How shortcut clinical trials may be misleading oncologists

surrogate approvals (2)Among 55 cancer drugs recently approved on the basis of a surrogate endpoint, less than one-fifth have been shown to improve survival in follow-up clinical trials.


Fully two-thirds of new cancer drugs in recent years gained regulatory approval based on a so-called surrogate end point, such as tumor shrinkage, rather than a clinical end point directly measuring how patients feel, how well they function or how long they survive.

This shortcut strategy makes sense if the surrogate reliably predicts improvements in survival or quality of life. But that connection remains unknown for a surprisingly large share of surrogate-approved cancer drugs in the U.S., according to a study appearing this week in Mayo Clinic Proceedings.

The authors analyzed cancer drug approvals by the Food and Drug Administration between January 1, 2009, and December 31, 2014. They found that 55 of 83 approvals were based on a surrogate end point. In 25 of the 55 surrogate approvals, the authors were unable to find any published research addressing whether the surrogate correlated with survival.

“How can you say it’s reasonably likely to predict true clinical efficacy if nobody has ever studied it?” says senior author Vinay Prasad, M.D., M.P.H., an OHSU Knight Cancer Institute hematologist-oncologist and assistant professor of medicine. “How can you say a surrogate is established when nobody can find a paper?”

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Engineering precision in cancer early detection

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Sadik Esener, Ph.D., the engineer tapped to lead a major new cancer early detection program at the OHSU Knight Cancer Institute.


Medical science has come up with only a few ways to detect incipient cancers in healthy people. None of them can distinguish the aggressive, life-threatening cases from those that are unlikely to become lethal.

Researchers have spent decades, for instance, trying to develop a screening test for ovarian cancer. Most women with this cancer are diagnosed with advanced disease, when five-year survival is no more than about 40 percent. The largest-ever ovarian cancer screening study, published in December, failed to demonstrate a significant survival difference, while the screened population of women more than doubled their risk of unnecessary surgery.1

It’s a similar story for the cancers that claim the most lives: lung, breast and prostate cancer. The PSA screening test, for example, misses nearly 50 percent of high-grade prostate tumors while also driving a high rate of overdiagnosis. Some 20 to 40 percent of cases arising from PSA screening are tumors destined to never cause harm because they are slow growing or unable to metastasize.2

“It’s our view that this is one of the biggest unmet needs in cancer,” says Brian Druker, M.D., director of the OHSU Knight Cancer Institute.

Solving the problem will require unusually broad thinking and fresh perspectives. Perhaps it’s no surprise, then, that Druker and colleagues have chosen an electrical and computer engineer to lead a major new initiative on the precision early detection of life-threatening cancers. With $1 billion in hand from a record-breaking philanthropic campaign initiated by Nike co-founder Phil Knight and his wife Penny, the Knight Cancer Institute is creating a Center for Early Detection Research with plans to hire 250 to 300 researchers and a mission to transform how cancers are diagnosed.

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Long after chemotherapy, nerve damage may increase a woman’s risk of falling

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Years after completing treatment, nearly half of women cancer survivors continued to experience chemotherapy-induced peripheral neuropathy in a new study that tracked more than 500 survivors.

Those with neuropathy had worse physical functioning and a significantly higher risk of falls, the researchers reported this week at the American Society of Clinical Oncology Cancer Survivorship Symposium in San Francisco.

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How cancer screening may fail to save lives

Pap drawing

Vaginal cells drawn by George Papanicolaou, inventor of the pap smear. Credit: Wellcome Images

With the advent of mass screening by Pap smear, cervical cancer incidence and death rates declined by more than 60 percent in the U.S. between 1955 and 1992. It was a triumphant demonstration of the value of early detection.

But the model has never worked so well for other common cancers. Mammography, for example, fails to detect one in four tumors in younger women while also delivering many false-positive results. Less than 5 percent of positive initial findings prove to be cancer.

And believe it or not, we still don’t know for sure whether any cancer screening test saves lives. The evidence in favor of screening is based on fewer deaths due to the target cancer, not reductions in overall mortality, according to a critique published in the British Medical Journal calling for higher standards of evidence for cancer screening.

