| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Trials |
Medicine [R. C. B., E. R., D. H., O. B., H-K. C., W. D. F., A. T., D. K., M. V. B.], Biostatistics and Data Management [S. M. S.], and Urologic Oncology [W. M. L.] Branches, National Cancer Institute, Bethesda, Maryland 20892; and Department of Medicine, University of Virginia, Charlottesville, Virginia 22908 [C. E. M.]
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
179,300 men and will result in death in 37,000 men (1)
. However, treatment options for metastatic prostate cancer remain limited, with disease progression being inevitable after initial hormone therapy (2)
. Despite extensive research using a variety of agents, no survival benefit has been definitively demonstrated for the treatment of hormone-refractory disease (3
, 4)
. The development of agents that target processes that are relatively unique to prostate cancer is a logical approach to the development of more effective therapies (5) . Recent advances have served to elucidate the molecular mechanisms underlying prostate cancer carcinogenesis and to guide the development of targeted therapy. Such an approach is currently being pursued by a number of investigators, with promising initial results (5, 6, 7, 8, 9, 10, 11, 12) . These approaches include targeting biochemical sites within the prostate cell nucleus, immunologically based methods, antiangiogenesis approaches, growth factor modulation, and antimetastatic approaches (5, 6, 7, 8, 9, 10) .
It has recently been shown that the estrogen agonist/antagonist, tamoxifen (1-[p-dimethylaminoethoxyphenyl]-1,2-diphenyl-1-butene), inhibits the growth of prostate cancer cells in preclinical studies (9) . Growth inhibition was not dependent upon estrogenic activity. It was, however, associated with inhibition of PKC3 (a known effect of tamoxifen), and direct activation of the TGF-ß signaling pathway, including induction of the cell cycle-inhibitory protein, p21waf1/cip1 (9 , 13 , 14) . TGF-ß plays an important role in regulating prostate cell growth; however, prostate cancer cells appear to lose their growth-inhibitory response to TGF-ß during the process of carcinogenesis (15, 16, 17, 18, 19, 20, 21, 22) . Whereas growth inhibition was only observed with tamoxifen concentrations exceeding 1 µM, prior studies have shown that micromolar concentrations can readily be attained in humans with high-dose tamoxifen therapy (23, 24, 25) . To determine whether high-dose tamoxifen therapy had activity in prostate cancer, we initiated a Phase II clinical trial in patients with hormone-refractory prostate cancer.
|
PATIENTS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Patients who were eligible for study were men who had histologically confirmed adenocarcinoma of the prostate, distant metastasis confirmed by either bone scan and/or CAT scan (i.e., stage D2 disease), and confirmed disease progression after hormone therapy. All patients had to have failed therapy with combined androgen blockade (medical or surgical castration in combination with a peripheral androgen receptor-blocking agent, such as flutamide). In addition, patients receiving androgen receptor-blocking agents as their last form of therapy had confirmed disease progression after drug withdrawal. Nonsurgically castrated patients continued to receive luteinizing hormone-releasing hormone agonist while on study. Patients had to be off other forms of therapy for at least 4 weeks prior to protocol entry.
All patients had measurable disease by either bone scan, CAT scan, or PSA. Patients whose only evidence of disease progression was PSA must have had prior evidence of metastasis by either bone scan or appropriate radiographic study. Other eligibility criteria included: Eastern Cooperative Oncology Group performance status of 0–2; preserved hematological, hepatic, and renal function; and castrate levels of serum testosterone. Patients with a history of brain metastasis, new lesions in the cortex of weight-bearing bones, or obstructive uropathy or with a QTc interval of >0.5 s on a standard 12-lead ECG were excluded.
Response Criteria.
