ORIGINAL ARTICLE

Int J Clin Oncol (2007) 12:37–41 © The Japan Society of Clinical Oncology 2007DOI 10.1007/s10147-006-0622-1

Koichi Wadasaki · Yuko Kaneyasu · Masahiro Kenjo Kanji Matsuura · Yuji Murakami · Yasutoshi Hashimoto Katsuhide Ito · Hiroshi Kiriu · Atsushi Ito

Treatment results of adjuvant radiotherapy and salvage radiotherapy after radical prostatectomy for prostate cancer

AbstractBackground. The indications for and the effi cacy of radia-tion therapy after radical operation for patients with pros-tate cancer are not clear. We analyzed the treatment results of adjuvant radiotherapy and salvage radiotherapy after radical prostatectomy.Methods. Between September 1997 and November 2004, 57 patients received adjuvant radiotherapy or salvage radio-therapy after radical prostatectomy. Fifteen patients re-ceived radiation therapy because of positive margins and/or extracapsular invasion in surgical specimens (adjuvant group). Forty-two patients received radiation therapy be-cause of rising prostate-specifi c antigen (PSA) during fol-low-up (salvage group). Radiation therapy was delivered to the fossa of the prostate ± seminal vesicles by a three-dimensional (3-D) conformal technique to a total dose of 60–66 Gy (median, 60 Gy). Biochemical control was defi ned as the maintenance of a PSA level of less than 0.2 ng/ml.Results. The median follow-up period after radiation ther-apy was 33 months (range, 12–98 months). Three-year bio-chemical control rates were 87% for the adjuvant group and 61% for the salvage group. For patients in the salvage group treated without hormone therapy, the preradiation PSA value was the most signifi cant factor for the biochemical control rate. The 3-year biochemical control rate was 93% in patients whose preradiation PSA was 0.5 ng/ml or less and 29% in patients whose preradiation PSA was more than 0.5 ng/ml. No severe adverse effects (equal to or more than grade 3) were seen in treated patients.

Conclusion. Radiation therapy after radical prostatectomy seemed to be effective for adjuvant therapy and for salvage therapy in patients with a preradiation PSA of 0.5 ng/ml or less. Also, radiation to the fossa of the prostate ± seminal vesicles, to a total dose of 60–66 Gy, using a three-dimen-sional (3-D) conformal technique, seemed to be safe.

Key words Prostate cancer · Radical prostatectomy · Adju-vant radiotherapy · Salvage radiotherapy

Introduction

Radical prostatectomy is the most common primary treatment for localized prostate cancer. About half of those patients whose tumors are clinically confi ned to the prostate have extracapsular extension or seminal vesicle invasion pathologically.1 Also, in 30%–40% of patients, surgical resection margins are positive.2 These pathological extracapsular extensions or positive margins are risk factors for biochemical and clinical recurrence. However, the effectiveness of adjuvant postoperative radiotherapy to the prostate fossa for high-risk patients is controversial,3 and adjuvant radiotherapy is not used routinely in Japan.

Nowadays recurrence after radical prostatectomy usual-ly emerges as biochemical recurrence without a clinically detectable lesion. The treatment options for patients with biochemical recurrence after radical prostatectomy are ra-diation therapy, hormone therapy, or both. Outcomes of salvage radiotherapy have been reported in many studies,4,5 but appropriate selection criteria, treatment timing, and treatment techniques for salvage radiotherapy remain unclear.

In this study we retrospectively reviewed the treatment results of prostate cancer patients who received adjuvant or salvage radiotherapy. We also discuss the usefulness and the safety of radiation therapy after radical prostatectomy.

K. Wadasaki (*) · Y. Kaneyasu · M. Kenjo · K. Matsuura · Y. Murakami · Y. Hashimoto · K. ItoDepartment of Radiology, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanTel. +81-82-257-5257; Fax +81-82-257-5259e-mail: wadasaki@hiroshima-u.ac.jp

H. Kiriu · A. ItoDepartment of Radiation Oncology, Hiroshima General Hospital, Hiroshima, Japan

Received: February 16, 2006 / Accepted: September 9, 2006

38

Patients and methods

Patient population

Between September 1997 and November 2004, 57 patients who had undergone radical prostatectomy for prostate ad-enocarcinoma received radiation therapy to the prostate fossa at Hiroshima University Hospital or Hiroshima Gen-eral Hospital. Of these 57 patients, 15 had adjuvant post-operative radiotherapy because of adverse pathological fi ndings such as positive surgical margins or extracapsular extension (adjuvant group). The other 42 patients had ra-diotherapy as salvage therapy because of rising prostate-specifi c antigen (PSA) levels in the follow-up period after operation (salvage group). Patients who were found to have pelvic lymph node metastases at the operation were ex-cluded and no patients had distant metastases. No clinically detectable lesions existed at the time of radiation in either group, and no patients received biopsy before the radio-therapy commenced.

