Combined Gold Seed Implantation and External Radiotherapy for Stage B2 or C Prostate Cancer

0022-534 7/88/1395-0989$02.00/0 Vol. 139, May Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright© 1988 by The Williams & Wilkins Co.

COMBINED GOLD SEED IMPLANTATION AND EXTERNAL RADIOTHERAPY FOR STAGE B2 OR C PROSTATE CANCER PETER 0. CAREY, MARGUERITE C. LIPPERT, WILLIAM C. CONSTABLE, DAVID JONES BROOKS M. TALTON

AND

From the Departments of Urology and Radiation Oncology, University of Virginia Medical School, Charlottesville, Virginia, and Holston Valley Medical Center, Kingsport, Tennessee

ABSTRACT

Patients with clinical stage B2 or C prostatic carcinoma represent a group for which there are several treatment options. We followed the course and outcome of 72 patients with clinical stages B and C prostate cancer who were treated with surgical staging, insertion of gold grains and external radiation at our institutions between 1975 and 1984. Of the patients 44 (61 per cent) had clinical stage B disease and the majority (89 per cent) of these were stage B2 lesions. The remaining 28 patients (39 per cent) had clinical stage C tumors. In our series 27 per cent of the clinical stage B and 68 per cent of the clinical stage C cancer patients had positive lymph nodes. The 5-year survival free of disease was 52 per cent for patients with both stages of disease. The 7-year survival free of disease was 47 per cent for patients with clinical stage B and 14 per cent for those with clinical stage C cancer. Lymph node status did not have a statistically significant effect on total survival but survival free of disease correlated significantly with node status. Local treatment failures were defined as patients who required transurethral prostatic resection or orchiectomy for palliation of obstructive symptoms related to local tumor regrowth. By these criteria we prevented local progression in 78 per cent of the patients at 5 years. (J. Ural., 139: 989-994, 1988) The best mode of treatment for localized prostatic cancer remains an unsettled issue. Only a small fraction of patients present with the small, well defined (Jewett staging) nodule needed for optimal candidacy for radical prostatectomy. Even patients believed to have minimal disease frequently have microscopically invasive tumor at prostatectomy. Survival data for these radical prostatectomy patients with clinically localized (stage Bl) disease show the 15-year survival rate to be approximately 50 per cent.1 In a recent review Stamey calculated that only 1 to 2 per cent of all prostate cancer patients can be cured by current treatment modalities. 2 Unlike stage Bl lesions, a much larger group of patients have extensive, intracapsular disease (stage B2) and stage C lesions. However, such patients are not ideally treated by radical surgery. Several alternative therapeutic options have been studied during the last few decades. Bagshaw and other proponents of definitive, external radiotherapy have indicated favorable survival data while avoiding surgical morbidity. However, the high dose of radiation needed to control or to eradicate localized prostatic cancer also was associated with a significant frequency of complications. Flocks and associates called attention to the option of localized, interstitial radiation with colloidal gold in the 1950s. Interstitial radiation offers the advantage of delivering a high dose of radiation to the tumor, while at the same time sparing the remaining pelvic organs from some of its deleterious effects. During the last 15 years this type of treatment has been pursued extensively by Whitmore and associates via staging pelvic lymph node dissection in conjunction with interstitial 125iodine (125I} seeds.a This regimen has provided a 9-year actuarial survival rate of 60 to 90 per cent for clinical stage B cancer patients and 45 per cent for those with stage C disease.a Scardino and associates advocated interstitial irradiation for localized prostate cancer with radioactive gold seeds (1 98Au) implanted at pelvic lymphadenectomy, followed by 4,000 to 5,000 rad delivered by linear accelerator. 4 The advantages of 198Au over 1251 are reflected by the enhanced tissue penetrance Accepted for publication September 8, 1987.

