4 Screening and Early Detection for Genitourinary Cancer

Ian M. Thompson,

^MD

and Joseph Basler,

^MD

CONTENTS

INTRODUCTION

CONFOUNDS ASSOCIATED WITH SCREENING FOR GU MALIGNANCIES

SCREENINGFOR PROSTATE CANCER

SCREENINGFOR KIDNEY CANCER

SCREENINGFOR BLADDER CANCER

SCREENINGFOR TESTICULAR CANCER

CONCLUSIONS

REFERENCES

INTRODUCTION

Genitourinary (GU) cancers constitute a significant fraction of all neoplastic disease.

GU cancers include neoplasms of the prostate, bladder, kidney, testis, ureter, urethra, adrenal, penis, and testicular adnexae. Among the tumors represented, prostate cancer is the most common cancer in men and testicular cancer is the most common cancer in men between the ages of 15 and 30. Like most other tumors, survival of virtually all of these sites is directly related to stage at diagnosis. (In the case of testicular cancer, although survival is excellent even for advanced disease, the extent of therapy required for advanced disease is extremely more complicated and morbid than for disease local- ized to the testis.) It is for this reason that concerted early detection efforts for some of these tumors has been suggested.

To be a reasonable proposition for a specific organ-site, there are a number of require- ments for early detection (or screening) that should be met. These include the following:

• The disease must have a high prevalence.

• Early detection tests must be available that have a high sensitivity and specificity.

• Effective treatment for early stage disease must be available.

• Early detection tests must detect disease at a stage when treatment is effective.

• The cost of the early detection program must be acceptable.

• The morbidity associated with early detection must be acceptable.

Ideally, early detection for neoplastic disease should be proven to improve survival (as well as reduce mortality from the disease: two different outcomes) while preserving a high quality of life and while using an acceptable quality of health care resources.

Unfortunately, no early detection test has been proven to meet all of these criteria. Even widely accepted early detection tests, such as screening mammography, continue to be the subject of debate regarding their efficacy (1). In no GU site has screening been demonstrated to affect survival, mortality, or quality of life. For prostate cancer, two studies are currently underway to evaluate the impact of screening on survival. The Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) study in the United States and the European Randomized Study of Screening will address this issue late in the first decade of this century. For all other organ sites, no studies are currently ongoing, and all data must be extrapolated from clinical observations.

CONFOUNDS ASSOCIATED WITH SCREENING FOR GU MALIGNANCIES

A number of authors have pointed out many potential confounds associated with screening for malignancies in general. First among these is the issue of lead-time bias.

This issue is graphically demonstrated in Fig. 1.

In this figure, it can be seen that in the upper case, a screening modality was used to identify a cancer early. Unfortunately, despite therapy, the disease recurred, metasta- sized, and ultimately led to the patient’s demise. In the second case, the disease pre- sented at a metastatic stage and the patient again ultimately died from the disease. The latter case presumes that the early detection effort was unable to affect the natural history of the disease. (A good example of this might be the use of chest x-ray for lung cancer when, by the time disease is diagnosed, it is beyond the ability of local excision to affect a cure.) In the former case, using early diagnosis, there is a perception that cancer survival is longer, whereas overall survival is actually unchanged.

Another confound with cancer screening is length-time bias. This concept reflects the propensity of screening tests that are generally administered on an infrequent basis to identify indolent, low-risk tumors. Figure 2 demonstrates this concept.

As can be seen in Fig. 2, there are three general types of tumors: those that grow quickly and rapidly lead to the demise of the individual (short and fat arrows), inter- mediate tumors, and tumors that develop and spread only over a long period of time (long, skinny arrows). If it is presumed that screening episodes are performed periodi- cally, the results are those seen. The tumors that are most likely to be identified early, when cure is likely, are the long, skinny arrows—the most indolent of tumors. (In the case of the long, skinny arrows, all are detected while still curable. Unfortunately, of these, only half would have actually led to the demise of the patient.) However, none of the four rapidly growing tumors was detected sufficiently early to affect a cure and in all of these, the patient died of the disease. We have previously demonstrated that length-time bias is operational in patients screened with digital rectal examination for prostate cancer (2). A concern of many authorities with respect to bladder cancer is the similar observation that the tumor that ultimately leads to the demise of the patient is

Fig. 1. Lead-time bias. Natural history of prostate cancer with and without early detection. If cancer is detected at the time of symptomatic metastases, short cancer survival is noted. If cancer is detected early with screening, much longer time (survival) is noted until death from cancer.

