Intra-operative iodine-125 prostatic implant following bilateral pelvic lymphadenectomy

6 Original Contribution INTRA-OPERATIVE IODINE-125 PROSTATIC IMPLANT BILATERAL PELVIC LYMPHADENECTOMY EDMUND

W. H. KWONG, M.D.,’ SUN H. HUH, AND

HOWARD

M.D.,‘*

S. SMITH,

‘Chief Resident. ‘Associate Attending. ‘Director. 4Attending. Department IO Nathan

D. Perlman

MYRON

FOLLOWING

P. NOBLER,

M.D.,?

M.D.4* of Radiation

Therapy.

Beth Israel MedIcal Center

Place. New York, NY 10003

Sixty-five patients with prostatic adenocarcinoma Stages B and C were treated with intraoperative Iodine-125 prostatic implantation following bilateral pelvic lymphadenectomy. Pelvic nodal metastases were found in 31% of the patients: 23% (7/31) in clinical Stage Bl disease, 29% (8/28) in clinical Stage B2, and 83% (S/6) in clinical Stage C. All the patients have been followed for a period of 1% to 6 years. Serial digital rectal examination revealed complete regression of the palpable disease in 15% of the patients at 6 months, 47% at 1 year, and 87% at 2 years. Post-operative complications were also evaluated: 13% of the patients became sexually impotent, 11 oh had impaired potency after the procedure, and 16% of patients complained of dry ejaculation; and 17% developed scrotal and/or penile swelling, which persisted up to 14 months, but usually subsided within 5 months. Two patients developed local recurrence. Both patients responded to subsequent external radiation therapy of 7000 rad in 11 to 14 weeks with clinical regression of palpable disease. Prostatic carcinoma,

Iodine-125

implant.

INTRODUmION Prostatic carcinoma is the most common cancer affecting males over the age of 50 and 70,000 new cases were diagnosed in 1981 in the United States.16 A nation-wide survey by the American College of Surgeons in 1979 revealed that less than a quarter of the patients were offered an approach to management with curative potential.4 A majority of the patients receive either no treatment at all or a transurethral resection of the prostate for relief of urinary obstruction, with or without hormonal therapy or orchiectomy. Iodine- 125 seed implant of the prostate is one of the curative treatments for localized early staged prostatic cancer, and good results have been previously reported in the literature. This is a review of our experience with the first 65 patients who were treated by this procedure in Beth Israel Medical Center since June 1977.

METHODS

AND

MATERIALS

Patients with well defined localized prostatic adenocarcinoma who were physically strong enough to withstand surgery were selected to be treated with an intraoperative radioactive Iodine-125 seed implant of the prostate following bilateral pelvic lymphadenectomy.

* Assistant Professor of Radiation Therapy. Mt. Sinai School of Medicine of the City University of Few York

Sixty-five patients were treated with this procedure in a period of 4% years from June 1977 to November 198 I Their ages ranged from 45 to 78, with a mean age of 61 The majority of the patients were in their 7th decade of life (Figure I). Most of the patients (65%) initially presented with a single or multiple prostatic nodules, which were subsequently biopsied and proven to be adenocarcinema. Some patients also presented with symptoms of prostatism. Nine patients had gross or microscopic hematuria (Table 1). The diagnosis of prostatic adenocarcinoma was confirmed in all cases by either prostatic needle biopsy or transurethral resection, The latter was performed in 17 patients and care was taken to leave sufficient prostatic tissue for the implant. The following studies were performed on every patient: complete blood counts. urinalysis, blood chemistries, serum prostatic acid phosphatase, alkaline phosphatase, chest X ray, bone scan. intravenous pyelogram and cystopanendoscopy. Some patients also had liver scans. bipedal lymphangiograms, skeletal X ray studies, pelvic CAT scans, and bone marrow biopsies. They were staged according to the current American Urological staging system.” Thirty-one (48%) patients had Stage Bl disease with a small discrete prostatic nodule; 28 (43%) patients had Stage B2 disease with

t Associate Professor of Radiation Therap) Mt. Sinai Schc>,;’ of Medicine. Accepted for publication I 4 Fehruar\ ! 48.1

