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Japanese Journal of Clinical Oncology Advance Access originally published online on November 2, 2006
Japanese Journal of Clinical Oncology 2006 36(12):789-793; doi:10.1093/jjco/hyl115
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© 2006 Foundation for Promotion of Cancer Research

A Randomized Trial Comparing Radical Prostatectomy Plus Endocrine Therapy versus External Beam Radiotherapy Plus Endocrine Therapy for Locally Advanced Prostate Cancer: Results at Median Follow-up of 102 Months

Koichiro Akakura1,, Hiroyoshi Suzuki1, Tomohiko Ichikawa1, Hiroyuki Fujimoto2, Osamu Maeda3, Michiyuki Usami3, Daisaku Hirano4, Yukie Takimoto4, Toshiyuki Kamoto5, Osamu Ogawa5, Yoshiteru Sumiyoshi6, Jun Shimazaki1,*, Tadao Kakizoe2,* and the Japanese Study Group for Locally Advanced Prostate Cancer{dagger}

1 Department of Urology, School of Medicine, Chiba University, Chiba
2 Urology Division, National Cancer Center Hospital, Tokyo
3 Department of Urology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka
4 Department of Urology, Nihon University School of Medicine, Tokyo
5 Department of Urology, Faculty of Medicine, Kyoto University, Kyoto
6 Shikoku Cancer Center, Matsuyama, Japan

For reprints and all correspondence: Koichiro Akakura, Department of Urology, Tokyo Kosei Nenkin Hospital, 5-1 Tsukudo-cho, Shinjuku-ku, Tokyo 162-8543, Japan. E-mail: akakurak{at}tkn-hosp.gr.jp

Received May 6, 2006; accepted August 14, 2006


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix: List of Investigators
 References
 
BACKGROUND: To investigate the optimal treatment of locally advanced prostate cancer, a prospective randomized trial was conducted to compare radical prostatectomy plus endocrine therapy versus external beam radiotherapy plus endocrine therapy.

METHODS: One hundred patients with T2b-3N0M0 prostate cancer were enrolled and 95 were evaluated. Of 95 cases, 46 underwent radical prostatectomy with pelvic lymph node dissection and 49 were treated with external beam radiation by linear accelerator with 40–50 Gy to the whole pelvis and 20-Gy boost to the prostatic area. For all patients, endocrine therapy was initiated 8 weeks before surgery or radiotherapy and continued thereafter. The long-term outcome and morbidity were examined.

RESULTS: Median follow-up period was 102 months. At 10 years overall survival rates in the surgery group were better than the radiation group (76.2% versus 71.1% for biochemical progression-free rates; P=0.25, 83.5% versus 66.1% for clinical progression-free rates; P=0.14, 85.7% versus 77.1% for cause-specific survival rates; P=0.06, and 67.9% versus 60.9% for overall survival rates; P=0.30), although none of them reached statistical significance. Erectile dysfunction was recognized in almost all patients as a result of continuous endocrine therapy. Incontinence requiring more than one pad per day was observed more frequently in the surgery group than the radiation group (P<0.01).

CONCLUSIONS: For the treatment of patients with locally advanced prostate cancer, when combined with endocrine therapy, either radical prostatectomy or external beam radiotherapy demonstrated favorable long-term outcomes. The radiation dose of 60–70 Gy might not be enough for the local treatment of locally advanced prostate cancer.

Key Words: prostate cancer • locally advanced • randomized trial • radical prostatectomy • external beam radiotherapy


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix: List of Investigators
 References
 
For the treatment of non-metastatic prostate cancer, definitive therapies such as radical prostatectomy or radiation therapy have been widely applied (1–4). Retrospective studies reported that the long-term outcomes of patients with localized and low-risk prostate cancer were equally favorable with radical prostatectomy or external beam radiation therapy (5,6). For locally advanced high risk-diseases, however, satisfactory results could not be achieved with such monotherapeutic modalities (7,8).Therefore, combination with endocrine therapy has been proposed to improve the outcomes (9,10). To investigate the optimal treatment of locally advanced prostate cancer, a prospective randomized trial was conducted to compare radical prostatectomy plus endocrine therapy versus external beam radiotherapy plus endocrine therapy (11,12). Here we report the long-term results of the trial at median follow-up of 102 months.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Appendix: List of Investigators
 References
 
