- Email: [email protected]
Effect of local tumor control on distant metastasis and survival in prostatic adenocarcinoma
EFFECT OF LOCAL TUMOR CONTROL ON DISTANT METASTASIS AND SURVIVAL IN PROSTATIC ADENOCARCINOMA DEBORAH
A. KUBAN, M.D.
ANAS M. EL-MAHDI,
M.D.,
PAUL F. SCHELLHAMMER,
D-SC. M.D.
From the Department of Radiation Oncology and Biophysics, and Department of Urology, Eastern Virginia Medical School, Norfolk, Virginia
ABSTRACT-Of 495 patients definitively irradiated for prostatic carcinoma, 286 with a minimum follow-up of thirty-six months were studied. While tumor histology appeared to predict prognosis, the poorly differentiated tumors showing the highest incidence of distant metastasis and the lowest survival, local tumor control was an important factor within the poorly differentiated group. Of those with local recurrence, distant metastases developed in 68 per cent compared with 37 per cent of those with no local disease (p = 0.025). Survival was similarly affected with 86 per cent of those with locally controlled tumor who were alive at five years (not significantly different from the more well-differentiated tumors) versus a 56 per cent actuarial survival in those with locally recurrent disease (p < 0.05).
If one takes to heart the evidence that only 1 to 2 per cent of all patients with carcinoma of the prostate are potentially curable,1-3 then we must ask the question, why do many more times this number of patients receive treatment for their primary disease .4 If ultimately, “the only patients who can be cured are those with welldifferentiated tumors confined to the prostate,“’ is our treatment of the poorly differentiated prostatic tumors of any value? Can we alter, at all, that grim prognosis so frequently associated with undifferentiated prostatic cancerPss It would seem only logical that, just as for other primary tumor sites,9 local control in prostatic adenocarcinoma would prove advantageous, rendering our therapeutic endeavors, after all, beneficial. To determine, then, whether or not there is actually a subset among those with poorly differentiated lesions who are
420
positively affected by our prescribed treatment, the relationship between local tumor control, distant metastasis, and survival was investigated. Material and Methods Of 495 patients with biopsy-proved adenocarcinoma of the prostate definitively irradiated at the Eastern Virginia Medical School’s Department of Radiation Oncology between January, 1976, and December, 1984, 286 patients, clinically Staged A2 to C, with a minimum follow-up of thirty-six months were studied. Patients’ ages ranged from forty-eight to eighty-five years with an average and a median age of sixty-six and sixty-seven years, respectively. One hundred seventy-eight patients were treated with external beam irradiation (XRT) consisting of 62-65 Gy to the prostate over six
UROLOGY
/ NOVEMBER
1987
/ VOLUME
XXX, NUMBER 5
and one-half weeks with 4 mV photons in earlier years and 10 mV photons more recently. Patients with more advanced stage disease concomitantly received 40-45 Gy to the pelvic lymph node drainage sites. One hundred eight patients were treated with iodine-125 (1251) implantation and pelvic lymph node dissection, using the Whitmore technique,‘O for an average prostatic dose of 160 Gy to an average volume of 5 x 5 x 5 cm. All tumors were histologically graded according to a modified Gleason system”: Well differentiated
TABLE I.
Tumor histology and stage by treatment modality XRT
Histology Well differentiated Moderately differentiated Poorly differentiated Stage
70 60 48
44 39 25
23 12 70 73
11
A2
B, I32
C
Gleason 2, 3, 4 (MD)Gleason 5, 6, 7 (PD)Gleason 8, 9, 10
Table I lists tumor differentiation by treatment modality. Tumors in all patients were clinically staged by digital rectal examination. Further evaluation included intravenous pyelography, chest xray film, radioisotopic bone scan and serum acid phosphatase, and liver enzyme laboratory studies. More recently, patients at risk for pelvic lymph node involvement were studied by computerized axial tomography while earlier cases had pelvic lymphangiography. Patients were classified using a modified Fowler-Whitmore staging system12: AS-Tumor, well differentiated, in more than 3 chips or any moderately or poorly differentiated tumor in chips removed for presumed benign disease. Bl-Tumor 1.5 cm or less in diameter and limited to one prostatic lobe. B2-Tumor greater than 1.5 cm in diameter or involving more than one lobe. C -Tumor with evidence of extension beyond the prostatic capsule or involving the seminal vesicles. Dl-Regional lymph node metastasis. DB-Disseminated disease. Table I gives the number of patients in each stage with reference to treatment modality. With the exception of two tumors, one Stage A2 and one Stage Bl, all poorly differentiated lesions were Stage B2 or C. Eleven patients, whose disease was upstaged by findings at pelvic lymphadenectomy, were assigned their clinical stage for the purpose of this study to maintain uniformity between treatment groups.
UROLOGY
9 59 29
(WD)-
Moderately differentiated Poorly differentiated
1251
Tumor
TABLE II.
