Management of high risk prostate cancer from an oncologist's perspective

Prostate cancer is of enormous significance in men's health. In the US,
it is the most common malignancy amongst adults and the second most
common cause of cancer death. It is probably one of the more complex
cancers to manage, in that, at almost every step in the process, from
detection, diagnosis, and management, there are controversies and often
lack of consensus. The widespread use of PSA testing has resulted in
detection of the disease at an earlier stage, however, with that has
come the challenge of distinguishing aggressive cancers from those that
may never become clinically significant in the patient's lifetime.

Prostate specific antigen testing (PSA):

The optimal screening for prostate cancer includes a digital rectal
examination (DRE) and a PSA test. There have been no randomised studies
supporting a reduction in mortality as a result of screening with PSA,
however, some evidence exists in support of its use.
Before the introduction of PSA testing, only 25 per cent of prostate
cancers were organ confined. Today, that figure has increased to 80 per
cent. Taking into account lead-time and length-time bias, there has been
an estimated decline in mortality from prostate cancer of 25 per cent
over the past five years.

Standard PSA testing measures total PSA, i.e. complexed and free PSA. In
men with prostate cancer the proportion of free PSA is lower. Assays
capable of distinguishing free and complexed PSA will help increase the
specificity of PSA testing. In the meantime, establishing a threshold at
which a prostate biopsy should be performed in an asymptomatic patient
is difficult. For the most commonly adopted reference ranges for biopsy
see Table 1.

In the Prostate Cancer Prevention Trial of biopsies performed on
asymptomatic men with PSA levels falling into the "normal range", 15 per
cent had prostate cancer on end of study biopsy and 15 per cent of these
had high grade cancers, representing 29 per cent of the entire
population. PSA velocity, or the rate of rise of PSA concentration, has
been shown in a number of studies to correlate directly with the risk
for cancer. In patients with biochemical failure after local treatment,
a PSA doubling time of <10 months has been associated with an increased
risk for local recurrence of disease, metastatic progression, and death.

Clinical staging and histopathological grading:

The clinical stage of the tumour and histopathological grade are used to
predict clinical outcome, determine the most appropriate treatment, and
assess the risk of disease progression. The most commonly used staging
system is the tissue, node, and metastasis (TNM) system of the American
Joint Committee on Cancer.

Grading:

Grading is performed based on the glandular architecture,
differentiation, and cellular and nuclear appearance. The Gleason system
is most commonly employed and uses a numeric scale. Primary and
secondary patterns are assigned a grade from one to five which, when
added, gives the Gleason score. (Two-to-four well differentiated,
five-to-six well-to-moderately differentiated, seven moderately
differentiated, eight-to-10 poorly differentiated).

High-risk prostate cancer:

No exact definition exists for "high-risk" prostate cancer,
nevertheless, 10 per cent of men with newly diagnosed prostate cancer
will have high-risk features including locally advanced disease.
Definitive treatment for organ confined disease is usually a radical
prostatectomy or radiotherapy in some form. The most significant feature
for this high-risk group is that, after definitive treatment, as many as
80 per cent of these will present with biochemical or clinical failure
within 10 years. These patients have a 19-fold higher risk of death from
prostate cancer compared to those with low-risk features at diagnosis.

Pre-treatment characteristics of high-risk prostate cancer:

Pre-treatment characteristics of this group include a Gleason score of
eight or more, high volume palpable tumours (T2b/c, T3, T4), a high PSA
(15-20ng/ml), involvement of >50 per cent of the biopsy core by cancer
or >50 per cent of the length of the biopsy core. All of these features
are present in the absence of lymph node involvement of systemic
metastases.

Pathological features of high-risk prostate cancer:

Pathological features of high-risk prostate cancer include: Gleason
pattern of four or >; extracapsular extension; positive surgical
margins; seminal vesicle invasion; and/or lymph node metastases.

It is a combination of the above characteristics that defines high-risk
disease. Various nomograms have been developed to assist. The D'Amico
classification uses pre-treatment characteristics to define low-,
intermediate-, and high-risk groups. The Partin nomogram predicts the
likelihood of finding adverse pathological features. The Kattan nomogram
predicts likelihood of biochemical failure based on pathological
findings.

Treatment of high-risk prostate cancer:

There is no consensus regarding treatment of high-risk disease. It is
generally agreed that prior to definitive treatment full staging is
performed, including a CT abdomen and pelvis, a bone scan, and, when
available, an MRI pelvis recognising the increased likelihood of locally
advanced or metastatic disease at presentation.

Initial local treatment:

The initial treatment is usually radical prostatectomy or radiotherapy,
the former being the most common treatment. Vicini et al concluded that,
for patients with high-risk disease, neither was satisfactory; and that
five-year PSA outcomes were suboptimal, regardless of the treatment
technique used. Adjuvant treatment with radiotherapy, androgen
deprivation, and chemotherapy has been studied with the objective of
increasing chances of cure in this patient group.

Adjuvant radiotherapy:

The EORTC 22911 trial randomised 1,005 patients after radical
prostatectomy with T3 N0 disease to receive 60Gy within 60 days of
surgery or no further treatment. Patients were accrued between 1992 and
2001. Clinical and biochemical progression-free survival was 72 per cent
compared to 52 per cent for no additional therapy. The hazard ratio was
0.52 with a p-value of p=0.0001. As yet, there is no difference in
overall survival.

