Fertility preservation guidelines overlooked by oncologists

Medical Tribune July 2009 P4
David Brill

The majority of US oncologists do not follow recommendations on discussing fertility preservation with cancer patients, a survey shows.

Although seventy nine percent of respondents reported broaching the subject with patients, less than 25 percent referred them to a specialist or provided educational materials.

Just 38 percent were even aware of the existence of the guidelines, issued by ASCO in 2006. [J Clin Oncol 2006 Jun 20;24(18):2917-31]

The findings could prompt the development of new training programs for physicians and nurses, said study author Dr. Gwendolyn Quinn of the H. Lee Moffitt Cancer Center and Research Institute, Miami, US.

“We send patients to get wigs before they lose their hair during chemotherapy. We give medications to prevent nausea. Discussing fertility preservation should be something else that we do early in a patient’s care, rather than waiting until infertility occurs,” she said.

The survey was mailed to 1,979 oncologists – 613 of whom completed it. Those working in gynecological oncology and hematological/medical oncology were the most comfortable with having fertility preservation conversations. Physicians’ views of fertility preservation were also a key factor: those with a favorable attitude towards preservation were nearly five times as likely to discuss the options.

The main reason given for avoiding the discussion was that patients were too ill to delay treatment. Of greater concern, however, was physicians who skipped it because they did not believe that the patient was going to survive their cancer, said Quinn.

“It’s the patient’s right. It’s their choice. They may never pursue it, and some of them can’t afford it, but just to be given that information is important, and it’s perhaps not the role of the physician to make decisions. The guidelines say all patients – they don’t specify the healthiest of patients or the ones most likely to survive,” she said.

Even those who do not survive may wish to review their options for “posthumous parenting,” she added, noting that many US couples cryopreserve embryos or sperm for this purpose before beginning treatment.

Quinn acknowledged, however, that there can be many barriers to discussing fertility preservation, including financial constraints for the patient, or a lack of physician resources in certain geographic areas.

“It’s important to bring it up very near to the time of diagnosis, but we understand that it’s an emotional time,” she said. Future training could move the emphasis towards nurses, who may be better placed to have an in-depth discussion with the patient, she added.

Statins could boost prostate health, studies show

Medical Tribune July 2009 P4

David Brill

Evidence is growing to suggest that statins could help to maintain a healthy prostate – protecting against both benign and malignant disease.

Recent studies have found that statins lowered the risk of developing prostate cancer, reduced the aggressiveness of cancers, and reduced the risk of cancer recurrence after surgery.

Other reports have suggested that the drugs can protect against lower urinary tract (LUT) symptoms, benign prostatic hyperplasia (BPH) and even erectile dysfunction.

Researchers, however, are urging caution, saying that further studies are needed before firm conclusions can be drawn.

Six key studies were presented recently at the annual meeting of the American Urological Association (AUA) in Chicago, US. Three come from a single cohort of 2,447 men aged 40 to 79, who have been followed since 1990 by researchers at the Mayo Clinic, Minnesota, US.

The first study found that men who were taking statins were three times less likely to develop prostate cancer than non-users. Just 6 percent of statin users developed cancer over a median of 14.1 years of follow-up – a considerable reduction compared to the US national average, which sees around 17 percent of all men diagnosed with prostate cancer in their lifetime.

The second study, which included only 1,480 of the men, found that statins reduced the risk of erectile dysfunction in those aged over 60. This apparent protective effect increased over time – men who had been taking statins for 9 years or more were 64 percent less likely to develop the condition than men not taking statins, whereas those taking statins for less than 3 years were equally as likely.

A third analysis of the Mayo Clinic cohort, meanwhile, reported that statin users had a 57 percent reduction in risk of developing BPH, and a 63 percent risk reduction for developing LUT problems.

"If you are taking a statin for a heart condition or to lower cholesterol, these studies suggest that statins could have other benefits," said one of the study authors Dr. Jennifer St. Sauver, an epidemiologist at the Mayo Clinic. "However, it's very clear we need more information before men are advised to start taking statins for their urological health."

The fourth study presented at the AUA meeting found that men taking statins at the time of radical prostatectomy for prostate cancer were 30 percent less likely to have a recurrence. They also had lower prostate-specific antigen levels than non-users, and were more likely to have T1-stage disease. The study included 1,325 men, of whom 237 were taking statins at the time of surgery.

“Our findings suggest that statins may slow prostate cancer progression after radical prostatectomy," said study author Dr. Robert Hamilton, of the University of Toronto, Canada.

“Although the results of these studies are exciting, they need to be confirmed,” he added. “At this point we cannot say with confidence that statins reduce the risk of prostate cancer recurrence after radical prostatectomy."