However, no impact is noted on the actual length of the patient’s life—just a longer time with the diagnosis of “cancer.”

Fig. 2. Length-time bias. Regular screening visits are more likely to detect slow growth-rate rather than rapidly growing tumors while still curable. As a result, rapidly growing tumors, those that pose the greatest threat to a patient’s life, are least likely to be found by screening.

rarely the one that develops after multiple superficial tumors; the lethal tumor gener- ally presents with high-stage, advanced disease, suggesting a more rapid proliferation and development rate, much akin to the short, fat arrows in Fig. 2.

SCREENING FOR PROSTATE CANCER

Perhaps the most contentious of all screening modalities in medicine today, screening for prostate cancer is a fait accompli: it is widespread in the United States and, unless a major change occurs in the patterns of care or in information from clinical trials, it will probably continue for the foreseeable future. To provide the very best discussion, the format for this section will be that of a debate: the pros and cons of screening.

The Pros of Prostate Cancer Screening P^ROSTATE C^ANCER I^SA P^UBLIC H^EALTH P^ROBLEM

It is clear that prostate cancer represents a major public health concern. With almost 200,000 new cases annually and nearly 30,000 deaths each year, the human toll is substantial (3). When one recognizes that approximately one man in four who under- goes prostate biopsy is found to have prostate cancer, then perhaps 800,000 prostate biopsies are being performed annually. If a man with prostate cancer lives, on average, 5–15 yr, then there are 1–3 million men in the United States with a diagnosis of prostate cancer and another 4–12 million who are at risk.

IF PROSTATE CANCER IS DETECTED AFTER IT IS SYMPTOMATIC, M^OST C^ASES A^RE M^ETASTATIC

Localized prostate cancer is almost always devoid of symptoms. Although it is frequently recommended that men with obstructive voiding symptoms consider an evaluation for possible prostate cancer, this is an unusual presenting complaint. The reason: prostate cancer generally arises in the peripheral zone of the prostate and rarely will lead to urethral obstruction. It is only when metastases to bone (pain) or to regional lymph nodes (lower extremity lymphedema or deep vein thrombosis) or to the retro- peritoneal lymph nodes (ureteral obstruction, flank pain, and uremia) occur that symp- toms develop.

O^NCE P^ROSTATE C^ANCER H^AS METASTASIZED, MOST MEN WILL DIE FROMTHE DISEASE

Despite advances in the management of advanced prostate cancer, the prognosis for a man with metastatic disease is quite poor. In a recent Phase III study of men with metastatic disease, median survival was only 30 mo (4).

T^ESTS A^RE A^VAILABLE T^HAT A^LLOWFOR E^ARLY D^IAGNOSISOF P^ROSTATE C^ANCER Since the advent of prostate-specific antigen (PSA) testing, in combination with digital rectal examination (DRE), prostate cancer diagnosis has been changed in a revo- lutionary manner. Approximately 10% of men tested with PSA will be found to have a value >4.0 ng/mL and between 3 and 10% will have an abnormal DRE. Of men under- going biopsy, between 25 and 33% will be found to have prostate cancer (5). With PSA screening, the more than 97% of prostate cancer cases diagnosed are clinically confined to the prostate (6).

I^F P^ROSTATE C^ANCER I^S D^IAGNOSED E^ARLY, TREATMENTS ARE GENERALLY EFFECTIVE

Clearly, the outcome of treatment is related to the extent of disease. Although failures are greater if nodal disease, seminal vesicle involvement, or extracapsular disease is present, for tumors that are confined to the prostate, the progression-free probability at 10 yr exceeds 90% (7).

S^CREENINGFOR P^ROSTATE C^ANCER H^AS L^EDTOAN I^NCREASEINTHE R^ATE

OF L^OCALIZED D^ISEASEANDA F^ALLINTHE R^ATEOF M^ETASTATIC D^ISEASE

PSA screening in the United States began in earnest in the late 1980s. In association with this was a dramatic increase in the detection of disease. After a period of almost exponential rise in detection, the incidence rate fell to relatively stable rates. Beginning in 1991, and virtually every year since, a fall in the rate of metastatic disease has been seen (8).

SCREENINGFOR PROSTATE CANCER HAS PRECEDED A F^ALLIN P^ROSTATE C^ANCER M^ORTALITY

Since the early 1990s when the rate of metastatic disease began to fall, there has been a gradual decrease in prostate cancer mortality (9). This was in the face of gradually increasing mortality rates in the late 1980s.