Table 1 shows the patients’ characteristics. In the adju-vant group, the median age of the patients was 66 years and median initial PSA was 18.7 ng/ml. Six patients received hormone therapy before operation. In the operative speci-mens, extracapsular extension and seminal vesicle invasion were observed in 12 and 6 patients, respectively, and surgi-cal margins were positive in 8 patients. In the salvage group, the median age of the patients was 69 years and median initial PSA was 12.7 ng/ml. Twenty-two patients received hormone therapy before operation. In the operative speci-mens, extracapsular extension and seminal vesicle invasion were observed in 20 and 9 patients, respectively, and surgi-cal margins were positive in 17 patients.

The interval between the operation and the initiation of radiation therapy was 1–3 months (median, 1 month) in the adjuvant group and 4–78 months (median, 14 months) in the salvage group. Preradiation PSA was less than 0.1 ng/ml in all patients in the adjuvant group and the value ranged from 0.25 to 2.8 ng/ml (median, 0.7 ng/ml) in the salvage group.

Treatment plan

All patients received high-energy photon beam irradiation (10 or 18 MV), given by a three-dimensional (3-D) confor-mal technique. The clinical target volume (CTV) was the prostate fossa without the inclusion of the pelvic lymph node area. In patients whose seminal vesicles were patho-logically involved, the seminal vesicle beds were also in-cluded in the CTV. The planning target volume (PTV) was the CTV plus a 10-mm margin in all directions for internal motion and set-up error. Five portal fi elds (both lateral, posterior, and two anterior oblique) were used. In the ad-juvant group the total radiation dose was 60 Gy/30 fractions (10 patients) or 63 Gy/35 fractions (5 patients). In the sal-vage group the total radiation dose was 60 Gy/30 fractions (26 patients), 64 Gy/32 fractions (11 patients), or 66 Gy/33 fractions (5 patients). The prescribed dose was calculated at the iso-center and the PTV included more than 95% of the area of the prescribed dose.

One patient in the adjuvant group and eight patients in the salvage group received hormone therapy during and after the radiation therapy (4–24 months).

Evaluations

The follow-up period after radiation therapy was 12–98 months (median, 33 months). PSA was measured at intervals of 2–3 months after the radiation therapy and we defi ned biochemical failure as a PSA level of 0.2 ng/ml or more. The period of biochemical control was calculated from the start of the radiation therapy to the date of the fi rst PSA level of 0.2 ng/ml or more, or to the last follow-up day. If the PSA was never less than 0.2 ng/ml after radiation therapy, the period of biochemical control was set at zero month. Calculation of the biochemical control rate was done by the Kaplan-Meier method, and the Wilcoxon test was used for statistical analysis. Student’s t-test and the χ2 test were used to analyze the statistical re-lationships between clinical factors and biochemical failure.

Table 1. Patients’ characteristics

Adjuvant group (n = 15) Salvage group (n = 42)

Age (years) 56–76 (median, 66) 57–76 (median, 69)Initial PSA (ng/ml) 5.3–71.3 (median, 18.7) 0.9–50.7 (median 12.7)Preoperative hormone therapy 6 (40%) 22 (52%)Operative fi ndings Extracapsular extension 12 (80%) 20 (48%) Seminal vesicle invasion 6 (40%) 9 (21%) Positive surgical margin 8 (53%) 17 (40%) Gleason score 2–6 7 (47%) 20 (48%) 7 5 (33%) 13 (31%) 8–10 3 (20%) 9 (21%)Postoperative hormone therapy 1 (7%) 0 (0%)Interval between operation and 1–3 (median, 1) 4–78 (median, 14) radiation therapy (months)Preradiation PSA (ng/ml) <0.1 in all patients 0.25–2.8 (median, 0.7)

39

Adverse effects of radiation were graded according to the common toxicity criteria for adverse events (CTC-AE) ver 3.0. Acute effects were evaluated in all 57 patients and late effects were evaluated in 39 patients who were followed up for adverse effects more than 2 years after the comple-tion of radiation therapy.

