Post Radiation Biopsy in Evaluation of Local Recurrence

Role of Post Radiation Biopsy and it's Significance

Post-radiotherapy biopsies are complex to interpret and requires an experienced pathologist. The findings vary depending on elapsed time interval following radiotherapy, whether anti androgen therapy was administered, as well as the original Gleason grade of cancer. Degree of treatment effect is influenced by the total dose of radiotherapy. Radiotherapy is known to induce a variety of histological changes in normal and cancerous prostate tissue, including atrophy, cytology atypia, mucinous metaplasia, cytoplasmic vacuolization, and diminution of neoplastic glands (1).

 

Crook et al studied prospectively studied 498 patients who underwent systematic 6 core trans-rectal ultrasound guided prostate biopsies at standard intervals following radiotherapy (at 12 months post radiation and every 6-12 months thereafter) (2). Thirty percent of patients with an initially positive first post-treatment biopsy at 12 months eventually converted to a negative biopsy at a mean time of 30 months. Indeterminate biopsies (those with profound treatment effect) at first post-treatment biopsy converted to negative in 30% and progressed to local failure in 18%. Finally, 19% of those with an initially negative post-treatment biopsy were found to have residual local disease at systematic 36-month biopsy. The authors concluded that the greatest predictive value of a post-radiation biopsy is between 30 and 36 months, and that biopsies with profound treatment effect (intermediate category) should be repeated as residual radiated tumor eventually declares its biological activity over time. (2).

 

In a clinical trial of post radiation biopsy in men with rising PSA, 56%  with initial negative biopsy had cancer on subsequent biopsy. All patients were treated with salvage surgery successfully.This study suggests that patients with initial negative prostate biopsies after radiation should have repeat biopsies if the PSA is rising. Whether negative biopsies were due to missed cancer during the initial biopsy versus continued growth of recurrent cancer which made the repeat biopsies positive is unknown.Whether the use of mpMRI  more  frequently to target recurrent lesions will reduce the  incidence of false negative biopsies is still under study. (3)


 

In 1999, ASTRO published a consensus statement regarding guidelines for re-biopsy after radiation. (4)  This group concluded that systematic prostate re-biopsy is not a standard of care for prostate cancer patients, that it should only be considered for patients who are candidates for effective salvage local therapy, and that it should be performed after two years following the conclusion of radiation therapy. PSA guidelines were not given in this statement. A later consensus stated that the newer Phoenix definition of recurrence (nadir plus 2) should be used to predict for metastatic failure, implying that biopsies to detect persistent local disease should occur before "nadir plus 2” is reached. (5)

 

Several studies have shown that when there is local recurrence as demonstrated by a positive post-radiation biopsy, there is an increased incidence of distant metastasis, and death from prostate cancer in patients (6,7,8).  

 

Stone et al conducted a literature review to assess the degree to which local recurrence occurs after prostate brachytherapy, as well as the treatment options available after such recurrence. (9) Local recurrence after prostate brachytherapy occurred in 2-20% of patients and was dose dependent. The biologic effective dose greater than 200 Gy2 was associated with a less than 2% recurrence rate. The investigators recommended that the pathologist be experienced in evaluating postirradiation tissue, owing to the difficulty in distinguishing benign irradiated prostate from residual or recurrent tumor. They also recommended that confirmatory biopsy include both the prostate and seminal vesicles. They found that whole-gland salvage sugery, whether by prostatectomy or cryoablation, was associated with high complication rates. Focal therapy had fewer complications, although targeting was less accurate. They found that multiparametric MRI and transperineal mapping biopsy were advantageous in lesion identification and ablation. They concluded that improved lesion identification and targeting may be associated with better cancer control and lower morbidity, and they suggested that transperineal mapping biopsy with interactive targeting software may offer the best approach to focused therapy. (9)

 

The largest Trial of post radiation biopsy shows that at 2 years after radiation presence of cancer in biopsy is associated with higher recurrence locally and for metastatic disease (10) 

The RTOG 9408 is the largest study evaluating presence of disease 2 years after biopsy. They evaluated 1979 men. The Hypothesis that a positive post radiation therapy biopsy is associated with inferior clinical outcomes was tested within the framework of a multi-institutional prospective randomized trial that overcomes many of the limitations of previous attempts to define its value. Namely, patient numbers are large, treatment is standardized, outcomes were recorded systematically in a prospective fashion under the auspices of an NCI-sponsored protocol.

