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Afatinib delays progression in advanced lung cancer

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Scientists identify origins of cervical cancer

Controversy over prostate cancer screening recommendations

June 2012July-August 2012

Jul-Aug 20122

Afatinib delays progression in advanced lung cancer

Christina Lau

A fatinib, an investigational drug that irreversibly blocks EGFR (ErbB1), HER2 (ErbB2), HER3 (ErbB3) and

HER4 (ErbB4), significantly extended pro-gression-free survival (PFS) vs pemetrexed plus cisplatin in the largest phase III trial in EGFR mutation-positive advanced lung ade-nocarcinoma. [ASCO 2012; abstract LBA7500]

The oral pan-ErbB inhibitor was particu-larly beneficial for patients with deletion 19 or L858R – common mutations that together accounted for 89 percent of all EGFR muta-tions in the trial.

“Unlike reversible EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib, afatanib blocks the entire ErbB family of receptors permanently,” said lead inves-tigator Dr. James Yang of the National Tai-wan University Hospital. “While gefitinib and erlotinib have demonstrated significant benefits vs first-line chemotherapy, LUX- Lung3 is the first trial in EGFR mutation-pos-itive lung cancer to use pemetrexed/cisplatin as a chemotherapy comparator.”

The global trial included 345 treatment-naïve patients from 25 countries who had stage IIIB (wet) or IV disease (median age, 61 years; ECOG performance status, 0-1; East Asians, 72 percent; never-smokers, 68 percent). Patients were randomized 2:1 to receive afatinib (40 mg) once daily or pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) q21d until progression.

“The trial met its primary endpoint of PFS.

After a median follow-up of 8 months, patients receiving afatinib had a significant 4.2-month improvement in PFS. Median PFS was 11.1 months with afatinib vs 6.9 months with pemetrexed/cisplatin [hazard ratio (HR), 0.58; P=0.0004],” Yang reported. “Twelve-month PFS rate was 47 vs 22 percent.”

Importantly, the PFS benefit of afatanib was consistent in all relevant subgroups, in-cluding gender, age at baseline, race (Asian or non-Asian), baseline ECOG performance status, and smoking history (never smoked, or smoked <15 pack-years and stopped >1 year).

“The benefit of afatinib was even great-er in patients with deletion 19 or L858RV [N=308],” he continued. “In these patients, afatinib doubled PFS to 13.6 months vs 6.9 months with pemetrexed/cisplatin [HR, 0.47; P<0.0001]. PFS rate at 12 months was 51 vs 21 percent.”

Patients treated with afatinib also had a significantly higher objective response rate (56.1 vs 22.6 percent with pemetrexed/cispl-atin; P<0.001), a longer duration of response (11.1 vs 5.5 months), and a higher disease control rate (90 vs 81 percent). In patients with deletion 19 or L858R, objective response rate was 60.8 vs 22.1 percent (P<0.0001).

In addition, afatinib significantly pro-longed the time to deterioration of cough and dyspnea, resulting in a better quality of life.

“Grade 3/4 adverse events that were in-creased with afatinib included diarrhea [14.4 vs 0 percent], rash/acne [16.2 vs 0 per-cent], stomatitis/mucositis [8.7 vs 0.9 per-

Jul-Aug 20123

Cancer drug shortages a global problemNaomi Rodrig

The European Hematology Association (EHA), the American Society of Hema-tology (ASH) and the European Can-

cer Patient Coalition (ECPC) issued a joint call to action to address the looming crisis of can-cer drug shortage. The announcement, issued at the recent 2012 EHA Congress, comes on the footsteps of the American Society of Clini-cal Oncology (ASCO) 2012 Annual Meeting, which also highlighted the problem.

According to ASCO officials, disrupted manufacturing and quality control are the main culprits behind the shortages that have left many cancer patients without necessary treatments. “We’re never sure when a generic drug is suddenly going to go out of supply,” said Dr. Richard Schilsky, Chair of the ASCO Government Relations Committee.

Hundreds of drugs have been in short sup-ply in the US over the past year, including methotrexate, used frequently for leukemia; liposomal doxorubicin, which treats ovarian cancer; paclitaxel, used in a variety of cancers; mustargen, used to treat lymphoma; and 5-flu-orouracil (5-FU), a key component of adjuvant therapy for colorectal and other cancers.

The situation in Europe seems to be

even more serious. “In the US, legislation is under way that may curb drug shortages, but in Europe we do not even have a proper understanding of the scope of the problem,” remarked EHA President, Dr. Ulrich Jager.

The US FDA is drafting legislation requir-ing mandatory 6-month advance notification by drug companies for withdra-wals or man-ufacturing interruption, with penalties for non-reporting. Early alerts may enable gov-ernment agencies to source the same or alter-native drugs from overseas manufacturers.

“The situation in Europe is undoubt-edly more complex. We are not one country; we are 27 countries, each with its own rules and regulations,” noted Dr. Anton Hagenbeek, The Netherlands, who emphasized that drug supply and pricing are subject to government policies.

cent], paronychia [11.4 vs 0 percent], and dry skin [0.4 vs 0 percent],” said Yang. “These adverse events were as expected with EG-FR-targeting therapies, and were manage-able and reversible. It is also important to note that patients in the afatinib arm re-ceived 16 cycles of therapy, vs 6 cycles in the

pemetrexed/cisplatin arm.”In LUX-Lung3, only 7.9 percent of

patients discontinued afatinib due to treat-ment-related adverse events (vs 11.7 per-cent with pemetrexed/cisplatin), and only about 1 percent discontinued the drug due to diarrhea.

NewsJul-Aug 20124

Yen Yen Yip

The recent call from a US governmental advisory group to end routine pros-tate-specific antigen (PSA) screening

for prostate cancer, regardless of age, has pro-voked substantial controversy and criticism in the medical community.

The US Preventative Services Task Force (USPSTF) gave PSA screening a “D” recom-mendation, citing a lack of benefit for this procedure.

“Prostate-specific antigen-based screen-ing results in small or no reduction in pros-tate cancer-specific mortality,” commented the task force in a recent issue of Annals of In-ternal Medicine. They added that PSA screen-ing may in fact cause “harms related to sub-sequent evaluation and treatments, some of which may be unnecessary.” [Ann Intern Med 2012; May 21. Epub ahead of print]

This recommendation was heavily weighted by two major randomized screen-ing trials.

The US Prostate, Lung, Colorectal and Ovarian (PLCO) trial followed 76,685 men who were randomized to receive annual PSA screening or “usual care”, which sometimes included a PSA test. After 13 years, the inves-tigators found no mortality benefit in favor of annual PSA screening. [J Natl Cancer Inst 2012;104:125-132]

In the European Randomized Study of Screening for Prostate Cancer (ERSPC), about 162,243 men were followed up, half of whom received regular PSA screening and

half who did not. The results showed a mod-est benefit. [N Engl J Med 2012;366:981-990] According to the investigators, “1,055 men would need to be screened and 37 cancers detected in order to prevent one death from prostate cancer over 11 years of follow-up.”

Criticism followed swiftly on the heels of the US taskforce recommendation. “We … believe that the USPSTF has underestimated the benefits and overestimated the harms of prostate cancer screening. Therefore, we dis-agree with the USPSTF’s recommendation,” a group of oncologists, preventive medicine specialists and primary care physicians stat-ed, in an accompanying editorial. [Ann In-tern Med 2012; May 21. Epub ahead of print]

In the editorial, the physicians referred to significant methodological flaws in the trials. For instance, the control “usual care” group in the PLCO study received opportu-nistic PSA screening, which “contaminated” the results, and two-thirds of patients with abnormal screening tests did not go through biopsy promptly. Furthermore, the median follow-up in both trials was roughly 10 years – an inadequate duration.

Controversy over recent prostate screening recommendations

NewsJul-Aug 20125“The long history and heterogeneity (both

indolent and aggressive) subtypes of pros-tate cancer will moderate the overall benefit of screening, and will require longer follow-up and careful statistical analyses to show the real picture,” said Dr. Sim Hong Gee, senior consultant, department of urology, Singapore General Hospital.

In Singapore, where prostate cancer is the third most common cancer among men, PSA screening is advised for men with longer life expectancy and minimal morbidity, especial-ly in those with urinary symptoms. It is also recommended for men with abnormal digital rectal examination and those with a family history of prostate cancer, said Sim, in an in-terview with Oncology Tribune.

Routine PSA screening for all men is not advocated, he underscored.

“However, there are concerns that the blanket statement against PSA screening, re-gardless of age, will send the wrong signal to men that PSA has no role in prostate cancer detection,” Sim commented. “Careful selec-tion based on their risk profile will improve the detection of significant prostate cancer.”

For instance, PSA screening has limited usefulness in elderly men above 75 years of age because of their shorter life expectancy, Sim noted. In contrast, the test can be life-sav-ing for younger men, as treatment modalities

have improved efficacy and decreased mor-bidity.

In the US clinical setting, however, close to one in two men aged 75 years or older contin-ue to be screened for their PSA levels. Survey results published recently suggested that the PSA screening rate among men above the age of 75 was 43.9 percent. [JAMA 2012;307:1692-1694]

That is not appropriate, said Gee. “Indolent cancers that will never progress or cause mor-bidity to men may be picked up and treated with the attendant risks of treatment side ef-fects when they can be left alone.”

In other words, the decision to screen or not has to be balanced between the associated risks and benefits.

Despite the controversy swirling around PSA tests, it is undeniable that prostate can-cer mortality worldwide has declined since screening was introduced. This could be due to early detection, better curative treatment and supportive care, commented Sim. “It may be difficult to isolate the specific contribution of PSA screening.”

“We have seen a dramatic increase in pros-tate cancer incidence, but an equally dramatic decrease in men presenting with metastatic cancers. Somewhere along the way, early de-tection with PSA screening must have some-thing to do with it.”

Rajesh Kumar

Women in their 40s are being remind-ed not to miss their yearly mammo-grams.

This follows a study which showed that more than half of women aged 40-49 diagnosed with breast cancer on screening mammography had no family history of the disease.

The reminder seeks to address the confu-

Yearly mammograms from age 40 save lives

NewsJul-Aug 20126

sion created by an earlier meta-analysis which questioned the benefit of regular screening for preventing cancers in this age group, compared with screening of older women; and the subse-quent advice from the US task force on preven-tive services.

Clinical radiologists analyzed all breast can-cers diagnosed between 2000 and 2010 at the Elizabeth Wende Breast Care in Rochester, New York, US, and found that 228 out of 373 cancers (61 percent) were found in women aged 40-49 with no family history.

Seventeen of the 228 patients did have a prior personal history of breast cancer or abnormal cells at a prior biopsy, and were not included in this analysis. Out of 211 women who remained in the study, 135 (64 percent) had invasive dis-ease, although they did not have either the fam-ily history or a prior personal history of breast cancer or abnormal cells, said lead author Dr. Stamatia Destounis.

The findings were presented at the American Roentgen Ray Society annual meeting held re-cently in Vancouver, Canada.

Invasive disease includes invasive ductal, invasive lobular, mucinous, tubular and papil-lary cancers. Ninety-two of the patients with in-vasive disease were treated with lumpectomy, eight going on to mastectomy after close or positive margins; 42 had a mastectomy and 1 patient did not have surgery due to metastatic disease, said Destounis.

“We have follow-up imaging available for 149 of the 211 patients, and 144 are doing well; 5 have been diagnosed with new or recurrent cancer,” she said.

Destounis and colleagues decided to look at the clinic’s register of patients diagnosed with breast cancer in the 40-49 age group following intense de-bate on the issue. In 2009, the US Preventive Servic-es Taskforce left the decision to screen up to women in their 40s and their doctors, rather than explicitly recommending it, after finding little evidence of benefit in that group.

The taskforce quoted evidence that showed one cancer death was prevented for every 1,904 women aged 40-49 screened for 10 years, compared with one death for every 1,339 women aged 50-59, and one death for every 377 women aged 60-69. The revised recommendation did not apply to women with risk factors for breast cancer.

Although the benefit of screening a wom-an in her 40s may be slightly less than a 60 year old, there is good reason to identify these tumors small where treatment is mini-mal and prognosis the best, said Destounis.

