When a patient is diagnosed with metastatic disease the primary site of the cancer is usually, but not always, evident. When the origin of the cancer is not identified it is described as a Cancer of Unknown Primary site, or CUP.

Each year in the UK over 10,000 people are diagnosed with CUP. This is a higher incidence than known cancers such as pancreatic, ovarian, uterine, kidney, brain, cervical or blood (leukaemia) cancers.

This October, the first international conference devoted to CUP will be held in London. It aims to bring together people of different disciplines and experiences to share knowledge and understanding and to look for ways forward. There will be a number of short presentations, expert panel discussions and the chance to interact and network with colleagues in the field.

The conference, titled: Overcoming the unknown: New approaches to the diagnosis and treatment of carcinomas of unknown primary, will be held on October 15th at the Royal College of Obstetricians and Gynaecologists, in Regents Park, London.

The conference is for oncologists, radiologists, pathologists, palliative care physicians, surgeons, nurses, researchers and all medical practitioners with an interest in CUP. There will also be representation from cancer charities and those whose lives are, or have been, touched by CUP.

The registration fee is £98 inclusive of lunch, refreshments, conference materials, VAT. There is a discount of £30 for anyone registering on or before 30 June.
To register, please see the website http://www.cupfoundjo.org/conference/index
.and download a registration form.

Bursaries

Several bursaries are available for anyone not funded by an organisation thanks to Matt’s Trust Fund for Cancer, in memory of Matt Hoyle who died with CUP in 2005 aged 26.. For an application form please eMail: john@cupfoundjo.org copied to dcs@delegate.uk.com. Please put “Bursary” in the eMail subject line.

Source
Matt’s Trust Fund for Cancer

Diabetelogia, the journal of the European Association for the Study of Diabetes (EASD), published a series of research papers today examining a possible link between insulin glargine (brand name, Lantus) and cancer. Findings from these research papers are conflicting and inconclusive, and the org/” rel=”nofollow”>American Diabetes Association cautions against over-reaction until more information is available.

Four different population based studies were reported and published in Diabetelogia and the data within these studies and between these studies are conflicting and confusing. Until more information is available, the American Diabetes Association advises patients using insulin not to stop taking it.

For patients using glargine and considering switching to another form of insulin, the data in these studies make it unclear as to whether any one type of insulin increases the risk of cancer more than other types of insulin.

Patients concerned about these studies or their insulin regimen should talk to their doctor and should not stop taking their insulin on the basis of the findings reported here.

Insulin is a hormone normally produced by the pancreas that helps the body use glucose for energy. All people with type 1 diabetes need to take insulin to survive; many patients with type 2 diabetes also need to take insulin to control their blood glucose.

Glargine insulin, which as been widely used since 2000, is an artificial form of insulin that is typically administered once a day.

Source
American Diabetes Association

View drug information on Lantus.

The risk of cancer possibly increases if patients with diabetes use the long-acting insulin analogue glargine instead of human insulin. The Institute for Quality and Efficiency in Health Care (IQWiG), in collaboration with the “Wissenschaftliches Institut der AOK” (WIdO), the research institute of the German Local Health Care Fund, analysed the data of almost 130,000 patients with diabetes in Germany who had been treated with either human insulin or the insulin analogues lispro (trade name: Lantus) between January 2001 and June 2005.

The analysis has now been published together with further studies in the scientific journal Diabetologia, the official organ of the European Association for the Study of Diabetes (EASD).

The disturbing result is that malignancies were found more frequently in patients treated with glargine than in those prescribed a comparable dose of human insulin. “Our analysis does not provide absolute proof that glargine promotes cancer,” says Peter T. Sawicki, IQWiG’s Director and co-author of the study. “Our study does, however, arouse an urgent suspicion which should have consequences for the treatment of patients.”

No difference was found between the short-acting insulin analogues, lispro and aspart, and human insulin. Insulin analogues are synthetic molecules that do not occur naturally, whereas human insulin matches the insulin that the human body manufactures itself.

Is glargine the cause?

IQWiG emphasises that the link found between prescribing glargine and an increased cancer risk is a statistical association. Thus, it is possible that other factors as yet unknown are the cause of the increased risk, rather than glargine. However, it is disturbing that of three further studies published in the same edition of Diabetologia, two also describe an increase in cancer risk associated with glargine.

Glargine has been approved in Germany since 2000. Since then, several laboratory trials have been published which indicate that, under certain conditions, insulin analogues can stimulate the growth of cancer cell lines more strongly than human insulin. “These indications are discussed in the scientific world but have never been dispelled by proper studies,” says Sawicki. According to IQWiG, the overall indications of a risk from glargine have now intensified to such an extent that the burden of proof has been reversed for precautionary reasons: as long as reliable studies do not prove the safety of glargine compared to human insulin, the drug should only be used if there are particularly important reasons for doing so.

