Medical updates

Two views of the latest study results
Reports from ASCO

From Jean Mossman of CancerBACUP
At this major cancer conference, the results from two new studies - the European OVAR-3 and the USA GOG-158 - showed that Taxol plus carboplatin administered over a three-hour infusion period is as effective as Taxol plus cisplatin given over 24 hours, with fewer side effects. This is good news for women with ovarian cancer.

Dr Bill McGuire from the University of Mississippi said that, in his opinion, the gold standard of care in ovarian cancer should now be a three-hour Taxol-carboplatin infusion. He went on to say that carboplatin alone, or CAP, both of which are often still used in the UK as first-line therapy, are "suboptimal" forms of treatment on the basis of current data (although it may be appropriate to use single-agent carboplatin in patients unable to tolerate Taxol and platinum).

In the UK, guidelines for the treatment of ovarian cancer were due to be published this spring, but have still not appeared. At ASCO, ICON-3 was presented prematurely, before survival data are available, and I very much hope these results will not be allowed to affect the guidelines (which are expected to recommend that Taxol plus a platinum drug should be first-line therapy).

I don't think that there was any underlying political agenda behind the decision to report the early findings from ICON-3. In fact, the Department of Health has been willing to listen to the evidence; we now need them to issue guidance to individual Health Authorities and Trusts that Taxol and platinum should be made available to all women who need it.

The UK government has recently launched an ambitious plan to cut deaths from cancer in people under 75 by 20% over the next 10 years: they should make the money available to achieve this.

From Dr Richard Needle
Chief Pharmacist, Colchester General Hospital
The Annual Meeting of ASCO, the Americal Society of Clinical Oncology, is the pivotal meeting of the year for innovations in cancer therapy, with nearly 20,000 delegates attending this year's meeting in Atlanta, Georgia.

One of the most interesting sessions of the second day was the gynaecological presentation, which attracted over 1000 delegates, many of whom had to stand around the walls of the hall. Two studies, GOG-158 and a German study, AGO, both looked at paclitaxel/cisplatin versus paclitaxel/ccarboplatin and concluded that, with the exception of neurotoxicity, carboplatin regimens were better tolerated.

The preliminary results of the ICON-3 studies were also presented, showing, at an early stage, no apparent difference between the control arms, CAP and carboplatin and the carboplatin/paclitaxel arm. There is no clear-cut reason for this apparent difference from the results of the GOG-111 and intergroup studies, although with further maturity the picture may change.

Surprisingly, no questions were asked of Dr Peter Harper, who presented the results, But Dr Bill McGuire, who summarised the sessions, emphasised the immaturity of the study and concluded by asserting that paclitaxel/carboplatin should still be the first-line treatment of choice.

Menopause, HRT and You

Some of you may recall that I asked members to help with a book on HRT for "women of all ages". The good news is that The Menopause, HRT and You will be published by Penguin on 26 August, as "an up-to-date and practical guide for women of all ages". Inside are chapters on different types of menopause: natural, premature, surgical and medical, and women who lack hormones from an early age due to genetic conditions.

The surgical menopause chapter describes problems which may lead to oophorectomy and explains why this causes an early menopause for younger women. It ends with personal stories from women who have faced this experience due to recurrent cysts, endometriosis and ovarian cancer. Two of these stories are by members of Ovacome.

My special thanks go to Betty, Teresa, Angela, Clair, Lynnette, Frances, Ali, Andrea and everyone else who wrote to me. In particular Clare Duchen offered her editing skills. I am also grateful to Alex Whates for replying after I'd read about Ovacome in Good Housekeeping. This article caught my eye because a friend of mine had ovarian cancer and I wanted to make a bequest. So it has been a personal pleasure to work with Ovacome and see it go from strength to strength.

For new members, my professional background is health education and my first book was Living with Endometriosis (Vermilion). My interest in HRT began after my surgical menopause, aged 36. During my search for relevant information, I realised that a surprising number of younger women need HRT.
Caroline Hawkridge
Cheshire

Richard Osborne reponds to Dr Schellander's specific comments and explores the reasons for differences in opinion between them

Intraperitoneal Hyperthermia

We agree that sound scientific studies suggest that hyperthermia and intraperitoneal chemotherapy may be useful for patients with ovarian cancer. The point I was at pains to make is that, unfortunately, the true value (compared with the possible value) of these two forms of treatment has yet to be scientifically conclusively proved. Hence it is foolhardy to adopt such therapies, with their undoubted toxicities, until "superiority" implies an overall improvement in outcome which may involve an increase in some aspects of the risk of a treatment, if the pay-off in terms of survival is worthwhile. Clearly these are difficult calculations to make. (An example of a superior treatment would be Taxol plus carboplatin, compared with carboplatin alone, because the significant added toxicity of Taxol, hair loss and nerve damage, is outweighed by a large improvement in duration of survival.)

