“Many new frontiers exist in integrative medicine,” NIH Director Francis Collins, MD, PhD, stated in his keynote address at the Eighth International Conference of the Society for Integrative Oncology (SIO) in Cleveland. “The evidence is overwhelming that these approaches are being used by many individuals in the United States, including those with cancer,” he said. “For wellness, immune function, and pain-related symptoms, there is a significant increase in interest among cancer survivors compared to other people who use complementary and alternative medicine.”
Survey data show that over a lifetime, complementary and alternative medicine (CAM) is used by “65% of cancer survivors vs 53% of noncancer respondents,” he said. When questioned about motivations to use CAM, cancer survivors “are more likely to be using this because they are unhappy that medical treatments have not helped them or because it has been recommended by the provider,” he noted.
“We have always had concerns about possible interactions between CAM and other standard cancer therapies, and there are certainly patients who are not telling their providers about their CAM use,” Dr. Collins added. He cited a recently reported study from The University of Texas MD Anderson Cancer Center showing that 52% of cancer patients are using CAM during phase I trials, but that 23% don’t disclose that information to trialists. This finding, he said, should encourage researchers to continue to ask patients questions aimed at eliciting information about complementary and alternative medicine use.
Comparative Effectiveness Research
Dr. Collins acknowledged that there are differences in opinion about the use of the terms complementary and alternative, as in NIH’s National Center for Complementary and Alternative Medicine (NCCAM), vs the term integrative, as in the Society for Integrative Oncology (SIO), but said that the strategy of NCCAM is “very much aligned” with that of the SIO.
He stressed the need for “rigorous evaluation” of complementary and alternative medicine and well-designed clinical trials “so you have evidence that can be shared with the public about whether or not a particular approach is going to help them.” One way to do that is through comparative effectiveness research, which is something NIH has been doing for many decades, although it was not always known by that term, he said. This is an important issue for the Patient-Centered Outcomes Research Institute (founded under the Patient Protection and Affordable Care Act), which is starting to support this kind of research “with a particular focus on patient-centered concerns,” he continued.
“We need to do this research, not only to find out what works, but to find out what interventions actually may be harmful,” no matter how unlikely that may seem, Dr. Collins commented. For example, he pointed to the story of beta-carotene in cancer prevention. In the 1980s, epidemiologic evidence suggested that beta-carotene might decrease lung cancer risk. Double-blind clinical trials were initiated, and in the 1990s, those trials showed that “not only is beta-carotene not protective, it actually increased lung cancer risk—16% in one study and 28% in another—and so the studies were halted.” A follow-up study in 2004 corroborated those results.
A more recent example concerned the use of vitamin E for the prevention of prostate cancer, again based on indirect evidence. When tested in a controlled trial, the results indicated that “vitamin E actually increased the likelihood of prostate cancer by about 17% in the men who took this over a course of a number of years,” Dr. Collins explained. “That’s the kind of data we need if we are going to be giving rational recommendations to patients and providers about how to practice better prevention and treatment,” he said.
“The science of understanding what causes a good cell to go bad—what causes malignancy to appear—has rocketed forwarded in the course of the past few years,” Dr. Collins stated. “Genomics has become a major driver of research in cancer because cancer is a disease of the genome.” Dr. Collins is noted for his leadership of the international Human Genome Project, which culminated with the completion of a finished sequence of human DNA, and he served as Director of the National Human Genome Research Institute at the NIH from 1993 to 2008.
Due to technologic advances over the past few years, we can now “look at the DNA of a cancer cell and catalogue all of the things that have gone awry,” Dr. Collins noted. “You don’t have to guess which of the 20,000 genes in a particular cancer cell might be driving the malignant behavior.” The challenge is to figure out “which mutations are actually drivers of the malignant phenotype and which of them are what we would call passengers—just mutations that that cell has taken on, with no real biologic consequences,” he explained.
‘You Need Big Numbers’
“You need big numbers to sort out what’s a driver and what’s a passenger,” he said. “You need hundreds of tumors of each type, and for each of those tumors you need matched DNA for that same individual, and then you can begin to see if there are in fact recurrent molecular changes that appear frequently in that particular class of tumors.” That is what The Cancer Genome Atlas is doing as a joint effort between the NCI and the National Human Genome Research Institute—systematically mapping genomic changes in the major types and subtypes of cancer.
Having already focused extensively on glioblastoma multiforme, ovarian cancer, and lung cancer, The Cancer Genome Atlas researchers are attempting to characterize all of the recurrent genomic changes for at least 20 of the most common cancers in the next 3 years, Dr. Collins reported. Once validated, the data will become immediately available to other investigators. This project “undoubtedly is going to revolutionize the field,” he said, particularly in stimulating the development of a new generation of targeted therapeutics.