and higher energy of the gold seeds, which allow more reliable tumor dosimetry. Scardino and associates reported on 232 patients with clinical stages A2, Bl, B2 and C disease, and they found an over-all 90 per cent actuarial survival rate at 5 years and a 68 per cent rate at 10 years. 4 This treatment approach (pelvic lymph node dissection, gold seed implants and external radiation) was adopted at our hospital in the mid 1970s for a somewhat different group of patients with bulkier tumors. Patients with somewhat more extensive, albeit local, disease (clinical stages B2 and C) have been offered the aforementioned interstitial radiation treatment regimen and their course provides the basis for our study of treatment efficacy. No other investigators have addressed the outcome of patients treated with the gold seed protocol of Scardino and associates. MATERIALS AND METHODS

A total of 72 patients with prostatic cancer followed between 1975 and 1984 form the basis for this survey. Mean patient age at operation plus gold seed implantation was 65. 7 years, with a range of 51 to 77 years. Average followup or interval to last contact was 5.0 years, with a range of 12 months to 9.1 years. All patients had biopsy proved, clinical stage B or C adenocarcinoma of the prostate, and they all underwent retropubic bilateral pelvic lymph node dissection and received radioactive 198Au seed implantation by a radiation oncologist. Radiotherapy. The volume implanted included the entire prostate. The seeds were inserted at varying depths through cannulae, the location of which were controlled by a finger in the rectum. Usually, 6 to 8 seeds of about 4 mCi. were required. Postoperatively, a computerized tomography scan provided localization of the seeds within the prostate as reported previously,5·6 as well as the data for computerized dosimetry in a number of planes (fig. 1). An advantage of 198Au is that the range of the photons tends to eliminate cold spots while at the same time still contributing a high dose centrally within the prostate. It was calculated preoperatively that a 3,000 to 3,500 rad isodose line would encompass the prostate and this was confirmed by the dosimetry obtained (fig. 2).

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CAREY AND ASSOCIATES

FIG. 1. Computerized dosimetry for gold seeds in patient. A, coronal plane. B, sagittal plane

FIG. 2. A, coronal plane isodose lines (see fig. 1, A) applied to anteroposterior pelvis x-ray. B, sagittal plane isodose lines (see fig. 1, B) applied to lateral pelvis x-ray.

After the brachytherapy and surgery, an additional 4,000 rad were delivered in 20 treatments given for 5 days per week with a 6 MV. linear accelerator. A rotational technique was used, with the radiopaque 198Au seeds providing a convenient localizing method. The usual field size was 6 X 6 or 7 X 7 cm. The essence of the combined radiotherapy was to decrease excessive irradiation to the sensitive tissues surrounding the prostate by delivering a substantial portion of the dose by brachytherapy. In addition, the range of the 198Au photons and the external radiation would tend to eliminate areas of underdosage within the prostate and provide a certain homogeneity. The preoperative clinical stage of disease in this series was deduced by all or several of the usual staging measures, including physical examination, excretory urography, acid and alkaline phosphatase levels, and bone scan. No patient with stage A disease was treated with the gold seed protocol, nor were any patients with detectable, distant spread of disease. Clinical stage B tumors were divided into stage Bl-tumors involving less than 1 lobe of the prostate and stage B2-tumors involving an entire lobe or both lobes. Clinical stage C tumors were those extending beyond the prostate on digital rectal examination.

Survival data for the 72 patients were calculated by total survival and survival free of disease. Total survival was based on whether patients were alive or dead and paid no heed to cause of death, disease status or interval use of other therapeutic modalities (for example orchiectomy, diethylstilbestrol and so forth). Survival free of disease described the interval until relapse in those patients who, for example, required hormonal treatment for recurrent disease. The free of disease status was judged by history, physical examination and acid phosphatase levels, with a chest x-ray and bone scan when clinically appropriate. Patients who had a steady increase in the acid phosphatase level were considered to have relapse even if they were asymptomatic. The various types of treatment failures were tabulated for our series. Local treatment failure was one that resulted in symptoms and signs of bladder outlet obstruction. Therefore, we categorized local progression as the requirement for transurethral prostatic resection or orchiectomy for palliation of symptoms related to local tumor recurrence. Total survival, survival free of disease and local control were interpreted to give actuarial probabilities with Kaplan-Meier

991

RADIOTHERAPY FOR STAGE B2 OR C PROSTATE CANCER

curves. 7 This actuarial method incorporates all followup information on the patient group regardless of how long an individual was followed. Comparisons of the curves for total survival or survival free of disease between patient groups (stage B vernus C, or positive versus negative nodes) were done with the test. 8 A list of p values thereby is generated to assess statistically significant differences between the survival curves. RESULTS

