Editorials

Localised prostate cancer: can we do better?

There have been some advances in local control, but little impact on survival

Prostate cancer is now the commonest male cancer and the second commonest cause of male cancer deaths. Death rates have doubled over the past 20 years, and mortality is predicted to exceed that for lung cancer in 15 years' time. This increased incidence of prostate cancer has led to considerable efforts to improve on local treatments and boost survival. In the United Kingdom 60% of patients with prostate cancer are diagnosed with metastatic disease. Screening for prostate specific antigen (PSA) in North America has led to increased detection of the disease at an earlier stage, but not yet to increased survival.¹ Screening has, however, meant that more patients have become candidates for radical local treatments. What evidence do we have that we are doing any better for localised prostate cancer?

Localised prostate cancer may be treated surgically or with radiotherapy or managed by "watchful waiting," with treatment only when disease progresses. Surgery has been suggested as offering the best chance of cure for patients with poorly differentiated tumours, with survival figures of 70-80% compared with 15% for radiotherapy.² The survival figures for patients with well and moderately differentiated tumours are identical whether they are managed by radiotherapy or by watchful waiting.^3-5 These figures are mainly from single institutions, with no significant data involving reasonable patient numbers available from randomised trials, but they have promoted a threefold increase in radical surgery in the United States.⁶

The argument against the validity of these data and their relevance is based on the high degree of selection involved in recruiting patients for treatment. Patients selected for surgery are invariably fitter than those who have radiotherapy, and fitter patients have an inherent survival advantage. Individual clinicians seem to be entrenched in their conviction that either surgery or radiation is preferable, so randomised trials will not be performed to establish which is more effective. Surgical technique has advanced over the past decade, and radical nerve sparing operations are thought to lead to less incontinence and impotence, although this is disputed. ^{7 8} What advances have been made in radiotherapy?

Of those patients with T2-T4 disease treated with conventional radiotherapy, about 80% will have a biochemical relapse (a raised prostate specific antigen value) over 10 years, and rebiopsy of the gland after treatment will show persistent disease in 14-92% of cases 18 months after treatment. An increase in prostate specific antigen may precede clinical recurrence by many years, but if the absence of raised prostate specific antigen is used as an endpoint recurrence free survival is thought to be 20-30% lower than previously noted.⁹

These observations have led to attempts to increase the radiation dose to the tumour.¹⁰ Both brachytherapy and conformal radiotherapy allow higher dosages of radiation with sparing of normal tissue and less toxicity. Brachytherapy, which involves implanting radioactive iodine or palladium seeds into the prostate, has the advantage of being a one-off outpatient treatment. It has become more popular over the past decade but appears to be most useful for patients with low grade small volume tumours with a prostate specific antigen value <10 ng/ml.⁹ Conformal radiotherapy has fewer side effects than conventional doses of radiotherapy,¹¹ and in phase 1 and 2 studies dose escalation has been attempted from the standard 64Gy to 81Gy, with early reports of improved response and equivalent toxicity.¹²

The strategy of combining radiotherapy with androgen deprivation for localised prostate cancer has become increasingly popular with radiotherapists, but is it of value? Hormonal treatment before definitive local therapy significantly changes the size and composition of the neoplastic prostate gland, reducing the radiotherapy planning target volume of the prostate by 30-40% in most patients,¹³ and thus it may potentially reduce morbidity.

Clinical studies reported over the past five years support the use of neoadjuvant and adjuvant antiandrogen therapy with radiotherapy. The RTOG (Radiation Therapy Oncology Group) 8610 study¹⁴ randomised 471 patients with T2C-T4 prostate cancer to radiotherapy alone or radiotherapy with eight weeks of neoadjuvant hormonal therapy, continuing throughout radiotherapy for 16 weeks. During a median follow up of 4.5 years the risk of local failure was almost halved in the group treated with combination therapy, and the five year biochemical disease free survival was 36% compared with 15% in those receiving radiotherapy alone. Overall survival was identical.

A study by the EORTC (European Organisation for Research and Treatment of Cancer) randomised 415 patients with localised prostate cancer to radiotherapy alone or radiotherapy and a luteinising hormone releasing hormone analogue for three years, starting on the first day of irradiation. With a median follow up of 45 months the five year overall survival in the combined treatment group increased from 62% to 79%. The five year disease free survival also increased, from 48% to 85%,¹⁵ showing for the first time a benefit in overall survival in addition to local control.

These studies have been criticised as patients were not randomised to receive hormone therapy alone, but nevertheless they offer hope that neoadjuvant and adjuvant therapy improves the outcome. A new trial instigated by the MRC and the NCI of Canada will look at the effect of hormone therapy with or without radiotherapy.

A recent review of 14 retrospective and six prospective randomised trials of hormonal therapy and radiotherapy concluded that, although the impact of combination treatment on overall and cancer specific survival was unclear, locoregional control, disease free survival, and biochemical control were all improved. It remains to be seen whether longer follow up and additional data from current trials will translate into a survival advantage.¹⁶

So we can conclude that adjuvant hormonal therapy improves local control, but the jury remains out as to whether there is also a survival advantage. There is still uncertainty about patient selection and the duration of adjuvant hormonal treatment. In many of the adjuvant studies hormonal therapy has been continued for two years. Antiandrogen therapy has significant side effects, and, although two years' treatment may improve local control, it will condemn the patient to two years of hot flushes, loss of sexual function, and decreased drive. In a disease that we may be palliating, but not curing, this is a significant cost.

Tova Prior, registrar in radiotherapy. 
Jonathan Waxman, professor of oncology. 

Department of Oncology, Hammersmith Hospital, Imperial College of Medicine, London W12 ONN