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GROUPS

Fig. I. Age incidence of the patients treated with iodine-125 prostatic implant. large or multiple prostatic nodules; 6 (9%) patients had Stage C disease localized to the periprostatic area (Table 2). All the patients were hospitalized for staging investigations, pelvic lymphadenectomy. and intra-operative prostatic Iodine-125 seed implant of the prostate for a duration of approximately one to two weeks. Technique of pelvic lymphadenectomy and Iodine- 125 prostatic implant Under general anesthesia, the patient was placed in a lithotomy position. A rubber rectal sheath was inserted into the rectum, to permit digital rectal examination under sterile conditions. A midline suprapubic incision from the umbilicus to the symphysis pubis was performed. An extraperitoneal bilateral pelvic lymphadenectomy was performed below the level of the distal portion of the common iliac arteries. The obturator, hypogastric and external iliac lymph nodes were dissected. The prostate was then exposed anteriorly and laterally, and the endopelvic fascia was excised to facilitate prostatic rotation and mobilization. The prostate was bimanually palpated and the dimensions of the volume to be implanted were measured. The average dimension was calculated. Based Table I. Presenting signs and symptoms

Symptoms

Prostatic nodules Urinary frequency Dysuria Prostatic hypertrophy Nocturia Hematuria (gross or microscopic) Weak urinary stream Urgency Urinary retention Hesitancy

Number of patients 42 15 13 13 II

Percentage 65 23 20 20 I7 14 9 8 6 3

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on the average dimension. the total activity of I-125 rc_ quired was then estimated by the dimension averaging method described by Hilaris et a1.9 Fifteen cm long 17gauge needles were inserted systematically into the tumor and the prostate at 0.5 cm to 1 cm intervals. A finger was inserted in the rectum under the rubber rectal sheath to monitor the depth of penetration of the needles and to minimize the risk of injury to the rectal wall and the urethra. The radioactive Iodine- 125 seeds were implanted through each needle successively, and were spaced 0.5 to I cm apart with the Henschke implant set. Post-operatively, X rays of the pelvis were obtained with stereoshift technique to localize the seeds. Computer print-outs of the isodose curves (Figure 2) were then made accordingly to outline the dose delivered in one year which corresponds to six half-lives of the I- 125 sources. The adequacy of the seed distribution and the minimum peripheral tumor dose were then evaluated. The dose distribution computation service of the Memorial Sloan-Kettering Cancer Center was used in our study. Hilaris er al. reported that the local control rate was invariably good (80 to 90%) if the matched peripheral dose (MPD) delivered by the Iodine- 125 prostatic implant was in the range of 16.000 to 18,000 rad in one year.’ All our patients had received this minimum MPD. However, a recent change has been made in the dose distribution calculations of I- 125 seeds. The specific dose rate factor has been changed from 1.6 to 1.1 rad cm*/mCi hr at 1 cm. The MPD of 16,000 rad in one year previously is approximately equivalent to I 1,000 rad in one year in the more recent computer print-out of the isodose curves, as shown in Figure 2. The specific technical parameters of all the implants are enumerated in detail in Table 3. One patient was found to have unsatisfactory distribution of the I-125 seeds to one side of the prostate on pelvic X ray. He subsequently received a boost dose of external radiation to the prostate to a dose of 3000 rad in 3 weeks using a rotational technique. One patient. who had a previous transurethral resection. voided 14 Iodine135 seeds in the urine within one week after implant. However, the minimal peripheral dose was still considered adequate for this patient, and clinical regression of Palpable disease was noted approximately one year after the implant

Table 2. Correlation between stages of disease and incidence of pelvic lymph node metastasis Pelvic lymph node metastasis

Stages

Number of patients

BI B2 C

31 28 6

TOI~I

h;

Positive cases 7 8 5 70

Percentage 23 29 83 31 ..___~

iodine-~ 25

prostatIc

Implant 0

E. W. H. KWONG FI a/

667

Fig. 2. kodose curves in a single coronal plane of an iodine-125 volume implant of the prostate. The numbers represent the dose in rad delivered by the implant in one year. Number of needles = 16: Number of l-l 25 seeds = 46; Total radioactivity = 24.5 mCi: Implant volume = 19 c.c.: Volume enclosed by I I000 rad isodose surfaces = 58 C.C.