“Pre-cancerous lesions may have been ig-nored or not taken into account... different regions of the breast were compared that may have had different rates of cancer, and women were not followed long enough in time to evaluate for survival differences,” she said of the studies the US task force re-lied upon.

With the advent of digital mammography, improved ultra-sound techniques and breast MRI, Destounis said radiologists are now identifying small treatable cancers and pre-cancerous lesions.

“As a radiologist specializing in breast cancer detection, my role is to identify tiny cancers that can be treated and the patient will have a good outcome,” she said.

Singapore breast surgeon Dr. Georgette Chan agreed with the findings and said more and more women in their 40s are real-izing this and coming forward for screening in her practice, but she added no statistics were available to see the wider trend.

Singapore’s Health Promotion Board has local statistics on the percentage of wom-en aged 50 to 69 years who participated in BreastScreen Singapore national breast screening programme during 2004-2010, but not for the younger women, Chan said, adding the recommendation remained for younger women to get yearly scans.

NewsJul-Aug 20127

Radha Chitale

Researchers from the Genome Institute of Singapore (GIS) have identified the mechanism that links hepatitis B

virus (HBV) with hepatocellular carcinoma (HCC).

When HBV DNA is integrated into the host’s genome, oncogenes become upregulat-ed, causing cancer cells to proliferate.

The researchers, including collaborators from the National University of Singapore, the University of Hong Kong, Beijing Genomics Institute China, Eli Lilly & Co., Merck Research Laboratories, and Pfizer Oncology, found that the higher the incidence of integration, the more likely that tumors would occur.

“In normal tissues, we also have HBV in-tegration, but less,” said Dr. Ken Sung, senior group leader of Computational and Systems Biology at GIS. “After integration, we mea-sured gene expression and [several oncogenes] were activated... in the past people just felt that this was true, but we saw clinical evidence that this is really true.”

The researchers analysed 88 Chinese patients with HCC who had undergone liv-er transplantation. Of these, 81 were HBV- positive and seven were HBV-negative. [Nat Genet 2012; May 27. DOI:10.1038/ng.2295. Epub ahead of print]

HBV integrations were present in 86.4 per-cent of the total samples compared with 30.7 percent in surrounding tissues.

Integrations can be benign occurrences in multiple types of tissue. However, among the patients included in the study, those with HBV

integration were more likely to have presented with HCC at a younger age, before developing HCC risk factors like liver cirrhosis.

Overall survival was significantly lower in patients with more HBV integrations com-pared with those with fewer HBV integrations (P=0.037).

“HBV integration causes more shuffling in the human genome, leading to a higher chance of having a tumor,” Sung said.

Over 40 percent of HBV integrations pre-sented at regulatory gene sites. Clinical analy-sis showed that these genes were more likely to have upregulated expression in tumor tis-sues compared with normal tissues.

Sung concluded that drugs which reduce oncogene expression level may help to treat patients with HCC in the future.

Mechanism linking hepatitis B to liver cancer identified

NewsJul-Aug 20128

Elvira Manzano

To establish its position as an emerging regional center for medical training and surgical oncology research, the

National Cancer Centre Singapore (NCCS) held the 1st NCCS Oncology Conference 2012 recently in Singapore.

Approximately 100 surgical oncologists, cancer experts and allied health professionals from across Southeast Asia attended the 3-day meeting which focused on the evolving role of surgery in the treatment of head and neck, sarcoma, gastrointestinal, and breast cancers which are common in the region.

“The conference stemmed from our desire to alleviate the sufferings of people afflicted with cancer,” said Dr. Tan Hiang Khoon, con-sultant, surgical oncology, NCCS and chairman of the conference organizing committee. “The best way to do this is to train as many doctors as possible so that they can go back and treat their local community. It will be even better if they can train their colleagues as the multiplier effect in the community will be greater.”

This year, the NCCS said a number of phy-sicians were chosen to receive the BNP Pari-bas-NCCS Fellowship Program though it did not disclose their names. Last year, four doc-tors from Vietnam got the slot and underwent post-graduate oncology training in oncology at the NCCS. “We are fortunate to have the support of a group like BNP Paribas [which shares] our vision to serve the wider commu-nity in Asia,” said Professor Soo Khee Chee, director of NCCS.

“In the long-term, medical outreach initia-tives like this will help countries in need to reach higher levels of medical training and research and benefit their communities,” said Mr. Jean-Pierre Bernard, BNP Paribas regional head for Southeast Asia.

Data from the World Health Organization indicates that more than 6 million new cases of cancer are diagnosed in Asia each year. Con-sequently, this would dramatically increase the demand for oncologists and quality cancer treatments.

NCCS holds first regional surgical oncology conference

NewsJul-Aug 20129

Arthritis drug to be tested in lymphomaChristina Lau

S ingaporean researchers are planning to test a Janus kinase 3 (JAK3) inhibitor in patients with natural killer (NK)/T-

cell lymphoma – a very aggressive form of lymphoma frequently found to harbor JAK3 mutations.

“NK/T-cell lymphoma is particularly prevalent in Asia, accounting for almost half of all T-cell lymphomas in some parts of the region,” said Professor Bin-Tean Teh of the National Cancer Center Singapore–Van An-del Research Institute Translational Research Laboratory and Duke–National University of Singapore Graduate Medical School.

“Very little was known about the genetic and molecular defects causing the aggres-sive disease before we started our study,” he continued. “With no effective treatment, the prognosis of patients with NK/T-cell lympho-ma is extremely poor.”

In their study, Teh and colleagues con-ducted whole-exome sequencing of NK/T-cell lymphoma cells from four patients, and identified JAK3 somatic-activating mutations in two of them. Further validation was con-ducted in another 61 patients with Sanger sequencing and high-resolution melt (HRM) analysis. In total, 23 of 65 cases (35.4 percent) harbored JAK3 mutations. [Cancer Discov 2012, e-pub 15 Jun]

The mutations enabled NK/T-cell lympho-ma cell lines to grow in culture without the normally essential growth factor, interleu-kin-2 (IL-2). This means that JAK3 mutations cause dysregulated activation of JAK3, sug-gesting that JAK3 may be a good drug target.

“There is a JAK3 inhibitor [CP-690550

(tofacitinib)] currently in phase III trials for treatment of rheumatoid arthritis. In our study, use of CP-690550 in the JAK3-mu-tant NK/T-cell lymphoma cell lines led to inhibition of STAT5 [signal transducer and activator of transcription-5] phosphory-lation, along with reduced cell viability,” reported Teh. “We are in the process of plan-ning a clinical trial to test the agent as a treat-ment for NK/T-cell lymphoma with JAK3 mutations.”

“It is tremendously rewarding to have identified genetic mutations that appear to have an important role in driving NK/T-cell lymphoma in a considerable proportion of cases,” he continued. “Although relatively rare in the USA, this form of lymphoma is responsible for the deaths of a large number of people in Asia, especially in China and Korea.”

NewsJul-Aug 201210

‘‘

Scientists identify origins of cervical cancerRajesh Kumar

A multinational research team, includ-ing scientists based in Singapore, has been credited with identifying the

origins of cervical cancer by discovering that a specific population of cells, found only in the region of the cervix called the ‘squamo-columnar junction’, can become cancerous when infected with human papillomavirus (HPV), while other cells in the cervix appar-ently do not.

“[This] discrete population of cells located in a specific area of the cervix could be re-sponsible for most, if not all, of HPV-asso-ciated cervical cancers,” said researcher Dr. Christopher Crum, Director of the women’s and perinatal pathology at Brigham Women’s Hospital in Boston, Massachusetts, US.

The finding uncovers a potential target for cervical cancer prevention, provides insight into the risk assessment of cervical lesions, and establishes a model for understanding the pathway to cervical cancer following car-cinogenic HPV infection, the scientists said. [PNAS 2012;109:10516-10521]

They showed that these cells have a unique gene expression that is also found in the cells of aggressive tumors of the cervix. This could potentially allow clinicians to dif-ferentiate benign from potentially dangerous precancerous lesions in the cervix and guide therapy.

“Our study also revealed that this exotic population of cells does not reappear after ablation by cone biopsy,” said Dr. Wa Xian, principal investigator at A*STAR’s Institute of Medical Biology.

“This finding helps to explain the low rate of new HPV infections in the cervix after ex-cisional therapy and also raises the distinct possibility that preemptive removal of these cells in young women could reduce their risk of cervical cancer. This could be an alterna-tive to current vaccines which only protect

against HPV 16 and 18.”But further research is needed to evaluate

the benefits and risks of this potential thera-py, he added.

The study further builds upon the previ-ous work by Drs Xian and Frank McKeon, se-nior group leader at A*STAR’s Genome Insti-tute of Singapore, which showed for the first time, in a mouse model, that some cancers originate from just a small set of cells that are unique from the other cells that reside around them. [Cell 2011;145:1023-1035]

“Our previous work on esophageal cancer opened up the possibility of preventive ther-apy to stamp out the disease by eliminating this small group of cells. This recent work in the cervix further validates this concept and raises important possibilities for early inter-vention to prevent malignancies linked to very small populations of these unusual, dis-crete population of cells,” said McKeon.

[This] discrete population of cells located in a specific area of the cervix could be responsible

for most, if not all, of HPV-associated cervical cancers

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Anticancer compound shows promise in NUS labRajesh Kumar

BPTES*, an anticancer compound currently undergoing preclinical tri-als in Singapore and the US, has been

shown to prevent tumor growth.This finding, by a team of scientists from

the department of biological sciences and mechanobiology institute at the National University of Singapore (NUS), could lead to more effective and less toxic cancer treat-ments. [PNAS 2012;109:7705-7710]

Cancer cells feed off the breakdown of the amino acid glutamine to gain energy and grow into a tumor. While it is known that hu-man glutaminase is the first enzyme in cata-lyzing this series of biochemical reactions, little is known about how its activity is con-trolled and how it can be manipulated, said the researchers.

They identified the mechanism by which the BPTES compound binds with and inhib-its glutaminase, effectively starving the can-cer cells of their energy source and potential-ly preventing tumor growth.

“We now provide the first detailed struc-ture of how BPTES inhibits glutaminase by inducing a dramatic allosteric shift… These findings could offer a new cancer treatment regime that is more potent but less cyto-toxic”, said co-researchers and associate professors Low Boon Chuan and Jayaraman Sivaraman.

“Intriguingly, this enzyme can be acti-vated by epidermal growth factor acting through a well known growth promoting Ras-Erk signaling pathway.”

Using the knowledge gained through the current study, the scientists said they would look into optimizing the tumor suppression property of BPTES to increase its efficiency and lower its side-effects.

“The encouraging results show promise for a new dual-drug cancer treatment which is more effective with fewer side effects, especially for cancers such as lymphoma, prostate, glioblastoma, breast and kidney cancer cells,” said Low.

More inhibitors targeting glutaminase are also being researched.

NewsJul-Aug 201213

Elvira Manzano

US researchers have developed a ge-netic test that can accurately predict if eye cancer will spread to other

parts of the body, particularly the liver. In a multi-center study involving 459 pa-

tients with uveal or ocular melanoma, the 15-gene expression profile test was able to classify tumors more than 97 percent of the time. Almost 62 percent of those tested (276 patients) had class 1 tumors and 32 percent (170 patients) had class 2 tumors. Three class 1 tumors and 44 class 2 cases had metastasized (P<10−14) one and a half years later. [Ophthal-mology 2012; Epub ahead of print]

Tumors with a class 1 gene expression rare-ly spread beyond the eye while those with class 2 frequently develop into metastatic can-cer.

Principal investigator Dr. J William Har-bour, from the Washington University School of Medicine in St. Louis, Missouri, US, said it is unlikely that any therapy is going to be effective when the cancer has spread beyond the eye.

“By identifying the type of tumor a patient has, we can first remove the tumor from the eye with surgery or radiation and then get those individuals at high risk into clinical tri-als that might be able to help them live lon-ger.”

The researchers tested tumor samples collected from 16 centers in the US and Canada and found that the test was very good at classifying tumors. “Our test was an accurate predictor of which patient will de-

velop metastasis. It also proved that the test can be performed successfully in most other clinics. At the moment, more than 70 centers around the world are using a commercially available version of the same test.”