S^CREENINGFOR P^ROSTATE C^ANCER I^S C^OST E^FFECTIVE

In a decision analysis, using a range of efficacy rates of screening as well as actual charges for medical care, we previously demonstrated that quality-adjusted life-years gained from prostate cancer screening was in a range of commonly accepted preventive health measures (10). Table 1 provides this data.

The Cons of Prostate Cancer Screening PROSTATE CANCER IS UBIQUITOUS:

W^E D^ON’^T W^ANTTO F^IND A^LLOFTHE C^ASES

A combination of autopsy data and national statistics suggest that although almost 70% of men will develop histological evidence of prostate cancer and 16% will be

Table 1

Results of Cost Analysis of Screening for Prostate Cancer

Intervention Cost per quality-adjusted life-year saved

Liver transplantation $ 237,000

Screening mammography (<50) $ 232,000

Worst case—prostate cancer screening $ 145,600

CABG—two vessels with angina $ 106,000

Captopril for hypertension $ 82,600

Hydrochlorothiazide for hypertension $ 23,500

Best case—prostate cancer screening $ 8700

Physician “stop smoking” message $ 1300

diagnosed, only 3–4% will die of the disease (11). Thus, if we were able to detect disease in all men who had it, we would treat 20 men to prevent one death. (Of course, we diagnose nowhere close to that rate of the disease.) What fraction of the 16% of men diagnosed during their lifetime who are treated unnecessarily is unknown.

S^CREENING T^ESTS A^RE I^NEFFECTIVE

Despite the fact that the combination of regular PSA and DRE testing significantly reduces the stage of prostate cancer at diagnosis, they are not perfect. In those men in the Washington University series who were diagnosed with prostate cancer at the time of their initial PSA, 37% had clinically or pathologically advanced disease. Among those with serial PSA measurements, 29% still had advanced disease (12). These observations suggest that, with time, even those men who are screened repetitively with PSA will be at risk for treatment failure and demise from their disease.

T^REATMENT I^S N^OT A^LWAYS S^UCCESSFUL

With prolonged follow-up after extirpative surgery (radical prostatectomy) even in men with organ-confined disease, there is a continued risk for disease recurrence (mea- sured by development of a detectable level of PSA; ref. 13). This risk of recurrence appears to increase over time (14).

TREATMENT CARRIES WITH IT SIGNIFICANT RISKSAND COMPLICATIONS

Treatment options for localized prostate cancer includes, generally, radiotherapy with external beam, brachytherapy, and surgery (radical prostatectomy). Each of these carries with it a unique spectrum of complications, including erectile dysfunction, uri- nary incontinence, urinary obstruction, radiation injury to the rectum or bladder, ure- thral strictures, and need for secondary therapies.

SCREENING IS COSTLY

We have demonstrated that the annual cost for screening for prostate cancer is in the range of $10–25 billion annually in the United States (15).

T^HERE I^S N^O E^VIDENCE T^HAT S^CREENING L^EADS

TOAN IMPROVEMENTIN SURVIVAL

To date, no appropriately powered and controlled clinical trials have demonstrated that screening neither improves survival of the general population nor enhances quality of life. Both the PLCO trial in the United States and the European trial should have results addressing these issues within the decade. Population observations regarding changes in mortality are subject to numerous confounds and do not clearly demonstrate an effect of screening or treatment.

SCREENING FOR KIDNEY CANCER

No studies have been conducted to evaluate the potential benefit of screening for kidney cancer. Nevertheless, there are interesting possibilities for investigation. Kidney cancer affects approx 30,000 individuals each year and causes about 11,000 deaths each year in the United States (16). Like most other GU cancers, the outcome of the disease is distinctly related to its stage with 5-yr survivals for localized, regional, and distant disease of 88, 61, and 9%, respectively (17).

High-Risk Groups

Clearly, the highest risk group for renal cell carcinoma (RCC) and the group in whom screening is standard-of-care are patients with Von Hippel-Lindau disease. In this patient population, although the incidence of renal cell carcinoma is between 25 and 50%, if a patient lives into his or her 70s, the risk of cystic or neoplastic disease is probably greater than 90% (18–20). Certainly, in this population and in family members in whom the mutation has been identified (on 3p25), periodic surveillance of the kidneys is required.

The age at which screening should begin has been disputed but certainly should have begun at or before age 20 (21).