Of the 72 patients studied preoperative clinical staging revealed 44 (61 per cent) with clinical stage B and 28 (39 per with stage C cancer. All but 5 of the former 44 patients had clinical stage B2 lesions (89 per cent). To assess the frequency of understaging clinically limited cancer, we compared clinical and pathological stages on results of lymph node dissection. Of the patients with clinical stages B and C disease 27 and 68 per cent, respectively, were already suffering from regional lymph node metastases at the time of diagnosis and treatment. Over-all, 43 per cent of the patients treated had positive lymph nodes. Probabilities for total survival and survival free of disease at TABLE 1.

Actuarial total suruiual and suruiual free of disease Survival Free of Disease*

Total Survival Total No. Pts. Clinical stage: B C Nodal status: Pas. Neg.

5-Yr. No.(%)

7-Yr. No.(%)

5-Yr. No.(%)

7-Yr. No.(%)

44 28

18 (74) 17 (73)

5 (60) 6 (63)

10 (52) 9 (52)

1 (47) 1 (14)

31 41

18 (70) 17 (79)

6 (61) 5 (63)

9 (38) 10 (69)

0 (0) 2 (69)

* Based on 67 of 72 adequately evaluated patients.

5 and 7 years are summarized in table 1. Total actuarial survival at 5 years was 73 to 74 per cent for clinical stages B and C disease. At 7 years total survival decreased to 60 and 63 per cent for both stages. To date we have had no IO-year survivors among the patients studied. There was no statistically significant difference in total survival rate for clinical stage B versus clinical stage C disease. Total survival percentages based on lymph node status also revealed no significant difference between patients with positive and negative lymph nodes using the log-rank test. Table 1 also shows the calculated survival probabilities free of disease. Of 72 patients 67 were evaluated sufficiently to be included in the no evidence of disease calculations. Five-year actuarial survival free of disease was obtained in 52 per cent of the patients with clinical stages B and C disease. At 7 years only 47 per cent of the stage B and 14 per cent of the stage C cancer patients were free of disease. Differences between stage-related survival rates free of disease were not significant. The effect of lymph node status on survival free of disease was similarly calculated. The 5-year rates were 69 per cent among patients with negative and 38 per cent with positive lymph nodes, while the 7-year rates were 69 and O per cent, respectively. Differences between nodal status-related survival free of disease were significant with the log-rank test. Figure 3 plots total actuarial survival probabilities based on clinical stage and lymph node status, respectively. Both curves are similar, and reflect the fact that clinical stage and nodal status had little effect on total survival in our patients. Figure 4 depicts survival free of disease among our 67 evaluable patients. Figure 4, A plots survival free of disease according to clinical stage. The curves suggest that patients with clinical stage B disease may experience longer intervals free of disease than those with clinical stage C cancer. The difference between these curves approached but did not reach statistical significance. In figure 4, B survival free of disease is analyzed

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992

CAREY AND ASSOCIATES

according to lymph node status. These curves confirm that patients with benign pelvic lymph nodes were more likely to remain free of recurrent disease than those with positive lymph nodes. Differences between these curves were significant (p = 0.0004). Of the total 72 patients 67 were evaluated sufficiently to assess for lack of local progression of the disease. Figure 5 illustrates the likelihood of no local progression in the gold seed-treated patients. The actuarial probability of lack of local progression at 5 and 7 years was 78 and 64 per cent, respectively. Most patients with locally recurrent disease. also suffered distant metastases (local and distant failures) and 14 more had distant metastases only. Over-all, 24 of the 67 evaluable patients (36 per cent) showed progression of the disease to bone, lung and so forth, and they were treated appropriately. Finally, 4 patients (6 per cent) had a consistently elevated acid phosphatase level and they were considered no longer to be free of disease although they are asymptomatic and the site of recurrence was undetermined. Morbidity and mortality. There were 2 postoperative deaths in our series. One patient died of a pulmonary embolus 5 weeks postoperatively and 1 died of cardiac failure 4 weeks postoperatively. Complications from surgery included conditions recognized by the urologist within 1 month postoperatively. Overall, our complication rate was comparatively high: 17 of 72 patients (24 per cent) had complications that ranged from minor problems with wound healing to more serious deep venous thromboses and pulmonary emboli (table 2). Reactions from irradiation were frequent but mild. The majority of the complaints during the postoperative external radiation therapy were attributable to mild radiation proctitis and cystitis. These radiation-related complaints resolved spontaneously in all patients. DISCUSSION

