Active Surveillance with High Resolution Color-Doppler
Transrectal Ultrasound Monitoring: Is it Foolproof?

Edited from PCRI Insights February 2007, vol. 10, no. 1
Duke Bahn, MD, Prostate Institute of America, Ventura, CA
Mark Scholz, MD and Richard Lam, MD
Prostate Oncology Specialists, Marina Del Rey, CA

To embark on Active Surveillance is not to forgo radical local treatment altogether. Rather it is to delay therapy as long as it is safe.

Introduction

It is well recognized that we are over-detecting and over-treating prostate cancer.1 Draisma et al reported an over-detection rate of 48% in their series; other studies have reported over-detection rates of 16-56%.2 This finding is due to the increased awareness of prostate cancer (PC), routine PSA testing, and low threshold for prostate biopsies. Bill-Axelson et al monitored 348 men with intermediate risk disease. They reported in the New England Journal of Medicine that the 10-year mortality rate was only 15%. They also stated that patents with low-risk disease or those without extended life expectancy might not benefit from treatment.3

Despite strong evidence that immediate treatment is often not beneficial, 75% of men 75 years or older with low risk disease undergo local treatment rather than pursue an Active Surveillance program. Overall, the lifetime risk of dying from PC remains less than 3%5 and yet, CaPSURE™ data shows that 94% of men with low-risk PC received radical treatment.4

Watchful Waiting is a widely accepted treatment for older men with PC. Since PC typically involves a slow-growing tumor, several decades often pass before it becomes a life-threatening disease. Traditionally, Watchful Waiting means not considering any local treatment such as surgery or radiation and initiating androgen deprivation therapy when the disease becomes symptomatic or systemic.

The concept of Active Surveillance is different from that of Watchful Waiting. To embark on Active Surveillance is not to forgo radical local treatment altogether. Rather it is to delay therapy as long as it is safe. Treatment is offered only when disease progression is confirmed during close clinical observation.6,7 Most importantly, state-of-the-art Active Surveillance should not lose the window of opportunity for successful local therapy.

The selection criteria for Active Surveillance as applied to low risk disease continues to evolve. The traditional clinical parameters used to predict cancer aggressiveness are PSA, Gleason score, and tumor stage. Favorable risk (low-risk) PC is characterized as a PSA of 10 or less, a Gleason score of 6 or less, and T1c - T2a disease8 on a digital rectal exam. For patients older than age 70 or with more comorbidities, the criteria can be relaxed. Choo et al allowed patients with a Gleason grade up to 7 (3 + 4) and a PSA up to 15 to remain on Active Surveillance.9,10 Factors such as >50% involvement of each core (or a PSA velocity above 2 ng/year, are other signs of more aggressive disease, suggesting the need for definite treatment rather than Active Surveillance.11

Using selection criteria of this nature, preliminary results from a prospective trial of Active Surveillance in 299 men has produced encouraging results. Klotz reported a disease-specific survival rate of 99% at eight years follow-up.12 Only two men died as a result of PC, and they had PSA doubling times of less than two years. However, only 22% of the patients exhibited either biochemical progression, clinical progression, or histological progression of the disease during Active Surveillance, and they were subsequently treated properly.

Despite these encouraging findings, there is still the sobering reality of 30,000 PC deaths in the US each year. So, how else can we avoid mistakenly under-staging a man with high-risk disease, delaying potentially curative therapy, and losing the window of opportunity for effective treatment? Reliance on state-of-the-art imaging may add another layer of safety.

Transrectal ultrasound in a crude form was introduced as a PC screening and diagnostic tool in the 1980s, but the results were disappointing. However, there has since been significant improvement in ultrasound technology, particularly during the last decade. High resolution, color-Doppler Ultrasound (HR-CDU) and tissue harmonic technology has improved cancer detection. In addition, a specific lesion-directed targeted biopsy along with the biopsy of potential routes of tumor escape (such as nearby neurovascular bundle and seminal vesicles) improved the accuracy of staging of the cancer and Gleason grading. Our previously published study in 1998 showed that 26% of the patients whose disease was thought to be organ-confined before HR-CDU staging actually had biopsy proof of extension outside the prostate gland.13

This article presents case studies showing how HR-CDU can be utilized for more accurate staging in men who are considering or who have been on active surveillance.

Materials and Methods

Cases were selected for presentation to illustrate the clinical impact of an HR-CDU-directed biopsy on men who are considering Active Surveillance or who have been on Active Surveillance after there was an initial diagnosis of PC by a conventional random, blind biopsy. Significant additional information was detected in many cases that led to drastic changes in the management of the disease.