The fifth study, led by Johns Hopkins University, US, found that prostate cancer was less aggressive in statin users than non-users. Of 1,282 men who underwent radical prostatectomy over 5 years, the 418 who were taking statins had lower tumor volume, lower prevalence of positive surgical margins, and lower percentage of cancer in their prostatectomy specimens.

The final study, meanwhile, suggests that statins might exert their beneficial effects by reducing inflammation within prostate tumors. Researchers from Duke University Medical Center, US, examined specimens from 254 men who had undergone radical prostatectomy, and found that inflammation was reduced by 72 percent in statin users compared to non-users.

Despite the positive results presented at the AUA, not all studies have shown benefits of statins of prostate cancer outcomes. One paper published earlier this year found that statin usage had no effect on progression-free survival after radiotherapy for prostate cancer. [Urology 2009 Jan;73(1):158-62. Epub 2008 Aug 22]

Some researchers have even suggested that statins could actually increase prostate cancer, and have called for further attention to be given to the issue. [Cancer Epidemiol Biomarkers Prev 2008 Feb;17(2):459]

Gemcitabine improves safety for adjuvant pancreatic cancer therapy

Medical Tribune July 2009 P8
David Brill

Gemcitabine is a safer option than 5-fluorouracil/folinic acid (5-FU/FA) for the adjuvant treatment of pancreatic cancer, results of a phase III trial suggest.

Investigators from the European Study Group for Pancreatic Cancer (ESPAC) found that there was no difference in survival between the two therapies, but fewer side effects with gemcitabine.

The study included 1,088 patients who were randomized to one of the two therapies following resection of pancreatic ductal adenocarcinoma. It is the largest adjuvant trial ever carried out in this patient population and the first to directly compare gemcitabine against 5-FU/FA in the adjuvant setting, the researchers say.

“This study is important because it shows no difference between these treatments in prolonging survival,” said lead author Professor John Neoptolemos, head of surgery and oncology at the University of Liverpool, UK.

“On the basis of the safety profile, however, this trial shows that gemcitabine is likely to be the preferred adjuvant therapy. We are now also looking at combining the two treatments to see if we get a better response, because the drugs have different mechanisms of action,” he said.

After a median of 34 months follow up, overall survival times were 23.6 months for patients receiving gemcitabine and 23 months for those receiving 5-FU/FA.

Ten percent of 5-FU/FA patients experienced treatment-related hospitalization, compared to 3.5 percent of gemcitabine patients. Other adverse events which were more common in the 5-FU/FA group included stomatitis (10 percent versus 0 percent; P<0.001) and diarrhea (13 percent versus 2 percent; P<0.001). Some gemcitabine patients, conversely, experienced a drop in platelet count which was not seen in the 5-FU/FA group (1.5 percent versus 0 percent; P=0.0034).

Gemcitabine is typically used in the US for the adjuvant treatment of pancreatic cancer, whereas 5-FU/FA is the standard in some parts of Europe. It was previously unclear which treatment offered a better prognosis.

The trial, known as ESPAC-3, included patients from 16 countries, who were randomized between 11 July 2000 and 12 Jan 2007. Ages ranged from 31 to 85, with a median of 63.

The results will also help to reinforce the design of the upcoming ESPAC-4 trial, added Neoptolemos. The study is set to compare gemcitabine alone against gemcitabine plus capecitabine – a prodrug which is converted to 5-FU in tumors.

No change needed for anal cancer treatment

Medical Tribune July 2009 P8

David Brill

Radiotherapy combined with 5-fluorouacil (5-FU) and mitomycin-C should remain the standard of care for anal cancer, say UK investigators.

Pull quote: “We recommend that radiotherapy with 5-FU and mitomycin-C remains the standard of care for this condition.”Results of the largest-ever trial for anal cancer showed no benefit from switching mitomycin-C for cisplatin, or from adding maintenance chemotherapy to the regimen.

The Second UK Phase III Anal Cancer Trial (ACT II) included 940 patients (median age 58), followed up for a median of 3 years. Those who relapsed or failed to respond to therapy were treated with surgery.

The results of the trial provide good news, despite the lack of benefit shown by the alternative treatment regimens, said lead investigator Dr. Roger James, a consultant radiation oncologist at Maidstone Hospital, Kent, UK.

“Overall the outcome for patients in this study is excellent, with a 95 percent complete response rate at 6 months and an 85 percent survival at 3 years. These are very good results relative to the international trials published so far. We recommend that radiotherapy with 5-FU and mitomycin-C remains the standard of care for this condition,” he said.

Patients were recruited from 2001 to 2008. All were given radiotherapy and 5-FU, and were randomized to receive either additional mitomycin-C or cisplatin. They were then further randomized: half received an extra round of maintenance chemotherapy, comprising two cycles of cisplatin and 5-FU at weeks 11 and 14, and half did not.

