Posttreatment biopsy results following interstitial brachytherapy in early-stage prostate cancer

PI1 SO360-3016(96)00390-2

ELSEVIER

l

Clinical

Investigation POSTTREATMENT BIOPSY RESULTS FOLLOWING INTERSTITIAL BRACHYTHERAPY IN EARLY-STAGE PROSTATE CANCER

BRADLEY R. PRESTIDGE, M.D.,* DAVID C. HOAK, HAAKON RAGDE, M.D.,” WILLIAM CAVANAGH~

M.D.,’ PETER D. GRIMM, D.O..‘.” AND JOHN C. BLASKO, M.D.3,s

*Department of Radiation Oncology. Wilford Hall Medical Center, San Antonio. Spokane, WA: *Northwest Tumor Institute, Seattle, WA; and “Pacific Northwest

TX; ‘Pathology Associates, Inc.. Cancer Foundation. Seattle. W,4

Purpose:To assess pathologiccontrol ratesfor prostatic carcinomaasdeterminedby postimplantprostatebiopsy inaisrge seriesof consecutivepatientswho have received permanentinterstitial brachytberapy usinga contemporary transrectal ultrasound-directed,transperineal,computer generated,volume technique. Methods and MaWiais: Four hundred and two patientsreceivedpermanent *“I or ‘qd interstitial brachytherapy asprimary treatment for early stageprostatic carcinomaat the NorthwestTumor Institute betweenJanuary 1988and January 1994.Of these,201 have consentedto biopsy 12 or more monthspostimplantwith a median follow-up of 40 months(range: 12-83 months).Nonehad receivedhormonalmanipulation.A total of361 biopsies wasperformedon 201 patientswith a rangeof oneto six annual biopsiesper patient (91 receivedm&ipk, serial biopsies).Of the 161 patients more than 12 months postimplant who have not been biopskd, most have been unwilling or unableto submit to biopsy. Only six patients with biochemicalprogressionhave not beenbiapsied. There wasno difference in the presentingcharacteristicsor implant parametersbetweenthosepatientsbiopsied and thosethat were not. One hundred and-forty-&ree received ‘=I (71%) prescriid to a MPD of 160Gy with a medianactivity of 35.5mCi, and 58 (29%) received lo3Pdprescribedto a MPD of 115Gy with a medianactivity of 123 mCi. Multipie biopsieswere performed under transrectal ultrasound guidance,and all specimenswere cla&ied as either negative, indeterminate,or positive. Results:At the time of last biopsy, 161(80%) have achievednegativepathology, 34 (17%) remain indeterminate, and 6 (3%) have beenpositive. Only 2 of the 186patients with a PSA < 4.0 rig/ml at the time of biopsy were positive. Among those33 indeterminatepatients with a subsequentbiopsy, 28 have converted to negative, 2 to positive, and 3 remain unchangedto date. Conckasions:Thesedata demonstrateat leastan 80% pathologically confirmed local control rate fottowing permanent interstitial brachytherapy for early stageprostate cancer. A higher local control rate is expectedwith further follow-up as the majority of indeterminate biopsiesconvert to negative over time. The indeterminate category of postirradiation biopsy describedhere includesspecimensthat have probably beeninterpreted as positive in other series,but correlate clinically and biochemicallywith negative biopsies.Theserest&s support the useof modern interstitial brachytherapy techniquesfor selectedpatients with early stageadenocarcinomaof the prostate. Copyright 0 1997 Elsevier Science Inc. Prostate cancer, Interstitial brachytherapy, Postimplantbiopsy.

INTRODUCTION

ma1 gland is notoriously poor. Although PSA is perhaps the most useful tumor marker in all of oncology, unless it is remarkably elevated. it does not distinguish between local and distant relapse. Posttreatment prostatic biopsy has long been held to be the gold standard in evaluating the efficacy of local modalities used in prostate cancer management. However, postirradiation prostatic biopsies are not without limitations. They are difficult to interpret,

Methods of assessing local control following treatment for early-stage prostate cancer are confined to digital rectal examination (DRE), prostate-specific antigen (PSA), and prostate biopsy. Digital rectal exam is useful in detecting recurrent or persistent disease in the presence of a palpable tumor: however, the specificity for DRE in a palpably nor-

_---. Presented in part at the 37th Annual Scientific Meeting of the American Society for Therapeutic Radiology and Oncology, Miami Beach, FL, October 9. 1995. The opinions or assertions contained herein are those of the authors and do not purport to reflect the official view of the Department of Defense or the Department of the Air Force.

