Jury still out on clinical exams for breast cancer screening

Medical Tribune October 2009 P12

David Brill

Controversy looks set to continue over the benefits of clinical breast examination (CBE) for cancer screening, following the publication of a large population-based study which could raise as many questions as answers.

Results from the Ontario Breast Screening Program show that adding CBE to mammography improves cancer detection rates, but considerably increases the number of false-positive results.

For every 10,000 women screened, the addition of CBE would detect four more cancers but expose 219 women to unnecessary further testing – along with its extra risks, costs and anxiety.

This risk-benefit ratio must be weighed up carefully, and women should be fully informed before consenting to CBE, wrote the researchers, led by Dr. Anna Chiarelli of Cancer Care Ontario, Toronto Canada. [J Natl Cancer Inst 2009 Aug 31; Epub ahead of print]

They screened 290,230 women aged 50 to 69 between 2002 and 2003, and followed them up for 12 months. Of these women, 232,515 received mammography plus CBE at 68 centers (nine regional and 59 affiliated), whereas 57,715 received mammography alone at 34 affiliated centers.

US experts called it “a steep price” for adding CBE to mammography but reserved judgment on how the findings should influence practice, concluding in an editorial that “more answers are needed on the role of CBE in breast cancer screening before definitive recommendations for or against its use can be made.”

“While we wait for those answers, the data presented by Chiarelli et al. suggest that CBE must be done well if it is to be done at all, with the acknowledgment that overall referrals and false-positive results will increase,” wrote Drs. Mary Barton and Joann Elmore, of the Agency for Healthcare Research and Quality, Rockville, and the University of Washington School of Medicine, Seattle, respectively. [J Natl Cancer Inst 2009 Aug 31; Epub ahead of print]

Barton and Elmore also called for the creation of universal standards for CBE, noting that inconsistency in the duration of examinations and the search pattern used can affect the accuracy of the test. They note that the highest-volume centers in the Ontario study also had the highest sensitivities and lowest false-positive rates – an observation which supports their case for standardization.

CBE has been advocated in some quarters since it can detect cancers which are missed by mammography – the gold standard for breast cancer screening. It has yet to be demonstrated conclusively, however, that addition of CBE to screening actually reduces mortality.

The practice is common in the US: one report found that 18 percent of screening centers surveyed performed CBE routinely alongside mammography, while another study found that 65 percent of women reported having CBE in the preceding 2 years. [Open Clin Cancer J 2008;2:32-43; AJR Am J Roentgenol 2005;184:433-8]

Breast cancer was traditionally less common in Asia than the West but rates are rising rapidly. In Singapore, the only Asian country with a national breast cancer screening program, it is now the number one cancer among women. The incidence rose 2.5-fold between 1968 and 2002, according to data from the national cancer registry.

First-line screening in the BreastScreen Singapore program is with mammography alone. CBE is included among possible follow-up tests, along with ultrasound, repeat mammography and biopsy.

Breast cancer has also become the leading cancer among women in Hong Kong – responsible for 21 percent of cancer cases in 2002. A self-referral, opportunistic mammography screening program at the Tung Wah Group of hospitals was shown to improve early detection and prognosis after 46,637 mammograms, with comparable results to Western programs. Screening was well received by the community, and the model has been proposed as a basis for a national program. [Hong Kong Med J 2007;13:106-13c]

Surveys in both Singapore and Hong Kong have shown, however, that public knowledge about breast cancer and screening is low, and myths and misconceptions are common. Only 57 percent of Singaporean women aged 40 and above had gone for a screening mammogram, while 58 percent of Hong Kong women had never even heard of mammographic screening. [Singapore Med J 2009;50:132-8; Breast J 2005;11:52-6]

New fears raised over hormone therapy cancer risk

Medical Tribune September 2009 P3

A new study of almost a million people has strengthened the link between postmenopausal hormone therapy and the risk of developing ovarian cancer.

Danish researchers reviewed registry data from 909,946 women aged 50 to 79, over an average of 8 years of follow up. They found that hormone therapy users had an incidence rate ratio of 1.38 (95 percent CI 1.26 – 1.51) for all ovarian cancers, compared to women who had never used therapy. Cancer risk was increased “regardless of the duration of use, the formulation, estrogen dose, regimen, progestin type and route of administration,” the authors wrote.

“Thus the risk of ovarian cancer is one of several factors to take into account when assessing the risks and benefits of hormone use,” they concluded.

[JAMA 2009 Jul 15;302(3):298-305]

Aspirin trial seeks to tackle colorectal cancer in Asia

Medical Tribune September 2009 P8
David Brill

A major new trial is set to launch in Asia to establish whether aspirin can prevent recurrence of colorectal cancer.

The ASCOLT study will involve over 2,000 patients from centers across Southeast Asia, China and India, and will be led jointly by the National Cancer Centre Singapore (NCCS) and the University of Oxford, UK.

Patients will be randomized to aspirin (200mg/day) or placebo for 3 years, following surgery and adjuvant chemotherapy for high-risk stage II and III colorectal cancer. The primary endpoint will be disease-free survival over 5 years of follow-up.