All studies were performed on Hitachi EUB-6500. The ultrasound probe used was an end-firing probe utilizing 5-9 MHz. The prostate gland was scanned from the seminal vesicles down to the midgland, to the apex, and to the level of the external sphincter in vertical and horizontal cross sections. Color-Doppler and tissue harmonic technology was used to improve the spatial and contrast resolution. Color-Doppler (power-Doppler) and gray-scale images were displayed simultaneously on a high-resolution monitor for the operator to view, and an extra monitor was placed in front of patient for his viewing.

Results

CASE #1: Mr. CW is a 68-year-old man with a PSA of 4.0. A routine eight-core biopsy showed a Gleason 6 malignancy in one core from the right lobe. (The exact location of the tumor in the right lobe was not specified in the biopsy report.) The clinical stage showed no palpable nodule (T1c).Multiple consultations were obtained. He was told that he could watch his cancer with PSA surveillance; if not, he would be a good candidate for radiation therapy or radical prostatectomy. The patient was leaning toward Active Surveillance, since all the clinical parameters were favorable for low-risk disease.

HR-CDU imaging showed the existence of an 18 mm x 12 mm, hypoechoic lesion in the right lobe with significantly increased blood flow. The lesion was close to the right seminal vesicle with an actual invasion.

Figure 1 presents the axial view. A gray-scale ultrasound image (at the left) shows a dark lesion (marked by the cursor) that was suspicious for known cancer by original biopsy. The color-Doppler ultrasound image (at the right) shows that the lesion receives much more blood flow (neovascularity) than the rest of the normal tissue. This finding suggests that it is most likely is an aggressive PC.

Figure 2 presents the sagittal view. The gray-scale image (at the left) shows a dark spot (outlined by the 4 markers) at the base portion of the prostate (the same lesion that is seen on the axial projection) with neovascularity. It is close to the right seminal vesicle (RSV), suggestive of an actual invasion of the cancer into the seminal vesicle.

Directed and staging biopsies were performed, and they confirmed the presence of Gleason 7 cancer involving the right base and right seminal vesicle. The clinical stage was upstaged to T3b. The previous decision to pursue Active Surveillance was abandoned, and more aggressive combination therapy was recommended.

CASE #2: Dr. CF is a 67-year-old man with a PSA level of 8 and significant BPH (benign prostatic hyperplasia). Due to the BPH, the PSA level was still within the predicted range. A 12-core biopsy performed by his physician showed no evidence of cancer. However, he subsequently used HR-CDU to verify the diagnosis. The HR-CDU showed a 5 mm x 5 mm hypoechoic lesion in the left apex transition zone. Actually, it was detected in retrospective observation in gray scale, but only after the color-Doppler detected a local area of increased blood flow.

As illustrated in Figure 3, the color-Doppler image (left side of image) clearly shows a small focal area of increased blood flow. The gray-scale image (at the right) shows a subtle dark spot that corresponds to the color-Doppler finding. It was actually picked up in retrospective observation, located upon seeing the color image.

A directed biopsy confirmed the Gleason 6 cancer. With the known size of the tumor (less than 1cc), a Gleason 6 histology, and a transition zone location, he was confirmed to be a good candidate for Active Surveillance. The patient and his physician agreed upon a program of Active Surveillance with close PSA monitoring and follow-up HR-CDU to objectively monitor the tumor volume. His cancer volume and his PSA have remained stable for several years.

CASE #3: Mr. GV is 70-year-old man whose Gleason 6 cancer was diagnosed in 1996 and placed on Watchful Waiting. In May 2002, he presented for an HR-CDU to re-evaluate his cancer because his most recent PSA level had risen to 12, up from 10 a year ago and up from 7.5 in 1996. A gray scale ultrasound was entirely normal. (The tumor was isoechoic, which means that the tissue texture is identical to the background normal tissue.)

As shown in Figure 4, only the color image (at the left) depicts a lesion with increased blood flow (neovascularity). The gray-scale image does not show any abnormality, even with retrospective observation.

Since the color-Doppler study clearly depicted a large, 17 mm x 10 mm lesion with intense neovascularity in the right apex, the large size of the cancerous area combined with the trend toward a higher PSA indicated the need to implement treatment.

Discussion

Active Surveillance has become an attractive option for many men who are assumed to have early-stage, low-risk disease.14 This approach allows men to safely delay surgery, radiation, cryotherapy or androgen deprivation therapy for years. However, patients and doctors remain concerned about mis-staging the disease, thereby mistakenly recommending Active Surveillance when actually occult high-risk disease is present.

Modern HR-CDU imaging offers improved spatial and contrast resolution that leads to a correct identification of the tumor, the exact location of the tumor, the size of the tumor, and the neovascularity of the tumor. It also enables us to perform a directed targeted biopsy of the lesion and staging biopsy if we suspect extra-capsular extension of the tumor. By doing so, we can determine an exact pathologic stage rather than just the clinical stage. Identification of the tumor is very important, as it enables the tumor to be objectively monitored with follow-up HRCDU. Along with other clinical parameters, this added information will provide further assurance to men who are on or considering Active Surveillance.

