© 2005 Foundation for Promotion of Cancer Research
Clinical Trial Note |
Randomized Controlled Trial to Evaluate Radiotherapy ± Endocrine Therapy Versus Endocrine Therapy Alone for PSA Failure after Radical Prostatectomy: Japan Clinical Oncology Group Study JCOG 0401
1 Department of Urology, Graduate School of Medical Science, Kyushu University, Fukuoka, 2 Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, 3 Radiation Oncology Division, National Cancer Center Hospital East, Kashiwa, Chiba, 4 Department of Urology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa and 5 Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka, Japan
For reprints and all correspondence: Seiji Naito, Department of Urology, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: naito{at}uro.med.kyushu-u.ac.jp
Received July 9, 2004; accepted November 3, 2004
 |
Abstract |
|---|
 TOP Abstract PROTOCOL DIGEST OF THE...PARTICIPATING INSTITUTIONS (FROM...References |
|---|
A randomized controlled trial has started in Japan to evaluate radiotherapy and endocrine therapy for prostate-specific antigen (PSA) failure after radical prostatectomy. Patients who have PSA failure after radical prostatectomy for localized prostate cancer (T1–2N0M0) are randomized into treatment groups of either radiotherapy ± endocrine therapy or endocrine therapy alone. The Urologic Oncology Study Group (UOSG) in the Japan Clinical Oncology Group (JCOG) composed of 36 specialized institutions will recruit 200 patients. The primary end-point is time to treatment failure (TTF) of bicalutamide, and secondary end-points are TTF of protocol treatment, progression-free survival, overall survival, adverse events and quality of life (QOL). The Clinical Trial Review Committee of the JCOG approved the protocol on April 13, 2004, and the study was activated on May 17, 2004.
Key Words: prostate cancer • prostatectomy • PSA failure • endocrine therapy • radiation
|
PROTOCOL DIGEST OF THE JCOG 0401 |
|---|
|
TOPAbstractPROTOCOL DIGEST OF THE...PARTICIPATING INSTITUTIONS (FROM...References |
|---|
TRIAL BACKGROUNDS
In spite of improvements in both the detection of early prostate cancer and surgical techniques,
35% of men develop prostate-specific antigen (PSA) failure after radical prostatectomy (1). Most of the recurrences after radical prostatectomy are detected only by a rise in the PSA level (2). Those who have local recurrence may benefit from radiation therapy, whereas those who have metastatic disease may benefit from systemic treatment, the most common of which is androgen deprivation (2). As computed tomography (CT) scans or bone scans usually cannot detect the recurrent sites, a standard has not yet been established for the treatment of PSA failure after prostatectomy.
PURPOSE
The purpose of the trial was to evaluate radiotherapy ± endocrine therapy in comparison with endocrine therapy alone for PSA failure after radical prostatectomy.
STUDY SETTING
The study was a multi-institutional (36 specialized centers), randomized controlled trial.
RESOURCES
The study was supported by Health Sciences Research Grants for Clinical Research for Evidenced Based Medicine and Grants-in-Aid for Cancer Research (14S-4), from the Ministry of Health, Labor and Welfare, Japan.
END-POINTS
In general, overall survival (OS) is supposed to be the best primary end-point to compare the clinical advantage in randomized trials. However, the 10 year overall survival rate is expected to be >80% in this study, therefore OS will not be a good candidate for the primary end-point. The clinical progression-free survival is also not adequate as the primary end-point for the same reason. Regarding ‘PSA failure’, it may be a potential candidate for the primary end-point, but PSA failure will occur at least three times more frequently in the experimental arm, which causes confusion in evaluation. Therefore, the adequate primary end-point would be time to treatment failure (TTF) of luteinizing hormone-releasing hormone (LH-RH) analog as a hormone-refractory state of prostate cancer. As the TTF of bicalutamide can be evaluated more quickly than that of LH-RH analog and thus should be its good surrogate end-point, the TTF of bicalutamide is selected as a primary end-point in this study. In summary, the primary end-point is the TTF of bicalutamide, and secondary end-points are TTF of protocol treatment, clinical progression-free survival, OS, adverse events and patient-reported quality of life (QOL).
ELIGIBILITY CRITERIA
Tumors are staged according to the General Rule for Clinical and Pathological Studies on Prostate Cancer (Japanese Urological Association, The Japanese Society of Pathology), which is the 1997 revision of the TNM Classification of Malignant Tumours by the International Union Against Cancer (UICC) (3).
INCLUSION CRITERIA
(i) A diagnosis of localized prostate cancer (clinical stage T1–2N0M0) which was treated by radical prostatectomy; (ii) pathological stage: pT0/2/3 and pN0/x; (iii) the serum level of PSA once it has reached <0.1 ng/ml after radical prostatectomy and then increased to 
0.4 ng/ml; (iv) a serum level of PSA 
1.0 ng/ml at study entry; (v) no clinical recurrence based on abdominal and pelvic CT, and a bone scan; (vi) no history of chemotherapy, radiation therapy or endocrine therapy for any cancer; (vii) age 20 and 79 years; (viii) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (ix) no blood transfusion within 28 days of entry; (x) sufficient organ function within 28 days of entry; and (xi) written informed consent.
