International Journal of Clinical Oncology

, Volume 15, Issue 6, pp 571–577

Long-term outcomes of three-dimensional conformal radiation therapy combined with neoadjuvant hormonal therapy in Japanese patients with locally advanced prostate cancer

Authors

  • Masato Sakamoto
    • Department of Radiation Oncology and Image-Applied TherapyKyoto University Graduate School of Medicine
    • Department of RadiologyJapanese Red Cross Society Wakayama Medical Center
    • Department of Radiation Oncology and Image-Applied TherapyKyoto University Graduate School of Medicine
  • Michihide Mitsumori
    • Department of Radiation Oncology and Image-Applied TherapyKyoto University Graduate School of Medicine
  • Kenji Takayama
    • Department of Radiation Oncology and Image-Applied TherapyKyoto University Graduate School of Medicine
  • Keisuke Sasai
    • Department of RadiologyJuntendo University School of Medicine
  • Yoshiki Norihisa
    • Department of Radiation Oncology and Image-Applied TherapyKyoto University Graduate School of Medicine
  • Toshiyuki Kamoto
    • Department of UrologyKyoto University Graduate School of Medicine
  • Eijiro Nakamura
    • Department of UrologyKyoto University Graduate School of Medicine
  • Osamu Ogawa
    • Department of UrologyKyoto University Graduate School of Medicine
  • Masahiro Hiraoka
    • Department of Radiation Oncology and Image-Applied TherapyKyoto University Graduate School of Medicine
Original Article

DOI: 10.1007/s10147-010-0109-y

Cite this article as:
Sakamoto, M., Mizowaki, T., Mitsumori, M. et al. Int J Clin Oncol (2010) 15: 571. doi:10.1007/s10147-010-0109-y

Abstract

Background

The outcomes of three-dimensional conformal radiation therapy (3D-CRT) combined with neoadjuvant hormonal therapy (NAHT) in Japanese patients with locally advanced prostate cancer who initiated salvage hormonal therapy (SHT) at a relatively early phase were evaluated.

Methods

Between April 1998 and April 2003, 70 Japanese patients with T3N0M0 prostate cancer who received radical 3D-CRT treatment were evaluated. The median age, initial prostate-specific antigen (PSA) level, and duration of NAHT were 73 years old, 26.3 ng/ml, and 4 months, respectively. Seventy grays were given in 35 fractions that were confined to the prostate and seminal vesicles. Adjuvant hormonal therapy was not administered after 3D-CRT in any of the cases.

Results

The median follow-up period was 64.9 months. The median PSA value at the time of initiation of SHT was 5.0 ng/ml (range 0.1–21.6 ng/ml). Overall, disease-specific, PSA failure-free (based on the Phoenix definition) and SHT-free survival rates at 5 years were 90.3% (95% CI 86.5–94.0), 96.5% (94.0–98.9), 60.5% (48.2–72.7), and 63.5% (57.2–69.8), respectively. Therefore, two-thirds of the patients were still hormone-free at 5 years.

Conclusions

PSA control rates in our series of Japanese patients with stage T3N0M0 prostate cancer treated with the standard dose of 3D-CRT combined with NAHT seemed higher than expected. This approach involving 3D-CRT combined with NAHT with the initiation of SHT at PSA values of around 5 ng/ml may be one option for Japanese patients with locally advanced prostate cancer, although further prospective study is required to confirm the validity.

Keywords

Prostate cancerNeoadjuvant hormonal therapyThree-dimensional conformal radiation therapyPSA failureSalvage hormonal therapy

Introduction

Prostate cancer is the most common form of cancer in men in the USA, with 218,890 cases diagnosed and 27,050 deaths annually [1]. This disease ranks first in morbidity rate and second in mortality rate among males in the USA [2]. On the other hand, among Japanese males, prostate cancer ranks sixth and eighth in morbidity and mortality rates, respectively [3, 4]. However, both rates have been increasing rapidly in recent years [5, 6].

Moreover, in Europe and the USA, most patients newly diagnosed with prostate cancer are at the T1-2N0M0 stage. In contrast, a significant number of locally advanced cases are still encountered in Japan, accounting for about 35% of all prostate cancer cases in Japan in 2000 [6]. Therefore, research into better treatment for stage T3-4N0M0 prostate cancer has immense significance for Japanese males in particular.