Risk of disease increases with dose

The researchers also found that the risk of cancer rose further with increasing glargine dose when compared to human insulin. This dose-dependent relationship with glargine also confirms the suspicion that the drug plays a causal role.

The increase in cancer risk was relatively small and was only detected when other, important factors such as age, sex and daily insulin dose were taken into consideration. The patients were on average between 65 and 70 years of age, thus in principle were already exposed to a certain degree of cancer risk. Out of 1000 patients treated with human insulin, about 41 developed malignancies within an average of 20 months. If “similar” patients were to be treated with glargine, the increases in cancer diagnoses would be as follows: in patients prescribed on average 10 glargine units daily, about 4 more patients per 1000 patients would develop cancer. In patients prescribed 50 glargine units daily, about 13 more patients per 1000 patients would develop cancer.

However, according to the German Local Health Care Fund data, most patients used glargine in relatively low doses. Of 100 patients using glargine, about 50 patients used less then 20 units daily, and only 5 of 100 patients used more than 50 units daily.

Don’t change treatment hastily

However, the latest investigation is no reason for patients with diabetes to change their treatment hastily, especially if the glargine dose used is low. Diabetes is a complex disease and many aspects need to be considered in its treatment. “However, if a patient can be treated equally well with human insulin as with glargine, then, after consultation with his or her doctor, the patient should consider changing to human insulin,” states Sawicki. “If at all possible, patients with an increased risk of cancer should use human insulin instead of glargine.”

The researchers have no evidence that glargine or other insulin agents transform normal cells to cancer cells. However, it may be possible that glargine stimulates the growth of existing cancer cells more strongly than other types of insulin.

In their study, IQWiG and WIdO had access to pseudonymous data on disease and invoices for 17.9 million insurants of the AOK, of which over 320,000 patients had diabetes (particularly type 2). The data were evaluated of approximately 130,000 patients with diabetes who had used either human insulin or an insulin analogue exclusively, and who had not developed malignancies up to 2001.

Source:
Dr. Anna-Sabine Ernst

Institute for Quality and Efficiency in Health Care

View drug information on Lantus.

The American Institute for Cancer Research (AICR) is launching a new campaign in partnership with Giant Food. The campaign, called Shop for Health, Eat for Life, will run in all Giant food stores from June 19 to July 2, 2009.

Shop for Health, Eat for Life aims to help individuals and families reduce their risk of cancer, encourage a healthy diet and raise funds for cancer research and education. The campaign encourages Giant customers to purchase specially marked products and offers several in-store promotions and recipes, free nutrition educational materials and product giveaways in select stores. Two to three cents per Shop for Health, Eat for Life item sold will be donated to the AICR, with a goal of contributing up to $150,000 for cancer research.

The campaign was announced at AICR’s Washington D.C. headquarters on Wednesday, June 10. Event participants included Kelly Browning, Executive Vice President and CEO of AICR; Robin Michel, Executive Vice President and General Manager of Giant Food; Susan Higginbotham, Ph.D. RD, Director of Research for AICR; and Gerard van der Wulp, Deputy Head of Mission for the Royal Netherlands Embassy.

Products included in Shop for Health, Eat for Life are:

- Nature’s Promise Whole Wheat Spaghetti 16 oz.
- Nature’s Promise Whole Wheat Linguini 16 oz.
- Nature’s Promise Premium Organic Spinach 16 oz.
- Nature’s Promise Premium Organic Peas 16 oz.
- Nature’s Promise Organic Black Beans 15.5 oz.
- Nature’s Promise Premium Organic Frozen Strawberries 10 oz.
- KRAFT 2% Shredded Cheese
- KRAFT Triscuit Baked Whole Grain Wheat Reduced Fat Crackers
- KRAFT Planters 16 oz. Dry Roasted Peanuts
- KRAFT Caprisun 100% Juices
- KRAFT 2% and non-fat Breakstone 16 oz. Cottage Cheese

“AICR provides Americans with practical information they can trust — information that will help them make the everyday choices that lower cancer risk,”said AICR’s Browning. “But they still have to make those choices for themselves, and that’s why we’re so pleased to be a part of this campaign with Giant Food.

“Shop for Health, Eat for Life puts AICR’s science-based advice where it can do the most good - right in the grocery aisle, where those all-important choices are actually made every day.”