A growing body of evidence suggests that aspirin is effective for primary prevention of colorectal cancer, but ASCOLT is thought to be the first prospective clinical study to investigate the drug in the adjuvant setting after chemotherapy.

If positive, the results could have a huge impact on the treatment of colorectal cancer in Asia and worldwide, according to Dr. Toh Han Chong, head of the department of medical oncology at NCCS and one of the ASCOLT lead investigators.

“It’s incredible how many people you could save from relapse with the addition of aspirin if this study is positive. If you go to a village in India you can’t really give costly [monoclonal antibodies], so there is compelling power of social responsibility here,” he told Medical Tribune.

“We have undervalued the power of simple drugs. It’s time to redress the balance – change the paradigm and go cheap.”

Recruitment for ASCOLT is already underway, with centers confirmed in Singapore, Hong Kong, Jakarta and several cities in India.

More study centers are still needed in order to reach the target of 2,000 patients however said Toh, who extended the invite to all Asian delegates at the recent ‘Best of ASCO’ conference in Singapore.

“It’s a drug trial that cannot be done in the West. Many people over the age of 50 in the US are popping aspirin over the counter for heart conditions or stroke prevention,” he said. “Fewer people are on aspirin in Asia. That’s why it’s a perfect study to do here.”

Colorectal cancer is the second leading cause of cancer death in North America, Europe and Australasia according to a 2007 global report from the American Cancer Society. In Southeast Asia, it is the third biggest killer (behind liver and lung cancer) – responsible for 7.9 percent of cancer deaths.

In Singapore, colorectal cancer is the leading cancer among men and the second most common among women, data from the national cancer registry show.

A recent study found that regular use of aspirin after a diagnosis of colorectal cancer was associated with lower overall mortality (hazard ratio [HR] 0.79; 95% CI 0.53 – 0.95) and cancer-specific mortality (HR 0.71; 0.53 – 0.95), after a median of 11.8 years of follow-up. [JAMA 2009;302(6):649-58]

A 2007 paper, meanwhile, reported that taking 300 mg/day or more of aspirin for 5 years was effective for primary prevention of colorectal cancer, according to pooled data from two large randomized trials (HR 0.74; 95% CI 0.56 – 0.97; P=0.02). [Lancet 2007;369(9573):1603-13] Earlier trials have also shown that aspirin can prevent colorectal adenomas – the precursors to cancer – both in patients with, and without, a prior history of cancer. [N Engl J Med 2003;348(10):883-90; N Engl J Med 2003;348(10):891-9]

“Why should oncologists do an aspirin trial? Because the epidemiological data is strong, the data on polyp reduction is very convincing, the retrospective observational studies are very compelling and remarkable in terms of hazard ratios, and the data preclinically is scientifically robust,” added Toh.

ASCO award set to boost Asian cancer research

Medical Tribune September 2009 P8
David Brill

A Singapore oncologist has become the first Singaporean, and one of the first Asia-based recipients, to pick up a prestigious research award from the American Society of Clinical Oncology (ASCO).

Dr. Daniel Tan of the National Cancer Centre Singapore (NCCS) will receive a US$50,000 grant as part of the Young Investigator Award, bestowed by the ASCO cancer foundation.

The money will help fund his research on the molecular mechanisms of tyrosine kinase inhibitors (TKIs) in nasopharyngeal cancer. The work aims to understand why some patients respond better to targeted therapies than others – so as to improve patient selection and avoid unnecessary exposure to ineffective treatment and side effects.

“One of the challenges with any of these new-generation drugs is to find out how we can use them better – to get the right drug to the right patient. Understanding the reasons for response and resistance can also allow us to develop much more effective treatment strategies that hopefully translate to improved survival,” said Tan, who will work alongside his mentor Professor Teh Bin Tean, director of the NCCS-VARI laboratory – a joint project with the Michigan-based Van Andel Research Institute.

Tan’s ASCO proposal was borne out of clinical observations from a phase II trial of pazopanib, which saw a subset of nasopharyngeal cancer patients respond better to therapy than others. This trial is currently ongoing under principal investigator Dr. Darren Lim, a senior consultant at NCCS specializing in thoracic and head and neck cancers.

The goal now is to understand which proteins are targeted by the drug, and how this differs between patients and tumor types. Tan’s work will be done largely in a series of co-culture experiments and mouse xenograft models – allowing detailed analysis of how the drug affects each cellular compartment within a tumor.

Tan is also aiming to secure more local funding for his research, and hopes in the long term to help establish a comprehensive drug development program, which would also provide patients with access to novel therapeutic agents.

He added that he was pleased to receive the award, and is especially encouraged that the proposal was deemed to have sufficient scientific merit for further study.

“It is heartening to know that one’s ideas are being taken seriously by a highly regarded scientific body. Furthermore, the award is rarely given out to institutions outside of America, so it’s a nice endorsement of the research infrastructure at NCCS,” he said.

Cetuximab offers hope for Asian lung cancer patients

Medical Tribune September 2009 P8
David Brill

A novel lung cancer therapy could be of particular benefit to Asian patients, results of a recent trial suggest.

The international FLEX* study reported that adding the monoclonal antibody cetuximab to chemotherapy prolonged survival of advanced lung cancer patients from 10.1 months to 11.3 months.

