Medical updates
New treatment for advanced ovarian cancer
Women with advanced ovarian cancer now have a new treatment option which uses innovative technology to minimise many of the side effects commonly associated with chemotherapy, including hair loss.
Caelyx (doxorubicin HCI liposome injection), marketed by Schering-Plough Ltd, has been licensed for the treatment of advanced ovarian cancer in women who have failed initial treatment with a drug containing platinum. It is administered intravenously, usually on an outpatient basis, as a single dose every 28 days for as long as the disease does not progress and the patient continues to tolerate treatment.
Caelyx uses unique 'stealth' technology that encapsulates the active drug doxorubicin - a widely used cytotoxic agent - in a special coating. This coating disguises the drug so it can evade detection by the immune system, allowing virtually 100% of it to reach the tumour, where it will start work on destroying abnormal cancer cells. This targeting mechanism enhances the treatment's effectiveness while minimising impact on healthy tissue and organs.
A recent study comparing Caelyx with topotecan in patients who had failed first-line platinum-based therapy found that, overall, Caelyx patients experienced fewer serious side effects. Efficacy and median overall survival were similar in both groups of patients (overall survival from the start of second line treatment was 60 weeks for Caelyx patients and 56.7 weeks for those taking topotecan).
The study showed a total hair loss incidence of 16% in Caelyx patients, of which 1% was grade 3-4 severity, compared with a total incidence of 49% in topotecan patients, of which 6% was grade 3-4 severity.
The most common side effects in Caelyx patients are palmar-plantar erythrodysesthesia (PPE, a skin complaint affecting the hands and feet) and stomatitis (inflammation of the lining of the mouth). Severe cases are usually managed success-fully with dose modification.
Jenny Denholm
Sante Communications Ltd, London
High dose chemotherapy
What's happening in ovarian cancer?
In the last decade we've seen many changes in the treatment of ovarian cancer. New drugs such as paclitaxel (Taxol™) have been shown to be beneficial, but overcoming tumour resistance to chemotherapy remains a major challenge.
Whilst the search for new drugs continues, alternative strategies are being considered; one of these is high dose chemotherapy. The aim of this treatment is to overcome drug resistance by significantly increasing the dose of drugs. The problem with this approach is that very high doses of drugs are toxic, particularly to the bone marrow. For this reason patients' bone marrow or peripheral blood stem cells are taken before treatment, frozen and then given back (similar to a blood transfusion after chemotherapy). Within a short time these cells grow and repopulate the blood and bone marrow with all the different cells that are normally present.
High dose chemotherapy with peripheral blood stem cell transplantation has become possible since the discovery of granulocyte colony stimulating factor (GCSF), a hormone that stimulates the release of stem cells into the blood. These stem cells can be 'harvested' and GCSF stimulates their growth following re-infusion into patients.
High dose chemotherapy is commonly used in the treatment of leukaemias and lymphomas. In these malignancies, increases in drug dose do appear to benefit some patients. This has led to interest in using this type of therapy for the more common solid tumours. The best example is breast cancer, where there has been much publicity about high dose therapy. The publication of seemingly good results in patients with a high risk of recurrence after initial surgery, and the suggestion that some patients with advanced disease may also benefit, have led to its widespread use in the USA.
On this side of the Atlantic, oncologists were more cautious about high dose chemotherapy as there was a lack of evidence from randomised trials.
High dose chemotherapy may also be effective in ovarian cancer as this is more sensitive to chemotherapy than breast cancer. However, as in breast cancer, evidence from randomised trials is lacking. Nevertheless, several hundred ovarian cancer patients in Europe and a similar number in the USA have undergone high dose chemotherapy.
Data collected by Transplant Registries have shown that it is only patients with small amounts of residual tumour, still chemo-sensitive to conventional drugs, who are likely to derive any benefit from this treatment. The good long-term survival of some of these patients following high dose chemotherapy is encouraging. However, until benefit is shown in randomised studies it is difficult to exclude the possibility that there has been selection of patients who would in any case be destined to do well.
These findings led to the launch of randomised trials in the USA and Europe a few years ago. What has happened?
Trials of high dose chemotherapy are more difficult to perform in ovarian cancer than in breast cancer. First, it is less common than breast cancer and many patients may be too frail to withstand the side effects of high dose therapy, or have very advanced diseases that may not be suitable for this type of treatment. Second, in the USA it was difficult to convince women that they should enter a randomised trial. Most of the women who felt motivated to undergo high dose treatment, and who had read about the thousands of women receiving high dose therapy for breast cancer, refused to enter the study in case they were allocated to the standard (non-intensive) arm of the trial. As a result, the trial in the USA closed prematurely due to poor accrual. Low accrual in Finland also led to early closure of the trial, but a randomised trial has been completed in France. The results should be available next year.
Two years ago the European Blood and Marrow Transplant (EBMT) Group, which analysed the results of treatment from their registry, launched a Europe-wide randomised study, with the aim of recruiting a much larger number of patients. In this study, OVCAT (Ovarian Cancer Trial), patients are randomised to receive either several sequential cycles of intensive 'stem cell-supported' high dose chemotherapy or standard treatment with paclitaxel and carboplatin. A German group is running a similar trial. Sequential high dose therapy was chosen as the use of several intensive cycles of treatment may be more effective than a single high dose cycle.
Although the EBMT OVCAT and German study are available in many European centres (including the United Kingdom), recruitment to the trial has been very slow. Why is this? First, the early results of the randomised high dose breast cancer trials that are now completed are not as yet conclusive. Second, some patients and physicians may be reluctant to embark on a treatment that is toxic and expensive. In the USA a new study is being designed which, it is hoped, will be more acceptable to patients; high dose chemotherapy is being offered at diagnosis or if patients relapse after first-line treatment.
However, in Europe promotion of the OVCAT trial continues as it is very important to establish whether this new and intensive treatment is beneficial to patients with ovarian cancer. If the trial fails to recruit patients it is likely that high dose chemotherapy will be laid to rest without an answer.
Jonathan A Ledermann
BSc MD FRCP
Consultant in Medical Oncology, University College London and Royal Free Hospitals Hospitals, London
