Reading The Emperor of All Maladies, Siddhartha Mukherjee’s “biography of cancer” from last year, one is struck by both the long and short history of cancer. Descriptions of breast cancer can be found as long ago as an Egyptian papyrus dated to 2500 BC and ancient Greek histories, and tumors have been found in thousand-year-old mummified remains from Peru. But the idea of cancer as a treatable disease is barely a hundred years old, and as recently as the 1940’s, clinicians could do little more than help patients die from the disease as comfortably as possible. Despite these deep historical roots, Mukherjee chooses to start his book in 1947, with Sidney Farber’s first experiments on chemotherapy for children with leukemia.
From there, the pace of the “war on cancer” (though not known by that phrase until 1971’s National Cancer Act) accelerates rapidly, as chemotherapy, radiation and surgical protocols were improved through scientific inquiry. Progress in understanding and treating cancer no doubt seemed incremental as it was happening, and even today some still question its overall success. But Mukherjee’s skillful portrayal presents an astonishing difference in the experience of cancer patients only 50 years apart – from being hidden in out-of-the way wards because of the hopelessness of their condition, to the ultra-modern cancer centers of today offering targeted treatments that offer the promise of a cure, if not yet a certainty.
But stumbling blocks still exist in the scientific progress against cancer. One place where reinforcements are desperately needed is at the level of clinical cancer trials, where the true benefits of laboratory discoveries are put to the test in a human population. While there is no shortage of ideas for new cancer therapies, clinical trials have struggled due to insufficient accrual of patients. Though 25,000 to 30,000 patients are enrolled in cancer trials each year, they only represent 3 to 5 percent of all U.S. adult cancer patients, Richard Schilsky, professor of medicine and chief of hematology/oncology, wrote in a commentary for Science Translational Medicine last week.
“Despite various attempts to remedy the accrual problem, such as awareness campaigns, establishment of clinical trial registries, and the development of search engines to match patients to trials, annual enrollment on cooperative group clinical trials has remained essentially unchanged throughout the past decade,” he writes. As a result, “up to 40% of cooperative group phase III trials have failed to complete accrual and closed without achieving study endpoints, wasting the contribution of those patients willing to enroll in the trial.”
There are plenty of barriers against getting cancer patients into appropriate trials, Schilsky says. Many are institutional – physicians outside of the academic world may not have dedicated research staffs than can help coordinate patients, deal with regulations and insurance issues, and fill out the extensive paperwork. To circumvent these issues, some doctors would rather write off-label prescriptions for drugs being tested in a clinical trial, getting the potential benefits of the drug without the logistical commitments. On the other side, patients may not be aware of the trials available to them, or may misunderstand the purpose of a clinical trial.
The new era of molecular medicine could raise some of these obstacles even higher or knock them down, Schilsky writes. In 2001, the drug Gleevec ushered in the age of smarter drugs that directly interfere with the cause of the disease, rather than general features of tumor growth. Testing these types of drugs requires new types of trials, with more biospecimens (blood, tumor tissue, DNA) collected from patients and tighter rules about who is eligible for the experiments. Classifying broad cancers into more specific subtypes may eventually improve treatment effectiveness, but in the short term could make testing those treatments even more difficult.
“The challenge is that many patients may need to be screened if the biomarker used for patient selection is of low prevalence in the tumor type under study,” Schilsky writes.
But all is not pessimistic. More specific criteria may lead to larger effect sizes in clinical trials and early evidence suggests that cancer patients prefer the new, “smart” trials. Meanwhile, patients have been given additional power thanks to the growth of advocacy organizations that can help people find trials for which they are qualified and nearby oncologists that will help them enroll. As with many other areas of cancer medicine, breast cancer groups are ahead of the curve. Schilsky uses the Love/Avon Army of Women as his example, an organization that launched a clinical trials database which has helped more than 300,000 women register for trials (their goal is 1 million). By opening channels that used to be controlled by physicians alone, the pathway leading patients to clinical trials is hopefully wider, and the next chapter of the fight against cancer can be written.
“The potential exists for patients themselves to take a more active role in finding trials, assessing their eligibility, and even submitting their biospecimens and clinical data to facilitate their enrollment,” Schilsky writes. “Proper attention to and investments in these areas by policymakers and funding agencies will accelerate our ability to deliver on the promise of molecular medicine.”
Schilsky RL (2011). Accrual to cancer clinical trials in the era of molecular medicine. Science translational medicine, 3 (75) PMID: 21430267