Per cent distant meta.stasis by tumor differentiation
Tumor
Distant Metastasis
Well differentiated Moderately differentiated Poorly differentiated
111114 30199 35173
%
P
10
o oo5
2;
0:05
All patients have been clinically examined at regular intervals by the same urologist and radiation oncologist with a median follow-up of fifty-four months for the entire group. Local recurrence of disease was defined as progressive palpable prostatic tumor on serial digital rectal examinations with rebiopsy confirmation of tumor in all equivocal cases. Local tumor control and its effect on distant metastasis and survival was assessed with attention to tumor grade and stage. Comparative analysis was appropriately carried out by using either Fisher’s exact test or chi-square test with survival analysis by the Berkson-Gage method. l3 Results In analyzing the incidence of distant metastasis by tumor histology for the entire group of 286 patients, a significant, progressive increase in tumor dissemination was seen with loss of histologic differentiation (Table II). Likewise, in calculating five-year actuarial and diseasefree survival for the complete group, there was a trend toward fewer survivors with the poorly differentiated tumors although the difference between the moderately and poorly differentiated groups was not statistically significant (Figs. 1 and 2). Within the poorly differentiated group, stage proved to be important since in 30 per cent of patients with Stage B2 tumors
/ NOVEMBER 1987 / VOLUME XXX, NUMBER 5
421
30
0
30
WD
?? MD 0
20
PD
-I
lo0 0
0 WD
1
m
MD
0
PD
loI 3
I 2
I 1 YEARS
AFTER
t 4
0
r 5
I 1
0
YEARS
TREATMENT
8
I
I
I
2
3
4
5
AFTER
TREATMENT
FIGURE 1. Comparison of survival by tumor differentiation.
FIGURE 2. Comparison differentiation.
metastatic disease developed compared with 61 per cent of patients with Stage C lesions. While there was no significant stage-dependent difference in five-year overall survival, survival without disease was significantly better for Stage B2 than for Stage C tumors (60% versus 28 %) (Table III). Local tumor control following definitive prostatic irradiation was assessed by tumor histology and treatment modality (Table IV). In
comparing lz51 implantation to external beam irradiation in the well and moderately differentiated neoplasms, there appeared to be no significant difference in the incidence of local tumor recurrence (9 % versus 4 % and 28 % versus 18%, respectively). However, when local failure was tabulated for the poorly differentiated group, in 56 per cent of those patients treated with 1251local tumor recurrence developed as opposed to only 23 per cent of those patients treated with external beam irradiation (p = 0.008). Therefore, while the incidence of local tumor recurrence was significantly higher for the lz51 group as a whole as compared with the external beam group (27 % versus 14 % , p = 0.025), this was only by virtue of the treatment-related difference in local tumor control in the poorly differentiated subset. In this histologic group, the treatment modality dependent-difference in local tumor control
TABLE III. Comparison of incidence of metasta.si.s, survival, and disease-free survival in Stage Bz vs Stage C poorly differentiated tumors Met. (%) Survival ( % ) NED survival ( % )
Bz
C
P
9/30 (30) 82 60
25/41 (61) 69 28
0.025 NS 0.05
TABLE IV. Incidence
Tumor Well differentiated Moderately differentiated Poorly differentiated TOTALS
422
of local recurrence,
-----Iodine-125No. of Local Pts. Recurrence
iodine-125
%
No. of Pts.
of NED survival by tumor
and XRT XRT Local Recurrence
%
44 39 25
4 11 14
9 28 56
70 60 -48
3 11 11
4 18 23
10s
29
27
178
25
14
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/ NOVEMBER1987
/ VOLUMEXXX,NUMBERS
TABLE V. Local recurrence by stage and treatment modality of poorly differentiated tumors
Tumor Stage
1251( % )
B2 C
5/14 (36) 9111 (82)
Local RecurrencXRT (%) 1116 (6) 10/30 (33)
P 0.059 0.997
TABLE VI.
Local recurrence within each treatment group according to stage in poorly differentiated tumors
Treatment Modality 1251
XRT
Local RecurrencC (%) 5114 (36) 9111 (82) l/l6 (6) 10130 (33) R, (%)
P 0.027 0.040
also was maintained within each stage (Table V) . Two patients with poorly differentiated disease, one each Stages A2 and Bl, were not included in this analysis for lack of appropriate comparison. Likewise, tumor stage appeared to affect local failure within each treatment group, lz51 and external beam irradiation (Table VI).
TABLE VII.
The question of whether local tumor control affects the incidence of distant metastasis was addressed by comparing the incidence of distant metastasis with primary tumor control versus primary tumor recurrence according to tumor differentiation and treatment modality (Table VII). Comparative analysis within each histologic group was difficult due to the small number of patients in some groups. However, in those patients treated with external beam irradiation, in 22 per cent of all patients whose tumor was locally controlled distant metastases developed compared with 52 per cent of those who failed local therapy (p = 0.005). Similarly, in those patients treated with lz51, in 11 per cent of those with local tumor control metastatic disease developed versus 69 per cent of those with local tumor recurrence (p = 0.005). Since there was no significant difference in the incidence of distant metastasis based on treatment modality when like groups were compared, those with the same tumor differentiation and local control, the incidence of distant metastasis based on local tumor status was determined for both rz51and external beam irradiation patients combined (Table VIII).
Incidence of distant metastasis with local tumor control vs local recurrence in XRT and lz51 groups Distant Metastasis Local % Recurrence
Local Control
Tumor
XRT group Well differentiated Moderately differentiated Poorly differentiated TOTALS Iodine- 125 group Well differentiated Moderately differentiated Poorly differentiated TOTALS
%
6167 15149 13137 341153
9 31 35 22
213 4111 7/11 13125
66 36 64 52
O/40 4128 5111 9179
0 14 45 11
314 7/11 10/14 20129
75 64 71 69
TABLE VIII.
