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NICE to evaluate Taxol

There is overwhelming international clinical opinion that paclitaxel (Taxol) should be part of routine chemotherapy for ovarian cancer. Of course, this does not mean everyone should receive Taxol; in some women illness will be diagnosed early and surgery alone is sufficient, while for patients with other medical problems or in old age, Taxol-based treatments may have too many side-effects to justify their use

Why then is the National Institute for Clinical Effectiveness (NICE) reviewing the use of Taxol in ovarian cancer?

NICE is an expert committee chaired by Sir Michael Rawlins and instructed by the government to provide advice on the appropriateness of routine treatments, particularly clinical developments such as new medicines. NICE has only recently started to function and soon hit the front page of the newspapers with its decision not to recommend a new treatment for influenza.

Concern has been raised that NICE is there simply to control budgets and slow down the increase in drug expenditure that most of us feel is so badly needed in the NHS, particularly for cancer. However, I believe this is an unfair judgement at this stage and we need to see the outcome of the first thirty treatments that NICE will evaluate over the coming months.

The decision to review the use of Taxol in ovarian cancer should not cause concern to those about to embark on this treatment or the several thousand patients treated over recent years. Indeed, I wish more of the many new cancer treatments were on the list of treatments to be evaluated because, without the support of NICE, I fear that many developments will be held back in the UK compared with the rest of the developed nations.

The evidence from the published clinical trials clearly indicates that Taxol improves the life-expectancy of patients with ovarian cancer. Providing NICE takes into account all the evidence and specialist advice, confirmation of previous national guidance from the Standing Medical Advisory Committee and the Joint Clinical Council for Oncology supporting the use of Taxol can be expected.
Recently, preliminary results from the Medical Research Council ICON 3 trial evaluating Taxol have been reported at various conferences. These suggested that the benefits of Taxol were not as great as those seen in the previous trials. However, it is important to realise that preliminary results are often misleading: I was recently pleased to hear that the trial co-ordinators have agreed that full publication of the ICON 3 results should be delayed until more mature, reliable results are available.

Additionally, trial results always vary due to chance and, because of this, statistical techniques to combine the results of trials have been developed to obtain an overview of the evidence. It was this type of statistical overview in the 1980s which removed the uncertainty about the use of adjuvant chemotherapy in breast cancer and led to the widespread use of this treatment in many women and a saving of thousands of lives. I am sure that a similar statistical approach to the Taxol trials will be performed in the not too distant future.

Hopefully, an endorsement of the use of Taxol in ovarian cancer will end the arguments still ongoing in some parts of the country between cancer centres and health authorities about the funding of Taxol and eliminate postcode prescribing.

There is still much to learn about the use of Taxol; weekly treatments may have some advantage over the usual three-weekly schedule and it many be worthwhile adding additional drugs to the current combination of carboplatin and Taxol. The pharmaceutical industry has a responsibility to show that a new drug has advantages over existing treatments and acceptable side effects. This has been achieved with Taxol.

It is now up to ovarian cancer specialists, with support from NHS research and development funds, to refine its use and achieve the best possible outcome for ovarian cancer patients. Routine availability of Taxol in the NHS will enable us to build on the improvements achieved in recent years.
Professor Rob Coleman
Cancer Research Centre, Weston Park Hospital, Sheffield

 

Meeting of UK ovarian cancer specialists reveals major research effort

The major research effort being put into ovarian cancer was illustrated at a recent meeting - Key Advances in the Effective Management of Ovarian Cancer - at the Royal College of Obstetricians and Gynaecologists in London (19 October 1999). New recommendations on treatment and a wide range of new clinical trials were discussed.

A central theme was the need to individualise treatment for each woman because of the great variations in ovarian cancer. "Patients with ovarian cancer are a very heterogeneous population. This is not one disease with one behaviour," warned Dr Martin Gore, Consultant Cancer Physician at the Royal Marsden Hospital in London. In a talk on first-line medical treatment, he suggested that platinum-based chemotherapy should form the basis of treatment.

