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Journal Article Summary Service
November 2005
Breast cancer advances
Deaths from breast cancer are decreasing. In developed countries the rate has dropped from 50 per 100 000 women in 1970 to below 40 per 100 000 at the turn of the century. The reasons for this decline in mortality are prevention, together with improvements in detection and treatment. Prevention, attributable to the number of pregnancies and breast feeding is dependent on population attitudes, as are behavioural factors such as exercise and obesity.
The detection debate continues, with the pendulum swinging towards screening mammography. The arguments are around the quality of screening programmes -equipment, interpretation and the selection of who is screened, at what age and how frequently.
The United States guidelines of starting screening women in their 40s are not shared internationally as menstrual changes in breast tissue and lower prevalences of the disease during this decade make the returns less attractive, with higher frequencies of false positive diagnoses with their attendant morbidity.
Digital mammography which is the capturing of the image in electronic format seems to be more efficient in the pre-50s age group when compared with standard film recording storage and reading. Digital mammography's computerisation allows the data to be manipulated as well as transmitted for reading at sites remote from the clinic. However, the costs and availability of the technology are unattractive and women should not be seduced into demanding or paying for an advance that has yet to prove its cost-effective wider application (1).
Screening can only reduce mortality if treatment is effective. Surgery has been modified to include less destructive options, and chemotherapy with cytoxic agents - notably the taxanes - has improved with the introduction of newer agents reducing local recurrence and metastases, but the biggest strides have been in adjuvant chemotherapy, both hormonal and now with monoclonal antibodies.
Trastuzamab (Herceptin - Roche)
Women with oestrogen-receptor positive tumours benefit with adjunct hormonal therapy such as tamoxifen and anastrozole after their surgery and cytotoxic chemotherapy. However, about a quarter of women have aggressive tumours which do not respond well to conventional treatment. This sub-group has been found to have an over-expression of a membrane-receptor called “the human epidermal growth factor receptor 2” (HER2) a protein discovered as the result of genomic research. Producing antibodies to this receptor was imagined to have therapeutic application and clinical trials followed. The reports using trastuzamab (Herceptin) are now published (2, 3) and the results have been a triumphal narrative of translational research.
The new approach has been hugely successful with dramatic differences between the antibody recipients and the controls, to the extent that the trials were halted after the first interim analysis as it would have been unethical to withhold treatment from the controls. The outcomes suggest this revolutionary change will “completely alter our approach to the treatment of breast cancer”.
The order of success was a one-third improvement in survival and a 50% reduction in recurrences after two years, figures seldom encountered in the world of oncology which moved Hortobagyi to call the results “simply stunning” in an editorial (4). Even the editor of the BMJ refers to trastuzamab as the “new wonder drug” (5).
This is encouraging news for breast cancer treatment and now all patients are being screened for the HER2 receptor in the hope of triaging women with this tumour subtype to more appropriate and new style management.
As Berry et al (6) point out; diligent screening programmes plus aggressive management reduce the morbidity and mortality of all types of breast cancer. The long-term outlook is excellent for all patients, with three-quarters of post-menopausal women living for 20 years or more after their diagnosis (7).
Points to ponder
Breast cancer carries with it huge emotional components but it may be helpful to consider it kills 1 in 2000 women - on a global scale - far fewer than HIV/AIDS, malaria, tuberculosis, obesity, pregnancy, unsafe abortions, heart disease, pulmonary embolism, stroke, suicide, homicides and motor vehicle accidents. In the cancer stakes lung, ovarian and pancreatic tumours are far more lethal as are a host of other malignancies.
Breast cancer is not a death sentence with the wider perspective changing in recent years.
Low-dose aspirin does not protect women against cancer - breast, bowel or lung - so that prophylactic door seems to be closed (8).
Is a predisposition to breast cancer part of intra-uterine influences? Many diseases and attributes appear linked to growth trajectories in pregnancy, be it growth-restriction or growth-acceleration. It is a tenuous connection but if this is true, then other manifestations of intra-uterine growth may appear - like left handedness. If you like this theory, then a new report will please you that states that “there is an association (2:1 in favour) of left handedness and breast cancer” (9). JASS finds this a bit too sinister.
