PSA Test Is Imperfect Tool: What to Do?

From Medscape Medical News
Nick Mulcahy

Authors and Disclosures

October 1, 2009 — The controversies surrounding population-based screening for prostate cancer — and the problems that plague the use of the prostate-specific antigen (PSA) test — will not go away anytime soon, suggest the authors of a new essay published online September 24 in the British Medical Journal.

There are a host of unanswered questions about PSA screening, including whether or not the test reduces mortality over the long term, assert the essayists.

New data from ongoing trials will provide some answers in the next 5 years or so, lead essayist Jennifer Stark, ScD, an epidemiologist from the Harvard School of Public Health in Boston, Massachusetts, told Medscape Oncology.

However, even with more data on the benefits and risks of the PSA test, it is an imperfect tool for screening men for prostate cancer, Dr. Stark and colleagues say.


"PSA screening cannot differentiate between indolent and lethal prostate cancer," they write.

The test sends many men down a path of diagnostic biopsies and treatment with no certainty of mortality benefit but with much anxiety and overtreatment, she said.

In the United States, the PSA test has triggered the mass overtreatment of men. An estimated 1 million men have been overtreated for prostate cancer since the advent of the widespread screening in the mid-1980s, as recently reported by Medscape Oncology.

What to Do?
Change is clearly in order, suggested a spokesperson for the American Urological Association (AUA). "A complete cultural overhaul is needed to change the perception that all prostate cancer needs to be treated," J. Brantley Thrasher, MD, from the University of Kansas in Lawrence, told Medscape Oncology. The change in perception needs to include clinicians and patients, said Dr. Thrasher.

The change will require physician "re-education" and the consideration of active surveillance as an alternative to treatment, he said.

However, the AUA remains in favor of PSA screening, unlike many other organizations that do not recommend population-based screening because of insufficient data on its benefits and harms. They include the European Urological Association, the US Preventive Services Task Force, Cancer Council Australia, the National Health Committee (New Zealand), the Japanese Urological Association, and the Swedish Board of Health and Welfare, note Dr. Stark and her colleagues.

Recently, at their annual meeting, the AUA issued a revision of their prostate cancer screening guidelines and dropped the age at which men should start to consider baseline PSA testing to 40 years, as reported by Medscape Urology.

"The AUA believes that, when offered and interpreted appropriately,the PSA test may provide essential information for the diagnosis, pretreatment staging or risk assessment, and post-treatment monitoring of prostate cancer," the AUA stated.

At the time, Otis Brawley, MD, chief medical officer of the American Cancer Society, told WebMD that the call for a baseline PSA at age 40 will likely lead to more screening and more overtreatment of men who will not benefit.

Patients Must Be Well Informed About Initial PSA — But How?

In their essay, Dr. Stark and colleagues agree that the PSA test needs to be offered appropriately, and describe that change as "urgently needed." Echoing the AUA, they recommend that men be well informed about the test before having the blood work done.

"You wouldn't just decide on the spot to do a mammogram," said Dr. Stark, explaining that such quick decisions are common with PSA testing.

"Somehow, we have to approach screening for prostate cancer with the same prudence we would have in screening for breast cancer or colon cancer," she added.

However, as recently reported by Medscape Oncology, the primary care setting, where most PSA testing is done initially, is currently ill-suited for discussing the complexities of prostate cancer screening.

"Today's practice environment presents few incentives or support tools for those clinicians and patients who prefer a discussion rather than simply marking a checkbox for PSA on a laboratory requisition form," Steven H. Woolf, MD, MPH, and Alex Krist, MD, MPH, from Virginia Commonwealth University in Richmond, write in an editorial published in the September 28 issue of Archives of Internal Medicine (2009;169:1557-1559).

That editorial accompanied a paper detailing results from a survey, which showed that nearly one third of men receiving a PSA test did not have any discussion with their doctor about the test (Arch Intern Med. 2009;169:1611-1618).

Interpretation of PSA Test

Another point highlighted by Dr. Thrasher in the interview with Medscape Oncology was that PSA test results should not be considered on their own, but need to be interpreted along with other information.

"PSA does not work well by itself in predicting prostate cancer," Dr. Thrasher said.

The interpretation of PSA tests by a urologist should always be done in conjunction with other factors that contribute to prostate cancer risk, such as overall health, family history, age, comorbidities, the rate of change in PSA value over time (PSA velocity), and physical examination, Dr. Thrasher explained, referring to the AUA's Prostate-Specific Antigen Best Practice Statement.

"I don't want people to walk away from PSA and say it's useless," he remarked. "We believe we are still saving lives with the test."

More Unanswered Questions

New data from ongoing trials will provide answers to some of the questions that remain about PSA testing, including the crucial question of whether it reduces mortality, Dr. Stark told Medscape Oncology.

Two major trials are evaluating the effectiveness of PSA screening — the European Randomized Study of Screening for Prostate Cancer (ERSPC) and, in the United States, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO).

Recent published data from these trials involved a median follow-up of 7 years in the United States and 9 years in Europe (N Engl J Med. 2009;360:1310-1319 and 1320-1328). Those results showed no affect on mortality from prostate cancer in the American trial, and a small reduction in mortality in the European trial, as reported by Medscape Oncology.