Further analysis revealed, however, that Asians treated with the drug survived for a median of 19.5 months, whereas non-Asians survived only 9.6 months.

The randomized trial involved 1,125 patients – 121 of whom were from Asian centers (predominantly in Hong Kong, Taiwan, Singapore and South Korea). [Lancet 2009;373(9674):1525-31]

There are several possible explanations for the ethnic discrepancy but also questions that remain unanswered, according to Professor Kenneth O’Byrne, one of the FLEX investigators, who spoke to Medical Tribune during the recent ‘Best of ASCO’ conference in Singapore.

Asian lung cancer patients are more likely to be women, non-smokers and have adenocarcinomas than non-Asian patients – all groups which tend to survive longer, he said. Moreover, epidermal growth factor receptor (EGFR) mutations are more common among Asians – a characteristic which not only improves prognosis in itself, but also makes patients eligible for first-line EGFR tyrosine kinase inhibitors which can further improve outcomes.

“So there is a combination of reasons as to why but it’s not just that – there may be some intrinsic sensitivity to treatment here that’s not present in the West,” said O’Byrne, adding that further study is needed to better understand these biological similarities and differences.

Cetuximab is presently licensed for use only in colorectal and head and neck cancers. An application for lung cancer licensing was recently rejected by the European Medicines Agency (EMEA), but is currently under appeal from the manufacturer, Merck Serono.

The verdict has also come as a surprise to many experts in the field and will face “a strong challenge,” said O’Byrne, a consultant medical oncologist at St. James’s Hospital and a clinical professor at Trinity College, Dublin, Ireland. The FLEX trial was published before the EMEA decision, with investigators concluding that cetuximab can be considered as standard first-line therapy for all patients with advanced non-small cell lung cancer (NSCLC).

“Cetuximab is the first drug to show a survival benefit in all histological types: adenocarcinoma, squamous carcinoma – across the board. Secondly, the toxicities are all very predictable – we know how to manage them and they’re straightforward. Thirdly, not only was the FLEX trial positive but when you take in all the other trials together … as a collective they show a positive result,” said O’Byrne. He added that US National Comprehensive Cancer Network guidelines already recommend that the drug be considered for lung cancer patients, and that many oncologists in Europe have begun off-label usage.

O’Byrne acknowledged that cetuximab therapy would be costly, but noted that around half of patients display a strong predictive marker in the form of a skin rash, which develops after one round of chemotherapy. These patients tend to survive for around an extra 5 months, which may justify the cost, he said. More work is needed to confirm whether cetuximab offers any benefit for those who do not develop a rash, but it appears likely that therapy could be discontinued after one cycle in these patients, he said.

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*FLEX: First-Line Erbitux in Lung Cancer

Urine test could allow for lung cancer risk prediction

Medical Tribune August 2009 P12
David Brill

A simple urine test could one day reveal which smokers are at greatest risk of developing lung cancer, according to a team of Singaporean, Chinese and American scientists.

The group recently reported the first link between elevation of certain urinary metabolites – total NNAL* – and increased lung cancer risk in humans. Cigarette smokers with the highest total NNAL levels were over twice as likely to develop lung cancer.

A commercially available test remains at least 5 years off, but the identification of these urinary biomarkers raises “an exciting possibility,” say the researchers.

“Such a test would enable doctors to screen more frequently for lung cancer in smokers with high levels of biomarkers, and provide a strong incentive for these smokers to quit smoking,” said study authors Associate Professor Yuan Jian-Min of the University of Minnesota, US, and Associate Professor Koh Woon-Puay of the National University of Singapore, in a joint statement to Medical Tribune.

“With the identification of new biomarkers, we could ultimately develop an assay that simultaneously quantifies a panel of tobacco carcinogens or their metabolites to best predict the risk of lung cancer for an individual smoker,” they said.

The work goes some way towards explaining why some smokers develop lung cancer while others do not. With over 60 established carcinogens in cigarette smoke, it may be that individual differences in the uptake and metabolism of particular chemicals play an important role in the development of cancer, the authors say.

One such carcinogen, NNK**, has been strongly linked to lung cancer but an epidemiological link had only been shown in animal studies.

Yuan, Koh and colleagues instead investigated levels of NNAL – a metabolite of NNK – in a nested case-control study using data on 63,257 men and women from the Singapore Chinese Health Study, and 18,244 men from the Shanghai Cohort Study. They identified 246 cases of incident lung cancer, and 245 matched controls. [Cancer Res 2009;69:2990-5]

The odds ratio of developing lung cancer was 2.11 for smokers who were in the highest tertile of urinary total NNAL before cancer diagnosis, compared to those in the lowest tertile (95% CI 1.25 – 3.54; P for trend = 0.005).

Combination with cotinine, a nicotine metabolite, further increased the predictive value of NNAL: the odds ratio for developing cancer was 8.47 for smokers in the highest tertile for both markers, compared to those in the lowest tertile (95% CI 3.69 – 19.46; P for trend – 0.005).

“Biomarkers for prediction of cancer risk are useful as proxy measures of outcome in interventional studies. Nevertheless, for smokers, the best intervention for the reduction of lung cancer risk is still to quit smoking,” added Yuan and Koh.