The role of Taxol (paclitaxel) in ovarian cancer was discussed at some length. Dr Gore clarified the position on one trial - ICON-3 (International Collaborative Ovarian Neoplasms study 3); early results were recently presented in America, leading to some controversy. Researchers presented early results at 18 months, suggesting that adding Taxol to platinum-based chemotherapy achieved smaller benefits than had been seen in recent trials. He pointed out that this was too short a time for the results to be meaningful.

Even at this very early stage, plotting data for women with advanced disease at 18 months showed a positive result for Taxol. But Dr Gore concluded: "The data need to be left until it is appropriate to analyse them for all subgroups. Five published examinations of the data have argued that the standard therapy for advanced OC is platinum-Taxol." One researcher from the trial agreed: "ICON-3 presents interesting results, but no clear results for the moment."

National Guidance on Gynaecological Cancers
Professor Robert Haward, Professor of Cancer Studies at the University of Leeds, explained how recent National Guidance on Improving Outcomes in Gynaecological Cancers was developed. "Expert groups were set up for each type of cancer to come up with detailed recommendations based on all available research." Key recommendations were:

"Ovarian cancer will primarily be managed at specialist centres. Evidence suggests that care is generally better when provided by specialists and women are willing to travel to obtain the best possible care," said Professor Haward. He suggested that surgery is the cornerstone of ovarian cancer treatment but that chemotherapy can also improve life expectancy.

One section of the guidelines causing most debate with the Department of Health concerned Taxol treatment. The guidance recommended that "women with advanced ovarian cancer and some women with earlier stages of the disease should be offered appropriate chemotherapy. Paclitaxel (Taxol) and carboplatin should be standard therapy unless there are particular concerns around toxicity in relation to individual patient fitness; in these circumstances, carboplatin may be appropriate. These recommendations will be reviewed when the results of ICON-3 are mature." He argued that health authorities were acting inappropriately by refusing to fund Taxol in ovarian cancer if they claimed that was what the Guidance advised. "Purchasers are using early data from the ICON-3 trial to deny Taxol to half the patients in this country," added Dr Gore.

Current clinical trials
Dr Jonathan Ledermann, Reader in Medical Oncology, The Royal Free and University College Medical School, London, outlined ongoing UK and international trials in ovarian cancer, looking at:


It was noted that the NHS research and development programme is now giving more help to cancer units enabling them to take part in cancer trials.

There was some discussion about surgery for ovarian cancer, with general agreement that surgery improves survival in advanced disease although very extensive surgery had to be weighed up carefully. "The extent of surgery needs to be carefully judged for each woman," suggested Mr Angus McIndoe, Consultant in Obstetrics and Gynaecology at the Hammersmith Hospital, London. Retrospective studies had suggested that debulking surgery (reducing tumour size) can improve survival slightly. A randomised trial is looking at this issue in younger women who relapse after more than 12 months of treatment-free survival after initial surgery and chemotherapy. They are then randomised to surgery followed by chemotherapy or chemotherapy alone.

Will early chemotherapy help in recurrence?
A new test is being examined to see if using a blood test to provide 'early warning' of relapse followed by prompt chemotherapy is better than waiting to treat until symptoms of recurrent disease become apparent. The study (MRCOVO5) is randomising patients in complete remission within three years of first-line platinum-based chemotherapy to three-monthly follow-up for levels of CA125 - a chemical in the blood, which increases in ovarian cancer. Once this reaches twice the upper limit of normal, patients will be randomised to two groups. In group one, patients' doctors will be told of the increase and start immediate treatment for recurrence. In the second group, doctors will not be told and patients will start treatment once recurrence causes symptoms.