----_I_

Reprint requests to: Bradley R. Prestidge. M.D., Chairman, Radiation Oncology/PSRT, Wilford Hall Medical Center 2200 Bergquist Dr.. Suite 1, Lackland AFB. TX 782?6-

5300. Accepted for publication 31

30 July 19%.

32

I. J. Radiation Oncology l Biology l Physics

subject to sampling error, and do not always correlate with clinical outcome (28). Despite these qualifications, posttreatment prostatic biopsy remains a useful tool in evaluating the efficacy of local therapy for early-stage prostate cancer. Results of postteletherapy prostatic biopsy series vary remarkably and probably depend on many factors including patient selection, timing of biopsy, experience and bias of the pathologist, and the zeal with which the biopsies are performed. Some of these data have, in part, refueled the recent resurgent interest in interstitial brachytherapy techniques as an alternative to external beam therapy for early stage prostatic carcinoma. Although early brachytherapy series demonstrated disappointing treatment outcomes (13), these series employed relatively primitive, open laparotomy, retropubic techniques that resulted in very poor dose homogeneity. Published reports of postimplant prostate biopsies series are few, and for the most part are limited to patients treated with combined external beam and varying interstitial techniques (3, 17, 21, 30, 32). Several technological advances in the fields of prostate ultrasonography, computer-generated conformal treatment planning, and volumetric implant techniques have allowed both dose conformity and homogeneity not previously attained. These advances are also responsible for the renewed interest in prostate brachytherapy. This study was undertaken to assess the pathologic control rate of permanent interstitial brachytherapy as determined by postimplant biopsy in a large series of consecutive patients using these contemporary techniques.

METHODS

AND MATERIALS

Between January 1988 and January 1994,402 patients with early-stage adenocarcinoma of the prostate received permanent “‘1 or lo3Pd transperineal interstitial brachytherapy as the sole modality of therapy at the Northwest Tumor Institute. Among these, 201 patients have consented to prostatic biopsy 12 or more months postimplant with a median follow-up of 40 months (range: 12-83 months). None had received hormonal manipulation. Patient selection for interstitial brachytherapy alone included relatively early-stage, low-volume disease. Following proper counseling regarding the alternative therapeutic options including watchful waiting, radical prostatectomy, and external beam radiation, those patients favoring implantation for personal or medical reasons were evaluated according to a treatment algorithm previously described (12) to determine eligibility. Contraindications to the procedure include Stage T3 disease, prior transurethral resection of the prostate (particularly if a large urethral defect is noted on ultrasound), gland volume *Prowess, SSGI, Chico, CA.

Volume 37, Number 1, 1997 > 60 cc, and substantial (> l/3 gland) pubic arch interference. The staging workup included a thorough history and physical including digital rectal exam (DIE), serum chemistries, complete blood count, prothrombin/partial prothrombin time, PSA, chest x-ray, American Urologic Association (AUA) symptom score index, and transrectal ultrasound (TRUS) directed biopsy of the prostate. Bone scan and pelvic CT or MRI scans were performed according to clinical suspicion for metastatic disease and according to the preferences of the referring physician. Serum PSA levels were assayed using the Hybritech radioimmunoassay technique (normal range: 0.1-4.0 ng/ ml). All patients were staged using TNM criteria (1). Interpretation of initial biopsy specimens was performed by the Laboratory of the Northwest Hospital, and assigned a Gleason Score (22). Treatment planning Prior to implantation, all patients underwent a detailed prostate volume study using a ~-MHZ radial transducer, or more recently a ~-MHZ biplane probe. Patients were placed in a dorsal lithotomy position and the probe was securely anchored. Transverse images of the prostate were obtained at 5-mm intervals from the base to apex. On each image was a superimposed grid representing the template coordinates that was aligned such that the first horizontal row was positioned just anterior to the posterior margin of the gland. The radiation oncologist outlined the prostate volume on each transverse image with a margin, which was typically 2-5 mm with more generous margins around the base and apex. These outlines were then used to define the target volume to which was prescribed the minimum peripheral dose (mPD) of radiation. The technique resulted in a modified homogenous spatial distribution of radioactivity throughout the gland. Preimplant dosimetry was performed using a dedicated prostate brachytherapy planning computer program, ’ which reconstructed the volume three dimensionally. Seeds were spaced at 1.0 cm center to center and needles were spaced 1.O cm apart. Average seed strength was 0.35 mCi for 125I and 1.4 mCi for lo3Pd. Among the 201 patients in this series, 143 (71%) received lz51prescribed to aMPD of 144 Gy T6-43 combined with a median total activity of 35.5 mCi, and 58 (29%) received lo3Pd prescribed to a MPD of 115 Gy with a median total activity of 123 mCi. interstitial brachytherapy technique Patients were placed on a clear liquid diet for 48 h and received a Fleets enema 2 h prior to the procedure. The procedure was performed in approximately 45-60 min on an outpatient basis. Following adequate spinal anesthesia, the patient was placed in a dorsal lithotomy position and the perineum was prepped with Betadine solution. The

