Dr. David Laub specializes in management of prostate disease, and was first to utilize College Hospital's Da Vinci surgical robot. To read more . . . .

The American Cancer Society estimates that 179,300 men were diagnosed with and 37,000 died of prostate cancer in the United States during 1999. These numbers actually represent a decrease in deaths compared to prior years. Review of our 1999 prostate cancer diagnosis rate in Santa Barbara has also identified a significant decrease in prostate cancer diagnosis. This national and local data support growing evidence that prostate cancer screening is saving lives. Prostate specific antigen (PSA) combined with digital rectal exam screening for prostate cancer became widely available in the early 1990's in Santa Barbara. These initial screenings were associated with an increase in prostate cancer detection. Now we are diagnosing a steady rate of new, lower stage cancers. It is believed that the early detection of low stage cancers will result in decreased mortality from prostate cancer. Because prostate cancer is slow growing, early studies questioned the clinical significance of many of the prostate carcinomas detected through these screening methods. Large, multicenter controlled randomized trials of the effectiveness of PSA screening methods in decreasing mortality from prostate cancer are rcurrently underway, and definitive results will not be available until 2006.¹ However, early data suggest a decrease in mortality rates due to prostate cancer since the advent of PSA screening.²

Recent studies clearly show that most cancers detected by elevated PSA and biopsy will become clinically significant.³ Most of these cancers staged as T1c (see glossary) can be cured with surgery or radiation treatment. The discussion that follows will address particular statistics gathered regarding diagnostic testing and treatment of prostate cancer in our community in 1999.

Starting in 1997, prostate cancer deaths nationally started to decline. The number of prostate cancer deaths is now lower than in any year since 1950.⁴ Screening for prostate cancer leads to an increased treatment of organ-confined cancer.

Until other approaches are proven as effective in a representative patient population, radical prostatectomy should be considered the preferred treatment for men with localized disease whose life expectancy exceeds 10 years.⁵

Graph 1. Cottage Hospital Relative Survival of Prostate Cancer Patients By AJCC Stage at Diagnosis, 1990-95	Graph 2. National Cancer Center Database Relative Survival of Prostate Cancer Patients By AJCC Stage at Diagnosis, 1985-90

Our detection of localized rather than advanced prostate cancer in Santa Barbara compares favorably to the national average. (See Graphs 3 and 4.)

Graph 3. Prostate Cancer Cases - Cottage Hospital 1999 AJCC Stage at Diagnosis Graph 4. Prostate Cancer Cases National Cancer Center Database (NCDB) 1995 AJCC Stage at Diagnosis

We have also seen a persistent decline in positive pelvic lymph nodes (Stage IV) detected at surgery. This is further evidence of the stage migration associated with screening. (See Table 2.)

Enhancing Detection of Prostate Cancer with PSA and Prostate Ultrasound Needle Biopsy

Although PSA is regarded as the best biochemical marker for prostate cancer, an important limitation regarding its use in cancer detection is the considerable overlap of patients with prostate cancer and those with benign prostatic hyperplasia (BPH) when serum PSA ranges from 4.0 to 10.0. Several concepts have been introduced to improve cancer detection (sensitivity) and reduce the number of negative or unnecessary prostate biopsies (specificity). Normally, PSA slowly increases with age, presumably because of non-cancerous prostate growth. To improve the sensitivity of PSA, age-specific PSA values have been used to identify prostate cancer in younger men by use of a PSA value less than 4.0 to indicate an abnormality. The rationale for lowering the normal PSA values is to be more aggressive in prostate cancer detection in younger men. This has created a lower threshold for recommending prostate biopsy. The use of a higher age-specific PSA value may prevent some unnecessary biopsies in older men with BPH. Overall, the use of PSA alone typically results in an initial 60-80% negative biopsy rate. Repeating the PSA over a period of several months (PSA velocity) before resorting to biopsy may prevent some biopsies if there is no change in the PSA, or it may delay the diagnosis of cancer. Our efforts to decrease the number of negative biopsies potentially limits our ability to diagnose organ-confined prostate cancer.

To evaluate our local efforts at diagnosing prostate cancer, the total number of prostate biopsies in southern Santa Barbara County in 1999 has been combined for review.

In an effort to improve our detection of prostate cancer, most urologists in our community have increased the number of ultrasound guided biopsy needle cores obtained from six (the previous standard to eight or more).^{6, 7} Our percentages of positive and negative biopsies are in line with other reports nationally.