- Pisano et al NEJM 2005;353:1773-83
- Biccart-Gebbhart et al NEJM 2005;353:1659-72
- Romond et al NEJM 2005;353:1673-8
- Hortobagyi NEJM 2005;353: pp1734-6
- Godlee - Editor's Choice BMJ 15 October 2005
- Berry et al NEJM 2005;353:1784-92
- www.cancerresearch.org/news/pressrelease
- Cook et al JAMA 2005;294:47-55
- Ramadhani et al BMJ 2005;331:882-3
Hypothermia for neonates
Infants born with cerebral damage often have low apgar scores, a low pH and a raised base deficit. They may have abnormal intrapartum CTG tracings possibly because of a compromised uterine environment when the mother is hypertensive, pyrexial or where complications such as haemorrhage, cord prolapse or uterine rupture have occurred.
The resultant hypoxic-ischaemic encephalopathy carries a high risk of morbidity or death, but it seems cooling the neonate for three days - starting immediately after birth - reduces cerebral damage (Shankaran et al NEJM 2005;353:1574-84). A multicentre trial in the US randomised over 200 babies with a mean pH of 6.9 and a base deficit of 19 to receive routine care or to be cooled to 33.5 degrees C within 5 hours of delivery. These were infants older than 36 weeks gestation, most of whom had shown evidence of intrapartum distress, with the resultant emergency caesarean section rate of 70%.
The research results were impressive with 24% deaths in the hypothermia group and 37% in the controls. Where moderate or severe disability was included, the rates were 44% and 62% respectively. Following up the infants at 20 months there was no increase in disability amongst survivors in each group, with cerebral palsy rates lower in those treated with hypothermia - 19% versus 30%.
It appears a potentially useful intervention if used soon after birth, carefully applied and diligently monitored in a sophisticated special care baby unit.
And while on the topic of cerebral damage, it seems that the duration of labour does not affect outcomes in very preterm infants. Intuitively, it may feel that infants born before 32 weeks could do better if they have shorter labours or caesarean sections, especially if they are in an infected intrauterine environment. However, a study by Locatelli et al (AJOG 2005;193:928-32) does not support such a notion, with the duration of the active phase of labour having no bearing on subsequent cerebral damage.
Gestational age is, of course, strongly linked to neonatal white matter damage, and it is an independent predictor of poor outcome in infants who have preterm rupture of the membranes (pp 947-51).
Big problem
If you doubted the enormity of the obesity epidemic, the journals will give you the big picture. In the US one third of adult women have become obese over the last 30 years, as defined as a BMI over 30. The lifetime risk of being overweight or obese is 80% for white American adults (Ann Int Med 2005;142:473-80).
This trend is reflected in young Scottish women who become pregnant. Kanagalingam et al (BJOG 2005;112:1431-3) showed a two-fold increase in obesity at booking visits over the last decade and the figures are now one in five women. The sequelae are threefold. Firstly, there has been an immediate increase in the rates of pre-eclampsia, diabetes, intrapartum complications and caesarean section rates. Secondly, there are long-term considerations for the mother in terms of her cardiovascular future and, thirdly, the child's risk of being born large and continuing towards overweight in maturity rises.
Reviewing obesity from the fetal growth perspective, Baird et al (BMJ 2005;331:929-31) related weight at birth to the risk of childhood obesity. Obese babies were nine times more likely than normal weight babies to grow into obese adults, and infants who grew rapidly were five times more likely to become obese. This latter growth observation supports the Barker hypothesis that intrauterine growth restriction is linked to cardiovascular disease in later life.
In fact, an article by Barker et al (NEJM 2005;353:1802-9) has expanded the theory of intrauterine “settings” to observe what happens to these infants as they grow. If they have been growth-restricted in utero, there is a catch-up phase during the first two years of life when they have a rapid increase in BMI until they are indistinguishable from their peers as they reach adolescence. However, they exhibit insulin resistance in adult life and this finds expression in the increased risk of cardiovascular events and diabetes. In addition, we now know that preterm infants exhibit similar patterns of growth and suffer from the metabolic syndrome in later life more frequently than normal weight infants.
