Early Lung Cancer Action Project Vindicated by National Cancer Institute

In 1993, the Early Lung Cancer Action Project (ELCAP) initiated a study of the early diagnosis of lung cancer in cigarette smokers with the use of annual screening with spiral computed tomography (CT scans). The project and study was led by Dr. Claudia I. Henschke, a professor of radiology at Weill Cornell Medical College in New York. The study examined 31,567 asymptomatic men and women who underwent baseline screening from 1993-2005. Then, 27,456 annual screenings were conducted between 1994 and 2005, each of which was performed 7 to 18 months after the previous screening. The study used 38 different sites for treating patients with lung cancer.

When the study was completed in 2006, data in the United States showed that annually, approximately 173,000 persons were diagnosed with lung cancer and 164,000 deaths were attributed to this disease, so that approximately 95% of those who are diagnosed with lung cancer die from it.

Dr. Henschke, and her colleagues, published the results of the ELCAP project in an article in the New England Journal of Medicine (NEJM). The results were also published in the Lancet. Her findings were significant: The estimated 10-year survival rate for all participants, regardless of tumor stage and treatment, was 80%. Additionally, of the 484 participants who received a diagnosis of lung cancer, 412 (85%) had clinical stage I lung cancer. In this subgroup, the estimated 10-year survival rate regardless of treatment was 88%.

Based on these findings, Dr. Henschke and her colleagues concluded that CT screening according to the I-ELCAP regimen could detect clinical stage I lung cancer in a high proportion of persons when it is curable by surgery. She further asserted that in a “population at risk for lung cancer, such screening could prevent some 80%” of 160,000 deaths from lung cancer.

Before her research could get the respect it deserved, and could be implemented into guidelines and recommendations, controversy began when it was discovered that Dr. Henscke’s research was funded by the tobacco industry, which she did not properly disclose. Over a decade after Dr. Henschke began her “relentless campaign against lung cancer by trying to convince the medical establishment that smokers and former smokers should be offered routine CT scans to detect lung cancer when tumors are still small enough to be cured,” her research was finally proven correct last week. In the time it took to show that the industry funding of Dr. Henschke’s research had no impact whatsoever, hundreds of thousands of lives could have been saved and prolonged.

It is important to understand that “no one forgives the tobacco industry’s historical resistance to acknowledging smoking’s health risks,” and certainly, no one encourages others to smoke. However, as David A. Shaywitz, an endocrinologist, and Thomas P. Stossel, an American Cancer Society professor of medicine at Harvard and senior fellow at the Manhattan Institute, noted in the Weekly Standard, “If ongoing research shows that spiral CT prevents death from lung cancer, the finding will deserve celebration, and journalists should keep their eye on the ball and focus on the quality of the science, rather than the character of its sponsors–and demand that pharmascolds do the same.”

2010 Results

In light of all the debate surrounding Dr. Henscke’s work, last week, the National Cancer Institute (NCI) published the results the National Lung Screening Trial, conducted by the American College of Radiology Imaging Network and NCI. NCI paid $250 million for study, which began in 2002 and was carried out at 33 sites. It involved more than 53,000 people ages 55 to 74 who had smoked at least 30 pack-years — one pack a day for 30 years or two packs a day for 15 years. Ex-smokers who had quit within the previous 15 years were included in the group.

Either each individual was given a standard chest X-ray or a low-dose CT scan at the start of the trial and then twice more over the next two years. Participants were followed for up to five years. There were 354 lung cancer deaths among those who received CT scans and 442 among those who got X-rays. Based on these findings, the 20.3 percent reduction in lung cancer mortality met the standard for statistical significance. The NLST results show that 24.2 percent of patients on the CT arm had positive findings, compared to a positive rate of 6.9 percent on the x-ray arm.

In other words, for every 300 people screened, one person lived who would otherwise have died during the study. These preliminary results were announced days after it was determined by an independent board that the benefits of CT scans were strong enough to stop the trial. Another significant finding was that deaths due to all causes declined by 7 percent among study participants who received CT scans, suggesting the tests helped to detect other life-threatening diseases besides lung cancer.

