A Targeted Approach to Reducing Lung Cancer Mortality
Frances A. Shepherd
[from JCO May 10, 2005]
Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada
Despite major efforts to reduce smoking rates, lung cancer continues to claim more lives than the next three major cancers combined. In the Western world, the incidence of lung cancer in men has begun to decline over the past 10 years, but it is expected that lung cancer in women will continue to rise, as the birth cohorts of women who have the highest smoking prevalence have not yet reached the age of greatest lung cancer risk. Unfortunately, lung cancer continues to increase in numbers in underdeveloped countries, particularly China, where smoking continues unabated. Indeed, many of the world's major tobacco manufacturers are focusing their advertising campaigns in these parts of the world, where children are their prime targets. Lung cancer, particularly in women, is truly an epidemic of global proportions.
In this era of targeted therapy, it is clear that we must be prepared to take a multitargeted approach to the diagnosis and treatment of lung cancer if we hope to have a major impact on the death rates from this malignancy. Tobacco use must be the first "target," since the most effective way to reduce lung cancer deaths undoubtedly will, in the long run, be prevention. However, the long latency period between exposure to tobacco-related carcinogens and the development of lung cancer means that the benefits of smoking cessation programs will not be realized until decades from now, since the chromosomal damage caused by tobacco may be irreversible. Indeed, in most Western countries, up to 50% of lung cancer cases occur in never or former smokers.[I didn't know this]
Since more than two thirds of lung cancer patients present at a stage for which curative therapy is not available, the second "target" must be early detection. Older screening studies, whether evaluating chest radiographs alone or radiographs coupled with sputum cytology, were all disappointingly negative and failed to reduce lung cancer mortality even though they concentrated on high-risk populations of male smokers. In this issue of the Journal of Clinical Oncology, James Mulshine1 has summarized the current status of screening for lung cancer, and provides evidence that, with state-of-the-art computed tomography scanning techniques, the ability to detect small, potentially curable lung cancer lesions is now a reality. However, all studies to date have lacked a randomly assigned unscreened control arm, and so the ability of computed tomography screening to reduce mortality awaits the results of prospectively randomized controlled trials. Functional imaging techniques, including positron emission tomography and dynamic-contrast magnetic resonance imaging, may play a role in determining the likelihood of malignancy in screen-detected cancers, although it appears that their greatest role will be in the area of more accurate staging and the early evaluation of response.
The final "target" in the war against lung cancer must be the development of better treatment. To this end, advances in our understanding of lung cancer biology have led to the development of numerous molecularly targeted therapies, and some agents are even being evaluated to determine whether they might play a preventative role in high-risk individuals. The greatest degree of research and clinical activity in lung cancer has been in the area of epidermal growth factor receptor inhibition and inhibition of angiogenesis, where recent trials have resulted in significant improvement in survival and symptom control in patients with advanced disease.
Initially, it was though that some of these targeted drugs might be cytostatic rather than tumoricidal, and that classical phase II testing looking for response might not be necessary or even applicable. This thinking resulted in the initiation of large clinical studies based only on laboratory models and phase I toxicity testing. Sadly, many initially promising treatments fell by the wayside as they failed to improve outcome when tested in large randomized trials. The unprecedented number of negative trials that included thousands of patients worldwide has led to a re-evaluation of drug development strategy for these molecularly targeted agents. Clearly, phase II testing is still necessary, and in fact, randomized phase II trials with an appropriate control arm should probably be conducted before large phase III studies are initiated. These should be considered only if an adequate "signal" is seen in phase II. The importance of this strategy is most clearly demonstrated in the development of bevacizumab in lung cancer, where a small phase II trial gave a strong signal that clarified the dose of bevacizumab to be studied, identified important toxicities and ultimately led to the design of a strongly positive phase III trial (2005 abstract submitted for publication).
Recent experience with targeted agents has also shown us that our standard approach of treating all patients with chemotherapy, yet knowing that the majority would not respond, is likely not appropriate for molecularly targeted agents. Experience with the small molecule tyrosine kinase inhibitors of epidermal growth factor receptor has clearly taught us that both the clinical characteristics of patients and the molecular characteristics of their lung cancers may have a significant effect on response and survival. It cannot be overemphasized how critical it will be to establish tumor banks for all future trials of targeted therapy in order to identify the appropriate patients to treat. [I had no idea that this was not routine practice]These banks must include samples from untreated control patients in order to clarify the prognostic impact of molecular changes, as well as to determine whether a differential treatment effect is seen in patients who express or overexpress the target of interest.
Despite all of the excitement surrounding molecularly targeted agents in the past decade, it is of interest to note that some of the most noteworthy advances in the treatment of lung cancer have come from trials of chemotherapy. The addition of chemotherapy to local treatments such as radiation or surgery is now considered the standard of care in the Western world for patients with stage III tumors. For surgically resected, early-stage lung cancer, in 2004, 30 years of adjuvant chemotherapy trials finally culminated in two definitive paradigm-shifting studies2,3 that clearly showed that adjuvant chemotherapy could prolong survival and improve cure in non–small-cell lung cancer. In fact, the 12% and 15% improvements in long-term survival in these trials were unprecedented and surpassed all expectation.
The death rate from lung cancer worldwide is unacceptably high, and this epidemic shows few signs of reversing in the foreseeable future. Prevention and early detection must surely be a health care priority for all nations if we are to have a major impact on this malignancy.
Author's Disclosures of Potential Conflicts of Interest
The author indicated no potential conflicts of interest.
REFERENCES
1. Mulshine JL: New developments in lung cancer screening. J Clin Oncol 23: 3198-3202, 2005[Abstract/Free Full Text]
2. Winton T, Livingston R, Johnson D, et al: Adjuvant chemotherapy improves survival post resection of non-small cell lung cancer. N Engl J Med: in press
3. Strauss GM, Herndon J, Maddaus MA, et al: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633. J Clin Oncol 22: 6215, 2004 (suppl; abstr 7019) |