Incidence of distant metastasis based on local tumor status, XRT and 125Zpatients Distant Metastasis Local Recurrence %
%
Tumor
Local Control
Well differentiated Moderately differentiated Poorly differentiated
61107 19177 18148
6 25 37
517 11/22 17125
71 50 68
431232
18
33154
61
0.005
TOTALS
UROLOGY / NOVEMBER1987 / VOLUMEXXX, NUMBER5
P
423
TABLE IX. Five-year survival related to local tumor status for Stages Be and C in poorly diflerentiated, well differentiated, and moderately differentiated tumors
Local Control
Treatment Modality Poorly differentiated tumors XRT + lz51 XRT 1251
Well and moderately differentiated tumors XRT + le51 XRT 1251
looQO80702 605:
K
502 8 4o 3020lo0t
0
WD
0
PD
I
12
0
PD
/
E2
(+I
= Total
2 C with
Local
Control
& C rlth
Local
Fallurm
+ of
In Each
PatIenta
Inltlally
Control
Tr.at*d
DrouD
I
I
I
I
,
1
2
3
4
5
YEARS
FIGURE 3. ferentiation mors.
??MD / B2 & C with Local
0
AFTER
TREATMENT
Comparison of survival by tumor difand local control, Stages B2 and C tu-
Within each histologic group, those patients failing local control had a significantly higher incidence of metastatic disease than those with locally controlled disease. A second interesting finding is that in those patients with no evidence of local tumor recurrence the incidence of distant metastasis progressively increases as the histology becomes more poorly differentiated (col. 1, Table VIII). When five-year actuarial survival was evaluated for the poorly differentiated (Stages B2 and C) tumors, a significant difference was seen between those patients with local tumor control and those with local recurrence, 86 per cent
424
% Survival
Local Recurrence
86 83 91
56 63 58
89 87 92
78 81 76
versus 56 per cent (p < 0.05). Similar differences based on primary tumor status were also noted when this group was broken down by treatment modality although there was no treatment modality-dependent survival difference within either the local control or the local recurrence categories (Table IX). Patients with well and moderately differentiated Stages B2 and C lesions were analyzed in the same manner but without significant difference based on local tumor control (Table IX). An important observation was subsequently made when the survival data for both the poorly and the well-differentiated tumors were assimilated. Patients with poorly differentiated tumors that were locally controlled had a fiveyear survival which was comparable to the survival of those with well and moderately differentiated tumors of equal stage (B2 and C). Those patients with poorly differentiated tumors that recurred locally exhibited a survival curve with a progressive downward trend with significantly different results at five years compared with the patients with local tumor control (56 % vs 86-89 % , P < 0.05). Figure 3 illustrates these findings graphically. Comment Several authors have addressed the significance of histologic grade in prostatic adenocarcinema. 1,7*8~14-16 The propensity for distant metastasis developing with poorly differentiated tumor histology has been noted.‘J5 Our study, likewise, reveals a stepwise progression in disease dissemination from the well differentiated (10 %), to the moderately differentiated (30%) to the poorly differentiated tumors
UROLOGY
/ NOVEMBER1987
/ VOLUMEXXX.NUMBER5
(48 % ) . Conflicting views emerge, however, when considering the influence of tumor differentiation on response to irradiation.“-re If response is measured in terms of local tumor control, our data do show patients with poorly differentiated lesions to be at a disadvantage when treated with lz51 implantation. In a previous comparison of definitive treatment modalities for high-grade prostatic carcinoma, we questioned whether or not the radiobiologic characteristics of the lz51 isotope were well suited to a biologically aggressive neoplasm.20 The “more poorly differentiated prostatic tumor types have high cell production rates”21 and shorter cell cycle times,22 preventing delivery of the “critical dose rate”23 by lz51interstitial therapy. While our overall recurrence rates for both external beam therapy and lz51 implant are comparable to other reported series,14s24,25only through dissection by tumor histology do we find a significantly higher local recurrence rate in the patients with poorly differentiated tumors treated with 1251. Although it has been stated that “the Gleason histologic grade represents the single most important observation”’ in prostatic carcinoma and that “local recurrence and distant disease appears to correlate well with the degree of histologic differentiation regardless of tumor stage,“26 within our poorly differentiated group, stage proved to be a significant factor in the incidence of local failure. We also found that tumor stage influenced the incidence of distant metastasis and survival without disease in those patients with like histology, all poorly differentiated. This effect of tumor stage has been noted by others as well.5.7Jg,27,28 Since irradiation is a locally directed therapeutic modality, it seems most appropriate to determine whether or not successful treatment of this primary tumor site has any effect on distant metastasis and survival. Indeed, we did see a significantly higher incidence of distant disease in those patients whose primary tumor recurred. Grossman et ~1.~~have suggested that “such metastases may result from recurrences.” It is also thought, however, that high-grade carcinoma has a greater tendency to be already disseminated at diagnosis,’ which supports the progressive increase in distant metastasis with decreasing tumor differentiation seen in our patients with adequately controlled primary disease. It, therefore, appears that distant failure may be a consequence of pretreatment meta-
UROLOGY
/ NOVEMBER 1987
stasis, incomplete local control, or, most likely, both factors.15 Survival also seems to be affected by local tumor control. Even those patients on whom high-grade histology has classically bestowed a poor prognosis do relatively well if their primary tumor has not recurred. In fact, in our study, those patients with poorly differentiated tumors which were locally controlled enjoyed a survival comparable to their locally controlled well and moderately differentiated counterparts while patients with locally recurrent poorly differentiated prostatic carcinomas retained a more dismal prognosis. The lack of survival advantage based on local control in the more well-differentiated tumors may be due to a lower biologic malignant potential and slower growth rate necessitating a longer follow-up period for detection of survival difference. In conclusion, then, local tumor control does indeed appear to affect the incidence of distant metastasis and, in poorly differentiated prostatic tumors, five-year survival. So that our patients may obtain maximum therapeutic benefit, we should perhaps be mindful of the improvement in local tumor control associated with external beam irradiation compared with 1251 therapy in high-grade lesions. Finally, within the time interval of our follow-up, it does appear that definitive irradiation can be successful in a subset of patients previously thought to have the most dismal prognoses. 600 Gresham Drive Norfolk, Virginia 23507 (DR. KUBAN) ACKNOWLEDGMENTS. To Therese Bahb and Rebecca Becker for their expert assistance in data collection and analysis as well as Myra Frost and Renee Sipe for help in preparing this manuscript.