A prospective randomized trial was conducted to compare radical prostatectomy versus external beam radiotherapy with a common endocrine therapy in both modalities for locally advanced prostate cancer. The design of the trial and the patient characteristics were described previously (11,12). Briefly, patients with histologically confirmed adenocarcinoma of the prostate, T2b-3N0M0 according to UICC 1987 classification (13), 75 years old or younger, and performance status of 0 or 1, were eligible. No evidence of lymph node metastasis was confirmed with CT scan in patients of the radiation group. Informed consent was obtained from all patients. Between 1989 and 1993, 100 patients were enrolled from six institutions in Japan. Five patients were excluded before randomization. After 8 weeks of neoadjuvant endocrine therapy by daily 300 mg of diethylstilbestrol, 95 patients were randomly assigned into surgery or radiation therapy. Randomization was based on stratification with institution, clinical stage and histological grade. For the surgery group, radical prostatectomy with pelvic lymph node dissection was performed. For the radiation group, irradiation by linear accelerator with a 40–50 Gy beam to the whole pelvis followed by a 20 Gy boost to the prostatic area for 6–7 weeks fractionated five times per week was carried out. Adjuvant endocrine therapy with orchiectmy or LHRH agonist with or without antiandrogen, alternatively reduced dose of estrogen, was continued until progression was evident. After the onset of progression, the choice of treatment was made according to each physician's opinion. Initial level of serum total-prostate specific antigen (t-PSA) was assayed with either Markit-F (three institutions) or Eiken (two institutions) kit. The two assay systems were known to have good correlation and show almost the same value (14).

Clinical records of the patients until the end of March 1997 were investigated and analyzed (12). Re-evaluation was performed at the end of July 2003. Three consecutive increases in serum PSA within reliable range were regarded as biochemical progression (15). Clinical progression was defined as local regrowth and/or appearance of distant metastasis. The survival rates were calculated by the Kaplan–Meier method and compared with the log-rank test. Statistical difference was examined by Student's t test and the chi-square test. Values of P less than 0.05 were considered statistically significant.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Appendix: List of Investigators
 References
 
Of the 95 evaluable patients, 46 and 49 patients were assigned into the surgery and radiation groups, respectively (Table 1). Between the two groups, there was no statistically significant imbalance of patients and disease characteristics, including age, performance status, clinical stage, histological grade and serum PSA level before treatment (Table 2). Median follow-up period was 102 months with a range of 6–178 months.


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  		Table 1. Number of patients from each institution

 

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  		Table 2. Patients' characteristics

 
For the biochemical and clinical progression-free rates, no significant difference was observed between the surgery and radiation groups (Fig. 1A and B). The surgery group tended to show better cause-specific survival rate than the radiation group (P=0.06), although the difference was not statistically significant (Fig. 2A). There was no significant difference in the overall survival rates between both groups (Fig. 2B). At 10 years, the survival rates in the surgery and radiation groups were 76.2% versus 71.1% for biochemical progression-free rates, 83.5% versus 66.1% for clinical progression-free rates, 85.7% versus 77.1% for cause-specific survival rates, and 67.9% versus 60.9% for overall survival rates, respectively.


Figure 1151
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  		Figure 1. Biochemical (A) and clinical (B) progression-free rates between surgery group (closed triangle) and radiation group (open triangle); P=0.25 (A), P=0.14 (B).

 

Figure 1152
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  		Figure 2. Cause-specific (A) and overall (B) survival rates between surgery group (closed triangle) and radiation group (open triangle); P=0.06 (A), P=0.30 (B).

 
Early and late morbidities were investigated during the time course (Fig. 3). Erectile dysfunction was seen in almost patients owing to continuous endocrine therapy. Incontinence requiring more than one pad per day was observed more frequently in the surgery group than the radiation group (P<0.01). Although micturition pain and pain on defecation were frequently seen in the radiation group for early morbidities, incidences of other morbidities were not remarkably different between the two groups.


Figure 1153
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  		Figure 3. Incidence of morbidities after therapy. The first, second, third and fourth bars represent 3 months, 1 year, 3 years and 10 years following surgery or radiation, respectively.

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Appendix: List of Investigators
 References
 
To evaluate the efficacy of distinct therapeutic modalities, several endpoints have been utilized for comparison. In the present study, biochemical and clinical progression-free rates as well as cause-specific and overall survival rates were compared between the surgery and radiation groups. Because the significance of the absolute value of serum PSA must be different following radical prostatectomy and radiation therapy (15), it would be difficult to define biochemical progression based on the common definition in the patients who had received surgery or radiation. In the present study, however, all the patients had been treated with endocrine therapy and thus three consecutive increases in serum PSA were considered as biochemical progression. Cause of death would be sometimes difficult to determine and overall survival might be less affected by the choice of treatment because intercurrent deaths are frequently observed in such an aged population of the patients. In the present study, however, all prognostic estimates including biochemical and clinical progression-free rates as well as cause-specific and overall survival rates demonstrated similar results. The previous report based on analysis of this trial at median follow-up of 58.5 months showed that radical prostatectomy combined with endocrine therapy might contribute to the survival benefit compared with radiation plus endocrine therapy (5-year cause-specific survival rates: 96.6% versus 84.6%, P=0.024) (12). On the contrary, the present analysis revealed no statistically significant difference in survivals between the two groups, probably owing to extended follow-up period. Long-term outcomes in locally advanced high-risk patients may be dependent on sensitivity to endocrine therapy rather than local therapy.

