Open, multi-center, phase IV study to assess the efficacy and tolerability of triptorelin in Taiwanese patients with advanced prostate cancer : Journal of the Chinese Medical Association

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Original Article

Open, multi-center, phase IV study to assess the efficacy and tolerability of triptorelin in Taiwanese patients with advanced prostate cancer

Kao, Chien-Changa; Chang, Yen-Hwab; Wu, Tonyc; Sun, Guang-Huana; Yu, Dah-Shyonga; Chang, Sun-Yrana; Cha, Tai-Lunga,*

Author Information
Journal of the Chinese Medical Association: June 2012 - Volume 75 - Issue 6 - p 255-261
doi: 10.1016/j.jcma.2012.04.010

    Abstract

    1. Introduction

    Prostate cancer remains one of the most common cancers afflicting men today. While prostate cancer rates are higher in Western countries and lower in Asian countries, the incidence of prostate cancer in Taiwan has increased dramatically in the past 20 years. In 1996, prostate cancer was Taiwan's the sixth most commonly diagnosed cancer (8.58/100,000 per year),1,2 with an annual mortality rate of 2.19/100,000 in 1992, increasing to 4.97/100,000 in 1999, and reaching 6.07/100,000 per year in 2001.3,4

    Taiwanese men have increased their dietary fat consumption in the last 20 years, which is believed to have contributed to the rapid rise in the incidence of the disease. In addition, the greater use of prostate-specific antigen (PSA) testing since its introduction in 1988 is probably the main contributing factor to the improved detection rate of prostate cancer. And further challenging medical practitioners, approximately one-half of all Taiwanese patients diagnosed with prostate cancer have locally advanced or metastatic diseases (stage III and IV) upon diagnosis.5

    More than 65 years have passed since Huggins and Hodges6,7 first treated men with prostate cancer with either orchiectomy or estrogen and suggested the use of hormone therapy for the management of advanced prostate cancer. Subsequently, androgen deprivation was shown to be effective in both delaying clinical progression and palliating symptoms of metastatic disease, becoming a mainstay of treatment for locally advanced and symptomatic metastatic disease.

    Medical castration with gonadotropin-releasing hormone (GnRH) agonists in prostate cancer patients was first reported in 1982,8 a strategy which thereafter became the most important approach for men with advanced prostate cancer.9 Long-term treatment with GnRH agonists leads to castration levels of patient testosterone within three weeks of treatment initiation. GnRH agonists usually cause a transitory rise in serum testosterone over the first two weeks of therapy that may cause tumor flare, resulting in an increase in pain and serious side effects such as urethral obstruction and paralysis in patients with extensive spinal column metastases.10 The initial surge in testosterone can be controlled by an association of an anti-androgen at initiation of the GnRH agonist.11 Randomized trials have shown that both surgical and chemical androgen ablation have a similar impact on survival in patients with stage IV PC.12

    The hypothalamic luteinizing hormone-releasing hormone (LHRH), also known as GnRH, was isolated and identified as a decapeptide in Schally's laboratory in 1971,13,14 and subsequently synthesized by Guillemin and colleagues.15 It controls the secretion of both gonadotropins from the pituitary gland, with a short native GnRH associated half-life of just 2 to 4 minutes.

    Triptorelin (D-Trp-6-LHRH) is a GnRH agonist in which the glycine at position six has been replaced with D-tryptophan.16,17 This substitution enhances resistance to degradation by endopeptidases, increases receptor binding affinity, and results in a more potent analogue of GnRH. Acute administration of triptorelin induces a rise of gonadotrophins luteinizing hormone (LH) and follicle- stimulating hormone (FSH), which in turn increases gonadal hormone production, achieving the so-called “flare up” effect, whereas prolonged administration of triptorelin results in down-regulation of the GnRH receptors in the pituitary and decreased secretion of luteinizing hormone. The outcome is a decreased production of testosterone by Leydig cells. This chemical, reversible castration is the basis for the use of GnRH analogues to treat androgen dependent-cancers such as prostate cancer.

    Pharmacokinetic studies show that, after a first plasma surge occurring 2.5 to 3.6 hours after injection and a second rise between Day 17 and Day 31, the mean triptorelin plasma level is stable (0.03 to 0.06 ng/ml) and maintained until day 91. Studies have shown the efficacy and safety of the monthly injected form of triptorelin as well as the 3-month sustained release form in advanced prostate carcinoma. Castration levels of testosterone are obtained in the first weeks of treatment and maintained in all patients for the duration of treatment. Triptorelin is an effective endocrine therapy for advanced prostate carcinoma, avoiding the psychological impact of surgical castration.18,19

    In this study we investigated the effect of the sustained release formulation of triptorelin (Diphereline prolonged release (PR) 11.25 mg) on men from Taiwan with advanced and metastatic prostate cancer.

