RATIONALE FOR THE TREATMENT OF
LOCALIZED PROSTATE CANCER

Peter T. Scardino, Baylor College of Medicine, Houston, TX

This year 200,000 men will be diagnosed with prostate cancer in the United States and 38,000 will die of this disease. Even among those who do not die many will suffer serious complications from local growth or distant metastases or from the complications of treatment. The age-specific mortality rate has increased steadily over the past 30 years. Prostate cancer will cause the death of 3% of all men alive today who are now >50 yr old. Since the mortality rate of prostate cancer increases more rapidly with age than any other cancer, and the most rapidly growing segment of the population is those >80 years old, and mortality from other causes is declining, the number of deaths from prostate cancer is expected to increase inexorably for many years.

Despite its epidemic proportions and similarity to breast cancer, prostate cancer evokes enormous controversy because of its unusual biological features and, until recently, the lack of firm data about the natural history of the disease. Prostate cancer is relatively slow growing, with doubling times for local tumors estimated at 2-4 years. often strikes elderly men with high comorbidity rates, so that the risk to life and health posed by the cancer itself have been difficult to quantify. Furthermore, unlike breast cancer, malignant cells which have the histologic appearance of prostate cancer can be found in about 40% of
men >50 years old. And, most importantly, satisfactory prospective randomized trials have never been completed to establish whether early detection or treatment of localized prostate cancer will decrease the mortality rate from the from now, the decision whether treat aggressively or conservatively must be made with the best available evidence.

Rationale for treatment. The rationale for aggressive treatment is based on the observations: 1) clinically detected cancer progresses, slowly but inevitably (Table 1); 2) prostate cancer cannot be cured once it extends beyond the immediateif the cancer is detected early (Table 2); and 4) treatment is reasonably safe. Effective treatment is available, either radical prostatectomy or radiotherapy. the relative efficacy of these two modalities is debatable, both can produce lifelong freedom from prostate cancer in a proportion of patients. with clinically localized (T1-2) prostate cancer [2].

Table 2. Actuarial nonprogression rates and hazard rates (risk of progression each for 407 T1-2 XMO patients treated with radical prostatectomy alone (no hormonal orradiotherapy) and followed 6 to 12 months with PSA for 12-134(mean 42.4) months. Note that 6.4% were pN+ and another 11.3% were pT3c (SVI).

Early Detection. Since prostate cancer causes no symptoms until it becomes advanced or metastatic, when it is no longer curable, it can only be detected while curable with a digital rectal (DRE) or prostate specific antigen (PSA) . In large screening trials a combination of DRE and PSA detects more cancers (5.6% vs. 1%) at an earlier stage (70% confined to the prostate pathologically vs. 30%) than DRE alone [3]. Cancers detected by DRE or PSA are clinically important (74-93%) and are generally distinct from cancers found incidentally at autopsy or in cytoprostatectomy specimens removed for other reasons {e e.g. bladder cancer) table 3)

Fig. 1. Actuarial onprogression rate (tie until clinical or PSA progression) i 478 cT1-2 M0 patients treated at Long-term freedom progression is rare for patients with seminal vesicle invasion (SVI) or lymph ode metastasis (pN+).

Table 3. Percent of cancer detected clinically (radical prostatectomy series) and incidentally (cystoprostatectomy series) that were latet, clinically important but curable, and advanced [4].

Treatment: the decision-analysis model. While several clinical trials have compared rawdical prostatectomy to expectant management or to radiotherapy for the treatment of localized T1-2) prostate cancer, none of these trials has been conducted in a satisfactory manner. Hence, there remains considerable debate about the merits of detecting and treating early stage prostate cancer in a symptomatic men. Recently, a Markov decision-analysis model has been used in an attempt to assess the possible best information from the literature used to predict the course of the These models are well and the computer programs that run data fed into the model has been criticized. Until recently, we have not had solid information about the natural history of the disease in large numbers of menfor in a variety of institutional the ability of radical prostatectomy (or radiotherapy) alone to decrease

In 1993 the Dartmouth Prostate Patient Outcomes Research Team (PORT) published benefits of treatment [6]. They found that treatment offered only marginal benefit over conservative management, increasing the year-old man with a grade II cancer by only 0.33 years (Table 4). In this model, the most important determinant of the benefit of treatment was the metastatic rate in conservatively managed patients.

We repeated the PORT analysis, using the model they provided but substituting the metastatic rates for each grade from the large series of conservatively managed patients published by Chodak et al [2], which were 3.3-7.8 times higher than the PORT analysis (Table 4) [7,8]. Table 4. Estimates of the benefits of therapy in the PORT analysis [6] and in a repeat of the analysis [7] using the metastatic rate for conservatively managed patients reported by Chodak [2].

In summary, prostate cancer poses serious risks to the life and health of millions of men. Treatrnent, especially radical prostatectomy, is generally safe and can interrupt the natural history of the disease. It is urgent that we complete the large randomized clinical trials necessary to document these benefits (9,10).

1.Scardino PT: Afterword: The perspective of a prostate cancer doctor. In: Martin W: My Prostate and Me: Dealing with prostate cancer. NY: Cadell & Davies, 1994, p. 215.

2.Chodak GW. Thisted RA. Gerber GS, Johansson JE. Adolfsson J, Jones GW, Chisholm GD, Moslcovitz B, Livne PM, Warner J: Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994; 330:242-248.

3.Catalona WJ. Smith DS, Ratliff TL, Basler JW: Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 270:948. 1993.

4.Ohori M, Wheeler TM. Dunn JK, Stamey TA, Scardino PT: The pathologic features and prognosis of prostate cancers detectable with current diagnostic tests. J Urol 1994; 152:1714- 1720.

5.Aihara M, Wheeler TM, Scardino PT: Incidental prostate cancers found at cysto-prostalectomy: pathologic features and DNA ploidy value. Cancer, in press 1994.

6.Fleming C. Wasson JH. Albertsen PC, Barry M1, Wennberg JE for the Prostate PORT: A decision analysis of alternative treatment strategies for clinically localized prostate cancer. JAMA 1993; 269:2650-2658

7.Beck JR, Kattan MW, Miles B: A critique of the decision analysis for clinically localized prostate cancer. J Urol 1994, 152:1894-1899.

8.Scardino PT, Miles BR, Beck JR: Conservative management of prostate cancer: Letter to the Editor. N Engl J Med 1994;330: 1831.

9.C;ohagan JK, Prorok PC, Kramer BS, Cornett JE: Prostate cancer screening in the prostate, lung, colorectal, and ovarian cancer screening trial of the national cancer institute. J. Urol. 1994; 152: 1905- 1909.

10.Wilt TJ, Brawer MK: The Prostate cancer Intervention Versus Observation trial (PIVOT: A randomized trial comparing radical prostatectomy versus expectant management for the treatment of clinically localized prostate cancer. J.Urol. 1994; 152:1910-1914.