References 1. Stamey TA: Cancer of the Prostate. An analysis of some important contributions and dilemmas, in Stamey TA (Ed): Monographs in Urology, Princeton, Custom Publishing Services, Inc., 1983, p 68. 2. Jewett HJ: The case for radical perineal prostatectomy, J Urol 103: 195 (1970). 3. Walsh PC, and Jewett HJ: Radical surgery for prostatic cancer, Cancer 45: 1996 (1980). 4. Murphy GR et al: The national survey of prostate cancer in the United States by the American College of Surgeons, J Urol 127: 928 (1982). 5. Cupps RE, et al: Definitive radiation therapy for prostatic carcinoma: Mayo Clinic experience, ibid 124: 855 (1980). 6. Harisiadis L, et al: Carcinoma of the prostate: treatment with external radiotherapy, Cancer 41: 2131 (1978).
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7. Grayhack JT, and Assimos DG: Prostatic significance of tumor grade and stage in the patient with carcinoma of the prostate, Prostate 4: 13 (1983). 8. Gleason DF, and Mellinger GT: Veterans Administration Cooperative Urological Research Group. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging, J Urol 111: 58 (1974). 9. Proceedings of the Third Rome International Symposium: The challenge of local tumor control and its impact on survival, Rome, Italy, May, 1985. 10. Whitmore WF: Interstitial radiation therapy for carcinoma of the prostate, Prostate 1: 157 (1980). 11. Gleason DF: Veterans Administration Cooperative Urological Research Group. Histologic grading and clinical staging of prostatic carcinoma, in Tanenbaum M (Ed): Urologic Pathology: The Prostate. Philadelphia, Lea and Febiger, 1977, p 85. 12. Fowler JE, and Whitmore WF: The incidence and extent of pelvic lymph node metastases in apparently localized prostate cancer, Cancer 47: 2941 (1981). 13. Be&son J, and Gage RP: Calculation of survival rates for cancer. Proc Staff Meet Mavo Clin 25: 270 (1950). 14. ‘Perez CA, Bauer W,‘Garza R, and Royce’RK: Radiation therapy in the definitive treatment of localized carcinoma of the prostate, Cancer 40: 1425 (1977). 15. Whitmore WF: Natural history and staging of prostate cancer, Urol Clin North Am 11: 205 (1984). 16. Bagshaw MA: Potential for radiotherapy alone in prostatic cancer, Cancer 55: 2079 (1985). 17. Bloom HJ: Prostate cancer: radiotherapy, recent results, Cancer Res 78: 132 (1981).
426
18. Muelenaere GF, and Sandison AG: Treatment of locally advanced prostatic carcinoma, Br J Radio1 49: 944 (1976). 19. Barzell W, Bean MA, Hilaris BS, and Whitmore WF: Prostatic adenocarcinoma: relationship of grade and local extent to the pattern of metastases, J Urol 118: 278 (1977). 20. El-Mahdi AM, Kuban DA, and Schellhammer PF: The treatment of choice for localized poorly differentiated adenocarcinema of the prostate, Am J Clin Oncol 8: 477 (1985). 21. Alison MR, and Wright NA: Prostate cancer: growth kinetics, recent results, Cancer Res 78: 29 (1981). 22. Boeden AE: Models for Prostatic Cancer. New York. Alan R. Liss, 1980. 23. Hall EJ: Radiobiology for the Radiologist, ed 2, Philadelphia, Harper & Row, 1978, p 153. 24. Bagshaw MA, Ray GR, and Cox RS: Radiotherapy of prostatic carcinoma: long- or short-term efficacy (Stanford University experience), Urology (Suppl) 25(2): 17 (i985j. 25. Whitmore WF, et al: Interstitial radiation: short-term palliation or curative therapy, ibid 25(2): 24 (1985). 26. Kramer SA, et al: Experience with Gleason’s histopathologic eradine in urostatic cancer. I Urol 124: 223 (1980). ;‘i-.“Redd;EK: Shankar G, andMansfield CM: External radiation therapy of localized prostatic cancer, J Nat1 Med Assoc 76: 61 (1984). 28. Forman JD, et aE: Improving the therapeutic ratio of external beam irradiation for carcinoma of the prostate, Int J Radiat Oncol Biol Phys 11: 2073 (1985). 29. Grossman HB, Batata M, Hilaris B, and Whitmore WF: rzsI implantation for carcinoma of prostate, Urology 10: 591 (1982).