Active Surveillance data based on clinical information is still encouraging. Dr. Klotz’s study showed that 22% of patients eventually required treatment within the first eight years of diagnosis. These results may well represent natural disease progression rather than mis-staging at the time of diagnosis. However, if an HR-CDU had been utilized along with directed and staging biopsies, many men in this group might have proven not to be candidates for Active Surveillance. The fact that under-staging often occurs when the standard 8-12 core biopsy is relied upon has been well documented in the surgical literature. The frequency of under-staging
in men with PC is so well-recognized that under-staging is often used as an argument against using Active Surveillance at all.

The ability of HR-CDU to locate the disease within the prostate has been demonstrated in a number of studies. Targeted and staging biopsies find more cancer both inside and outside the prostate capsule with greater frequency than systemic random biopsies. In our experience, “upstaging” cancer with this technique is a relatively common occurrence as the case examples in this article illustrate. Clearly, pathologic proof of previously unsuspected seminal vesicle invasion, extra-capsular disease, or high Gleason grade disease is a clinically relevant and useful discovery. It can also be argued that such findings are important even in men not on Active Surveillance. Certainly, selection of the best local therapy can be improved if the presence and location of extra-prostatic disease can be ascertained before embarking on surgery or radiation.

One might argue that a man opting for Active Surveillance may take on a significant psychological burden since he is living with known cancer for a long period of time. The alternative of receiving a cancer treatment may reduce the burden, but the side effects and complications of therapy may carry their own psychological burdens. A recent Swedish study that was a randomized trial of observation versus prostatectomy concluded that there was no difference in psychological burden at 5 years.15

That PC is over treated in the United States is widely acknowledged, but only in the abstract sense. Clinicians, when confronted with living, breathing, and frightened patients seem unable to provide sufficient assurance to their patients that delaying radical treatment truly represents a safe alternative. HR-CDU imaging can be used to greatly narrow this gap, although it is neither perfect nor foolproof yet. Even so, the information provided by skillfully administered HR-CDU can help us come closer to the point where sufficient reassurance can be provided, so that the overuse of radical therapy can be reined in.

References

1. Thompson, I M, Goodman, P J Tangen, C M et al: The influence of finasteride on the development of prostate cancer. N Engl J Med, 349:215, 2003.

2. Draisma G, Schoeder, F H et al: Lead time and over-detection due to PSA screening: Estimates from European randomized study of screening for prostate cancer. J Natl Cancer Inst 2003. Jun 18; 95 (12):868-78.

3. Bill-Axelson, A, Holmberg, I: Radical prostatectomy versus watchful waiting: N Engl J Med. 2005 May 12:352 (19): 1977-84.

4. Albertsen, P C, Hanley, J A, Fine, J: 20 year outcomes following conservative management of clinically localized prostate cancer. JAMA 293:2095-2101, 2005.

5. Jemal, A, Tiwari, R C, Murray, T et al: Cancer statistics. 2004. CA cancer J Clin. 54:8, 2004.

6. Parker, C,: Active surveillance: Towards a new paradigm in the management of early prostate cancer. Lancet Oncol, 5:101, 2004.

7. Parker, C: Active surveillance: An individualized approach to early prostate cancer. BJU Int, 92:2, 2003.

8. D’Amico, A, Whittington, R, Malkowicz, S B et al: Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA, 280 (11); 969-74, 1998.

9. Choo, R, Klotz, L, Danjoux, C et al: Feasibility study: Watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression. J Urol, 167:1664, 2002.

10. Choo, R, DeBoer, G, Klotz, L et al: PSA doubling time of prostate carcinoma managed with watchful observation alone. Int J Rad Oncology, Biology, Physics. 50:615, 2001.

11. D’Amico, AV, Chen, MH, Roehl, KA, Catalona, WJ: Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004 Jul 8; 351(2):125-35.

12. Klotz, L: Active surveillance for prostate cancer: For Whom? J of Clinical Oncology Vol 23, Number 32, Nov 10, 2005: 8165- 8169.

13. Lee, F, Bahn, D K et al: The role of TRUS-guided biopsies for determination of internal and external spread of prostate cancer. Seminars in Uro Oncology 16:129-136, 1998.

14. Galper, SL, Chen, MH, Catalona, WJ et al: Evidence to support a continued stage migration and decrease in prostate cancer specific mortality. J Uro.2006 Mar; 175 (3 Pt 1):907-12.

15. Steineck, G, Helgesen, F, Adolfsson, J et al: Scandinavian prostatic cancer group study No 4: Quality of life after radical prostatectomy or watchful waiting. N Engl J Med. 347:790- 796, 2002.

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