This may seem unfair on the second group, but the trial is needed because it is not yet known if early treatment of recurrence brings any benefit. "Chemotherapy can cause unpleasant side-effects so it is currently considered good practice not to treat until recurrence is causing symptoms," explained Dr Chris Poole, Macmillan Senior Lecturer in Medical Oncology and Palliative Care, University Hospital, Birmingham. The problem with this approach is that the first symptom of relapse may be bowel obstruction, and chemotherapy after this will not help. "Earlier treatment, before obstruction occurs and while the tumour burden is relatively low, may be better. The trial will investigate whether this is so."

Screening women at high risk
Professor Ian Jacobs, Professor of Gynaecological Oncology at St Bartholomew's Hospital, London, reviewed the latest developments in screening for ovarian cancer in women at high risk. He noted that women at high risk include those with two or more first-degree (mother or sister) relatives with ovarian cancer or one first-degree relative with ovarian cancer and one with breast cancer (under the age of 50 years). Screening is based on measuring CA125 (which is increased in cancer) and carrying out an ultrasound scan to detect abnormalities in the ovaries. "However, we don't yet know if regular screening reduces mortality in high risk women," he warned. The UK Familial Cancer Screening Trial started one year ago and is collecting data systematically to develop an ovarian screening strategy. A total of 3000 volunteers registered with the UK Familial Ovarian Cancer Registry will undergo regular testing for CA125 and ultrasound as part of the five-year study.

For more information about any of the trials in this report, contact the Medical Research Council (020 7636 5422) or for further information on ovarian cancer and its treatment contact CancerBACUP (tel: 0808 800 1234).

 

Screening for sporadic ovarian cancer

One way of fighting cancer is to detect it in the pre-cancerous or early stage before it causes symptoms and when it is easier to treat. This involves screening healthy people. Cervical cancer is one cancer where this policy has been successfully introduced and shown to save lives. Ovarian cancer is another cancer where screening may be effective. This article aims to address the issues involved in screening for ovarian cancer in the general population. A future article will address screening for ovarian cancer in women at increased risk due to a family history of ovarian or breast cancer.

Why screen for OC?
Ovarian cancer is the fourth commonest cause of death from cancer amongst women in the UK. The majority of women unfortunate enough to develop it have few symptoms until it has spread outside the ovaries. By this time it is difficult to treat, even with modern surgery and chemotherapy. In contrast, the outlook is good for the small proportion of women diagnosed before disease has spread and when treatment is simpler. The aim of screening is to detect the disease in the early stages before it produces symptoms.

Who should be screened for sporadic OC?
Deciding whom to screen is important. Even with cervical cancer, where mass screening is the norm, age is used to define the screened population. In the UK, screening is limited to women between 20 and 64 years. Only 9% of deaths from OC occur before the age of 50; after this incidence and death rate increase steeply. OC accounts for 1 in 20 of female deaths from all causes in the UK in the 50-59 age group; incidence and mortality remain high in the 60s and 70s. Screening studies for ovarian cancer in the general population have therefore involved women aged 50 years and over. As screening strategies are accurate in post-menopausal women, we recommend limiting screening to after the menopause.

What screening methods are available?
Over the last two decades, two strategies for screening for ovarian cancer have emerged. One method uses ultrasound scanning, similar to the scans used in early pregnancy, to screen all women. The ultrasound probe is placed in the vagina to obtain a detailed picture of the size and texture of the ovaries. The ovaries' appearance depends on the woman's menopausal status. Cysts and changes in ovarian size are common during the menstrual years, making ovarian scans more difficult to interpret. If cysts are found, it is sensible to repeat the scan after six to eight weeks to see if the changes are a result of normal hormonal fluctuations in the menstrual cycle. After the menopause, the ovaries are inactive and scans are easier to interpret.

Twelve ultrasound trials of screening for ovarian cancer in the general population have been reported. A high proportion of cases of ovarian cancer were detected before symptoms developed.