Postimplant biopsy 0 B. R. PRESTILXE ultrasound probe was inserted into the rectum and attached to a stepping unit. A custom designed stabilization bracket then fixed the stepping unit/probe apparatus to the operating room table. The ultrasound probe was aligned such that the first horizontal row on the grid was parallel to the posterior margin of the prostate through all transverse images and such that every 5 mm image was identical to the preimplant volume study. The base of the gland was identified on transverse imaging according to the volume study and was designated the top or zero plane. The template was then anchored to the stepping unit 2 to 3 cm from the perineum to allow digital direction of needles if necessary. Prior to the procedure, specially designed sterile 18 gauge, 2 1 cm needles’ were loaded with either free ‘25I3 or “‘“Pd’ seeds separated by 5 mm spacers (No. 3 chromic catgut suture). More recently, lZ51in an absorbable stiffened vicryl suture that obviated the need for spacers and allowed for a more satisfactory parallel array of sources has been employed.’ Isotope selection was based on tumor parameters that basically restrict the use of io3Pd to those patients with higher grade and/or stage of disease. The tips of the needles were plugged with anusol suppository or bone wax that had been melted down to uniform thickness to prevent premature dislodging of the seeds. The first needle was advanced to the base of the gland, and the distance from the needle hub to the template was measured and served as a reference. The position of the base was monitored throughout the procedure using these measurements as well as the transverse and sagittal ultrasound images. To assist with the prevention of cephalad migration of the base, a stabilization needle6 was placed in the lateral aspect of the right and left lobe. The ultrasound transducer was adjusted in 5-mm increments in the caudal direction for those template coordinates that did not call for seeds at the base of the gland. Intraoperatively, each ultrasound image plane was carefully reviewed and anteroposterior fluoroscopy was employed at the conclusion of the procedure to assess seed distribution within the gland. Extra seeds were implanted in any perceived cold portions of the gland. Cystoscopy was performed to retrieve seeds that were occasionally discharged in the bladder or urethral wall. A Foley catheter was placed until recovery from the spinal anesthesia and all patients received an 8-day course of trimethoprim-sulfa. Many patients perceived to be at high risk for urinary obstructive symptoms (based on American Urologic Association symptom score) also received terazosin and/or a nonsteroidal antiinflammatory agent.

rr d.

.I ::

Postimplant surveillance Patients are jointly followed by the urologist and radiation oncologist with DRE (after one isotope half-life) and serum PSA typically 2 weeks postimplant and at 3-month intervals for 2 years, every 4-6 months through year 5. and annually thereafter. Patients are questioned in detail regarding erectile potency and any bladder or rectal symptoms. Multiple ultrasound-directed biopsies of the prostate. including the site of the original lesion (when known), and any focal hypoechoic areas of suspicion, were obtained by a single urologist (H.R.) using an automatic biopsy system 7 with an 18 gauge biopsy needle. ’ Biopsies were obtained at yearly intervals postimplant when possible. Postimplant biopsies were not obtained in all cases due to patient refusal, referring physician preference. or geographic distance. However, a special effort was made to biopsy all patients with a rising PSA or other features suspicious for local recurrence. A total of 361 biopsies were obtained on 201 patients with a range of l-6 yearly biopsies per patient; 91 received multiple biopsies. and the remaining 110 had a single biopsy. Pathology All postimplant biopsy specimens were stained with hematoxylin and eosin (H&E) and reviewed by a single genitourinary pathologist (D.C.H.) and classified as either negative, indeterminate, or positive, depending on cellular, architectural, and immunohistochemical criteria (Fig. la-c). The pathologist was blinded as to the PSA level or other clinical parameters at the time of interpretation. Definitions for the three classifications are as follows: negative-typically benign appearing glands that appear atrophic with compressed contours and slit-like lumina. The epithelium is disorganized and generally multilayered. There is marked nuclear atypia characterized by enlarged and hyperchromatic nuclei. Positive-glands that resemble tie IZOVOcarcinoma with oval or rounded lumina and usually more than five cells radially oriented about the lumen. Nucleoli are prominent and mitotic figures are rarely seen. Indeterminate-these glands have features of residual carcinoma with radiation effect. Small. irregular glands that show an infiltrative pattern, composed of one to three cells with no distinct basal cell layer. The cytoplasm is amphophilic, foamy, or vacuolated, and the cell borders are indistinct. Mitotic figures are not seen. lmmunohistochemical markers for high molecular weight cytokeratin (34PE12) and proliferating cell nuclear anti_.-

‘GRB Prostate Implant Needle, Manon, Northbrook, IL. ’ Medi-Physics, Arlington Heights, IL. “Theragenics. Norcross, GA. ‘Rapid Strand. Medi-Physics. hMorgarwter~z needle. Medical Devices Technologies, Inc., Gainesville. FL..

-. .- - _.._____

-.

‘Radiplast AB. Uppsala. Sweden. ‘Biopty-Cut biopsy needle. Bard Urologic Division. Coving-

ton. GA.