Post-treatment evaluation  included  prostate biopsy at 2 years provided there was no clinical or biochemical evidence of disease recurrence/progression, no additional/salvage hormone therapy was administered, and there were no contraindications to performing biopsy. Both the initial diagnostic and post-treatment biopsies underwent central pathologic review. Positive post-treatment biopsies were graded according to Gleason score and assessed for the presence of therapy effect. For purposes of analysis, any biopsy specimen with cancer present was regarded as positive, regardless of the degree of therapy effect identified.

Of the 1979 men who underwent radiation in the RTOG NCI trial, 831  (42%) underwent post radiation biopsy at 2 years; none of these men had rising PSA or other signs of recurrence. Among them 398 were treated with Radiation alone and 433 with Radiation and Total Androgen Suppression.  Median follow up was nine years. Patients with positive post-radiation biopsies had higher rates of biochemical failure  and distant metastasis as well as reduced cancer specific survival. Positive biopsy remained predictive of these outcomes after correction for potential confounders such as Gleason score, tumor stage, and anti androgen therapy. Patients with Gleason score ≥ 7 with a positive biopsy additionally had reduced overall survival compared to those with a negative biopsy.

 

Clinicopathologic factors associated with a higher positive biopsy risk were clinical stage T2 vs. T1 (34% vs. 24%), Gleason score ≥ 7 (36% vs. 27%), and treatment with RT alone (no hormones) (39% vs. 21%).

The authors state in their discussion that prostate biopsy is not routinely performed following the completion of radiation unless there is biochemical failure or other evidence of recurrence. However studies where biopsies have been done show positive correlation between positive biopsies and inferior outcomes.

Crook et al. describe outcomes of 205 men who underwent post-radiotherapy prostate biopsy between 24–30 months post-treatment. Only 12% of biopsies were positive but a significant difference in progression free survival was detected between those patients with positive and negative biopsies. This included an increased risk of developing distant metastases and inferior prostate cancer specific mortality. (11).

Zelefsky et al. demonstrated inferior biochemical control and inferior distant metastasis free survival in patients with a positive post-RT biopsy. (7)   

Additional studies examining the clinical implications of a positive post-RT biopsy have shown similar outcomes with respect to biochemical control, but have not demonstrated inferior outcomes with respect to the relevant clinical endpoints of distant metastases and survival. (8,12).

The large number of patients undergoing post-RT biopsy on RTOG 9408 has enabled a more comprehensive analysis of clinical outcomes than has been done in any prior study. Namely, there were more positive post-treatment biopsies on this study than there were total performed biopsies in nearly all of the other analyses looking at this issue. The number of positive biopsies reported was more than double that of any prior series. As such, not only could clear clinical consequences of a positive post-RT biopsy be defined, but subset analyses could be performed to perhaps identify which patients may be most likely to clinically benefit from such a procedure in the future. While increased rates of distant metastases and inferior cause-specific survival was appreciated for the group as a whole, the relatively low rates of these events may not necessarily warrant the risks/invasiveness of post-RT biopsy on a routine basis. However, for the 279 patients with Gleason score ≥ 7, the estimate of distant metastases jumps to nearly 16% at 10 years and cause-specific survival falls to just below 85%. These numbers could certainly be improved, whether through local salvage therapies or additional androgen suppression, and the high-grade disease subset of patients likely represents the ideal group within which to investigate this issue further.