UROLOGY
/
NOVEMBER
1987
/
VOLUME
XXX. NUMBER
5
A. KUBAN, M.D.
ANAS M. EL-MAHDI,
M.D.,
PAUL F. SCHELLHAMMER,
D-SC. M.D.
From the Department of Radiation Oncology and Biophysics, and Department of Urology, Eastern Virginia Medical School, Norfolk, Virginia
ABSTRACT-Of 495 patients definitively irradiated for prostatic carcinoma, 286 with a minimum follow-up of thirty-six months were studied. While tumor histology appeared to predict prognosis, the poorly differentiated tumors showing the highest incidence of distant metastasis and the lowest survival, local tumor control was an important factor within the poorly differentiated group. Of those with local recurrence, distant metastases developed in 68 per cent compared with 37 per cent of those with no local disease (p = 0.025). Survival was similarly affected with 86 per cent of those with locally controlled tumor who were alive at five years (not significantly different from the more well-differentiated tumors) versus a 56 per cent actuarial survival in those with locally recurrent disease (p < 0.05).
If one takes to heart the evidence that only 1 to 2 per cent of all patients with carcinoma of the prostate are potentially curable,1-3 then we must ask the question, why do many more times this number of patients receive treatment for their primary disease .4 If ultimately, “the only patients who can be cured are those with welldifferentiated tumors confined to the prostate,“’ is our treatment of the poorly differentiated prostatic tumors of any value? Can we alter, at all, that grim prognosis so frequently associated with undifferentiated prostatic cancerPss It would seem only logical that, just as for other primary tumor sites,9 local control in prostatic adenocarcinoma would prove advantageous, rendering our therapeutic endeavors, after all, beneficial. To determine, then, whether or not there is actually a subset among those with poorly differentiated lesions who are
420
positively affected by our prescribed treatment, the relationship between local tumor control, distant metastasis, and survival was investigated. Material and Methods Of 495 patients with biopsy-proved adenocarcinoma of the prostate definitively irradiated at the Eastern Virginia Medical School’s Department of Radiation Oncology between January, 1976, and December, 1984, 286 patients, clinically Staged A2 to C, with a minimum follow-up of thirty-six months were studied. Patients’ ages ranged from forty-eight to eighty-five years with an average and a median age of sixty-six and sixty-seven years, respectively. One hundred seventy-eight patients were treated with external beam irradiation (XRT) consisting of 62-65 Gy to the prostate over six
UROLOGY
/ NOVEMBER
1987
/ VOLUME
XXX, NUMBER 5
and one-half weeks with 4 mV photons in earlier years and 10 mV photons more recently. Patients with more advanced stage disease concomitantly received 40-45 Gy to the pelvic lymph node drainage sites. One hundred eight patients were treated with iodine-125 (1251) implantation and pelvic lymph node dissection, using the Whitmore technique,‘O for an average prostatic dose of 160 Gy to an average volume of 5 x 5 x 5 cm. All tumors were histologically graded according to a modified Gleason system”: Well differentiated
TABLE I.
Tumor histology and stage by treatment modality XRT
Histology Well differentiated Moderately differentiated Poorly differentiated Stage
70 60 48
44 39 25
23 12 70 73
11
A2
B, I32
C
Gleason 2, 3, 4 (MD)Gleason 5, 6, 7 (PD)Gleason 8, 9, 10
Table I lists tumor differentiation by treatment modality. Tumors in all patients were clinically staged by digital rectal examination. Further evaluation included intravenous pyelography, chest xray film, radioisotopic bone scan and serum acid phosphatase, and liver enzyme laboratory studies. More recently, patients at risk for pelvic lymph node involvement were studied by computerized axial tomography while earlier cases had pelvic lymphangiography. Patients were classified using a modified Fowler-Whitmore staging system12: AS-Tumor, well differentiated, in more than 3 chips or any moderately or poorly differentiated tumor in chips removed for presumed benign disease. Bl-Tumor 1.5 cm or less in diameter and limited to one prostatic lobe. B2-Tumor greater than 1.5 cm in diameter or involving more than one lobe. C -Tumor with evidence of extension beyond the prostatic capsule or involving the seminal vesicles. Dl-Regional lymph node metastasis. DB-Disseminated disease. Table I gives the number of patients in each stage with reference to treatment modality. With the exception of two tumors, one Stage A2 and one Stage Bl, all poorly differentiated lesions were Stage B2 or C. Eleven patients, whose disease was upstaged by findings at pelvic lymphadenectomy, were assigned their clinical stage for the purpose of this study to maintain uniformity between treatment groups.
UROLOGY
9 59 29
(WD)-
Moderately differentiated Poorly differentiated
1251
Tumor
TABLE II.
