Timing and patterns of recurrences and deaths from prostate cancer ...

Prostate Cancer and Prostatic Diseases (2006) 9, 254–260 & 2006 Nature Publishing Group All rights reserved 1365-7852/06 $30.00

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ORIGINAL ARTICLE

Timing and patterns of recurrences and deaths from prostate cancer following adjuvant pelvic radiotherapy for pathologic stage T3/4 adenocarcinoma of the prostate MS Anscher1, R Clough1, CN Robertson2, LR Prosnitz1, P Dahm2, P Walther2, CF Donatucci2, DM Albala2, P Febbo3, DJ George3, L Sun2 and JW Moul2 1

Department of Radiation Oncology, Virginia Commonwealth University Medical Center, Richmond, VA, USA; 2Department of Surgery, Division of Urology, Duke University Medical Center, Durham, NC, USA and 3Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA

To determine the timing and patterns of late recurrence after radical prostatectomy (RP) alone or RP plus adjuvant radiotherapy (RT). Between 1970 and 1983, 159 patients underwent RP for newly diagnosed adenocarcinoma of the prostate and were found to have positive surgical margins, extracapsular extension and/or seminal vesicle invasion. Of these, 46 received adjuvant RT and 113 did not. The RT group generally received 45–50 Gy to the whole pelvis, then a boost to the prostate bed (total dose of 55–65 Gy). In the RP group, 62% received neoadjuvant/adjuvant androgen deprivation vs 17% in the RT group. Patients were analyzed with respect to timing and patterns of failure. Only one patient was lost to follow-up. The median follow-up for surviving patients was nearly 20 years. The median time to failure in the surgery group was 7.5 vs 14.7 years in the RT group (P ¼ 0.1). Late recurrences were less common in the surgery group than the RT group (9 and 1% at 10 and 15 years, respectively vs 17 and 9%). In contrast to recurrences, nearly half of deaths from prostate cancer occurred more than 10 years after treatment. Deaths from prostate cancer represented 55% of all deaths in these patients. Recurrences beyond 10 years after RP in this group of patients were relatively uncommon. Despite its long natural history, death from prostate cancer was the most common cause of mortality in this population with locally advanced tumors, reflecting the need for more effective therapy. Prostate Cancer and Prostatic Diseases (2006) 9, 254–260. doi:10.1038/sj.pcan.4500903; published online 1 August 2006

Keywords: adjuvant radiotherapy; recurrence; survival; patterns of failure

Introduction One of the most controversial topics in urologic oncology is the role of adjuvant therapy after radical prostatectomy (RP) for those patients at high risk for recurrence. For patients at high risk of local failure, that is, those with positive surgical margins, adjuvant radiotherapy (RT) results in permanent local control in the majority of patients.1–17 Whether adjuvant RT offers an advantage in survival or reduces deaths from prostate cancer compared to radiation delivered at the time of prostate-specific antigen (PSA) recurrence remains unknown. The majority of studies, which address this issue, are small, retrospective and suffer from short follow-up. The only published randomized trials report an advantage for early RT in terms of local control and recurrence-free survival, but follow-up is too short Correspondence: Dr MS Anscher, Department of Radiation Oncology, Virginia Commonwealth University Medical Center, 401 College Street, PO Box 980058, Richmond, VA 23298-0058, USA. E-mail: [email protected] Received 14 May 2006; revised 7 June 2006; accepted 11 June 2006; published online 1 August 2006

to address the issues of cause-specific and overall survival.2,18,19 Late recurrences of prostate cancer are a well-documented phenomenon. Few series describing the results of adjuvant RT report results beyond 5 years. Long-term data, even of a retrospective nature, might help to better guide physicians in the management of patients at high risk for local failure after RP, as well as provide information on patterns of recurrence, which would be useful in the design of future clinical trials. Herein, we describe long-term results of our series of patients with pathologic stage T3/4 prostate cancer, originally reported in 1987 and 1990,1,20 who now have up to 30 years of follow-up after treatment for their disease with either surgery alone or surgery plus adjuvant RT.

