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Adjuvant hormonal therapy added to radiation therapy for localized prostate cancer

Prof J Armstrong, Consultant Radiation Oncologist at UCD, examines the biological behaviour and treatment of prostate cancer

The biological behaviour of prostate cancer can be predicted using clinically- available data. The combination of clinical stage, tumour grade (usually described as Gleason score, a method of grading histology — high scores have a bad prognosis) and the level of prostate specific antigen (PSA) can be used to predict the risk category of individual patients. The TNM staging system is described it Table 1.

Non-rnetastatic prostate cancer can be divided into broad clinical groups. The least aggressive cancers ate usually incidentally diagnosed (T1 in the staging system), are clinically confined to the prostate, have low Gleason scores and low serum PSA. The prognosis of these patients is generally so good that some advocate expectant management.
If the cancer is palpable and small and has not spread beyond the capsule of the gland (T2 in the staging system) then it can be treated with radiation or surgery. If there are no histologically aggressive features and the PSA is not high, the prognosis is excellent. If the cancer is more extensive and has penetrated the capsule or invaded the seminal vesicle (T3 in the staging system) then radiation therapy is the standard treatment.

Despite effective local treatment, T1 and T2 tumours with Gleason scores of seven or more and/or PSA levels above 20 and all T3/T4 cancers are at high risk of relapse by spread to other parts of the body (predominantly the bones). Similarly, all patients with nodal metastases are at extremely high risk of metastatic disease. It is these two risk categories which are considered for adjuvant hormonal therapy. (Table 2)


Theoretical Basis of Adjuvant Therapy:
The rationale for adjuvant therapy is the hypothesis that micro-metastatic deposits are easier to eradicate than macroscopic, clinically evident tumours. Thus, a treatment which is demonstrated to induce remission in cases of metastatic disease, albeit partial or short-lived, may actually enhance the potential for cure or prolong survival when it is used as an adjuvant to purely local treatment for apparently localized disease. In designing strategies fur adjuvant therapy, it is usual to select a drug regimen which is demonstrated to be the most biologically active in the treatment of metastatic disease. For previously untreated metastatic prostate cancer various types of anti-androgen therapy are the mainstay of management. The optimal anti-androgen therapy is very controversial but the usual approach is to use an LHRH agonist alone or in combination with a peripheral antiandrogen.

Trials of Adjuvant Hormonal Therapy
Initial hormonal therapy before radiation:
The Radiation Therapy Oncology Group (RTOG) randomised 471 patients to radiation with and without induction neo-adjuvant hormone therapy. Patients had bulky T2-3 rumours. The hormonal therapy was an LHRH agonist once-monthly for two months before, and twice during, radiation combined with flutamide, orally 250mgs three times daily also given before and during radiation.

There was a significant improvement in biochemical freedom from relapse in favour of the combined hormonal-radiation arm. At three years follow-up, 46 per cent of those receiving adjuvant therapy were relapse-free, compared to 26 per cent for those receiving radiation alone. The clinical disease- free survival at three years was 61 per cent for combined therapy versus 43 per cent for radiation alone. Further follow-up of this trial will be necessary to determine the effect on overall survival

Hormonal therapy during and after radiation
The EORTC performed a randomized trial of an LHRH analogue beginning during radiation and continuing for a total of three years compared to radiation alone. The hormonal therapy was an LHRH agonist once a month for three years, with cyproterone acetate 150 mgs daily for the first month.

A total of 415 patients with T1/2 WHO grade III tumours, or T3/4 tumours of any grade were randomized. At five years, adjuvant hormonal therapy conferred a significant survival advantage (56 versus 78 per cent), significantly increased local control (95 versus 75 per cent), freedom from metastases (89 versus 56 per cent), and clinical disease-free survival (78 versus 56 per cent). This trial established a very clear benefit due to prolonged hormonal therapy added to radiation for selected patients.
Duration of adjuvant hormonal therapy

In 1997, the Irish Clinical Oncology Research Group commenced a randomized trial comparing short (four months) versus long (eight months) non- adjuvant hormones prior to radiotherapy. A total of 276 patients enrolled, of whom 256 are analyzed.

Stratification risk factors were PSA of at least 20, Gleason score of at least 7, and staging of T3 or more. The intermediate-risk stratum had one factor; the high- risk stratum had more than two factors. Hormonal therapy consisted of monthly LHRH agonist (triptorelin – decapeptyl) and flutamide (Drogenil) 250mg three times daily. Localized radiotherapy was 66Gy in a minority and 92 per cent got 7OGy using 3-D technology to the prostate and seminal vesicles.

The primary end-point was PSA relapse-free survival (P-RFS), calculated by the RTOG method from the date of the last neo-adjuvant injection to avoid bias.

The preliminary results show that the high-risk patients had a significantly higher prospect of reaching a PSA nadir of <0.5 (a surrogate of ultimate outcome) when treated with eight months of neo-adjuvant hormonal therapy compared to four months. There is a trend in PSA-RFS in the high-risk stratum favouring the eight-month arm. Further follow-up will be required to determine the ultimate outcome of this randomized trial.

In 2000, the USA Radiation Therapy Oncology Group (RTOG) reported the results of a randomized trial involving 1,554 prostate cancer patients with T2b-T4 tumours treated with radiation therapy. Patients were randomized to receive four months or 28 months of adjuvant hormonal therapy. For patients with Gleason score 8-1O histology five-year survival was 69 pen cent with the short course of hormonal therapy compared to 80 per cent with the longer course.

In a previous randomized trial the RTOG compared radiation with and without four months of hormonal therapy. For patients with less aggressive histology the short course of adjuvant hormonal therapy prolonged survival. For more aggressive histology it had no impact.

Adjuvant systemic therapy is advisable for patients with high PSA levels at diagnosis, aggressive histology or advanced tumour stage. When administered to appropriately- selected patients, it can confer a large survival benefit. The optimal sequence of adjuvant hormonal therapy and local treatment is not determined. More trials are needed to optimize the variables of adjuvant hormonal therapy (drug combination, sequencing, duration, optimal radiation technique and dose etc). We currently use combination of an LHRH agonist with a peripheral anti-androgen (Casodex-bicalutamide) and recommend a minimum of eight months adjuvant hormones.

There is a growing awareness of cancer in the general community. Indeed, prostate cancer may soon equal breast cancer in terms media attention and public debate. The medical profession and administrative bodies must prepare for the increased level of services that will be demanded. National cooperative clinical research and audit is the best way to ensure proper standards of management, pro-vision of quality care, and equitable access to health care resources. Patients with prostate cancer must be encouraged to participate in trials such as the one outlined in Table 3. In a small country such as this, it should be possible to ensure that the majority of suitable patients are offered this option.

References available on request.