This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Schiller, J. H. Search for Related Content PubMed PubMed Citation Articles by Schiller, J. H.

Study Design Issues and Early Stage Non–Small Cell Lung Cancer

Authors' Affiliation: University of Wisconsin Comprehensive Cancer Center, University of Wisconsin, Madison, Wisconsin

Requests for reprints: Joan H. Schiller, University of Wisconsin Hospital Comprehensive Cancer Center, University of Wisconsin, 600 Highland Avenue, Room K4/548 Madison, WI 53792-0001. Phone: 608-263-5343; Fax: 608-265-6575; E-mail: jhschill{at}facstaff.wisc.edu.

	Abstract

Top Abstract Trial Design Timely Completion of Trials Optimizing Patient Selection Conclusion Open Discussion References

 
The most common type of clinical trial in oncology enrolls patients with advanced disease. End points for phase II trials in advanced disease typically include response rate or time to progression, based upon the presumption that these may serve as surrogates for the ultimate end point of improved survival. Unique problems arise with the design of adjuvant trials, for which response rates clearly are not appropriate end points. In addition, survival is much longer, making rapid completion of phase III trials difficult. For lung cancer, the proportion of patients with stage I and II disease is much lower than with other types of cancer, and the absolute number of these patients is relatively low. To conduct large adjuvant trials in lung cancer more efficiently, we need to optimize our trials as much as possible. "Targeted therapies," by definition, inhibit a specific target, thus offering the theoretical advantage of enriching the patient population by restricting enrollment to patients whose tumor expresses the target of interest. Education of health care professionals regarding the benefits of adjuvant therapies, to decrease a sense of nihilism and to increase referrals, and international collaborations may also be necessary to increase accrual.

	Trial Design

Top Abstract Trial Design Timely Completion of Trials Optimizing Patient Selection Conclusion Open Discussion References

 
The most common type of clinical trial in oncology deals with patients with advanced disease. End points for phase II trials in metastatic disease typically include response rate or time to progression, based upon the presumption that these may serve as surrogates for the ultimate end point of improved survival. Despite the disadvantages and controversies surrounding these end points, the advantage of phase II studies is that they allow one to pick the most promising drugs for large phase III studies in advanced NSCLC, thus conserving resources and decreasing the risk of exposing patients to inactive drugs. Unfortunately, these "proof-of-concept" studies are less applicable to the adjuvant setting, where drugs identified as potentially active in advanced disease often go straight into phase III adjuvant trials, bypassing the proof-of-concept phase II step.

Unique problems arise with the design of phase III adjuvant trials. Response rates, of course, are not applicable as end points. In addition, survival is much longer, making rapid completion and turnover of phase III trials difficult. Furthermore, survival could be impacted by first-, second-, or even third-line therapy for metastatic disease.

Another unique aspect to adjuvant studies surrounds the issue of quality of life and adverse effects. In the advanced disease setting, where patients clearly know they have incurable cancer, patients are sometimes willing to tolerate more adverse effects and a detriment in quality of life in an effort to prolong survival. In the secondary prevention setting, however, patients may be less willing to put up with significant adverse effects in a situation where they may be unsure of a benefit. This is particularly problematic where the drugs could be taken for prolonged periods of time, as with oral targeted therapies. The degree and magnitude of toxicities that patients may consider tolerable for a few months may be very different from those they consider tolerable when taking drugs on a chronic basis. For example, in the advanced disease setting, a grade 2 or 3 rash is often considered of minimal significance when compared with adverse effects such as vomiting, fatigue, or infection; however, the persistence of a grade 3 rash for 2 years may be a very different matter.

	Timely Completion of Trials

Top Abstract Trial Design Timely Completion of Trials Optimizing Patient Selection Conclusion Open Discussion References

 
Because the majority of adjuvant or neoadjuvant studies will be phase III trials, rapid completion of large randomized studies is another issue that needs to be addressed. The proportion of patients with stage I and II disease (15%) is much lower than with other types of cancer, such as breast (63%), and the absolute number is relatively low (1). Thus, completion of large phase III clinical trials in this setting may take considerably longer than for advanced disease. Innovative trial designs, such as phase II/III studies and "pick-the-winner" trials designed to identify promising drugs early and move them rapidly into the phase III setting, are irrelevant in a setting in which there is no measurable disease.