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Overcoming the impasse in acute myeloid leukemia research

AML drug combination figure

A heat map by Kurtz et al. comparing the sensitivities of leukemia cells to drug combinations.

Nine drug companies and six universities have now joined an unusual collaboration to break the logjam in research on acute myeloid leukemia (AML), a blood cancer lacking effective treatments. Less than 25 percent of newly diagnosed patients survive beyond five years with a standard of care based on 40-year-old chemotherapy agents.

The research initiative, Beat AML, is supplying a stock of drug candidates and treatment ideas, a dozen of which were presented on Dec. 5-8 at the American Society of Hematology Annual Meeting in Orlando, Florida.

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Genomic drivers of a poorly understood kidney cancer

genomic drivers

Researchers have identified many of the altered genes and cell signaling pathways that drive papillary renal cell carcinoma, a poorly understood form of cancer that accounts for about 15 percent of kidney tumors.

The findings, published today in the New England Journal of Medicine, are likely to affect clinical recommendations, and should help guide the development of more precisely targeted therapies. No effective treatment exists for advanced papillary renal cell carcinoma.

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News hype clouds public understanding of cancer research

cancer breakthrough

Breakthrough. Game changer. Revolutionary. Transformative. Life saver. A new analysis of media coverage found that half of new cancer drugs described with such superlatives had not received Food and Drug Administration approval for any indication. Worse, 14 percent of the hyped treatments had not been tested in human subjects.

“While some cancer drugs in development are good and important, the majority are not game changers, and that means we as researchers have to do a better job at communicating the right amount of promise a therapy has,” said senior author Vinay Prasad, M.D., M.P.H., a hematologist-oncologist with the OHSU Knight Cancer Institute and assistant professor of medicine in the OHSU School of Medicine.

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How targeted exercise helps men with prostate cancer

LAF Kessler

Losing bone and muscle mass while gaining fat is a troubling problem for men receiving androgen deprivation therapy for prostate cancer, putting them at risk for heart disease, frailty and broken bones. Depletion of bone in these men is even more rapid than that associated with menopause in women.

But a first-of-its-kind randomized clinical trial is providing evidence that targeted exercise can slow bone loss, reverse muscle weakness, and prevent gains in body fat in men with prostate cancer undergoing androgen deprivation therapy, or ADT.

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Tracking metastasis with cell-free DNA

Sequencing the fragments of tumor DNA that circulate in blood may give a more accurate picture of a patient’s metastatic cancer than can be obtained from biopsies.

Researchers at the OHSU Knight Cancer Institute recently showed that sequencing cell-free DNA can find the same clinically relevant mutations identified in DNA from tumor tissue, and it can provide additional information about the evolution of a particular patient’s disease and how best to treat it.

That’s significant because drawing blood to obtain cell-free DNA is less invasive and safer for patients than taking a biopsy of tumor tissue. The “liquid biopsy” approach makes it feasible to repeatedly sample tumor DNA over the course of treatment.

“It takes out the risk — and a lot of the cost,” says Paul Spellman, Ph.D., a professor of molecular and medical genetics at OHSU who led the study, published in the open access journal PLOS ONE.

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Uncovering the ways cancer manipulates immune cells

Killer T-cells surrounding cancer

Three cytotoxic T lymphocytes surround a cancer cell. (Credit: National Institutes of Health)

Cancer cells have a remarkable ability to reshape their surroundings to gain survival advantages. A developing tumor can, for instance, attract and reprogram immune white blood cells to help the tumor grow. Some of the co-opted immune cells, called macrophages, in turn release molecules that can both boost tumor growth and fend off other immune cells, such as cytotoxic T lymphocytes that would otherwise target and kill cancer cells.

Lisa Coussens, Ph.D., associate director of basic research for OHSU Knight Cancer Institute, is leading an effort to discover new therapies that block critical steps in the interactions between tumors and infiltrating immune cells. She will present recent results from her research at the first International Cancer Immunotherapy Conference, a sold-out event Sept. 16-19 in New York City.

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