Response to therapy was assessed every 2 months, and toxicity was assessed monthly. A complete response required resolution of all signs of disease for a duration of at least 1 month: normalization of PSA, resolution of all soft tissue lesions, and disappearance of all lesions on bone scan. A PR required a decrease by >50% of the sum of the product of the perpendicular diameters for all soft tissue lesions, a decrease in PSA by >80% for at least 1 month, or a resolution of lesions on bone scan in the absence of new lesions. PD required: a >50% increase in PSA, a >25% increase in the sum of the product of the perpendicular diameters for all soft tissue lesions, or the appearance of new lesions (either soft tissue or on bone scan). For PD to be scored by PSA criteria alone, a confirmatory PSA determination was required and obtained 2 weeks after the value representing a >50% increase. Patients who experienced decline in performance status, onset of intractable pain, renal obstruction, or spinal cord compression due to prostate cancer were also considered to have PD. Patients who had improvement in one objective parameter while meeting the criteria for PD by another parameter were scored as having PD. Patients who did not experience a response or exhibit PD were scored as having stable disease, if they remained clinically stable for a period of at least 2 months. All responses were independently confirmed by two senior staff observers.
Quality of Life Assessment.
Starting with patient 13, patients were asked to complete the Functional Living Index-Cancer questionnaire prior to receiving treatment and at the 2-month time point. The content, administration, and analysis of the Functional Living Index-Cancer were as described previously (26
, 27)
.
Treatment.
Treatment consisted of oral tamoxifen 80 mg/m2 b.i.d. (160 mg/m2/day) in the form of tamoxifen citrate (Nolvadex; Zeneca Pharmaceuticals Inc., Wilmington, DE). The first six patients entered onto study initially received 100 mg/m2 b.i.d. (200 mg/m2/day). Treatment was administered on a continuous basis, reevaluated monthly, and discontinued for toxicity higher than grade 3 (National Cancer Institute Common Toxicity Criteria) or disease progression. In patients experiencing grade 3 toxicity, drug was restarted with a 20% reduction in dose once symptoms had decreased to below grade 1. Patients experiencing grade 4 toxicity were not retreated. In three patients who experienced grade 2 gastrointestinal toxicity (i.e., vomiting), tamoxifen was administered at 40 mg/m2 four times a day (160 mg/m2/day).
Because no toxicity criteria exists for prolongation of QTc, patients with a QTc interval of >0.5 s were considered to have grade 3 toxicity. The QTc interval was determined from a standard 12-lead ECG, according to the following equation: QTc = (QT interval/square root of the r–r interval). ECGs were obtained every week for the first 4 weeks and then monthly thereafter.
Pharmacokinetics.
Tamoxifen plasma concentrations were determined as described.4
Briefly, tamoxifen was isolated from plasma by liquid-liquid extraction using methyl tert-butyl ether. Samples were then separated on a Waters Nova-Pak C-18 (3.9 x 150 mm) column (Milford, MA) using a gradient mobile phase containing acetonitrile with 0.1% triethylamine-0.05 M ammonium acetate (pH 7.0) on a Hewlett Packard 1090 Series II Liquid Chromatograph (Palo Alto, CA) equipped with a photodiode-array detector. Plasma samples were obtained pretreatment and then at each monthly clinic visit for all enrolled patients. Posttreatment plasma samples were used for estimating steady-state tamoxifen concentrations. All blood samples were taken from venous lines and collected into heparinized tubes. Plasma was stored at -70°C until analysis. Posttreatment samples were sorted based upon tamoxifen dose level, and the mean and SD were determined for each dose level.
Statistical Methods.
All patients entered onto study were formally registered, and all registered patients were included in the data analysis. Periodically, chart reviews and data entry methods were evaluated by an external panel of individuals to ensure the accuracy of data.
This study was designed as a Phase II trial, with two stages for accrual: if at least one response or stabilization was observed in the first 14 patients, then accrual would continue until at least 30 evaluable patients had been enrolled. No responses or stabilizations in the first 14 patients would have resulted in termination of accrual. Because of the two-stage design, determination of the two-sided confidence limits for the proportion with stable disease or response was determined by a method taking this design into consideration (28) . Survival and time to progression were calculated from on study date, until date of progression, death, or last follow-up. The Kaplan-Meier method was used to calculate the probability of survival or progression-free survival as a function of time (29) .
