In/ J. Rodrarron Oncology Lb/ Phys Vol. 24. pp. 423-430 Printed I” the U.S.A. All ri&ts reserved.

0360.3016192 $5.00 + .oO Copyright 0 1992 Pergamon Press Ltd.

??Clinical Original Contribution

PROGNOSTIC SIGNIFICANCE OF PELVIC RECURRENCE AND DISTANT METASTASIS IN PROSTATE CARCINOMA FOLLOWING DEFINITIVE RADIOTHERAPY PETER P. LAI, PH.D., Radiation Oncology

Center,

M.D.,*

CARLOS

Mallinckrodt

Institute

A. PEREZ, of Radiology,

M.D. Washington

AND MARY ANN LOCKETT, University

School of Medicine,

M.B.A.

St. Louis, MO

This report is a retrospective analysis of 317 patients with recurrent prostate carcinoma, following definitive radiation therapy to 738 patients with histologically confirmed, clinical Stage Tlb-T4(A2-D1) adenocarcinoma of the prostate. Seventy-four patients (10%) experienced pelvic recurrence only; 100 (13%) both pelvic recurrence and distant metastasis, while 143 (20%) developed distant metastasis only. The diagnosis of prostate recurrence was histologically confirmed in 92/174 (53%), while in the others diagnosis was based on clinical and radiographic evidence. Ninety percent of all recurrences occurred within 7 years of initial treatment. The median survival from time of recurrence for all patients was 27 months, with 5-,8-, and lo-year survival rates of 24%, 12%, and 7%, respectively. In patients who experienced pelvic recurrence only, the 5-,8-, and IO-year survival rates were 50%, 30%, and 22%, respectively (p i 0.0001). The 5-year survival rate from time of recurrence for patients who experienced pelvic recurrence with initial Stage TIL(AZ)and T*(B) disease was 71% as opposed to 39% for patients with initial Stage TJ(C) disease. The time of recurrence (i.e., the disease-free interval from initial treatment) significantly affected subsequent survival: the 5-year survival rates from time of recurrence for patients with pelvic recurrence were 20%, 49%, and 94% for those who recurred within 2 years, 2 to 5 years, and more than 5 years, respectively. Two-thirds of the patients with recurrence received hormonal therapy, including bilateral orchiectomy. Salvage therapy with hormones, including bilateral orchiectomy, has a favorable impact on patient survival: The 5-year survival rate from time of pelvic recurrence salvaged with hormones was 70% compared with 21% for patients not receiving hormonal therapy. In conclusion, the prognostic factors that affect subsequent patient survival after pelvic recurrence include initial stage, disease-free interval from initial treatment, and salvage therapy with hormones. Patients with distant metastasis with or without pelvic recurrence showed statistically worse survival and were apparently not influenced by initial tumor stage, or disease-free interval from initial treatment. Prostate cancer, Radiation therapy, Pattern of recurrence, Pelvic failure, Distant metastasis, Prognostic variables.

INTRODUCIION

Little has been written on those patients who experienced recurrences after receiving definitive radiation treatment for localized prostate carcinoma. Hanks et al. ( 16) reported an overall recurrence rate of 43% among the patients surveyed in the Patterns of Care Study. The present analysis was undertaken to review the survival of patients after recurrence of prostate cancer and to analyze the prognostic significance of factors that affect subsequent patient survival. A thorough understanding of the pattern of recurrence of prostate cancer after definitive radiation therapy will help in better understanding the natural history of the disease and may facilitate design or modification of the initial curative treatment for prostate cancer. Moreover, the information would be invaluable in coun-