Lead time, or the interval of time by which screening advances a diagnosis, is necessary to reduce morbidity and mortality associated with disease, write the Dr. Stark and her coauthors. It has been estimated that mean lead times for PSA testing were 11 to 13 years among men aged 50 to 69 years, which is "much longer" than for other cancer screening, they write. This time frame explains Dr. Stark's contention that, in another 5 years, ERSPC and PLCO will provide answers to some currently unanswered questions about PSA screening.

With continued follow-up in these major trials, there should be answers to questions about the predictive value of a negative PSA result (what percentage of men go on to have prostate cancer despite the negative result?), and solid information on the percentage of men who are overdiagnosed, Dr. Stark said. The screening trials will also be able to firmly determine how many men need to be treated to avert 1 death; the ERSPC estimate is currently 48, she added.

With regard to the question of what percentage of men are overtreated, although the trials will be helpful, the answer might require more extended follow-up, said Dr. Stark.

"Because of the long life expectancy of many men diagnosed with prostate cancer, combined with the long lead time for PSA screening, it is going to take considerably longer to determine who ultimately benefits from treatment of a screen-detected cancer and how this benefit compares with the side effects and mortality associated with treatment," she said.

The essay authors have disclosed no relevant financial relationships.

BMJ. 2009;339:b3601. Abstract


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CARCINOMA PROSTATE

The risk of carcinoma of the prostate increases with age, being increasingly detectable from 50-80 years. Though the cause is unknown, several factors influence the risk. Geographical (Sweden and USA), racial (blacks) and occupational (rubber workers) factors and altered oestrogen and androgen levels are some of the risk factors.



Adenocarcinoma arising from the glandular acini is the most common. Sarcomas, and squamous cell, transitional cell and small cell carcinomas are other tumours. Apart from these, metastases to prostate are seen from the bladder, lung, colon and lymphomas. Grossly, multifocal lesions and invasion of the prostatic capsule are the characteristic features of this disease. It most commonly metastasises to bone, with dense osteoblastic or osteolytic lesions, and less frequently to the liver and lung with paraneoplastic syndromes.

Early prostatic carcinoma is usually asymptomatic and can be detected by routine rectal examination. Induration or non tender nodularity are the frequent findings. The presence of symptoms indicates advanced disease. Urinary symptoms like sudden onset of urinary tract obstruction, poor urine flow, urgency and terminal haematuria, back pain or paraplegia may be due to extradural secondaries. Acute and chronic prostatitis, nodular hyperplasia and benign adenomas have to be clinically differentiated from prostatic carcinoma.

The histological diagnosis is established by transperitoneal needle biopsy or by transrectal fine-needle aspiration cytology (FNAC). Routine investigations like urine analysis, complete blood picture, renal and liver profile, serum alkaline phosphatase, serum calcium and phosphorus levels, chest X-ray, and X-ray of bony secondary sites are carried out (Fig. 14.6). Ultrasonography, CT scan, isotope bone scan and lymphangiogram are optional. Estimation of acid phosphatase levels in serum is not considered very specific for carcinoma prostate. Prostate-specific antigen (PSA) is more sensitive and useful. Carcinoembryonic antigen is increased in a few cases.

Routine and careful examination of the prostate after 50 years of age is essential for prevention and early diagnosis of carcinoma prostate. Surgery, radiotherapy and hormonal manipulation are modalities of treatment.In cases diagnosed incidentally at histology during transurethral resection of suspected benign prostatic hyperplasia, random multiple needle biopsies are carried out. If no further foci are detected, patients are kept on follow-up without any further treatment.A tumour which is palpable but is confined to the prostate (single nodule of less than 2 cm) is managed with radical prostatectomy. However, few patients with carcinoma are diagnosed early and are fit for surgical treatment. Tumours with multifocal lesions or those localised to the periprostatic area are managed by radical prostatectomy or radiotherapy. This group of patients needs pelvic lymphadenectomy for pathological staging before prostatectomy, as radical treatment depends on the stage of the disease. The increased incidence of impotency, lymphoedema, pulmonary embolism are limiting factors of radical surgery.

External radiotherapy is widely employed in the management of carcinoma prostate, either alone or as adjuvant to radical prostatectomy. Interstitial implant irradiation using I-125, Ir-192, Au-198, P-32 isotopes is also used. Neither hormonal therapy nor chemotherapy has improved survival in early stages of carcinoma prostate.In advanced stages transurethral resection of the prostate is done to relieve the bladder outlet obstruction as a purely palliative measure. Orchidectomy is also effective. Radiotherapy is useful in isolated painful bony secondaries, spinal cord compression, pelvic pain syndromes and haematuria. Endocrine therapy is the mainstay of treatment of symptomatic prostatic malignancy. Orchidectomy, luteinising hormone-releasing hormone (LH-RH) agonists and oestrogens result in dramatic improvement. Long-acting oestrogen chlorotriamisene (TACE), progestins, flutamide (anti-androgen), aminoglutethamide and diethylstilbesterol diphosphate can be used. Chemotherapy is given for hormone-resistant cases. Multi-drug chemotherapy has not shown superior results over single-agent therapy. Adriamycin, 5-fluorouracil, methotrexate, cyclophosphamide, cisplatin and DTIC are used.

Survival is directly related to stage: stages I and II-70%, stage III-56% and stage IV-25% at 5 years. Well differentiated carcinomas have better prognosis. Grades I, II, III and IV carry 5-year survival of 60%, 35%, 15% and 5%, respectively. Involvement of seminal vesicles is associated with poor prognosis.

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