Unfortunately the medical literature is littered with examples of "good ideas" with an element of scientific merit which are adopted enthusiastically, but which are later found to have major deficiencies. The "experience" of apparent experts with new treatments has often been shown to be a very poor predictor of the true value of the therapy. Hyperthermic intraperitoneal chemotherapy for ovarian cancer may be found to fall into this category.

In response to Dr Schellander's statement that "all chemotherapy agents are highly toxic in systemically used therapeutic doses", I would point out firstly that this is not correct for all anti-cancer drugs, and secondly that chemotherapy is among the most thoroughly studied treatments in medical practice. Chemotherapy drugs are used in a particular fashion for excellent reasons. Major adjustments in dose, route of delivery or frequency of administration cannot be safely introduced until they are shown to result in superior effects when compared with the standard regimen. There is certainly no evidence from randomised trials that hyperthermic chemotherapy has any advantages over conventional intravenous therapy in any patient with ovarian cancer.

Fortunately, in the modern era, these sorts of lessons have been learned by clinicians who devote themselves to pushing forward the boundaries of treatment. The clinical trial is the optimum tool for achieving this aim. As a scientist with a well developed sense of scepticism and a finely honed ability to analyse clinical trial design and methodology, I am convinced that the steps taken to protect the interests of patients in such trials are very carefully considered. There is no doubt that some interventions in clinical trials carry risks, but these are not uncritically accepted by the designers and reviewers of trials. Every attempt is made to minimise risk and inconvenience. The policy of informed consent specifically aims to ensure that patients can make educated decisions about whether the possible benefits of trial participation outweigh the drawbacks, from their individual perspective.

Because of the deficiencies of current treatments, patients should be counselled to enter clinical trials as a way to ensure that they have access to the optimal management for their condition, while minimising risks from ad hoc treatments. The failure of previous trials to demonstrate a benefit is certainly not a reason for avoiding future research, as suggested in Dr Schellander's paragraph. Obviously, some patients will find the clinical trial approach unsuitable for them as individuals, and are best served by providing access to optimal, established therapy. Those who wish to pursue unproven therapies, for whatever reason, should be informed of the risks and possible deficiencies of such approaches, but all doctors should leave an open door so that this group continue to have access to conventional medicine as and when they wish.

To conclude, it appears to me that there are three major differences between my stance as a scientific oncologist, and that of Dr Schellander: first, my willingness to be cautiously sceptical about apparently promising new therapies; second, my readiness to accept the science behind established treatments; and third, my confidence in the validity and merits of the clinical trial process. Happily, we both agree that there are research areas which must be encouraged to allow the future of anti-cancer treatment to improve.
Richard Osborne

Treatment-induced menopause due to ovarian cancer:
Facing the issues

What is the menopause?
The menopause is a natural process, during which oestrogen levels gradually fall, and follicle-stimulating and luteinising hormone increases. As a result, the woman's periods become irregular, and eventually stop altogether. She may experience physical and psychological changes and there is a risk of osteoporosis and heart disease (see Table 1).

The average age for the menopause is 50 years, and a woman is described as post-menopausal when her period has not returned for one year.

Some treatments for gynaecological cancer may lead to premature ovarian failure, and induce early menopausal symptoms.

Chemotherapy
The impact of various chemotherapeutic agents (listed in Table 2) is dependent on:

• Type of drug: some are known to be more toxic on ovaries
• Dose: high doses increase risk of ovarian failure, though this is unpredictable
• Drug combinations: increased toxicity to ovaries with more than one drug
• Age: increased risk of ovaries failing over the age of 35. Younger women are also at risk, but may be several years later
• Fertility status/previous treatments: in the general population 1-3% of all women under 40 years experience premature ovarian failure (no known cause). Previous gynaecological problems may reduce ovarian function before cancer treatment

