ESMO 2011 Report – New opportunity for pain control in metastatic carcinoma of the prostate

by Dr Sunil Upadhyay – Prostate cancer is one of the leading causes of death due to cancer in men all over the world. Most of the prostate cancer-related deaths are due to disseminated disease and bone is the commonest site for metastases. Though the incidence of osteoblastic metastases is common, many patients develop osteolytic or mixed lesions. Skeletal Related Events (SREs) such as bone pain, pathological fractures, spinal cord compression, hypercalcaemia, impaired mobility and the need for radiotherapy can be frequent, resulting in poor quality of life and shortened survival. Though the exact mechanism of pain relief is unknown, traditionally, palliative radiotherapy (external and/or systemic) is frequently used for control of cancer related bone pain with a high success rate. There is no gold standard for the amount and duration of palliative radiotherapy for the control of bone pain. However, it is widely accepted that 8Gy single fraction to the painful site is similar in efficacy to fractionated longer duration of therapy, particularly non-weight bearing bones. Provided the patient survives long enough, re-treatment to the already treated site is common with a single fraction regimen.

Over the last decade, the use of bisphosphonates in the management of bone secondaries has become a standard option. There is plenty of evidence to support the efficacy of bisphosphonate particularly second and third generation agents in the reduction of SREs including bone pain by 10-30%. The results of the first, large, prospective, randomised Phase III multicentre trial on the use of single agent intravenous ibandronate compared to single dose radiotherapy for localised metastatic bone pain in prostate cancer (RIB trial) was presented by Peter Hoskin of UCL at EMCC 2011.  In this multicentre trial 470 patients with metastatic prostate cancer were randomised to receive either 8Gy single dose of local palliative radiotherapy or a single intravenous infusion of 6mg ibandronate. Patients reported their primary site of pain at baseline, then 4, 8, 12, 26 and 52 weeks after treatment.

After reassessment at 4 weeks, non-responders were allowed to cross over to the alternative therapy, receiving their second treatment no later than week 8. The primary end point was pain relief at 4 and 12 weeks compared to the baseline pain. The pain relief was measured using a combination of analgesic use and pain score, based on two methods: (i) WHO pain ladder and (ii) analgesic use defined in morphine equivalents (Mercadante 1993), where a positive difference from baseline indicates worsening pain relief. The results presented confirmed that the baseline characteristics between the two treatment options were well balanced. Only a small number of patients had chemotherapy. The median follow-up was 11.6 months. The WHO response rate at 4 weeks was 53% (RT) vs 49% (IB) p=0.49 and at 12 weeks 49% vs 56%, p=0.24. Using the Mercadante score, the mean difference from base line to 4 weeks was -3.2 units (RT) vs +1.2 (IB), p=0.11 and at 12 weeks -0.2 vs -1.7, p= 0.73.  However, the proportion of patients with a high score difference at 4 weeks in favour of radiotherapy was 10% (RT) vs 20% (IB), p=0.004. At 6 months the mean difference was + 3.99 (RT) vs + 1.95 (IB) p=0.66. There was no difference at 12 months. The proportion crossing over treatments was 31% (IB) and 24% (RT) p=0.10. The median survivals were 11.8 (only RT), 11.4 (only IB), 12.7 (RT then IB) and 16.8 (IB then RT) months. The side effects were few, expected and short lived including nausea, diarrhoea and flu-like symptoms.

These results of the RIB trial do not show any difference in pain control from a single fraction of radiotherapy or single infusion of ibandronate provided non-responders had the other option of therapy available to them. Though a relatively larger proportion of patients in the IB group needed re-treatment after 4 weeks, there was no long-term difference in pain relief between ibandronate and radiotherapy at 6 and 12 months. Therefore, a single dose of bisphosphonate could have an important role in the management of metastatic bone pain, particularly treatment which can be prescribed and delivered in local hospitals closer to home for patients living a long distance from the radiotherapy centre. It is also encouraging to know that ibandronate is effective in pain control sites where radiotherapy may be contraindicated and radiotherapy is effective in patients pre-treated with ibandronate. Analysis of urine samples for markers of bone turnover may help individualisation of the treatment. (Abstract 7LBA)