Materials and methods Patient selection From 1970 to 1983, 319 patients with newly diagnosed adenocarcinoma of the prostate underwent RP at Duke University Medical Center. Of these patients, 159 (50%)

Timing and patterns of recurrences and deaths from prostate cancer MS Anscher et al

had histologically positive surgical margins, complete capsular penetration and/or seminal vesicle involvement. These patients form the basis for this analysis. Of the 159 patients, 46 (30%) were referred for adjuvant RT and the remaining 113 (70%) were not. Referral for postoperative therapy was at the discretion of the attending urologist. Preoperative evaluation generally consisted of a history and physical examination, blood work and radiographic studies, including acid and alkaline phosphatases, chest X-ray, intravenous pyelography, computed tomography of the pelvis, skeletal survey, radioisotope bone scan and lymphangiography. PSA was not available in this era. Patients were retrospectively assigned a clinical stage according to the American Joint Committee on Cancer System (4th edition).21 Postoperatively, pathology reports were reviewed to determine the extent and grade of cancer present. Only patients with positive surgical margins, capsule penetration and/or seminal vesicle invasion (pathologic stage T3/4) were included in the study. Gleason sums of 2–4, 5–7 and 8–10 correlated with well, moderate and poor differentiation, respectively.

are similar. The median duration of follow-up was longer for the irradiated group, as the patients treated with surgery only had a shorter median survival than the patients receiving adjuvant RT (Figure 1). However, the median follow-up of the surviving patients in both groups is nearly identical (Table 1). Only one patient, in the surgery group, was lost to follow-up (at 3 years). A higher percentage of irradiated patients underwent lymph node dissection and were found to have nodal metastases. A much larger percentage of patients treated without radiation received androgen deprivation, which was given at the discretion of the attending urologist. Androgen deprivation was used in the neoadjuvant and/or adjuvant setting. Irradiated patients were more likely to have positive surgical margins, but there was no difference in the groups with respect to the presence of capsule penetration or seminal vesicle involvement. Table 1 Patient characteristics Surgery No. of patients (%)

Surgery+radiotherapy No. of patients (%)

113

46

Age (years) Median (range)

64 (40–78)

61 (43–77)

Follow-up (years) Median (range)

10 (0.1–30)

15 (0.6–23)

No. of patients

Radiotherapy technique The RT technique used has been described previously.1,22 In brief, a four-field box technique (AP–PA, right and left lateral fields) was used most commonly. Usually, 45–50 Gy in daily doses of 1.8–2 Gy were delivered to the whole pelvis, followed by an additional 10–15 Gy to the prostate bed. In general, customized blocking was used to protect the small bowel, bladder and rectum. Androgen deprivation therapy Androgen deprivation therapy was used in the neoadjuvant and/or adjuvant setting. Patients received it at the discretion of their attending urologist. Preoperative androgen deprivation was given on a temporary basis, whereas postoperative treatment was either temporary or permanent.1,22 Statistical analysis Patients lost to follow-up were censored at the date of last contact. Local failure was defined as serial changes on rectal examination confirmed by biopsy. Distant metastases were detected by physical examination and/or radiographic evaluation. Initially, three categories of failure were scored: local, distant and local plus distant. Beginning in 1987, biochemical failure was added as a fourth category. This was defined as a rise in the PSA of 10% or more on two consecutive values at least 4 weeks apart. In addition to the patterns of failure, end points included overall survival, cancer-related and non-cancerrelated deaths. Survival curves were calculated by the Kaplan–Meier method.23 Differences between curves were compared using the Cox–Mantel test.24

Results The characteristics of the two patient populations are summarized in Table 1. In many respects, the two groups

255

Follow-up of surviving patients (years) No. of patients N¼9 Median (range) 20.5 (3–30) Clinical stage T1 T2 T3/4 N+ Elevated preoperative acid phosphatase Lymphadenectomy Yes No Androgen deprivation

20 84 8 1 20

(18) (74) (7) (1) (18)

N ¼ 11 20 (18–22) 8 35 2 1 13

(17) (76) (4) (3) (28)

77 (68) 36 (32) 69 (62)

39 (85) 7 (15) 8 (17)

Histologic grade Well Moderate Poor Not given Positive nodes

16 62 23 12 3

7 27 9 3 4

Capsule penetration Yes No Unknown

61 (54) 43 (38) 9 (8)

23 (50) 17 (37) 6 (13)

Positive margins Yes No Unknown

59 (52) 52 (46) 2 (2)

36 (78) 20 (22) 0

Seminal vesicle involvement Yes No Unknown

44 (39) 68 (60) 1 (1)

21 (46) 23 (50) 2 (4)

(14) (55) (20) (11) (3)

(15) (59) (20) (6) (9)

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256

1

1

SURVIVAL PROBABILITY OF SURVIVAL

PROBABILITY OF SURVIVAL

0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20

0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10

0.10

0

0 0 KEY:

CAUSE-SPECIFIC SURVIVAL

0.90

3

6

9

12 15 18 21 24 27 30 YEARS GRP= SURGERY TOTAL FAILED MEDIAN GRP= SURG & RT 104 10.0 113 46 35 15.0 P= 0.102 STAT= 1.636

Figure 1 Actuarial survival comparison of patients treated with surgery alone (solid line) vs those treated with surgery plus adjuvant postoperative RT (broken line).

