| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 2000;70:1139-1141
© 2000 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, University of Rochester, Rochester, New York, USA
Address reprint requests to Dr Feins, Division of Cardiothoracic Surgery, University of Rochester, Rochester, NY 14642
Presented at the Thirteenth Annual General Thoracic Surgical Club Meeting, Tucson, Arizona, March 10, 2000.
Every doctor who treats lung cancer faces the stark reality that we fail more than 85% of the time. Even for Stage I disease, 30% of patients will not be cured. Whether we like it or not, these facts describe reality: our overall results are dismal and more effective therapy is desperately needed.
If we are ever to find better treatments for lung cancer, prospective, randomized Phase III trials are the best means for doing so. Yet, less than 1% of eligible patients in the United States are enrolled in these clinical trials. Why is this? Well, there are several reasons and I have chosen to classify them under the headings of "Truth," "Justice," and "the American Way."
Truth
One of the biggest reasons that surgeons do not enter patients into clinical trials is that we continue to rely on supposed "truths" which in reality have never been shown to be true at all. All too often, our "truths" are based on reports of small, single institution, Phase II studies or, worse yet, on intuition and anecdotes. Here are just a few examples of where the widespread adoption of Phase II results proved to be incorrect. During the 1960’s, several single institution, non-randomized Phase II trials showed that preoperative radiation therapy for lung cancer increased resectability and produced surgical specimens devoid of viable tumor cells. Yet, when preoperative radiation was put to the test in a randomized, Phase III trial headed by Tom Shields in the 1970s, it not only proved to offer no survival advantage but may well have been harmful [1]. Postoperative radiation therapy for resected stage II and IIIA squamous cell tumors had a very similar story, initially thought to improve survival but subsequently shown in a prospective, randomized Phase III trial conducted by the Lung Cancer Study Group (LCSG) to offer no survival benefit at all. More recently, the Eastern Cooperative Oncology Group (ECOG) showed in a prospective, randomized Phase III trial that adding chemotherapy to postoperative radiation therapy doesn’t help either.
A second misconception is the belief that patients who are enrolled in Phase III randomized trials are exposed to increased risk or "less effective" treatment. Nothing could be further from the truth. Dosage and toxicity tests are all completed in Phase I and Phase II trials before any treatment gets to Phase III. Furthermore, the LCSG showed in 1985 that enrolled control patients who receive standard of care actually do better than similar patients receiving the same care outside the trial [2].
Finally, it is a mistake to think that physicians must be affiliated with a large academic institution to participate in prospective, randomized Phase III trials. Each of the cooperative groups—ECOG, Cancer and Leukemia Group B (CALGB), Radiation Therapy Oncology Group (RTOG), Southwest Oncology Group (SWOG), North Central Cancer Treatment Group (NCCTG)—has a program for including physicians in community hospitals. The new cooperative oncology group for surgeons, the American College of Surgeons Oncology Group (ACSOG), allows participation by any thoracic surgeon who is an ACS member.
Justice
In the world of clinical research, there appears to be a decided lack of justice. For example, although Phase III trials are the gold standard for evaluating new treatments and although they are far more difficult to perform than most Phase II trials, a surgeon who dutifully participates in them is rarely recognized for doing so. Academic centers traditionally give far more weight to small, single armed studies that are rapidly published than to a major contribution to a cooperative effort. You just don’t get promoted by participating in Phase III trials. Even the NCI itself, while prioritizing cooperative Phase III trials, often puts greater emphasis on in-house Phase I and II protocols when it comes to funding cancer centers.
There is also a lack of justice for surgeons in the funding mechanisms for clinical trials. Why is this? When the LCSG ended in 1988, the task of organizing Phase III trials for lung and other thoracic malignancies was awarded to the other five established cooperative groups, CALGB, ECOG, NCCTG, RTOG, and SWOG. The designated principal investigator at each member institution controls all funding related to the group’s clinical trials in that institution. Since none of these groups is surgically focused, none of the principal investigators is a surgeon. The result is that in most institutions, data managers, who are the keys to accrual, have to be "borrowed" from either medical or radiation oncology. Even in primarily surgical protocols, funding traditionally has not gone to surgeons. Recently the Minimally Invasive Thoracic Surgery Grant headed by David Sugarbaker and ACSOG headed by Valerie Rusch have directed funds directly to thoracic surgeons for data management. Unfortunately, start-up funds with which to hire the data manager in the first place are not included.
The American Way
There are several characteristics of "the American Way" which may hinder the conducting of clinical trials. In this country, medical oncologists receive income from buying chemotherapeutic agents wholesale and selling them to patients or insurance companies after retail markup. Radiation oncologists receive income based upon how much radiation they give and surgeons receive income based on doing surgery. Revenue is lost if a patient is randomized to a no-treatment arm. This can significantly influence how a study is constructed. For example, ECOG 3590 put radiation therapy in both arms of its post-resection treatment for resected Stage II and IIIA tumors despite the fact that the LCSG had shown it to offer no survival benefit. The reason for this is that the investigators felt that radiation oncologists would not participate in the study unless they could give radiation therapy to everyone.