    2. Methods

    2.1. Study design

    This was a multicenter and open labeled study designed to investigate the efficacy and safety of three-month treatment with Diphereline PR 11.25 mg in men with advanced prostatic cancer in Taiwan. This open labeled study was passed through each Internal Review Board, and then those patients also signed informed consent before receiving treatment.

    2.2. Inclusion and exclusion criteria

    Inclusion criteria were de novo or untreated male patients age ≥ 18 years; histologically-proven prostate cancer with locally advanced or metastatic diseases amenable to hormonal therapy; serum PSA levels ≥ 5 ng/ml; testosterone concentration within the normal laboratory ranges, or testosterone concentration lower than normal range but higher than 0.5 ng/ml that investigator considered the subject could be recruited for treatment (documented within 4 weeks in advance of inclusion); life expectancy of more than nine months; Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; and informed consent in writing.

    Exclusion criteria were previous surgical castration or low testosterone levels (< 0.5 ng/ml); patient at risk of a serious complication in the case of tumor flare (especially patients having vertebral metastases with spinal cord compression or with significant obstructive uropathy); previous administration of a GnRH agonist, estrogens or anti androgens, concomitant treatment with coumarin- or indanedione- derivatives;history of hypersensitivity to GnRH analogues or to any of the ingredients;patient having received an unlicensed drug, within the last 30 days; any significant medical or psychiatric condition that might prevent the patient from complying with the study procedures; other known associated malignancy (except curatively treated basal skin carcinoma); or patient unwilling to comply fully with the protocol.

    2.3. Patient disease status at baseline

    Five patients in the intent-to-treat population had previously had surgery for advanced prostate cancer. Four patients were classified as tumor, lymph node, and distant metastasis (TNM) Stage III and 36 patients as TNM Stage IV (AJCC 7th edition). Twenty-four patients had bone metastases.

    2.4. Hormone therapy protocol

    The suspension of the drug was prepared immediately before the intramuscular injection, according to the manufacturer's instructions. All eligible patients received two injections of triptorelin 11.25 mg on baseline and on Day 90, and bicalutamide 50 mg once daily for 28 days starting 7 days before the first injection of triptorelin 11.25 mg.

    2.5. Primary and secondary objectives

    The primary objective was to evaluate the efficacy of triptorelin based on the percentage of patients with a testosterone concentration of ≤5 ng/ml on Day 90. The secondary objectives were to investigate the effect of triptorelin on clinical symptoms and quality of life; PSA concentrations on Days 90 and 180; the development of bone metastases; maintenance of castration based on percentage with testosterone concentrations ≤0.5 ng/ml on Day 180; efficacy of triptorelin, based on the percentage of patients presenting with testosterone concentrations≤0.2 ng/ml on Day 180; disease progression on Day 180, and tolerability.

    2.6. Assessments

    Testosterone and PSA concentrations were measured on Days 90 and 180. Clinical symptoms were recorded on Days 0, 90, and 180. Bone scintigraphy was used to assess bone metastases at baseline and at the end of study (on Day 180). Disease progression was measured either by the development of new metastatic lesions in bone, or clinical evaluation during the study period or death. To assess the effect of triptorelin on quality of life, all men answered the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire QLQ-C30, version 3.0, a cancer-specific questionnaire, at baseline and at the end of study.

    2.7. Safety evaluation

    All adverse events were recorded by the patient or monitored by the investigator throughout the study and were coded using the 12th Quarter Medical Dictionary for Regulatory Activities (MedDRA 12.0). On October 2009, International Conference on Harmonisation (ICH) used MedDRA 12.0 to application to adverse drug reaction/ adverse events & medical and social history and indication.

    2.8. Statistical methods and analysis

    Three data sets (safety, intent-to-treat, per-protocol) were introduced for statistical analysis. The safety population consists of patients who had received at least one injection of triptorelin at 11.25 mg. The intent-to-treat (ITT) population consisted of patients who had received at least one dose of triptorelin 11.25 mg and who provided any follow-up data for one or more key efficacy variables. The per-protocol (PP) population consists of patients who had received at least one dose of triptorelin 11.25 mg and followed the protocol without any major deviations.