0

3

KEY:

6

9

12 15 YEARS

GRP= SURGERY GRP= SURG & RT P= 0.084 STAT= 1.727

18

21

24

27

30

TOTAL FAILED MEDIAN 59 14.8 113 46 18 19.7

Figure 2 Actuarial cause-specific survival of patients treated with surgery alone (solid line) vs those treated with surgery plus adjuvant postoperative RT (broken line).

Irradiated patients were more likely to have an elevated preoperative acid phosphatase.

1

DISEASE-FREE SURVIVAL

Survival Of the 113 patients treated with surgery alone, 104 (92%) have died. Fifty-nine (57%) of the deaths in this group were from prostate cancer. In the group treated with surgery and adjuvant RT, 35 of 46 (76%) patients have died, 18 (51%) from prostate cancer. The median time to death in the surgery-alone group was 10 vs 15 years in the adjuvant RT group (P ¼ 0.1). At 15 years, the actuarial survival in the surgery-alone group was 35 vs 52% for the patient receiving adjuvant RT (P ¼ 0.1) (Figure 1). Considering only deaths owing to prostate cancer, the actuarial cause-specific survival at 15 years was 48% in the surgery-only group vs 63% in the irradiated patients (P ¼ 0.08) (Figure 2). The median time to death from prostate cancer in the surgery-alone group was 15 vs 20 years in the adjuvant RT group. Although these differences are not statistically significant, adjuvant RT appears to be associated with a 15% reduction in deaths from prostate cancer at 15 years. Late deaths from prostate cancer were common in both groups of patients. Of the 59 deaths from prostate cancer in the surgeryalone group, 28 (47%) occurred beyond 10 years and 13 (22%) occurred more than 15 years after treatment. Similarly, of the 18 deaths from prostate cancer in the adjuvant RT group, eight (44%) occurred beyond 10 years and four (22%) occurred more than 15 years after therapy. In contrast to deaths from prostate cancer, late relapses were relatively less common in both groups of patients. The median time to relapse in the surgery-alone group was 7.5 vs 14.7 years in the adjuvant RT group. Of the 67 relapses in the surgery group, only six (9%) occurred beyond 10 years and only one (1%) recurred more than 15 years after treatment. Late relapses were more common in the group receiving adjuvant RT vs the surgery-only patients. In the group receiving adjuvant Prostate Cancer and Prostatic Diseases


0.90 0.80 0.70 0.60 0.50 0.40 0.30 KEY:

0.20

GRP= SURGERY GRP= SURG & RT P= 0.100 STAT= 1.645

0.10 0 0

3

6

9

12

TOTAL FAILED MEDIAN 113 67 7.5 46 23 14.7

15 18 YEARS

21

24

27

30

Figure 3 Actuarial disease-free survival of patients treated with surgery alone (solid line) vs those treated with surgery plus adjuvant postoperative RT (broken line).

RT, 4/23 (17%) relapses occurred beyond 10 years and two (9%) occurred more than 15 years after treatment. The addition of adjuvant RT was associated with prolongation in the time to relapse, although this difference was not statistically significant (Figure 3).

Timing and patterns of failure In the group treated with RP alone, there were an equal number of local and distant failures (40 local, 42 distant). In contrast, the group receiving adjuvant RT had three times as many distant failures as local recurrences (five local, 16 distant). At 15 years, the actuarial local control rate for the patients treated with surgery alone was 53 vs 89% for the patients receiving adjuvant RT (P ¼ 0.001) (Figure 4). The median time to local failure has not been


reached for either group. In the surgery-alone group, the actuarial freedom from distant failure rate at 15 years was 55% compared to 62% for the adjuvant RT group (P ¼ 0.7) (Figure 5). The median time to development of distant metastases has not been reached in either the surgery or adjuvant RT group. Reflecting the era in which these patients were treated, biochemical failure was the initial sign of recurrence in only 13 patients, seven in the surgery group and six in the surgery plus RT group. Late distant failures were relatively uncommon in both groups. In the surgery-only patients, 8/42 (19%) of distant failures occurred beyond 10 years and two (5%) occurred more than 15 years after treatment. In the group receiving adjuvant RT, late distant metastases were even less common. Only 1/16 (6%) distant metastasis in this group developed more than 10 years after treatment. Late local recurrences were very uncommon in the surgery-only group, with none occurring more than