Per cent distant meta.stasis by tumor differentiation
Tumor
Distant Metastasis
Well differentiated Moderately differentiated Poorly differentiated
111114 30199 35173
%
P
10
o oo5
2;
0:05
All patients have been clinically examined at regular intervals by the same urologist and radiation oncologist with a median follow-up of fifty-four months for the entire group. Local recurrence of disease was defined as progressive palpable prostatic tumor on serial digital rectal examinations with rebiopsy confirmation of tumor in all equivocal cases. Local tumor control and its effect on distant metastasis and survival was assessed with attention to tumor grade and stage. Comparative analysis was appropriately carried out by using either Fisher’s exact test or chi-square test with survival analysis by the Berkson-Gage method. l3 Results In analyzing the incidence of distant metastasis by tumor histology for the entire group of 286 patients, a significant, progressive increase in tumor dissemination was seen with loss of histologic differentiation (Table II). Likewise, in calculating five-year actuarial and diseasefree survival for the complete group, there was a trend toward fewer survivors with the poorly differentiated tumors although the difference between the moderately and poorly differentiated groups was not statistically significant (Figs. 1 and 2). Within the poorly differentiated group, stage proved to be important since in 30 per cent of patients with Stage B2 tumors
/ NOVEMBER 1987 / VOLUME XXX, NUMBER 5
421
30
0
30
WD
?? MD 0
20
PD
-I
lo0 0
0 WD
1
m
MD
0
PD
loI 3
I 2
I 1 YEARS
AFTER
t 4
0
r 5
I 1
0
YEARS
TREATMENT
8
I
I
I
2
3
4
5
AFTER
TREATMENT
FIGURE 1. Comparison of survival by tumor differentiation.
FIGURE 2. Comparison differentiation.
metastatic disease developed compared with 61 per cent of patients with Stage C lesions. While there was no significant stage-dependent difference in five-year overall survival, survival without disease was significantly better for Stage B2 than for Stage C tumors (60% versus 28 %) (Table III). Local tumor control following definitive prostatic irradiation was assessed by tumor histology and treatment modality (Table IV). In
comparing lz51 implantation to external beam irradiation in the well and moderately differentiated neoplasms, there appeared to be no significant difference in the incidence of local tumor recurrence (9 % versus 4 % and 28 % versus 18%, respectively). However, when local failure was tabulated for the poorly differentiated group, in 56 per cent of those patients treated with 1251local tumor recurrence developed as opposed to only 23 per cent of those patients treated with external beam irradiation (p = 0.008). Therefore, while the incidence of local tumor recurrence was significantly higher for the lz51 group as a whole as compared with the external beam group (27 % versus 14 % , p = 0.025), this was only by virtue of the treatment-related difference in local tumor control in the poorly differentiated subset. In this histologic group, the treatment modality dependent-difference in local tumor control
TABLE III. Comparison of incidence of metasta.si.s, survival, and disease-free survival in Stage Bz vs Stage C poorly differentiated tumors Met. (%) Survival ( % ) NED survival ( % )
Bz
C
P
9/30 (30) 82 60
25/41 (61) 69 28
0.025 NS 0.05
TABLE IV. Incidence
Tumor Well differentiated Moderately differentiated Poorly differentiated TOTALS
422
of local recurrence,
-----Iodine-125No. of Local Pts. Recurrence
iodine-125
%
No. of Pts.
of NED survival by tumor
and XRT XRT Local Recurrence
%
44 39 25
4 11 14
9 28 56
70 60 -48
3 11 11
4 18 23
10s
29
27
178
25
14
UROLOGY
/ NOVEMBER1987
/ VOLUMEXXX,NUMBERS
TABLE V. Local recurrence by stage and treatment modality of poorly differentiated tumors
Tumor Stage
1251( % )
B2 C
5/14 (36) 9111 (82)
Local RecurrencXRT (%) 1116 (6) 10/30 (33)
P 0.059 0.997
TABLE VI.
Local recurrence within each treatment group according to stage in poorly differentiated tumors
Treatment Modality 1251
XRT
Local RecurrencC (%) 5114 (36) 9111 (82) l/l6 (6) 10130 (33) R, (%)
P 0.027 0.040
also was maintained within each stage (Table V) . Two patients with poorly differentiated disease, one each Stages A2 and Bl, were not included in this analysis for lack of appropriate comparison. Likewise, tumor stage appeared to affect local failure within each treatment group, lz51 and external beam irradiation (Table VI).
TABLE VII.
The question of whether local tumor control affects the incidence of distant metastasis was addressed by comparing the incidence of distant metastasis with primary tumor control versus primary tumor recurrence according to tumor differentiation and treatment modality (Table VII). Comparative analysis within each histologic group was difficult due to the small number of patients in some groups. However, in those patients treated with external beam irradiation, in 22 per cent of all patients whose tumor was locally controlled distant metastases developed compared with 52 per cent of those who failed local therapy (p = 0.005). Similarly, in those patients treated with lz51, in 11 per cent of those with local tumor control metastatic disease developed versus 69 per cent of those with local tumor recurrence (p = 0.005). Since there was no significant difference in the incidence of distant metastasis based on treatment modality when like groups were compared, those with the same tumor differentiation and local control, the incidence of distant metastasis based on local tumor status was determined for both rz51and external beam irradiation patients combined (Table VIII).
Incidence of distant metastasis with local tumor control vs local recurrence in XRT and lz51 groups Distant Metastasis Local % Recurrence
Local Control
Tumor
XRT group Well differentiated Moderately differentiated Poorly differentiated TOTALS Iodine- 125 group Well differentiated Moderately differentiated Poorly differentiated TOTALS
%
6167 15149 13137 341153
9 31 35 22
213 4111 7/11 13125
66 36 64 52
O/40 4128 5111 9179
0 14 45 11
314 7/11 10/14 20129
75 64 71 69
TABLE VIII.