An estimated 132,000 new cases of cancer of the prostate will be diagnosed in the United States in 1992 accounting for 34,000 deaths (4). Numerous institutional retrospective reports (2, 15, 2 I), as well as multiinstitutional, randomized prospective studies ( 1, 23), demonstrate the efficacy of radiation therapy in the definitive management of localized prostate carcinoma. Survival and tumor control for patients with Stage Tlb(A2) and T2(B) disease are comparable to those obtained with radical prostatectomy (5, 10, 13, 17, 19). For Stage T,(C) patients, the probability of survival after irradiation is similar to that noted after hormonal therapy (14, 28, 29). Reprint requests to: P. P. Lai, Ph.D., M.D., Radiation Oncology Center, Mallinckrodt Institute of Radiology, 4939 Audubon Avenue, Suite 5500, St. Louis, MO 63110. * Dr. Lai is a recipient of an American Cancer Society Clinic Oncology Career Development Award. Presented at the 33rd Annual Meeting of the American Society

for Therapeutic 3-8 November

Radiology and Oncology in Washington, DC, 199 1. Acknowledgement-The authors wish to thank Ms. Gwendolyn Jackson for her secretarial help in the preparation of this manuscript. Accepted for publication 29 May 1992.

423

1. J. Radiation Oncology 0 Biology 0 Physics

424

seling individual patients about prognosis after disease recurs. METHODS

AND MATERIALS

Between January 1967 and December 1988, 738 patients with histologically proven adenocarcinoma of the prostate, localized to the pelvis, were treated with definitive radiotherapy at the Radiation Oncology Center, Mallinckrodt Institute of Radiology, and affiliate hospitals (Table 1). All patients have been followed up for a minimum of 3 years, or until death, with a median follow-up of 6 years. The median patient age was 67 years (range 42-82 years). Patients were initially staged according to the American Urological Association Classification, which has corresponding ACJ-TNM stages as indicated in Table 1. Clinical Stage D, as used at the Mallinckrodt Institute of Radiology refers to patients with tumor extension in the bladder or rectum or extensive pelvic disease to the pelvic wall (T4). Each patient had a complete physical examination, rectal examination, routine blood count, chemistry profile, urinalysis, and determination of serum prostatic, acid and alkaline phosphatase level. Chest xray, intravenous pyelogram, and radionuclide bone scan were also obtained. Initially, the regional lymph nodes were evaluated by pedal lymphangiogram, but later this study was replaced by computed tomography scans of the pelvis and abdomen. Cystoscopy was routinely performed; in most patients diagnosis was obtained by needle biopsy, although in about 20%, transurethral resection of the prostate (TURP) provided the definitive diagnosis. Patients were followed up periodically during and after therapy or until death by the staff of the Radiation Oncology Center, the referring urologist, and occasionally the family physician. Sometimes contact was made directly with the patient’s relatives. Tumor control was assessed by periodic rectal examination, serum acid phosphatase determinations, and, when indicated, radionuelide bone scan or other radiographic studies, Initially, postirradiation biopsy of the prostate was carried out almost routinely to ascertain the radiation effect on the tumor. However, later this procedure was limited only to patients suspected of recurrence by rectal examination (tumor persistence over 18 months after irradiation or evidence of regrowth). Thus, the diagnosis of prostate re-

Table 1. Pattern

of failure in prostate

carcinoma

following definitive

Volume 24, Number 3, 1992

currence was made histologically in 92/l 74 (53%) of patients. For the remainder of the patients, the diagnosis was based on clinical or radiographic evidence. The analysis by site of recurrence, was therefore based on overall recurrence instead of site of first recurrence. Prostatic specific antigen (PSA) was not available during the study period. The different methods of salvage therapy among the 317 patients with recurrence are listed in Table 2. They include castration (i.e., bilateral orchiectomy), hormones (i.e., Diethylstilberol (DES), Leuprorelin * Flutamide), TURP, chemotherapy, interstitial implant, pelvic exenteration, or other types of surgery (laminectomy for cord compression, etc.). Some patients received no salvage treatment, whereas others received more than one type of salvage therapy. All radiation oncology records were reviewed; the information was coded on computer-compatible forms and analyzed on a computer program with multiple cross-reference checks to ensure reliability of the data. All survivals and survival functions use the actuarial life-table as applied by Cutler and Ederer (7) and test statistics provided are Generalized Wilcoxon (Breslow), Generalized Savage (Mantel-Cox), and Tarone-Ware (20,27). Trend analysis was performed by the Tarone Method (26). The MantelCox was used to test for potentially significant factors for survival. Irradiation techniques The techniques of treatment with either 22 MV photons from a betatron or 16-25 MV photons from linear accelerators have been previously described (22). With the betatron (22 MV photons) the pelvic disease received 4500 to 5000 cGy through AP-PA portals (15 X 15 cm for Stage T,(B) or 15 X 18 cm for Stages T,(C) and T4(DI). Following this, the posterior portal was discontinued and the anterior portal decreased to 14 X 14 cm to deliver an additional 1000 cGy (calculated at midplane) to external iliac and hypogastric lymph nodes. The AP portal was further reduced to 6 X 8 cm or 8 X 10 cm, depending on the size of the prostate, to deliver an additional 1000 cGy, for a total dose of 6000 to 6500 cGy for Stage TIb(AZ) and T,(B) or 7000 cGy for Stage TX(C) and T4(D1) tumors. After 1974, 18-25 MV photons from a linear accelerator were used to administer 4500 cGy to the pelvis through AP-PA portals; additional 2000 to 2500 cGy with 270-

