200 Postradiotherapy prostate biopsies: What do they really mean? 5 year results for 498 patients

252

I. J. Radiation

1.99

Oncology

THE IMPORTANCE EXTERNAL BEAM

Martinez

AA,

Kestin

* Physics

OF ADEQUATE IRRADIATION

LL; Vicini

Hospital,

0 Biology

Volume

FOLLOW-UP FOR PROSTATE

45, Number

IN DEFINING CANCER

3 Supplement

TREATMENT

I999

SUCCESS

AFTER

FA

William

Beaumont

Royal

Oak, MI,

USA

Purpose: (EBRT) ASTRO

We reviewed our institution’s experience treating prostate cancer patients with to detetmine how differences in the length of follow-up affect the determination Consensus Panel Definition of biochemical failure (BF).

external beam radiation therapy of treatment outcome using the

Methods: From January 1987 through December 1997, 1096 patients with localized prostate cancer were treated with definitive EBRT at William Beaumont Hospital, Royal Oak, Michigan, and had sufficient prostate-specific antigen (PSA) follow-up to determine their biochemical status. All patients received EBRT alone (no adjuvant hormones) to a median total prostate dose of 66.6 Gy (range: 59.4-70.4 Gy). To test the impact of differences in follow-up on the calculation of BF, 389 patients with at least five years of PSA follow-up were selected for initial analysis. BF was then retrospectively determined using the Consensus Panel definition at yearly intervals, discounting the remainder of each patient’s follow-up. The median follow-up for this group of patients was 6.6 years (range: 5.0-l 1.6 years). In a second analysis, patient cohorts were randomly selected with varying median PSA follow-up intervals in order to more accurately represent a population whose follow-up is distributed continuously over a defined range. Seven cohorts were randomly selected with 200 patients in each cohort. Cohorts were individually identified such that half of the patients (100) had 2 years or less follow-up than the stated time point for analysis and half (100) had up to 2 years more follow-up than the time point chosen for analysis. For example, in the cohort with a median follow-up of 3 years, 100 patients with a PSA follow-up from l-3 years were randomly selected, and 100 patients with a follow-up from 3-5 years were randomly selected, thus generating a median follow-up of 3 years for this cohort (range: 1-5 years). This process was repeated five times for five random samples of seven cohorts each. BF was calculated according to the Consensus Panel definition. Results: In the Iirst analysis, significantly different rates of biochemical control (BC) (varying by 15.30%) were calculated for the same actuarial year chosen for analysis depending only upon the length of follow-up used (Table 1). For example, the 3.year actuarial rate of BC varied from 71% when calculated with 3 years of follow-up versus 50% with 7 years (p
Table 1. Actuariai Table 2. Actuarial samples)(p~o.OoI)

200 Crook Princess

BC Rates with Biochemical Status Determined at Various Intervals after RT (n=389)@@.001) BCfor Patient Cohorts with Varying Median Follow-up Intervals (mean offive random

POSTRADIOTHERAPY PROSTATE RESULTS FOR 498 PATIENTS JM’,

Malone

Margaret

treatment success with EBRT for prostate cancer, after treatment, significantly different rates of for analysis. We recommend that data should only at leastbeyond the time point at which actuarial

S’, Bahadur Hospital,

Y’, Perry

Toronto,

BIOPSIES:

G’, Robertson

ON, Canada’;

Ottawa

WHAT S*, Abdolel Regional

DO THEY

REALLY

MEAN?

5 YEAR

Ml Cancer

Centre,

Ottawa,

ON, Canada’

Purpose: Although most investigators rely on serum PSA as a surrogate marker of outcome, many clinical protocols use postradiotherapy (RT) prostate biopsies as a gold standard of local therapy effect. Unfortunately, false negatives due to sampling error, false positives due to delayed tumor regression, and indeterminate biopsies showing RT effect in residual tumor of uncertain viability, make interpretation difficult.

Proceedings

of the 41 st Annual

ASTRO

Meeting

253

Materials and Methods: 498 men treated with radical RT using standard dose (66 Gray) and technique, from 06/87-lo/96 were followed prospectively with systematic TRUS-guided post RT prostate biopsies, starting 12-l 8 months after RT. If there was residual tumor but further decline in serum PSA, biopsies were repeated every 6-12 months. Negatives were rechecked at 36 months. Residual tumor was evaluated for RT effect and proliferation markers (PCNA [proliferative cell nuclear antigen] and mibl). 498 men had 978 biopsies. Median time of the first biopsy n=498) was 13 months, biopsy #2 (n=342) 28 months, biopsy #3 (n= 110) 36 months, biopsy #4 (n=28) 44 months and biopsy #5 (n=4) 55 months. Median follow-up is 54 months (range 13-131). 175 patients (34%) had prior hormonal therapy for a median of 5 months (range l-60) at the discretion of the referring urologist. Results: Stage distribution was tlb:46, tlc:50, t2a:115, t2b/c:170, t3:108, t4:11, tx: 1. 28% had Gleason score 2-4, 42%: 5-6, 18%:7, and 12% 8-10. 71 men died, 26 of prostate cancer and 41 of other causes. Actuarial failure free survival by T-stage at 66 months is tlb:69%, tlc:64%, t2a:60%, t2b/c:48%, t3:32% and t4:0%. Actuarial freedom from local failure at 66 months is tlb:85%, tlc:89%, t2a:72%, t2b/c:69%, t3:57% and t4:0%. The proportion of indeterminate biopsies decreases with time, being 33% for biopsy 1, 24% for biopsy 2, 18% for biopsy 3, and 7% for biopsy 4. 30% of indeterminate biopsies resolved to NED status, regardless of the degree of RT effect, 18% progressed to local failure and 34% remained as biopsy failures with indeterminate status. Positive staining for proliferation markers was strongly associated with subsequent local failure (p=O.O009 for mibl and 0.003 for PCNA). Of patients with positive biopsies, 30% showed delayed tumor resolution (n=81) with conversion to NED status at a mean time of 30 months. False negatives were seen in 19% with later progression to local failure at a mean time of 43 months. Mean PSA nadir was 0.5 rig/ml @ 25 months for NED patients, but was significantly higher and earlier for all types of failure: 1.6 rig/ml @ 16 months for biochemical, 2.1 rig/ml @ 17 months for local, and 5.8 rig/ml @ 10 months for distant failures (p=O.OOOl).In multivariate analysis, only PSA nadir (p=O.OOOl) and biopsy status at 24-36 mo(p=0.0005) were independent predictors of outcome. Conclusion:

Post RT prostate biopsies Staining for markers of cellular showing marked RT effect cannot

outcome.

when

20 1 Sandler

OVERALL EXTERNAL HM,

The University

Dunn

are not a gold standard of treatment efficacy, but are an independent predictor of proliferation is associated with subsequent local failure. Indeterminate biopsies, even be considered negative.

SURVIVAL REMAINS BEAM RADIOTHERAPY RL,

McLaughlin

of Michigan,

PW:

Ann Arbor,

HIGH

Hayman MI,

AFTER (RT)

JA, Sullivan

PSA FAILURE MA,

Taylor

FOLLOWING

CONFORMAL

JMG

USA

Purpose/Objective: Given the long potential natural history of endpoints such as biochemical relapse, which might indicate, more significant failures after radiotherapy. This may have relevance counseling an individual patient about appropriate salvage treatment. patients who developed biochemical relapse following conformal

prostate cancer, there is interest in discovering surrogate quickly than overall survival, when patients have clinically when different treatments are compared or when one is Thus, we studied the overall survival, after recurrence, of radiotherapy.

Materials and Methods: Of the 1,844 patients in the Radiation Oncology prostate cancer database, 697 were deemed eligible. Patients excluded were those with Nl or Ml disease, those treated after radical prostatectomy, those who received hormone therapy before RT, those who died, failed clinically, or had no PSA response in the first 6 months after RT, and those treated to doses less than 60 Gy or greater than 85 Gy. Patients included required at least two post-RT PSAs separated by at least one week. Biochemical relapse was defined as three consecutive PSA rises. This resulted in 153 patients with biochemical failure. Survival is calculated from the third PSA elevation. The rate of rise of PSA was calculated by fitting a regression line to the four rising PSAs on a In PSA vs. time plot. Results: There were 32 deaths among the 153 patients with failure. The overall survival after failure is 84% at 3 years (95% CI * 77%.91%) and is 54% at 5 years (95% CI * 40%.69%). Among the 153 failures, several factors were evaluated for an association with survival: age at failure, pre-RT PSA, PSA at second rise, PSA nadir, time from RT to failure, time to nadir, Gleason score, T-stage, and rate of rise, both from the nadir and from the beginning of The rise. None of these factors were significantly associated with an increased risk of death. As expected, the group of patients with biochemical failure have significantly worse prognostic factors than those without biochemical failure: median pre-RT PSA 15.8 vs. 9.0 @=O.OOOl, Wilcoxon rank-sum test), and Gleason score of 7 or greater for 48.3% of subjects vs. 41.1% (~~0.036, x-square test). Conclusion: Overall survival after conformal radiotherapy for prostate cancer remains high at 3 and 5 years after biochemical failure. This high survival rate occurs even though the group of patients with biochemical failure has worse than average adverse pre-radiation prognostic factors. Thus, although biochemical failure can identify patients who have recurrent disease after RT, the ultimate relationship between this recurrence and death remains to be better defined.

202

OXALIPLATIN: CLINICAL

Blackstock Wake Forest

Awl,*,

IN VITRO OBSERVATIONS

Hess S’, Chaney

University,

Winston-Salem,

EVIDENCE RELEVANT S’. Tepper NC,

OF ITS RADIATION TO CLINICAL

SENSITIZING TRIALS

ACTIVITY

- PRE-

JE* USA’;

UNC-Chapel

Hill,

Chapel

Hill,

NC,

USA’

Introduction: Oxaliplatin [trans.L-dach (IR-diaminocyclohexane) oxaliplatin, L-OHP] is a platinum-based compound that has demonstrated anti-neoplastic activity in a variety of in vitro and in vivo tumor models. The retention of the bulky DACH ring by activated oxaliplatin is thought to result in the formation of platinum-DNA adducts, which appear to be more effective at blocking DNA replication and are more cytotoxic than adducts formed from cisplatin. Unlike other platinum compounds, Oxaliplatin has demonstrated significant clinical activity in gastrointestinal malignancies. This study was designed to determine if oxaliplatin possesses radiation sensitizing activity, and if so, if the timing of the radiation and oxaliplatin is important. Materials and Methods: The HT-29 colon carcinoma cell line was obtained from the UNC Lineberger Comprehensive Cancer Center. Radiation survival data were generated for cells treated with single graded doses of ionizing radiation either alone or before or after a 1 hour or 24 hour oxaliplatin exposure. The 1 hour and 24 hour drug exposures were at the same concentration of oxaliplatin. 0.48 uM. Cell survival was determined via clonogenic survival at lo-14 days post-treatment.