Dr. Christine Berg of NCI noted, “This is the first time that we have seen clear evidence of a significant reduction in lung cancer mortality with a screening test in a randomized controlled trial.” In contrast to Dr. Henschke’s study, which had just one arm and measured only survival, the NLST result represents the first time anyone demonstrated a cause-specific mortality benefit from lung cancer screening in this population. NCI Deputy Director Douglas Lowy further noted that NLST overcame deficiencies of prior trials by being a randomized trial, and using as the endpoint decrease in mortality from lung cancer.

Cancer doctors and others predicted that the study’s results would soon lead to widespread use of CT scans, in particular for older smokers, who have a one in 10 chance of contracting lung cancer. Cheryl Healton, president and CEO of the American Legacy Foundation, started with tobacco settlement funds, which has also long funded the work of Dr. Henschke, asserted, “These findings suggest that CT screening for lung cancer should be incorporated into evidence-based practice and reimbursed in the same manner as mammography screening.”

Once again however, health officials involved in the study refused to endorse widespread screening of current or former smokers, saying more analysis of the study’s results is needed to further identify who benefited most (i.e. age, gender, etc.). They cited past concerns about scans finding anomalies that were benign, and the risks of biopsies and thoracic surgery. Other concerns were that the study offers no reassurance about the safety of smoking or the advisability of CT scans for younger smokers or nonsmokers.

Dr. Edward F. Patz Jr., professor of radiology at Duke who helped devise the study, said he was far from convinced that a thorough analysis would show that widespread CT screening would prove beneficial because the biology of lung cancer has long suggested that the size of cancerous lung tumors tells little about the stage of the disease. He did however acknowledge that the study showed “some benefit in high-risk individuals.”

In response to the results from NLST, Dr. Henschke, now a clinical professor of radiology at Mount Sinai Medical Center, said the study was likely to have “underestimated the benefits of CT scans because participants were screened only three times. Had the screening continued for 10 years, as many as 80 percent of lung cancer deaths could have been averted,” she said. She also noted the tremendous potential of low-dose CT scans because her research has shown that it gives information on cardiovascular disease, emphysema and other pulmonary diseases, the three big killers of older people.

Discussion

Today, 46 million people in the United States smoke and tens of millions more once smoked. While a widespread screening program could cost billions annually, any further refinement of those most at risk could reduce those costs, and it could save one out of every 300 screened. There is no question that changing screening guidelines must be handled delicately, given that little is known about how the cumulative risks of years of such scans would balance the benefits, although the radiation would be about the same radiation levels as mammograms.

Now what’s left, according to Laurie Fenton, president of the Lung Cancer Alliance, which has lobbied for widespread CT lung screening, is to develop the “proper quality standards, infrastructure and guidelines to bring this needed benefit to those at high risk for the disease — now.” It needs to be determined who should be screened and how frequently.

With respect to abnormal findings, Dr. Harold E. Varmus, director of NCI, noted that if in the helical CT, there were abnormal findings that, in general, required the next step, which is a diagnostic helical CT scan.” He added that this process requires standards and guidelines for how this technology should be used even in this high-risk group.

Additionally, now that science has proven the effectiveness of CT screens detecting lung cancer, there is a significant chance that funds from tobacco company settlements could now have sufficient evidence to be used for CT scans of former smokers. Moreover, given the emphasis on reducing costs in health care in the Obama administration, this “study suggests that, at least in lung cancer, spending more on tests saves lives.” This study will prove important because the Medicare program will soon reconsider paying for such screens, which can cost $300, and most insurers do not regularly cover such scans unless an illness is suspected.

Background

When Dr. Henschke published her results in 2006, no one disputed that the scans found small tumors. And it was common sense that because lung cancer is usually found later, too late to cure, that the earlier lung cancer was found, the better odds for a cure. In a story run by the New York Times Dr. Peter B. Bach, a pulmonologist and epidemiologist at Memorial Sloan-Kettering Cancer Center and a cancer policy adviser for Medicare and Medicaid praised Dr. Henschke’s work as “a tremendous achievement.”

However, criticism surrounding the study soon grew, as people began to question whether CT scans picking up small tumors really saved lives for two reasons. First, CT scans could detect tiny cancers that would never have progressed and lead to risky and costly procedures like biopsies and lung surgery that are not really needed. Some patients could die from the surgery, or have their lives shortened by complications. Despite this concern, Dr. Henschke’s team minimized needless biopsies, by using certain traits like size, growth rate and appearance to decide which abnormalities should be tested and which ones left alone.