In the past, chromosome tests have been used to identify eye tumors that are likely to spread. But results vary depending on which part of the tumor gets sampled. Harbour said the 15-gene expression profile test is more ac-curate as it takes a more complete “snapshot” of the entire tumor. It can also identify which patients will need the closest monitoring.

“We won’t have to use high-intensity surveillance on everyone, only those patients with a class 2 molecular signature because they’re the ones at risk for metastatic cancer,” Harbour said.

The authors hope their findings will lead to more cancerous tumors being identified and treated early, which will prolong and save lives.

Genetic test can predict if tumor will spread beyond the eye

NewsJul-Aug 201214

Radha Chitale

Fertility drugs were associated with a lower risk of breast cancer before age 50 among women who did not conceive,

according to the results of a large case-control study in the US. However, if a woman became pregnant for 10 weeks or more, the risk of young-onset breast cancer increased.

“The widespread use of ovulation-stimu-lating fertility drugs has raised concern about possible implications for breast cancer,” said researchers from the National Institute of En-vironmental Health Sciences in Research Park Triangle, North Carolina, US.

“Breast cancers in women younger than age 50 years are rare but can be aggressive and carry a worse prognosis compared with those in older women, and distinct risk factors are associated with such young-onset disease.”

The retrospective sister-matched case-con-trol study included 1,422 women diagnosed with breast cancer at younger than 50 years and 1,669 cancer-free control sisters. [J Natl Cancer Inst 2012; DOI: 10.1093/jnci/djs255]

Among the case participants, 288 reported using ovulation-stimulating drugs – 193 used clomiphene citrate (CC), 29 used follicle-stim-ulating hormone (FSH, and 66 used both.

Fertility drug use overall was associated with a non-statistically significant decrease in the risk of breast cancer (OR 0.82, 95% CI 0.63 to 1.08) compared with nonusers.

Unsuccessful fertility drug use was associ-ated with a statistically significant decreased young-onset breast cancer risk (OR 0.62, 95% CI 0.43 to 0.89) compared with nonusers.

Successful fertility drug use (10+ week pregnancy) was associated with a statistical-ly significant increased risk in young-onset breast cancer compared with unsuccessfully treated women (OR 1.82, 95% CI 1.10 to 3.00), but it was not increased compared with non-users (OR 1.13, 95% CI 0.78 to 1.64).

The researchers could not distinguish risk based on CC or FSH used alone versus togeth-er. The study was limited due to self reported fertility drug use and no diagnostic data for those who were infertile. In addition, the case sisters were overall younger than the control sisters.

“In young women, increased breast cell differentiation during pregnancy can lead to a long-term protective effect. Ovulation stimu-lating treatment causes abnormally high ex-posure to ovarian hormones during the first 9 weeks of pregnancy and could potentially raise risk by modifying breast tissue remodel-ling,” the researchers said. “Our data suggest that exposure to a stimulated pregnancy is

Fertility drugs linked to breast cancer risk in young women

NewsJul-Aug 201215enough to undo the reduction in risk associ-ated with a history of exposure to ovulation-stimulating drugs.”

In an accompanying comment, Dr. Louise Brinton of the US National Cancer Institute, suggested other explanations for the higher risk of breast cancer among women who be-came and stayed pregnant for at least 10 weeks following hormone treatments, including the “well recognized dual effect of pregnancy on breast cancer risk... a short term transient in-crease that dissipates with time and eventu-ally leads to a long term risk reduction,” es-pecially when the pregnancy is carried out to

term. [J Natl Cancer Inst 2012; DOI: 10.1093/jnci/djs275]

She noted that genetic factors, such as BRCA gene mutations, and tolerance for fer-tility drugs also play a role in cancer risk, par-ticularly among women who are diagnosed before age 50.

“The results are difficult to interpret in the context of previous studies, given that findings have ranged from reduced risks to increased risks to the absence of any relationship” she said. “Further resolution of relationships is ultimately dependent on cohort studies...”

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Conference CoverageJul-Aug 201216 48th Annual Meeting of the American Society of Clinical Oncology, 1-5 June, Chicago, Illinois, US

Promising drug combination benefits HER2+ breast cancer patients Radha Chitale

A novel agent linking the antibody trastu-zumab (Herceptin) to a potent chemotherapy drug improved progression free survival in women with HER2-positive (HER2+) meta-static breast cancer compared with standard therapy, according to interim results from the phase III EMILIA* trial.

The new agent, called T-DM1, may also have positive implication for overall survival.

“T-DM1 is a brand new way of treating HER2+ breast cancer,” said lead researcher Dr. Kimberly Blackwell, Duke University Medical Center in Durham, North Carolina, US. “I think it is the first of many antibody drug conjugates to follow that will link a po-tent anti-cancer agent to the targeted delivery system of an antibody.”

The trial, supported by Genentech, in-cluded 978 women with confirmed HER2+ metastatic breast cancer who were on or had recently been treated with taxane and trastu-zumab.

Patients were randomized to infusions of the HER2 antibody trastuzumab linked to the microtubule inhibitor emtansine (trastuzum-ab emtansine, T-DM1) or oral lapatinib plus capecitabine. Median follow-up was just over 1 year for both groups.

Median progression free survival improved 35 percent with T-DM1, 9.6 months versus 6.4 months with lapatinib plus capecitabine (P<0.0001).

Overall survival at 1 and 2 years was 84.7 percent and 65.4 percent, respectively, in the T-DM1 group and 77 percent and 47.5 percent

* EMILIA: An Open-Label Study of Trastuzumab Emtansine (T-DM1) vs

Capecitabine+Lapatinib in Patients With HER2-Positive Locally Advanced

or Metastatic Breast Cancer

in the lapatinib plus capecitabine group. Median overall survival was 23.3 months

with standard therapy but was not reached in the trastuzumab group (P=0.0005).

The novel trastuzumab emtansine combi-nation appeared to be safe and well tolerated.

Emtansine is too toxic to administer sys-temically and linking it to trastuzumab helps guide it to tumor cells with HER2 receptors.

Fewer severe adverse events occurred in the T-DM1 group compared to the lapatinib group (40.8 percent and 50.0 percent, respec-tively) with thrombocytopenia and increased liver enzymes as the most common adverse events.

“T-DM1 really works in this patient pop-ulation,” said Dr. Louis Weiner, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington, D.C., US, and noted the previously limited targeted therapy options for breast cancer patients with pro-gressive disease.

“The improved survival is particularly no-table since effective palliative treatment of metastatic breast cancer has rarely been asso-ciated with improved survival in a refractory setting,” he said.

Blackwell said the novel agent should offer important therapeutic options for HER2+metastatic breast cancer patients.

Conference CoverageJul-Aug 201217

Radiation therapy in childhood increases breast cancer risk

Radha Chitale

Adult survivors of childhood cancers treated with radiation therapy have an increased risk of breast cancer,

similar to that of women who carry BRCA gene mutations, even if the radiation dose was low.

Prior studies showed girls treated with radiation to the chest have increased risk of breast cancer, but lead researcher Dr. Chaya Moskowitz, Memorial Sloan-Kettering Can-cer Center in New York City, New York, US, said the comparison to risk from BRCA gene mutations is unknown.

The researchers compared 1,268 female 5-year cancer survivors from the Childhood Cancer Survivor Study (CCSS) and 4,570 first-degree female relatives of women with breast cancer from the Women’s Environmental Cancer and Radiation Epidemiology (WEC-ARE) to estimate the incidence of BRCA-1 and -2 carriers.

The rate of breast cancer in the general public was 4 percent by age 50, according to analysis of the Surveillance, Epidemiology, and End Results (SEER) study.

Among the WECARE cohort, 324 women were diagnosed with breast cancer by median age 55. Cumulative incidence of breast can-cer was 31 percent among those with BRCA-1 mutations and 10 percent among those with

BRCA-2 mutations. In the CCSS cohort, 175 were diagnosed

with breast cancer at median age 38 with a median 23 years lag until diagnosis. Medi-an follow up of study participants was 26 years.

The overall incidence of breast cancer was 24 percent among girls who survived any type of cancer but the incidence among Hodgkin’s lymphoma (HL) survivors was 30 percent by age 50, similar to that of wom-en with BRCA-1 mutations.

Moskowitz said the discrepancy could be the result of a larger area of the chest ex-posed to radiation during treatment for HL, which increases the risk of breast cancer.

Typically, people who receive radiation doses of 20 Grays (Gy) or more are current-ly recommended for cancer screening.

However, Moskowitz said it was “re-markable” that women treated for cancers other than HL with moderate doses of ra-diation (10-19 Gy) to large areas of the chest also have elevated risk of breast cancer sim-ilar to that of BRCA-2.

These women are not currently recom-mended for screening but Moskowitz sug-gested they would benefit from breast can-cer surveillance strategies as their risk is higher than previously recognized.

48th Annual Meeting of the American Society of Clinical Oncology, 1-5 June, Chicago, Illinois, US


Elvira Manzano

Two relatively new drugs for patients with recurrent or metastatic breast cancer failed to beat old stand-by pa-

clitaxel in a phase III cooperative group trial. Treatment with paclitaxel resulted in a lon-

ger median progression-free survival (PFS) of 10.6 months compared with 9.2 months and 7.6 months for novel nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and ixabep-ilone, respectively. Rates of peripheral neu-ropathy and hematologic toxicity were also higher with both agents than with paclitaxel.

“Neither weekly nab-paclitaxel nor ixabep-ilone is superior to weekly paclitaxel,” said study author Dr. Hope Rugo, of the Univer-sity of California, San Francisco, US. “In com-bination with bevacizumab, weekly paclitaxel is the better tolerated drug.”

The study involved 799 patients – with lo-cally advanced or metastatic breast cancer and no prior chemotherapy – randomized to nab-paclitaxel 150 mg/m2, ixabepilone 16 mg/m2), or paclitaxel 90 mg/m2 (as a control) plus bevacizumab every 2 weeks. Each treatment cycle lasted for 3 weeks, followed by a 1-week break. The primary endpoint was PFS or time from randomization to disease progression or

Newer agents no better than paclitaxel as first-line breast cancer therapy


death from any cause. Median follow-up pe-riod was 12 months. The study was powered to detect a hazard ratio of 1.36 (median PFS of 10 vs. 13.6 months).

Ixabepilone was dropped earlier from the trial after it demonstrated significantly worse PFS. “Our data showed that we should not simply assume that newer drugs are always better than the standard therapies for meta-static breast cancer,” said Rugo. She explained that dosing schedules are constantly being examined and refined, new therapies tested, and molecular characteristics of tumors are looked at closely to determine the right treat-ment for the right patient, with least toxicities.

However, she said nab-paclitaxel may be a useful alternative in patients who cannot tolerate paclitaxel or in a setting where pacli-taxel is not readily available.

The US Food and Drug Administration in November 2011 revoked bevacizumab’s con-ditional approval as a treatment for metastat-ic breast cancer because of potentially serious side effects such as high blood pressure and hemorrhage. At that time, enrolment for the trial, called CALGB 40502/NCCTG N063H, had already started.


Better strategies needed for ALL in adolescents and young adults


Christina Lau

A dolescents and young adults with high-risk acute lymphoblastic leu-kemia (ALL) have poorer survival

and higher toxicity from treatment than their younger counterparts, according to new data from a major phase III study which highlights the need for better treatment strategies for this group of patients. [Abstract CRA9508]

“Historically, ALL patients older than 16 years have an inferior outcome compared with patients aged 1 to 15 years because older patients have higher rates of relapse and tox-icity,” said lead author Dr. Eric Larsen of the Maine Children’s Cancer Program in Scarbor-ough, Maine, USA. “In the Children’s Oncol-ogy Group [COG] study ALL0232, we tested dexamethasone vs prednisone during induc-tion and high-dose methotrexate vs escalating Capizzi methotrexate plus PEG asparaginase during interim maintenance 1 in a 2 x 2 fac-torial design. For the fist time, patients aged 21-30 years were eligible for enrollment in an ALL study.”