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* NNAL: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Total NNAL is the sum of NNAL and its glucuronides.
**NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

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.

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]

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.

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.

Rifts widen in prostate screening debate

Medical Tribune June 2009 P1&9
David Brill

American and European experts have diverged in their stances on prostate cancer screening, as debate intensifies over the benefits of prostate-specific antigen (PSA) testing.

The subject has held center stage since the publication of two major studies in March: one showed that PSA testing every 4 years reduced mortality by 20 percent but carried a high risk of overdiagnosis; the other showed that annual screening had no impact on death rates.

The American Urological Association (AUA) has since aligned itself with the first study – recommending PSA testing in all well-informed men, and lowering the age for a first test from 50 to 40. It has also adjusted its criteria for proceeding to biopsy.

The European Association of Urology (EAU), meanwhile, has advised against population screening until more data are available – warning of the dangers of overtreatment and calling for urgent development of new diagnostic markers and screening algorithms.

Singapore experts are taking a similar stance to their European counterparts, although they note that the lower incidence of prostate cancer in Asia makes screening less worthwhile than in Western populations.

The Singapore Urological Association (SUA) nonetheless intends to downplay the role of PSA screening in this year’s upcoming Prostate Awareness Month, according to Professor Kesavan Esuvaranathan, SUA president and senior consultant, department of urology, National University Hospital.

“I wouldn’t be in a hurry to recommend screening. We don’t know for sure whether there is a benefit,” he said.

“My feeling is that it’s too early to say that PSA screening is inappropriate, but I also think that it is probably wrong to unconditionally recommend PSA screening. I think we have to wait for the long-term results of these studies.”

Associate Professor Weber Lau, senior consultant, department of urology, Singapore General Hospital, also urged caution in the use of PSA testing, stressing the need to select the right patients.

“We are quite clear that screening is not a goal for Singapore at this juncture. For people who are asking to be tested, the key words are risk stratification,” he said.

“PSA can be used as a tool for early detection of prostate cancer in the right patients. But on the other hand it can be harmful too if used in health screening without understanding the risks of the patient group and the general health of the patient.”

The 20 percent mortality reduction with PSA screening was reported in the European Randomized Study of Screening for Prostate Cancer, which included 162,387 men aged 55 to 69 from seven countries. They were assigned to PSA screening every 4 years on average, or to no screening. [N Engl J Med 2009 Mar 26;360(13):1320-8]

After a median of 9 years’ follow-up, the adjusted rate ratio for prostate cancer death in the screening group was 0.80, as compared to the control group (95 percent CI, 0.65 – 0.98; P=0.04). The absolute risk difference was 0.71 deaths per 1,000 men – meaning that to prevent one death from prostate cancer, 1,410 men would need to be screened and an additional 48 cases would need to be treated.

The second study – the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial – included 76,693 men aged 55 to 74, recruited at 10 US centers. Men were randomized to annual screening – with PSA for 6 years and digital rectal exam for 4 years – or to the control group. [N Engl J Med 2009 Mar 26;360(13):1310-9]

After 7 years’ follow-up, there were 50 prostate cancer deaths in the screening group and 44 in the control group (rate ratio 1.13; 95 percent CI, 0.75 – 1.70). Ten-year data showed similar patterns but follow-up was only complete for 67 percent of patients at the time of publication.

Despite the lack of national recommendations, PSA tests are commonly offered in Singapore as part of executive health screens, according to Kesavan. This situation need not change in light of the studies, he said, but he emphasized the importance of explaining the potential consequences before testing.

“It would place the patient in a quandary if it was not explained properly and then he had an abnormal test. Then to put that worry to rest it would require him to undergo a biopsy.”

Alcohol ‘flush’ signals cancer risk in Asians

Medical Tribune June 2009 P4

David Brill

East Asians who ‘flush’ when drinking alcohol could be at increased risk of esophageal cancer if they do not drink responsibly, a recent study has warned.

The characteristic red cheeks and nausea are a well-recognized phenomenon, but few people are aware that the underlying enzyme deficiency also predisposes heavy drinkers to squamous cell esophageal carcinoma, say the researchers.

With some 36 percent of East Asians displaying the flush response, there is potential to save “a substantial number of lives” by counseling affected individuals against heavy drinking. [PLoS Med 2009 Mar 24;6(3):e50]

"Cancer of the esophagus is particularly deadly, with 5-year survival rates ranging from 12 to 31 percent throughout the world,” said lead researcher Dr. Philip Brooks, of the US National Institute on Alcohol Abuse and Alcoholism. “And we estimate that at least 540 million people have this alcohol-related increased risk for esophageal cancer.

"We hope that by raising awareness of this important public health problem, affected individuals who drink will reduce their cancer risk by limiting their alcohol consumption," he said.

Flushing is caused by a deficiency in aldehyde dehydrogenase 2 (ALDH2) – an enzyme which breaks down acetaldehyde, a carcinogenic by-product of ethanol metabolism. People with normal ALDH2 function can convert acetaldehyde safely into acetate, but in ALDH2-deficient individuals it accumulates in the body, leading to facial redness, nausea and tachycardia.