radiotherapy: Pattern

Stage Tib (AZ) TZ (B) T3

(Cl

T4 (D,)

Number of patients

5-year NED survival

Pelvic

48 252 412 26

75% 72% 50% 19%

1 (2%) 28 (11%) 41 (10%) 4 (15%)

738

74 (10%)

Mallinckrodt

of Radiology

1967- 1988

of failure

Pelvic and distant metastasis 3 15 74 8

Institute

(6%) (6%) (18%) (31%)

100 (13%)

Distant metastasis 7 37 91 8

(15%) (15%) (22%) (31%)

143 (20%)

Total 11 80 206 20

(23%) (32%) (50%) (77%)

317 (43%)

425

Recurrent prostate carcinoma after definitive treatment 0 P. P. LAI et al.

Table 2. Salvage therapy among 3 17 patients with recurrent prostate carcinoma+ Pelvic recurrence Castration Hormones TURP Chemotherapy Radioisotope implant Pelvic exenteration Other No treatment

24 21 13 3 1 I 3 31

Distant metastasis + pelvic recurrence 121 99 15 52 1 1

6 46

+ Some patients received from than one type of salvage therapy.

degree anterior arc rotation (7 X 9 cm or 8 X 10 cm ports) was given to the prostatic volume. Beginning 1980, the rotational boost was given with bilateral 120-degree arcs, with 60-degree skipped vectors anteriorly and posteriorly. Petiaortic lymph nodes were irradiated in seven patients (one with Stage Tz(B) and six with Stage Ts(C) disease) because of known metastasis and in 54 patients electively as part of a Radiation Therapy Oncology Group (RTOG) protocol (four with Stage TIr,(AZ); seven with Stage T,(B): 43 with Stage TX(C)). The petiaortic lymph nodes were treated with a dose of 4500 to 5000 cGy in 5 to 6 weeks through AP-PA portals. The usual daily dose was 180 cGy, 5 weekly fractions.

In some patients, irradiation was temporarily discontinued for 1 to 2 weeks after the fourth or fifth week of treatment because of acute side effects (acute cystitis, proctitis, skin reaction, etc.). RESULTS Of 738 patients, 3 17 (43%) had recurrent prostate carcinoma following definitive radiation therapy for localized disease. As shown in Table 1,74 ( 10%) patients developed pelvic recurrence, 100 (13%) both pelvic recurrence and distant metastasis (overall recurrence), while 143 (20%) patients had distant metastasis only. The overall pelvic recurrence rate (with or without distant metastasis) for