Incidence of distant metastasis based on local tumor status, XRT and 125Zpatients Distant Metastasis Local Recurrence %
%
Tumor
Local Control
Well differentiated Moderately differentiated Poorly differentiated
61107 19177 18148
6 25 37
517 11/22 17125
71 50 68
431232
18
33154
61
0.005
TOTALS
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P
423
TABLE IX. Five-year survival related to local tumor status for Stages Be and C in poorly diflerentiated, well differentiated, and moderately differentiated tumors
Local Control
Treatment Modality Poorly differentiated tumors XRT + lz51 XRT 1251
Well and moderately differentiated tumors XRT + le51 XRT 1251
looQO80702 605:
K
502 8 4o 3020lo0t
0
WD
0
PD
I
12
0
PD
/
E2
(+I
= Total
2 C with
Local
Control
& C rlth
Local
Fallurm
+ of
In Each
PatIenta
Inltlally
Control
Tr.at*d
DrouD
I
I
I
I
,
1
2
3
4
5
YEARS
FIGURE 3. ferentiation mors.
??MD / B2 & C with Local
0
AFTER
TREATMENT
Comparison of survival by tumor difand local control, Stages B2 and C tu-
Within each histologic group, those patients failing local control had a significantly higher incidence of metastatic disease than those with locally controlled disease. A second interesting finding is that in those patients with no evidence of local tumor recurrence the incidence of distant metastasis progressively increases as the histology becomes more poorly differentiated (col. 1, Table VIII). When five-year actuarial survival was evaluated for the poorly differentiated (Stages B2 and C) tumors, a significant difference was seen between those patients with local tumor control and those with local recurrence, 86 per cent
424
% Survival
Local Recurrence
86 83 91
56 63 58
89 87 92
78 81 76
versus 56 per cent (p < 0.05). Similar differences based on primary tumor status were also noted when this group was broken down by treatment modality although there was no treatment modality-dependent survival difference within either the local control or the local recurrence categories (Table IX). Patients with well and moderately differentiated Stages B2 and C lesions were analyzed in the same manner but without significant difference based on local tumor control (Table IX). An important observation was subsequently made when the survival data for both the poorly and the well-differentiated tumors were assimilated. Patients with poorly differentiated tumors that were locally controlled had a fiveyear survival which was comparable to the survival of those with well and moderately differentiated tumors of equal stage (B2 and C). Those patients with poorly differentiated tumors that recurred locally exhibited a survival curve with a progressive downward trend with significantly different results at five years compared with the patients with local tumor control (56 % vs 86-89 % , P < 0.05). Figure 3 illustrates these findings graphically. Comment Several authors have addressed the significance of histologic grade in prostatic adenocarcinema. 1,7*8~14-16 The propensity for distant metastasis developing with poorly differentiated tumor histology has been noted.‘J5 Our study, likewise, reveals a stepwise progression in disease dissemination from the well differentiated (10 %), to the moderately differentiated (30%) to the poorly differentiated tumors
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(48 % ) . Conflicting views emerge, however, when considering the influence of tumor differentiation on response to irradiation.“-re If response is measured in terms of local tumor control, our data do show patients with poorly differentiated lesions to be at a disadvantage when treated with lz51 implantation. In a previous comparison of definitive treatment modalities for high-grade prostatic carcinoma, we questioned whether or not the radiobiologic characteristics of the lz51 isotope were well suited to a biologically aggressive neoplasm.20 The “more poorly differentiated prostatic tumor types have high cell production rates”21 and shorter cell cycle times,22 preventing delivery of the “critical dose rate”23 by lz51interstitial therapy. While our overall recurrence rates for both external beam therapy and lz51 implant are comparable to other reported series,14s24,25only through dissection by tumor histology do we find a significantly higher local recurrence rate in the patients with poorly differentiated tumors treated with 1251. Although it has been stated that “the Gleason histologic grade represents the single most important observation”’ in prostatic carcinoma and that “local recurrence and distant disease appears to correlate well with the degree of histologic differentiation regardless of tumor stage,“26 within our poorly differentiated group, stage proved to be a significant factor in the incidence of local failure. We also found that tumor stage influenced the incidence of distant metastasis and survival without disease in those patients with like histology, all poorly differentiated. This effect of tumor stage has been noted by others as well.5.7Jg,27,28 Since irradiation is a locally directed therapeutic modality, it seems most appropriate to determine whether or not successful treatment of this primary tumor site has any effect on distant metastasis and survival. Indeed, we did see a significantly higher incidence of distant disease in those patients whose primary tumor recurred. Grossman et ~1.~~have suggested that “such metastases may result from recurrences.” It is also thought, however, that high-grade carcinoma has a greater tendency to be already disseminated at diagnosis,’ which supports the progressive increase in distant metastasis with decreasing tumor differentiation seen in our patients with adequately controlled primary disease. It, therefore, appears that distant failure may be a consequence of pretreatment meta-
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stasis, incomplete local control, or, most likely, both factors.15 Survival also seems to be affected by local tumor control. Even those patients on whom high-grade histology has classically bestowed a poor prognosis do relatively well if their primary tumor has not recurred. In fact, in our study, those patients with poorly differentiated tumors which were locally controlled enjoyed a survival comparable to their locally controlled well and moderately differentiated counterparts while patients with locally recurrent poorly differentiated prostatic carcinomas retained a more dismal prognosis. The lack of survival advantage based on local control in the more well-differentiated tumors may be due to a lower biologic malignant potential and slower growth rate necessitating a longer follow-up period for detection of survival difference. In conclusion, then, local tumor control does indeed appear to affect the incidence of distant metastasis and, in poorly differentiated prostatic tumors, five-year survival. So that our patients may obtain maximum therapeutic benefit, we should perhaps be mindful of the improvement in local tumor control associated with external beam irradiation compared with 1251 therapy in high-grade lesions. Finally, within the time interval of our follow-up, it does appear that definitive irradiation can be successful in a subset of patients previously thought to have the most dismal prognoses. 600 Gresham Drive Norfolk, Virginia 23507 (DR. KUBAN) ACKNOWLEDGMENTS. To Therese Bahb and Rebecca Becker for their expert assistance in data collection and analysis as well as Myra Frost and Renee Sipe for help in preparing this manuscript.