Six-month response rates were 94.5 percent for mitomycin-C and 95.4 percent for cisplatin (P=0.53). Non-hematological toxicity was comparable between the groups, affecting 60.2 percent of mitomycin-C patients, compared to 64.6 percent of cisplatin patients (P=0.17). There was, however, more hematological toxicity in the mitomycin-C group (24.7 percent) compared to the cisplatin group (13.4 percent; P<0.001).>

Maintenance chemotherapy had no impact on 3-year recurrence-free survival rates, which were 75 percent for both groups. Overall survival at 3 years was also not significantly different between those who received maintenance therapy (85 percent) and those who didn’t (84 percent).

The ACT II trial results bring another blow to hopes that cisplatin would prove beneficial in anal cancer. Early data had shown anal tumors to be sensitive to a combination of cisplatin and fluorouacil, but a trial of 682 patients, published last year, found that it offered no survival benefits over mitomycin-based therapy. Moreover, cisplatin-treated patients were almost twice as likely to undergo colostomy as those treated with mitomycin (19 percent versus 10 percent; P=0.02), the US Gastrointestinal Intergroup trial Radiation Therapy Oncology Group reported. [JAMA. 2008;299(16):1914-1921]

Hypertension study named ‘Trial of the Year’

Medical Tribune July 2009 P9

David Brill

The Hypertension in the Very Elderly Trial (HYVET) has been named as 2008’s Trial of the Year, reflecting its potential to change healthcare and “improve the lot of mankind.”

The study found that antihypertensive treatment reduced the risk of cardiovascular events, death from stroke, and death from any cause in over-80s.

The largest clinical trial of its kind, HYVET was carried out against a backdrop of uncertainty about the benefits of blood pressure (BP) lowering in the very elderly.

The award was bestowed recently by the Society for Clinical Trials (SCT) and Project ImpACT (Important Achievements of Clinical Trials). HYVET was also voted Medscape’s most important clinical trial of the year, and named in the American Heart Association’s top 10 advances in stroke and heart disease research for 2008.

“The results of HYVET will have important implications for the generation of future guidelines and mean that very elderly individuals with sustained systolic BPs of 160 mmHg or more should now be appropriately assessed and treated in accordance with these findings,” said trial coordinator Dr. Nigel Beckett, from the Care of the Elderly group at Imperial College London, UK.

Dr. Deepak Bhatt, director of the Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital, US, added: “HYVET is a landmark study that challenges current paradigms which question the risk to benefit of treating hypertension in patients older than 80 years of age. The results of this study should encourage practitioners to treat elevated systolic BP in the very elderly.”

HYVET involved 3,845 patients from 13 centers in Europe, China, Tunisia and Australasia, who had a sustained systolic BP of 160mmHg or more. They were randomized to placebo or sustained release indapamide (1.5 mg), with perindopril (2 or 4mg) to be added if the BP target of 150/80 mmHg could not be reached. [N Engl J Med 2008 May 1;358(18):1887-98]

After a median of 1.8 years of follow-up, treatment reduced the risk of death from stroke by 39 percent (unadjusted hazard ratio [HR] 0.61; P=0.046), death from any cause by 21 percent (unadjusted HR 0.79; P=0.02), risk of any cardiovascular event by 34 percent (unadjusted HR 0.66; P<0.001)>

There were also non-significant risk reductions for outcomes of any stroke (unadjusted HR 0.70; P=0.06) and death from cardiovascular cause (unadjusted HR 0.77; P=0.06) in the treatment group.

The SCT / Project ImpACT awards are given to trials which are deemed, among other criteria, to “have improved the lot of mankind,” and “provided the basis for a substantial, beneficial change in health care.”

Hong Kong symposium: Facing up to the diabetes epidemic

Medical Tribune July 2009 P10
David Brill

The global diabetes epidemic has transcended medical specialties and become a priority for all healthcare professionals, say the organizers of this year’s Hong Kong Diabetes and Cardiovascular Risk Factors – East Meets West (EmW) symposium.

The meeting, to be held in September, will bring attendees up to speed on the latest research into the twin burdens of diabetes and cardiovascular disease (CVD).

With topics ranging from lifestyle interventions and nutrition to the management of diabetes in pregnancy, the symposium promises to deliver a host of practical insights for day-to-day patient care. Leading cardiologists will review strategies for assessing cardiovascular status in people with diabetes, while other sessions will address the crucial importance of good glycemic control, particularly in light of major recent studies such as ACCORD*, ADVANCE** and VADT***.

Other highlights include cutting-edge sessions on the pathogenesis of type 2 diabetes, including pancreatic beta-cell pathology, the developmental-origins hypothesis of diabetes and the role of lipid metabolism in insulin resistance.