RESULTS Pelvic l_vmph node metastasis Twenty of the 65 patients (3 I %) had

histological

evi-

of metastasis in some of the lymph nodes dissected, including the obturator, hypogastric and external iliac lymph nodes. Between 22 and 26 lymph nodes were usually removed. The relative incidences of pelvic nodal metastases in each stage were outlined as in Table 2.

dence

Clinical

regression

of palpable

disease in prostale

All the patients

examination.

were followed with serial digital rectal Of the evaluable patients. 15% (S/54) of the

Table 3. Parameters

of the iodine-125

Implant volume Average dimension Number of needles used No. of iodine-125 seeds implanted Total activity of the implant

prostatic

implant

Range

Average

4.2 to 52 cm’ 2.3 to 4.1 cm IO to 28

18 cm’ 3 cm 16

21 to 71 7 to 32 mCi

43 20 mCi

patients had complete clinical regression of the palpable disease at six months after the I-125 implant. 47? (2 l/47) at one year, and 87% (34/39) at two years (see Figure 3). Complications

Complications were observed post-operatively and during the follow-up periods (see Table 4). Eleven patients developed various degrees of scrotal and/or penile edema which persisted for 1 to I4 months with an average duration of 5 months. Six patients developed more severe edema of the lower extremities which subsided in 4 to 24 months with an average of 14 months. The cause of this edema was probably due to lymphatic or vascular compromise related to the lymphadenectomy. Four patients complained of paresthesia of the groin and thighs for a period of up to 6 months. This may be related to obturator nerve injury during surgery. Five patients also received post-operative teletherap! because of pelvic nodaI metastasis or unsatisfactory dos<, distribution of the I-l 25 implant. Excluding these 5 Ptients, 12 patients complained of frequency, urgency and nocturia after the I-125 implant. Seven patients had dvs-

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than one year. Forty-five patients were sexually potent before the Iodine- 125 implant. Six became completely impotent (13%) and five had impaired potency ( I 1%) after the I-125 implant. Seven patients also complained of dry ejaculation or diminished amount of semen.

i

3c MONTHS AFTER IODINE-125 PROSTATIC IMPLANT Fig. 3. Clinical regression rate of palpable prostatic disease. uria. The urinary symptoms usually disappear in three to four months; however, one patient had persistent pollakiuria. and one has had urinary incontinence for more Table 4. Incidence

of postoperative

Comphcations

complications

Number of patients

Percentage

(A) Related to pelvic Iymphadenectomy Edema of gemtaha Edema of lower extremities Paraesthesia of groin and thighs Lower limb paresis and foot drop Wound infection and delayed healing lncisional hernia Lymphocele

II

6

17 9

d

6

1

2

IO

I5 5 3

3 2

(W Related to the iodine-125 prostatic implant Frequency, nocturia. urgency Dysuria Urinary incontinence Hematuria Complete impotence Impaired potency Dry ejaculation Transient hematospermia

Local failure All of the 65 patients (except those who died sooner) have been followed regularly for at least I l/2 years: 55 patients have been followed for two years or more: 4 I patients for at least three years; and 19 patients for four years or more. Two patients developed recurrence at 27 and 40 months respectively. One patient had Stage C disease with diffuse involvement of the prostate and seminal vesicles. The second patient had a fairly extensive Stage B2 tumor: the oval-shaped implant volume was 52 cubic centimeters (i.e.. r/6 X 5 X 5 X 4) and was the largest in our series. Both cases were actually considered suboptimal for treatment with Iodine- I25 implantation because of the involvement of seminal vesicles and the large implant volume. Neither patient had evidence of pelvic lymph node metastasis. Both patients were subsequently treated with external radiation therapy to the prostate to a tumor dose of 7000 rad in 11 to 14 weeks by antero-posterior portals and rotational technique. using a IO MV photon beam from a linear accelerator. The treatments were protracted because of urinary frequency and diarrhea. At completion of the teletherapy treatments. one patient had complete regression of palpable disease. and the other had significant regression. Morralit) During the follow-up period of up to 72 months. there were no cancer-related deaths. Three patients died of myocardial InfarctIon at 16, 21 and 29 months after l-l 35 implant. None of them received any hormonal therapy. A post-mortem examination of one patient revealed liver metastasis which was asymptomatic. Only five patients developed bone metastases at IO. 14. 35. 40 and 45 months after I- I25 implant, and were subsequently treated with palliative radiation therapy. None of them had evidence of local recurrence. Two of the patients with bone metastasis also had metastatic lesions in the lungs or supraclavicular lymph nodes. The overall disease-free survival is 90%. at II/‘? to 6 years following treatment.