The American College of O & G Committee on Obstetric Practice has released a report defining the risk factors of obesity in pregnancy and enumerating recommendations for women who are planning a pregnancy or who have conceived. It makes serious reading (Obstets Gynecol 2005;106:671-4).
Complementary and alternative medicine
Complementary and alternative medicine is big business. Chiropractic, homeopathy, osteopathy, acupuncture and herbal remedies constitute the Big Five and seem to have great intrigue, wide followings and considerable profits. Whether they are cost-effective and, therefore, should be included in State-funded services is the present debate. Medical Aids in many countries balk at covering CAM costs and the United Kingdom's National Health Service is weighing the issue.
The problem is that few of the processes in CAM have been subjected to controlled trials and it seems only acupuncture and spinal chiropractic manipulation have been rigorously studied. These do show some benefits in the short-term, but at considerable manpower cost (Canter et al BMJ 2005;331:880-1).
The Smallwood Report, commissioned by Prince Charles, suggests that some traditional CAM methods do provide individual benefit at a reduced direct cost. The problem is the funds required to set up, maintain and regulate the infrastructure and personnel to run the services which would add considerably to the costs of providing these to the public (Thompson & Feder BMJ 2005;331:856-7).
Even a widely-used remedy like black cohosh for menopausal flushes does not stand up to the scrutiny of a placebo-controlled trial (Newton et al Maturitas 2005;16:134-46). The researchers found it is just as effective as placebo and concede that other herbs and supplements, such as soya bean products, have gained popularity without evaluation.
One in ten UK citizens consults a complementary or alternative practitioner every year, possibly because of their holistic approach - but mainly because they believe they will be helped.
Preterm labour
Despite research into the epidemiology of preterm delivery, there has been no reduction into the incidence of preterm births in developed countries. In fact, over the last two decades, there has been an increase until they now constitute 12% of all deliveries in the US (Green et al AJOG 2005;193:626-35).
It remains the major cause of neonatal mortality and morbidity, accounting for one in five children with mental retardation, one in three with visual impairment, and half those with cerebral palsy. The prediction of preterm birth has focused on obstetric history, biochemical or bacteriological markers and cervical assessment by digital and ultrasonic means. No satisfactory screening methods have been found and, where specific risk factors are present, the treatment options are limited.
Cervical cerclage
There is little evidence for the wide application of cervical cerclage in the prevention of preterm birth. Stitches are inserted for specific indications, such as a history of recurrent mid-trimester deliveries, a short cervix detected ultrasonically or digitally, or for high-order multi-fetal pregnancies. No conclusive large studies have been published recently, so individual decisions have to be reached on a case-by-case basis.
Where a stitch has been inserted - for whatever reason - it seems unhelpful to re-stitch in the same pregnancy if the cervix shortens. A study by Baxter et al (AJOG 2005;193:1204-7) showed that re-suturing or adding a second reinforcing stitch gave worse results than expectant management.
Triplet pregnancies, where there is no history of preterm birth, do not benefit from cervical cerclage (Reharber et al AJOG 2005;193:1193-6).
Transabdominal cerclage is indicated where there has been cervical destruction, but it remains a highly specialised manoeuvre. In a series of 40 cases, Farquharson et al (BJOG 2005;112:1424-6) describe a 90% success rate, but warn about dual pathology, such as bacterial vaginosis or antiphospholipid syndrome. It requires strict protocols, early insertion at about 11 weeks, meticulous technique and experience - so the abdominal approach should only be used in the experimental setting.
Progesterone
In women with previous preterm birth(s), giving weekly injections of progesterone significantly prolongs the index pregnancy. Spong et al (AJOG 2005:193:1127-31) have reworked the original data and have shown that most benefit accrues to those with a history of delivery prior to 34 weeks gestation.
17 hydroxyprogesterone caproate given weekly till 36 weeks delays delivery, allowing steroids and natural maturation to benefit the fetus. Speculation about 17P's modes of action are widening from myometrial inhibition to anti-inflammatory or immuno-suppressive activity which ties in with the aetiology of preterm labour often being infectious or inflammatory in origin. The bottom line is that five women with the history of very preterm birth would have to be treated to prevent one subsequent preterm delivery.