In people who are homozygous for the ALDH2-deficiency gene, the response to alcohol is so unpleasant that they cannot consume large quantities, and are thereby protected from the associated risk of esophageal cancer.

Heterozygotes, however, can develop tolerance to acetaldehyde and may become heavy drinkers. Studies from Japan and Taiwan have shown that ALDH2-deficient heterozygotes who drink heavily are over ten times as likely to develop esophageal cancer, [Jpn J Clin Oncol 2003 Mar;33(3):111-21; Int J Cancer 2008 Mar 15;122(6):1347-56]

Dr. Michael Wang, a radiation oncology consultant at the National Cancer Centre Singapore, agreed that the link between flushing and esophageal cancer is not likely to be common knowledge among doctors.

“From the article, it is fair to comment that there is a causative relation between deficiency of the gene and increased risk of esophageal cancer,” he said.

“However, there has been a lot of material published since the 1970s regarding this condition. This relationship may be confounded by smoking, which is also related to esophageal cancer. Before we say something drastic like ‘people who flush when drinking have a higher risk of contracting esophageal cancer,’ we should research all the previously published articles first.”
Wang added that all heavy alcohol drinkers should be counseled, since drinking also predisposes to other medical conditions and to drink-driving.

The study authors advise clinicians to determine whether East Asian patients are ALDH2 deficient by asking simple questions about their history of flushing when drinking alcohol. Identified flushers should then be advised of their cancer risk and encouraged to moderate their consumption, they say.

End-of-life discussions reduce costs and relieve suffering

Medical Tribune June 2009 P7

David Brill

The decision to prolong life in advanced cancer patients presents an ethical, emotional, and financial challenge. Buying time can be costly, and a heavy legacy is often left for families and healthcare providers alike.

A new study suggests that physicians can play a major role in relieving this burden, simply by talking patients and families through their options and helping them to make plans in advance. Patients who had these end of life discussions received fewer aggressive interventions and had substantially lower medical costs, researchers found.

Economics aside, these discussions could also be in the patient’s best interests: the study found that high medical costs in the last week of life correlated to increased physical and psychological distress, and a worse quality of death. Moreover, survival was not significantly longer in patients who received aggressive therapies – raising questions as to whether the expense is justified.

Senior author Dr. Holly Prigerson said that patients ultimately have the right to choose, but that physicians can help to ensure that they make an informed decision.

“We’re not saying you should or you shouldn’t [prolong llfe], but you should at least realize what you’re buying with this more aggressive care. There is not improved quality of life,” she said.

“Whether they want to endure that pain is up to the patient to decide, but at least they should have the information to know that when they’re resuscitated, the likelihood that they’re going to survive an extra week really isn’t that much greater.”

Prigerson, director of the Center for Psychosocial Oncology and Palliative Care Research at the Dana-Farber Cancer Institute, Harvard Medical School, US, said that the study was born out of a belief among some oncologists that having end of life conversations would make patients “needlessly hopeless and depressed.” With data now showing that these discussions actually improve quality of life, she hopes that the study will bolster the confidence of physicians to address these “very difficult” subjects in future.

Singapore palliative care expert Dr. Cynthia Goh agreed that these conversations are important but stressed the need to approach them correctly. Physicians should listen to what patients and families want and guide them through their options, rather than pushing them towards a decision, she said.

“When talking about, for example, ‘do not resuscitate’ orders, the wrong way of doing things is to say: ‘do you want us to save your father or not?’” said Goh, director of the Lien Centre for Palliative Care at Duke-NUS Graduate Medical School, Singapore.

“What they’re talking about in this paper is a different kind of end of life conversation, which is certainly not initiated in the hospital corridor. It’s not about ‘do you want this or do you want that’ – really it’s a conversation to say what is important for the patient. People go bankrupt for this kind of treatment, so having the chance to reflect on whether it is likely to fulfill their life goals is a very good thing.”

Prigerson and colleagues interviewed advanced cancer patients from several US institutions, and followed them up until death. Of 603 patients, 188 (31.2 percent) reported having had an end of life conversation with a physician at baseline. [Arch Intern Med 2009; 169(5):480-8]

The mean cost of care for these patients was US$1041 (35.7 percent) lower than in those who did not have such conversations (P=0.002). Medical costs did not correlate to survival time (P=0.70) but were associated with worse quality of death, as assessed by caregivers and family members (P=0.006).

Another recent study led by Prigerson found that cancer patients who used religion to cope with the advent of death were more likely to receive intensive life-prolonging care. [JAMA 2009; 301(11):1140-7]

The explanation remains unclear but the effect appears to be driven by be a subset of patients who are not lifelong believers but rather turn to religion as death approaches, she said. Their new-found beliefs could therefore be a proxy for psychological distress, which manifests in a desire to remain alive for longer.

Goh, who is also honorary secretary of the Asia Pacific Hospice Palliative Care Network and co-chair of the newly formed Worldwide Palliative Care Alliance, said that the findings were very interesting but may not be applicable to Asian populations since the study patients were all American Christians. She added, however, that religion is an important factor in end of life decisions, and said that physicians should take these beliefs into account on a patient-by-patient basis.