I. J. Radiation Oncology l Biologyl Physics

Volume 37, Number 1, 1997

(4

6) Fig. 1.Photomicrographs of postbrachytherapyprostatebiopsyspecimens. (a) Negative-benign glandwith radiation induced atypia. The gland has becomecollapsed,and there is relative basalcell hyperplasia.Note the nuclear pleomorphismand hyperchromasia.The nuclei tend toward tangentialorientationto the lumen of the gland. (b) Indeterminate-residualcarcinomaglandwith profoundradiationeffect. The glandsare poorly formedandcontain only a few cells per gland. The nuclei appearwashedout, and the cytoplasmis foamy or granular.(c) Positiverecurrentcarcinomaglandforming a cribiform pattern with nuclei orientedradially with respectto the lumen.Note the number of cells per gland. Thesegland resemblede MM or untreatedcarcinoma(magnification400x, hematoxylin and eosin).

gen (PClO) (PCNA) were occasionally employed to confirm but not supercede H&E interpretation.

as is typical for most permanent interstitial brachytherapy series. The presenting characteristics of the 201 patients that underwent postimplant biopsy is compared to the re-

Statistical analysis An independent samples t-test for equality of means was employed to statistically compare the follow-up interval for the three postimplant pathology categories (5). The Wilcoxon Rank Sum Test was used to assess the significance of the differences of posttreatment PSA values between patient subgroups (10). Differences were deemed significant for p-values less than 0.05.

maining 201 implant patients in Table 1. These two groups were also found to be nearly identical when treatment parameters were compared.

Study population The majority of the 402 patients in this study had rel-

Biopsy rest&s Of the 361 total postimplant biopsies performed, 283 (78%) were negative, 71 (20%) had histology with features of residual neoplastic cells, but with pronounced radiation effect and were therefore classified as indeterminate, and 7 (2%) were positive. At the time of last biopsy, 161 of the 201 patients biopsied (80%) had achieved negative pathology with a median follow-up of 30.8 months. To date, only 6 (3%) pa-

atively early stage, moderately well-differentiated tumors

tients have been classified as positive at the time of their

RESULTS

Postimplant biopsy

Table 1. Comparison of presentation characteristics for patients receiving postimplant biopsy vs. unbiopsied patients Unbiopsied (%) n = 201

Biopsied (%) n = 201

Stage

Tla Tlb Tic T2a T2b T2c Gleason score

4 5 47 125 18

2 to 4 5 to 6 27

ungraded Presentation median

4 6 41 125 22 3

(2) (3) (20) (62) (11) (2)

89 (44) 87 (43) 22 (11)

69 112 15 5

(34) (56) (8)

8 (2)

(2)

PSA (@ml) 1.2 0.2-50 1 (I) 37 (18) 112 (56) 50 (25) 1 (1)

range 0. I to

(2) (3) (23) (62) (9) 2 (1)

1.0

L.l to 4.0 3.1 to 10.0 > 10.0 PSA = prostate-specific

6.6 0.7-74.6 5 (2) 54 (27) 96 (48) 46 (23) 0 (0)

antigen.

last biopsy (one converted from positive to negative). The last biopsy of the remaining 34 patients (17%) was indeterminate. The stages, Gleason scores, and PSA at presentation according to postimplant pathology category are shown in Table 2.

Table 2. Comparison

of presentation

0

B. R.

PRESTIDGE

PI al.

35

Positive biopsies The six patients with a positive biopsy are characterized in Table 3. The median follow-up for these six patients is 33 months. Patients 1 and 2 converted from an indeterminate at 38 and 12 months, respectively, to positive at 53 and 24 months. respectively, postimplant. Patients 3 and 5 both had a negative biopsy at 12 months and a subsequent positive biopsy at 37 and 33 months, respectively. Patient 4 had only a single positive biopsy at 32 months. Patient 6 had a single positive biopsy at 12 months, but has subsequently had a decreasing PSA level at each visit without intervention. Of the 133 patients with a PSA of less than 1.O rig/ml at the time of biopsy, patient 6 is the only one to have had a positive biopsy. His PSA was 0.3 rig/ml at last follow-up. 42 months postimplant. To date he has declined a repeat biopsy. Among the 158 patients with a PSA less than 4.0 rig/ml at the time ot biopsy, only two (patients 3 and 6) have had a positive result. Of these six patients, only one (patient 2) has been found to have distant relapse to date. After a detailed analysis of these six cases, no apparent deficiencies in brachytherapy technique or dosimetry were identified. PSA projiles Prostate specific antigen levels at the time of postimplant biopsy, PSA nadir (defined as the lowest postimplant PSA value obtained), and time to nadir clearly separate the indeterminate from the positive group on biochemical grounds (Table 4). As would be expected. those patients

characteristics

by postimplant

biopsy status (n = 201)

PostImplant Positive (%) IZ = 6 Stage Tla Tlb TIC T2a T2b T2c Gleason Score 2 to 4 5 to 6 27 ungraded

Indeterminate

__-___-

biopsy

(o/o) n = 34

Negative ( % ) n = 16 I L-

0 0 l(l7) 3 (50) 2 (33) 0

0 3 (9) 8 (34) 23 (68) 0 0

4 (7) 3 12) ‘2 (30) 09 (61) ‘0112) 3 (2)

3 (50) 3 (50) 0 0

10 19 4 I

56 90 II -I

(29) (56) (12) (3)

(35) (56) 17) (2)

Presentation PSA (rig/ml) median range 0.1 to 1.0 1.1 to 4.0 3.1 to 10.0 >lO.O

PSA = prostate-specific

13.1 0.7-32.4 0 0 2 (33) 4 (67) antigen.