The disadvantage of ultrasound screening is that, for each case of OC detected, about 20 women without ovarian cancer are suspected to have the disease and undergo surgery. In an attempt to reduce these numbers, colour doppler imaging (CDI) was introduced. Cancers contain new blood vessels with abnormal blood flow patterns. CDI detects these altered patterns to differentiate cancerous tumours from normal and benign ovarian cysts. So far the promise of the ability of CDI to differentiate between malignant and benign ovarian masses has not been sustained as many benign tumours also have abnormal blood flow patterns.

The second screening method involves measuring a substance in the blood called CA125, which is released in large amounts into the circulation by ovarian cancer cells. Blood levels of CA125 are also elevated in other cancers (pancreas, breast, bladder, liver and lung), as well as in benign disease (diverticulitis, uterine fibroids, endometriosis) and normal conditions like pregnancy and menstruation. Fortunately in post-menopausal women many of these non-malignant conditions do not occur, making it a more effective marker. Elevated CA125 in a post-menopausal woman has been shown to be associated with a 36-fold increased risk of OC. With this screening strategy, the small group of women with a raised CA125 have ultrasound to assess their ovaries. The advantage is that for each case of ovarian cancer detected, only four or five women without ovarian cancer are suspected to have the disease and undergo surgery. The disadvantage is that the strategy does not detect all cases of ovarian cancer in the screened women. The strategy has been further refined by using a more sophisticated approach to interpretation of CA125 results. Decisions about whether to perform an ultrasound scan are now based upon the pattern of CA125 over time rather than a single measurement. Interpretation of scan findings in women with elevated CA125 levels has also been refined.

Women suspected to have ovarian cancer based on either screening strategy undergo inspection or removal of the ovaries either by keyhole surgery (laparoscopy) or formal laparotomy to make a final diagnosis of ovarian cancer.

What are the problems associated with screening?
Ideally, the screening methods should detect only those women who have ovarian cancer, i.e. true positives, and no women with the disease should be missed, i.e. there should be no false negatives. In reality, no such ideal screening protocol exists. Using the screening strategies described above, it seems likely that over 80% of women with ovarian cancer will be identified before they have symptoms. Some women with ovarian cancer will be missed in spite of screening. In addition, as described above, the tests will be positive in some women who do not have cancer (false positives) and these women will undergo unnecessary surgery with its associated risks and complications before they can be told definitely that they do not have the disease. There are also the cost and logistics of providing such a programme on a national scale.

What questions have been answered?
Large trials involving over 60,000 women have shown that, by screening apparently healthy women, we can detect ovarian cancer before symptoms develop. Early this year, preliminary evidence was published in The Lancet from St Bartholomew's Hospital that such screening can prolong life in women with ovarian cancer. However, it still remains to be proved that screening for OC saves lives as opposed to prolonging life. The problems that arise from screening - in terms of anxiety and trauma to women who are wrongly thought to have ovarian cancer (false positives) and those who are wrongly reassured that they do not have it (false negatives), as well as the financial implications of large-scale screening are yet to be fully explored.

What's needed next ?
A major trial is required to answer the crucial question of whether screening can reduce deaths due to ovarian cancer in the general population. The Medical Research Council is currently considering a proposal for such a trial of ovarian cancer screening in the general population. The new trial, if it proceeds, will involve 200,000 post-menopausal women in the UK and will directly compare women undergoing screening using ultrasound, women undergoing screening using CA125 and a control group of women not undergoing screening. The trial will take 10 years to complete and will also provide data on the physical and psychological side effects of screening and the costs of running such a programme.

What is the current recommendation?
While there is definitive evidence that screening can detect ovarian cancer, it is not yet proved that this leads to lives being saved. In addition, the side effects of screening in terms of psychological and physical morbidity are not known. Therefore, at present, screening for ovarian cancer should not be offered to the general population.

Usha Menon
Ian J Jacobs
St Bartholomew's Hospital, London

Editor's Note: Trials are also taking place at ERTOCS centres in Aberdeen, Manchester, Middlesborough and Derby. The telephone number for the Derby centre is 01332 625647.

 


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