Projects currently underway are posted on The Cancer Genome Atlas website (cancergenome.nih.gov). “The colon cancer project is well along, and I think they are in the middle of the data analysis right now.… There will be a publication on what they’ve found within half a year,” Dr. Collins said.
“It’s a major undertaking and it does involve really big numbers,” he said. “For each of these tumor types, they aim to identify 500 tumors that are highly characterized, very pure without much stroma, and for which the DNA is available and full consent has been given to make the data accessible. It’s quite a challenge,” he said. “That’s 500 tumors and 500 blood samples, all of which have to have complete genome sequencing done. That’s 1,000 samples for each of those 20 tumor types, or 20,000 human genome projects. It’s amazing.”
As “a dramatic example” of the new targeted, personalized approach to cancer treatment, Dr. Collins described the case of a woman, a nonsmoker who was diagnosed with very aggressive, stage IV non–small cell lung cancer in both lungs about 4 years ago. Following standard chemotherapy, she participated in a clinical trial with crizotinib (Xalkori). Prominent lung metastases shown on x-ray in July 2009 “were essentially gone by November 2009,” Dr. Collins reported. “So she has had a dramatic response, and she continues to do extremely well,” he added.
“Of course this drug doesn’t work for everybody with this kind of lung cancer. So what’s the difference? It depends on whether the particular cancer has a fusion involving the ALK gene,” Dr. Collins explained. “Crizotinib was not developed with that particular target in mind, but it turned out after the fact that this was going to be a very responsive situation.” The success of crizotinib when used in a targeted personalized approach led to its approval by the FDA several months ago. Yet the drug may not have been approved if it “had been tried on thousands of people with lung cancer without having stratified them by the specific molecular findings,” Dr. Collins said.
Harnessing the Immune System
Another advance, and “one that I am sure resonates” with SIO members, Dr. Collins said, is harnessing the immune system to search out and destroy malignant cells. He cited two papers published last summer in The New England Journal of Medicine1 and Science Translational Medicine,2 describing three patients with chronic lymphocytic leukemia (CLL) in an effort to activate the patients’ own T cells to attack the leukemic cells. The result was an “unprecedented success,” he said, and two of the three patients achieved sustained remissions with no evidence of disease. Based on this success, a similar strategy is being considered for other cancers. While “immune therapies for cancer have been around for a long time,” Dr. Collins said that the success with CLL is a significant advance that “gives us all the sense that we are on the right path.”
“We also have great excitement about a new era in therapeutics based on natural remedies,” Dr. Collins said. The NCI has an ongoing program looking for anticancer activity in extracts from plants, marine invertebrates, and microbes. “We are also seeking opportunities by looking at traditional medicines, many of them from China, for how we can decrease the side effects of treatment.”
Research Funding Threatened
While NCCAM is an important focus of efforts at NIH, other institutes within NIH also have initiatives in complementary and alternative medicine, Dr. Collins noted. “The NCI has the largest one by far,” he said, and “the budget for CAM in the NCI is actually slightly larger than the entire budget of NCCAM. The total investment that NIH makes in complementary and alternative medicine research in 1 year is about a half-billion dollars. I wish it was more, but I wish everything we are doing in biomedical research could be more,” he said.
“The opportunities for medical research have never been greater than they are right now, and yet the threat to the support of biomedical research has—in the memories of anybody who is currently working in the field—never been greater either,” Dr. Collins stated. He noted that in fiscal year 2011, “for only the second time in 40 years, the NIH budget sustained a real cut.” If the failure of the Joint Select Committee on Deficit Reduction (the so-called supercommittee) to cut $1.2 trillion from the budget results in sequestering of discretionary budgets, “a dramatic downturn in support for biomedical research” could occur in fiscal year 2013, Dr. Collins said.
“I am optimistic because it seems to me our case is so strong,” he said. “The value of what we do for transforming human health has been well proven and is more promising now than ever. The opportunity we have to contribute to a turnaround of the economy, considering the return on investment for what NIH does, is extremely compelling. But these are difficult times, and it is up to all of us to effectively make that case and ensure that it is being heard.” ■
Disclosure: Dr. Collins reported no potential conflicts of interest.
1. Porter DL, Levine BL, Kalos M, et al: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365:725-733, 2011.
2. Kalos M, Levine BL, Porter DL, et al: T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3:95ra73, 2011.