5.5 1.4-29 0 I1 132) 16 (47) 7 (21)

6.7 0.7 --32.4 5 (3) -c3 (27) 78 (48) .3s (22)

I. J. Radiation Oncology l Biology l Physics

36

Volume 37, Number 1, 1997

Table 3. Characteristics of patients with a positive postimplant biopsy (n = 6) Presentation

Biopsy

PSA

Patient #

Stage

GS

PSA

Nadir

Time to nadir

First Bx

# Bx

Time to +Bx

Clinical status

Follow-up

1

T2b

6

74.6

7.5

23 months

Ind.

2

54 months

54 months

2

T2b

5

4.3

2.3

8 months

Ind.

2

25 months

3

Tic

3

15.5

0.8

19 months

Neg.

3

37 months

4

T2a

4

8.9

1.6

14 months

Pos.

1

32 months

5

T2a

5

10.7

1.5

14 months

Neg.

3

33 months

6

T2a

4

16.3

0.3

42 months

Pos.

1

12 months

Alive, local failure only Deceased, distant failure Alive, local failure only Alive, local failure only Alive, local failure only Alive, N.E.D.

71 months 62 months 50 months 39 months 42 months

GS: Gleason sum; Neg: negative; Ind: indeterminate; Pos: positive; BX: biopsy.

with negative biopsies tended to achieve a lower PSA nadir and required a longer time to achieve it. Although 201 patients have not submitted to biopsy, 40 of these are less than 12 months postimplant. Of the remaining 161 patients, 133 have a PSA less than or equal to 1 .Orig/ml at last follow-up. Of the 28 with a PSA greater than 1.0 rig/ml, only six have evidence of biochemical progression, defined as a PSA greater than 1.0 rig/ml and two consecutive elevations on serial examinations. Of the 38 patients biopsied at the time of a PSA greater than 1.0 rig/ml, 5 have been positive, 9 indeterminate, and 24 negative. Of the 16 patients with biochemical progression at postimplant biopsy, 5 have been positive, 1 indeterminate, and 10 negative. Indeterminate

biopsies

The 34 patients with indeterminate pathology at last postimplant biopsy had a significantly shorter follow-up than the remaining 167 with a definitive pathology classification (21.0 vs. 30.6, p < 0.0005). Among the 33 patients with indeterminate pathology who had a subsequent biopsy, 28 converted to negative, 2 to positive, and 3 have

remained indeterminate at 25, 28, and 34 months postimplant. The proportion of biopsies classified as indeterminate was time dependent, decreasing from 33% of biopsies taken between 12 and 18 months, to 14.2% at 18 to 30 months, to 5% for biopsies taken 54 or more months postimplant (Fig. 2). DISCUSSION The few published series of postimplant biopsy results are comprised primarily of combined external beam/ brachytherapy boost patients reporting a biopsy positivity rate of 22-52% (3, 17, 21, 30, 31). While these results vary, they are quite favorable compared to most postteletherapy series reporting positivity rates of l&93% (7, 15, 16, 25, 32), especially considering the inclusion of many T2b-T3 patients in the brachytherapy reports. Our findings demonstrate a striking 3% positive postimplant biopsy rate, excluding the indeterminate biopsies. Even if the indeterminate biopsies are included as positive, the positivity rate does not exceed 20% in this group of patients who were not selected for postimplant biopsy.

Table 4. Prostate specific antigen correlation to postimplant biopsy status Postimplant biopsy status PSA

Negative (rig/ml)

Indeterminate (r&ml)

Positive (@ml)

0.2 0.1-7.4

0.5 0.1-2.2

8.1 2.6-26

p = 0.0001

0.1 0.1-6.3

0.4 0.1-2.8

1.6 0.3-7.5

p = 0.0005

30.5 2.1-78.6

26.4 3.4-63.8

16.60 8.3-41.7

p = 0.0590

At Biopsy Median Range Nadir Median Range Time to Nadir (months) Median Range PSA = prostate-specific antigen.

Postimplant biopsy 0

Fig. 2. The proportions of negative, indeterminate, and positive prostate biopsies as a function of the postimplant time interval.

However, many clinical and pathologic parameters indicate that the indeterminate biopsy group behaves biologically like the negative group as is discussed below. Schelhammer and colleagues (33) first described the histological characteristics of postimplant prostate tissue and reported the first and only other series of prostate biopsy results following interstitial implant alone. Among 57 patients, they found a 26% positive postimplant biopsy rate, with all positives found among the T2b-T3 patients. Considering the low-tech nature of their retropubic technique relative to today’s ultrasound-guided transperineal procedure, these results are impressive. The issue of patient selection must be considered in all posttreatment biopsy series. Patients selected for permanent transperineal interstitial brachytherapy alone should include only those with early stage, low- to moderategrade tumors. However. more important than the initial patient selection is selection at the time of postimplant biopsy. The widely varying results in the literature may be explained in part by varying selection criteria for rebiopsy. If only patients with an abnormal DRE and/or rising PSA are biopsied, a higher positivity rate would be expected. The converse is true if only clinically and biochemically controlled patients are biopsied. As is indicated in Table 1, the biopsied and unbiopsied groups were nearly identical at presentation. Postimplant biopsy was requested of all 402 patients with special effort to obtain biopsies on those at highest risk. Only six patients with biochemical progression (defined as PSA > 1 .O rig/ml and two consecutive PSA elevations) have not been biopsied. It would be expected that these patients would have positive biopsies. However, of the 16 patients with biochemical progression biopsied, only 5 have been positive, 1 indeterminate, and 10 negative. This could reflect some false negative biopsies, the presence of distant relapse in the setting of locally controlled disease, or both. Although it was the objective to obtain postimplant biopsies on all patients, many refused, given their low PSA level and discomfort associated with the biopsy procedure. Others were advised by referring physicians not to un-