What about the large percentage of men who undergo an initial prostate biopsy and have no evidence of cancer? Studies that have examined the incidence of carcinoma on repeat biopsies have shown that even when the prior biopsy was benign, the incidence of carcinoma on repeat biopsy is approximately 10-25%.^8,6,9 This number may seem surprisingly high, but is confounded by important variables. Only selected patients with a benign diagnosis underwent a second biopsy. Those who did may have had good clinical evidence of prostate cancer (i.e., very high PSA, rising PSA, suspicious DRE, or a low % free PSA).

In an effort to decrease the number of unnecessary repeat biopsies, many urologists are relying on the % free PSA value. In a recent study, 1,051 men with a PSA between 4.0 and 10.0 underwent biopsy. Initial biopsy was negative in 820 men. Prostate cancer was detected on repeat biopsy in 10% of these men. The most reliable predictor of cancer on repeat biopsy was a % free PSA of less than 30%. This cutoff value detected 90% of the cancers and would have eliminated 50% of the repeat negative biopsies.¹⁰

In our local review, needle core biopsies of the prostate were separated into three basic categories: benign, malignant, and "suspicious for malignancy." The first two categories are self-evident. The last category encompasses lesions that for architectural or cytological reasons are worrisome, but are not diagnostic for carcinoma. Most of these lesions are small acinar groups that would be compatible with carcinoma, but due to the small size of the lesion (sometimes only 3 or 4 acini), the presence of an infiltrative growth pattern cannot be established. In other instances, cytological features of malignancy are absent, such as nuclear enlargement or prominent nucleoli. Rarely, cytological features are worrisome, but the glandular arrangements appear to be more compatible with a benign or reactive process.

A retrospective analysis of 132,426 prostate biopsies received at UroCor, a pathology laboratory specializing in urologic pathology, showed a cancer rate on prostate biopsy of 38.2%. Benign diagnoses were rendered in 55.3% of cases, high-grade PIN in 3.7% and suspicious in 2.8% of cases.⁸ A similar rate of suspicious biopsies was reported by the Mayo Clinic.^11,12 The cancer rate in follow-up biopsies of these patients was 47.9 and 59.3% respectively. Similar results have been previously published.^13,6 Because of the high rate of cancer in follow-up biopsies with a diagnosis of suspicious for malignancy, rebiopsy of these patients is recommended.^12,13

It should be noted that all malignant and suspicious biopsies at MGPL and SBCH are reviewed at daily intradepartmental conference which is attended by three to six pathologists. Dissenting opinions are usually resolved by obtaining outside consultation from a nationally recognized expert in prostate pathology. The consultants most often used are Drs. R.L. Kempson from Stanford University and D.G. Bostwick. Biopsies reviewed at St. Francis Hospital are also sent for an outside opinion if there is any question.

The rate of atypical or suspicious biopsies interpreted by the pathologists at MGPL and Santa Barbara Cottage Hospital was 6.6% in 1999, a rate twice that in the published literature.^11,8,12 This difference was due to less aggresiveness in the diagnosis of malignancy based upon small atypical proliferations at this institution, compared to large centers specializing in urologic pathology. The trend toward more aggressiveness in the diagnosis of carcinoma is evidenced by data from MGPL from this year, which shows a suspicious rate of 2.2% This figure is closer to that reported in the literature. Some of the reluctance to diagnose cancer is based on the premise that small cancers might not be clinically significant. As more recent data suggested, this was not the case; pathologists at this institution (and elsewhere) have become more aggressive in diagnosing cancer, even when only a few malignant glands are present.

The rate of carcinoma on repeat biopsies of patients with a suspicious initial biopsy is 40-60%.^8,13 This figure underscores the importance of repeat biopsies and close follow-up of patients with a suspicious biopsy result. The Santa Barbara Cancer Committee is reviewing mechanisms it can use to assist our community urologists and pathologists in their efforts to assure appropriate follow up on all suspicious prostate biopsies in the community.

Treatment of Prostate Cancer with Intent to Cure

Once the diagnosis of prostate cancer is made, the patient assisted by the physician then has the difficult task of selecting an appropriate treatment plan based on a variety of factors. An individualized treatment decision is based on the patient's general health and life expectancy, the clinical stage and grade of the tumor. A Partin Multivariate analysis table can help predict the pathologic stage and assist the patient in his decision process. Watchful waiting should be considered a legitimate option for older men with a life expectancy less than ten years who have well-differentiated tumors. Nevertheless, the men are at risk for significant morbidity and mortality related to local and distant cancer spread during that ten years.

A man with clinically organ-confined prostate cancer who has a primary goal of curing himself of his cancer should consider radical prostatectomy as the standard of treatment. Despite the fact that surgery provides excellent long-term cure rates, radiation seed implants are gaining popularity as an acceptable alternative to prostatectomy.