ALL0232 enrolled patients with newly-di-agnosed B-precursor high-risk ALL. Of 2,571 eligible patients, 501 (20 percent) were aged 16-30 years. “This represents the largest co-hort of adolescent and young adult ALL pa-tients to date in a single clinical trial,” he said.

At 5 years, patients aged 16-30 years had significantly poorer event-free survival (EFS) and overall survival (OS) than those <16 years

(68 vs 80.9 percent and 79.8 vs 88.4 percent, respectively; p<0.0001 for both).

“Relapses were significantly more frequent in adolescent and young adult patients, pri-marily due to a higher rate of bone marrow relapse,” reported Larsen. “The 5-year cumu-lative relapse rate was 21.3 percent in patients aged 16-30 years, vs 13.4 percent in younger patients [p=0.002]. Marrow relapse at 5 years was 15.3 vs 9 percent, respectively [p=0.0007].”

Central nervous system (CNS) relapse was similar between the two groups (5 years, 5.2 vs 3.7 percent; p=0.58). According to the investigators, the treatment strategy of the

Conference CoverageJul-Aug 201220trial was to try to improve disease control in the CNS.

Remission, defined as <5 percent marrow blasts at the end of induction, was also signifi-cantly lower in adolescent and young adult patients (97.2 vs 98.8 percent; p=0.0134). Mor-tality during post-induction remission was significantly higher among those aged 16-30 years vs those <16 years (5 years, 5.5 vs 2.1 per-cent; p<0.0001), although there was no signifi-cant difference in induction mortality between the two groups (2.4 vs 1.8 percent; p=0.36).

“Adolescent and young adult patients treated in ALL0232 had improved outcome

compared with previous studies that showed EFS rates of 50-60 percent,” remarked Larsen. “However, our results suggest that we need to find novel agents that improve leukemia control with reduced toxicity. As ‘older’ ALL patients don’t tolerate chemotherapy as well as younger patients, their compliance is often lower and treatment protocols for them tend to be less intense in terms of the number of drugs, dosages and treatment duration. As a result of our study, the COG is considering several options to both enhance leukemia control and reduce toxicity.”


Yen Yen Yip

Bendamustine, a drug developed during the 1960s, is expected to change clinical practice for doctors treating indolent

and mantle-cell lymphomas. Originally developed and used to treat dif-

ferent types of non-Hodgkin’s lymphomas in the former East Germany, the drug had not been available elsewhere until 1990. “After re-unification, doctors in western Germany were a bit skeptical to adopt this compound, as one can imagine,” said Dr. Matthias Rummel, pro-fessor of medicine at the University Hospital Giessen, Germany.

But the latest findings from the Study Group for Indolent Lymphoma (STiL) trial will likely reverse any skepticism that still remains.

The results demonstrated that a regimen of bendamustine combined with rituximab (BR) was not only more effective, it was also less toxic, than standard R-CHOP chemotherapy.

The STiL trial was the first study to random-ize 514 previously untreated patients for indo-lent non-Hodgkin’s lymphomas to six cycles of BR or standard R-CHOP chemotherapy.

For years, R-CHOP, which includes ritux-imab plus the drugs cyclophosphamide, doxo-rubicin, vincristine and prednisone, has been the preferred therapy for non-Hodgkin lym-phomas such as mantle cell and follicular lym-phomas, among others.

The BR regimen more than doubled pro-gression-free survival (PFS) compared with R-CHOP. At a median follow-up of 45 months, the BR regimen was associated with a signifi-cantly longer median PFS of 69.5 months vs. 31.2 months for R-CHOP (P=0.00001).

Of note, patients on R-CHOP experienced significantly higher rates of grade 3 and 4 he-matotoxicity compared with BR, with more leukocytopenia (38.2 vs. 12.1 percent) and neu-tropenia (46.5 vs. 10.7 percent), thus requiring more use of granulocyte colony-stimulating factor (20 vs. 4 percent, all P<0.0001).

“BR shows by far a lower toxicity profile,” said Rummel, also lead author of the STiL study. “Alopecia is a very prominent differ-ence: nearly all patients had hair loss after R-CHOP, but not a single patient experienced hair loss with BR,” he added.

BR was also associated with fewer cases of infections and neuropathy than R-CHOP. While a higher incidence of skin reactions such as erythema and allergies occurred in the BR group, these events were generally much bet-ter tolerated.

“Bendamustine-based therapy allowed patients to have a better quality of life while undergoing therapy,” noted Rummel. “These long-term findings should be strong enough to change clinical practice ... BR should be con-sidered as a preferred first-line treatment for patients with these disease entities.”

Bendamustine-based regimen benefits lymphoma patients



Elvira Manzano

The BRAF inhibitor dabrafenib and the MEK inhibitor trametinib stall cancer progression or death in patients with

advanced or metastatic melanoma, results from two separate randomized phase III trials have shown.

Both agents demonstrated statistically sig-nificant benefits compared with standard che-motherapy in both studies.

In the BREAK3* trial, which involved 250 patients with advanced melanoma harboring common BRAF mutations, dabrafenib signifi-cantly reduced the risk of disease progression or death by 70 percent (hazard ratio [HR] 0.30; P<0.0001) relative to standard chemotherapy (with dacarbazine). Median progression free survival (PFS) was 5.1 months for dabrafenib versus 2.7 months for chemotherapy, while corresponding overall response rates (ORRs) were 53 percent and 19 percent, respectively.

In the study, patients were randomized to receive either dabrafenib 150 mg twice daily or chemotherapy with dacarbazine 1,000 mg given intravenously every three weeks. The most common side effects reported in patients receiving dabrafenib were hyperkeratosis, ar-thralgia, headache, pyrexia, fatigue, headache and squamous cell carcinoma.

“Dacarbazine is no longer the standard of care for BRAF-mutated patients… they need a BRAF inhibitor. It’s the beginning of a new era in treatment of metastatic melanoma,” said

study author Dr. Axel Hauschild of the Uni-versitaetsklinikum Schleswig-Holstein in Kiel, Germany. “The next step is to combine BRAF and MEK inhibitors not only for stage IV mela-noma but also in the adjuvant setting.”

In the METRIC** study of 322 patients with V600E or V600K BRAF-mutated tumors, those who received trametinib lived longer without their cancer worsening than those treated with chemotherapy (dacarbazine or paclitaxel). Me-dian PFS was 4.8 months for trametinib vs. 1.5 months for chemotherapy, a 55 percent reduc-tion in the risk of disease progression (HR 0.44; P<0.0001).

An interim analysis showed there was im-provement in overall survival with a 46 percent reduction in risk of death (HR 0.53; P=0.0181). The ORR to trametinib was 22 percent com-pared with 8 percent for chemotherapy. None of the patients developed cutaneous squa-mous cell carcinomas observed with BRAF in-hibitors. Rates of hypertension and rash were higher with trametinib (12 percent and 8 per-cent, respectively) than with chemotherapy (8 percent and 0 percent, respectively).

“We have better PFS, better response rate and prolonged survival. The safety profile is manageable,” said lead study author Dr. Caro-line Robert, head of dermatology at the Insti-tute Gustave Roussy in Villejuif, Paris, France. “This trial provides a positive risk-benefit ratio of trametinib for patients with BRAF-mutant melanoma and delivers an alternate treatment option for this group of patients.”

New agents beat standard chemo in advanced melanoma


Conference CoverageJul-Aug 201223Moreover, data from a phase I/II trial dem-

onstrated that the combination of dabrafenib and trametinib further delayed cancer progres-sion in untreated patients with metastatic mel-

anoma. Median PFS was 7.4 months, compa-rable to what was observed in the vemurafenib studies. Phase III trials for the combination therapy have already started.

Feeding, not starving, tumors improves response to therapies and overall survival Radha Chitale

Cancer patients may live longer if their tumor microenvironment is normal-ized, rather than starved of blood and

other nutrients, so that therapeutic treatments are more effective, said Professor Rakesh Jain, of the Steele Lab for Tumor Biology, Massa-chusetts General Hospital, Harvard Medical School in Boston, Massachusetts, US.

This approach has implications for the half billion people worldwide with diseases char-acterized by abnormal vessels, he said.

As tumors grow, vessels can become disor-ganized, misshapen or blocked, creating areas without oxygen. This hypoxic environment creates high interstitial fluid pressure and contributes to genetic instability, angiogen-esis, resistance to cell death and metastasis.

However, chemotherapy, radiation therapy and immunotherapy are demonstrably more effective when the tumor microenvironment is in a normal state.

In a study of 30 patients with recurrent glioblastoma treated with an anti-vascular endothelial growth factor (VEGF), seven had increased tumor blood perfusion for more than 1 month, which was associated with increased survival of 6 months compared to

patients in whose tumors blood perfusion re-mained stable or decreased (P=0.019). [Cancer Res 2012;72:402-407]

“Normalization induced blood flow has the potential to increase survival in patients,” Jain said.

However, dose matters when treating with anti-VEGF therapy to improve blood flow to tumors; too little anti-angiogenic agent re-sults in no change to the blood vessels and too much leaves only a small window for normal-ization before excessive pruning and hypoxia set in.

Smaller molecules, about 10 nm, were the optimal size for drug delivery to promote normalization and tumor response.

Alleviating hypoxia in tumors makes the mass immunostimulatory, Jain said, and ves-sels are able to bring more T-cells to the tumor to increase the efficacy of immunotherapy.

“Five to 10 years from now we would see normalization be combined with a variety of immunotherapies,” he said.

Jain also noted that a similar normalization strategy could be used for lymphatic vessels and the tumor cellular matrix as well to im-prove perfusion and improve the efficacy of chemotherapy, radiation therapy and immu-notherapy and overall survival.


Yen Yen Yip

Recently released clinical data are re-shaping assumptions about resistance towards vascular endothelial growth

factor (VEGF)-targeted therapies. “Almost all malignancies are inherently

resistant to VEGF targeted therapies,” com-mented Dr. Lee Ellis from the department of surgical oncology and cancer biology at the University of Texas MD Anderson Cancer Center, Houston, Texas, US. “To understand resistance, we need to better understand the mechanisms of action [in angiogenic path-ways].”

While scant attention was given to VEGF resistance 20 to 40 years ago, today’s cancer clinicians and scientists consider resistance to be an inevitable part of VEGF therapy, he said. This has led to a hunt for agents which can improve or prolong therapeutic benefit by targeting unique angiogenic pathways.

New therapies have been designed to in-hibit both VEGF and as well as mechanisms of resistance against anti-VEGF activity, such as fibroblast growth factor (FGF) and pla-centa growth factor (PlGF). [Clin Cancer Res 2008;14:6371-6375]

However, clinical trials reported at ASCO 2012 indicate that “dual targeting of bypass pathways have not led to major advances,” said Ellis, adding that resistance may not be as certain as once thought. “Continuation of therapy may be of some benefit.”

Brivanib is a tyrosine kinase inhibitor (TKI)

targeting both VEGF and FGF receptors. In an early phase study, brivanib demonstrated promising efficacy results when combined with cetuximab in patients with advanced gastrointestinal malignancies. [Br J Cancer 2011;105:44-52]

However, reports on the phase III CO.20 trial, which randomized patients with meta-static colorectal cancer (mCRC) to second-line treatment with cetuximab either with brivanib or placebo, showed that the addition of brivanib did not significantly improve the primary endpoint of overall survival (OS).

Median OS was 8.8 months in patients who received added therapy with brivanib vs. 8.1 months with the placebo group, and the difference was not statistically significant (P=0.12, HR 0.88 [95% CI, 0.74-1.03]). Positive effects were observed in progression-free sur-vival (PFS), a secondary endpoint. [J Clin On-col 2012 (suppl 4; abstr 386)]

“This trial did not hit its primary end-point,” stated Ellis. “There were some hints of activity … there was an increase in PFS … but clearly this approach is not the way to go.”