References 1. Stamey TA: Cancer of the Prostate. An analysis of some important contributions and dilemmas, in Stamey TA (Ed): Monographs in Urology, Princeton, Custom Publishing Services, Inc., 1983, p 68. 2. Jewett HJ: The case for radical perineal prostatectomy, J Urol 103: 195 (1970). 3. Walsh PC, and Jewett HJ: Radical surgery for prostatic cancer, Cancer 45: 1996 (1980). 4. Murphy GR et al: The national survey of prostate cancer in the United States by the American College of Surgeons, J Urol 127: 928 (1982). 5. Cupps RE, et al: Definitive radiation therapy for prostatic carcinoma: Mayo Clinic experience, ibid 124: 855 (1980). 6. Harisiadis L, et al: Carcinoma of the prostate: treatment with external radiotherapy, Cancer 41: 2131 (1978).
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7. Grayhack JT, and Assimos DG: Prostatic significance of tumor grade and stage in the patient with carcinoma of the prostate, Prostate 4: 13 (1983). 8. Gleason DF, and Mellinger GT: Veterans Administration Cooperative Urological Research Group. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging, J Urol 111: 58 (1974). 9. Proceedings of the Third Rome International Symposium: The challenge of local tumor control and its impact on survival, Rome, Italy, May, 1985. 10. Whitmore WF: Interstitial radiation therapy for carcinoma of the prostate, Prostate 1: 157 (1980). 11. Gleason DF: Veterans Administration Cooperative Urological Research Group. Histologic grading and clinical staging of prostatic carcinoma, in Tanenbaum M (Ed): Urologic Pathology: The Prostate. Philadelphia, Lea and Febiger, 1977, p 85. 12. Fowler JE, and Whitmore WF: The incidence and extent of pelvic lymph node metastases in apparently localized prostate cancer, Cancer 47: 2941 (1981). 13. Be&son J, and Gage RP: Calculation of survival rates for cancer. Proc Staff Meet Mavo Clin 25: 270 (1950). 14. ‘Perez CA, Bauer W,‘Garza R, and Royce’RK: Radiation therapy in the definitive treatment of localized carcinoma of the prostate, Cancer 40: 1425 (1977). 15. Whitmore WF: Natural history and staging of prostate cancer, Urol Clin North Am 11: 205 (1984). 16. Bagshaw MA: Potential for radiotherapy alone in prostatic cancer, Cancer 55: 2079 (1985). 17. Bloom HJ: Prostate cancer: radiotherapy, recent results, Cancer Res 78: 132 (1981).
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18. Muelenaere GF, and Sandison AG: Treatment of locally advanced prostatic carcinoma, Br J Radio1 49: 944 (1976). 19. Barzell W, Bean MA, Hilaris BS, and Whitmore WF: Prostatic adenocarcinoma: relationship of grade and local extent to the pattern of metastases, J Urol 118: 278 (1977). 20. El-Mahdi AM, Kuban DA, and Schellhammer PF: The treatment of choice for localized poorly differentiated adenocarcinema of the prostate, Am J Clin Oncol 8: 477 (1985). 21. Alison MR, and Wright NA: Prostate cancer: growth kinetics, recent results, Cancer Res 78: 29 (1981). 22. Boeden AE: Models for Prostatic Cancer. New York. Alan R. Liss, 1980. 23. Hall EJ: Radiobiology for the Radiologist, ed 2, Philadelphia, Harper & Row, 1978, p 153. 24. Bagshaw MA, Ray GR, and Cox RS: Radiotherapy of prostatic carcinoma: long- or short-term efficacy (Stanford University experience), Urology (Suppl) 25(2): 17 (i985j. 25. Whitmore WF, et al: Interstitial radiation: short-term palliation or curative therapy, ibid 25(2): 24 (1985). 26. Kramer SA, et al: Experience with Gleason’s histopathologic eradine in urostatic cancer. I Urol 124: 223 (1980). ;‘i-.“Redd;EK: Shankar G, andMansfield CM: External radiation therapy of localized prostatic cancer, J Nat1 Med Assoc 76: 61 (1984). 28. Forman JD, et aE: Improving the therapeutic ratio of external beam irradiation for carcinoma of the prostate, Int J Radiat Oncol Biol Phys 11: 2073 (1985). 29. Grossman HB, Batata M, Hilaris B, and Whitmore WF: rzsI implantation for carcinoma of prostate, Urology 10: 591 (1982).
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