As the outcomes of radical prostatectomy in patients with locally advanced (stage T3N0M0) prostate cancer are considerably inferior to those for patients with stage T1-2N0M0 disease [7], external beam radiotherapy (EBRT) combined with hormonal therapy (HT) is recommended as the first choice for treating patients with locally advanced (stage T3N0M0) prostate cancer [8, 9]. In addition, a combination of long-term adjuvant hormonal therapy (AHT) with EBRT is recommended based on the results of a randomized trial [1012].

However, it has not been proven that the findings described above can be also applied to the Japanese (Asian) population. This is because Japanese urologists generally tend to readily administer HT, even after giving definitive treatment, and the effects of HT may differ in the Japanese population [6, 13]. In addition, there have been very few reports regarding the outcome of EBRT when it is not used in combination with long-term AHT in cases of prostate cancer among Japanese male. At Kyoto University Hospital, we applied EBRT via the three-dimensional conformal radiotherapy (3D-CRT) technique in conjunction with neoadjuvant hormonal therapy (NAHT) in patients with stage T3N0M0 prostate cancer without any AHT. We reported the outcomes for patients treated with this strategy involving strict adherence to our protocol of 3 months of NAHT [14]. However, a considerable number of the patients treated at our institution were referred from other institutions and had already been administered HT for more than 3 months.

Therefore, in the present study, a retrospective evaluation of outcomes of patients treated consecutively with 3D-CRT combined with NAHT for stage T3N0M0 prostate cancer at a single institution was performed to demonstrate the prognostic outcomes of Japanese patients not given AHT.

Patients and methods

Patient characteristics

Between April 1998 and April 2003, 177 Japanese men with T1-4N0M0 (according to the classification of the International Union Against Cancer: UICC ’97) prostate cancer were treated consecutively with EBRT at our institution. Among them, 104 patients were staged as T3N0M0, and there was no T4N0M0 case. These 104 patients consisted of 10 patients with hormone-refractory prostate cancer, 6 patients who received long-term (>30 months) intermittent HT, and 15 who elected for the intensity-modulated radiation therapy (IMRT) protocol conducted as a pilot or a phase I/II dose escalation study. In addition, 1 patient was treated with 3D-CRT alone and 2 patients elected for whole-pelvis irradiation (Table 1). Therefore, 70 patients who were treated with short-term NAHT followed by localized 3D-CRT with definitive intent were analyzed in this study.
Table 1

Patient characteristics and treatment parameters

Number of cases

70

Age (years)

48–80 (median 73)

T stage (UICC’97)

 T3a

54

 T3b

16

Gleason score

 ≤6

10

 7

32

 ≥8

27

 Unknown

1

Initial PSA value (ng/ml)

3.7–430 (median 26.2, average 54.7)

Follow-up period (months)

8.0–117.7 (median 65.7)

NAHT period (months)

3–16 (median 4)

NAHT regimen

 MAB

61

 LH-RH analog alone

9

RT dose (Gy)

 60

1

 64

3

 66

1

 69.4

1

 70

64

RT method

 4-port → arcs

65

 4-port → 4-port

1

 Arcs → arcs

4

The median age of the 70 patients was 73 years (range 48–80) at the beginning of RT. T stages (UICC ’97) were distributed as follows: 54 cases with T3a and 16 with T3b. T-stage was classified based on the findings of digital rectal examination, transrectal ultrasound, or magnetic resonance imaging (MRI). However, MRI was applied to less than one-third of this cohort of patients. Thus, for the patients who were referred after initiating HT, we adopted the staging assessed by the urologist at the initial visit if validation could not be achieved with the available imaging and clinical data. With respect to the Gleason scores (GS), 10, 32, and 27 cases had grades of ≤6, 7, and ≥8, respectively. The GS of the remaining patient was unknown. Initial prostate-specific antigen (PSA) levels ranged from 3.7 to 430 ng/ml, with median and average values of 26.3 and 54.7, respectively.

Hormonal therapy

Before initiating 3D-CRT, NAHT consisting of maximum androgen blockade for 3 months was planned. However, there were variations in the duration and content of HT because considerable numbers of patients were referred from other institutions after having started HT. Therefore, the duration of NAHT ranged from 3 to 16 months, with a median duration of 4 months. Among the 70 patients included in this study, 61 patients received maximal androgen blockade (MAB), LH-RH analog (goserelin acetate or leuprorelin acetate), plus anti-androgen (flutamide, bicalutamide, or chlormadinone acetate). Another 9 patients were administered LH-RH analog alone because of liver dysfunction. No AHT was given to any patient after the completion of 3D-CRT until PSA failure or clinical failure occurred.