In the VELOUR trial, aflibercept, an in-hibitor of VEGF and PlGF, was evaluated as second-line treatment in mCRC patients who failed oxaliplatin and had received prior bev-acizumab. The study randomized patients to receive FOLFIRI chemotherapy plus either aflibercept or placebo. [J Clin Oncol 2012 (sup-pl; abstr 3505)]

The investigators showed that the addi-tion of aflibercept resulted in a consistent

No major advances targeting VEGF-resistance pathways


Conference CoverageJul-Aug 201225trend of improvements in OS (primary end-point) and PFS. Aflibercept was associated with a significant 1.4 month increase in median OS (P=0.0032; HR 0.817 [95.34% CI, 0.713-0.937]).

Despite the positive results, Ellis pointed out: “If PlGF is important in VEGF resis-tance, aflibcercept should be more effective … we should have done better than what we saw in this trial.”

Using toxicity to predict response Yen Yen Yip

As predictive biomarkers for metastatic renal cell carcinoma (mRCC) remain elusive, oncologists are turning to increased toxicity levels as indicators for treatment response.

Drug efficacy is one of the most important considerations in determining the choice of therapy, said Dr. Daniel Heng, clinical as-sociate professor, Tom Baker Cancer Center, University of Calgary, Canada. The current mRCC treatment algorithm recommends the use of the vascular endothelial growth factor (VEGF) inhibitors sunitinib, pazopanib and bevacizumab plus interferon as first-line ther-apy in good or intermediate risk patients, and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus in poor risk patients. [Heng & Choueiri, ASCO Educational Book 2012]

However, while comparative studies are underway, there are currently no clear data demonstrating which targeted therapy is more efficacious as a first-line option, said Heng.

Even without such evidence, “predictive biomarkers can help us decide which drug is best for which patient,” he added. “But pre-dictive biomarkers are currently elusive.”

Thus, other indications are being used. For instance, adverse events such as hyperten-sion, hand-foot syndrome, and hypothyroid-

ism after sunitinib use have been associated with better treatment response.

Hypertension following the first cycle of sunitinib has been linked to a better over-all response rate, progression-free survival (PFS) and overall survival. [J Natl Cancer Inst 2011;103:763-773] Hypothyroidism in suni-tinib-treated patients has been established as an independent prognostic factor for sur-vival. [J Clin Oncol 2012 (suppl 5; abstr 466)] The presence of hand-foot syndrome has also been linked with a significant improvement in PFS. [J Clin Oncol 2011 (suppl 5; abstr 320)]

These adverse events may be a reflection of adequate drug dosage levels, suggested Heng. “The story is very consistent … toxicity may predict response.”

“However, that is only helpful once treat-ment is started; that is, you have to start treat-ment before you know it is working,” he pointed out. Also, the predictive accuracy of such toxic events is still limited: patients who do not develop these side effects should not necessarily be withdrawn from therapy.

Besides predicting treatment response, drug toxicity profiles can also guide treat-ment decisions in other ways. For instance, patients with poor pulmonary function and refractory diabetes would not be good candi-dates for mTOR inhibitors due to the risk of non-infectious pneumonitis and hyperglyce-mia, he commented. Similarly, patients with

Conference CoverageJul-Aug 201226refractory hypertension should not be pre-scribed VEGF inhibitors because of the risk of developing hypertension.

Other considerations that can determine the choice of treatment include prognostic profile, patient preference, physician experi-ence and oral vs. IV administration.

Nonetheless, treatment decisions are still hampered by the lack of evidence identifying the most effective first-line targeted therapy option. Upcoming results from the COMPARZ

trial, a head-to-head phase III comparison of sunitinib vs. pazopanib as first-line treatment, will provide an indication of efficacy. The RE-CORD-3 trial, which randomizes patients to first-line sunitinib followed by everolimus, vs. everolimus followed by sunitinib will in-dicate whether starting out with a VEGF or mTOR inhibitor will be more efficacious.

“Clinical trial results are eagerly antici-pated to guide treatment decisions,” Heng commented.


Antidepressant relieves chemo-induced neuropathic painYen Yen Yip

For the first time, a randomized con-trolled trial has found the serotonin-norepinephrine reuptake inhibitor

(SNRI) duloxetine to be effective against chronic neuropathic pain associated with tax-ane- or platinum-based chemotherapy. [Ab-stract CRA 9013]

In the study, duloxetine conferred a ≥30 per-cent reduction in pain score for 33 percent of patients. In the placebo group, only 17 percent achieved a similar reduction in pain. “A 30 per-cent decrease in pain is clinically significant and important to patients,” commented lead investigator Dr. Ellen Lavoie Smith, University of Michigan School of Nursing, Ann Arbor, USA.

A total of 220 patients with peripheral neu-ropathic pain associated with paclitaxel or ox-aliplatin were randomized to receive dulox-etine (30 mg daily in the first week, then 60 mg daily for 4 weeks) or placebo.

Although mean pain scores fell in the pla-cebo group as well, patients who received du-loxetine achieved a significantly greater degree of pain relief (p=0.003).

Overall, 59 percent of patients taking du-loxetine achieved some degree of pain re-lief vs 38 percent of placebo recipients. Pain scores fell by half in 21 percent of patients on duloxetine vs 9 percent on placebo. However, a small proportion of patients felt more pain after receiving treatment; fewer patients on duloxetine experienced this effect compared

with the placebo group.“Not everyone responded to duloxetine,”

Lavoie Smith said. “Duloxetine... works by increasing amounts of pain-inhibiting neu-rotransmitters; we think patients who respond may have some abnormalities in the way their brain processes pain … and we have to identify who might respond so we can target the use of this drug.”

The drug was generally well tolerated. Fa-tigue, insomnia, nausea, somnolence and diz-ziness were the most common adverse events. Seven percent of recipients experienced se-vere adverse events and 11 percent dropped out of the study as a result of side effects.


Regorafenib offers hope for GIST patients failing TKIsChristina Lau

T he multi-kinase inhibitor regorafenib may represent the first targeted treat-ment option for patients with metastatic

and/or unresectable gastrointestinal stromal tumor (GIST) who progressed despite prior use of both imatinib and sunitinib.

The phase III GRID (Regorafenib in Pro-gressive Disease) trial included 199 patients from 17 countries who failed at least imatinib and sunitinib – the only two drugs approved for GIST worldwide. Patients were random-ized to receive regorafenib 160 mg once daily plus best supportive care (BSC) (n=133), or placebo plus BSC (n=66), on a 3-weeks-on 1-week-off schedule. The trial was unblinded on disease progression, when placebo-treated patients were eligible for crossover to open-label regorafenib and regorafenib-treated patients continued on their treatment. On the next progression, patients were taken off treatment. [Abstract LBA10008]

“The trial met its primary endpoint, with progression-free survival [PFS] being four times longer in the regorafenib arm. Median PFS was 4.8 months for regorafenib vs 0.9 months for placebo [HR, 0.27; p<0.0001],” re-ported Dr. George Demetri, Dana Farber Can-cer Institute, Massachusetts, USA. “PFS rates at 3 and 6 months were 60 vs 11 percent and 38 vs 0 percent, respectively.”

The same PFS benefit was maintained in patients with KIT exon 11 (n=51) or exon 9

(n=15) mutation, the most common mutations in GIST (HR, 0.212 and 0.239, respectively).

Disease control and objective response also favored regorafenib, at 52.6 vs 9.1 percent and 4.5 vs 1.5 percent, respectively.

“Although overall survival [OS] favored regorafenib [HR, 0.77], the difference between the two arms did not reach statistical signifi-cance as 85 percent of patients in the placebo arm crossed over to receive open-label rego-rafenib,” pointed out Demetri.

Regorafenib was generally well tolerated in the trial, with side effects similar to those of imatinib and sunitinib. The most common grade 3 adverse events were hand-foot skin reaction, hypertension and diarrhea.

“The side effects were all manageable with dose modifications,” he noted.

“Positive results of the trial were submit-ted to regulatory authorities in March 2012. If approved, regorafenib will fulfill an urgent unmet need for GIST patients who have exhausted all other treatment options,” he suggested. “While imatinib and sunitinib have increased patient survival in metastatic GIST from 3-6 months to 5 years or more, 85-90 per-cent of patients ultimately develop resistance to these tyrosine kinase inhibitors [TKIs] that target KIT or PDGFRA. Regorafenib is a struc-turally distinct oral inhibitor of KIT, VEGFR-1, murine VEGFR-2, PDGFR-b, RET, BRAF and FGFR-1 that appears to target GIST in a possi-bly more powerful way, making it a potentially significant new option to help patients.”


Bevacizumab slows down ovarian cancer progression Elvira Manzano

Adding bevacizumab to standard chemo-therapy delayed cancer progression in wom-en with platinum-resistant ovarian cancer, results of a phase III AURELIA* trial showed.

Median progression-free survival (PFS) – a primary endpoint of the study – was 6.7 months for combination therapy compared with 3.4 months for chemotherapy alone. The objective response rate more than doubled with the addition of bevacizumab – 12.6 per-cent to 30.9 percent (P=0.001).

“For the first-time in platinum-resistant ovarian cancer, we have been able to signifi-cantly improve progression-free survival with a combination therapy,” said lead study au-thor Dr. Eric Pujade-Lauraine, professor, Uni-versité de Paris Descartes, France and head of the Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), a clinical trials cooperative group based in France. “The risk of the disease getting worse was halved in patients treated with the com-bination therapy. This is a breakthrough and will definitely change the practice in treating patients with ovarian cancer.”

In the study, 361 women with epithelial ovarian, fallopian tube or primary peritoneal cancers that had not responded to platinum-based chemotherapy were randomized to receive standard chemotherapy or bevaci-zumab plus chemotherapy (with one of three standard chemotherapy agents – topotecan,

liposomal pegylated doxorubicin or weekly paclitaxel). Secondary endpoints were ob-jective response rate, overall survival, safety, and quality of life.

After a median follow-up of 13.5 months, 91 percent of patients in the chemotherapy-alone group had progressed compared with 75 percent in the combination therapy group. The difference translated into a 0.48 hazard ratio of progression (P<0.001). Data on overall survival is expected next year.

Rates of hypertension and proteinuria were higher among the bevacizumab group than with the chemotherapy-only group but bleeding events, febrile neutropenia and con-gestive heart failure were the same. These ad-verse effects were consistent with the known effects of bevacizumab and the different che-motherapeutic agents used in the study.

“These results are very significant. The ad-dition of bevacizumab offers a new treatment option for 20 percent of women who have primary platinum-resistant disease as well as those whose disease later becomes platinum-resistant,” Lauraine concluded.

Bevacizumab is a humanized anti-human vascular endothelial growth factor A (VEGF-A) monoclonal antibody (mAb) indicated for metastatic colon cancer, renal cancer, certain lung cancers and glioblastoma multiforme of the brain typically in combination with stan-dard chemotherapy. *AURELIA: A Study of Avastin (Bevacizumab) Added to Chemotherapy

in Patients With Platinum-resistant Ovarian Cancer


Continuous androgen deprivation still standard of care for prostate cancer

Yen Yen Yip

C ontinuous androgen deprivation remains standard of care in hor-mone-sensitive metastatic prostate

cancer, according to a large multinational phase III study. [Abstract 4]

“Some doctors recommend intermittent hormonal therapy to men with metastatic pros-tate cancer, believing it will reduce their risk of side effects without compromising outcome, but our findings demonstrate a clear downside to this approach for certain men,” said lead in-vestigator Dr. Maha Hussain from the Univer-sity of Michigan, Ann Arbor, USA.

The primary objective of the SWOG (South-west Oncology Group) 9346 study, which spanned 17 years, was to determine if inter-mittent androgen deprivation was non-inferi-or to continuous therapy.

The study included more than 1,500 pa-tients newly diagnosed with hormone-sen-sitive prostate cancer, with prostate-specific antigen (PSA) levels ≥5 ng/mL prior to initia-tion of androgen deprivation therapy, and a SWOG performance status of 0 to 2. The sub-jects were treated with goserelin and bicalu-tamide for 7 months, and those who achieved PSA ≤4 ng/mL at the 6th or 7th month were then randomized to receive continuous or in-termittent therapy.

After a median follow-up of 9.2 years, the primary endpoint of overall survival (OS) was inferior in the intermittent therapy group (5.1

years vs 5.8 years with continuous therapy; HR, 1.09). Among patients with minimal disease, OS was significantly better for those who received continuous therapy (7.1 vs 5.2 years; p=0.034).