“The rate of diabetes is now rampant in Asia, especially in young to middle-aged people. In some countries, the prevalence can be as high as 10 percent,” said Dr. Gary Ko, chairman of the organizing committee for the EmW symposium, now entering its eleventh year.

“The economic burden of diabetes to governments, and the health impact to individuals, cannot be overemphasized. Diabetes can be linked to all systems and specialties. We believe that a good and up-to-date understanding of diabetes is essential for all practicing doctors, be they family physicians, specialists or from other fields,” he said.

“We hope to arouse the attention of our clinicians, particularly those working in Asia, to the increasing epidemic of diabetes, its devastating morbidity and mortality, and what needs to be done to minimize the impact of diabetes and CVD on society.”

Managing weight and diet in type 2 diabetics is just one of the many challenging areas which will be addressed in depth at the EmW symposium, said Professor Ronald Ma, chairman of the EmW scientific committee. He highlighted a presentation by world-renowned endocrinologist Professor Harold Lebovitz, who will introduce a new gastrointestinal ‘pacemaker’ known as Tantalus, which can regulate appetite and help patients to lose weight. Leading Hong Kong nutritionist Ms. Lorena Cheung will offer a different angle – providing insights on how to advise patients on glycemic index and glycemic load.

US obesity expert Professor John Foreyt will also share his knowledge and experience as an investigator on the Look-AHEAD (Action for Health in Diabetes) trial – a successful lifestyle intervention study which helped overweight diabetics to lose an average of 8.6 percent of their weight, improve fitness, reduce medications and lower HbA1C by 0.7 percent, after just one year. [Diabetes Care 2007 Jun;30(6):1374-83]

The ACCORD, ADVANCE and VADT trials have shown the critical need to balance the benefits of blood glucose lowering against potential drug-related side effects, notably weight gain and hypoglycemia. In this session, Professor Brian Frier, of the University of Edinburgh, UK, will give an overview of hypoglycemia: its impact on cardiovascular events and the underlying mechanisms.

Hong Kong expert Professor Terrence Lao, meanwhile, will provide an Asian perspective on the ever-growing problem of gestational diabetes, while Professor Edwin Lee will probe the link between anti-psychotic medications and metabolic disorders. Finally, world expert Professor Edward Fisher will share his wisdom on the rationale and evidence for peer support in the management of diabetes.

Over 600 attendees from all over the world are expected at the EmW symposium, which will take place at the Hong Kong Convention and Exhibition Centre from 30 September to 1 October 2009.

The event is jointly organized by the Hong Kong Institute of Diabetes and Obesity at the Chinese University of Hong Kong, CMPMedica Pacific Limited, the Hong Kong Atherosclerosis Society, the Hong Kong Association for the Study of Obesity and the Hong Kong Foundation for Research and Development in Diabetes, with support from the Hong Kong Dietitians Association.

For more information, see: http://www.eastmeetswest.org.hk/

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*ACCORD: Action to Control Cardiovascular Risk in Diabetes
**ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation
***VADT: Veterans Affairs Diabetes Trial

Singapore moves center stage in childhood vaccine manufacturing

Medical Tribune July 2009 SFI

David Brill

Singapore is set to produce GlaxoSmithKline (GSK)’s new pediatric pneumococcal conjugate vaccine, following the opening of a S$600 million manufacturing plant in Tuas.

Commercial production of the vaccine, which protects against diseases such as bacteremic pneumonia, meningitis and acute otitis media, is expected to begin in 2011.

The new plant is GSK’s first primary vaccine manufacturing facility in Asia, and only the second site in the world to manufacture the pneumococcal vaccine, after Belgium.

It is also one of the first centers in Singapore to produce biologic drugs – a considerably more complex process than manufacture of non-biologic agents. Four other biologics production plants are under construction in Singapore, and five more have been announced.

“The burden of childhood pneumococcal diseases is considerable and every year around 1 million children under 5 years of age die from pneumococcal infections,” said Mr. Emmanuel Amory, vice president, global industrial operations, GSK Biologics. “This plant is part of GSK’s commitment to ensure maximum availability of this life-saving vaccine.”

The pneumococcal vaccine protects children against Streptococcus pneumoniae and Nontypeable Hemophilus influenza – two of the major pathogens responsible for pediatric illnesses, particularly in developing countries.

The opening of the plant in June by Prime Minister Lee Hsien Loong marked the 50th anniversary of GSK’s business in Singapore – an investment which now exceeds S$1.5 billion and sees over 1,000 staff employed here. The company already has two other production and supply centers in the city-state.

GSK’s Chief Executive Officer Mr. Andrew Witty also announced the establishment of a S$30 million endowment fund to support graduate students in healthcare policy and green chemistry. Singapore’s Economic Development Board will add a further S$20 million, bringing the total fund to S$50 million.