Results

Survival and biochemical control

One patient in the adjuvant group died of hepatic cancer 35 months after completion of the radiation therapy. He had no clinical or biochemical recurrence of prostate cancer. No patients in either group died of prostate cancer. One patient in the salvage group showed clinical failure at 10 months after completion of the radiation therapy; pelvic lymph node metastasis had been found by computed tomography (CT) scan after biochemical recurrence. None of the other 41 patients in the salvage group and none of the patients in the adjuvant group experienced clinical recurrence or metastases.

Figure 1 shows the biochemical control rates in the two groups. The 3-year biochemical control rate was 87% in the adjuvant group and 61% in the salvage group. In the salvage group the 3-year biochemical control rate was 100% in pa-tients with hormone therapy and 53% in patients without hormone therapy (Fig. 2). Table 2 shows the relationship of surgical margins, Gleason score, interval between operation and start of radiation, and preradiation PSA with biochemi-cal failure in patients in the salvage group without hormone therapy. Of these factors, preradiation PSA was the only signifi cant predictive factor for biochemical failure. Median preradiation PSA was 0.9 ng/ml in the patients with bio-chemical failure and 0.4 ng/ml in patients without biochemi-

cal failure. In the salvage group without hormone therapy, the 3-year biochemical control rate was 93% in patients with a preradiation PSA of 0.5 ng/ml or less and 29% in patients with a preradiation PSA of more than 0.5 ng/ml (P < 0.05; Fig. 3).

Adverse effects

Table 3 shows the number of patients who suffered acute or late adverse effects of radiation therapy. Most adverse effects were grade 1 and these included pollakisuria, urinary hesitancy, mild rectal discomfort, and rectal bleeding re-quiring no therapy. Grade 2 acute adverse effects were seen

0

20

40

60

80

100

0 12 24 36 48 60

%

Adjuvant group

Salvage group

month

Fig. 1. Biochemical control rate (adjuvant group and salvage group)

0

20

40

60

80

100

0 12 24 36 48 60

month

Hormone (-)

Hormone (+)

%

Fig. 2. Biochemical control rate of salvage group (with hormone ther-apy and no hormone therapy)

0

20

40

60

80

100

0 12 24 36 48 60

month

Pre-RT PSA < 0.5

Pre-RT PSA>0.5

P<0.05%

Fig. 3. Biochemical control rate in salvage group without hormone therapy (pre-RT PSA � 0.5 ng/ml and pre-RT PSA > 0.5 ng/ml). pre-RT PSA, pre radiotherapy prostate-specifi c antigen

40

for urological (4%) and gastrointestinal (9%) morbidity The rates of grade 2 late adverse effects were 2% and 0%, respectively, for urological and gastrointestinal morbidity. No patients experienced adverse effects of grade 3 or more in either the acute or late periods.

Discussion

Pathological extracapsular extension and positive surgical margins are risk factors for recurrence after radical prosta-tectomy for T1-2 prostate cancer. Kupelian et al.6 reported a 5-year relapse-free survival rate of 37% in margin-positive patients compared with 80% in margin-negative patients. In our study, the 3-year biochemical control rate after ad-juvant radiotherapy in patients with extracapsular exten-sion or a positive margin was 87%. Although our follow-up periods were short, this fi gure seems to compare favorably with the data for patients with no adjuvant therapy. In many reports, postoperative adjuvant radiotherapy improved bio-chemical disease-free survival in patients with adverse path-ological factors.7–9 Valicenti et al.10 reported, in a matched-pair analysis of 72 patients with pT3 prostate cancer, that the 5-year freedom from PSA relapse rate was 89% with adjuvant radiotherapy and 55% without radiotherapy. However, most reported series were retrospective studies and im-provements of overall survival were not demonstrated. Recently, the results of a phase III randomized study of adjuvant radiotherapy versus observation in pT3 prostate cancer patients (Southwest Oncology Group Protocol 8794) were published.11 In that study, adjuvant radiotherapy sig-nifi cantly improved the 10-year biochemical disease-free survival rate (47% vs 23%), and none signifi cantly improved overall survival rate (74% vs 63%). Although all high-risk patients would not get benefi t from adjuvant radiation, we think that, in the light of these fi ndings, postoperative ad-

juvant radiotherapy should be considered as a benefi cial option for patients with extracapsular extension or positive margins.