Surgery

• Both ovaries removed (bilateral oophorectomy): sudden onset of menopausal symptoms can occur postoperatively.
• One ovary removed or simple hysterectomy: even when one ovary remains, there may be an advanced onset of the menopause, but this does not usually occur immediately.
• Oophoroplexy (moving the ovaries): surgical transposition may alter the blood supply to the ovaries, and can induce a premature menopause. However, this is uncommonly used in the treatment of ovarian cancer.
• Pelvic radiotherapy: ovaries are markedly susceptible to radiation effects, but this is dependent on two factors.
  (a) Radiation dosage: two to three fractions can results in premature infertility and ten to 13 fractions can induce an early onset menopause. Symptoms may not always occur immediately, but more commonly occur within a few months of treatment.
  (b) Women's age: radiation tolerance of the ovaries is reduced over age 35 years, but all women undergoing pelvic radiotherapy are at risk of the ovaries failing.

What is a treatment-induced premature menopause?
This differs from a natural menopause, as there is a sudden rather than gradual change in hormone levels as a direct side effect of cancer treatment. How quickly this occurs will vary from woman to woman and depending on the treatment: for example, surgical removal of the ovaries has an immediate effect, but after chemotherapy and radiotherapy it may be several months before symptoms occur (see Table 2).

A woman is described as prematurely menopausal when she experiences a sudden onset of symptoms, her periods stop, and do not return within a year. At a time when a woman is undergoing change and personal challenge relating to a cancer diagnosis, the treatment and its side effects, the overall impact of the menopause may be exacerbated. With an early induced menopause the woman has a prolonged period without the natural benefits of oestrogen, so she may wish to consider how to manage the change. There are many choices, and this article will focus on lifestyle and non-hormonal management.

What can you do to help yourself?
Each woman is different, and symptoms, severity and duration will vary, and may determine the management option you choose. Some choices are based on other women's experiences of what they found useful, and anecdotal evidence rather than proven research trials.

Hot flushes
This is the most common symptom, and affects four in five women. Flushes can occur at any age if oestrogen levels are reduced, and vary in severity and duration. You may wish to try the following:

• Keep a diary of your hot flushes: you may see a pattern developing. You may have more hot flushes at a particular time of day or in a particular situation. You may be able to avoid activities at those times or avoid some situations if you feel they exacerbate the frequency of the flushes.
• Choose clothes carefully: wear natural fabrics next to the skin rather than synthetic. Cotton nightclothes and bedlinen may be more comfortable, particularly if you suffer from night sweats. Loose clothing in layers will enable you to remove them more easily during a hot flush.
• Find ways to cool down quickly: keep iced water nearby, use a spray such as "Evian spray mist", and carry a small fan or a pack of moist wipes. Take cool showers and keep rooms well ventilated, particularly at night if prone to night sweats.
• Cut down on smoking (if possible stop completely): it is reported that the first puff of each cigarette can trigger hot flushes.
• Regular exercise improves circulation, and may help reduce the intensity and frequency of hot flushes as the body adapts to coping with extremes of temperature.
• Limit foods and drinks which trigger hot flushes and night sweats. These may include spicy hot foods, salty dishes, sugary goods, chocolate, alcohol, tea, coffee and soft drinks containing caffeine. Limiting hot drinks late at night may help to reduce night sweats. These affect the blood vessels, and make you prone to flushing.
• Relaxation techniques: any exercises which help you unwind and reduce stress may help your hot flushes. Deep breathing exercises, visualisation and listening to relaxing music or tapes may be useful.
• Complementary therapies - aromatherapy, homeopathy, massage, reflexology, herbal medicine, acupuncture and yoga - may promote a feeling of well being during the menopause, and help you cope with hot flushes. It is essential to consult a qualified therapist specialising in the field, and liaise with your doctor.
• Gammalinolenic acid (GLA) is found in evening primrose oil and efemast, and many brands are available, containing various amounts of GLA. Always follow the instructions regarding daily dose, or check with your doctor or nurse. Many women report that they find these oils useful in reducing hot flushes; however, research has not proved their value.
• Women have reported benefits from vitamin B6 (pyridoxine) during the menopause. However, a placebo response has been thought likely, and research has not proved its suggested benefits in reducing hot flushes. It is important that you check with your doctor before using vitamin B6, and it should only be taken in small dosages (check recommended dose on packet). Side effects have been reported with high doses.
• Clonidine (Dixarit) may reduce the severity and frequency of hot flushes. Like all drugs, it may cause side-effects; dry mouth, dizziness and nausea have been reported. Clonidine is used less and less to treat hot flushes during the menopause, as new studies indicate its effectiveness is low.
• Progesterone may be prescribed to relieve hot flushes. Side effects include abdominal bloating, breast tenderness, increased appetite and mood swings. It is usually only prescribed short-term for hot flushes and it may not suit every woman.