Voglibose prevents diabetes in high-risk Asians

Medical Tribune July 2009 SFII
David Brill

Alpha-glucosidase inhibitors could play an important role in preventing, as well as treating, the growing epidemic of type 2 diabetes in Asia.

A recent trial found that adding voglibose to diet and exercise counseling almost halved the risk of developing diabetes in Japanese patients with impaired glucose tolerance (IGT).

The study extends similar findings from Western populations, where acarbose has been shown to reduce the progression from IGT to diabetes – notably in the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial. [Lancet 2002;359(9323):2072-7] Equivalent studies in Asian populations, however, were previously lacking.

The researchers, led by Professor Ryuzo Kawamori, Juntendo University School of Medicine, Tokyo, randomized subjects to placebo or voglibose (0.2 mg three times a day). The trial was terminated early, following an interim analysis. [Lancet 2009;373(9675):1607-14]

At a mean of 48 weeks of treatment, 50 of 897 patients taking voglibose had developed diabetes, compared to 106 of 881 who took placebo (hazard ratio 0.595, 95 percent CI 0.43 – 0.82; P=0.0014). More people achieved normoglycemia in the voglibose group: 559 of 897, versus 454 of 881 in the placebo group (P<0.0001).

Singapore diabetes expert Dr. Kevin Tan said that alpha-glucosidase inhibitors offer a good option in cases which need more aggressive intervention than lifestyle therapies alone.

“The results of this study mirror those of acarbose in STOP-NIDDM and demonstrate the efficacy of this group of alpha-glucosidase inhibitors in preventing type 2 diabetes – now in an Asian population as well,” said Tan, vice president of the Diabetic Society of Singapore and a private practitioner at Mount Elizabeth Medical Centre.

“Lifestyle interventions remain central as they are simple and available to all and, moreover, their effects are sustainable. However, lifestyle interventions are notoriously difficult to maintain at the same intensity over time and therefore safe and effective medications to complement them are needed as well. Alpha-glucosidase inhibitors are amongst the safest of compounds as there is minimal absorption into the body and no interference with the metabolism of other drugs,” he said.

The epidemic of type 2 of diabetes continues to boom in Asia, with total numbers predicted to increase from some 114 million patients in 2007 to 180 million in 2025. The prevalence of IGT is expected to rise from 157 million to 213. [JAMA 2009 May 27;301(20):2129-40]

The worst-affected countries appear to be those undergoing significant economic and dietary changes: the overall prevalence in China, for example, rose from 1 percent in 1980 to 5.5 percent in 2001. For affluent urban areas such as Hong Kong and Taiwan, the figure is as high as 10 percent. [Diabetes Res Clin Pract 2006 Aug;73(2):126-34]

Adverse events in the Japanese study were more common with voglibose than placebo (P<0.0001) – mostly comprising gastrointestinal symptoms such as flatulence, abdominal distention and diarrhea. There were also six serious advents in the voglibose group, consisting of colonic polyp, cholecystitis, inguinal hernia, liver dysfunction, rectal neoplasm and subarachnoid hemorrhage. Two placebo patients experienced serious events – one cerebral infarction and one case of cholecystitis.

Alpha-glucosidase inhibitors could feasibly be given in combination with metformin, which has also shown good results in diabetes prevention studies, wrote Dr. André Scheen of the University of Liège, Belgium, in an accompanying commentary. This dual approach, using acarbose, is currently being trialed in Canada. [Lancet 2009 May 9;373(9675):1579-80; Diabetes Obes Metab 2006;8(5):531-7]

Stockings ineffective for DVT prevention after stroke

Medical Tribune July 2009 SFIV

David Brill

Compression stockings do not reduce the risk of deep vein thrombosis (DVT) in stroke patients, despite their widespread usage for this purpose, a major international study shows.

The multicenter CLOTS* 1 trial, involving 2,518 patients, found that stockings were not only ineffective, but increased the risk of ulcers, blisters and skin necrosis.

The results have prompted calls for revision of guidelines, as experts point to substantial cost and time savings from abandoning the practice. Some hospitals in Asia are already reviewing the findings, and may stop using stockings for stroke patients in the near future.

The trial was carried out across 64 centers in the UK, Australia and Italy. DVT occurred in 10 percent of patients who were randomized to thigh-length stockings, and 10.5 percent who were randomized to no stockings. [Lancet 2009 Jun 6;373(9679):1958-65]

All patients were immobile and had been admitted to hospital within a week of acute stroke. They were assessed for DVT at 7 to 10 days, and again at 25 to 30 days.