1

LOCAL CONTROL


0.90 0.80 0.70 0.60 0.50 0.40 0.30

KEY:

0.20 0.10

TOTAL FAILED MEDIAN GRP= SURGERY 113 40 GRP= SURG & RT 46 5 P= 0.001 STAT= 3.438

0 0

3

6

9

12

15 18 YEARS

21

24

27

30

Figure 4 Actuarial local control of patients treated with surgery alone (solid line) vs those treated with surgery plus adjuvant postoperative RT (broken line).

1

METASTASIS-FREE SURVIVAL


0.90 0.80 0.70 0.60 0.50 0.40 0.30

KEY: TOTAL FAILED MEDIAN GRP= SURGERY 113 42 GRP= SURG & RT 46 16 P= 0.656 STAT= 0.445

0.20 0.10 0 0

3

6

9

12

15 18 YEARS

21

24

27

30

Figure 5 Actuarial freedom from distant metastases of patients treated with surgery alone (solid line) vs those treated with surgery plus adjuvant postoperative RT (broken line).

11 years after treatment. In contrast, a significant proportion of local failures in the adjuvant RT group occurred late. In this group, 2/5 (40%) of the local failures occurred more than 10 years after treatment, including one, which occurred at 20 years. Table 2 demonstrates the patterns of failure following adjuvant RT on local and distant failure as a function of site of involvement with prostate cancer. Adjuvant RT was associated with a reduction in the risk of local recurrence in patients with seminal vesicle involvement by 32%, in patients with capsular penetration by 27% and by 23% in patients with positive margins. In contrast, adjuvant RT was associated with a reduction in distant metastases of only 2–4% in these same patient populations.

257

Discussion The present study, to our knowledge, reports the longest follow-up data on a group of patients treated with adjuvant RT after RP for pathologic stage T3 disease. In addition, a unique feature of the study is the completeness of the data set. Only one patient was lost to followup, and 138 of the remaining 158 (87%) have been followed until death. Thus, these data, although retrospective and therefore not definitive with respect to the role of adjuvant RT, may prove useful in guiding future clinical trial design. Nevertheless, the study does have several weaknesses. Given the fact that the RT was not given according to the predetermined guidelines, no definite conclusions can be drawn regarding its values as an adjuvant to prostatectomy for patients with locally advanced prostate cancer. Similarly, because androgen deprivation therapy was used in a significant number of patients and in an uncontrolled manner, no definite conclusions may be drawn regarding its role in the treatment of this population of patients. Despite these drawbacks, the data do provide some insights into the timing and pattern of relapse in patients with locally advanced prostate cancer, and support the value of long-term data collection. In this series, late recurrences were relatively uncommon. More than 80% of all recurrences, both local and distant, occurred within 10 years of treatment. Late recurrences were more commonly distant in the surgeryalone group, whereas late local failures were more frequent in the adjuvant RT group. This finding suggests that the burden of residual local disease tends to be greater than that of occult distant metastases in patients with pathologic T3 prostate cancer; thus, local recurrences tend to appear sooner. In addition, adjuvant RT, if unsuccessful in eradicating local residual tumor, merely delays local regrowth of cancer. The finding of such late local recurrences after adjuvant RT reinforces the need for long-term follow-up of these patients, and suggests the need for higher doses of radiation to achieve permanent local control (X60 Gy). Alternatively, as these patients were treated using outdated RT techniques, it is possible that better results may be achieved using modern three-dimensional conformal or intensity-modulated RT approaches. Adjuvant RT resulted in a significant improvement in local control and a trend toward reduction in deaths Prostate Cancer and Prostatic Diseases


258

Table 2 Patterns of relapse after adjuvant RT as a function of site of involvement Site

Local failure No RT No. of patients (%)

Distant metastases RT No. of patients (%)

No RT No. of patients (%)

RT No. of patients (%)

Yes

No

Yes

No

Yes

No

Yes

No

23 (51) 17 (25)

22 (49) 51 (75)

4 (19) 1 (4)

17 (81) 24 (96)

25 (56) 17 (25)

20 (44) 51 (75)

11 (52) 5 (20)

10 (48) 20 (80)

Capsule penetration Positive 20 (32) Negative 20 (39)