Our referral system also significantly influences our ability to enter patients into clinical trials. When a medical or radiation oncologist asks a thoracic surgeon to operate on a patient who has been preoperatively treated, refusal may well jeopardize future referrals. There always seems to be someone who will do the operation even though the preoperative treatment has no proven benefit.
The "American Way" also extends to approval of clinical trials by Institutional Review Boards (IRB’s). All of the large national cooperative group prospective, randomized Phase III trials in any area have spent literally months and even years in committees where every possible detail and safety precaution is considered. And yet, after all this, when the protocol is finally released, every hospital goes through the exact same process before allowing the study to start. This can add many more months to the process without adding a single bit of safety or improved science to the study. The unnecessary duplication of the IRB process in this country adds significantly to the time it takes to get the answers our patients need and discourages investigators from trying to get studies approved.
Solutions
Certainly there have to be solutions to these problems because now completion of prospective, randomized Phase III trials takes far too long. ECOG 3590 took over 6 years to accrue 488 patients. During that time over one million Americans developed lung cancer. JBR 10, a cooperative study of post-operative chemotherapy, will take more than 6 years to complete, while the national neoadjuvant study for N2 patients (9309) is in its sixth year and another two will be needed. There are however remedies to these problems.
First is that Medicare should stop reimbursing for treatments that have not been proven effective. Examples include postoperative radiation therapy for N1 disease, adding chemotherapy to postoperative radiation, and resecting lung in the face of known multi-station N2 disease. Admittedly, for many circumstances a consensus standard of care has not been determined. Where it has, however, Medicare should withhold payment and use the money saved to further encourage participation in NCI approved investigational protocols.
Next, physicians and surgeons who participate in Phase III trials should get extra compensation. This could easily be done by allowing a CPT modifier for treatment rendered under an approved protocol. The clinical trials CPT modifier would promote accrual, compensate investigators fairly, and in the long run, save money.
Then there should be a mechanism to provide start-up funds to enable surgeons interested in clinical research to hire data managers. Once in place, the per case reimbursement currently in place will perpetuate the program. It would be worthwhile and relatively inexpensive to at least pilot this idea to see if increased accrual occurs.
Also, surgeons should develop training programs to train thoracic surgeons in the nuances of running clinical trials. Most of us are poorly equipped to compete for funding. Nor do we know the trial approval process, the "stop early" rules, site visit priorities, or bookkeeping and reporting requirements. A formal training program would allow thoracic surgeons to move up from the present secondary roles to true leadership roles in thoracic surgical protocols. The ACSOG has now given every thoracic surgeon the opportunity to run clinical trials but we still need to be taught the skills necessary to do so.
An independent, national Institutional Review Board should be put in place to review the multigroup Phase III trials in a more timely fashion. This board should have representation from a broad spectrum of interested parties to ensure safe, well run trials. By also including representation from lay interest groups, the trials would have a much larger constituency supporting them. Local hospitals would be relieved of the tremendous cost in time and money of having to review these trials and completion of the trials would likely occur years sooner.
It is time for our academic institutions to weigh participation in cooperative, multi-institutional prospective randomized clinical trials much more heavily. A surgeon who is a good "citizen" and makes major contributions to these important studies should expect to be promoted just as readily as those participating in the usual Phase I/Phase II trials.
Finally, and perhaps most importantly, all of us involved with lung cancer should change our attitude, recognize that we don’t have good enough treatments, and support the prospective randomized Phase III trials that can give us those treatments. In the pediatric population it is readily accepted that patients with cancer will go into clinical trials. This cooperation and high enrollment have produced tremendous improvement in survival for lymphoma, leukemia, Wilm’s tumor, and neuroblastoma. It is time we stop kidding ourselves, recognize our limitations, embrace evidence–based medicine, and take the lead in seeking solutions. All of our patients will benefit.
References
This article has been cited by other articles:
|
|
 |
|
  H. C. Grillo Development of tracheal surgery: a historical review. Part 2: treatment of tracheal diseases Ann. Thorac. Surg., March 1, 2003; 75(3): 1039 - 1047. [Full Text] [PDF]
|
|
|
|
|
|
H. C. Grillo Development of tracheal surgery: a historical review. Part 1: techniques of tracheal surgery Ann. Thorac. Surg., February 1, 2003; 75(2): 610 - 619. [Full Text] [PDF]
|
|
|
|
|
|
F. W. Grannis Jr A response to ""Clinical Trials in Lung Cancer: Truth, Justice, and the American Way"" Ann. Thorac. Surg., October 1, 2001; 72(4): 1438 - 1438. [Full Text] [PDF]
|
|
|
|
|
|
R. H. Feins A response to ""Clinical Trials in Lung Cancer: Truth, Justice, and the American Way"": Reply Ann. Thorac. Surg., October 1, 2001; 72(4): 1438 - 1439. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