B. R. PRESTIDGE

et ol.

37

dergo rebiopsy, and others simply lived too far away to return for biopsy. This pathologic classification system recognizes a distinct entity termed indeterminate. The indeterminate classification recognizes a substantial number of biopsies after radiation (7 1 out of 361, 20% in this series) that have features of residual neoplasia but differ from their de now appearance by the presence of significant radiation effect (4). Crook et ul. have also recognized a group of patients with indeterminate biopsies following external beam irradiation (8). As in the present series, the majority (52%) have converted to negative on serial biopsies while 16% have progressed to positive. and 32% remain indeterminate. There is substantial evidence that the mechanism of death for the majority of malignant cells is a mitotic event (23). Cells suffering sufficient radiation injury to their nucleus during the sensitive phases of their cell cycle do not die instantly, but rather fail to divide during mitosis and undergo a delayed demise at the time of attempted cell division. Given the low proliferative rate of prostatic carcinoma relative to other neoplasms, the time interval for this delayed demise may be quite protacted. The duration of the process of cell death described above depends largely on the length and phase of the cycle at the time the lethal injury was inflicted on the nucleus of the cell. For prostate carcinoma, this cell cycle may be many months in duration (24). These radiobiological considerations would support the use of a low, continuous radiation dose rate, as is obtained with permanent interstitial brachytherapy, to eradicate prostate cancer. This consideration has been used to select isotopes for permanent interstitial brachytherapy, the rationale being that higher grade lesions tend to be more aneuploid with higher proliferative rales and a shorter cell cycle, and that an isotope with a shorter half-life (i.e., ““Pd. Tl/2 17 days) might be more effective at eradicating tumor. Tumors comprised primarily of lower grade malignant cells, on the other hand, might then be most effectively treated with an isotope with a longer half-life (i.e., 1251,TIE 60 days) (20). They also support the concept that prior to cell death, radiation effect may be seen in and around malignant cells, and an evolution of histologic changes would be expected including the gradual loss of malignant cells. This concept of histologic progression of cell death has been previously described ( 14) for prol;tate cancer. The indeterminate category merely recognizes a stage in this histological involution in which cells have the appearance of residual cancer but have lost their ability to divide, and consequently, their viability. At least three clinical observations support the distinction of a separate indeterminate category. 1) Most indeterminate biopsies would be expected to be seen relatively early in the time course following treatment. Indeed, in this series patients had ;m indeterminate

38

I. J. Radiation Oncology l Biology l Physics

biopsy at a median follow-up of 21 months compared to 32 months for those with a clearly positive or negative biopsy @ < 0.0005). 2) It would be expected that if these indeterminate cells are not viable, subsequent biopsies would eventually be negative, and therefore over time, the number of indeterminates would decrease and the number of negatives would increase. This was found as is shown in Fig. 2. The observation by Cox and Stoffel (7) and subsequently others that the number of positive biopsies decreases with time following radiation also supports the third indeterminate category in addition to positive and negative. In the absence of a third, indeterminate category, most pathologists interpret the presence of any malignant cells irrespective of the presence of radiation effect, to be positive. It is likely that many of those biopsies read as positive within the first 2 years of treatment actually represented an indeterminate group. 3) If the cells seen in indeterminate biopsies have no malignant potential, it would be expected to correlate with PSA data. This series found that the PSA at the time of biopsy for the negative and indeterminate groups was significantly lower than for the positive group (0.2 and 0.5 vs. 8.1, respectively, p < 0.005). In addition, the PSA nadir for the indeterminate group was significantly less than for the positive group (0.4 vs. 1.6, p < 0.01). Time to PSA nadir was also shorter. All of these observations support the concept that the biologic behavior of glands in indeterminate biopsies is quite different from those in positive biopsies and much more in keeping with the biologic behavior of glands found in negative biopsies. Although histological criteria are used primarily for this classification system and immunohistochemical analysis was not universally applied in this study, it has been our observation that indeterminate biopsies have an immunohistochemical profile that shows a very low proliferative rate. Proliferating cell nuclear antigen (26) and MIB-1 (1 l), a monoclonal antibody to Ki-67, which may be used on formalin-fixed, paraffin-embedded tissue sections shows very weak reactivity in the indeterminate glands. However, these proliferation markers are clearly present in the malignant glands of positive biopsies. The fact that a third, indeterminate category has not been widely recognized might be a partial explanation