Salvage radiotherapy for patients with rising PSA after radical prostatectomy had worse treatment results than ad-juvant radiotherapy in most reported series, with 5-year biochemical disease-free survival rates ranging from 20% to 70%.12–14 In the present study, the 3-year biochemical control rate was 53% in the salvage group without hormone therapy. The differences between the results in many stud-ies are probably due to the variability of clinical factors in their patient populations. Prognostic factors reported to infl uence the treatment results of salvage radiotherapy were operative margin status, Gleason score, interval between operation and radiation, PSA doubling time and preradia-tion PSA.13,15,16 Of these factors, preradiation PSA was the most important, and several authors reported excellent bio-chemical relapse-free survival rates if preradiation PSA was low.15,17 In the present study, the 3-year biochemical control rate was 93% when preradiation PSA was equal to or less than 0.5 ng/ml and 29% when preradiation PSA was more than 0.5 ng/ml. We think that patients with rising PSA after radical prostatectomy but PSA values of 0.5 ng/ml or less are good candidates for salvage radiotherapy. But patients with PSA of 0.5 ng/ml or more must be considered for sys-temic therapy, because in some of these patients, PSA con-tinued to rise after salvage radiotherapy and so the possibility of their having microscopic metastasis seemed to be high. Our outcomes in patients who received both sal-vage radiotherapy and hormone therapy were very good, regardless of their preradiation PSA values, but the number of patients was small and the follow-up periods were short. For patients with high preradiation PSA, further evaluation is needed to determine whether radiation therapy with hor-mone therapy is benefi cial. We used a PSA value of 0.2 ng/ml or more as the defi nition of biochemical failure. For ad-juvant and salvage radiotherapy, many different defi nitions of biochemical failure have been used, but the best defi ni-tion is not clear. In our study, patients who were free from biochemical failure continued to have stable PSA values, and so the effect of different defi nitions of biochemical failure seemed to be very small.

Regarding the dose of radiation therapy after radical prostatectomy, the tolerable dose seems to be less than that for radical radiotherapy because of the displacement of the bladder and rectum into the prostate fossa and injury to the surrounding tissues caused by operative maneuvers. So a total radiation dose of more than 70 Gy after radical pros-

Table 2. Factors affecting biochemical failure in salvage group without hormone therapy

Biochemical failure (+) Biochemical failure (−) (14) (20)

Surgical margin (+) 5 (36%) 5 (25%)Gleason score 7–10 7 (50%) 9 (45%)Interval between op. and RT (months) 5–78 (median, 16) 4–62 (median, 12)Pre-RT PSA (ng/ml) 0.5–2.8 (median, 0.9)* 0.25–1.1 (median, 0.4)*

* P < 0.05

Table 3. Adverse effects

Grade 1 Grade 2

Acute effects (in 57 patients) Urological morbidity 33 (58%) 2 (4%) Gastrointestinal morbidity 31 (54%) 5 (9%)

Late effects (in 39 patients) Urological morbidity 16 (41%) 1 (2%) Gastrointestinal morbidity 8 (21%) 0 (0%)

Grades according to CTC-AE ver 3.0No patients experienced grade 3 or higher adverse effects.

41

tatectomy is thought to be excessive, and usually a dose of 60–70 Gy is used.18,19 Zelefsky et al.18 reported the morbidity of 3-D conformal radiation therapy after radical prostatec-tomy. Their median dose was 64.8 Gy and they experienced grade 2 toxicity in fewer than 10% of patients and grade 3 toxicity in no patients. Our treatment doses were 60–63 Gy for adjuvant radiotherapy and 60–66 Gy for salvage radio-therapy with a 3D-conformal technique and we also expe-rienced no acute or late severe adverse effects of grade 3 or more. The recommendation of the American Society for Therapeutic Radiology and Oncology Consensus Panel20 was 64 Gy for salvage radiotherapy. We think the dose 64 Gy is acceptable for both adjuvant radiotherapy and sal-vage radiotherapy, so nowadays we use a dose of 64 Gy in both situations after radical prostatectomy.

In conclusion, adjuvant radiotherapy after radical pros-tatectomy for patients with positive margins and/or extra-capsular invasion was effective. Also, salvage radiotherapy for patients whose PSA was rising after radical prostatec-tomy was also effective when preradiation PSA was 0.5 ng/ml or less. The 3-D conformal radiation therapy with doses of 60–66 Gy to the fossa of the prostate ± seminal vesicles was quite safe and caused no serious morbidities.