A new campaign, Shop for Health, Eat for Life, an initiative of Giant Food and the American Institute of Cancer Research, was announced on Wednesday, June 10, 2009. Kelly Browning, Executive Vice President and CEO of AICR; Robin Michel, Executive Vice President and General Manager of Giant Food and Gerard van der Wulp, Deputy Head of Mission for the Royal Netherlands Embassy, spoke about the relevance of healthy diet and nutritious food choices with cancer prevention. The Shop for Health, Eat for Life program will be in all Giant Food stores from June 19 to July 2, 2009.

Giant Chef Mike Reed prepares delicious healthy food options for guests at the Shop for Health, Eat for Life launch event, Wednesday, June 10, 2009 at the American Institute of Cancer Research (AICR). Shop for Health, Eat for Life is a program designed by Giant Food and AICR to educate consumers about cancer prevention and raise funds for research. The program will be in all Giant Food stores from June 19 to July 2, 2009.

About Giant Food

Giant Food LLC, headquartered in Landover, MD, operates 182 supermarkets in Virginia, Maryland, Delaware and the District of Columbia, and employs approximately 22,000 associates. Included within the 182 stores are 164 full-service pharmacies. For more on Giant visit http://www.giantfood.com.

Source
American Institute for Cancer Research

WHEELING, W.Va., June 23 — Excess body weight during young adulthood both increases the likelihood of eventually developing pancreatic cancer and reduces the average age of disease onset, researchers said.

Compared with individuals with a body mass index (BMI) less than 25 before age 39, those considered overweight (BMI 25 to 29.9) had an odds ratio of 1.67 for developing pancreatic cancer (95% CI 1.20 to 2.34), according to Donghui Li, PhD, of the M.D. Anderson Cancer Center in Houston, and colleagues.

Participants who were obese (BMI greater than 30) from the age of 20 to 49 had an odds ratio of 2.58 for pancreatic cancer (95% CI 1.70 to 3.90), they wrote in the June 24 issue of the Journal of the American Medical Association.

Earlier research had implicated obesity as a risk factor for pancreatic cancer, but their case-control study of some 1,600 people is the first to show that fatness at an early age may be especially dangerous, the researchers said.

• Explain to interested patients that pancreatic cancer is among the least treatable and most often fatal malignancies.
• Explain that excess weight and obesity are linked to a wide range of health problems.
• Note that the study used a case-control design, a weaker form of evidence than a prospective approach that follows patients over a long period of time.

Their study also indicated that obese and overweight individuals past the age of 30 with pancreatic cancer had reduced survival rates, irrespective of other prognostic factors such as disease stage.

Dr. Li and colleagues matched 841 patients with pancreatic adenocarcinoma with 754 healthy people for age, sex, and race. Participants were interviewed about their history of height and weight starting in their teen years.

Median follow-up for calculations of pancreatic cancer survival was 22.1 months, covering 609 of the patients for whom at least one year of follow-up was available.

Dr. Li and colleagues said the strongest associations were seen in participants who were overweight or obese during their 30s, and even more so in those who had gained at least five BMI units since their teens.

“Even though the prevalence of overweight and obesity continued to increase until ages 70 to 79 years, the increased risk of pancreatic cancer with weight gain leveled off for gains coming after ages 40 to 49 years,” the researchers noted.

History of smoking and male gender appeared to magnify the effect of excess weight.

Dr. Li and colleagues estimated the population-attributable risk of pancreatic cancer associated with BMI at 10.3% for lifetime nonsmokers and 21.3% for those who had smoked at some point.

Additionally, BMI of 25 or more before age 50 was associated with receiving a pancreatic cancer diagnosis from two to six years earlier than normal-weight patients.

Median age of disease onset for normal-weight, overweight, and obese patients was 64, 61, and 59, respectively (P<0.05).

And, excess weight from the ages of 30 to 79, or in the year before study entry, significantly increased the risk of death from pancreatic cancer after controlling for disease stage and tumor resection status.

Hazard ratio for death among overweight patients was 1.26 (P=0.04); for obese patients, it was 1.86 (P<0.001).

“While our observations require confirmation, they provide support for a role of excess body weight in the development and progression of pancreatic cancer,” Dr. Li and colleagues concluded.

“These observations have great public health implications because it implies that weight gain in young adults is associated with a greater risk of pancreatic cancer than in older adults,” they said.

The researchers speculated that insulin dysregulation associated with excess weight could be a mechanistic factor underlying the relationship.

They noted, though, that the case-control approach has inherent weaknesses, and said a further limitation was that participants were drawn from a single institution. The study also relied on participants’ self-reports of past weight.