This issue may be further complicated by a lack of interest, education, or awareness on the part of primary care physicians, pulmonologists, and general surgeons in referring patients with early stage NSCLC. A certain degree of nihilism exists in the community regarding the treatment of lung cancer, which may result in some patients not being referred for adjuvant treatment, thereby impacting trial accrual. Health care professionals need to be educated regarding the benefits of adjuvant therapies.

Collaborating with our international colleagues may be one way to increase accrual. Japanese investigators have evaluated a number of drugs in the adjuvant setting, recently reporting on the improvement in survival with uracil-tegafur (2). Two randomized phase III studies in Europe were completed before similar studies in the U.S. (3, 4). However, regulatory issues between countries and continents make initiation of an international trial within the near future unlikely.

	Optimizing Patient Selection

Top Abstract Trial Design Timely Completion of Trials Optimizing Patient Selection Conclusion Open Discussion References

 
To conduct large adjuvant trials in lung cancer more efficiently, we need to optimize our trial design as much as possible. "Targeted therapies," by definition, inhibit a specific target, thus offering the theoretical advantage of enriching the patient population by restricting enrollment to patients whose tumor expresses the target of interest. Problems, of course, include the fact that the marker of interest, or the target of a drug, may not be known. A number of instances can be cited in the oncology literature of a pathway thought to be important in predicting response, or of a drug that was supposed to hit one target, when subsequent research found that another element of the pathway was of greater therapeutic interest. For example, levels of tumor growth factor- and epidermal growth factor receptor (EGFR) protein in head and neck squamous cell carcinoma correlate with survival, but not with response to EGFR tyrosine kinase inhibitors (5). EGFR mutations in exons 19 to 21 clearly predict response to EGFR-tyrosine kinase inhibitors (6, 7). However, it is arguable that the degree of improvement in survival observed with erlotinib in the second- and third-line disease was such that patients without a mutation must have derived clinical benefit (8).

In the absence of information regarding a proven target, however, we continue to struggle with the issue of trial design, and what we will require from a drug in order to move forward. Do we continue to enroll an unselected patient population, knowing that this will increase our trial size and decrease our ability to detect activity? Do we wait until we have a validated target in the lab, knowing that we may miss another target in the human animal? Or do we continue as we have, taking observations in the lab into the clinic, but also continuing to experiment in humans, and taking those clinical observations back to the lab?

	Conclusion

Top Abstract Trial Design Timely Completion of Trials Optimizing Patient Selection Conclusion Open Discussion References

 
Moving drugs active in advanced NSCLC to the adjuvant setting makes eminent sense. However, to conduct large adjuvant trials in lung cancer more efficiently, we need to optimize our trials as much as possible. This includes education of health care professionals regarding the benefits of adjuvant therapies to decrease a sense of nihilism and to increase referrals, and international collaborations to increase accrual. More work needs to be done in determining and validating targets for targeted therapies, so as to enrich the study population by restricting enrollment to patients whose tumor expresses the target of interest.

	Open Discussion

Top Abstract Trial Design Timely Completion of Trials Optimizing Patient Selection Conclusion Open Discussion References

 
Dr. Thomas Lynch: Let's say the ECOG study of carboplatin/paclitaxel plus bevacizumab is positive and shows the first survival benefit. Do you think that we will need to do another randomized trial in adjuvant disease—randomized as opposed to a feasibility study? Or do you think that practicing physicians will go ahead and use bevacizumab in the adjuvant setting? For other types of lung cancer, that leap of faith is being made with docetaxel, gemcitabine, and other regimens shown effective in the metastatic setting. What do you think about that?

Dr. Schiller: If E-4599 is positive, I think we do need to do a randomized adjuvant study. The examples you gave of how we extrapolate from the metastatic disease setting primarily involved chemotherapy, and when it comes to chemotherapy we have pretty much agreed that as a class, they all are more or less the same. But this agent is going to be the first in its class, in lung cancer at any rate, and we do need to prove both efficacy and safety in the non–small cell lung cancer patients.

Dr. Karen Kelly: I think we need to be scientifically rigorous, and while there may be a survival advantage, bevacizumab does possess worrisome toxicities in lung cancer. While I think that it's important to move it forward, I'm just not sure it is appropriate to conduct a randomized phase III trial without having pertinent toxicity data in this early stage setting. I am in favor of conducting a feasibility study in the adjuvant setting.

Dr. Schiller: Let me just say that we proposed such a feasibility study to the NCI ECOG, and they turned us down on that. They said we could monitor toxicity well enough as we went along with a randomized trial in the adjuvant setting.