There has been accumulated evidence that radical prostatectomy, external beam radiotherapy and brachytherapy demonstrate favorable efficacy as curative therapeutic modality of prostate cancer, although it seems controversial which is superior to the others (5,6). To our knowledge, the present study is the only randomized trial to compare surgery with radiation for the management of non-metastatic locally advanced prostate cancer, except for the old trial by Paulson et al. (16). For localized low-risk diseases, either of radical prostatectomy, external beam radiotherapy or brachytherapy has been reported to be equally effective for the long-term prognosis (5,6). On the contrary, for locally advanced high-risk prostate cancer, the results have been unsatisfactory with any single treatment and there must be limitation of efficacy achieved with monotherapy. The long-term survivals with external beam radiotherapy were shown to be improved when combined with neoadjuvant and/or adjuvant endocrine therapy (17,18). However, survival benefit could not be demonstrated for radical prostatectomy with neoadjubvant endocrine therapy (19,20). It was reported that adjuvant endocrine therapy was effective to improve long-term survival for prostate cancer patients who had undergone radical prostatectomy and proved to have lymph node metastasis (21). In the present trial, radical prostatectomy was compared to external beam radiotherapy as a definitive local therapy, with a common endocrine therapy in both modalities. When the cancer extends to the bilateral lobes (T2b), accuracy of clinical diagnosis was reported to be low (0–36%) and the prognosis became poorer than that of unilateral lesions (T2a) (22). T2b cancer was therefore treated in a similar fashion to locally advanced T3 disease in the present study.

Micrometastasis in regional lymph nodes has frequently been observed in locally advanced prostate cancer. The results of definitive radiation therapy became better for patients who were surgically staged as negative for lymph node metastasis (23). Thus, in the present study, 13 patients (28%) with positive lymph node micrometastasis in 46 surgery group patients were not excluded because of justification of comparison of the two groups.

The rate of incontinence seems to be relatively high in this group operated before 1993, possibly because of difficulty of surgery and/or tumor invasion to the apex in the locally advanced disease. Recently, surgical technique has improved to reduce the incidence of incontinence. To obtain the satisfactory results with definitive external beam radiotherapy, sufficient dose of irradiation should be delivered to the prostate gland without significant morbidity of surrounding normal tissues (24). In fact, a randomized trial showed that higher dose of irradiation of 78 Gy demonstrated better biochemical failure-free rate than conventional dose of 70 Gy (62% versus 43% at 6 years in those with a pretreatment PSA of greater than 10 ng/ml) (25). Recent advancement of radiation technology, such as conformal radiotherapy, intensity modulated radiotherapy and heavy particle radiotherapy, made it possible to irradiate greater dose to the prostate without severe complication (26–28). In this context, the applied dose of irradiation in the present study might be smaller than the optimal dose. If more dose of irradiation had been applied safely, the outcomes of the radiation in the present trial would have become better.

It was reported that the patients with localized and locally advanced prostate cancer could be well controlled with endocrine therapy alone (29,30). Thus, the use of definitive local therapy is yet to be justified for the management of locally advanced prostate cancer. However, the patients who had been treated with endocrine therapy alone tended to develop local progression and symptoms during the long-term observation period (31). Therefore, the patient with locally advanced prostate cancer without distant metastasis could be considered for the definitive treatment such as radical prostatectomy and radiation therapy, unless his life expectancy would be short.

In the previous report on this trial, quality of life was compared between the two groups using the quality-of-life questionnaire, showing that the radiation group had enjoyed a better quality of life than the surgery group (12). Unfortunately, quality of life could not be analyzed in the present report because of lack of the number of available patients.

In conclusion, for the treatment of patients with locally advanced prostate cancer, when combined with endocrine therapy, either radical prostatectomy or external beam radiotherapy demonstrated favorable long-term outcomes. The radiation dose of 60–70 Gy might not be enough for the local treatment of locally advanced prostate cancer. Technical improvement of surgery and radiation would expect better outcomes in the aspect of both efficacy and morbidity for the treatment of locally advanced prostate cancer.


   Appendix: List of Investigators
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix: List of Investigators
References
 
Chiba University: S. Isaka, S. Akimoto, H. Ito

National Cancer Center: K. Tobisu

Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka: T. Kotake

Nihon University: T. Hachiya, K. Okada

Kyoto University: Y. Arai, O. Yoshida

Tokyo University: Y. Ohashi


   Acknowledgments
 
This study was supported by grants from the Ministry of Health and Welfare, Japan (1989–1991, principal investigator: T. Kakizoe; 1991–1993, principle investigator: J. Shimazaki).