Radiation therapy

Planning CT scans were obtained using a CT simulator (CTS-20; Shimadzu, Kyoto, Japan) with a slice thickness of 5 mm, without a gap from the iliac crest to 8 cm below the ischial tuberosity. Patients were placed in the supine position without any fixation devices. They were instructed to void the bladder and rectum about 1–1.5 h before CT simulation, according to their individual urinary conditions. Target delineations and treatment planning were performed with CadPlan (ver. 6.2.7) or Eclipse (ver. 7.1.35) (Varian Medical Systems, Palo Alto, CA). The 15-MV photon beams of a Clinac 2100C or 2300 C/D (Varian Medical Systems). The final dose distributions for all plans were calculated using a pencil beam convolution algorithm with a calculation grid resolution of 2.5 × 2.5 mm, in which the modified Batho heterogeneity correction was applied.

The clinical target volume (CTV) was defined as the prostate and seminal vesicles. No planning target volume (PTV) was used in this protocol. Instead, the edges of the multileaf collimator (MLC) were fitted directly to the CTV with designated margins as described below. A total irradiation dose of 46 Gy in 23 fractions was initially given by the 4-field box technique with MLC conformation to the CTV, followed by an additional 24 Gy in 12 fractions with the dynamic arc conformal technique [14, 15]. In 4-field irradiation, the edges of the MLC were fitted directly to the CTV with a 15-mm margin in all directions based on the beam’s eye view of each field. If part of the posterior rectal wall was included within the irradiated field in the lateral opposing fields, the MLC position was adjusted manually to completely shield the posterior rectal wall from the irradiated volume of the bilateral fields (Fig. 1). In dynamic arc conformal radiotherapy, two lateral arcs with 100° of rotation (from 36° to 136°, and 226° to 326°) were used with dynamic conformal fitting of the MLC to the CTV with a 7-mm margin. This technique enables continuous beam delivery while the MLC position can be changed dynamically to conform to the target as the gantry rotates. The margin from the superior and inferior jaw to the edge of the CTV was 13 mm.
https://static-content.springer.com/image/art%3A10.1007%2Fs10147-010-0109-y/MediaObjects/10147_2010_109_Fig1_HTML.jpg
Fig. 1

An example of the lateral port (from left to right) of the multileaf collimator (MLC)-shaped 4-port technique is shown. The clinical target volume (CTV) was defined as the prostate and seminal vesicles. A 15-mm MLC margin was added to the CTV. The position of the MLC was adjusted manually to prevent irradiation of the posterior rectal wall by the bilateral lateral ports

The prescribed dose was 70 Gy in 35 fractions at the center of the CTV, which was the isocenter of the fields (Fig. 2). The total dose was reduced to 4–10 Gy in patients with at least one of several possible risk factors, including diabetes mellitus, collagen disease, etc.
https://static-content.springer.com/image/art%3A10.1007%2Fs10147-010-0109-y/MediaObjects/10147_2010_109_Fig2_HTML.gif
Fig. 2

An example of the dose distribution is shown. A total of 70 Gy was delivered in 35 fractions to the prostate and seminal vesicles combined using the multileaf collimator (MLC)-shaped 4-port technique (46 Gy/23 fractions) and the dynamic arc conformal technique (24 Gy/12 fractions)

Patient follow-up and salvage hormonal therapy

After the completion of EBRT, patients were followed up without the administration of AHT. The PSA value was examined every 2–4 months. Salvage HT (SHT) was, in principle, initiated when the PSA value exceeded 4 ng/ml after PSA failure, or when any clinical failures were detected.

Outcome evaluation and statistical analyses

The overall survival (OAS), disease-specific survival (DSS), PSA failure-free survival (PFS), and SHT-free survival (SHFS) rates were calculated by Kaplan–Meier estimation from the initiation date of EBRT [16]. The PFS rates were evaluated based on both the modified ASTRO definition and the Phoenix definition [17, 18]. Because NAHT was initiated, we applied the modified ASTRO definition; (1) fluctuations of PSA below 0.5 ng/ml were not counted, (2) elevations of 0.1 ng/ml or more were counted as significant increases. The statistical significance of a difference in survival was estimated by the logrank test. All statistical analyses were performed using JMP (version 5) (SAS Institute Inc., Cary, NC, USA).