Second, some tumors, despite being tiny, may be so aggressive and deadly that surgery simply cannot be done soon enough to prolong a person’s life. As a result, Dr. Robert Smith, director of screening at the American Cancer Society (ACS), noted that lung CT is not likely to save as many lives as its proponents claim. He did state however, CT scans do potentially have “an opportunity to reduce deaths.” Nevertheless, influential bodies like the ACS and the NCI refused to endorse the scans, and asserted that the “need for further study” over her results.  

Other experts, such as Dr. Barnett Kramer, associate director for Disease Prevention at the National Institutes of Health, said Dr. Henscke’s study was inadequate, and that there needed to be randomized controlled trials. This would entail a study comparing two sets of patients, a group given CT scans and a control group given chest X-rays or no screening at all, to see whether the scans really do lower the death rate from lung cancer in the long run.

This suggestion raised practical concerns because the study would require too many patients, cost too much, and take too long to provide answers. In addition, Dr. Henschke said that CT technology is advancing so rapidly that scanners can become obsolete even before a study is done. Dr. Henschke also challenged the study on moral grounds, asking if it is ethical to give some patients only chest X-rays when it is already known that CT picks up more tumors.

Amidst all of these concerns, “and prodded by Dr. Henschke’s work, the National Cancer Institute decided to spend $300 million on a study to compare CT and chest X-ray in 50,000 people.

Conflict of Interest?

But before the results of that study were published (last week), another controversy about Dr. Henschke’s work arose, almost two years after her research was published. In 2008, the New York Times again published a story about Dr. Henschke, this time noting that her study published in NEJM had been financed in part by a little-known charity called the Foundation for Lung Cancer: Early Detection, Prevention & Treatment.

A review of tax records by The New York Times showed that the foundation was underwritten almost entirely by $3.6 million in grants from the parent company of the Liggett Group, maker of Liggett Select, Eve, Grand Prix, Quest and Pyramid cigarette brands. The foundation got four grants from the Vector Group, Liggett’s parent, from 2000 to 2003. Vector issued a press release on Dec. 4, 2000, saying that it intended to give $2.4 million to Weill Cornell to finance Dr. Henschke’s research. Articles in Business Week and USA Today mentioned the gift. Paul Caminiti, a Vector spokesman, confirmed that the company donated $3.6 million to the foundation over three years, and stated that the company “had no control or influence over the research.”

Dr. Henschke was President of the Foundation for Lung Cancer, and her longtime collaborator, Dr. David Yankelevitz, was its secretary-treasurer. Dr. Antonio Gotto, dean of Weill Cornell, and Arthur J. Mahon, vice chairman of the college board of overseers, were directors. As a result, “prominent cancer researchers and journal editors, told of the foundation by The Times, said they were stunned to learn of Dr. Henschke’s association with Liggett.”

Dr. Jeffrey M. Drazen, editor in chief of NEJM in 2008, was surprised when he learned of this source of funding, and told the Times that NEJM had never knowingly published anything supported by a cigarette maker in his seven-year tenure.

Mainly, people were concerned about the improper disclosure of these funds in Dr. Henschke’s article. Dr. Otis Brawley, chief medical officer of the American Cancer Society, which gave Dr. Henschke more than $100,000 in grants from 2004 to 2007, said if the Society had known of Liggett’s grants to her, they would not have provided money.

In response to these criticisms, Drs. Henschke and Yankelevitz asserted in an email that in no way was Cornell trying to conceal this gift. They firmly stated that the gift was announced publicly, the advocacy and public health community knew about it, it was quite easy to look it up on the Internet, its board had independent Cornell faculty on it, and it was fully disclosed to grant funding organizations. They further acknowledged that the Vector grant represented a small part of the study’s overall cost, and the foundation no longer accepts grants from tobacco companies.