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. A total of 34 patients were enrolled onto study. Patients had a median performance status of 1 (range, 0–2) Osseous disease was present in 33 patients (97%), 10 patients (29%) had evidence of soft tissue disease, and 32 patients (94%) had an elevated PSA level. Six, 50, and 32% of patients had Gleason scores of 2–4, 5–7, and 8–10, respectively; four biopsies (12%) were from sites other than the prostate gland and were not scored. The median time from diagnosis of prostate cancer to study entry was 41 months (range, 15–184 months).
|
. All patients had received prior treatment with combined androgen blockade. Twenty-one patients (62%) received further hormone therapy (i.e., second- or third-line hormone therapy), after failing primary hormone therapy. Twenty patients (59%) had received chemotherapy, and 13 (38%) had received external beam radiation therapy for metastatic disease. Considering both hormone and chemotherapy, patients had received a median of three prior treatment regimens (range, one to eight prior regiments). In this study, patients received a total of 84 cycles (months) of therapy with tamoxifen (median, 2.3 cycles; range, 0.3–9.0 cycles).
|
. Overall, 11 patients (35%) required dose reduction due to grade 3 toxicity: 8 patients (26%) experienced ataxia only, 1 patient (3%) prolongation of QTc only, and 2 patients (6%) experienced both. The first 6 patients on study received tamoxifen at 100 mg/m2 b.i.d. (200 mg/m2/day). Three (50%) of these first six patients experienced grade 3 toxicity. Subsequent patients received tamoxifen at 80 mg/m2 b.i.d. (160 mg/m2/day), and of these, 8 patients (29%) experienced grade 3 toxicity (1 patient experienced prolongation of QTc only, 7 patients experienced ataxia only). With only one exception, grade 3 toxicities due to tamoxifen resolved within 4 days of stopping the drug.
|
All other toxicities had an unclear relationship to tamoxifen therapy. Specifically, patients were extensively counseled to report any visual changes; six such minor and transient episodes were reported. There was no clear pattern to the symptomatology, and immediate examination by an ophthalmologist failed to reveal any objective findings. Therapy was continued in all cases, and symptoms did not recur. Likewise, there was no clear pattern to neurosensory changes, which were minor in nature and variously consisted of subjective changes in taste, hearing, and distal light touch.
Pharmacokinetics.
Plasma steady-state tamoxifen concentrations as a function of dose are listed in Table 4
. Plasma concentrations from all patients who were receiving a given dose of tamoxifen for more than a month were averaged and ranged from 1.71 ± 0.27 (mean ± SD) to 2.94 ± 1.15 µM for patients receiving 90 and 200 mg/m2/day tamoxifen, respectively. There was no association between plasma tamoxifen concentration and toxicity (P = 0.44, two-sided t test; Fig. 1
). Likewise, there was no significant difference (P = 0.40) in the concentration of tamoxifen at the 1-month time point between patients who experienced PR or stable disease (2.80 ± 0.26 µM; mean ± SE) and those who experienced PD (3.20 ± 0.60).
|
|
One patient (3.3%) experienced a PR, based upon a >80% reduction of PSA for 9 months. Six patients (20%) were scored as having stable disease. The overall PR plus stable disease response rate was 23% (95% confidence interval, 10–42%). Twenty-three patients (77%) exhibited disease progression on or prior to initial restaging. With continued follow-up, 29 patients (97%) experienced disease progression. Disease progression was scored on the basis of the following: PSA (22 patients), bone scan (16 patients), soft tissue (3 patients), intractable pain (2 patients), spinal cord compression (2 patients), and hydronephrosis (1 patient). No improvement in soft tissue or osseous disease was observed. Of interest, stabilization of exponentially rising PSA was observed in six individuals, coincident with tamoxifen treatment (Fig. 2)
.
|
). At the time of analysis (June 1997), the median potential follow-up time was 28.6 months. Median survival was 10.5 months (Fig. 4)
. Currently, 7 patients (23.3%) are alive.
|
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Although tamoxifen has previously been tested in clinical studies involving patients with metastatic prostate cancer, this study differs in a number of important ways (36, 37, 38) . In prior studies, tamoxifen was used as an estrogen agonist/antagonist and, thus, was given at conventional doses. Furthermore, patients were not uniformly hormone-refractory, nor were they uniformly castrate at the time of treatment. Because estrogens, such as diethylstilbestrol, have known activity in prostate cancer through their ability to suppress testicular androgen secretion and because tamoxifen has known estrogenic agonist activity, castrate levels of testosterone are necessary to rule out a hormone-based mechanism (39) . In this study, castrate levels of testosterone were documented prior to treatment, and luteinizing hormone-releasing hormone agonists were continued for patients already on such therapy.