The literature is replete with uncontrolled reports of various treatment modalities for carcinoma of the prostate. Whether a patient with, for example, stage B carcinoma is treated by a radical operation, external radiation, interstitial radiation, hor-

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monal therapy or no therapy seems to depend more on which medical center is directing the treatment than on any rational scientific basis. Our results unfortunately do not solve this therapeutic dilemma for localized prostatic cancer. Rather, we add our results to those already reported for comparison to help the clinician who must advise and treat patients with prostatic cancer. Our figures for morbidity (24 per cent) and mortality (2 of 72) are less favorable than those from reports of staging lymph node dissection and interstitial (with or without external) radiation. Scardino and associates reported 2 deaths among 542 patients, 4 while Whitmore and associates reported only 4 deaths among 900 patients. 3 Many patients believed to have clinically localized prostate cancer already have regional, pelvic lymph node metastases at diagnosis and treatment. In our series 27 per cent of the clinical stage B and 68 per cent of the clinical stage C cancer patients had surgical state Dl disease as determined by node dissection. These percentages are in accord with previous reports on pelvic lymph node dissections. In a report on 1251 implantation Whitmore found positive nodes in 11 of 52 patients (21 per cent) with clinical stage B and 24 of 39 (62 per cent) with clinical stage C disease. 9 Scardino and Wheeler found pelvic lymph node metastases in 28 per cent of the patients with clinical stage Band 43 per cent with clinical stage C cancer. 10 Most of our clinical stage B cancer patients (89 per cent) treated with gold grains had stage B2 lesions. This finding differs from previous studies of interstitial radiotherapy in which clinical stage Bl cancer patients were commonly included in the protocol. Nonetheless, total survival probabilities in our series were similar to those of earlier reports. Our total survival probability curves reflect little influence by clinical stage or even nodal status. Five-year survival was approximately 75 per cent among our patients regardless of lymph node status or clinical staging (B versus C). This figure is in accord with the results of Scardino and associates, who attained 5-year survival in 100 per cent of the patients with clinical stage Bl, 81 per cent with clinical stage B2 and 86 per cent with clinical stage Cl disease.• Their data suggested a correlation between survival and nodal status, although the differences were not statistically significant. A recent update by Whitmore and associates included crude 5-year survival data (not actuarial) that were similar to those of the gold seed studies. 3 At their institution, using 1251 implantation, crude 5-year survival was attained in 138 of 155 (89 per cent) of the clinical stage B cancer patients (Tl and T2) and in 50 of 85 (59 per cent) of the clinical stage C cancer patients (T3 and T4). Among 143 patients with benign pelvic lymph nodes 125 (87 per cent) lived for 5 years, compared to 63 of 96 (66 per cent) with positive lymph nodes. Admittedly, prostatic cancer is a slowly progressive disease and 10-year survival figures are the best gauge of treatment efficacy. Unfortunately, most of our 72 patients underwent treatment after 1977 and we currently do not have any 10-year survivors from whom to generate meaningful figures. However, we do offer 7-year survival data as an approximation of the desired, longer term followup. We show 60 and 63 per cent actuarial 7-year survival rates for clinical stages Band C cancer, respectively, and again there is little if any variability based on lymph node status. By comparison, Scardino and associates achieved 10-year actuarial survival in 84, 52 and 73 per cent of the patients with clinical stages Bl, B2 and Cl disease, respectively.• Their 10-year survival rate was 75 per cent for patients with negative lymph nodes versus 49 per cent for those with positive nodes. Our 7°year survival rate was 61 to 63 per cent regardless of nodal status. As mentioned previously, the majority (89 per cent) of our clinical stage B cancer patients had stage B2 disease. Patients of the appropriate biological age with well localized stage B 1 disease usually have undergone radical prostatectomy at our institution.