    The analyses of the safety data were performed based on the safety population. The primary analysis based on the primary efficacy endpoint, the percentage of patients presenting a testosterone level ≤0.5 ng/ml on Day 90, was performed on the ITT population. In addition, the PP population was performed as secondary. Other analyses on the secondary efficacy endpoints were performed on ITT and PP populations.

    The primary and secondary efficacy analyses were performed based on both the ITT and PP populations. The last-observation-carried-forward (LOCF) approach was used to evaluate missing data. All statistical tests were to be two-sided which was evaluated at 5% level significance. As for the dichotomous variables, the 95% confidence interval corresponding to the incidence was calculated using Clopper-Pearson method. For all continuous parameters, descriptive statistics such as number of observations, mean, median, standard deviation, minimum, maximum, upper and lower quartile were calculated. The changes (and percentage changes) from baseline at each evaluation time in the PSA level were analyzed by using paired t-test. The number and percentage of patients who experience adverse events were summarized. Descriptive analysis of laboratory tests was presented. The number and percentage of patients who experience potentially clinically significant changes in laboratory results, and those who discontinue, were also tabulated.

    3. Results

    3.1. Patient selection

    A total of 44 patients were screened from three medical centers (Tri-Service General Hospital, Taipei Veterans General Hospital, and Kaohsiung Veterans General Hospital, Taipei, Taiwan, R.O.C.). The first patient was screened on February 19, 2008, and the last patient was screened on October 15, 2008. Three patients became ineligible after the screening period; therefore, at total of 41 patients were treated with triptorelin 11.25 mg. The last patient visit took place on April 8, 2009. Thirty-eight of the 41 patients (92.7%) completed the 6 month-study period (Fig. 1).

    F1-4
    Fig. 1:
    Flow diagram of patient progress through the trial.

    3.2. Demographic and baseline characteristics

    Summary statistics of demographic characteristics for all patients of ITT (40 patients) and PP (38 patients) population are listed in Table 1. Results in the PP population were similar to the ITT population (Table 1).

    T1-4
    Table 1:
    Summary of demographic and baseline characteristics.

    3.3. Disease characteristics

    Details of disease characteristics, including previous treatment, classification, and bone metastasis sites, are summarized in Table 2. Among the ITT population, 5 of 40 (12.5%) patients had previous surgical treatment for his their advanced prostate cancer. Four patients were classified as Stage III and 36 patients as Stage IV. Twenty-four (60%) had bone metastasis. Pelvis, ribs, and spinal column were the most frequent sites of bone metastasis, followed by lower limbs, upper limbs and skull (Table 2).

    T2-4
    Table 2:
    Characteristics of the ITT population.

    3.4. Efficacy

    On Day 90, 39 men (97.5%) had reduced their testosterone concentration to ≤ 0.5 ng/ml, and all men had a testosterone concentration of ≤ 0.5 ng/ml on Day 180 (Fig. 2). Twenty-nine men (72%) had a testosterone concentration of 0.2–0.5 ng/ml on Day 90, and 30 men (75%) had a testosterone concentration of 0.2-0.5 ng/ml on Day 180. On both Days 90 and 180, 10 men (25%) had a testosterone concentration of ≤ 0.2 ng/ml.

    F2-4
    Fig. 2:
    Testosterone concentrations at Days 0, 90, and 180.

    Treatment with triptorelin reduced the median PSA concentration from 122.69 ng/ml at baseline to 10.40 ± 23.42 ng/ml on Day 90, and to 11.49 ± 23.40 ng/ml on Day 180 (Fig. 3). This amounts to a 99.2% (CI: 98.3–99.4) reduction on Day 90 and a 99.2% (CI: 98.6–99.6) on Day 180.

    F3-4
    Fig. 3:
    PSA concentrations at Days 0, 90, and 180. PSA = prostate-specific antigen.

    The incidence of clinical symptoms (such as dysuria, pollakiuria, hematuria, urinary retention, urinary incontinence, asthenia, and localization of pain) was reduced on Day 90 and further reduced on Day 180 (Table 3). Sexual dysfunction evaluation was only available for eight patients: one patient reported sexual dysfunction that was resolved on Day 180.

    T3-4
    Table 3:
    Effect of treatment with Triptorelin on clinical symptoms after 90 and 180 days.

    At baseline, 24 (60%) of men had bone metastases, which dropped to 23 (57.5%) patients by the end of the study. The most frequently reported sites at the end of the study were the same as baseline (pelvis, ribs and spinal column). Eight patients (20%) developed new lesions during the study. One patient had a complete response to the metastases lesion on his spinal column by the end of study. Eight patients had new lesions found during bone scintigraphy during the study, and one patient had disease progression judged by clinical evaluation giving a disease progression rate of 22.5% (95% CI: 10.84–38.45).