Dr. Lynch: Dr. Heymach, you spent a lot of time thinking about angiogenesis inhibitors and where they are in lung cancer. If the E-4599 study turns out positive, what do you think about the prospects for this translating to improved outcome in the adjuvant setting?

Dr. John Heymach: I'd be optimistic that, if anything, it might actually be a setting where you would see a bigger benefit. In preclinical models, VEGF inhibitors typically have greater efficacy against micrometastatic disease than against larger established tumors, most likely because it is more difficult to inhibit established vasculature than nascent vessels. So, biologically, if it worked in the metastatic setting, there is a high likelihood that it would work better in the adjuvant setting. I certainly agree that a phase III randomized trial would be needed to establish that.

Dr. Lynch: Dr. Gurubhagavatula, you are the PI of our study. What modifications have you made in response to the safety concerns for bevacizumab?

Dr. Sarada Gurubhagavatula: We modified the eligibility criteria to exclude all patients over 65 and also those with a prior history of coronary artery disease, MI, TIA, or stroke.

Dr. David Gandara: How is that going to extrapolate to a phase III randomized trial that is going to require a pretty large population?

Dr. Lynch: I agree with you, but in light of the bevacizumab warnings that went out, we felt very uncomfortable about going forward with an adjuvant study until we had better safety data.

Dr. Kelly: I concur with Dr. Lynch. While I hope the ECOG study is positive, we need to address the toxicity issues of this agent because this could be an obstacle in moving this particular drug forward.

Dr. Heymach: Regarding the toxicity issues raised with bevacizumab from some of the earlier clinical trials, it seems that most of the toxicity is related to endothelial damage and that is exacerbated by combining chemotherapy with VEGF blockers. For example, in a study by Kuenen and colleagues with cisplatin, gemcitabine, and SU5416, they had a very high incidence of cardiovascular incidents, and this was correlated with a rise in markers of endothelial damage such as E-selectin [J Clin Oncol 2002;20:1657-67]. So, I think it is worth considering a maintenance design with carboplatin and paclitaxel, for example, followed by maintenance bevacizumab. Although we don't have a longstanding experience, one would predict that the cardiovascular toxicity for bevacizumab would be significantly lower as a single agent than in combination regimens.

Dr. Glenwood Goss: As far as moving into the adjuvant setting drugs that have shown no activity in the metastatic setting, I think it is a very risky thing to do. In NCI Canada we have done two large randomized studies in small cell lung cancer with metalloproteinase inhibitors, which have shown no upfront activity in the disease, and both of them have been negative. We have decided that we are definitely not going to do another trial like that.

Dr. James Mulshine: These questions could be partly addressed by doing neoadjuvant window-of-opportunity trials where you do 30-day exposures before surgery then look at single-agent response rates. I think these studies present opportunities to see some direct responses to these drugs. It is not going to be the whole story, but you'd certainly feel a little bit better if you saw some activity and if you saw some of the molecular targets being modified.

	Footnotes

 
Presented at the International Conference on Early-Stage Lung Cancer: New Approaches to Evaluation and Treatment, October 1-2, 2004, Cambridge, Massachusetts.

	References

Top Abstract Trial Design Timely Completion of Trials Optimizing Patient Selection Conclusion Open Discussion References

 

1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8–29.[Abstract/Free Full Text]
2. Kato H, Ichinose Y, Ohta M, et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 2004;350:1713–21.[Abstract/Free Full Text]
3. Le Chevalier T. Results of the Randomized International Adjuvant Lung Cancer Trial (IALT): cisplatin-based chemotherapy (CT) vs. no CT in 1867 patients (pts) with resected non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2003;24:abstract # 6.
4. Tonato M. Final report of the Adjuvant Lung Project Italy (ALPI): an Italian/EORTC-LCG randomised trial of adjuvant chemotherapy in completely resected non-small cell lung cancer (NSCLC)[abstract #1157]. Proc Am Soc Clin Oncol 2002;21.
5. Rubin Grandis J, Melhem MF, Gooding WE, et al. Levels of TGF- and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 1998;90:824–32.[Abstract/Free Full Text]
6. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–5000.[Abstract/Free Full Text]
7. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–39.[Abstract/Free Full Text]
8. Shepherd F, Pereira J, Ciuleanu E, et al. A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. Proc Am Soc Clin Oncol 2004;22:abstract #7022.

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Schiller, J. H. Search for Related Content PubMed PubMed Citation Articles by Schiller, J. H.