“In this study, we have shown conclusively that compression stockings do not work for stroke patients,” said study author Professor Martin Dennis of the University of Edinburgh, UK. “National guidelines need to be revised and we need further research to establish effective treatments in this important group of patients.

“Given that most national guidelines recommend stockings in at least some patients, the results of our study will affect the treatment of millions of patients each year. Abandoning this ineffective and sometimes uncomfortable treatment will free up significant health resources – both funding and nurse time – which might be better used to help stroke patients,” he said.

DVT is thought to be less common among Asians than Western populations, but compression stockings are nonetheless commonly used for prophylaxis in stroke patients with lower limb weakness. [Ann Acad Med Singapore 2007 Oct;36(10):815-20]

Dr. Lee Sze Haur, senior neurology consultant at the National Neuroscience Institute (NNI), Singapore, said, however, that this practice “will likely change” in light of the new data.

“Based on the CLOTS trial, there is good reason to consider discontinuing the use of graded compression stockings for prevention of DVT in patients with acute stroke, as this will save cost and time as well as reduce the incidence of skin complications,” said Lee.

National University Hospital, meanwhile, is currently reviewing the evidence before changing its use of compression stockings, according to senior neurology consultant Dr. Bernard Chan. He noted that stockings remain effective for DVT prevention in post-surgical patients, but said that the usage for stroke has been “a long-standing practice without good clinical evidence.”

Two other studies are in progress to establish alternatives for post-stroke DVT prevention. CLOTS 2 compares thigh-length and below-knee stockings, but is now expected to finish early in light of CLOTS 1. The third trial is testing the effects of intermittent pneumatic compression, and is scheduled for completion in 2013.

Blisters, ulcers, skin breaks and necrosis were reported in 64 of the 1,256 patients given stockings in CLOTS 1 (5 percent), compared to just 16 of 1,262 control patients (1 percent; odds ratio 4.18; 95 percent CI 2.40 – 7.27).

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*CLOTS: Clots In Legs Or Stockings After Stroke

Tumor compartments: A ‘revolution’ in cancer surgery

Medical Tribune July 2009 SFIV
David Brill

A novel approach to treating cervical cancer may signal the end of the radical hysterectomy and could one day revolutionize the field of surgical oncology, says a pioneering team of German surgeons.

By removing only the embryologically defined ‘compartments’ in which tumors are most likely to spread, the surgeons can spare surrounding tissues and minimize collateral damage.

The technique reduces complications and recurrence rates, removes the need for radiotherapy, and could improve survival rates by as much as 20 percent compared to conventional hysterectomy, the group reported recently in The Lancet Oncology.

Research is already underway to extend the concept to vulvar and endometrial cancers, said lead researcher Professor Michael Höckel, chairman of the department of obstetrics and gynecology at the University of Leipzig, Germany.

“We have found that the tumor is confined for a long time in its natural course to a defined tissue compartment – it’s not like an explosion infiltrating all tissues around the tumor,” said Höckel.

“This new perspective in surgical anatomy enables you to see and operate on the tissue in which the tumor is spreading, irrespective of the tumor entity. This is a general principle which could really revolutionize surgical treatment for malignant disease,” he said.

The cervical cancer procedure – total mesometrial resection (TMMR) – targets only the non-distal part of the Müllerian compartment. Surgeons remove the proximal vagina, uterus and extra-cervical mesenchyme but spare nearby non-Müllerian tissues, including the nerves which supply the vagina, bladder and rectum.

Results from 212 women who underwent TMMR without radiotherapy at the University of Leipzig show an overall 5-year survival rate of 96 percent, and recurrence-free survival of 94 percent. The study was conducted prospectively from October 1999 to July 2008 on women with early-stage cancers: International Federation of Gynecology and Obstetrics (FIGO) stages IB, IIA and selected IIB. [Lancet Oncol 2009 May 29; Epub ahead of print]

Sixty two percent of procedures were complication-free at a median of 41 months’ follow-up; 35 percent of patients had grade one complications and 9 percent had grade two. Three patients had developed pelvic cancer recurrence, five developed distant recurrences, and two developed both pelvic and distant recurrence.

Höckel and colleagues developed the principle of TMMR by studying uterovaginal development in embryos and fetuses – enabling discrimination of tissue compartments on the basis of their embryological origin. Previous work showed that early cervical tumors grow largely along these lines. [Lancet Oncol 2005 Oct;6(10):751-6]

Singapore surgeon Adjunct Associate Professor Yam Kwai Lam said that he would be “open to any new technique” as long as it provided “substantial overall benefit to the patient.”

“The published results look impressive, but lacking in long-term survival data. In order for the technique to replace conventional hysterectomies, validation would require a large randomized controlled trial to provide the answer,” said Yam, head and senior consultant in the department of gynecological oncology at KK Women’s and Children’s Hospital.

