NC; Jeffery C. Ward, Edmonds, WA; and Isreal Wiznitzer, Highland Park, IL.
1. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-refractory prostate cancer: a Canadian randomized trial with palliative care endpoints. J Clin Oncol 1996; 14:1756-1764. 2. Kantoff PW, Halabi S, Sonaway M, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol 1999; 17:2506-2513. 3. 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; 351:1502-1512. 4. 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; 351:1513-1520. 5. Berry WR, Hathorn JW, Dakhil SR, et al. Phase II randomized trial of weekly paclitaxel with or without estramustine phosphate in metastatic hormone-refractory prostate cancer. Clin Prostate Cancer 2004; 3:104-111. 6. Bubley GI, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-specific Antigen Working Group. J Clin Oncol 1999; 17:3461-3467. 7. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Soc Assoc 1958; 53:457-481. 8. 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; 17:3160-3166. 9. Hudes G, Ross E, Roth B, et al. Improved survival for patients with hormone-refractory prostate cancer receiving estramustine-based antimicrotubule therapy: final report of a Hoosier Oncology Group and Fox-Chase Network phase III trial comparing
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vinblastine and vinbalstine plus oral estramustine phosphate. Proc Am Soc Clin Oncol 2002; 21:177a (Abstract #704). Yagoda A, Watson RC, Natale RB, et al. A critical analysis of response criteria in patients with prostatic cancer treated with cis-diaminedichloride platinum II. Cancer 1979; 44:1553-1562. Miglietta L, Canobio L, Boccardo F. Assessment of response to carboplatin in patients with hormone-refractory prostate cancer: a critical analysis of drug activity. Anticancer Res 1995; 15:2825-2828. Kelly WK, Curley T, Slovin S, et al. Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer. J Clin Oncol 2001; 19:44-53. Solit DB, Morris M, Slovin S, et al. Clinical experience with intravenous estramustine phosphate, paclitaxel, and carboplatin in patients with castrate, metastatic prostate adenocarcinoma. Cancer 2003; 98:1842-1848. Urakami S, Igawa M, Kikuno N, et al. Combination chemotherapy with paclitaxel, estramustine and carboplatin for hormone refractory prostate cancer. J Urol 2002; 168:2444-2450.
15. Oh WK, Hagmann E, Manola J, et al. A phase I study of estramustine, weekly docetaxel, and carboplatin chemotherapy in patients with hormone-refractory prostate cancer. Clin Cancer Res 2005; 11:284-289. 16. Oh WK, Halabi S, Kelly WK, et al. A phase II study of estramustine, docetaxel, and carboplatin with granulocyte-colony-stimulating factor support in patients with hormone-refractory prostate cancer: Cancer and Leukemia Group B 99813. Cancer 2003; 98:2592-2598. 17. Oh WK, George DJ, Tay MH. Response to docetaxel/carboplatin in patients with hormone-refractory prostate cancer not responding to taxane-based chemotherapy. Clin Prostate Cancer 2005; 4:61-64. 18. Kelly WK, Scher HI, Mazumdar M, et al. Prostate-specific antigen as a measure of disease outcome in metastatic hormone-refractory prostate cancer. J Clin Oncol 1993; 11:607-615. 19. Verbel DA, Kelly WK, Smaletz O, et al. Estimating survival benefit in castrate metastatic prostate cancer: decision making in proceeding to a definitive phase III trial. Urology 2003; 61:142-144.
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