At Cottage Hospital, there has been a decrease in radical prostatectomy surgery performed and, consistent with national trends, there has been an increase in the number of radiation cases performed from 1996 to 1999 as shown in Tables 6 and 7. Of all patients receiving radiation therapy, the percent receiving brachytherapy has increased from 20% in 1996 to 54% in 1999. Prostate Brachytherapy has increased significantly in popularity in the United States over the last decade. This has occurred as a result of numerous factors, including those of a technical and societal nature. Advances in computer technology for instance have resulted in vast improvements in radiation therapy planning and dosimetric precision, which in turn has increased the dose delivered to target tissues and reduced the side effects secondary to normal tissue irradiation. Higher doses have been shown to correlate with improved local control of prostate cancer.⁶

Brachytherapy, also called radiation seed implantation, is the use of radiation sources placed close to or within the area of intended treatment. Brachytherapy actually has a long history, dating back to the time of the discovery of radium by Pierre and Marie Curie in 1898. With respect to prostate cancer treatment, brachytherapy has been utilized since the 1960's, these early implants being performed with an "open" technique with seeds being randomly placed throughout the gland.¹¹ Results with this technique were less than optimal, with an unacceptably high local recurrence rate.⁸ Analysis of the dose distributions obtained revealed marked inconsistency with areas of over-dosage leading to normal tissue complications and areas of under-dosage leading to recurrence of disease.

The transperineal ultrasound guided technique of radiation seed placement, popularized and refined by the group at the Swedish hospital in Seattle, has led to the ability to deliver a uniform dose to the prostate in a reproducible reliable manner.¹² Long term results from this group have demonstrated the efficacy of this treatment.¹³ Those considered to be ideal candidates for Brachytherapy as the sole treatment have a PSA of less than ten, a Gleason score of less than eight, and are without contraindications for anesthesia. Higher grade/PSA patients will typically receive combined external beam/Brachytherapy, in an attempt to increase the dose to the periprostatic tissues.Relative contraindications to brachytherapy are large prostate glands, large volume tumor at the base of the gland, large median globe, or prior transurethral prostate surgery.

Implant therapy in Santa Barbara is performed with the treatment planning computer in the operating room, allowing increased accuracy of seed placement. Having the actual planning system in the operating room eliminates patient movement and positioning as sources of error in seed placement. The widespread dissemination of information over the World Wide Web, other media channels, and through advertising, has placed scientific and lay press articles at patient's fingertips. Patients no longer come to the physician's office to be told what treatment they will receive; rather, they arrive with numerous articles in hand expecting to discuss all options available for treatment. Articles such as Andy Grove's dissertation on prostate brachytherapy which appeared in Fortune magazine, and the mayor of New York's treatment with external beam radiation therapy and brachytherapy are both examples of the significant widespread media coverage of prostate implant therapy.

Iodine-125 is the most common isotope implanted, with Palladium-103 being reserved for patients with high-grade disease. A recent development in seed technology has been the use of seeds embedded in vicryl. This type of seed, called Rapid Strand, possesses many important advantages over conventional I-125 seeds. As the seeds are linked together by the vicryl, the risk of embolization is reduced. It allows the placement of seeds outside of the prostate, which improves dose distribution. The alignment of the seeds is maintained after implantation, again improving the dose distribution. They are easier for the technical staff to load, reducing radiation exposure to personnel in the operative suite. These seeds have been in use in Santa Barbara since March of 2000.

The average hospital stay for radical prostatectomy has decreased to two and a half days, also consistent with national trends. Decreased operative times and shorter hospital stays are attributed to improved surgical techniques and the development of clinical pathway guidelines. Refinements in surgical technique have dramatically decreased the need for blood transfusion, decreased the incontinence rate; and with nerve-sparing procedures, improved the potency rate in carefully selected patients.

Because of the current lack of reliable and objective outcomes data, it is not yet feasible to compare directly the morbidity of radical prostatectomy with that of radiation therapy. Serious life threatening complications are exceedingly rare following either surgery or radiation. No deaths related to surgery or radiation treatment of prostate cancer have been reported in Santa Barbara. Both radiation therapy and surgery have undergone important modifications that have diminished treatment-related morbidity.

The complications most commonly associated with both treatments have quality-of-life implications. The two biggest fears for men facing prostate cancer treatment, besides recurrence of cancer, are loss of urinary control and erectile dysfunction (ED). At this time, urinary problems related to surgery or radiation are statistically equivalent, are rarely severe, usually temporary, and if required, readily treatable. ED can be avoided with the use of nerve sparing surgical techniques in selected patients. When ED occurs after surgery, it may improve over time. After radiation therapy, ED may occur in a delayed fashion. Whatever the cause, ED can be treated by the urologist with medications or other modalities so that sexual functions can be preserved after prostate cancer treatment.