Prior studies suggested that patients would be able to tolerate tamoxifen at 100 mg/m2 b.i.d. (200 mg/m2/day). Trump et al. (23) reported that high-dose tamoxifen therapy was well tolerated when it was given at 150 mg/m2 b.i.d. (300 mg/m2/day) for 13 days of a 28-day treatment cycle, after an initial loading dose. In other studies, tamoxifen was administered to women with breast cancer for up to 1 year and to both men and women with renal cell carcinoma at 100 mg/m2 b.i.d. (200 mg/m2/day), and it was well tolerated (40 , 41) . In this study, three of the first six patients treated at the 100 mg/m2 b.i.d. level experienced grade 3 toxicity, and subsequent patients were, therefore, reduced to 80 mg/m2 b.i.d. (160 mg/m2/day). Differences in the study population (e.g., older males versus females) may underlie the increased toxicity observed at the 200 mg/m2/day dosing level initially used in this study. Whereas 29% of patients experienced grade 3 toxicity at the 160 mg/m2/day dosing level in this study, symptoms came on gradually, were easily detectable at early onset, and were reversible with discontinuation of drug. Steady-state plasma tamoxifen concentrations in patients receiving 160 mg/m2/day were 2.96 ± 1.32 µM and were, thus, in the range in which in vitro growth inhibition was observed (9) . Within the concentration ranges attained in this study, plasma tamoxifen concentration did not appear to correlate with either response or toxicity. However, all concentrations except one were >1 µM and were, thus, in the range in which direct growth-inhibitory effects were observed in vitro. Therefore, once micromolar concentrations are attained, other factors appear to account for differential response and toxicity.
Grade 3 toxicities were limited to those previously associated with high-dose tamoxifen therapy, namely, gait disturbances and prolongation of QTc interval (23) . Of note, the schedule of ECG monitoring used in this study to detect prolongation of QTc interval is felt to be optimal and is recommended for all patients on high-dose tamoxifen therapy. All abnormalities were detected within the first month, except in one patient, thus supporting weekly monitoring within the first month. In one patient, prolongation QTc was detected on a routine monthly ECG and appeared to be associated with binge alcohol consumption. Alcohol consumption may have altered metabolism of tamoxifen by the liver (a known site of tamoxifen metabolism) because abstinence was associated with resolution of the conduction defect once drug was restarted (38) . Whereas a retinopathy has been associated (rarely) with both conventional and high-dose tamoxifen therapy, no eye toxicity was observed in patients on high-dose tamoxifen in this study (42) .
Although not used as a criteria for scoring stable disease, a notable stabilization in the rate of PSA increase was observed coincident with commencing high-dose tamoxifen therapy. Because declines in PSA have been associated with longer survival in other clinical trials, a prospective analysis of the prognostic significance of this form of active PSA stabilization is warranted. The response rate associated with high-dose tamoxifen therapy in this study does not warrant clinical application outside of an investigational setting at this time. However, the identification of clinical activity in a heavily pretreated patient population, with therapy that was shown to directly activate TGF-ß signaling pathways in preclinical studies, identifies high-dose tamoxifen therapy as worthy of further clinical investigation. It is possible that high-dose tamoxifen therapy may be more effective in a less heavily pretreated patient population or more appropriately applied as an adjuvant to local therapy.
|
FOOTNOTES |
|---|
1 This study was supported by the United States Government. 
2 To whom requests for reprints should be addressed, at Division of Hematology/Oncology, Northwestern University Medical School, Olson Pavilion 8524, 710 North Fairbanks, Chicago, IL 60611-3008. Phone: (312) 908-5284; Fax: (312) 908-5717.