Pre-eclampsia
Genetics
There is no doubt there is a genetic component to pre-eclampsia. Women whose mothers had pre-eclampsia are more likely to develop the disease than women whose mothers did not have the disease. It is less clear what triggers pre-eclampsia but two main possibilities are suggested by Skjaerven et al BMJ 2005;331:877-9).
Firstly, a woman may inherit a predisposition from her mother in which case she is more susceptible, meaning her physiology is more vulnerable. Secondly, she could transmit genes to her fetus which trigger the disease in her. If the second mechanism exists, then a father from pre-eclamptic pregnancy could also pass on “trigger genes” to his fetus.
If both mechanisms exist, then mothers from pre-eclamptic pregnancies are much more at risk, but the father from an affected pregnancy will contribute to a lesser degree. The Norwegian birth registry study supports this dual theory as it shows that daughters of pre-eclamptic women have twice the chance of pre-eclampsia, compared with control cases. Where the father was from a pre-eclamptic pregnancy the odds ratio is 1.5. They also note that brothers and sisters can pass on the fetal trigger gene. It also appears that severe early-onset pre-eclampsia has a much stronger genetic component than late-onset pre-eclampsia.
Invasive management
The management of severe, early-onset pre-eclampsia is best handled in a tertiary referral centre. It is a genuine perinatal problem in that buying time for the fetus is essential, while not endangering the mother. This requires sophisticated judgment and sometimes invasive monitoring.
One logical approach is to plasma volume expand these women on the basis that reversing their reduced intravascular volume will allow anti-hypertensives to act without precipitous hypo-perfusion of vital organs and the uterus. Whether this aggressive approach gives better neonatal outcomes is not known, so a randomised trial of plasma expansion versus fluid restriction plus conventional management was deemed ethical, and a study is now reported from The Netherlands (Ganzevoort et al BJOG 2005;112:1358-68).
They studied over 200 patients with severe pre-eclampsia or HELLP syndrome around 30 weeks gestation, split between fluid loading and active anti-hypertensive management that was not invasive. The results were unconvincing with neonatal morbidity similar in both groups, with a trend against volume expansion being helpful. Not all patients had invasive cardiovascular monitoring which seems risky, and certainly the outcomes argue for severe disease to be handled by those with experience in these matters. Certainly giving intravenous fluids to a group of patients already critically haemodynamically balanced cannot be advocated and such manoeuvres should be kept for the research situation and never used speculatively.
SNIPPETS
HELLP history
JASS summarises only data published within the last few months, but an article by Weinstein on the discovery of the HELLP syndrome is a little gem worth reporting. He tells how gutted he felt in 1979 when a patient under his care died of a variant of pre-eclampsia that did not make sense. His pursuit of clinical and biochemical connections which led to the discovery of the HELLP syndrome is now history, but his non-evidence-based observations subsequently are interesting.
He notes that the disease is progressive, non-self-limiting and the patients are usually sicker than they appear. This translates into a high level of suspicion when minor symptoms don't add up. In particular, he advises a very low threshold for requesting platelets or liver enzymes in women presenting with right upper quadrant pain or those who have suddenly started taking lots of antacids! Other advice is to repeat the biochemistry at regular intervals, and especially blood sugar levels, as hypoglycaemia is the killer. He counsels that it is not possible to “run these patients on signs and symptoms”.
Like the Dutch physicians treating severe pre-eclampsia, he believes that intensive monitoring and early delivery are the keystones to the correct management of HELLP. So the message from the present and the past is clear: monitor closely and intervene actively in severe cases (Weinstein AJOG 2005;193:859-63 and 1982;142:159-67!).
Antibiotics for UTIs
If a woman presents with symptoms of a urinary tract infection, should she be given antibiotics? Some say only if the dipstix is positive for leucocytes and nitrites, but others say give the antibiotics any rate.
To try to settle the issue, a trial was done treating - or not treating - women with UTI symptoms but negative dipstix. Three days of trimethoprim 300mg daily reduced the dysuria and general symptoms of fever and rigors. This was research conducted in general practice and the researchers accept that a policy of symptomatic treatment of suspected UTIs may lead to some over-prescription of antibiotics, but this is a pragmatic approach in the primary care setting, and can be safely used in the specialist-care service (Richards et al BMJ 2005;331:143-6).