It should be remembered that the moribidity of advanced prostate cancer includes impotence, urinary retention, painful lower urinary tract symptoms, gross hematuria and clot retention, ureteral obstruction, painful bone metastasis and spinal cord compression. In the future, with the increased public awareness of prostate cancer screening, even fewer men will suffer from the slow, often agonizingly painful death associated with advanced prostate cancer.

Men aged 50 and older, should have a yearly PSA and digital rectal exam. Afro-Americans and men with a family history of prostate cancer should be checked starting at age 45.

1. Gohagan JK, Prorok PC, Kramer BS, Hayes RB, Cornett JE. "The prostate, lung, colorectal, and ovarian cancer screrening trial of the National Cancer Institute." Cancer 75:1869, 10:1995.

2. Surveillance, Epidemiology, and End Results (SEER) Program. "Age-adjusted US cancer death rates." J Natl Cancer Inst 89:12, 1997.

3. Dugan JA, Bastwick DG, Myers RP, et al. "The definition and preoperative prediction of clinically insignificant prostate cancer." JAMA 275:288, 1996.

4. Catalona W, et al. "Contemporary results of anatomic radical prostatectomy." CA Cancer J Clin 49:282-296, 1999.

5. Hoedemaeker R, et al. "Histopathological prostate cancer characteristics at radical prostatectomy after population based screening." Journal of Urology 164:411-415, 2000.

6. Hodge KK, McNeal JE, Terris MK, et al. "Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate." J Urol 142:71, 1989.

7. Naughton C, et al. "A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection." J Urol 164:388-392, 2000.

8. O'Dowd GJ, Miller MC, Orozco R, Veltri RW. "Analysis of repeated biopsy within one year after a noncancer diagnosis." Urology 55:553, 2000.

9. Norberg M, Egevad L, Holmber L, et al. "The sextant protocol for ultrasound guided core biopsies of the prostate underestimates the presence of cancer." Urology 50:562, 1997.

10. Djavan B, et al. "Optimal predictors of prostate cancer on repeat prostate biopsy: a prospective study of 1,051 men." J Urol 163:1144-1149.

11. Bostwick DG, Quian J, Frankel K. "The incidence of high-grade prostatic intraepithelial neoplasia in needle biopsies." J Urol 154:1791, 1995.

12. Iczkowski KA, Orozco RE, Bostwick DG, et al. "Diagnosis of 'suspicious malignancy' in prostate biopsies: predictive value for cancer." Urology 51:749, 1998.

13. Allen EA, Kahane H, Epstein JI. "Repeat biopsy strategies for men with atypical diagnoses on initial prostate needle biopsy." Urology 52:803, 1995.

SURVIVAL ANALYSIS

Actuarial Survival Method: Provides a means for the use of all follow-up information accumulated until the close of the study and provides additional information on the survival pattern of the group under study.

CLASS OF CASE

Analytic: Cases that are first diagnosed and/or receive all or part of their first course of treatment at Santa Barbara Cottage Hospital. These cases are included in all statistical reports.
Non-Analytic: Cases that have been diagnosed and have received their entire first course of treatment elsewhere and are first seen at Santa Barbara Cottage Hospital for recurrent, persistent, or metastatic disease, or were first diagnosed at autopsy. These cases are not generally included in statistical reports.
First Course of Treatment: The initial cancer-directed treatments or series of treatments planned and usually initiated within the first four months following diagnosis.

AMERICAN JOINT COMMITTEE ON CANCER TNM STAGING SUMMARY (varies with primary site)

Stage 0	Carcinoma in situ; a tumor that fulfills all the microscopic criteria for malignancy except invasion.
Stage 1	Localized disease with no evidence of lymph node or distant spread.
Stage 2	Generally, direct extension of disease without lymph node extension.
Stage 3	Generally, lymph node extension but may have direct extension also.
Stage 4	Generally, any tumor with distant metastasis.
Unknown	Tumors that cannot be staged due to lack of diagnostic documentation.

AJCC STAGING GUIDELINES FOR PROSTATE CANCER

TX	Primary tumor cannot be found.
T1	No evidence of primary tumor.
T0	Clinically inapparent tumor not palpable or visible by imaging. T1a Tumor incidental histological finding in 5% or less of tissue resected. T1b Tumor incidental histological finding in 5% or more of tissue resected. T1c Tumor identified by needle biopsy (e.g., because of elevated PSA).
T2	Tumor confined within the prostate. T2a Tumor involves one lobe. T2b Tumor involves both lobes.
T3	Tumor extends through the prostate capsule. T3a Extracapsular extension, unilateral or bilateral. T3b Tumor invades seminal vesicles.
T4	Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles, and/or pelvic wall.