the duration of observation is 4/48 (8%), 43/252 (17%), 115/412 (28%) and 12/26 (46%). Table 3 describes in detail the anatomical site of failure at any time after definitive radiotherapy. The actuarial probability of pelvic recurrence in patients treated with definitive irradiation by stage is shown in Figure 1. The 5-year actuarial pelvic recurrence rate (with or without distant metastasis) is 12%, 18%, 30%, and 48% for Stage Tlh(AZ), T,(B), T3(C), and T4(D,), respectively. The cumulative time course of recurrence of prostate carcinoma following definitive radiation therapy is shown in Figure 2. Ninety percent of recurrences occurred within 7 years of initial treatment with almost all recurrences occurring within 10 years; however, a few recurrences after 10 years have been observed. This emphasized the need for long-term follow-up of prostate cancer patients. The overall survival of patients with recurrent prostate carcinoma after definitive irradiation is shown in Figure 3. The median survival, from time of recurrence, for all patients was 27 months, with 5-, 8-, and IO-year actuarial survival rates of 24%, 12%, and 7%, respectively. For those who experienced a pelvic recurrence only, the 5-, 8-, and IO-year survival rates were significantly better (50%, 30%, and 22%, respectively) (a < .OOO1). There was no difference in survival for the group with pelvic recurrence and distant metastasis compared with the group who experienced distant metastasis only (approximately 20% at 5 years and 2% to 5% at 10 years). The favorable prognosis of patients with isolated pelvic recurrence is further illustrated by the cause specific survival as shown in Figure 4A & B. Patients who showed no evidence of recurrence in the prostate/pelvis had the best survival, followed by those with an isolated local/ regional recurrence. Initial tumor stage influenced survival after the patient experienced pelvic recurrence: the 5-year survival rate for patients who experienced pelvic recurrence with initial Stage Tlb(AZ) and T2(B) disease was 71% as opposed to 39% for patients with initial Stage T3(C) disease (Fig. 5a,b). There was no difference in survival after recurrence between T1b(A2)and T2( B) patients and Stage T3(C) patients when distant metastasis was involved.

Table 3. Anatomical site of failure in prostate carcinoma following definitive radiotherapy: Mallinckrodt Institute of Radiology 1967- I988 Stage Site of failure

T,b n

Prostate only Prostate + pelvis Prostate + distant mets Prostate + pelvis + distant mets Pelvis only (excludes prostate) Pelvis + distant mets (excludes prostate) Distant metastasis only n = Number of patients.

;)

=

642)

48

8.3%

T2

@I

J-3 K3

n = 252

:;}

0 0 7

2 0 38

11

80

15.9% ~~

Ta

n = 412

j] 2 10 93 206

24.5%

PI)

n = 26

;} 0 2 8 20

38.5%

1. J. Radiation Oncology 0 Biology 0 Physics

426 ACTUARIAL

PROBABILITY

OVERALL

OF PELVIC RECURRENCE

100 -

SURVIVAL W

STAGE a-.c-.4

.

80

80

c

..‘..

All Recurrences Pelwc Ret Only P&c + DM DM

e-.4 . .....

A2 B

? .? . ..n

Dl

:D

t

s

Volume 24, Number 3, 1992

/

I

60

0 i

26

0

I.

2

30

I.

4

YEARS AFTER

I.

I

6

I

“_I

I

I,

,

.

I.

1.

1.

I

4

6

8

10

YEARS FROM RECURRENCE

INITIAL TREATMENT

Fig. 1. Actuarial probability of pelvic recurrence treated with definitive irradiation by stage.

I

2

0

10

8

in patients

Fig. 3. Overall survival of patients cinoma after definitive irradiation.

with recurrent

prostate

car-

CAUSE SPECIFIC SURVIVAL

Time of recurrence (i.e., the disease-free interval from initial treatment) significantly affects subsequent survival. For patients with pelvic recurrence only, the 5-year survival rates from time of recurrence were 20%, 49%, and 94% for those who recurred within 2 years, 2 to 5 years, and more than 5 years, respectively (Fig. 6a,b,c). Patients who recurred in the pelvis within 2 years, their survival was no different than those with distant metastasis. The disease-free interval did not affect subsequent patient survival when distant metastasis was involved, irrespective of the time of recurrence. Patients with tumor control in the prostate/pelvis exhibited a significantly lower incidence of distant metastasis compared with those who failed in the local/regional tumor volume (Fig. 7). Different salvage therapies have been used in the management of patients with recurrent prostate carcinoma.

8C

..‘a

h..

. . --..

