Outcome

Assessing the outcome of radiation treatment for prostate cancer is both difficult and confusing. The ultimate outcome measure for the treatment of all forms of cancer is the number of people who die from it, but prostate deaths may not occur until ten, fifteen, or more years after treatment. Because the average age of men with prostate cancer who are treated with radiation has traditionally been older than that of men treated with surgery, many will die from other causes before living long enough to ascertain whether or not their prostate cancer would have killed them.

In lieu of using death as an outcome measure, most researchers on radiation treatment use a rising PSA level, as do those who measure the outcome of surgical treatment. However, there is a major difference: Following surgical removal of the prostate, the PSA level is expected to drop to zero; following radiation treatment, this is not always the case. Radiation is expected to kill all the cancer cells, but not necessarily all the normal prostate cells. The same is true in radiation treatments for cancers of the breast or pituitary gland; radiation is expected to kill all cancer cells but not all normal cells, so the breast and pituitary continue to function after radiation treatments have been completed.

Following radiation treatment for prostate cancer, the PSA is expected to fall, but the level to which it is expected to fall is widely debated. Some researchers say it should become less than 1.0, others 0.5, and others 0.3. In an attempt to establish a standard, the American Society for Therapeutic Radiology and Oncology (ASTRO) decreed in 1997 that, following the fall of the PSA to its lowest level (nadir), a recurrence of prostate cancer should be said to have occurred when the PSA then rises on three consecutive measurements. In practice, the descent of the PSA to its nadir after radiation treatment may take two or more years. Since the PSA is usually measured only two or three times per year, it is often not until three, four, or more years after radiation treatment that the failure of the treatment becomes evident.

Assessing the recurrence of cancer following radiation treatment is still more complicated, however, because of what is called the PSA bounce. In approximately one third of men treated with radiation, PSA levels increase one to three years after treatment, then return to a lower level. This rise does not signify the recurrence of cancer but is instead thought to be caused by a delayed release of PSA from irradiated cancer cells. The PSA increase associated with the bounce may last for as long as a year. During this time, there is no way to tell whether the PSA increase is merely a PSA bounce that has no clinical significance, or whether it indicates a failure of radiation treatment and a recurrence of the cancer. If it is a PSA bounce, it will go back down; if not, it will continue to rise.

Despite the problems in assessing the effectiveness of radiation treatment using the PSA, there is strong evidence that the lower the PSA goes after radiation, the less are the chances of recurrence. In one study, men whose PSA was 1.0 or lower following beam therapy had only a 4 percent chance of metastases eight years later, whereas men whose PSA did not go below 2.0 had a 39 percent chance of having metastases eight years later. In another study, men whose PSA was 0.2 or less had only a 1 percent chance of having cancer recurrence eight years later, compared to a 16 percent chance for those with higher PSAs.15 Thus, the absolute level of the PSA nadir following radiation treatment is important in predicting recurrence.

As noted in Chapter 2, another significant predictor of outcome following beam radiation therapy is the pretreatment PSA velocity. Men who had had PSA increases of 2.0 or more in the years prior to the diagnosis of their prostate cancers had a much higher rate of recurrence and death, compared to men who had had PSA increases of less than 2.0.16

Comparing the outcomes of different studies of radiation treatment also generates problems. Some studies use the ASTRO guidelines cited above, while other studies modify those guidelines or use an absolute PSA nadir, such as 1.0 or 0.5. Statistical problems are abundant: some studies use the actual numbers for the follow-up period and others estimate future numbers based on the follow-up period (actuarial numbers).

A study may follow men for five years after treatment and then estimate the ten-year recurrence rate based on the findings from the

Table 3. Outcome of Seed Therapy: Percentage of Patients with Evidence of Cancer Recurrence as Measured by Rising PSA

Average

Period at which

Number

follow-up

Recurrence

recurrence is

Clinical

Study

of men

period

rate

estimated

information

Grado et al., 1998

392

2.5 years

20%

5 years

median age 70.4

Scottsdale, Ariz.

20% Gleason >7 median PSA 7.3

Ragde et al., 2000

147

1 2.2 years

34%

10 years

average age 70.5

Seattle

0% Gleason >7 average PSA 8.8

Beyer and Brachman, 2000

695

4.3 years

29%

5 years

median age 74

Scottsdale, Ariz.