EXCLUSION CRITERIA
(i) Synchronous or metachronous (within 5 years) malignancy other than carcinoma in situ; (ii) mental disease or mental symptoms which would affect the participant's decision to participate; (iii) continuous medication of steroids (exclude external use of steroids for skin); (iv) ischemic heart disease or arrhythmia which needs medical treatment; (v) poorly controlled hypertension; (vi) poorly controlled diabetes mellitus; (vii) history of cerebral infarction or myocardial infarction within 6 months; (viii) liver cirrhosis; and (ix) interstitial pneumonia which requires ventilation assistance, oxygen inhalation, steroids or diuretic medicine.
RANDOMIZATION
Using telephone or fax contact with the JCOG Data Center after confirmation of the above criteria, patients are randomized by the minimization method of balancing the groups according to the Gleason score of the radical prostatectomy specimen, period from operation to PSA failure, and institution.
TREATMENT METHODS
Endocrine therapy alone group (standard arm). The protocol treatment includes the bicalutamide medication (80 mg/day). After TTF of bicalutamide, it is followed by LH-RH analog (leuprorelin acetate 3.75 mg/4 weeks or 11.25 mg/12 weeks, goserelin acetate 3.6 mg/4 weeks or 10.8 mg/12 weeks).
Radiotherapy ± endocrine therapy group (experimental arm). The total dose of 64.8 Gy/36 Fr (50 days) external beam irradiation is delivered to the prostatic bed. If the patient has no treatment failure, no additional therapy will be given. In case of treatment failure of radiation therapy, bicalutamide medication will be started in the same way as in the standard arm. After the treatment failure of bicalutamide, a LH-RH analog is given to the patients as in the case of endocrine therapy alone.
DEFINITION OF TREATMENT FAILURE
- PSA increase beyond 0.4 ng/ml if previous value is <0.4 ng/ml
- Any PSA increase if previous value is 0.4 ng/ml
- Clinical progression or clinical recurrence
- Adverse event
- Patient refusal to continue treatment
- Any cause of death
- Poor compliance (less than two-thirds of planned dose) of oral bicalutamide at two consecutive visits (only for bicalutamide treatment failure)
FOLLOW-UP
All patients are followed-up by their urologist at least every 3 months for more than 5 years. Blood tests including PSA and urinalysis are performed during the follow-up interval. Abdominal and pelvic CT, chest X-ray and bone scan are carried out every 12 months. The symptoms and adverse events are surveyed at each visit.
STUDY DESIGN AND STATISTICAL METHODS
This trial is designed to evaluate the superiority of radiotherapy ± endocrine therapy to endocrine therapy alone in terms of the TTF. Almost half of the patients can be cured by radiation therapy alone (4–6), therefore, these patients are expected to have a greatly prolonged TTF after radiation (radiation responder). In contrast, the other half of the patients irradiated are expected to have a treatment failure of radiation therapy (non-responder) and they will have a TTF not significantly shorter than that of those on bicalutamide therapy. In the standard arm, there have been no published data concerning the TTF of bicalutamide for PSA failure after radical prostatectomy. Therefore, we assumed the TTF of bicalutamide therapy in this study to be 4–5 years, based on the report in which the median TTF of bicalutamide therapy for localized prostate cancer was 63.5 months (7). The median TTF in the experimental arm can be calculated on the assumption that the TTF in a radiation responder (50% of the experimental arm) is prolonged three times more than in the non-radiation responders (50% of the experimental arm). Therefore, the median TTF in the experimental arm will be 6.6 years (4.0 years in non-responders and 12.0 years in responders) and 8.3 years (5.0 years in non-responders and 15.0 years in responders). We calculated sample sizes based on Shoenfeld and Richter's methods (8) with 5 year follow-up after 4 years of accrual. If the TTF in the standard arm is 4.0 years, the detectable difference in TTF and sample size per arm will be 2.6 years and 83 cases, respectively. If TTF in the standard arm is 5.0 years, the detectable difference in TTF and sample size per arm will be 3.3 years and 93 cases, respectively. This will provide an 80% power to detect the difference between the assumed TTF in the experimental arm and the TTF in the standard arm (non-responder in the experimental arm compatible) at a 5% one-sided alpha level. Based on these data, the planned sample size is 100 cases in one arm.
QOL
All the patients are enrolled prospectively in a QOL survey using a validated assessment tool and are evaluated before the treatment and 1-year after the treatment. The health-related QOL is assessed using the Japanese version of the RAND Health-Item Short Form 36 (SF-36) version 2.0 (9), and cause-specific QOL is analyzed by the UCLA Prostate Cancer Index which was established by Litwin et al. (10). The Japanese version of SF-36 and that of UCLA PCI were assessed as described previously (11–13).