Extreme parity
Stillbirths occur in 5 -10 per 1000 pregnancies in developed countries. It is not known what influence parity has on stillbirth rates, so Aliyu et al looked at over 27 million birth records in the US over the last decade and analysed the effect of high parity on the risk of stillbirth (Obstets Gynecol 2005;106:446-53).
Adjusting for age, it was clear that up to 10 births did not move women into higher risk categories but after that the risk rose rapidly in a “dose related” curve. Having 18 or more births (!) was associated with a 16-fold increase in stillbirth risk and was unsurprisingly more common in very low education groups.
Another article looking at women less than 35 years of age having 5 to 9 babies found that they actually outperformed primiparous women obstetrically. They were less likely to experience fetal distress, instrumental deliveries, caesarean section or any intrapartum complications. They did, however, have more preterm deliveries and the social implications are simply another story (Ellis Simonsen et al pp 454-60).
And extreme age
Age of first birth is increasing in developed countries, probably because of social and career trends for women. With age, becoming and staying pregnant is harder and over the age of 35 problems arise and over 40 they skyrocket.
Fecundity decreases with age but some women reckon IVF will counter this reproductive senescence, but poorer outcomes of pregnancy multiply with the years. Increased miscarriage, ectopic pregnancy, twinning, chromosomal abnormalities, pre-eclampsia, haemorrhage, preterm rupture of membranes and placenta praevia are all statistically raised. Co-morbid conditions also rise with age, such as obesity, hypertension, diabetes, and labours are more likely to be dysfunctional with caesarean section rates concomitantly raised.
The social and financial implications of pregnancies in older women are difficult to quantify but are highly significant and need to be factored into any discussions on delaying parenting (Bewley et al BMJ 2005;331:588-9).
Extended contraception
There is a trend towards extended regimens of hormonal contraception. Taking the placebo pills after 21 days of active pills to induce a withdrawal bleed is not necessary for contraceptive efficiency - in fact it increases the chances of ovulation - albeit theoretically, and the dogma that women on contraception should menstruate is changing.
Longer cycles - up to 84 days - before the spacer pills are now acceptable and contraceptive patches used weekly are being extended to 12 week cycles (JASS Aug p57). Now the contraceptive vaginal ring is being used for longer cycles and the results of trials of bleeding patterns are reported (Miller et al Obstets Gynecol 2005;106:473-82). Leaving the NuvaRing (Organon) in situ for 21 days then replacing it with another once, twice or more times before taking a break is acceptable if women wish to prolong their amenorrhoea. They may have to tolerate some spotting but they have fewer withdrawal periods with high contraceptive efficiency.
Misoprostol for miscarriage
Another study has shown that misoprostol is as effective as manual vacuum aspiration in the management of incomplete miscarriage (Weeks et al Obstets Gynecol 2005;106:540-7). Ugandan women who were given 600 microg of misoprostol orally had as good outcome after miscarrying as did those evacuated by aspiration, reinforcing the findings other trials that misoprostol is a safe option (JASS Sep p69).
Athol Kent © All rights reserved November 2005 ***SAMPLE***
JOURNAL ARTICLE SUMMARY SERVICE
www.jassonline.com - Summaries of the leading obstetrics and gynecology journals
November 2005
Dear Colleague
Seldom do editorials in the NEJM and BMJ use words like “results were simply stunning” and “exceeding all previously-reported therapeutic benefits in breast cancer” or “new wonder drug”.
This is how trastuzamab treatment of breast cancer reports have been hailed and, indeed, its success is a triumphal narrative of translational research. Genomic research discovered an oncogene that, when over-expressed, transformed normal cells into cancer cells. Raising antibodies against this protein was the crucial step in the development process and it also redefines the natural history of breast cancer - a classic bench to bedside research development (Burstein NEJM 2005;353:1652-4).
In the same issue is an instructive piece on an HIV positive woman and her HIV negative partner who wanted to become parents (pp 1725-32).
The mammography screening debate continues but it seems that digital mammography is not the giant leap forward some had hoped for and at up to four times the cost of conventional film screening it will not have wide application.
Kind regards
Yours sincerely
Athol Kent
MBChB MPhil FRCOG
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