Results

The median and average PSA values at the initiation of radiotherapy were 0.3 and 0.8 ng/ml, respectively (range 0.02–4.7 ng/ml). The prescribed dose of 70 Gy was delivered to 65 patients. However, it was reduced to 60–66 Gy in the remaining 5 patients because of diabetes mellitus (n = 5) or severe acute adverse urinary effects (n = 1).

Sixty-seven patients were treated with MLC-shaped 4-field ports followed by two arcs of the dynamic arc conformal technique. However, one patient was treated with MLC-shaped 4-field ports alone, and two patients were irradiated with dynamic conformal arcs alone.

The follow-up periods ranged from 8.0 to 117.7 months, with a median value of 64.9 months.

The 5-year PFS based on the modified ASTRO definition and the Phoenix definition were 53.5% (95% CI 40.9–66.0) and 60.5% (95% CI 48.2–72.7), respectively (Fig. 3). The 5-year OAS and DSS were 90.4% (95% CI 83.2–97.7) and 96.5% (95% CI 91.7–100.0), respectively (Fig. 4). The 5-year SHFS rate was 63.0% (95% CI 50.7–75.2) (Fig. 5). PSA values at the time of initiation of SHT were 0.1–21.6 ng/ml, with a median value of 5.0 ng/ml. The choice of the regimen of salvage hormone therapy employed was left in the hands of the physician in charge.
https://static-content.springer.com/image/art%3A10.1007%2Fs10147-010-0109-y/MediaObjects/10147_2010_109_Fig3_HTML.gif
Fig. 3

Kaplan–Meier estimate of prostate-specific antigen failure-free survival (PFS) rate based on the modified ASTRO definition and the Phoenix definition. The 5-year PFS rates were 53.5% (95% CI 66.0–40.9%) and 60.5% (95% CI 72.7–48.2%) for modified ASTRO and Phoenix definitions, respectively

https://static-content.springer.com/image/art%3A10.1007%2Fs10147-010-0109-y/MediaObjects/10147_2010_109_Fig4_HTML.gif
Fig. 4

Kaplan–Meier estimates of overall survival (OAS) rate and disease-specific survival (DSS) rate in all patients. The 5-year OAS and the 5-year DSS were 90.4% (95% CI 97.7–83.2) and 96.5% (100.0–91.7), respectively

https://static-content.springer.com/image/art%3A10.1007%2Fs10147-010-0109-y/MediaObjects/10147_2010_109_Fig5_HTML.gif
Fig. 5

Kaplan–Meier estimate of the salvage hormonal therapy (SHT)-free survival (SHFS) rate. The 5-year SHFS was 63.0% (95% CI 75.2–50.7). The median prostate-specific antigen (PSA) value at the time of the initiation of SHT was 5.0 ng/ml (range 0.1–21.6 ng/ml)

To date, clinical failures consisting of bone metastases have occurred in 2 patients. With respect to the toxicity, no patient had grade 3 or higher acute complications (CTCAE ver. 3.0), and 8 patients had grade 2 or higher late complications (RTOG late-toxicity criteria). Five patients developed grade 2 rectal bleeding and required steroid suppository and/or hyperbaric oxygenation therapy (HBO). One patient developed grade 3 rectal bleeding and required laser coagulation. Two cases had episodes of macrohematuria, and 1 of these 2 patients also developed urethral stricture, which was managed successfully by bougienage.

Discussion

There have been many reports regarding the outcomes of EBRT in patients with locally advanced prostate cancer, mainly from Western countries [8, 10, 11, 1923]. In these studies, long-term PFS was reported to be around 30% [8, 10, 11, 1921], although it was never acceptably high when the patients were treated with EBRT alone.

On the other hand, in Japan, surgical operation combined with AHT or permanent HT alone has been widely adopted for patients with T3N0M0 prostate cancer. Therefore, there have been few reports of the results of EBRT alone or EBRT combined with NAHT for T3N0M0 prostate cancer, although some results of EBRT combined with long-term AHT were reported [24, 25]. Therefore, this is one of only a few reports regarding EBRT not combined with long-term AHT in Japanese (Asian) patients with T3N0M0 prostate cancer.