In an accompanying editorial, Robert McWilliams, MD, and Gloria M. Petersen, PhD, both of the Mayo Clinic in Rochester, Minn., agreed that the implications of the study are important.

“The additional evidence of knowing that obesity could contribute to earlier onset of disease and worsened survival adds further to the call for interventions at the public health level to stem the increasing rates of obesity at all ages in the U.S. population,” they wrote.

Drs. McWilliams and Petersen added that the findings that increased weight may affect all aspects of the pancreatic cancer process from initial development to final outcome “may provide biological insight into why pancreatic cancer portends such a poor prognosis.”

The study was supported by the National Institutes of Health. No potential conflicts of interest were reported by study authors or the editorialists.

Primary source: Journal of the American Medical Association

Source reference:

Li D, et al “Body mass index and risk, age of onset, and survival in patients with pancreatic cancer” JAMA 2009; 301: 2553-62.

Additional source: Journal of the American Medical Association

Source reference:

McWilliams R, et al “Overweight, obesity, and pancreatic cancer: beyond risk alone” JAMA 2009; 301: 2592-93.

HOUSTON, June 24 — An investigational cancer therapy demonstrated significant antitumor activity in patients with BRCA1/2 mutations, according to the investigators in the most recent string of favorable studies.

• Explain to patients that an investigational drug showed activity in tumors that have certain types of genetic mutations.
• Emphasize that the drug is not yet available.

Almost two-thirds of mutation carriers had a clinical benefit from treatment with olaparib, Johann S. de Bono, MD, PhD, of the Royal Marsden Hospital in London, and colleagues reported in the June 24 issue of the New England Journal of Medicine.

In fact, only mutation carriers had responses to the oral inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP). However, the agent demonstrated activity in patients with breast, ovarian, and prostate cancer.

The drug was well tolerated, and analysis of patient blood, hair, and tissue samples confirmed PARP inhibition.

The findings point to a need to rethink the drug approval process to accelerate development of anticancer therapies, the authors concluded.

“This study raises the possibility that for some anticancer drugs, the traditional processes of clinical development and registration need to be altered,” they said.

“Due consideration must now be given to developing rationally designed molecularly targeted therapies for patients whose tumors have the same molecular defect but different origins, such as the ovary, breast, or prostate. Such a radical change in drug evaluation and registration may be key to accelerating the development of anticancer drugs.”

PARPs have a major role in DNA repair mechanisms, including the repair pathway for the tumor-suppressor proteins BRCA1 and BRCA2. Mutations in the proteins disrupt normal repair processes and allow emergence of a tumor with aberrant DNA repair not found in normal tissues.

“This tumor-specific defect can be exploited by using PARP inhibitors to induce selective tumor cytotoxicity, sparing normal cells,” the authors said. “PARP inhibition in these tumor cells with deficient homologous-recombination repair generates unrepaired DNA single-strand breaks that are likely to cause the accumulation of DNA double-strand breaks and collapsed replication forks.”

In vitro studies showed that BRCA1/2-deficient cells were as much as 1,000-fold more sensitive to PARP inhibition compared with wild-type cells. Moreover, PARP inhibition prevented the growth of BRCA2-deficient tumor xenografts.

Success in the laboratory led to a phase I clinical trial reported by Dr. de Bono and colleagues. The trial involved 60 patients with solid tumors that had proved refractory to standard therapy or for which no suitable therapies existed. By design, the trial was enriched with 21 patients with BRCA-deficient tumors and one patient who had a strong BRCA-positive family history but refused testing.

Treatment with olaparib started at a dose of 10 mg a day for two of every three weeks. The dose subsequently was increased to 600 mg or more twice a day, given continuously for three weeks in four-week cycles.

Dose-limiting toxicity was defined as a grade 3 or 4 adverse effect occurring in the first cycle of treatment with a given dose of olaparib.

That occurred in patients who received 400 or 600 mg bid. The observations established 400 mg bid as the maximum tolerated dose.

Adverse effects possibly related to the study drug were primarily grade 1 or 2 in severity and included nausea (in 32% of patients), fatigue (30%), vomiting (20%), taste alteration (13%), and anorexia (12%). Three patients had anemia and two developed grade 4 thrombocytopenia.

Two patients died during the study: one with advanced non-small cell lung cancer and a history of lower respiratory tract infections and one with ovarian cancer, who died of septicemia. Neither death seemed related to treatment with olaparib.

Two patients had rapidly progressive disease. Both had tumors usually not associated with BRCA mutations: small-cell lung cancer and vaginal adenocarcinoma.