Adjuvant hormone treatment:

The question of when androgen deprivation therapy should be introduced
has been examined. The role of ADT has been recognised in metastatic
prostate cancer for over 60 years, and it is now generally recommended
that ADT should be introduced no later than when the bony metastases are
documented. Several recent randomised prospective trials have indicated
that for patients with aggressive local disease, ADT, either alone or in
combination with surgery or radiotherapy, has demonstrated significantly
improved overall survival compared to similar primary treatment and
deferred ADT. Specific groups of patients for whom early ADT has shown
benefit include: those with extensive local/regional disease treated
with ADT alone; during and after external beam RT; and men with nodal
metastases treated either with pelvic RT or RP and bilateral pelvic
lymphadenopathy. The use of ADT in low-risk prostate cancer has not been
shown to improve survival.

Neoadjuvant chemotherapy:

Several phase II studies have established feasibility of neoadjuvant
chemotherapy for high-risk prostate cancer prior to radical
prostatectomy. The Cancer and Leukaemia Group B have opened a phase III
clinical trial comparing neoadjuvant docetaxel followed by RP to RP
alone. The primary end point is to determine if early systemic treatment
with neoadjuvant chemotherapy before RP will decrease five-year
recurrence rates when compared with RP alone.

Adjuvant chemotherapy:

The role of adjuvant chemotherapy in prostate cancer is still under
investigation. One recent study giving four cycles of mitoxantrone
suggested a survival benefit in patients with locally advanced prostate
cancer. A phase III trial is underway (SWOG 9921) which is randomly
assigning patients with high-risk prostate cancer to receive adjuvant
hormone therapy with or without chemotherapy after RP.

Chemotherapy for metastatic disease and androgen independent prostate
cancer (AIPC):

Two large-scale phase III studies were conducted in 1999 to determine if
docetaxel conferred a survival benefit in
AIPC.

The results of SWOG 99-16, as shown in Table 2, demonstrate a 20 per
cent reduction in the risk of death among patients treated with
docetaxel/estramustine compared to those randomised to mitoxantrone and
prednisolone. The median time to disease progression was also superior
in the docetaxel arm.

The second trial, TAX 327, randomised 1,006 patients with AIPC to one of
three arms (see Table 3). The primary end point was overall survival.

Results demonstrated an improved median survival of approximately two
months among patients enrolled on docetaxel/prednisolone given every
three weeks compared to mitoxantrone/prednisolone (18.9 months compared
16.4 months).
These large phase III trials show that docetaxel does confer a survival
advantage on men with AIPC. Docetaxel with prednisolone has been
approved for the treatment of AIPC by the FDA.

Conclusion:

Prostate cancer remains an enormous challenge in men's health. It is
estimated that one in six men will be diagnosed with prostate cancer at
some point in their lives. A recent retrospective analysis looked at the
natural history of prostate cancer in a large cohort of untreated
patients in the UK. Two-thousand-four-hundred-and forty-four men, with
an age range of 30-to-75 years, were identified between 1990 and 1996 as
meeting the inclusion criteria: baseline serum PSA <100ng/ ml,
cT1-3NxM0; survived six months without evidence of metastasis; and had
no definitive local treatment. The median follow up was 88.9 months. The
study showed that 30 per cent of these patients had died from prostate
cancer while 30 per cent had died from other causes within 12 years. For
the patients who did not die of another cause, the probability of
metastases, death from prostate cancer, or additional therapy within 12
years was 90 per cent.

Neoadjuvant and adjuvant chemotherapy is standard in the treatment of
other cancers. Recently, adjuvant treatment in non-small lung cancer has
been shown to confer a 10-to-15 per cent improvement in survival,
similarly in breast cancer the use of adjuvant trastuzumab, a monoclonal
antibody directed at Her-2 neu, was shown to reduce the probability of
distant recurrence by 53 per cent at three years. Similar improvements
in survival have been achieved in the metastatic settings for these
cancers.

Several trials discussed in this article will report over the coming
years and several novel agents being studied in prostate cancer, such as
Calcitriol (1, 25 dihydroxy vitamin D) show promise in combination with
docetaxel, mitoxantrone, cisplatin and carboplatin. The androgen
independent prostate cancer study of clacitriol enhancing taxotere
(ASCENT) is currently recruiting. The vascular endothelial growth factor
inhibitor bevacizumab in combination with docetaxel is also being
evaluated.

Epothilones are macro-lides that stabilise microtubules thereby
arresting cell proliferation. These agents are being studied in
combination with taxanes. Probably the step that will assist most in the
effective diagnosis and subsequent management of patients is the
multidisciplinary collaboration among urologists, radiation oncologists
and medical oncologists at all stages of the disease.

Dr Catherine MA Kelly is a Specialist Registrar in Medical Oncology in
the Department of Medical Oncology and
Dr John McCaffrey is a Consultant in Medical Oncology in the Department
of Medical Oncology in the Mater Hospital, Dublin

 

knowledge is power - growing old is mandatory - growing wise is optional    
"Many more men die with prostate cancer than of it. Growing old is
invariably fatal. Prostate cancer is only sometimes so."
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