Age no barrier to continued cervical screening

Medical Tribune June 2009 P9

David Brill

Cervical cancer screening should not stop at age 50, even in women who have had several all-clears in the past, new evidence suggests.

An analysis of national data from the Netherlands found that older women were just as likely to develop cancer after three negative smear tests as younger women.

Previous studies had found that pre-invasive disease is rare in well-screened over-50s, prompting calls for screening to be stopped at this age.

The Dutch study, however, focused instead on the incidence of full-blown cancers. It included data from 445,382 women aged 30 to 44 at the time of their third negative smear, and 218,847 women aged 45 to 54. [BMJ 2009 Apr 24;338:b1354]

After 10 years of follow-up the cumulative incidence of cancer was similarly low: 41 per 100,000 in the younger age group, and 36 per 100,000 in the older age group (P=0.48).

The findings suggest that age should not be the decisive factor for early cessation of screening in well-screened women, said lead author Dr. Matejka Rebolj. They do not, however, provide a definitive answer as to whether it will ultimately prove worthwhile to continue universal screening after three negative tests.

“We cannot really say with these data whether you should continue screening or not. However we can say that if you’re screening younger women, then in order to make your policy consistent you should continue screening women above the age of 50,” said Rebolj, a postdoctoral researcher at the University of Copenhagen, Denmark.

“The next logical step would be to do a proper cost-effectiveness analysis to determine whether this low absolute level of risk does warrant further screening. Until then we should encourage women to continue screening at the regular interval recommended in each particular country.”

Singapore oncologist Dr. Francis Chin praised the quality of the data, and said that the findings support Singapore’s policy of continuing screening up to age 69.

“This study confirms the importance of screening in the age group over 50 years old, because the risk of cervical cancer after several negative smears is similar in older versus younger patients,” said Chin, consultant radiation oncologist at the National Cancer Centre Singapore.

“The predilection of doctors has always been that screening and early detection is better than treating cancer in the later stages. These data confirm and validate this policy,” he said.

Singapore’s Health Promotion Board (HPB) agreed that the study supports the current guidelines of its CervicalScreen Singapore initiative, implemented in 2004. The program, which promotes screening every 3 years, will continue to focus on increasing its coverage of eligible women, said Dr. Shyamala Thilagaratnam, director, Healthy Ageing Division, HPB.

Several previous studies have proposed that cervical screening should stop at 50, notably a 1997 paper which found that only 1 percent of 23,440 previously screened over-50s had significant cytological abnormalities. The authors concluded that ending screening in this group could reduce anxiety and enable better allocation of resources to targeting higher-risk women. [Br J Obstet Gynaecol 1997 May;104(5):586-9]

The case against this argument, however, could be furthered strengthened by another recent paper, supporting the findings of the Dutch study. UK researchers, reviewing National Health Service screening records for 2 million women, found that two thirds of all the lesions detected in over-50s were found in women who had had previously had negative smears results. Discontinuation of screening would therefore lead to the majority of important abnormalities being missed, the researchers say. [Br J Cancer 2009 May 5; Epub ahead of print]

Singapore physician Dr. Siew Wei Fong concurred with the conclusion that screening should continue beyond the age of 50, in light of the recent evidence. She added that she does not expect any change in screening practices at the Singapore Polyclinics, where she is senior family physician.

Urine test shows promise for prostate cancer detection

Medical Tribune April 2009 P4

David Brill

A prototype urine test has been shown to be highly specific for detecting prostate cancer and could even help to reduce the number of unnecessary biopsies, US researchers suggest.

Moreover the results showed some correlation to disease severity markers, suggesting that the test could be used to distinguish between mild and aggressive forms of cancer.

The urine test detects the presence of a fusion between the TMPRSS2 (T2) and ERG genes, which is found in around 50 percent of prostate cancers.

“Many cancers detected at biopsy are low volume, low grade. There is a real need for tests that can help determine which of those men should receive aggressive treatment such as prostatectomy, and which could potentially be monitored more conservatively,” said lead researcher Dr. Jack Groskopf, who presented the results at the recent Genitourinary Cancers Symposium in Orlando, US.

“The key next steps here are to follow up and confirm the results that we have generated to date and, perhaps more importantly, to start looking at the correlation between the urine test and pathologic features in prostatectomy tissues, such as tumor volume stage and grade,” he said.

Commenting on the results, Dr. Howard Sandler, chair of radiation oncology at Cedars-Sinai Medical Center, Los Angeles, said: “The fact that this gene fusion is related to the progression and development of prostate cancer in half of all men who develop prostate cancer has major implications for diagnosis but hopefully for therapy as well. This unique fusion protein might become a therapeutic target at some point in the future.”

In a preliminary study of 556 men due to undergo prostate biopsy the urine test was 84 percent specific, reported Groskopf, a senior research scientist at Gen-Probe Incorporated, the San Diego-based company which is developing the test. For serum prostate-specific antigen (PSA) testing this figure is just 27 percent, he said, adding that the other current screening method – digital rectal exam – is also hampered by its low specificity.

“As a result the majority of prostate biopsies are negative, and you could argue that we are doing too many biopsies,” he said.