42 (68) 31 (61)

1 (5) 4 (17)

21 (95) 20 (83)

25 (40) 17 (33)

37 (60) 34 (67)

8 (36) 8 (33)

14 (64) 16 (67)

Margins Positive Negative

68 (65) 5 (55)

5 (12) 0

37 (88) 4 (100)

38 (37) 4 (44)

66 (63) 5 (55)

14 (33) 2 (50)

28 (67) 2 (50)

Seminal vesicles Positive Negative

36 (35) 4 (44)

Abbreviation: RT, radiotherapy.

from prostate cancer. However, adjuvant RT was not associated with a reduction in distant metastases. Consequently, no improvement in overall survival could be demonstrated with the addition of RT. These findings are consistent with those of other retrospective studies reported in the literature.1,3–17,20,22 Recently, a large randomized trial of more than 1000 patients was published with findings similar to ours, although followup to date is only 5 years.2 It is possible that with longer follow-up, a survival advantage attributed to the use of adjuvant RT will emerge. Two other large randomized trials have been published only in abstract form, and no survival data are available.18,19 Thus, the present study is one of the few to shed light on the long-term outcome, which might be expected for patients receiving adjuvant RT after RP. After RP, patients with seminal vesicle invasion, capsule penetration and/or positive surgical margins are at high risk for recurrence.2,19,25–27 In the present study, the patients who did not receive adjuvant RT had an actuarial risk of failure at 15 years of 70%. These failures were equally distributed between local and distant sites. Furthermore, the study suggests that patients treated surgically, and are found to have disease outside the prostate, are likely to live long enough to fail, as the median time to failure was 7.5 years, whereas the median survival was 10 years (Figure 3). In addition, the patients seem to remain at risk for failure indefinitely. Although infrequent, local recurrences occurred more than 10 years after surgery and distant metastases occurred more than 18 years postoperatively (Figures 4 and 5). The high rate of distant metastases in this patient population is concerning. Adjuvant RT did not seem to reduce the incidence of distant metastases, suggesting that approximately half of these patients already had micrometastatic disease at the time of diagnosis. The role of systemic therapy, either in the form of androgen deprivation or chemotherapy, in this patient population remains to be defined.14,28–33 Long-term androgen deprivation therapy has been demonstrated to improve survival in other groups of prostate cancer patients at high risk for metastatic disease treated either with RT or RP.34–36 As androgen deprivation therapy, in the present study, was not given according to the predetermined Prostate Cancer and Prostatic Diseases

written guidelines, its role cannot be definitively determined. It is possible, however, that the frequent use of adjuvant and/or neoadjuvant androgen deprivation therapy in the patients treated without RT altered the timing and pattern of recurrence in this group of patients. The fact that this group was relatively less likely to develop distant metastases than the adjuvant RT group may be a reflection of the efficacy of androgen deprivation therapy. Thus, the role of androgen deprivation therapy in pathologic stage T3/4 disease deserves further study. The group of patients described in the present report were all diagnosed and treated initially in the era predating PSA. Thus, they likely had more extensive disease at the time of surgery than the typical patient presenting today, that is, most commonly with an elevated PSA and negative digital rectal exam. Patients diagnosed earlier in the course of their disease, yet who are found to have histologic evidence of local extension outside of the prostate, might be less likely to have occult metastases and more likely to benefit from adjuvant RT. The findings of the recently published randomized trial of adjuvant RT vs observation for patients with positive margins, capsule penetration and/or seminal vesicle involvement would support this hypothesis.2 In this randomized study, patients in the observation arm were four times more likely to have a locoregional than a distant failure. In contrast, the patients receiving immediate adjuvant RT were equally likely to have locoregional or distant failure. Compare this finding to the present study, in which the surgery-only arm had an equal incidence of local and distant failures, whereas the RT group had three times more distant than local failures. With longer follow-up of the randomized trial, it should become apparent whether early local intervention for pathologic stage T3 prostate cancer diagnosed in the PSA era would translate into improvement in survival.

Conclusion Recurrences beyond 10 years after RP in this group of patients were relatively uncommon. Late local failures


after adjuvant RT were a surprising finding, suggesting the need for higher doses of radiation in this setting. Reflecting the long natural history of prostate cancer after recurrence,37 deaths beyond 10 years from treatment were common. Despite its long natural history, death from prostate cancer was the most common cause of mortality in this population with pathologic stage T3/4 tumors, reflecting the need for more effective systemic therapy.

16

17

18

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