However, in patients with extensive disease spread, intermittent and continuous therapies were comparable.

Androgen deprivation therapy leads to sig-nificant setbacks in quality of life, and is also associated with increased fractures, decreased cognitive function, increased risk of diabetes and altered lipid profiles. In addition, many patients eventually progress to castration-re-sistant disease, commented Dr. William Oh from the Mount Sinai School of Medicine, New York, USA.

Previous preclinical data have suggested that intermittent therapy can re-induce apop-tosis and prolong time to castration resistance. [Cancer 1993;71:2782-2790]

The advantages of the intermittent ap-proach and its comparable efficacy were con-firmed by at least 23 phase II trials, Oh noted. “However, these studies were essentially un-derpowered to evaluate survival.”

“The SWOG 9346 findings will be practice changing for many doctors who routinely use intermittent therapy,” said Hussain.

“Neither SWOG 9346 nor any randomized trial has ever shown a superior cancer out-come with intermittent androgen deprivation therapy,” said Oh. “This preclinical concept [supporting intermittent therapy] must no longer be propagated.”



Abiraterone before prostatectomy clears tumor in some men

Elvira Manzano

Adding abiraterone to standard hor-mone therapy leuprolide prior to prostate resection suppressed andro-

gen levels and eliminated or shrinked tumors in one-third of men with localized, high-risk prostate cancer, results of a preliminary clini-cal study have shown.

Dihydrotestosterone (DHT) and dehydro-epiandrosterone (DHEA) levels were signifi-cantly lower in patients treated with the com-bination therapy than in those who received leuprolide alone. At prostatectomy, total pathologic complete response – absence of re-sidual invasive tumor – or near pCR (<5 mm residual tumor) were confirmed in 34 per-cent of patients treated with abiraterone for 6 months. Similar responses were seen in 15 percent of patients treated with abiraterone for 3 months.

“These patients had very bulky tumors … to have that amount of shrinkage was remark-able,” said study author Dr. Mary-Ellen Tap-lin of the Dana-Farber Cancer Institute in Bos-ton, Massachussets, US. “These data suggest that abiraterone may have clinical benefits when used earlier in the treatment paradigm for high-risk patients.”

The study enrolled 58 men with localized or high-risk prostate cancer (Gleason score of ≥7, with stage T3 disease and prostate specific antigen (PSA) levels of ≥20 ng/mL and had ≥3 positive biopsies) randomized to leupro-lide and abiraterone, or leuprolide alone for 3 months.

At 3 months, 90 percent of patients treat-ed with the combination regimen achieved PSA levels of <0.2 ng/mL compared with only 4 percent in those who had leuprolide monotherapy (P<0.0001).

The first group continued treatment with leuprolide/abiraterone for 3 more months; the second group was started on the same combination of drugs. There was an eleva-tion of liver enzymes in five patients and hypokalemia in three, but no grade 4 toxici-ties were observed.

“These results support further evaluation of aggressive androgen deprivation therapy [ADT] as neoadjuvant/adjuvant therapy for localized, high-risk prostate cancer,” Taplin said.

Dr. Nicholas Vogelzang, co-chair of the genitourinary and research executive com-mittees for US Oncology Research and chair of ASCO’s communication committee, said the findings may constitute a landmark de-velopment in the treatment of prostate can-cer.

Previous studies have shown that treat-ment with leuprolide prior to surgery had limited benefits in localized high-risk pros-tate cancer. Abiraterone, which is approved for use with prednisone in patients with metastatic castration-resistant prostate can-cer who have not responded to docetaxel chemotherapy, works by blocking the pro-duction of testosterone and related me-tabolites that fuel cancer growth. Adding abiraterone to leuprolide is said to further inhibit cancer cell proliferation.


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Market WatchJul-Aug 201233

VSL#3 Probiotic: Feasible and Friendly Protection Against CID and RID

Radiation and chemotherapeutic regimes are typically associated with various gastrointestinal disturbances. Diarrhoea, specifically termed as chemotherapy-induced diarrhoea (CID) or radiation-induced diarrhoea (RID), is one of the common side effects of these treatments; when not properly managed, it may significantly impact patient morbidity and mortality. The underlying pathophysiology of this gastrointestinal complication has yet to be established, although evidence shows that its manifestation is potentially induced by cytotoxic agents that are capable of impairing the intestinal mucosa and normal water absorption.1,2 More importantly, these noxious components of radiation and chemotherapy may alter the homeostatic gut microflora, hence, the eventual development of CID or RID.3 In the face of numerous remedies that have emerged over time, the complexity of this diarrhoea only gives rise to further complications (e.g., bleeding, faecal incontinence); thus it is expedient to formulate novel therapies targeting the elements of the disease pathophysiology.

VSL#3 ProbioticsVSL#3 is a probiotic dietary supplement of

112.5 billion freeze-dried bacteria comprising 8 strains of lactic acid bacteria and bifidobacteria enclosed in a high-potency capsule; it also comes in powder form, containing 450 billion bacteria per commercially-available sachet. Each preparation contains non-pathogenic strains of streptococcus (S. thermophilius), bifidobacteria (B. longum, B. infantis, and B. breve), and lactobacilli (Lactobacillus acidophilus, L. casei, L. delbrueckii subspecies bulgaricus, and L. plantarum), all of which naturally occur in the intestinal tract. These beneficial bacteria are able to survive the digestive environment in the presence of surging gastric acid, bile and pancreatic secretions. They colonise and adhere to the gastrointestinal tract to serve as a protective barrier. As they flourish, possible pathogenic microbes are prevented from multiplying4 and VSL#3 consequently confers anti-inflammatory features.5

VSL#3 is particularly indicated to alleviate symptoms of inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), pouchitis, ulcerative colitis, and CID or RID. This compound may also be administered to enteral-fed patients with diarrhoea or children with rotavirus diarrhoea. Due to its high-potency, initial results are observed during the first week of use, with maximum

Chemotherapy and radiotherapy alter the homeostatic gut microflora, resulting in gastrointestinal disturbances, such as diarrhoea. VSL#3 is a probiotic scientifically proven

to reduce the incidence and severity of chemotherapy- or radiotherapy-induced diarrhoea. VSL#3 is a safe and effective supplement that can help reduce the risk of treatment-induced diarrhoea among cancer patients.

Market WatchJul-Aug 201234effects within 2 to 3 weeks; however, patients may develop possible transient bloating in the first few days of consumption.

Clinically Proven Efficacy Against RID A strong body of evidence has demonstrated

the clinical benefits of VSL#3 in the milieu of chemotherapy and radiation. One notable study was a double-blind, placebo-controlled trial which investigated the efficacy of this compound for the prevention of RID.6 Eligible patients included those who underwent adjuvant postoperative radiation therapy for sigmoid, rectal, or cervical cancer. These patients were allocated in either VSL#3 (one sachet TID) or placebo arm, each treatment to begin from the first day of radiation therapy. Efficacy endpoints were incidence and severity of RID, daily number of bowel movements, and the time from the start of the study to the use of loperamide as rescue medication. A total of 490 patients were accrued and equally randomised to both arms. However, 243/245 patients in the VSL#3 arm and 239/245 in the placebo arm were only included in the analysis due to patient withdrawal (n=8) or sudden myocardial death (n=1). Nevertheless, analysis of the results all favoured the VSL#3 arm. A reduced incidence of RID was achieved in the VSL#3 arm compared with the placebo arm (77/243, 31.6% vs. 124/239, 51.8%; p<0.001).

Fewer patients in the VSL#3 arm experienced severe toxicity symptoms from radiation than the placebo arm; only 8/77 (1.4%) patients treated with VSL#3 reported grade 3 or 4 diarrhoea, whereas 69/124 (55.4%) patients treated with placebo reported such toxicity grade (p<0.001). Those who developed grade 1 or 2 diarrhoea were 34/77 VSL#3-treated patients and 50/124 placebo-treated patients (NS), although this particular endpoint was of no statistical significance. The documented mean daily number of bowel movements for patients with RID was 14.7± 6 in the placebo-treated while only 5.1 ± 3 in the VSL#3-treated patients (p<0.05). The mean time to the use of loperamide as rescue medication for diarrhoea was extended in patients allocated with VSL#3 versus those allocated with placebo (122 ± 8 h vs. 86 ± 6 h; p<0.001). Furthermore, there were no symptoms of toxicity or cases of bacteraemia, sepsis, or septic shock reported during the active treatment of patients with VSL#3.

Reduces CID in in vivo preclinical trials Parallel outcomes were obtained in an

animal trial that examined the potential of VSL#3 in the prevention of CID. 7 All experiments were conducted in 48 female DA rats using a model of mucositis. The rats were randomised to 8 study cohorts: no-treatment control, irinotecan only, irinotecan and probiotic (21 days pre-treatment, 28 days combined pre- and post-treatment, or 7 days post-treatment), or probiotic only (21 days or 28 days of treatment). Irinotecan was intraperitoneally administered to these rats to induce mucositis and diarrhoea, followed by subcutaneous administration of atropine to prevent any cholinergic reaction. Experimental assessments were closely carried out for 7 days to document incidence of diarrhoea and weight loss. At the study close-out, histopathological examination, goblet cells

A reduced incidence of RID was achieved in the VSL#3 arm

compared with the placebo arm.”

‘‘

Market WatchJul-Aug 201235analysis, and apoptosis and crypt proliferation assessments were simultaneously performed to provide in-depth data. Results verified the undesirable weight loss response of rats to irinotecan; rats that received irinotecan alone had a body weight loss of 12.6% (p < 0.05), while rats that received the combination irinotecan and VSL#3 for a period of 21 days or 7 days had a body weight loss of 14.8% (p < 0.01) and 12.5% (p < 0.05), respectively. Those extensively treated with irinotecan and VSL#3 for 28 days demonstrated an insignificant amount of weight loss (5.3%). In contrast, rats under the no-treatment and VSL#3 cohorts were non-reactive to the probiotic administration and remained gaining weight until trial completion. With respect to diarrhoea prevention, those treated with irinotecan alone had both early onset (24 hours after irinotecan treatment) and late onset of diarrhoea. Initially, diarrhoea was described as mild to moderate with transient occurrence. After 48 hours, mild diarrhoea recurred in 50% of rats while moderate diarrhoea recurred in 17%. After 4 days (96 hours), diarrhoea progressed to a severe case in 50% of rats while 17% developed moderate diarrhoea; this incidence was completely resolved at day 7. Remarkably, the VSL#3-treated subsets demonstrated preventive

outcomes, where a delayed first onset of mild diarrhoea was observed and only occurred after 48 hours. This was evident in approximately 25% of rats and was resolved immediately at day 6. Furthermore, rats that received pre- and post-treatment of VSL#3 with irinotecan did not develop moderate or severe diarrhoea at any time point. The prevention of moderate and severe diarrhoea was directly linked to a significant increase in crypt proliferation as well as inhibition of apoptosis in both the small and large intestines. VSL#3 also reduced goblet cells within jejuna crypts, which was stimulated by the irinotecan treatment.

Summary These results clearly indicate that

probiotic therapy with VSL#3 plays a significant role in the prevention or reduction of diarrhoea in patients undergoing radiation and chemotherapy. Clinical evidence has validated its efficacy in executing anti-diarrhoeal functions such as enhancing epithelial proliferation and reducing apoptosis in the intestines. The addition of VSL3# therapy to radiation and chemotherapy has likewise been shown to be safe and beneficial without causing homeostatic damage or toxicity. Probiotics, such as VSL#3, offer an easy, safe, and feasible approach to protect cancer patients against the risk of diarrhoea.

References:1. Stringer AM, et al. J Support Oncol. 2007

Jun;5(6):259-67.

2. Gibson RJ, Keefe DM. Support Care Cancer. 2006 Sep;14(9):890-900.

3. Stringer AM, et al. Exp Biol Med (Maywood). 2007 Jan;232(1):96-106.

Rats that received pre- and post-

treatment of VSL#3 with irinotecan did not develop

moderate or severe diarrhoea at

any time point.”