RADIOTHERAPY FOR STAGE B2 OR C PROSTATE CANCER

Our results indicate that we were as successful in obtaining prolonged survival free of disease as earlier investigators. Of the evaluable patients with clinical stages B and C disease 52 per cent had no evidence of disease at 5 years. In comparison, Scardino and associates achieved a 5-year actuarial survival free of disease in 71 per cent of the clinical stage Bl, 59 per cent of the clinical stage B2 and 46 per cent of the clinical stage Cl cancer patients.• Our curves for survival free of disease confirm the fact that patients with negative pelvic lymph nodes will remain free of disease longer than those with positive lymph nodes. Scardino and associates also found that nodal status had a statistically significant effect on survival free of disease.• In their series the 5.,year actuarial survival free of disease was 76 per cent for patients with negative nodes and 30 per cent for those with positive pelvic lymph nodes. Our figures were 69 and 38 per cent, respectively, for the 2 groups. Our results confirm that local progression of clinical stages B and C prostate cancer is preventable in most patients with combined interstitial and external radiation. While we did not pursue systematic re-biopsy of treated prostates, with the clinical criteria outlined previously we prevented local progression in 78 per cent of our evaluable patients at 5 years. According to Walsh and Jewett in 1980, 15-year survival for clinical stage B2 cancer patients treated with radical prostatectomy is poor (18 per cent). 1 Thus, our patients probably would not have been treated best with radical prostatectomy. In an attempt to determine the best method to treat patients with larger stage B or stage C tumors, one can compare the risks and benefits of our 198Au seed protocol against those of pure external beam megavoltage irradiation and against the risks of rendering no immediate therapy. While prostatic cancer often is referred to as a heterogeneous tumor, one can estimate the natural history of patients with bulkier prostatic cancer from the Veterans Administration Cooperative Urological Research Group study of 1967. 11 A different staging system was used but their stage III cancer patients (which would now be called clinical stage C) had a 5-year actual survival of only 50 to 55 per cent when treated with placebo. Furthermore, Hanash and associates in 1972 noted a 5-year survival rate of 20 per cent among clinical stage B prostatic cancer patients treated with transurethral resection only. 12 Most of these patients (85 per cent) had clinical stage B2 lesions. These 2 studies confirm the lethal nature of even localized prostatic cancer, against which the therapeutic effects of various types of treatment can be measured. The alternative of treating stages B and C cancer patients with definitive external beam radiation has been advocated by some investigators during the last decade. Bagshaw and associates reported a 70 per cent actual 5-year survival rate for disease limited to the prostate, versus 37 per cent for patients with extracapsular extension. 13 In comparison, with interstitial gold seeds we attained 73 to 74 per cent actuarial survival at 5 years for clinical stages B and C cancer patients, as did Scardino and associates. 4 Use of interstitial gold seeds allows delivery of a biologically more effective dose of radiation to the initially resistant hypoxic center in the larger prostatic cancers. The increased biological effect of brachytherapy compared to conventional fractionation has been demonstrated clinically by Ellis and Sorenson, 14 and Pierguin and associates. 15 This absence of a decreased response to low dose rates also has been observed in animal models and it is attributed to the combined effect of re-oxygenation that increases radiosensitivity and the decreased rate of sublethal damage for chronically hypoxic cells. 16• 17 Thus, it is likely that 198Au interstitial radiation therapy is an effective means to treat patients with stage B2 or C prostate cancer. Cure of patients with bulkier forms of local disease, however, remains an elusive goal and the optimal regimen for survival free of disease has yet to be determined.