Moreover, Dr. Gotto said in an interview that Dr. Henschke, Dr. Yankelevitz were allowed to set up the foundation without the university’s approval. Dr. Gotto added that he and Mr. Mahon later joined the board to ensure that the Vector grants were handled correctly. He further asserted that they “behaved honorably in setting up the foundation, and there was no attempt to set up a foundation to hide tobacco money.” Additionally, Dr. Henscke noted that the Vector grants helped raise “the initial funding needed to support the research and data collection on the effectiveness of spiral CT screening.”

Despite these statements, Dr. Jerome Kassirer, a former editor of NEJM asserted that the Weill Cornell had created the foundation to hide its receipt of money from a cigarette company. He believed that tobacco companies wanted to support Dr. Henschke’s research to show that “lung cancer is not as bad as everybody thinks because screening can save people.”

The Times suggested that “the tobacco industry has a long history of underwriting research — sometimes through independent-sounding foundations — to make cigarettes seem less dangerous.” But exactly how does this argument apply to using preventive measures, screening patients with CT scans, to help diagnose, and thus treat cancer sooner?

In response to the Times story, David A. Shaywitz, an endocrinologist, and Thomas P. Stossel, an American Cancer Society professor of medicine at Harvard and senior fellow at the Manhattan Institute, noted in the Weekly Standard that journalists seem more interested in advancing a facile “saints vs. sinners” story line rather than objectively challenging the research. Instead of accusing researchers of taking “blood money” from corporations, they assert that journalists should be asking whether the Cornell findings hold up. Is the study methodologically sound? Has it been subjected to a peer review process? Have other researchers duplicated their results?

 Drs. Stossel and Shaywitz recognized that “these are the questions serious scientists ask when they review any research, regardless of who paid for it, and journalists should be doing the same, instead of conforming to a highly stylized, moralistic plot. Moreover, they noted the discrepancy in journalists describing critics of the sponsored research (the pharmascolds) “glowingly, while investigators with industry funding are routinely maligned.”

Another issue that was raised about Dr. Henschke’s research was that she and Dr. Yankelevitz failed to disclose in articles and educational lectures a patent and 10 pending patents related to CT screening and follow-up. General Electric, a maker of CT scanners, licensed the issued patent beginning in 2001. Jonathan Weil, a Weill Cornell spokesman, said Dr. Henschke did not disclose the patents in some articles and lectures because she did not deem them relevant.

As a result, The Journal of the American Medical Association published corrections about unreported financial disclosures from Drs. Henschke and Yankelevitz. Dr. Catherine D. DeAngelis, the journal’s editor in chief, issued an editors’ note stating that the patent and pending patents reported by The Cancer Letter were “relevant to these publications.” Although Weill Cornell shared in the proceeds of Dr. Henschke’s patent and pending patents, Dr. Gotto recognized that “Weill Cornell has a very strict oversight policy for conflicts of interest,” and he dismissed any suggestion that the university could not police and benefit from faculty members’ financial deals.

Even though there was controversy, Dr. Henschke’s work was embraced by many lung-cancer advocacy organizations, which have pushed for legislation in California, New York and Massachusetts to create trust funds to pay for lung cancer screening — often with language tailored to benefit Dr. Henschke’s group.

Conclusion

The pessimism surrounding Dr. Henschke’s work started from anti-tobacco activists two years ago who believed that lung cancer management might be misinterpreted to encourage smoking. These worries, were expanded by reporters who have learned that they can “generate a buzz by identifying corporate sponsorship of academic research and eliciting outraged soundbites from the pharmascolds, who are always ready to castigate the sinner in their midst while extolling their own implied virtue.”

Absent from all these stories is objective, careful reporting, which would have shown that corporate sponsorship of research has proved highly beneficial for medical innovation. Industry-sponsored research enabled the introduction of cholesterol-lowering statin drugs, for example, contributing to spectacular declines in deaths due to heart attacks and strokes.

We agree with Dr. Varmus, director of NCI, that “No one should come away from this thinking that it’s now safe to continue to smoke.” But as Dr. Henscke noted to MSNBC, this research has “now taken 10 years. “If you think about it, in the United States we have 160,000 deaths each year from lung cancer. That’s 1.6 million.”

Think about all the lives that could have been saved or improved between Dr. Henscke’s initial report and the research published this week, and then tell that to those families who lost someone to lung cancer between 2006 and the present. Could industry funding have helped these people, or was it the way media portrayed industry funding that prevented industry from helping them?