   Footnotes
 
* The principal investigators. Back

{dagger} Other members are listed in the Appendix at end of paper. Back


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix: List of Investigators
 References
 
1 Epstein JI, Partin AW, Sauvageot J, Walsh PC. (1996) Prediction of progression following radical prostatectomy. A multivariate analysis of 721 men with long-term follow-up. Am J Surg Pathol 20 286–92.[CrossRef][ISI][Medline]

2 Gerber GS, Thisted RA, Scardino PT, Frohmuller HG, Schroeder FH, Paulson DF, et al. (1996) Results of radical prostatectomy in men with clinically localized prostate cancer. JAMA 276 615–9.[Abstract]

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5 Kupelian PA, Elshaikh M, Reddy CA, Zippe C, Klein EA. (2002) Comparison of the efficacy of local therapies for localized prostate cancer in the prostate-specific antigen era: a large single-institution experience with radical prostatectomy and external-beam radiotherapy. J Clin Oncol 20 3376–85.[Abstract/Free Full Text]

6 Kupelian PA, Potters L, Khuntia D, Ciezki JP, Reddy CA, Reuther AM, et al. (2004) Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy ≥72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1–T2 prostate cancer. Int J Radiat Oncol Biol Phys 58 25–33.[CrossRef][ISI][Medline]

7 van den Ouden D, Davidson PJT, Hop W, Schroder FH. (1994) Radical prostatectomy as a monotherapy for locally advanced (stage T3) prostate cancer. J Urol 151 646–51.[ISI][Medline]

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11 Isaka S, Shimazaki J, Akimoto S, Okada K, Yoshida O, Arai Y, et al. (1994) A prospective randomized trial for treating stages B2 and C prostate cancer: radical surgery or irradiation with neoadjuvant endocrine therapy. Jpn J Clin Oncol 24 218–23.[Abstract/Free Full Text]

12 Akakura K, Isaka S, Akimoto S, Ito H, Okada K, Hachiya T, et al. (1999) Long-term results of a randomized trial for the treatment of stages B2 and C prostate cancer: radical prostatectomy versus external beam radiation therapy with a common endocrine therapy in both modalities. Urology 54 313–8.[CrossRef][ISI][Medline]

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14 Kuriyama M, Akimoto S, Akaza H, Arai Y, Usami M, Imai K, et al. (1992) Comparison of various assay systems for prostate-specific antigen standardization. Jpn J Clin Oncol 22 393–9.[Abstract/Free Full Text]

15 American Society for Therapeutic Radiology and Oncology Consensus Panel. (1997) Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 37 1035–41.[CrossRef][ISI][Medline]

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17 Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff R-O, et al. (2002) Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trail. Lancet 360 103–8.[CrossRef][ISI][Medline]

18 Lawton CA, Winter K, Murray K, Machtay M, Mesic JB, Hanks GE, et al. (2001) Updated results of the phase III Radiation Therapy Oncology Group (RTOG) Trail 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 49 937–46.[CrossRef][ISI][Medline]

19 Soloway MS, Pareek K, Sharifi R, Wajsman Z, McLeod D, Wood DP Jr, et al. (2002) Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxM0 prostate cancer: 5-year results. J Urol 167 112–6.[CrossRef][ISI][Medline]

20 Klotz LH, Goldenberg SL, Jewett MAS, Fradet Y, Nam R, Barkin J, et al. (2003) Long-term followup of a randomized trial of 0 versus 3 months of neoadjuvant androgen ablation before radical prostatectomy. J Urol 170 791–4.[CrossRef][ISI][Medline]

21 Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. (1999) Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341 1781–8.[Abstract/Free Full Text]

22 Fair WR, Cookson MS, Stroumbakis N, Cohen D, Aprikian AG, Wang Y, et al. (1997) The indications, rationale, and results of neoadjuvant androgen deprivation in the treatment of prostatic cancer: Memorial Sloan–Kettering Cancer Center results. Urology 49 46–55.[Medline]

23 Akakura K, Akimoto S, Ohki T, Igarashi T, Murakami S, Shimazaki J, et al. (1994) Radiation therapy for prostate cancer confined to pelvis. Int J Urol 1 268–72.[Medline]

24 Perez CA and Michalski J. (2000) Outcome of external-beam radiation therapy for localized carcinoma of the prostate (stages T1b, T2, and T3). In Greco C and Zelefsky MJ (Eds.). Amsterdam Harwood Academic 155–84 Radiotherapy of Prostate Cancer.

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This Article
Right arrow Abstract Freely available
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