Declining cancer death rates — cause for optimism, caution
In many respects, this year’s report of cancer incidence and mortality from American Cancer Society, Cancer Statistics 2020, tells a familiar story.
The report shows a continuing decline in overall cancer death rates, driven mainly by reductions in death of lung, colorectal, breast and prostate cancers; relatively little change in mortality of a few cancers, notably pancreatic cancer; and truly remarkable changes in some less common cancers such as chronic myeloid leukemia, for which life expectancy among those affected now approaches that of the general population.
Other familiar themes are the variability among states and the ongoing disparities in outcome associated with geography and race, particularly for preventable cancers.
In other respects, the news this year is different.
Reductions in death rates for breast and colorectal cancers have been less marked, and prostate cancer death rates now appear stable. Whether this means the impact of current prevention and early detection strategies is now maxed out or whether there are other reasons for the apparent slowdown is unclear.
On the positive side, the 2.2% reduction in the overall cancer mortality rate from 2016 to 2017 was the largest ever recorded in 1 year, driven mostly by a remarkable decline in lung cancer deaths. Researchers also reported a similar and equally remarkable decrease in deaths of metastatic melanoma.
What makes these changes especially notable is that, whereas such declines are usually attributable to improved prevention and screening interventions, these death rate reductions are thought to be most likely due to the impact of new treatments — specifically immune checkpoint inhibitors.
‘Rapid expansion’ of immunotherapy trials
As the use of immunotherapy in different contexts continues to expand, it will be interesting to see whether these gains in survival data are maintained or accelerate.
Results of the multiple ongoing studies of checkpoint inhibitors in these diseases should help to define their role, as well as their impact on outcome.
But will they?
There has been a rapid expansion in the number of clinical trials exploring the use of checkpoint inhibitors in a variety of cancers. These trials are evaluating many different agents in different clinical contexts and in multiple combinations, with and without chemotherapy, radiation and molecularly targeted agents.
Estimates suggest that more than 500,000 patients are enrolled in more than 2,000 trials of checkpoint inhibitors. There have been concerns that these trials are competing for patients, which ultimately could result in some studies failing to reach their projected accrual — in addition to the missed opportunity that characterizes closure of trials for poor accrual, there is also the misdirection of limited resources into studies that do not ultimately contribute new knowledge.
Additionally, some of the combinations being tested in these trials do not appear to be based on clear scientific rationale, but rather on the basis that they can be combined. This and the possible early closure of these trials represent failures to uphold our ethical obligations to patients who agree to participate in trials.
It’s interesting to speculate on what has driven the proliferation of immunotherapy trials. Of course, these are blockbuster drugs that have generated enormous promise and excitement. Providing our patients with rapid access to these agents is a high priority.
From a funding and reputational perspective, it’s important for individual investigators and academic institutions to be seen as actively involved in these studies — within the last hour I received an email from one major institution reporting on Cancer Statistics 2020 and then listing the multiple immuno-oncology trials it has open.
Impacts of venture capitalism
In a viewpoint published last month in JAMA Oncology, Huang and Nambudiri discuss the role of venture capital investment in oncology and point out the high level of investment in immuno-oncology compared with other areas of cancer therapeutics, such as genome-driven therapies.
The authors also observe that much of this investment is used to fund clinical trials and that the strategy favors later-stage investment compared with the early stages of drug development.
In oncology, where the current regulatory environment is relatively favorable to small clinical trials, investment in immuno-oncology carries less risk and an opportunity for a relatively quick return on investment — or a quick exit if a new agent does not show promise.
In addition to the potential effects of venture capital in this landscape, the potentially high profit from effective cancer drugs is a driver for established pharmaceutical companies to activate multiple trials.
Although the large number of clinical trials is a positive trend in many respects, the duplicative nature of many of these studies is a cause for concern. This is partly a numbers issue — half as many studies with twice as many patients in each will likely have more statistical power to answer a question about the effectiveness of a new agent.
Additionally, there are concerns about so-called “multiplicity” in clinical trials of these agents and the possibility that through reporting bias, if multiple trials address the same agent in the same situation, only those with positive results may be reported — and those could be a minority.
Nonreporting of clinical trials is, of course, a well-documented problem, and the rapid proliferation of immuno-oncology trials has the potential to exacerbate this.
In 2007, the FDA introduced a law that required clinical trials to report results directly to ClinicalTrials.gov within 1 year of the last participant’s last visit for the final primary outcome of the trial. A study published last month in The Lancet showed that compliance with this law has been poor. Although not restricted to immuno-oncology studies, or even to cancer clinical trials, the analysis — which included large cancer centers, as well as pharmaceutical companies — confirms that slow reporting or underreporting can still obscure the true effectiveness of new treatments.
Putting the data into perspective
In summary, the latest cancer mortality data from American Cancer Society are encouraging and underline the impact that treatment advances have had in recent years.
The declining mortality for lung cancer is remarkable but needs to be put into real-world perspective — lung cancer is still the leading cause of cancer death in the U.S., responsible for more deaths than breast, colon and prostate cancers combined. Mortality rates from state to state track closely with smoking rates and are three to four times higher in states with the most smokers compared with those with the least.
Continued evaluation of checkpoint inhibitors and other targeted agents for lung cancer should remain a major priority to improve the outcome for these patients, but the long-term solution to this major public health challenge lies in enhanced prevention and early detection.
DeVito NJ, et al. Lancet. 2020;doi:10.1016/S0140-6736(19)33220-9.
Huang KB and Nambudiri VE. JAMA Oncol. 2020;doi:10.1001/jamaoncol.2019.5348.
Kaiser J. Science. 2018;doi:10.1126/science.359.6382.1346.
Prasad V and Booth CM. Lancet Oncol. 2019;doi:10.1016/S1470-2045(19)30744-2.
Siegel RL, et al. CA Cancer J Clin. 2020;doi:10.3322/caac.21590.
For more information:
John Sweetenham, MD, FRCP, FACP, is HemOnc Today’s Chief Medical Editor for Hematology. He also is associate director for clinical affairs at Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center. He can be reached at firstname.lastname@example.org.
Disclosure: Sweetenham reports no relevant financial disclosures.