‘..

‘R.

Stages A2& B +.+

-

’w

***.*

. .. . . .

..c’* ‘9

Pelvic Rec. Only P&c + DM

.**a DM Only . . . . . . NED

i!

22

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8 2 4 6 YEARS AFTER INITIAL TREATMENT

,’ 6

IO

(a) CAUSE SPECIFIC SURVIVAL loo-

TIME COURSE OF RECURRENCE * .. . . . ...’ ?? .0

loo-

s

60Stagec *.Pelvic

? 540-

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p: 2

c.4

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_

P&K

+ DM

. .. ...

DM only

(N0’146)

OP I

0

4

8

. . . . . . NED

20-

(Noz96)

0

I

12 YEARS AFTER INITIAL TREATMENT

16

Fig. 2. Cumulative time course of recurrence in patients treated with definitive irradiation by site of recurrence.

8 2 4 6 YEARS AFTER INITIAL TREATMENT

10

(b)

Fig. 4. Cause specific survival in patients treated with definitive irradiation (a) Stage Tlb(AZ) and T,(B); (b) Stage Ta(C).

427

Recurrent prostate carcinoma after definitive treatment 0 P. P. LAI el al. SURVIVAL

SURVIVAL BY DISEASE FREE INTERVAL FROM INITIAL TREATMENT

BY SITE OF RECURRENCE Stages A2& B 6.4 PelvicRec.Only Pelvic+ DM w***=DM Only

80-

..

80

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.’“LI. ‘rn

**.W.a..

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II*Ic”“‘~II

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..

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FROM RECURRENCE

a

6

IO

SURVIVAL BY DISEASE FREE INTERVAL FROM INITIAL TREATMENT

SURVIVAL BY SITE OF RECURRENCE SIage e-4

PelwcRet Only

).“‘m

P&c + DM DM Only

20 O-

4

FROM RECURRENCE (a)

(a)

-

2

IOOC

-.-

Ret + DM 5 Years

a

a’

IO

FROM RECURRENCE (c)

Fig. 6. Actuarial survival from time of recurrence by diseasefree interval from initial treatment in patients treated with definitive irradiation: (a) pelvic recurrence only; (b) pelvic recurrence and distant metastasis; (c) distant metastasis only.

I. J. Radiation Oncology 0

428

STAGE B tYoo2

Biology0 Physics STAGE C P!OOl

Fig. 7. The incidence of distant metastasis in patients treated with definitive irradiation by pelvic tumor control versus pelvic failure.

nocarcinoma of the prostate, there is a scarcity of information on the outcome of those patients who experienced a recurrence. Based on the Patterns of Care Study, Hanks et al. ( 16) reported on 266 patients who developed recurrence from a total of 608 patients who received definitive radiation therapy for Stage T*(B) and Stage Tj(C) prostate carcinoma. The overall recurrence rate of 44% (266 of 608) is almost identical to our recurrence rate of 43% (3 17 of 738). In the Patterns of Care Study, the median survival among all patients with recurrent adenocarcinoma of the prostate was 30 months, with 5- and 8-year actuarial survival rates of 28% and 13%, respectively. These rates are also very similar to those we observed: median survival of 27 months with 5-, 8-, and lo-year actuarial survival rates of 24%, 12%, and 7%, respectively. After initial treatment the cumulative percent of recurrence is almost 100% by 10 years, with 90% of recurrences occurring within 7 years. However, distant metastasis alone has been observed among our patient population at 15 years, thus emphasizing the need for

SURVIVAL

AFTER SALVAGE THERAPY WITH HORMONES

p.*., \

\ 2..

: .\:‘.. \ :

4’h. 1, :.

z

‘w-c-a.

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Ret only; Hormone&

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‘h .,

?? ..-O

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t

Ret,

Fig. 8. Actuarial survival after salvage therapy with hormones for patients with recurrent prostate carcinoma after definitive irradiation.