Höckel has previously presented TMMR to surgeons in Southeast Asia – performing live demonstrations in Hong Kong in December 2006, and Bangkok in August 2008.

A multicenter trial is due to launch soon in Germany, with a view to comparing results of 200 TMMRs against 200 conventional hysterectomies. Publication is expected in around 4 years, said Höckel, who has not performed a standard hysterectomy since first developing TMMR some 10 years ago.

“The conventional techniques have no right to exist any longer because they are wrong. Now that we know how a tumor is spreading … it’s no longer acceptable to use these sub-prime concepts and techniques,” he said.

Pain perception: Personality goes a long way

Medical Tribune July 2009 P12

David Brill

Personality has a major influence on the way people perceive headaches, and should be considered when assessing patients, say Italian researchers.

In a recent study they found that ‘emotionally overwhelmed’ people report a greater affective dimension to their pain than those with other personality types, yet score the same on a simple measure of pain intensity.

The other personality types – conversive, depressive and copers – did not differ significantly in their perception of pain.

The findings should encourage physicians to routinely consider a patient’s personality and emotions before simply prescribing medications, said lead researcher Professor Franco Mongini, of the Headache and Facial Pain Unit at the University of Turin.

Moreover, presentation with a headache or migraine could be a warning sign of an underlying personality disorder or mental health problem, he said, adding that early recognition could facilitate referral to a specialist before the pain gets worse.

“I keep seeing patients with chronic migraine and chronic tension-type headache together, and they have been receiving new drugs. But very often the patient’s personality and the consequences of this personality have not been considered,” said Mongini, who typically questions new patients on their history of phobias, panic attacks and sleep disturbances, among others, before considering whether to treat with cognitive behavioral therapy.

“I’m convinced after years and years of work that the approach to the problem of chronic head pain should be remodeled and widened. I’m not saying that drugs should not be prescribed – I prescribe a lot of medications myself – but other factors should be considered and treated also with non-pharmacological methods,” he said.

Mongini and colleagues assessed 317 patients with migraine and/or tension-type headache with myogenic facial pain. They performed two types of pain assessment: the verbal MacGill Pain Questionnaire (MPQ), which classifies pain in a range of dimensions, and the visual analog scale (VAS), which measures pain intensity alone. [Pain 2009 Jul;144(1-2):125-9]

Personalities, meanwhile, were classified using 10 scales of the Minnesota Multiphasic Personality Inventory (MMPI). ‘Copers’ score normally across all domains, whereas ‘depressive’ and ‘conversive’ personalities show various elevation in scores of depression, hypochondria and hysteria. The ‘emotionally overwhelmed’ personality has elevation in all three of these scores, plus one other MMPI dimension.

The affective dimension of the MPQ was significantly higher in emotionally overwhelmed than in coper (P=0.003), depressive (P=0.027) and conversive (P=0.002) people, regardless of sex, age and type of pain. VAS score did not vary significantly between groups.

Mongini and colleagues also recently reported on a successful intervention to reduce head and neck pain in the office place. A combined educational and physical program reduced the frequency of headaches by 41 percent and the use of analgesics by 50 percent, when tested in a study of 384 civil servants in Turin. [Cephalalgia 2008 May;28(5):541-52]

Breast cancer prediction and prevention could start younger

Medical Tribune July 2009 P13
David Brill

Risk assessment for breast cancer could one day start in girls as young as 15, according to a recent paper which may open up new opportunities for early disease prevention.

Canadian researchers found that breast tissue composition – a known risk factor in middle age and above – begins to vary at a much younger age, and could provide a quantifiable way to predict risk.

It is the first extensive study to look at breast tissue composition in young women, say the authors, who used MRI in order to avoid the radiation exposure of mammography.

Percent breast water was found to decrease with age (P=0.04) – a finding which could explain why breast tissue is thought to be most susceptible to carcinogens at a young age.

The researchers also found strong correlations to height and weight – suggesting that breast composition could be influenced by factors relating to growth and development. Percent breast water was also strongly linked to mammographic density in the subjects’ mothers – lending support to a hereditary component to breast formation.

“What [this study] suggests is that prevention is going to be most effective if started earlier in life, and that measurement of breast tissue characteristics might be one way of modifying and monitoring prevention,” said lead author Professor Norman Boyd, of the Campbell Family institute for Breast Cancer Research, Toronto, Canada.

Further research is needed before risk assessment could be practiced routinely in young girls, said Boyd, noting two key areas of uncertainty. First would be to establish the most appropriate method for assessing breast composition in young women, and second would be to be determine which interventions would be appropriate and safe in those found to be at high risk.