Volume 37, Number 1, 1997

for the disparity of positive postimplant biopsy rates observed in the literature ranging from 19-93% (6, 9, 15, 16, l&25, 29, 32) and everywhere in between. It is quite probable that those series reporting higher positivity rates are misinterpreting many indeterminate specimens as positive. This disparity underscores the importance and largely qualitative nature inherent in the pathologic interpretation of postirradiation prostate biopsies. The positivity rate is most certainly dependent in part on the skill, experience, bias, and confidence of the pathologist. While PSA parameters are useful in predicting treatment failure (19, 27, 34) we believe that with the implementation of the three pathologic category system, knowledge of the posttreatment biopsy status can still be very useful in complementing the clinical and biochemical data for prognostic purposes and when aggressive local salvage therapy is contemplated. We plan to examine in more detail the role of immunohistochemistry as an adjunct to interpretation of postirradiation biopsies and possibly earlier detection of those patients at greatest risk for truly recurrent local disease.

CONCLUSION These data demonstrate that contemporary transperineal interstitial brachytherapy results in the pathologic eradication of tumor in early stage prostate carcinoma patients in at least 80% of cases and likely much higher. Biochemically, both the depth and time to PSA nadir correlate well with the pathologic findings. These findings coupled with PSA-based disease control data (2) support the efficacy of this technique in the management of early-stage carcinoma of the prostate. The indeterminate postimplant biopsy category is a previously underappreciated entity that is pathologically, clinically, and biochemically distinctly different than positive. This study also supports prior observations that the validity of a posttreatment biopsy is directly proportional to the posttreatment interval. Therefore, except in the case of clinical suspicion of recurrence, a rebiopsy less than 18-24 months after brachytherapy, especially in a patient with a normal PSA, is not indicated.

REFERENCES ing of cancer, 4th ed. Philadelphia, PA: Lippincott Co; 1992:181-186. 2. Blasko, J. C.; Wallner, K.; Grimm, P. D.; Ragde, H. Prostate specific antigen based disease control following ultrasound guided lz510dine implantation for stage Tl/T2 prostatic car-

external beam irradiation for carcinoma of the prostate. J. Urol. 135722-726; 1986. 4. Bostwick, D. G.; Egbret, B. M.; Fajardolf, L. F. Radiation injury of the normal and neoplastic prostate. Am. J. Surg. Pathol. 6:541-551; 1982. 5. Bulmer, M.G. principles of statistics. Edinburgh, Scottland:

cinema. 3. Bosch, Golgai, results

Oliver and Boyd; 6. Cox, J. D.; Kline, of biopsies after Urol. 1:237-242;

1. American

Joint Committee

on Cancer. In: Manual for stag-

J. Urol. 154:1096-1099; 1995. P. C.; Forbes, K. A.; Prassvinichai, S.; Miller, J. B.; H.; Martin, D. C. Preliminary observations on the of combined temporary ‘92iridium implantation and

1967. R. W. The lack of prognostic significance radiotherapy for prostatic cancer. Semin. 1983.

Postimplant biopsy I. Cox. J. D.; Stoffel, T. J. The significance of needle biopsy after irradiation for stage C adenocarcinoma of the prostate. Cancer 40:156-160; 1977. 8. Crook, J. M.; Perry, G. A.; Robertson, S.; Esche, B. A. Routine prostate biopsies following radiotherapy for prostate cancer: Results for 226 patients. Urology 45:624-63 1; 1995. 9. Freiha, F. S.: Bagshaw, M. A. Carcinoma of the prostate: Results of postirradiation biopsy. Prostate 5: 19-25; 1984. IO. Gehan, E. A. A generalized Wilcoxon test for comparing arbitrarily singly sensored samples. Biometrka 52:202-233: 1965. 11. Gerdes, J.: Becker, M.: Key, G. Immunohistological detection of tumor growth fraction (Ki-67 antigen) in formalin and-fixed and routinely processed tissues. J. Pathol. 168:8587: 1992. 12. Grimm, P. D.; Blasko. J. C.; Ragde, H. Ultrasound-guided transperineal implantation of Iodine- 125 and palladium- 103 for the treatment of early stage prostate cancer. Atlas Urol. Clin North Am. 2(2):113-125; 1994. 13. Grossman. H. B.; Batata, M.; Hilaris, B.; Whitmore, W. F. “‘1 implantation for carcinoma of the prostate. Further follow-up of first one hundred cases. Urology 20:591-597; 1982. 14. Helpap, B. Histopathlogical effects of radiotherapy. In: Bruggmosur. B. D.; Sommercamp, H.; Mould, R. F., eds. Brachytherapy of prostate cancer, proceeding of international symposium, interstitial radiotherapy of prostate cancer: The state of the art. 30 Nov- I Dee 1990. Great Britain: BPCC Hazel1 Books; 1991:41-52. IS. Kabalin. J. N.; Hodge. K. K.; McNeal. J. E.; Freiha, F. S.; Stamey. T. A. Identification of residual cancer in the prostate following radiation therapy: Role of transrectal ultrasound guided biopsy and prostate specific antigen. J. Urol. 142:326-331; 1989. Ih. Kiesling, V. J.; McAninch, J. W.; Goebel, J. L. External beam radiotherapy for adenocarcinoma of the prostate: A clinical follow-up. J. Urol. 142:851-854; 1980. I? Klein. A. F.: Ali, M. M.; Marks, S. E.; HackIer, R. H. Bilateral pelvic lymphadenectomy, iridium 192 template. and external beam therapy for localized prostatic carcinomas: Complications and results. South. Med. J. 81:27-34; 1988. 18. Kuban, D. A.; El-Mahdi, A. M.; Schellhammer, P. F. The significance of post irradiation prostate biopsy with longterm follow-up. Int. J. Radiol. Oncol. Biol. Phys. 24:409414: 1992. IY. Lange, P. H.; Ercole, C. J.; Lightner, D. J.; Fraley, E. E.; Vessella, R. The value of serum prostate specific antigen determinations before and after radical prostatectomy. J. Ural. l41:873-876: 1989. 20. Ling, C. C. Permanent implant using Au-198, Pd-103, I-125: Radiobiological consideration based on the linear quadratic model. lnt. J. Radiol. Oncol. Biol. Phys. 23:81-86; 1992.