993

Dr. Donald Kaiser assisted in the statistical analysis of our data. REFERENCES

1. Walsh, P. C. and Jewett, H.J.: Radical surgery for prostatic cancer. Cancer, 45: 1906, 1980. 2. Stamey, T. A.: Cancer of the prostate. Monogr. Urol., 4: 67, 1982. 3. Whitmore, W. F., Jr., Hilaris, B., Batata, M., Sogani, P., Herr, H. and Morse, M.: Interstitial radiation: short-term palliation or curative therapy. Urology, suppl. 2, 25: 24, 1985. 4. Scardino, P. T., Guerriero, W. G. and Carlton, C. E., Jr.: Surgical staging and combined therapy with radioactive gold grain implantation and external irradiation. In: Genitourinary Tumors: Fundamental Principles and Surgical Techniques. Edited by D. E. Johnson and M. A. Boileau. New York: Grune & Stratton, Inc., chapt. 6, pp. 75-90, 1982. 5. Elkon, D., Kim, J. A. and Constable, W. C.: Anatomic localization of radioactive gold seeds of the prostate by computer-aided tomography. CT, 5: 98, 1981. 6. Elkon, D., Kim, J. A. and Constable, W. C.: CT scanning and interstitial therapy. CT, 5: 268, 1981. 7. Kaplan, E. L. and Meier, P.: Nonparametric estimation from incomplete observations. J. Amer. Stat. Ass., 53: 457, 1958. 8. Petro, R. and Petro, J.: Asymptomatically efficient rank invariant test procedures. J. Roy. Stat. Soc., series A, 135: 185, 1972. 9. Whitmore, W. F., Jr.: Interstitial radiation therapy for carcinoma of the prostate. Prostate, l: 157, 1980. 10. Scardino, P. T. and Wheeler, T. M.: Prostatic biopsy after irradiation therapy for prostatic cancer. Urology, suppl. 2, 25: 39, 1985. 11. The Veterans Administration Co-operative Urological Research Group: Treatment and survival of patients with cancer of the prostate. Surg., Gynec. & Obst., 124: 1011, 1967. 12. Hanash, K. A., Utz, D. C., Cook, E. N., Taylor, W. F. and Titus, J. L.: Carcinoma of the prostate: a 15-year followup. J. Urol., 107: 450, 1972. 13. Bagshaw, M. A., Ray, G. R., Pistenma, D. A., Castellino, R. A. and Meares, E. M.: External beam radiation therapy of primary carcinoma of the prostate. Cancer, 36: 723, 1975. 14. Ellis, F. and Sorenson, A.: A method of estimating biological effect of combined intracavitary low dose rate radiation with extended radiation in carcinoma of the cervix uteri. Radiology, 110: 681, 1974. 15. Pierquin, B., Calitchi, E., Mazeron, J. J., Le Bourgeois, J. P. and Leung, 8.: A comparison between low dose rate radiotherapy and conventionally fractionated irradiation in moderately extensive cancers of the oropharynx. Int. J. Rad. Oncol. Biol. Phys., 11: 431, 1985. 16. Hill, R. P. and Bush, R. S.: The effect of continuous or fractionated irradiation on a murine sarcoma. Brit. J. Rad., 46: 167, 1973. 17. Baker, D. G., Sager, H. T. and Constable, W. C.: The response of a solid tumor to x-irradiation as modified by the dose rate, fractionation, and hyperthermia. Cancer Invest., in press.

EDITORIAL COMMENTS Most men who require treatment for localized prostatic cancer do not have low stage disease, for which radical prostatectomy and external beam irradiation each provide good survival results at 10 years. Radical prostatectomy alone is applicable to only a small proportion of patients with clinical stages B2 and C disease and it has limited curative potential. Although practically all such patients can be treated with definitive external beam irradiation, local control with this approach erodes with time and the frequency of serious long-term complications (proctitis, rectal ulceration, urethral stricture and chronic cystitis) is approximately 10 per cent, with a higher incidence of long-term impotence. It is well known that pelvic nodal involvement in patients with clinical stages B and C disease makes long-term survival free of disease unlikely after any form of local treatment, since it usually is a harbinger of bone metastases. Given these considerations, an approach that combined staging information from pelvic lymphadenectomy with the ability to implant accurately in the cancerous gland radioactive sources with high energy but limited penetration to adjacent normal tissues carried with it the anticipation of good local control, reduced incidence oflate complications and more accurate prognostication of the ultimate outcome. After pioneering work in this area by Flocks with interstitial colloidal gold, Whitmore and associates developed a technique with