In this study, both PFS and the frequency of treatment-related complications were at least comparable to those reported in other institutions. With respect to the PFS in the present study, it seemed rather higher than expected from the literature reported from Western countries. These observations confirmed that EBRT is an effective treatment method for Japanese men with locally advanced prostate cancer. In our series, about two-thirds of the patients remained hormone-free at 5 years.

In a randomized trial that compared EBRT alone and EBRT plus long-term AHT, a significant survival benefit was observed in the AHT arm [10, 11]. In addition, long-term (3 years) AHT was better than short-term (6 months) AHT for high-risk patients with prostate cancer in terms of survival [12]. Therefore, EBRT combined with long-term HT is currently considered the standard treatment strategy for local advanced prostate cancer [26], although short-term NA-HT is still an option for this patient group in Prostate PDQ® [27].

Our approach was different from the standard approach because the protocol was designed before the publication of the abovementioned trials reporting the survival benefits of adding long-term HT. However, we are still using this approach because about two-thirds of our patients remained hormone-free at 5 years, while both OAS and DSS seemed excellent compared to those in similar studies conducted in Western countries, even though no AHT was administered. In fact, the 5-year OAS rate is currently almost comparable to the expected survival rate of age-matched Japanese men calculated from the life table for Japanese men published by the Japanese Ministry of Health, Labor, and Welfare [28].

A number of explanations for our observations are possible. First, a combination of NAHT with EBRT was applied in our series. NAHT, if combined with EBRT, can also improve PFS and DSS (OAS) compared to EBRT alone [8, 22, 2932]. In fact, RTOG 9202, in which EBRT combined with NAHT and 2 years of AHT was compared with EBRT plus NAHT alone, resulted in no significant impact on the OAS of adding AHT to the original patient group (45% of the patients were T2c stage), although a survival benefit was observed in a subset analysis for the high-risk group of patients with GS ≥ 8 [21].

Another possibility is the timing of the initiation of SHT after PSA or clinical failure. Shipley et al. suggested that delayed initiation of SHT would result in a poorer survival outcome. They reported that the prognoses of patients who started SHT when their PSA values were less than 20 were superior to those of patients in whom SHT was initiated at PSA ≥ 20 or those who started HT after the detection of clinical failure [33]. In the present study, SHT was started when the PSA value exceeded 4 ng/ml (median value 5.0 ng/ml), and this earlier initiation of SHT may have contributed to the improved prognosis.

The third possibility is that there may be ethnic differences in sensitivity to HT between Western and Asian populations. A retrospective comparison of Japanese Hawaiian and white patients with prostate cancer who were treated with HT alone with respect to the rate of tumor response and survival suggested that Japanese patients with prostate cancer would probably be more sensitive to the treatment than white patients, resulting in a better survival rate [13].

Therefore, our study suggested that Japanese patients with locally advanced prostate cancer can be appropriately managed with EBRT combined with NAHT if SHT is initiated at around 5 ng/ml. However, a longer follow-up is needed to draw conclusions regarding survivals, and the adequacy of this approach should be validated by a prospective randomized trial.

Fortunately, with respect to Japanese patients with locally advanced prostate cancer, a randomized controlled trial is currently underway involving treatment with 72 Gy EBRT by 3D-CRT combined with 6 months of NAHT followed by randomization of continuous androgen ablation (arm 1) or intermittent androgen ablation (arm 2) [34]. In this study, the initiation of HT in the intermittent HT group (arm 2) is scheduled for a PSA level of ≥5 ng/ml (initially ≥10 ng/ml). Therefore, this study is expected to compare the adequacy of short-term AHT with early initiation of SHT with that of long-term AHT in Japanese (Asian) patients with locally advanced prostate cancer.

Conclusions

The outcomes of three-dimensional conformal radiation therapy combined with NAHT for Japanese patients with T3N0M0 prostate cancer suggested that OAS may be comparable to the expected survival rate if SHT is initiated earlier (>4 ng/ml), and that two-thirds of cases are free from HT at 5 years. This should be validated by a future prospective randomized trial in the near future, as well as by the outcome of an ongoing prospective randomized trial comparing the adequacies of permanent and intermittent AHT after EBRT with NAHT for Japanese patients with locally advanced prostate cancer.

Acknowledgments

This work was partially supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (20229009).

Conflict of interest statement

Authors have no conflicts of interest.

Copyright information

© Japan Society of Clinical Oncology 2010