INTERIM ANALYSIS AND MONITORING
An interim analysis is planned to be performed once, taking into account multiplicity using the Lan and DeMets approach. The Data and Safety Monitoring Committee (DSMC) of the JCOG independently reviews the interim analysis report, and an early termination of the trial may be considered at that stage. In-house interim monitoring is performed by the Data Center to ensure data submission, patient eligibility, protocol compliance, safety and on-schedule study progress. The monitoring reports are submitted to and reviewed by the UOSG and the DSMC every 6 months.
|
PARTICIPATING INSTITUTIONS (FROM NORTH TO SOUTH) |
|---|
|
TOPAbstractPROTOCOL DIGEST OF THE...PARTICIPATING INSTITUTIONS (FROM...References |
|---|
Hokkaido University, Sapporo Medical University, Tohoku University, Miyagi Cancer Center, Akita University, Tsukuba University, Tochigi Cancer Center, Gunma University, Chiba Cancer Center, Chiba University, National Cancer Center Hospital, Tokyo Women's Medical School, Keio University, The Jikei University, Nippon Medical School, Kitasato University, Niigata Cancer Center Hospital, Niigata University, Yamanashi University, Shinshu University, Hamamatsu Medical School, Shizuoka Cancer Center, Nagoya University, Mie University, Kyoto University, Osaka Medical Center for Cancer and Cardiovascular Diseases, Kobe University, Nara Medical University, Shimane University, Kurashiki Central Hospital, Okayama University, Kagawa University, National Shikoku Cancer Center, Kyushu University, Kurume University and Kagoshima University.
A. Yokomizo, Study Coordinator; H. Kawamoto, Protocol Coordinator; K. Nihei, Radiation Oncology Study Coordinator; N. Ishizuka, Study Statistician; Y. Kakehi, QOL Coordinator; K. Tobisu, Chair of Urologic Oncology Study Group; S. Naito, Study Chair.
|
References |
|---|
|
TOPAbstractPROTOCOL DIGEST OF THE...PARTICIPATING INSTITUTIONS (FROM...References |
|---|
1 Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. J Am Med Assoc 1999;281:1591–7.
2 Carroll P. Rising PSA after a radical treatment. Eur Urol 2001;40:Suppl 2:9–16.
3 International Union Against Cancer, Urological tumours. In: Sobin LH, Wittekind C, editors. TNM Classification of Malignant Tumours, 5th edn. New York: Wiley-Liss 1997;170–3.
4 Morris MM, Dallow KC, Zietman AL, Park J, Althausen A, Heney NM, et al. Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 1997;38:731–6.[CrossRef][Medline]
5 Pisansky TM, Kozelsky TF, Myers RP, Hillman DW, Blute ML, Buskirk SJ, et al. Radiotherapy for isolated serum prostate specific antigen elevation after prostatectomy for prostate cancer. J Urol 2000;163:845–50.[CrossRef][Web of Science][Medline]
6 Anscher MS, Clough R, Dodge R. Radiotherapy for a rising prostate-specific antigen after radical prostatectomy: the first 10 years. Int J Radiat Oncol Biol Phys 2000;48:369–75.[CrossRef][Web of Science][Medline]
7 Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Van Poppel H, Tammela TL, et al. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol 2000;164:1579–82.[CrossRef][Web of Science][Medline]
8 Shoenfeld DA, Richter JR. Nomograms for calculating the number of patients needed for a clinical trial with survival as an endpoint. Biometrics 1982;38:163–70.[CrossRef][Web of Science][Medline]
9 Ware JE, Kosinski M, Turner-Bowker DM, Gandek B. How to Score Version 2 of the SF-12® Health Survey (With a Supplement Documenting Version 1). Lincoln, RI: Quality Metric Incorporated, 2002.
10 Litwin MS, Hays RD, Fink A, Ganz PA, Leake B, Brook RH. The UCLA Prostate Cancer Index: development, reliability, and validity of a health-related quality of life measure. Med Care 1999;36:1002–12.
11 Fukuhara S, Ware JE Jr, Kosinski M, Wada S, Gandek B. Psychometric and clinical tests of validity of the Japanese SF-36 Health Survey. J Clin Epidemiol 1998;51:1045–53.[CrossRef][Web of Science][Medline]
12 Kakehi Y, Kamoto T, Ogawa O, Arai Y, Litwin MS, Suzukamo Y, et al. Development of Japanese version of the UCLA Prostate Cancer Index: a pilot validation study. Int J Clin Oncol 2002;7:306–11.[Medline]
13 Suzukamo Y, Kakehi Y, Kamoto T, Arai Y, Ogawa O, Fukuhara S. Translation and adaptation of the UCLA prostate cancer index for use in Japan. Nippon Hinyokika Gakkai Zasshi 2002;93:659–68 (in Japanese).[Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Naito Evaluation and Management of Prostate-specific Antigen Recurrence After Radical Prostatectomy for Localized Prostate Cancer Jpn. J. Clin. Oncol., July 1, 2005; 35(7): 365 - 374. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||