Of 19 BRCA carriers evaluable for tumor response, 12 (63%) had either radiologic or tumor-marker responses or disease stabilization for at least four months. Nine of the 12 met RECIST criteria for tumor response, one of which was sustained for 76 weeks. Two other patients had responses that persisted for a year or longer.

No tumor responses occurred in patients who did not have known BRCA mutations.

“These data indicate that using PARP inhibition to target a specific DNA-repair pathway has the necessary selectivity profile and a wide therapeutic window for BRCA-deficient cells, supporting the clinical relevance of the hypothesis that BRCA mutation-associated cancers are susceptible to a synthetic lethal therapeutic approach,” the authors said.

The positive results follow those from two breast cancer studies reported in May at the American Society of Clinical Oncology meeting. One study involved only patients with triple-negative disease, and the other was limited to patients with BRCA mutations. (See New Drug Class Promising in Breast Cancer)

The study was supported by KuDOS Pharmaceuticals, a subsidiary of AstraZeneca. Additional support was provided by Cancer Research U.K., the Experimental Cancer Medicine Center, the National Institute for Health Research Biomedical Research Center, and Breakthrough Breast Cancer. Co-authors Andrew Tutt, Mark J. O’Connor, Alan Ashworth, and Stan B. Kaye reported financial relationships with KuDOS or AstraZeneca. Co-authors included employees of KuDOS and AstraZeneca.

Primary source: New England Journal of Medicine

Source reference:
Fong PC, et al “Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers” N Engl J Med 2009; 361(2): DOI: 10.1056/NEJMoa0900212.

Related Article(s):

• ASCO: New Drug Class Promising in Breast Cancer

SAN FRANCISCO, June 24 — Even high-risk childhood acute lymphoblastic leukemia (ALL) can be safely treated without prophylactic cranial irradiation when using personalized chemotherapy, researchers found.

In a prospective clinical trial, risk-based intensification of therapy without cranial irradiation yielded a five-year cumulative risk of isolated central nervous system relapse of 2.7% (95% confidence interval 1.1 to 4.3), according to a study reported in the June 25 issue of the New England Journal of Medicine.

This relapse rate was well within the 1.5 to 4.5% range in clinical trials that used prophylactic cranial irradiation, Ching-Hon Pui, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues said.

Children who would have received prophylactic cranial irradiation under prior treatment criteria had significantly longer continuous complete remission than historical controls who were irradiated (five-year rate 90.8% versus 73.0%, relative risk 0.34, P=0.04).

These clinical findings further chip away at the once standard use of prophylactic cranial irradiation, Dr. Pui’s group wrote.

• Explain to interested patients that cranial irradiation was once standard for all childhood cases of ALL to prevent cancer recurrences in the central nervous system.
• Explain that new treatment regimens can now achieve the same or better results without it.
• Note that the trial provided comparisons only with historical controls rather than an active comparator arm.

Radiation-associated late complications such as second cancers, cognitive deficits, and endocrine problems, have led researchers to progressively reduce dosages and limit use to only the highest-risk children.

Now only about 20% of childhood ALL cases in the U.S. are treated with cranial irradiation to prevent central nervous system relapse, Dr. Pui said.

But his group saw potential to eliminate its use entirely.

Their Total Therapy XV trial tested whether intensified systemic treatment for central nervous system control plus optimal intrathecal treatment would be enough to maintain overall survival rates without prophylactic cranial irradiation in 498 consecutive children with newly diagnosed ALL.

The intensity of the treatment regimen followed an algorithm based on each child’s level of risk determined by presenting features and sequential measurements of minimal residual disease after remission-induction treatment.

All patients were successfully measured for levels of minimal residual disease, which resulted in reclassification of risk status from low to standard risk for 30 patients, from low to high risk for six patients, and from standard to high risk for 22 patients.

Chemotherapy doses were adjusted on the basis of pharmacogenetics and pharmacokinetics.

The overall five-year survival rate of 93.5% (95% CI, 89.8 to 97.2) for all 498 patients under this treatment strategy was “superior to results of all major studies reported to date,” the researchers noted.

This rate also compared favorably with the 87.5% survival rate reported by the Surveillance, Epidemiology, and End Results Program for patients younger than 15 treated in clinical practice between 2000 and 2004, they noted.

They found an estimated five-year rate of event-free survival of 85.6% (95% CI 79.9% to 91.3).

Overall, only 9.3% of the treated children had any relapse (95% CI, 6.0 to 12.6), and just 3.9% had any central nervous system relapse (95% CI 1.9 to 5.9).