Vaginal dryness

• Water-based lubricants such as KY jelly (available to buy over the counter), Replens (available to buy over the counter) and Astraglide (available by mail order) are recommended rather than oil-based ones.

Osteoporosis
The National Osteoporosis Society recommends the following daily allowances of calcium for menopausal women:
Without HRT  1500 mg
With HRT       1000 mg
The body absorbs calcium from food better than from calcium supplements.

Bisphosphonates. Two bisphosphonates, etidronate and elendronate, are currently licensed for the treatment of established osteoporosis. Controlled clinical trials show they may offer long-term prevention of bone loss, by trying to prevent the natural turnover of bone.

However, they are poorly absorbed and must not be taken at the same time as any other medication or calcium supplement. Some women may find them difficult or inconvenient to take. Reported side-effects include nausea, abdominal discomfort and skin rashes.

Etidronate (Didronel) may be prescribed by a doctor, and is taken on a 90-day cycle: 400 mg etidronate disodium daily for 14 days, followed by a 500 mg calcium supplement for the next 76 days. The cycle is repeated and continued for a recommended three years. It is taken with water or fruit juice, on an empty stomach two hours before food.

Alendronate (Fosamax). This is stronger than etidronate, and also needs to be prescribed. Dosage is 10 mg daily, on a continuous basis. It needs to be taken with a full glass of water 30 minutes before breakfast, and you need to remain upright for 30 minutes after each dose. Research has shown an increase in average bone mineral density with its use.

Raloxifene (selective oestrogen receptor modulator), widely known as "SERMS", is the latest non-hormonal treatment to prevent bone loss. Early research indicates that raloxifene may protect against cardiovascular disease and osteoporosis, with no known risk of causing cancer of the womb or breast. Raloxifene (one of the first SERMS) is now licensed for the prevention of osteoporosis in the UK. However, all the currently available SERMS can cause hot flushes and sweats and there is no evidence that they alleviate the other physical or psychological symptoms that women may experience due to a premature menopause.
Karen Summerville
Specialist Gynae-Consultant Nurse

Table 1. Symptoms and risks associated with the menopause
Short-term/immediate symptoms

• Hot flushes
• Mood changes
• Night sweats
• Poor concentration
• Poor memory
• Anxiety
• Palpitations
• Irritability
• Insomnia
• Loss of self-esteem 
   

Intermediate symptoms

• Vaginal dryness/painful intercourse
• Skin thinning/dryness
• Loss of sex drive/desire
• Incontinence/bladder symptoms
• Joint aches and pains
• Infertility

Long-term risks

• Heart disease
• Osteoporosis
• Possible risk of Alzheimer's disease

Table 2. Impact of various chemotheraputic agents on the ovaries
Severe effects on ovaries

• Chlorombucil
• Cyclophosphamide
• Busulfan
• Melphelan 
   

Moderate effects on ovaries

• Cisplatin
• Adriamycin
• Carboplatin
• Etoposide
   

Less effect on ovaries

• Methotrexate

Unknown effects on ovaries

• Taxanes
• Caelyx
• Topotecan

Research on these newer drugs is limited, but they are thought to have a moderate effect on ovarian function. However, there remains a degree of uncertainty

Useful addresses

The Amarant Trust
Head Office and Clinic, 80 Lambeth Road, London SE1 7PW
Tel: Office 0171 401 3855 Helpline 01293 413000

The National Osteoporosis Society
PO Box 10, Radstock, Bath, Avon BA3 3YB
Tele: Office 01761 471771 Helpline 01761 472721

Women's Nutritional Advisory Service
PO Box 268, Lewes, East Sussex BN7 2QN
Tele: 01273 487366

Suggested reading
Miriam Stoppard: The Natural Menopause. Dorling Kindersley. £4.99
Dr Anne MacGregor: Is HRT Right forYou. Sheldon Press. £9.90
Dr Anne MacGregor: Understanding the Menopause. British Medical Association. £2.99
Dr Robert CD Wilson: Understanding HRT and the Menopause. Which? Consumer Guides. £6.99
Healthy Eating: A Guide for Cancer Patients. Hochland Communications (0161-929 0190)
Overcoming Eating Dificulties. Hochland Communications (0161-929 0190)