The sensitivity of the urine test was 42 percent – a favorable result considering that with only half of cancers containing the T2:ERG gene fusion, the theoretical maximum would be 50 percent, Groskopf added.

The urine test showed significant correlations to aggressiveness indicators such as the Gleason Score, the percentage positive prostate cores and the Epstein criteria.

Researchers from the University of Michigan, who are collaborating with Gen-Probe on the test, recently published another research paper linking sarcosine, a glycine derivative, to more aggressive forms of prostate cancer. This metabolite and its pathways could not only serve as a disease severity marker but also as a target for therapeutic intervention in future, they suggest. [Nature 2009 Feb 12;457:910-4]

Singapore center set to tackle childhood cancer in Asia

Medical Tribune April 2009 SFIV

David Brill

A new Singapore center could help raise childhood cancer survival rates across Asia, thanks to a recent $24 million funding boost.

The money will expand treatment facilities and strengthen research at the Viva-University Children’s Cancer Centre, which has already treated some 40 overseas children and begun training visiting specialists.

Around four out of five children with leukemia are cured in Singapore but in nearby countries this figure can be as low as one in 20.

“There is an urgent need for us to respond to the cries of children with cancer in Singapore and the whole region,” said Mrs. Jennifer Yeo, director and secretary of Singapore-based Viva Foundation for Children with Cancer.

“We are confident that with the support of all our donors, volunteers and strategic partners we can save many young lives,” she said.

The center, known as VUC3, has been operational for a year but was officially opened last month. Two specialists from the Philippines have already trained there, and one each from Myanmar and Brunei are currently in training.

The new funding comprises a $12 million gift from the Goh Foundation – a nonprofit private group – matched like-for-like by the Singapore government.

Four main research programs will be established, comprising bone marrow transplantation, childhood leukemia, bone cancer and ‘after completion of therapy,’ which focuses on the long-term impact of cancer treatment. This research will have a strong translational clinical focus with a view to raising cure rates, lowering treatment costs and minimizing side effects, said Associate Professor Allen Yeoh, medical director of VUC3.

“This will provide us with a quantum leap in the care of childhood cancer in Singapore, and help ensure that no child dies in the dawn of life. In the current severe recessionary climate, we are truly grateful to the Goh Foundation for their generosity,” said Yeoh, also a consultant at the University Children’s Medical Institute, National University Hospital, which houses VUC3.

Pediatric cancer survival is “dismal” in low-income countries, according to a study published last year. Five-year survival in the Philippines was estimated at 10 percent and in Vietnam just 5 percent. [Lancet Oncol 2008 Aug;9:721-9]

Between 120 and 140 new pediatric cancer cases are diagnosed in Singapore each year – some 40 percent of which are leukemia. Around 40 local children have been treated at VUC3 so far.

The center has already installed five new bone marrow transplant rooms and raised the number of inpatient beds from 12 to 17. The funding has also helped establish the Viva-Goh Foundation Professorship in Pediatric Oncology.

VUC3, built at a cost of $5 million from the Singapore Tote Board and Viva Foundation, is working closely with the St. Jude Children’s Research Hospital in Memphis, US – one of the world’s leading childhood cancer centers.

Everolimus shows promise for advanced stomach cancer treatment

Medical Tribune March 2009 P9
David Brill

Everolimus could provide a viable new treatment option for advanced gastric cancer, Japanese investigators said recently, following the conclusion of a phase II trial of the drug.

After 8 weeks of therapy everolimus halted tumor growth in 55 percent of patients, with 45 percent showing signs of tumor shrinkage.

A phase III trial involving some 500 patients will open for enrollment later this year, the drug’s manufacturer, Novartis, announced following the presentation of the new data at an American Society of Clinical Oncology symposium in January.

The multicenter, open-label study involved 54 Japanese patients of Asian descent who had previously undergone heavy treatment with chemotherapy.

"There are very limited treatment options for patients who progressed despite the standard treatment for this aggressive cancer," said lead researcher Dr. Atsushi Ohtsu, director of the Research Center for Innovative Oncology at the National Cancer Center Hospital East, Chiba, Japan. "The results from this study demonstrate that [everolimus] has the potential to provide an effective new option for these patients."

Patients in the study took 10 mg oral everolimus daily for an average of 57 days. The overall rate of adverse events – including anorexia, vomiting and stomatitis – was around 10 percent, with serious adverse events occurring in some 3 percent.

The median progression-free survival with everolimus was 83 days. At 4 months, around 30 percent of patients were still progression-free.

Everolimus inhibits the mammalian target of rapamycin (mTOR) – a cell signaling protein which is implicated in the development of several cancers. The drug has already shown promise for advanced renal cancer carcinoma and is currently under regulatory review in Europe and the US for this indication. A phase III randomized controlled trial, published last year, found that the drug prolonged progression-free survival by a median of 2.1 months over placebo in patients with metastatic renal cell carcinoma. [Lancet 2008 Aug 9;372(9637):449-56]

Gastric cancer is the most common type of cancer in East Asia, accounting for 18.9 percent of new cases in 2007, according to data from the American Cancer Society. Globally, it is the second leading cancer and is responsible for some 866,000 deaths worldwide each year, according to the WHO.