Of the 11 patients who had an isolated central nervous system relapse, all remained alive and in a second remission for 0.4 to 5.5 years (median 2.5).

Independent factors in isolated central nervous system relapse included T-cell ALL, black race, the genomic translocation t(1;19)(TCF3-PBX1), and any central nervous system involvement.

However, the researchers argued against prophylactic cranial irradiation even for patients with these risk-associated features because “approximately 90% of such patients would have received unnecessary irradiation.”

Also, “since central nervous system and hematologic relapses are competing events,” they wrote, “eradication of occult central nervous system leukemia by means of cranial irradiation alone may allow overt systemic relapse from residual leukemia in the bone marrow or other sites,” which is more difficult to treat with salvage therapy.

Despite intensive treatment, the strategy was associated with a cumulative risk of death from toxic effects during chemotherapy of only 1.4% (95% CI 0.4 to 2.4).

The higher doses of dexamethasone (Decadron, Intensol, Dexpak) and asparaginase (Elspar) given to the standard- and high-risk groups caused more osteonecrosis, thrombosis, and hyperglycemia than seen in the low-risk group.

“Rates of disseminated fungal infection and thrombosis were substantial, but no patient died of these complications,” Dr. Pui’s group noted.

Notably, they said they expected a low rate of therapy-induced cancers since etoposide (Etopophos, Vepesid) and irradiation were given only to the small subgroup of patients who underwent hematopoietic stem cell transplantation.

Extrapolating from long-term results of prior studies, the investigators predicted five- to 10-year major adverse event rates of no more than 4% and a 10-year survival rate — “and perhaps a cure rate”– of 90%.

The study was supported by grants from the National Institutes of Health and an American Cancer Society F.M. Kirby Clinical Research Professorship and by the American Lebanese Syrian Associated Charities. Dr. Pui reported receiving lecture fees from Enzon Pharmaceuticals. Co-authors reported conflicts of interest with Enzon Pharmaceuticals, Genzyme, sanofi-aventis, EUSA Pharma, the American Society for Investigative Pathology, Genome Explorations, and a patent concerning molecular diagnosis of thiopurine-S-methyltransferase deficiency.

Primary source: New England Journal of Medicine

Source reference:

Pui C-H, et al “Treating childhood acute lymphoblastic leukemia without cranial irradiation” N Engl J Med 2009; 360: 2730-41.

WHEELING, W.Va., June 24 — Ewing’s sarcoma strikes white Americans at nearly 10 times the rate it affects blacks and about double that in Pacific Islanders, researchers said.

• Explain to interested patients that Ewing’s sarcoma is a rare form of cancer that primarily affects children and young adults.
• Explain that five- and 10-year survival rates are both about 50%.
• Note that the study was a retrospective analysis of database records, which could be faulty or incomplete.

Annual age- and population-adjusted incidence of the disease from 1973 to 2005 was 0.155 per 100,000 in whites, 0.017 in blacks, and 0.082 in Pacific Islanders, reported Sean P. Scully, MD, PhD, of the University of Miami, and colleagues online in Cancer.

Moreover, the rate among whites has been increasing significantly — by an average of 0.84% annually (P<0.05), the researchers found.

Rates for other racial groups have not changed significantly, although the small number of patients — a total of 1,631 cases were analyzed in the study, 92% white — may have made significance impossible.

Hispanic ethnicity did not markedly affect incidence among whites.

The study was the first comprehensive epidemiological and outcomes study of Ewing’s sarcoma, using data from the Surveillance, Epidemiology and End Results database maintained by the CDC.

The disease afflicts mostly children and young adults. The highest incidence was in 10- to 19-year-olds, at about 0.95 cases per 100,000.

Incidences between 0.3 and 0.4 per 100,000 were found for children younger than 10 and for people in their 20s. Starting at age 30, rates fell below 0.1 per 100,000 and declined steadily with increasing age.

In addition to the incidence data, the researchers examined survival records and their relation to patient and disease characteristics:

• Five- and 10-year survival rates were 55% and 53%, respectively, and did not differ with age.
• Survival rates were significantly lower for males — 10-year rates were 50% for males and 58% for females (P<0.004).
• Blacks showed poorer survival than whites — 46% versus 52% — but the difference was not significant, perhaps because there were only 35 blacks with the disease.
• Tumor size greater than 8 cm reduced survival probabilities by 25% (P<0.001).
• Distant metastasis cut survival rates by more than half (P<0.001).
• Patients treated surgically had higher survival rates — 62% versus 43% for nonresected patients at 10 years (P<0.001).
• Survival rates have improved substantially over time, from 39% at five years in 1973-1975 to 57% in 1996-2005 (P<0.001).