Discussion Since 1970. 20 ( I2/60*) 12 (7/60*) 2 I; (6/45t)

I I (5/45-t) 16 (7/45-t) 2

* Only 60 patients were evaluable. Five patients who received post-operative external prostatic irradiation were excluded. t Only 45 patients were sexually potent before the procedure.

radioactive bilateral

Iodine-125 implant pelvic lymphadenectomy

of the

has been a therapeutic option for localized and early staged prostatic carcinoma. In comparison with other curative approaches such as radical prostatectomy and external radiation therapy, the I-125 prostatic implant has been shown to give good therapeutic results with minimal morbidity. Hilaris er ‘11.~have reported a 10% incidence of local recurrence or persistence in I I2 implanted patients, and the S vear disease-free survi\,al has been comprostate

following

parable

\vith clthcr :reurmcnt

modalities

tTahle

5) 41s).

lodlne-125

Implant 0 E W

prosratlc

Table 5. Results of radiotherapeutic

Author Hill er al.‘”

Year

Radiotherapeutic method

1974

Pelvic and prostatic

H

management

KWONG et al

of prostatic

5 year disease-free survival

No. of patients

adenocarclnoma

Local failure

40%

68

669

9%

Distant metastasis

Impotence

N.A.

N-A.

irradiation

15%

‘2%

30%

9oi

‘0%

N.A

9% 14%

26.5% N.A. 26%

41 N.A. N.A.

10%

23%

Perez er al.”

1980

Pelvic and prostatIc irradiation

183

62Y
Harisiadis

1978

Pelvic and prostatic irradiation Prostatic Irradiation

98

60%*

48

73%’

430 107 I54

53% 58% 580/t

II%

I I?

58%

et al.’

Bagshaw et al.’ McGowan” Neglia et al.‘”

1975 1977 1977

Prostatic Prostatic Prostatic

Hilaris et a1.6

1979

I- 125 prostatic implant

irradiation irradiation In-adiatlon

7%

* Actuarial 5 year survival rate. t 2 to 9 year disease-free survival rate. N.A. = Not available.

there has been a significantly

lower incidence

of impotence

of 7% (S/109), and severe urinary or bowel complications of 2% (2/ 1 12). Our experience is too early to show any significant long term results; however, the short term results have been satisfactory, with relatively low morbidity and low local failure rate. Only 13% of the patients became sexually impotent after the procedure. The urinary complications, which were not uncommon in our experience. usually subsided within one year. The regression time for the palpable disease in our study is comparable to that reported by Whitmore.” Approximately half of the patients will have complete regression of palpable disease in one year. At the end of one year. which roughly corresponds to six half-lives, the I-125 seeds have delivered 98% of the total dose. The residual radioactivity has become negligible, and is less than 2%. Despite this fact. the palpable disease in many patients continues to regress. By 2 years, 87% of the implanted patients have complete regression of the tumor. Therefore, it is important nor to be misled by persistent palpable tumor present even two years after the I- 125 implant as long as there is continual regression. Also, it has been shown that post-irradiation prostatic biopsies obtained even after two or three years are of limited value and cannot be used to definitely diagnose active residual disease.” However, if there is clinical reappearance of palpable disease after complete regression, with a new positive biopsy. the diagnosis of local recurrence becomes manifest. as in 2 ofour patients.

Retreatment of recurrent local disease with external radlation is possible and may be successful, although there is a higher incidence of bladder and bowel complications which may protract the course of treatments. Hilaris ef ui reported tumor involvement of the pelvic lymph nodes in lymphadenectomy in 39% of their 256 implanted patients.’ In our experience. a similarly high percentage of of 83% in 3 1% was found, with a very high incidence patients with Stage C disease. Since it has not been demonstrated that, if the nodes were histologically positive for metastases, post implant pelvic irradiation will produce an improvement in long term survival,3 this procedure is not performed routinely in our department. It is too early to assess the long term implication of positive pelvic lymph nodes in our study, but it has been previously reported by Batata’ to be associated with a higher incidence of bone metastasis, local recurrence, and lower survival rate. Thus, interstitial implantation ofthe prostate with I- I25 seeds is a curative approach indicated in selected cases of localized prostatic carcinoma, and probably should not be attempted in late (i.e., Stage C) cases. Clinical response and tumor regression are usually slow. In general, the tumor response to I-125 implantation has been excellent, long-term local control rates are quite high, and the morbidity is low, indicating that this procedure is an acceptable alternative to teletherapy in-adlation in carefully selected, vigorous, early stage (B I and 82) patients with prostatic adenocarcinoma.