1 6% Gleason >7 31% PSA >10

Blasko et al., 2000

230

3.5 years

18%

9 years

median age 69

Seattle

40% Gleason >7 median PSA 7.3

Grimm etal., 2001

125

4.3 years

13%

10 years

median age 70

Seattle

0% Gleason >7 22% PSA >10

source: G L. Grado, T. R. Larson, C. S. Balch, et al.( Actuarial disease-free survival after prostate cancer brachytherapy using interactive techniques with biplane ultrasound and fluoroscopic guidance, International Journal of Radiation Oncology, Biology, Physics 42 (1998): 289-298; H. Ragde, L. J. Korb, A.-A. Elgamal, et al., Modern prostate brachytherapy: Prostate specific antigen results in 219 patients with up to 12 years of observed follow-up, Cancer 89 (2000): 1 35-141; D. C. Beyer and D. G. Brachman, Failure free survival following brachytherapy alone for prostate cancer: Comparison with external beam radiotherapy, Radiotherapy and Oncology 57 (2000): 263-267; J. C. Blasko, P. D. Grimm, J. E. Sylvester, et al., Palladium-103 brachytherapy for prostate carcinoma, International Journal of Radiation Oncology, Biology, Physics 46 (2000): 839-850; P. D. Grimm, J. C. Blasko, J. E. Sylvester, et al., 10-year biochemical (prostate-specific antigen) control of prostate cancer with 1251 brachytherapy, International Journal of Radiation Oncology, Biology, Physics 51 (2001): 31-40.

Table 4. Outcome of Beam Therapy: Percentage of Patients with Evidence of Cancer Recurrence as Measured by Rising PSA

Study

Number of men

Average follow-up period

Recurrence rate

Period at which recurrence is estimated

Clinical information

Kupelianetal., 1997 253 3.5 years

Cleveland

Beyer and Brachman, 2000 1,527 3.4 years Scottsdale, Ariz.

Zelefsky et al., 2001 New York

1,100 5.0 years

Hanlon etal., 2002 615 5.3 years

Philadelphia

15% low risk 45% int. risk 62% high risk

30% by PSA 7% metastases

5 years

5 years

5 years

5.3 years median age 71 31 % Gleason >7 58% PSA >10 median age 74 26% Gleason >7 54% PSA >10 average age 69 risk defined by Gleason score, PSA, and stage average age 69 22% Gleason >7 average PSA 15

Klein and Kupelian, 2003 Cleveland

Zeitman et al., 2004 Boston

578 4.3 years

205 8.6 years 51% by PSA

18% metastases

10 years

8 years

42% PSA >10 average age 72

38% Gleason >7

D'Amico et al., 2004 Boston

104 4.5 years

5 years

48% PSA >10 median age 73

74% Gleason >7 median PSA 11

source: P. Kupelian, J. Katcher, H. Levin, et al., External beam radiotherapy versus radical prostatectomy for clinical stage T1-2 prostate cancer: Therapeutic implications of stratification by pretreatment PSA levels and biopsy Gleason scores, Cancer Journal from Scientific American 3 (1997): 78-87; D. C. Beyer and D. G. Brachman, Failure free survival following brachytherapy alone for prostate cancer: Comparison with external beam radiotherapy, Radiotherapy and Oncology 57 (2000): 263-267; M. J. Zelefsky, Z. Fuks, M. Hunt, etal., High dose radiation delivered by intensity modulated conformai radiotherapy improves the outcome of localized prostate cancer, Journal of Urology 166 (2001): 876-881; A. L. Hanlon, H. Diratzouian, G. E. Hanks, et al., Posttreatment prostate-specific antigen nadir highly predictive of distant failure and death from prostate cancer, International Journal of Radiation Oncology, Biology, Physics 53 (2002): 297-303; E. A. Klein and P. A. Kupelian, Localized prostate cancer: Radiation or surgery? Urologie Clinics of North America 30 (2003): 315-330; A. L. Zeitman, C. S. Chung, J. J. Coen, et al., 10-year outcome for men with localized prostate cancer treated with external radiation therapy: Results of a cohort study, Journal of Urology 171 (2004): 210-214; A. V. D'Amico, J. Manola, M. Loffredo, et al., 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer, Journal of the American Medical Association 292 (2004): 821 -827.

first five years. It is known that the shorter the period of real follow-up, the less accurate the actuarial estimates are apt to be. It has also been demonstrated that actual and actuarial numbers may differ considerably. In addition to these problems, different studies of radiation treatment outcomes include men of different average ages, different severity of cancers, different types of seed and beam therapies, and different amounts of radiation.