Cox proportional hazards analysis identified local or regional disease confinement, an appendicular location, and tumor size of 8 cm or less as independent and significant predictors of improved survival.

Dr. Scully and colleagues said the reasons for the racial differences and the rising incidence among whites were unclear.

“Environmental factors and exposures to potential mutagens or viruses change over time, and Caucasians could carry a genetic propensity to respond to specific kinds of mutagens that cause Ewing’s sarcoma,” the researchers speculated.

Ewing’s sarcoma is characterized by a particular chromosomal alteration, which may or may not actually cause the disease, they said.

However, if it is causal, “then explanations for the racial disparities in incidence and sex disparities in outcome could be explained by differences in genetic replication machinery,” Dr. Scully and colleagues wrote.

They said more research is needed to clarify these issues.

Dr. Scully and colleagues noted several limitations of the study, including its retrospective nature and its reliance on database information that may be faulty or incomplete.

No external funding for the study was reported. No potential conflicts of interest were reported.

Primary source: Cancer

Source reference:

Jawad M, et al “Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973-2005″ Cancer 2009; DOI: 10.1002/cncr.24388.

WHEELING, W.Va., June 24 — Women with rare, placental site trophoblastic tumors (PSTT) are unlikely to survive if the disease is diagnosed more than four years after their last pregnancy, British researchers found.

• Explain to interested patients that placental site trophoblastic tumors, which occur in women following pregnancy, are extremely rare.
• Explain that, according to this study, outcomes are poor when the disease is diagnosed more than four years after pregnancy, but most such tumors are found sooner than that and are usually curable.

In fact, all women diagnosed with the disease more than four years after pregnancy were dead within 65 months, while the 10-year survival rate among those diagnosed within four years of pregnancy was 98% according to Peter Schmid, MD, PhD, of Imperial College London, and colleagues.

The findings, reported online in The Lancet, were based on records for all PSTT cases in Great Britain from 1976 to 2006 — a total of 62 — as obtained from national registry data.

Thirteen women were diagnosed more than four years after pregnancy. Of the other 49 diagnosed sooner, only one died, the researchers found.

As those numbers indicate, PSTT is an extremely rare complication of pregnancy, arising months or even years afterward. The outcome of the pregnancy — normal delivery, abortion, miscarriage, or hydatidiform mole — does not seem to matter.

Dr. Schmid and colleagues examined outcomes for the 62 patients with PSTT, out of a total of about 36,000 gestational trophoblastic disease cases.

Those diagnosed at stage I had a 10-year survival rate of 90% (95% CI 77% to 100%), with no evidence that postoperative chemotherapy improved outcomes.

Later-stage patients appeared to benefit from surgery and adjuvant chemotherapy, the researchers found.

Among five patients with stage II disease, the two who were treated exclusively with surgery both had disease recurrence, while three patients who had surgery plus chemotherapy have survived recurrence-free, Dr. Schmid and colleagues said.

Of 23 patients with stage III or IV metastatic disease, 14 had both surgery and chemotherapy. The combined approach led to durable remissions in eight patients, with recurrence seen in five and no response at all in one.

Among eight patients receiving just chemotherapy, only two had long-term disease control. The sole patient treated exclusively with surgery has survived recurrence-free.

Dr. Schmid and colleagues calculated overall 10-year survival for stage III and IV disease to be 49% (95% CI 26% to 72%).

For all disease stages, recurrence was a bad omen. Only one-third of patients relapsing could achieve a second, durable remission, the researchers found.

Multivariate analysis indicated that time from last pregnancy to diagnosis was by far the strongest predictor of survival, even after controlling for tumor size, depth of myometrial invasion, and other factors that might influence prognosis.

The area under the receiver-operator characteristic curve for time since antecedent pregnancy as a prognostic measure was 0.981 (95% CI 0.942 to 1.019).

Using four years as the cutoff, the positive predictive value was 100% and negative predictive value was 98%.

Dr. Schmid and colleagues said time from pregnancy to diagnosis could perhaps guide treatment.

In particular, they recommended that patients diagnosed more than four years after pregnancy receive adjuvant chemotherapy, even for those with stage I disease.

Such an approach for early-stage patients would also make sense when there are other risk factors for poor outcomes, such as vascular invasion or serosal involvement, they said.

In an accompanying commentary, Ernest Kohorn, MD, of Yale University, noted that careful diagnosis, including histological confirmation, is essential in dealing with potential PSTT cases.