“The long-term vision would be that we would have a method of assessing breast tissue composition as soon as the breast forms, essentially. MRI is what we’ve used, but MRI is clearly not the answer to this because it’s so expensive and there are so few machines,” he said.

“It’s difficult to know how technology is going to advance but at the moment, ultrasound looks very appealing. It can be done quickly, it can be done quantitatively, it can give us measurements of tissue volumes, which mammography does not do, it can be done very, very quickly… and it’s completely free of risk.”

Boyd and colleagues measured levels of water and fat in the breasts of 400 women aged 15 to 30, and their mothers. The percentage of water on MRI correlated strongly with mammographic density in a randomly selected subset of 100 of the mothers (r=0.85). [Lancet Oncol 2009 Apr 29; Epub ahead of print]

Height, weight and maternal mammographic density were all strongly associated with per cent breast water in young women (P<0.0001). Height and weight also correlated strongly to total breast fat, and maternal mammographic density correlated strongly to total breast water (P<0.0001).

The association between weight and percent breast water was inverse – suggesting that heavier young women are at lower risk of breast cancer. Previous studies have also shown similar findings but the mechanisms for the association remain unclear, said Boyd. The authors did, however, report an association between percent breast water and serum levels of growth hormone – a finding which could underlie the associations with height and weight, they say.

Further research is already ongoing to better understand the genetic factors that influence breast composition, added Boyd.

Dieticians call for action on overweight mothers-to-be

Medical Tribune July 2009 P16

David Brill

Overweight women should receive nutrition counseling before, during and after pregnancy, leading US dietitians have advised.

With the global obesity epidemic showing no signs of slowdown, the health of mothers and babies alike is at risk unless eating habits improve, cautions a recent joint statement from the American Dietetic Association (ADA) and the American Society of Nutrition (ASN).

Studies show that obese mothers are more likely to experience preeclampsia, gestational diabetes mellitus (GDM), gestational hypertension, postpartum anemia and cesarean delivery than women of normal weight. Their offspring, meanwhile, face an increased risk of birth defects, fetal macrosomia, childhood obesity and even perinatal death.

Ms. Ximena Jimenez, a consultant dietitian and national ADA spokesperson, said that healthcare professionals across the spectrum should work together to promote healthy eating and physical activity in women who are pregnant or planning to conceive. Physicians, for example, can play “a big role” in reinforcing the advice given by dietitians and other specialists, she said.

“A lot of the time it takes more than one type of counseling to get these women to change their lifestyle. I would encourage any healthcare professional to encourage these women to seek nutrition counseling,” she said.

“The principles are that you want them to increase whole grains and decrease refined carbohydrates like cakes, pastries and white breads. We also want them to replace saturated fat with healthy fats like omega-3 fats or fats from olive oil, canola oil or avocado, and also to increase their intake of fruits and vegetables. We also want them to be physically active,” she added.

Some 52 percent of women aged 20 to 39 in the US are overweight or obese (BMI 25 or above), according to data from the National Health and Nutrition Examination Survey of 2003-2004. Twenty-nine percent are obese (BMI 30 or above) and 8 percent are extremely obese (BMI 40 or above). Among adolescent girls aged 12 to 19, almost 32 percent are overweight or at risk of being overweight. [JAMA 2006 Apr 5;295(13):1549-55]

Despite the scale of the task, Jimenez remains optimistic that overweight women can be successfully counseled.

“I think it’s a very realistic target. There has to be promotion of healthy eating among women,” she said. “Imagine the benefits. As a society we are all going to benefit because we are going to have healthy women and healthy children.”

Jimenez highlighted studies showing the success of dietary interventions in overweight mothers, such as the Nurses’ Health Study, which found that risk of GDM was approximately halved by following a low-glycemic, high-cereal fiber diet. [Diabetes Care 2006 Oct;29(10):2223-30] The risk of preeclampsia can also be halved by taking calcium supplements, a meta-analysis of 12 studies shows. [Cochrane Database Syst Rev 2006 Jul 19;3:CD001059]

The new ADA / ASN position statement also reviews the literature on the prevalence of various pregnancy outcomes for overweight mothers and their babies. [J Am Diet Assoc 2009 May;109(5):918-27]

The risk of developing GDM, for example, is reported to double in overweight women, and increase over eightfold in the extremely obese. [Diabetes Care 2007 Aug;30(8):2070-6] Preeclampsia risk is around three times higher in pregnant women who are obese than those of normal weight. [Obstet Gynecol 2007 Feb;109:419-33]

The offspring of obese mothers are around twice as likely to have neural tube defects such as spina bifida, according to the US National Birth Defects Prevention Study. [Arch Pediatr Adolesc Med 2007 Aug;161(8):745-50] Oral clefts, hydrocephaly and cardiac abnormalities were also found to be more common in these infants than those born to normal-weight mothers.