    Treatment with triptorelin increased global health status significantly from 59.58 ± 24.72 at baseline to 66.46 ± 17.24 at the end of the study (p < 0.05). All domains on the functional scale (such as physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning) increased. Patients showed a decrease in score of most domains on the symptom scale (that is, a decrease in symptoms), with the results reaching significance for fatigue, pain and appetite loss (p < 0.05).

    3.5. Safety

    Of the 41 patients analyzed for safety, 25 (61.0%) experienced at least one adverse event during the 6-month study period. The most frequently reported adverse events were constipation (9.8%), diarrhea (7.3%), and dysuria (7.3%) (Table 4). One patient had an allergic reaction that caused him to drop out. Three other patients experienced serious adverse events; in one of these men their disease progressed leading to death. The patient that died had extremely low PSA (0.05 ng/mL) and testosterone (0.23 ng/mL) levels.

    T4-4
    Table 4:
    Treatment-emergent adverse events.

    3.6. Tolerability

    In general, triptorelin was well tolerated. On Day 90 patients reported the following: hot flushes (n = 2; 4.9%); decrease of libido (n = 2; 4.9%); impotence (n = 3; 7.3%); gastric pain (n = 1; 2.4%); and nausea (n = 1; 2.4%). At the end of the study patients reported decrease of libido (n = 2; 4.9%), impotence (n = 3; 7.3%), and transient and spontaneously resolving high blood pressure (n = 1; 2.4%).

    3.7. Laboratory tests

    Platelets, overall white blood cell, monocyte and basophil count were reduced significantly by the end of the study (p < 0.05). Significant changes were also seen in phosphate, uric acid, and ALT. All of these changes were minor and none was clinically significant.

    4. Discussion

    In this study, we showed that the sustained release formulation of triptorelin 11.25 mg was effective in reducing testosterone and PSA levels significantly, as well as reducing clinical symptoms. One patient had a complete response at the end of the study. Treatment with triptorelin also resulted in improvement of quality of life scores, with significant improvement in emotional functioning pain and appetite loss. During the study nine patients developed new lesions, giving a progression rate of 22.5%.

    The most commonly seen adverse event was gastrointestinal disturbance including abdominal pain, diarrhea and constipation, which did not need medication and recovered spontaneously. The withdrawal rate as a result of adverse events was 2.5%; this included one patient who had allergic reaction that caused him to drop out of the study. It is not know whether the reaction was caused by triptorelin. Triptorelin, like all GnRH agonists, acts by initially stimulating the pituitary cells to release follicle-stimulating hormone and luteinizing hormone, but chronic use desensitizes the pituitary GnRH, resulting in the shutdown of LH and FSH production and the suppression of testosterone production in the testes. Hormone therapy for prostate cancer results in regression, improvement in bone pain, lower urinary tract symptoms and quality of life.20 For registration studies GnRH inhibitors are required to achieve a serum testosterone level of 0.5 ng/mL, a castration level of testosterone on Day 29, and to maintain castration concentrations while on long-term therapy. The reduction in and maintenance of castration concentrations of testosterone on Day 180 triptorelin in this study confirms the efficacy of triptorelin in Taiwanese men.

    Serum PSA concentrations are used to measure disease progression in prostate cancer. In this study triptorelin reduced PSA by over 99% in men with prostate cancer, suggesting disease regression. Indeed a disease progression rate of 22.5% was seen. Eight patients developed new bone lesions during the study. The survival rate was 97.5% within the six-month period of this study. Because of the shortness of the study, it is not possible to compare survival, or time to treatment failure with other studies in the literature. However triptorelin has previously been shown to have a nine-month survival rate of 97%, significantly higher than leuprolide with a survival rate of 90.5%.20 Triptorelin may also more reliably maintain castration concentrations of testosterone than leuprolide.20

    In conclusion, triptorelin 11.25 mg is effective in decreasing and maintaining serum testosterone to castration level for a period of three months. Significant reduction of serum PSA levels was also seen in most patients, suggesting that their disease is under control. Adverse events were mild and self-limiting, except for one patient who had serious allergic reaction. In conclusion, triptorelin 11.25 mg is an effective, and convenient GnRH agonist for the treatment of advanced and metastatic prostate cancer with a good safety and tolerability profile.

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    Keywords:

    advanced prostate cancer; efficacy; triptorelin

    © 2012 by Lippincott Williams & Wilkins, Inc.