3 The abbreviations used are: PKC, protein kinase C; TGF-ß, transforming growth factor-ß; PSA, prostate-specific antigen; CAT, computer-assisted tomography; QTc, corrected QT interval; ECG, electrocardiogram; PR, partial response; PD, progressive disease; b.i.d., twice a day.
4 B. R. Simmons, R. M. Lush, N. A. McCall, and W. D. Figg, A simple analytical procedure for the quantitation of tamoxifen in human plasma using reverse-phase high performance liquid chromatography with ultraviolet detection and liquid-liquid extraction, submitted for publication.
Received 1/ 8/99; revised 5/18/99; accepted 5/25/99.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  G. Pandini, M. Genua, F. Frasca, S. Squatrito, R. Vigneri, and A. Belfiore 17{beta}-Estradiol Up-regulates the Insulin-like Growth Factor Receptor through a Nongenotropic Pathway in Prostate Cancer Cells Cancer Res., September 15, 2007; 67(18): 8932 - 8941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. I. Moreira, J. Custodio, A. Moreno, C. R. Oliveira, and M. S. Santos Tamoxifen and Estradiol Interact with the Flavin Mononucleotide Site of Complex I Leading to Mitochondrial Failure J. Biol. Chem., April 14, 2006; 281(15): 10143 - 10152. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Dehm and D. J. Tindall Editorial Commentary on Zhu et al J Androl, July 1, 2005; 26(4): 509 - 510. [Full Text] [PDF]
|
|
|
|
 |
|
 M. McNaughton-Collins, E. Walker-Corkery, and M. J. Barry Health-Related Quality of Life, Satisfaction, and Economic Outcome Measures in Studies of Prostate Cancer Screening and Treatment, 1990-2000 J Natl Cancer Inst Monographs, October 1, 2004; 2004(33): 78 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Neubauer, A. M. McNulty, M. Chedid, K. Chen, R. L. Goode, M. A. Johnson, C. D. Jones, V. Krishnan, R. Lynch, H. E. Osborne, et al. The Selective Estrogen Receptor Modulator Trioxifene (LY133314) Inhibits Metastasis and Extends Survival in the PAIII Rat Prostatic Carcinoma Model Cancer Res., September 15, 2003; 63(18): 6056 - 6062. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ferrandina, F. O. Ranelletti, L. M. Larocca, N. Maggiano, E. Fruscella, F. Legge, G. Santeusanio, A. Bombonati, S. Mancuso, and G. Scambia Tamoxifen Modulates the Expression of Ki67, Apoptosis, and Microvessel Density in Cervical Cancer Clin. Cancer Res., September 1, 2001; 7(9): 2656 - 2661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Taplin and S.-M. Ho The Endocrinology of Prostate Cancer J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3467 - 3477. [Full Text] [PDF]
|
|
|
|
|
|
L. G. Horvath, S. M. Henshall, C-S. Lee, D. R. Head, D. I. Quinn, S. Makela, W. Delprado, D. Golovsky, P. C. Brenner, G. O'Neill, et al. Frequent Loss of Estrogen Receptor-{beta} Expression in Prostate Cancer Cancer Res., July 1, 2001; 61(14): 5331 - 5335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. V. Blagosklonny and A. B. Pardee Exploiting Cancer Cell Cycling for Selective Protection of Normal Cells Cancer Res., June 1, 2001; 61(11): 4301 - 4305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-M. Lau, M. LaSpina, J. Long, and S.-M. Ho Expression of Estrogen Receptor (ER)-{{alpha}} and ER-{beta} in Normal and Malignant Prostatic Epithelial Cells: Regulation by Methylation and Involvement in Growth Regulation Cancer Res., June 1, 2000; 60(12): 3175 - 3182. [Abstract] [Full Text]
|
|
|
|
|
|
G. M. Dick, C. F. Rossow, S. Smirnov, B. Horowitz, and K. M. Sanders Tamoxifen Activates Smooth Muscle BK Channels through the Regulatory beta 1 Subunit J. Biol. Chem., September 7, 2001; 276(37): 34594 - 34599. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
, plasma concentrations from all other patients.