If we keep these serious limitations in mind, what are the results of radiation outcome studies for prostate cancer? The major studies are summarized in Tables 3-5. Following seed therapy (Table 3) the recurrence of cancer, as measured by a rising PSA, is approximately 15 to 30 percent at five years posttreatment and appears to be approximately the same at ten years, depending in part on the number of men in the study with high PSAs or high Gleason scores. However, most men in these studies had less severe forms of prostate cancer; in the five studies cited, an average of only 15 percent of the men had pretreatment Gleason scores of 7 or higher. Thus, most men in these studies would be expected to have a low rate of recurrence.

For beam therapy (Table 4), the recurrence of cancer, as measured by a rising PSA, is approximately 25 to 40 percent at five years post-treatment, and approximately 35 to 50 percent at ten years. The men in these studies had significantly more advanced cancers at the time of treatment than the men in the seed therapy studies; for example, approximately half of them had Gleason scores of 7 or higher.

Men treated with a combination of seed and beam therapy (Table 5) appeared to have a comparatively favorable outcome, similar to that for seed therapy. As noted previously, some researchers believe that adding beam therapy to seed therapy for men with low- and intermediate-grade cancers improves the outcome; other researchers disagree.

In summary, three facts stand out. First, multiple studies have demonstrated that the higher the dose of radiation given, the lower the recurrence rate.

Second, it is evident that the higher the dose of radiation given, the more serious the complications affecting the urinary tract, the ability to have erections, and the rectal function. These two facts put men and their oncologists squarely between a rock and a hard place.

The third fact is that the selection of patients for any outcome

Table 5. Outcome of Seed and Beam Therapies When Given Together: Percentage of Patients with Evidence of Cancer Recurrence as Measured by Rising PSA

Average

Period at which

Number

follow-up

Recurrence

recurrence is

Clinical

Study

of men

period

rate

estimated

information

Grado etal., 1998

62

2.0 years

28%

5 years

median age 70.2

Scottsdale, Ariz.

37% Gleason >7 median PSA 8.7

Ragde etal., 2000

75

12.2 years

21%

10 years

median age 70.4

Seattle

18% Gleason >7 average PSA 14.7

Critz etal., 2000

689

4.0 years

12%

5 years

median age 66

Decatur, Ga.

23% Gleason >7 27% PSA >10

Merrick etal., 2004

119

5.4 years

2%

7 years

median age 58.1

Wheeling, W.Va.

82% low risk by Gleason, PSA, and stage

source: G. L. Grado, T. R. Larson, C. S. Balch, et al.( Actuarial disease-free survival after prostate cancer brachytherapy using interactive techniques with biplane ultrasound and fluoroscopic guidance, International Journal of Radiation Oncology, Biology, Physics 42 (1998): 289-298; H. Ragde, L. J. Korb, A.-A. Elgamal, et al.( Modern prostate brachytherapy: Prostate specific antigen results in 219 patients with up to 12 years of observed follow-up, Cancer 89 (2000): 1 35-141; F. A. Critz, W. H. Williams, A. K. Levinson, et al., Simultaneous irradiation for prostate cancer: Intermediate results with modern techniques, journal of Urology 64 (2000): 738-743; G. S. Merrick, W. M. Butler, K. E. Wallner, et al., Permanent interstitial brachytherapy in younger patients with clinically organ-confined prostate cancer, Urology 64 (2004):754-759.

study profoundly affects the results. At one end of the patient-selection spectrum is a study in which 67 percent of the men had a Gleason score of at least 7 or a PSA of at least 10, with 28 percent having PSA scores of over 20; a five-year recurrence rate of 43 percent is not surprising among men with such serious forms of cancer. At the other end of the spectrum is a study that included only younger men (average age 58.1) with less serious forms of cancer. This study reported a recurrence rate of 2 percent at seven years posttreatment. In evaluating claims of better results for individual treatment centers or specific treatments, we must always examine the selection of men who were included in the treatment study.

One final measure of outcome is how satisfied men are retrospectively with the treatment they chose. Relatively few studies have been made on this question, and most men say they are satisfied with their decision. One study reported that, approximately three years after treatment, fifteen of ninety-six men wished they had chosen a different treatment. Those who were dissatisfied included three of fifty-six (5 percent) who had had surgery; one of eleven (10 percent) who was pursuing watchful waiting; three of sixteen (19 percent) who had chosen beam therapy; and eight of thirteen (62 percent) who had undergone seed therapy.17 These numbers are small and the differences not statistically significant; more such studies are needed in order to obtain a useful measure of outcome.

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