Based on the RTOG study it is prudent for all men to undergo biopsy at 2 years  and men with positive biopsies especially those who have Gleason score 7 prior to radiation should seriously consider local salvage therapy if biopsies are positive

 

With availability of  a treatment such as HIFU for ablation of prostate tissue there is potential to treat these patients earlier with less side effects  and this may  reduce their chances of metastases and increased mortality from prostate cancer

 

In order to reduce the chances of delaying detection of local failure after radiation, evaluation of other criteria such as timing and pattern of PSA decrease after radiation therapy may be useful (6). The scenario is further complicated in patients who receive both radiation and hormone therapy. When hormone therapy is  given for 9-12 months after radiation and then stopped, these men have a higher probability of local recurrence. Kuban et al reported that the most sensitive and specific  definitions of biochemical recurrence after brachytherapy maybe current nadir + 1ng/ml (13). Waiting until PSA elevation reaches nadir+2 may be detrimental for local treatment. 

 

​With regards to PSA doubling time, a short PSA doubling time under 3 months indicates a rapidly growing tumor with likelihood of metastatic disease.(14) A longer PSA time over 6 months is associated with local recurrence (15). 

 

There are also patients whose PSA may be low after radiation therapy even though cancer is still present in the prostate. In patients with prostate cancer who had radiation therapy and later underwent prostate and bladder removal for bladder cancer, it was found that 50% had pathologic evidence for prostate cancer  in their prostates even though their PSA was not suggestive of cancer recurrence (16). The significance of these findings are unclear at present.

​When patients have recurrence after radiation and hormone therapy combination, the use of Gleason Score to grade biopsies is not recommended because of hormone induced changes causing an inaccurate reading. Genetic markers in future may be useful to provide more information about grade of cancer in such patients. 

In summary men who have had radiation therapy for prostate cancer should have prostate biopsy to evaluate for local recurrence at two years after radiation if the PSA nadir is 0.5ng/ml or higher. Any man whose PSA is rising three or more consecutive times should have a prostate biopsy. If the biopsy is negative and the PSA is continuing to rise the biopsy should be repeated. Men who have a rising PSA after radiation should have evaluation with a combination of multi parametric MRI, bone scan and one of the newer F11 or F18 Choline PET scans to evaluate pelvic and distant metastases. mpMRI may help to detect local recurrence and in targeted biopsy.Men who have a PSA doubling time of less than 3 months after radiation are at high risk for metastatic disease and should have aggressive work up to document metastatic disease and start on early systemic therapy.

1) GAUDIN P et al. Am J Surg Pathol; 1999; 23: 1021-31

2)Crook J; et al. Int J Radiat Oncol Biol Phys 2000; 48-355

3) Cohen J et al. Int. Braz J Urol. vol.36 no.1 Jan./Feb. 2010

4) COX J. J Clin Oncol. 1999; 17: 1155.

5) Roach M et al. Int J Radiat Oncol Biol Phys. 2006; 65: 965

6) Kuban DA, et al. Int J Radiat Oncol Biol Phys. 1992; 24: 409-14. 

7) Zelefsky MJ, et al. J Urol. 2008; 179: 1368-73; discussion 1373

8) Vance W, Int J Radiat Oncol Biol Phys; 2007; 828

9) Stone, N, et al. Am Brachytherapy Society, 2015; 14:124

10) Krauss DJ, et al. Int J Radiat Oncol Biol Phys. 2015 Jul 15;92(4):863

11) Crook J et al, Cancer. 2009;115:673–679

12) Kestin et al Int J Radiat Oncol Biol Phys. 2002;54:107–118

13) Kuban et al. 2006; 65:1487–1493.

14) Delouya G, et al, Cancer Epidemiol 2012; e137

15) D'Amico AV, et al; J Clin Oncol 2005; 4975

16) Kaplan DJ, et al, Urology 2008; 654

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