References

1. Kupelian PA, Katcher J, Levin HS, et al. (1997) Stage T1-2 pros-tate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys 37:1043–1052

2. Obek C, Sadek S, Lai S, et al. (1999) Positive surgical margins with radical retropubic prostatectomy: anatomic site-specifi c pathologic analysis and impact on prognosis. Urology 54:682–688

3. Collette L, Poppel H, Bolla M, et al. (2005) Patients at high risk of progression after radical prostatectomy: do they all benefi t from immediate post-operative irradiation? (EORTC trial 22911). Eur J Cancer 41:2662–2672

4. Taylor N, Kelly JF, Kuban DA, et al. (2003) Adjuvant and salvage radiotherapy after radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 57:755–763

5. Hayes SB, Pollack A (2005) Parameters for treatment decision for salvage radiation therapy. J Clin Oncol 23:8204–8211

6. Kupelian PA, Katcher J, Levin HS, et al. (1996) Correlation of clinical and pathologic factors with rising prostate-specifi c antigen

profi les after radical prostatectomy alone for clinically localized prostate cancer. Urology 48:249–260

7. Choo R, Hruby G, Hong J, et al. (2002) Positive resection margin and/or pathologic T3 adenocarcinoma of prostate with unde-tectable postoperative prostate-specifi c antigen after radical prostatectomy: to irradiate or not?. Int J Radiat Oncol Biol Phys 52:674–680

8. Petrovich Z, Lieskovsky G, Langholz B, et al. (2002) Postoperative radiotherapy in 423 patients with pT3N0 prostate cancer. Int J Radiat Oncol Biol Phys 53:600–609

9. Vargas C, Kestin LL, Weed DW, et al. (2005) Improved biochemi-cal outcome with adjuvant radiotherapy after radical prostatecto-my for prostate cancer with poor pathologic features. Int J Radiat Oncol Biol Phys 61:714–724

10. Valicenti RK, Gomella LG, Ismail M, et al. (1999) The effi cacy of early adjuvant radiation for pT3N0 prostate cancer: a matched-pair analysis. Int J Radiat Oncol Biol Phys 45:53–58

11. Swanson GP, Thompson IM, Tangen C, et al. (2005) Phase III randomized study of adjuvant radiation therapy versus observation in patients with pathologic T3 prostate cancer (SWOG 8794). Int J Radiat Oncol Biol Phys 63:S1

12. Anscher MS, Clough R, Dodge R (2000) Radiotherapy for a rising prostate-specifi c antigen after radical prostatectomy: the fi rst 10 years. Int J Radiat Oncol Biol Phys 48:369–375

13. Catton C, Gospodarowicz M, Warde P, et al. (2001) Adjuvant and salvage radiation therapy after radical prostatectomy for adenocar-cinoma of the prostate. Radiother Oncol 59:51–60

14. Peyromaure M, Allouch M, Eschwege F, et al. (2003) Salvage ra-diotherapy for biochemical recurrence after radical prostatectomy: a study of 62 patients. Urology 62:503–507

15. Cheung R, Kamat AM, Crevoisier R, et al. (2005) Outcome of salvage radiotherapy for biochemical failure after radical prosta-tectomy with or without hormonal therapy. Int J Radiat Oncol Biol Phys 63:134–140

16. Vicini FA, Ziaja EL, Kestin LL, et al. (1999) Treatment outcome with adjuvant and salvage irradiation after radical prostatectomy for prostate cancer. Urology 54:111–117

17. Stephenson AJ, Shariat SF, Zelefsky MJ, et al. (2004) Salvage radiotherapy for recurrent prostate cancer after radical prosta-tectomy. JAMA 291:1325–1332

18. Zelefsky MJ, Aschkenasy E, Kelsen S, et al. (1997) Tolerance and early outcome results of postprostatectomy three-dimensional con-formal radiotherapy. Int J Radiat Oncol Biol Phys 39:327–333

19. Kamat AM, Babaian K, Cheung MR, et al. (2003) Identifi cation of factors predicting response to adjuvant radiation therapy in pa-tients with positive margins after radical prostatectomy. J Urol 170:1860–1863

20. Cox J, Gallagher M, Hammond E, et al. (1999) Consensus state-ments on radiation therapy of prostate cancer: guidelines for pros-tate re-biopsy after radiation and for radiation therapy with rising prostate-specifi c antigen levels after radical prostatectomy. Ameri-can Society for Therapeutic Radiology and Oncology Consensus Panel. J Clin Oncol 17:1155–1163