The risk of gastric cancer is thought to be increased by eating a diet high in salted, pickled and smoked foods, and by long-term infection with Helicobacter pylori. Male gender, smoking and age above 50 are also important risk factors.

Gefitinib reduces toxicity for advanced lung cancer patients

Medical Tribune January 2009 P11

David Brill

Gefitinib is a viable second-line alternative to chemotherapy for advanced non-small-cell lung cancer, offering similar survival rates with fewer side effects, a large-scale international study has shown.

The drug represents “an important shift in the treatment paradigm for this disease,” the authors of the INTEREST* trial reported in The Lancet. [2008 Nov 22;372(9652):1809-18]

Patients who took oral gefitinib also had improved quality of life compared to those who received intravenous infusions of docetaxel.

Asian patients, women, non-smokers and patients with adenocarcinoma all had longer survival with gefitinib – echoing the findings of previous trials which have shown the drug to be of particular benefit in these subgroups. Unexpectedly, however, INTEREST also found similar survival patterns with docetaxel, suggesting that these may be generally-applicable prognostic factors unrelated to the specific treatment.

Gefitinib is not currently approved for routine use by the US FDA. However in some Asian countires it is authorized for second-line use. For example in Singapore patients are typically given a choice between second-line treatment options in the event that initial chemotherapy is unsuccessful.

“Should the patient go on to further chemotherapy or should they go on to other drugs like gefitinib? This study confirmed that gefitinib is just as good as chemotherapy but may have fewer side effects,” said Dr. Toh Chee Keong, a consultant medical oncologist at the National Cancer Centre Singapore (NCCS).

Given the choice, most patients prefer an oral drug to chemotherapy but the higher cost of gefitinib can sometimes be a prohibitive factor, he said.

It remains unclear exactly who will benefit most from each treatment and why, he added, but noted that in his experience a non-smoking status is the most powerful predictor of a positive response to gefitinib.

In contrast to previous trials, neither epidermal growth factor receptor (EGFR) gene copy-number nor EGFR protein expression predicted survival with gefitinib in INTEREST.

The study is one of the few phase III clinical trials to directly compare the efficacy of docetaxel with an EGFR tyrosine kinase inhibitor. The analysis included 1,433 patients who had not responded to previous chemotherapy, recruited from 149 centers in 24 countries between March 1 2004 and February 17 2006.

The most frequent side effects of gefitinib were acne, rash and diarrhea. Just 4 percent of patients taking the drug experienced serious adverse events – a similar rate to that seen at NCCS, where Toh estimates that “less than 5 percent” of patients on gefitinib develop side effects to the point where they have to stop therapy.

For docetaxel the most common side effects in the trial were hematological toxic effects, hair loss and weakness. Serious adverse events occurred in 18 percent of patients in this group.

The non-inferiority of gefitinib was demonstrated by the median overall survival, which was 7.7 months in patients taking the drug compared to 8 months for those taking docetaxel. One-year survival rates were 32 and 34 percent in the respective groups.

Gefitinib patients were twice as likely to have a “sustained and clinically relevant improvement in quality of life,” as measured by the Functional Assessment of Cancer Therapy-Lung score (odds ratio 1.99; P<0.0001).>

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*Iressa NSCLC Trial Evaluating REsponse and Survival versus Taxotere

NUS to receive $3.5 million oncology funding boost

Medical Tribune December 2008 SFIII
David Brill

Singapore’s rapidly-expanding cancer research field has received a further boost with the recent signing of a $3.5 million deal for translational research.

The agreement will see the National University of Singapore’s (NUS) Yong Loo Lin School of Medicine embark on three joint projects with Bayer Schering Pharma, the Germany-based pharmaceutical company.

One of the aims is to profile new cancer drugs within Asian populations, where certain types dominate in comparison to the West.

The deal with NUS is just the first stage of a larger project for Bayer, which intends to invest S$20 million over the next 6 years in research and development in Singapore.

The focus of the present deal is on gastric, liver and lung cancer, but future projects could extend to other cancer types, said Associate Professor Manuel Salto-Tellez, assistant dean of research at NUS.

"We are very proud of this collaboration and believe that the partnership will have significant benefits for patients, academia and industry alike," he said.

"Some of the drugs that are currently with patients have taken up to 20 years to
be developed. By linking with industry in this way we’ll be able to make this process faster. What we are doing is at the core of what our institution is supposed to do, which is to serve patients better."

The project also seeks to identify new predictive biomarkers and to study new clinically-relevant tumor models.

Oncology research in Singapore is booming, with collaborations between academia and industry apparently on the rise. Another deal, signed in August, will see AstraZeneca provide promising new compounds for clinical and preclinical trials at National University Hospital and the National Cancer Centre Singapore.

"We are facing a big problem because cancer is one of the biggest killers in Singapore and the incidence continues to rise," said Salto-Tellez.

"Soon it’s going to develop into an extraordinary contradiction where the majority of cancer patients will come from Asian countries, yet the knowledge of the patients and how to treat them will be based on the results from other parts of the world and other ethnicities. Thus we cannot overemphasize how important it is to build clinical and scientific knowledge in Asia that will be directly and immediately applicable to Asians," he said.