Other at-risk groups have been identified but not for RCC but for Wilm’s tumor. In patients with Beckwith–Wiedemann syndrome, abdominal ultrasonography is indicated for both Wilm’s tumor as well as hepatoblastoma (22). Similar screening has been recommended for patients with hemihypertrophy and aniridia (23). Finally, although some authorities have suggested screening kidneys being considered for transplantation, the risk of a tumor present at the time of transplant or developing over a 7-yr followup was 0.27 and 0.145%, respectively (24).

Rationale for Screening

The primarily rationale for screening for RCC arises from repeated observations from the serendipitous detection of renal tumors through abdominal imagine performed for other reasons. Multiple authors have explored this concept and have repeatedly reached the following conclusions:

• With the increased use of abdominal imaging (for conditions such as cholelithiasis or evaluation of nonspecific complaints), the rate of serendipitous detection of renal tumors has increased dramatically.

• Tumors detected serendipitously:

• Are smaller. In the series of Masood and colleagues (25), the average size of serendipitously detected tumors was 5.9 cm compared with 9.2 cm for symptomatic tumors.

• Are of a lower T-stage. In the series of Tsui and colleagues (26), Stage I tumors constituted 62% of serendipitous tumors compared with 23% of tumors detected by virtue of symptoms.

• Are more likely to be organ-confined (26).

• Are less likely to be metastatic (25).

• Have a dramatically improved survival (27).

As a result of these observations, a number of authors have suggested that early detection of RCC should be considered. One large series has attempted to use abdominal ultrasonography to screen for abdominal disease processes (28). In this remarkable report, the authors summarize the results of screening of 219,640 individuals over a period of 13 yr. A total of 192 RCCs were detected (0.09% of examinees) during this time and of these, 189 were organ-confined. Survival for cases was 97% at 5 yr and 95% at 10 yr.

In addition to the relatively low prevalence of RCC, another obstacle to widespread screening is the prevalence of cystic or complex renal masses that could be identified with imaging studies. These lesions are of such a complex issue that a system for their classification has been developed—the so-called Bosniak classification system.

Nonsolid lesions are grouped into four categories: group I are simple cysts, group II are mildly complicated but clearly benign cysts, group III are more complicated cysts that require histological confirmation for diagnosis, and group IV are overt cystic neoplasms (29). Obviously, if the prevalence of RCC is as low as was seen in the Japanese expe- rience and if there is a measurable rate of Bosniak III lesions in the general population, screening for RCC could not be considered.

At this time, early detection of RCC by routine screening of any group of patients other than the high-risk populations described above cannot be supported by data. However, the intriguing repeated observations relative to serendipitously detected tumors of a dramatic improvement in survival in “screen-detected” tumors strongly supports calls for prospective studies to evaluate this hypothesis.

SCREENING FOR BLADDER CANCER

Bladder cancer is the second most common GU cancer with 54,300 new cases annu- ally and 12,100 deaths from the disease (30). Almost all of these tumors arise from the bladder urothelium and are known as transitional cell (urothelial) carcinoma. The con- cept of early detection is well-supported by the substantial decrease in survival in advanced disease. Five-year survival rates for localized, regional, and distant disease for the period 1989–1996 were 93, 49, and 6%, respectively (31).

In addition to the rationale for screening is the repeated observation that rarely is there a clinical progression from symptoms to local disease to regional and then advanced disease in most patients. Indeed, more than 90% of patients with advanced disease, present for the first time with symptoms at an advanced stage (32). A final rationale for early diagnosis of bladder cancer is that treatment for superficial, noninvasive bladder cancer is generally considerably less morbid than that for more advanced disease. For tumors confined to the urothelium, simple transurethral resection is curative. For more deeply invasive tumors, partial or radical cystectomy is required with its attendant com- plications and impact on quality of life. The likelihood that tumors of no clinical signifi- cance would be identified in a screening program is extremely low as most studies have documented that tumors almost never are detected in patients without a history of blad- der cancer at the time of autopsy (33).

High-Risk Groups

Bladder cancer incidence increases with age and the primary risk factor for the disease is cigarette smoking. Other etiologies include exposure to various chemical agents.

Screening programs have been conducted for employees exposed to these chemical agents and have confirmed that, for these very high-risk groups, early detection is a reasonable option (34). A relatively unique population of patients at high risk for both urothelial and squamous cell carcinoma are spinal cord injury patients who often have indwelling Foley catheters. This group of individuals may have a 2–10% risk of bladder cancer over their lifetimes (35).

Methods of Screening CYSTOSCOPY

No studies to date, with the exception of studies of spinal cord injured patients (in whom screening cystoscopy may influence survival through early detection in this very