“It is now accepted that placental-site trophoblastic tumors differ from other trophoblastic neoplasms in that the tumor load is not accurately correlated with the concentration of hCG, and that the tumor might be less sensitive to chemotherapy that is effective in the other types of trophoblastic neoplasia,” he wrote.

He also applauded Dr. Schmid and colleagues for recommending aggressive treatment of PSTT.

“It is gratifying to find that the investigators advocate adjuvant chemotherapy even for stage I disease,” Dr. Kohorn said.

The study was funded by the National Commissioning Group. No potential conflicts of interest were reported by the study authors or Dr. Kohorn.

Primary source: The Lancet

Source reference:

Schmid P, et al “Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study” Lancet 2009; DOI: 10.1016/S0140-6736(09)60618-8.

Additional source: The Lancet

Source reference:

Kohorn E “Long-term outcome of placental-site trophoblastic tumours” Lancet 2009; DOI: 10.1016/S0140-6736(09)60791-1.

Collaboration in prostate cancer translational research in Europe is not only vital to sustain the progress achieved in recent years but also to streamline current efforts between researchers and clinicians and avoid duplication or overlaps. This was amongst the goals of the two-day Prostate Cancer Translational Research in Europe (PCTRE) Meeting which opened recently in Amsterdam, The Netherlands.

“It is important that people with research background can communicate with clinicians and vice versa. By doing so we maximise the interaction amongst specialists. It is essential that we show our results to each other,” said Prof. Peter Mulders (Nijmegen, The Netherlands), chairman of the European Association of Urology Research Foundation (EAU-RF), organiser of the PCTRE meeting.

With more than 170 participants, the conference opened with lectures and updates on the work of prostate cancer consortia based in Europe. Within the European Community based framework programme these consortia received around €40 million in funding covering scientific topics such as the search for diagnostic and prognostic markers for prostate cancer.

Dr. Thorunn Rafnar (Reykjavic, IS) spoke on the current work regarding the identification of common genetic variants that affect the risk of prostate cancer. 42% of prostate cancer has a genetic cause. The lifetime risk of a man in the European Union to acquire prostate cancer is 10% and it is the third leading cause of death from cancer in men.

“First risk models including low risk variants are appearing,” Rafnar said as she added that “the search for genetic determinants of disease severity is ongoing.”

Polygene, one of the participating consortia, uses Genome-wide Association studies (see http://www.genome.gov) to analyse genomes responsible for cancers of the prostate and breast. However, current genetic risk models do not predict who will get progressive disease. Promark, another consortium, searches for genetic variants that do associate with aggressive cancer forms.

She also noted that the information on PSA genetics may improve utility in screening. Rafnar also pointed out that although “…much work remains…. finding causative variants at known loci define functions.”

The lecture by Prof. Freddie Hamdy (Oxford, UK), ‘What is the best practice in bio-banking?’ focussed on the dilemmas in prostate cancer (how to identify the population at risk, how to prevent overtreatment and treatment failure). “We can treat, we can cure, but who should we treat and cure?”, he said. Collection and cohorts of prostate cancer samples are important in order to look for new biomarkers. But the search for prognostic markers needs a multi-targeted approach. “The focus should be on the benefit to the patient; it should result in e.g. a reduction in mortality or of side effects”, says Hamdy.

Dr Schenk-Braat (Rotterdam, NL) says: “The incidence of prostate cancer will increase and PSA is not a sensitive enough tool to identify men at risk”. The P-Mark project evaluates promising biomarkers and has selected 3: osteoprotegerin (a bone turnover protein discovered by the group of Prof Hamdy), PCA3 (Jacques Schalkens (Nijmegen, NL) group) and multikallikreins (project of Profs Lilja (New York, US) and Petterson). An across marker validation study is ongoing. “We can name the European prostate biobank, increased support of the validation of biomakers and the prostate risk indicator as a few results from the P-Mark project”, says Schenk-Braat.

In another update lecture, Dr. O. Kallioniemi (Helsinki, Finland) discussed the integration of high-throughput technologies to identify drug targets and new therapeutic options for prostate cancer. Amongst his conclusions are:

* Majority of anti-cancer drugs are equally effective in cancer and control cells.

* TSA, thiram, disalfiram and monensin (are) identified as cancer selective compounds inhibiting VCaP cell growth at nanomolar concentrations.

* In vivo studies using VCaP cell xenografts showed reduced tumour growth in response to disulfiram exposure; disulfiram was not able to block tumour growth indicating the need for combined approaches.

* Disulfiram induced metallothionein expression, knockdown of MTI increased efficiency by five-fold.

Source:
Lindy Brouwer
European Association of Urology

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