‘‘

Market WatchJul-Aug 2012364. Madsen K, et al. Gastroenterology. 2001

Sep;121(3):580-91.5. Petrof EO, et al. Gastroenterology. 2001

Sep;121(3):580-91.6. Delia P, et al. World J Gastroenterol. 2007 Feb

14;13(6):912-5.7. Bowen JM, et al. Cancer Biol Ther. 2007

Sep;6(9):1449-54.

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Research Rev iewsJul-Aug 201237

Aspirin and cancer prevention

Two successive papers in the Lancet have addressed the anticancer effects of

aspirin.Data from all five large randomized

trials in the UK of aspirin versus control for cardiovascular prophylaxis have been reanalysed from the point of view of an effect on cancer metastasis. A total of 17,285 subjects were followed up for an average of 6.5 years and 987 developed a new solid cancer during follow-up. Among subjects randomized to aspirin, the risk of cancer with distant metastases was reduced significantly by 36 percent overall. For adenocarcinoma, the reduction was 46 percent. For other solid tumours, there was a nonsignificant 18 percent reduction. There was a highly significant reduction of 48 percent in the proportion of adenocarci-nomas with metastatic rather than local disease. Aspirin reduced both the risk of metas-tasis at diagnosis of adenocarcinoma and the risk of subsequent metastasis, especially in patients with colorectal cancer. Aspirin was associated with reduced cancer mortality among patients who developed adenocarcinoma and also reduced the overall risk of fatal adenocarcinoma in trial participants. The effect was greatest in smokers.

A search of the world literature has identified 51 trials of aspirin versus control (77,549 subjects) for cardiovascular prophylaxis. Aspirin reduced cancer deaths significantly by 15 percent, particularly after 5 years or longer. Non-vascular deaths were reduced sig-nificantly by 12 percent. In trials of primary prevention, 91 percent of deaths prevented would have been nonvascular deaths. In six trials of low-dose aspirin for primary pre-vention, aspirin reduced cancer incidence after 3 years, by 24 percent in women and 25 percent in men. The absolute reduction in cancer risk from 3 years onwards amounted to 3.13 per 1,000 patients per year.

Aspirin reduces the risk of metastasis from adenocarcinomas as well as the overall incidence of and mortality from cancer. Lancet commentators remain wary about recom-mending general use of aspirin for cancer prevention.

Rothwell PM et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers dur-ing randomised controlled trials. Lancet 2012; 379: 1591–601; Rothwell PM et al. Short-term effects of daily aspirin on cancer incidence, mortality and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Ibid: 1602–12; Chan AT, Cook NR. Are we ready to recommend aspirin for cancer prevention: Ibid: 1569–71 (comment).


Radioiodine treatment for thyroid cancer

Giving radioiodine (131I) after total thyroidectomy for thyroid cancer has three pur- poses: ablation of normal-thyroid remnants to achieve undetectable serum thyroglob-

ulin levels, irradiation of any remaining neoplastic cells to reduce the risk of recurrence, and performance of a total body 131I scan for persistent cancer. For patients with low-risk thyroid cancer, there is uncertainty about the optimal dose of radioiodine. Temporary thy-roid hormone withdrawal is performed 2 to 4 weeks before ablation but can be avoided by using recombinant human thyrotropin. Two successive papers, one from France and one from the UK, address problems in the treatment of low-risk thyroid cancer.

At 24 centers in France, a total of 752 patients with low-risk differentiated thyroid cancer were randomized to four groups: recombinant human thyrotropin and low-dose 131 I (1.1 GBq), recombinant human thyrotropin and high-dose 131I (3.7 GBq), thyroid hormone withdrawal and low-dose 131I, and thyroid hormone withdrawal and high-dose 131I. Among 684 patients with complete data at 8 months after 131I administration, 95 percent had a normal neck ultrasound scan and 95 percent had a stimulated thyro-globulin level of 1.0 ng/mL or less without detectable thyroglobulin antibodies. Thyroid ablation was complete in 92 percent. The ablation rate was similar with either 131I dose and with either thyrotropin-stimulation method.

A similar study at 29 UK centers included 438 patients (421 with complete data). Rates of successful ablation were 85 percent (low-dose 131I), 88.9 percent (high-dose 131I), 87.1 percent (recombinant human thyrotropin) and 86.7 percent (thyroid hormone withdraw-al), showing noninferiority of any option. Hospitalization lasted 3 days or more in 36.3 percent of patients given high-dose 131I versus 13 percent given the low dose. Adverse events were significantly more frequent with the high dose (33 percent vs 21 percent).

Low-dose radioiodine plus recombinant human thyrotropin may be the best com-bination after surgery for low-risk thyroid cancer. Low dosage reduces the risks of radioiodine administration but some patients may not need radioiodine. Using recombi-nant human thyrotropin may have advantages over thyroid hormone withdrawal but is expensive.

Schlumberger M et al. Strategies of radioiodine ablation in patients with low-risk thyroid cancer. NEJM 2012; 366: 1663–73; Mallick U et al. Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. Ibid: 1674–85; Alexander EK, Larsen PR. Radioiodine for thyroid cancer – is less more? Ibid: 1732–3 (editorial).


Vemurafenib for advanced melanoma

About half of melanomas carry an activating mutation in the gene en-

coding the serine-threonine protein kinase B-RAF (BRAF), the BRAF V600 mutation. This causes activation of the mitogen-ac-tivated protein kinase (MAPK) pathway, enhancing cell proliferation and inhibiting apoptosis. Vemurafenib is a potent kinase inhibitor acting preferentially on cancer cells with the BRAF V600 mutation. Initial studies have suggested that vemurafenib might be active against such melanomas. A multicentre, phase II trial has provided confirmation.

A total of 132 patients were treated at ten US centers and three centers in Austra-lia. All had previously treated metastatic melanoma with the BRAF V600 mutation (184 of 328 patients (56 percent) had tested positive for the mutation). Median follow-up was 12.9 months. The overall confirmed response rate was 53 percent with 6 percent having a complete response. Responses lasted 6.7 months on average and the median progression-free survival was 6.8 months. Only 14 percent had primary progression. Some patients responded only after 6 months or more of treatment. Median overall survival was 15.9 months. The most common adverse effects were arthralgia, rash, photosensitivity, fatigue and alopecia. A quarter of the patients (26 percent) developed squamous cell skin cancers.

Among patients with metastatic melanoma with a BRAF V600 mutation vemuraf- enil produced a clinical response in 53 percent and an overall median survival of 16 months.

Sosman JA et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. NEJM 2012; 366: 707–14.


Colorectal cancer screening: colonoscopy vs. fecal immunochemical testing

Screening for colorectal cancer is performed using either stool tests (occult blood, exfoliated DNA) or visual testing (colonoscopy, flexible sigmoidoscopy, computed tomo-

graphic colonography). Stool tests are usually used in Europe and Australia but colonoscopy is favored in the US. There is evidence that screening colonoscopy reduces the risk of death from colorectal cancer and that polypectomy can prevent up to 80 percent of colorectal cancers. A new fecal test (semiquantative fecal immunochemical testing, FIT) is more accurate than guiac testing for fecal occult blood. Now a multicenter study in Spain has compared FIT with colonoscopy since present evidence suggests that, although colonoscopy is more accurate, FIT may be more effective as it is taken up more readily.

The study included 57,404 asymptomatic men and women aged 50–69 who were ran-domized by household to once-only colonoscopy or FIT every 2 years (this preliminary report only gives data after the first FIT testing, with colonoscopy or FIT testing with 2 years of follow-up). In the colonoscopy group 4,953 people had colonoscopy and 1,628 requested, and had, FIT instead. In the FIT group, 8,983 people had FIT and 106 re-quested, and had, colonoscopy. The rate of participation was higher in the FIT group (34 percent vs 25 percent). The rates of detection of colorectal cancer were similar in the two groups (0.1 percent, 30 subjects in the colonoscopy group and 33 in the FIT group). Ad-vanced adenomas were detected in 514 subjects (1.9 percent) in the colonoscopy group and 231 (0.9 percent) in the FIT group, a highly significant difference, and non-advanced adenomas in 1,109 (4.2 percent) vs. 119 (0.4 percent).

People are more likely to agree to FIT testing than colonoscopy. The two methods detect similar numbers of colorectal cancers but colonoscopy detects considerably more adenomas. It is intended to assess the effects on deaths from colorectal cancer after 10 years of follow-up (in the year 2021). The authors of an editorial suggest that once-only colonoscopy followed by surveillance for subjects with, but no surveillance for those with-out, adenomas might be a suitable arrangement in the meantime.

Quintero E et al. Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening. NEJM 2012; 366: 697–706; Bretthauer M, Kalager M. Colonoscopy as a triage screening test. Ibid: 759–60 (editorial).


Screening and cervical cancer mortality

There is uncertainty about whether screening for cervical cancer reduces cervical cancer mortality or simply increases the time from diagnosis to death (lead time). A study in

Sweden has shown that screening improves prognosis.The study included all 1,230 women who had a diagnosis of invasive cervical cancer

between 1999 and 2001 in Sweden. For women aged 23 to 65 years the cure rate was 92 percent for cancers detected by smear test screening and 66 percent for cancers detected because of symptoms, a significant difference. The rate of cure was also significantly higher among women screened at recommended intervals than among women overdue for screening.

Smear-test screening for cervical cancer increases cure rates and the effect is indepen-dent of lead-time bias.

Andrae B et al. Screening and cervical cancer cure: population based cohort study. BMJ 2012; 344 (March 24): 18 (e900); Arbyn M et al. Effect of screening on deaths from cervical cancer in Sweden. Ibid: 11(e804) (editorial).

Cost-effectiveness of HPV vs. cytology screening for cervical cancer

Human papillomavirus (HPV) testing for cervical cancer screening is more sensitive but less specific than cytological screening. Cost-effectiveness analyses have given varying

results partly because key factors vary between countries. A microsimulation model (MIS-CAN) has been used to compared the cost-effectiveness of more than 1,500 screening poli-cies in five European scenarios. The model was validated using Dutch data and costs were derived from studies in the Netherlands. The model showed that HPV testing was usually preferable. Primary cytological screening might be preferred when the cost of cytology was low and when HPV was highly prevalent and testing for HPV costly.

HPV screening is often preferable to cytological screening in cervical cancer screening programs in Europe.

De Kok IMCM et al. Primary screening for human papillomavirus compared with cytology screening for cervical cancer in European settings: cost effectiveness analysis based on a Dutch microsimulation model. BMJ 2012; 344 (March 1): 17 (e670).


Chemoradiotherapy for muscle-invasive bladder cancer

Surgery (cystectomy) is standard treatment for muscle-invasive bladder cancer but radio-therapy may be used to avoid cystectomy in patients who might not tolerate operation.

The results of radiotherapy alone, however, are unsatisfactory and interest has turned to combined chemotherapy and radiotherapy (chemoradiotherapy). A multicenter UK trial has shown that adding chemotherapy to radiotherapy improves locoregional cancer control.

A total of 360 patients (median age 72 years, 80 percent men) with muscle-invasive bladder cancer were randomized at 45 centers to radiotherapy with or without chemo-therapy. Chemoradiotherapy consisted of fluorouracil during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C on day 1. Rates of locoregional disease-free survival at 2 years were 67 percent (chemoradiotherapy) vs. 54 percent (radiotherapy alone). With an average follow-up of 70 months there was a significant 32 percent advantage in lo-coregional disease-free survival in the chemoradiotherapy group compared with the ra-diotherapy group. Overall 5-year survival was 48 percent vs. 35 percent, a nonsignificant difference. Grade 3 or 4 adverse events were slightly more common in the chemoradio-therapy group during, but not after, treatment.

Chemoradiotherapy improved locoregional control when compared with radiothera-py alone. Editorialists describe the study as a ‘landmark study’ writing that it shows that as primary treatment, cystectomy can now be regarded as one of several options for the patient..

James ND et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. NEJM 2012; 366: 1477–88; Shipley WU, Zietman AL. Old drugs, new purpose – bladder cancer turning a corner. Ibid: 1540–1 (editorial).