l

B. R. PRESITIXE IV trl.

-3Y

21. Marinelli. D.; Shanberg, A. M.; Tansey, L. A.; Sawyer. D. E.; Syed, N.; Puthawala. A. Follow-up prostate biopsy in patients with carcinoma of the prostate treated by “‘iridium template irradiation plus supplemental external beam radiation. J. Urol. 147(3):922--9X; 1992. 22. Mellinger. G. T.; Gleason. D.: Bailar. J. The histology and prognosis in carcinoma of the prostate. Front. Radiat. Ther. Oncol. 9:267-273; 1967. 23. Mostofi, F. K.; Davis. C. J.; Sesterhan. 1A. Pathology of carcinoma of the prostate. Cancer Suppl 70:235--253; 1993. 24. Mostofi, F. K.: Sesterhan, I. A.: Davis, c’. J. A pathlogist’s view of prostatic carcinoma. Cancer Suppl. 7 1:906-931; 1993. 25. Nachtsheim, D. A.; McAninch. J. W.: Stoutzman, R. I:,. Latent residual tumor following external radiotherapy fog prostate adenocarcinoma. J. Ural. 13O:i I2-3 14; 1978. 26. Nemoto, R.: Kawamurah, H.; Miyakawa. 1.; Uchida, K.; Hattori, K.; Koiso, K.; Hariada. M. Immunohistochemical detection of proliferating cell nuclear antigen (PCNA)/ cyclin in human adenocarcinoma. J. ITrol 159: 165-169: 1993. 27. Paulson. D. F.: Maul, J. W.: Walther, P. J. Radical prostatectomy for clinical stage T I-2 NOM0 prostatic adenncarcinoma long-term results. J. I.Irol. 143: I 180-l 184: 1990. 28. Prestidge. B. R.; Kaplan, I.; Cox. R. S.: Bag?;haw, M. A. Predictors of survival after a positive postirradiation prostate biopsy. Int. J. Radiol. Oncol. Biol. Phys. 28: 17-22; 1094. 29. Prestidge, B. R.; Kaplan, I.; Cox, R. S.: Bagshaw, MA. The clinical significance of a positive postirradiation biopsy without metastases. lnt. J. Radio]. Oncol. Biol. Phys. 24:X408: 1992. 30. Ross. G.; Borkon, W. D.: Landrey. L. J.; Edwards, F. M.; Weinstein, S. H.: Abadir. R. Preliminary observations on the results of combined ‘?odine seed implantation and external irradiation for carcinoma of the prostate. .i. L!roI. I27:69% 705; 1982. 31. Scardino, P. T.; Wheeler, T. M. Local control of’ prostate cancer with radiotherapy: Frequency and prognostic signif. ^ .. icancr ot posltlve results atter postlrraulation prostate bi-, opsy. Natl. Cancer Inst. Monogr. 7:95-- 103; 1988. 32. Scardino, P. T.; Wheeler, T. M. Prostatic biopsy after irradiation therapy for prostate cancer. 1Iroltrgy ?S(Suppl. 2):39-47: 1985. 33. Schellhammer, P. F.; Ladaga. L. E.; El Mahdi. A. Histological characteristics of prostatic biopsies after I25 iodine implantation. J. Urol. 123:700-706; 1980. 34. Zeitman. A. L.: Coen, J. J.: Shipley, I+. ti.: Willett. C. G.; Efird. J. T. Radical radiation therapy in the tnanagement of prostatic adenocarcinoma: The initial prostate specific antigen value is a predictor of treatment outcome. J. 1~1~1. I5 I :640-645: I9’,3.