FORT LAUDERDALE, Fla--The key feature of prostate cancer that distinguishes it from most other solid tumors is the large discrepancy between annual incidence (about 250,000) and mortality (about 41,000).
"This means that there are many patients who are at risk for overtreatment, and we need to refine the prognostic features that tell us which patients are going to be in which risk category," said Randy Milliken, MD, in his presentation of the updated prostate cancer guidelines at the 2nd annual meeting of the National Comprehensive Cancer Network (NCCN).
Dr. Milliken, of the M.D. Anderson Cancer Center, was standing in for Christopher Logothetis, MD, chairman of the prostate cancer guidelines committee and professor of genitourinary medical oncology at M.D. Anderson.
Coming up with a prognosis that will guide the treatment choice requires looking at two "biological clocks," he said--that of the cancer (determined by the staging workup) and that of the host (life expectancy).
The consensus view is that after diagnosis (based on PSA, DRE, and Gleason score), if life expectancy is less than five years and the patient is asymptomatic, "one should not bother to do a single additional test," Dr. Milliken said.
Prostate cancers staged as T1A disease are incidental cancers that are neither palpable nor apparent on imaging apparent, and the treatment recommendation is watchful waiting. "But in some cases, even these cancers may be appropriately treated if life expectancy is good and other factors suggest that the disease may not be biologically indolent," Dr. Milliken said. Such factors include Gleason score greater than 7 and PSA greater than 10 ng/mL after transurethral resection.
The bulk of prostate cancers are potentially curable (stage T1 subgroups, stage T2A, B and C). The first task in deciding on treatment in these patients is to consider the probability that the patient will have organ-confined disease.
"Approaches based on assessments of probability of cure are going to become increasingly important as we think about how to steer patients toward definitive local therapy," Dr. Milliken said.
He cited, for example, the work done at Johns Hopkins by Dr. Patrick Walsh. More than 1,000 consecutive prostatec-tomy patients were stratified by preop-erative PSA level, Gleason score, and pathologic stage, and a table was created showing the likelihood of freedom from recurrence after prostatectomy based on these factors.
Once the probability of organ-confined disease is determined, "the next question to grapple with is the issue of life expectancy," he said. The combination of these two factors will determine treatment (no treatment until symptoms, radiotherapy, or prostatectomy).
In patients with advanced disease, androgen ablation, radiotherapy, or both is recommended, with androgen ablation alone for the most advanced cases.
The exception would be patients with T3A disease, for whom prostatectomy may be considered if they have low volume disease and Gleason score less than 7. "Patients with these favorable features may have about a 40% chance of cure with surgery," he said.
For patients who were initially observed and have a limited life expectancy, the guidelines recommend that therapy be withheld and, consequently, that surveillance be withheld until the patient has symptoms.
If the initial decision was to observe, but life expectancy is greater than 10 years, then the recommendation is to measure PSA twice a year and consider annual biopsy "because of the well-described tendency for the Gleason score to change with time," he said.
For patients who had definitive therapy, PSA should be checked twice a year for five years and then annually along with a digital rectal exam. "The lead time that PSA gives you in this setting is quite good, at least seven months or longer," Dr. Milliken said, "and so a PSA every six months seems to be adequate to preserve the appropriate therapeutic options."
For patients who are initially metastatic, surveillance is more extensive and frequent. "One thing to point out is that antiandrogens do have a certain tendency to upset the liver," he said, "and in patients taking these drugs, we think that the liver function test should be checked occasionally (every month for three antiandrogen cycles)."
For patients with uncharacteristic presentations (visceral disease or lytic bone metastases), biopsy is recommended. "These are red flags for a high probability of some histologic variant, such as small-cell carcinoma, for which cytotoxic chemotherapy may, in fact, be the preferred treatment, and it should be given earlier rather than later," Dr. Milliken stressed.
A member of the audience asked why the guidelines for salvage workup call for a biopsy at the prostate bed in patients who have failed radical prostatectomy or radiation therapy, even though they have a positive DRE and an increase in PSA.
"The main reason is to look for histologic variance," Dr. Milliken answered. "At M.D. Anderson, we've accumulated a large number of patients with relapsing cancers, especially those that relapse as a large mass in the pelvis, where the biopsy clearly shows neuroendocrine differentiation, and that implies a very different treatment strategy." He added that "the point is well taken that this may not be absolutely necessary as part of the workup of every such patient."
Primary Salvage Therapy
The guidelines endorse salvage radiotherapy or androgen ablation for patients who have failed prostatectomy and have negative bone scans, but, conversely, salvage prostatectomy is not recommended for those who have failed radiotherapy.
"Obviously, there are individual patients for whom salvage prostatectomy is appropriate, but it should never be the first option," Dr. Milliken said, sparking a member of the audience to suggest that it was not the guidelines' intent to make salvage prostatectomy an option at all, except in the case of clinical trials.
Dr. Milliken agreed, reiterating that salvage prostatectomy is not on the main treatment pathway of the guidelines. "I was trying to make a conciliatory remark because we all have seen patients who are many years out, have no detectable disease outside the pelvis, are still young and in good shape, and I think that for some of these patients, a salvage prostatec-tomy makes a certain amount of sense."
In patients with positive bone scans, androgen ablation is the standard of care. "At the top of the list is orchiectomy, which continues to be the simplest, cheapest, and most definitive way of achieving androgen ablation," he said.
If the patient and physician opt for an LHRH agonist, "there is increasing recognition that this should be coupled with a measurement of the serum testosterone a couple of months later," Dr. Milliken said. "If serum testosterone is high, then you can either suggest to the patient that he have an orchiectomy or add an antiandrogen."
At the first sign of rising PSA, the antiandrogen should be withdrawn. Once androgen-independent progression is documented, options for symptomatic palliation include local radiotherapy, glucocorticoids, or a trial of cytotoxic chemotherapy.