New gemtuzumab ozogamicin regimen for adult AML

Standard induction treatment for acute myeloid leukaemia (AML) is cytarabine for 7 days with daunorubicin for the first 3 days (the 3+7 regimen). Gemtuzumab ozogamicin (G-O)

is a conjugate of a humanized anti-CD33 monoclonal antibody and calicheamicin. Used as second-line treatment after relapse G-O showed some effectiveness but unacceptable toxicity. Now researchers in France have had greater success with a smaller-dose regimen (3 mg/m2 on days 1, 4, and 7 instead of 9 mg/m2 on day 1 and 14).

A total of 280 patients aged 50 to 70 years with previously untreated AML were ran-domized at 26 centers to the standard 3+7 regimen alone or with five doses of i.v. GO 3 mg/m2 on days 1, 4, and 7 and on day 1 of each of two consolidation chemotherapy courses. A complete response to induction occurred in 81 percent (G-O) vs. 75 percent (controls), a nonsignificant difference. At 2 years, however, the rate of event-free survival was significantly better in the G-O group (40.8 percent vs. 17.1 percent) and overall sur-vival was also significantly better (53.2 percent vs. 41.9 percent). Relapse-free survival was also significantly improved in the G-O group (50.3 percent vs. 22.7 percent). Persis-tent thrombocytopenia was more frequent in the G-O group (16 percent vs. 3 percent), but was not associated with increased mortality.

The new regimen was an improvement. A Lancet commentator suggests that G-O might be approved for patients with acute promyelocytic leukaemia and, in combination with chemotherapy, for patients with favorable or intermediate-risk cytogenetics.

Andrae B et al. Screening and cervical cancer cure: population based cohort study. BMJ 2012; 344 (March 24): 18 (e900); Arbyn M et al. Effect of screening on deaths from cervical cancer in Sweden. Ibid: 11(e804) (editorial).


Molecular assay for prognosis in non-squamous NSCLC

After resection for early-stage non-small-cell lung cancer (NSCLC) there

is a recurrence rate of 35–50 percent due to occult metastases at the time of resec-tion. A test that revealed the probability of such disease might enable physicians to se-lect patients for more intensive treatment. A molecular assay has been developed in California.

They used a 14-gene expression assay depending on quantitative PCR on forma-lin-fixed, paraffin-embedded tissues sam-ples, initially on a cohort of 361 patients in San Francisco after resection of non-squamous NSCLC. Subsequent validation was performed on a second Californian cohort of 433 patients and a cohort of 1,006 patients in China. In the second California cohort 5-year overall survival was 71.4 percent with low predicted risk from the assay, 58.3 percent with intermediate risk, and 49.2 percent with high risk. The corresponding figures for the Chinese cohort were 74.1 percent, 57.4 percent, and 44.6 percent. Use of standard clinical risk factors could not provide similar prognostic information.

The new assay could provide important prognostic information for patients with early-stage, resected non-squamous NSCLC.

Kratz JR et al. A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies. Lancet 2012; 379: 823–32; Xie Y, Minna JD. A lung cancer molecular prognostic test ready for prime time. Ibid: 785–7 (comment).


Genetic variation in different parts of renal cancers

Genetic analyses of tumor samples may aid prognosis and treatment. Person-

alised-medicine strategies often depend on a single tumor biopsy sample but intratu-mor heterogeneity may make such sam-pling invalid. Now a study in London, UK has shown the extent of intratumor hetero-geneity.

Exome sequencing, chromosome aberration analysis and ploidy profiling were per-formed on multiple spatially separated samples from the primary tumors and metastatic sites of four patients with advanced renal carcinomas. There was intratumor heteroge-neity with 63 to 69 percent of somatic mutations not being present at all sample sites of the same tumor. This heterogeneity was found for an mTOR kinase mutation and for multiple tumor-suppressor genes. Different regions of the same tumor could have gene-expression signatures indicating good or bad prognosis. Allelic composition and ploidy profiling analysis also revealed extensive intratumor heterogeneity. Two of the four tu-mors showed ploidy heterogeneity and 26 of 30 samples from the four tumors showed divergent allelic-imbalance profiles.

Genetic analyses from multiple sites in a single tumor may give different results. Man-agement decisions based on a single sample may not be reliable.

Gerlinger M et al. Intratumour heterogeneity and branched evolution revealed by multiregion sequencing. NEJM 2012; 366: 883–92; Longo DL. Tumor heterogeneity and personalized medicine. Ibid: 956–7 (editorial).

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Dutasteride for localized prostate cancer

Localized prostate cancer is relatively benign and many men may receive unnecessary treatment. Treatment with a 5α-reductase inhibitor might reduce the need for more

aggressive therapy. Researchers in North America have suggested that dutasteride treatment might benefit men with low-risk prostate cancer.

The trial, at 65 centers in the US and Canada, included 289 men aged 48 to 82 with low-volume, Gleason score 5–6 prostate cancer and at least one repeat biopsy dur-ing follow-up. They had all chosen active surveillance rather than more aggressive treatment. Randomization was to dutasteride 0.5 mg daily or placebo, and follow-up was for 3 years with repeat biopsies at 18 months and 3 years. At 3 years, the rate of prostate cancer progression was 38 percent (dutasteride) vs. 48 percent (placebo), a significant difference. The rates of adverse events were similar in the two groups. Sexual adverse events or breast enlargement occurred in 24 percent vs. 15 percent. There were no deaths from prostate cancer and no subject developed metastatic disease. Cardiovascular adverse events occurred in 5 percent of each group.

Dutasteride might benefit men with low-risk prostate cancer who choose active sur-veillance. A Lancet commentator, however, points to previous evidence that dutasteride might have no effect on prostate cancer mortality (or might even increase the risk) and concludes that dutasteride, or any other treatment, cannot be recommended for these men. He believes that neither treatment nor diagnosis should be attempted for low-risk disease.

Fleshner NE et al. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. Lancet 2012; 379: 1103–11; Parker C. What (if anything) to do about low-risk prostate cancer. Ibid: 1078–80 (comment).

CalendarJul-Aug 2012473rd Oncology Forum of Hong Kong21/7/2012Hong KongInfo: PC Tours and Travel Tel: +852 2734 3312 / +852 2734 3315Fax: +852 2367 3375E-mail: [email protected] http://www.hkcr.org/

5th Latin American Conference on Lung Cancer25/7/2012 to 27/7/2012Rio De Janeiro, BrazilInfo: International Conference Services Ltd. (ICS) – Grit SchoenherrTel: +1 604 681 2153Fax: +1 604 481 1049E-mail: [email protected]://www.lalca2012.org/index.html

10th Annual Meeting of the Japanese Society of Medical Oncology26/7/2012 to 28/7/2012Osaka, JapanTel: +81 3 6809 1250Fax: +81 3 6809 1138E-mail: [email protected]://jsmo2012.umin.jp/en/

2012 American Association for Cancer Research (AACR)/ASCO Workshop: Methods in Clinical Cancer Research28/7/2012 to 3/8/2012Vail, USAInfo: AACRTel: +215 440 9300Fax: +215 599 0111E-mail: [email protected]://www.vailworkshop.org/index.html

2012 World Cancer Congress27/8/2012 to 30/8/2012Montreal, CanadaInfo: International Union for Cancer ControlTel: +41 22 809 1811E-mail: [email protected]://www.worldcancercongress.org

ASCO 2012 Multidisciplinary Symposium in Thoracic Oncology6/9/2012 to 8/9/2012Chicago, USATel: +706 502 1550Fax: +703 502 7852http://www.thoracicsymposium.org/

ASCO 2012 Breast Cancer Symposium13/9/2012 to 15/9/2012San Francisco, USATel: +888 282 2552Fax: +571 483 1300E-mail: [email protected]://breastcasymposium.org/Home.aspx

International Liver Cancer Association 6th Annual Conference14/9/2012 to 16/9/2012Berlin, GermanyTel: +32 (0) 789 2345Fax: +32 (0) 743 1550E-mail: [email protected]://www.ilca2012.org/

32nd Congress of the European Society of Surgical Oncology (ESSO)19/9/2012 to 21/9/2012Valencia, SpainInfo: European Cancer OrganizationTel: +32 2 775 02 01 Fax: +32 2 775 02 00E-mail: [email protected]://www.ecco-org.eu/Conferences/Conferences/ ESSO-32.aspx

European Conference of Oncology Pharmacy (ECOP)27/9/2012 to 29/9/2012Budapest, HungaryInfo: European Cancer OrganizationTel: +32 2 775 02 01 Fax: +32 2 775 02 00E-mail: [email protected]://www.ecco-org.eu

International CardiOncology Society Annual Meeting28/9/2012 to 29/9/2012Milan, ItalyTel: +39 02 36753900Fax: +39 02 43911650 / +39 02 49542900E-mail: [email protected]://www.cq-travel.com/index.php?id_page=1

37th ESMO Congress28/9/2012 to 2/10/2012Vienna, AustriaTel: +41 (0)91 973 19 39Fax: +41 (0)91 973 19 18E-mail: [email protected]://www.esmo.org/events/vienna-2012-congress.html

CalendarJul-Aug 20124844th Congress of the International Society of Pediatric Oncology 5/10/2012 to 8/10/2012London, UKInfo: European Cancer OrganizationTel: +32 (0) 2 775 02 01Fax: +32 (0) 2 775 02 00E-mail: [email protected]://www.siop2012.org

Markers in Cancer – Joint Meeting by ASCO, EORTC, and NCI11/10/2012 to 13/10/2012Hollywood, Florida, USATel: +888 282 2552Fax: +571 483 1300E-mail: [email protected]://molecularcameeting.org/Home.aspx

24th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics6/11/2012 to 9/11/2012Dublin, IrelandInfo: European Cancer OrganizationTel: +32 (0) 2 775 02 01Fax: +32 (0) 2 775 02 00E-mail: [email protected]://www.ecco-org.eu/Conferences/Conferences/EORTC_NCI_AACR-2012.aspx

ASCO’s Quality Care Symposium30/11/2012 to 1/12/2012San Diego, USATel: +888 282 2552Fax: +571 483 1300E-mail: [email protected]://www.asco.org/ASCOv2/Meetings/ASCO%27s+Quality+Care+Symposium

Oncology Tribune is published 6 times a year by UBM Medica, a division of United Business Media. Oncology Tribune is a controlled circulation publication to medical practitioners in Asia. It is also available on subscription to members of allied professions. The price per annum is US$48 (surface mail) and US$60 (overseas airmail); back issues at US$5 per copy. Editorial matter published herein has been prepared by professional editorial staff. Views expressed are not necessarily those of UBM Medica. Although great effort has been made in compiling and checking the information given in this publication to ensure that it is accurate, the authors, the publisher and their servants or agents shall not be responsible or in any way liable for the continued currency of the information or for any errors, omissions or inaccuracies in this publication whether arising from negligence or otherwise howsoever, or for any consequences arising therefrom. The inclusion or exclusion of any product does not mean that the publisher advocates or rejects its use either generally or in any particular field or fields. The information contained within should not be relied upon solely for final treatment decisions.

© 2012 UBM Medica. All rights reserved. No part of this publication may be reproduced in any language, stored in or introduced into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photocopying, recording or otherwise), without the written consent of the copyright owner. Permission to reprint must be obtained from the publisher. Advertisements are subject to editorial acceptance and have no influence on editorial content or presentation. UBM Medica does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature. Printed by Fortune Printing International Ltd, 3rd Floor, Chung On Industrial Building, 28 Lee Chung Street, Chai Wan, Hong Kong.

ISSN: 2078-2535

Dr. Goh Boon Cher (National University Cancer Institute Singapore)

Prof. Pierce Chow (Duke-NUS Graduate Medical School)

Asst. Prof. Jeffrey Low (National University Cancer Institute Singapore)

Asst. Prof. Jiade J. Lu (National University Cancer Institute Singapore)

Dr. Khoo Kei Siong (Parkway Cancer Centre)

Dr. Tan Yew Oo (Consultant Medical Oncologist)

Dr. Eng-Hseon Tay (Novena Medical Centre)

Editorial Advisory Board – Singapore

Oncology Tribune contains articles from Cancer Network, under license from UBM Medica LLC. Copyright © 2012 UBM Medica LLC.

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