Volume 24, Number 3, 1992

long-term follow-up of prostate carcinoma patients after definitive management. In this analysis, we have examined several prognostic variables that might affect patient survival after recurrence of prostate carcinoma. These possible variables include initial tumor stage, time to recurrence (i.e., duration of disease-free interval), and salvage therapy with hormonal treatment. Initial stage of disease was a significant prognostic factor for patients who experienced a recurrence; this is more prominent for patients who experienced pelvic recurrence only. Initial stage is a reflection of tumor burden, that is, the higher the stage, the more cancer cells to be sterilized by irradiation. When distant metastasis was involved, initial stage had no influence on subsequent patient survival. One striking observation is that the pattern of recurrence (i.e., isolated pelvic recurrence) is associated with favorable prognosis; whereas distant metastasis, with or without pelvic recurrence, the prognosis is uniformly poor. For patients with pelvic recurrence, the median survival from time of recurrence was 5 years, which is more than twice the median survival for patients when distant metastasis is involved. Moreover, wheu pelvic recurrence occurred more than 5 years after initial treatment, the 5year actuarial survival rate from recurrence was 94%. This may be a result of selection of patients with indolent disease. In contrast, for those patients who experienced a pelvic recurrence within 2 years of initial treatment, subsequent survival was similar to the group of patients with distant metastasis. When hormonal treatment (including bilateral orchiectomy) was given to patients with pelvic recurrence only, the 5-year actuarial survival rate from time of recurrence was 70%. The issue of pelvic recurrence is of particular interest to the radiation oncologist because radiation treatment is primarily a localized modality influencing local tumor control, hopefully thereby reducing the incidence of distant metastasis from tumor seeding from uncontrolled primary cancer. In fact, as shown in our analysis and by Fuks et al. (12) in patients treated with interstitial 112’,when tumor control in the prostate is achieved after initial treatment, the incidence of distant metastasis is lower than in patients with local/regional recurrence. In head and neck epithelial carcinoma, the rate of primary tumor regression or resolution of the neck node metastasis is an indicator of the overall response of the tumor to irradiation and is a prognostic indicator of long-term tumor control (3). In contrast, for adenocarcinema of the prostate, tumor resolution after definitive irradiation took months or years and was not correlated with long-term survival (22). Moreover, the correlation of long-term tumor control with the presence of tumor cells in the prostate biopsy after definitive irradiation is still controversial. Cox and Kline (6) reported no prognostic significance for long-term survival of patients with a positive prostate biopsy obtained 1 or 2 years after radiation treatment. Scardino and Wheeler (25) noted a higher incidence of subsequent pelvic recurrence in pa-

Recurrent prostate carcinoma after definitive treatment 0 P. P. LAI ef ul.

tients whose postirradiation biopsies were positive for cancer. Freiha and Bagshaw (11) noted that a positive postirradiation biopsy is likely to indicate active disease and identify patients at a higher risk for development of metastasis. Prestidge et al. (24) reported that a positive postirradiation biopsy is associated with a higher incidence of subsequent distant metastasis but has no influence on overall patient survival. The excellent survival associated with isolated pelvic recurrence more than 5 years after initial treatment suggests that these late pelvic recurrences might be biologically or pathologically different: this is reminiscent of the discrepancy between the high prevalence of prostate cancer at autopsy in men over the age of 50 who died of other causes (8) and the relatively lower incidence of clinical prostate cancer. The observation that tumors that recur later have a better prognosis has also been reported in other malignancies ( 18).

429

Despite 15 years of efforts to develop effective chemotherapy to be administered before, during, or after hormonal therapy, no active drugs have been identified, and the median survival of patients with disease in progression after hormonal therapy is less than 11 months (9). The most effective form of salvage therapy remains hormonal treatment. Different types of hormonal therapy such as bilateral orchiectomy versus DES, LH-RH agonists, or complete androgen blockade have not been shown to be different in terms of improving patient survival (data not shown). Hormonal treatment is very effective in prolonging patient survival, with the results being more pronounced in patients with pelvic recurrence only than in those with distant metastasis. Some patients with pelvic recurrence only were rendered clinically disease-free (NED) by hormonal therapy. This observation has practical implications in the management of patients with isolated pelvic recurrence.

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