REFERENCES I. Bagshaw, M.A., Ray, G.R., Pistenma. D.A., Castellano, R.A., Meares, G.M.: External beam radiation therapy of primary carcinoma of the prostate. Cancer 36: 723-728. 1975. 2. Batata, M.A.: Cancer of the prostate: Results of I- I li urnplantation and biological behavior ofprostate cancer p:~wntc

with nodal metastasis treated by I-125 implantation and lymphadenectomy. In The 2nd Annual Brachyfherapj. L-p<> 1981. Hilaris. B.S.. and Nori. D. (Eds.). New York. Memorial Sloan-Kettering Cancer Center. I98 I. pp. ?‘7-

7’ 13;1131:1 \I

:

I l~i,~rtc.13S (^‘hu. F .(‘.H

Whitmow.

R

F..

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Song, H.S., Kim, Y., Horowitz, B., Song, KS.: Radiation therapy in adenocarcinoma ofthe prostate with pelvic lymph node involvement on lymphadenectomy. Inl. J Radial. Oncol. Biol. Phys. 6: 149-153, 1980. 4. Bolsen, B.: More aggressive treatment urged for patients with prostatic cancer. JAMA 246: I757- 1758, 198 I. 5. Harisiadis, L., Veenema, R.J., Senyszyn, J.J.. Puchner, P.J., Tretter, P., Ramos, N.A., Chang, C.H., Lattimer, J.K., Tannenbaum, M.: Carcinoma ofthe prostate-Treatment with external radiotherapy. Cancer 41: 2 13 1-2 142, 1978. 6. Hilaris, B.S., Batata, M.A., Chu. F.C.H., Whitmore, W.F., GrabstaId, H., Sogani, P.R.: Radiation treatment and results in localized carcinoma of the prostate. In Advances in Medical Oncology, Research and Educurion. Vol. 1 I, I st edition, Wilkinson, P.M. (Ed.). Oxford and New York, Pergamon Press. 1979, pp. 301-31 I. Hilaris, B.S., Sogani, P.C., DeCosse, J.J., Montie, J., Whitmore, W.F., Grabstald, H.: Carcinoma of the prostate: Treatment with pelvic lymphadenectomy and iodine- I25 implants. Clin. Bull. 9: 24-3 I, 1979. Hilaris, B.S., Whitmore, W.F.. Batata, M.A.: Iodine-125 implantation of the prostate: Dose response considerations. Fronf. Radial Ther. Oncol 12: 82-90. 1978. Hilaris. B.S., Whitmore, W.F.. Batata. M.A., Grabstaid, H.: Cancer of the prostate. In Handbook oflntersrrtiul Bruchyrherupy, Hilaris, B.S. (Ed.). New York, Publishing Sciences Group, Inc. 1975, pp. 219-234.

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IO. Hill, D.R.. Crews, Q.E.. Walsh, P.C.: Prostate carcinoma: Radiation treatment of the primary and regional lympha&. Cancer 34: 156-160, 1974. I I. Kagan. A.R., Gorden, J.. Cooper, J.F.. Gilbert, H., Nussbaum, H.. Chan, P.: A clinical appraisal of post-irradiation biopsy in prostatic cancer. Cancer 39: 637-64 I, 1977. 12. McGowan. D.G.: Radiation therapy In the management of localized carcinoma of the prostate, a preliminary report. Cancer 39: 98-103, 1977. 13. Murphy, G.P., Gaeta, J.F., Pi&en, J.. Wajsman, Z.: Current status of classification and staging of prostate cancer. Cancer 45: 1889-1895, 1980. 14. Neglia. W.J.. Husscy, D.H.. Johnson, D.E.: Megavoltage radiation therapy for carcinoma of the prostate. Inr. J. Rudrum. Oncol. Biol. Phys 2: 873-882. 1977. 15. Perez. C.A.. Walz, B.J., Zivnuska. F.R.. Pllepich. M., Prasad, K., Bauer. W.: Irradiation of carcinoma of the prostate localized to the pelvis: Analysis of tumor response and prognosis Inr J Radial Oncnl B/o/ PhJ,s 6: 555-563. 1980. 16. Silverberg. E.: Cancer statlstlcs. 31: 13-28. 1981

198 I :

C.-f-,4

Cancer J C/in

of I-125 in the 17. Whitmore. W.F.: Retropublc lmplantatlon treatment of prostatic cancer. frog. Clrn BIoI. Rex 6: 223233, 1976