It Takes More Than a Village
Conquest - Summer 2007
By Carol Bryce
More isn’t always better, an old adage says.
But when it comes to conducting late-phase clinical research trials, having more participants isn’t just better, it’s essential to ensuring that novel and more effective therapies are made available to patients sooner.
“To get definitive answers to important research questions, we need large randomized trials that may require 1,000 to 2,000 people,” says Maurie Markman, M.D., vice president for clinical research at M. D. Anderson. “Often these studies are comparing novel drugs to existing excellent treatment regimens to try to come up with something even better. The only way to get answers in a reasonable period of time is to do the trials on a national level.”
Research discoveries can result from close collaborations among an institution’s physicians, scientists, nurses, biostatisticians and other health professionals. But it’s not always feasible or even advisable to conduct a scientific research project in only one institution, even one as multidisciplinary as M. D. Anderson. That’s when the National Cancer Institute’s clinical trials cooperative groups can enter the picture.
The NCI Clinical Trials Cooperative Group Program is designed to promote and support clinical trials of new cancer treatments, explore methods of cancer prevention and early detection, and study quality of life issues and rehabilitation both during and after cancer treatment.
M. D. Anderson plays a leading role in many NCI cooperative groups, whose members include cancer centers and individual researchers and community physicians throughout the United States, Canada and Europe. While the groups differ in their structure and focus, they share a common purpose: to develop and conduct large-scale clinical trials in multi-institutional settings.
As one of the world’s largest and most respected cancer centers, M. D. Anderson makes important contributions to cooperative research groups, Markman says.
“By participating in the trials, we help increase patient accrual and help get the studies completed in a timely manner. Through our leadership, we also can influence in a very positive way the kinds of trials that take place, the quality of questions that are asked and the analyses that are done,” Markman adds.
One of the largest NCI cooperative groups is the Southwest Oncology Group, which includes
more than 5,000 physician-scientists. SWOG members work in university teaching hospitals, community hospitals, community-based physician cooperatives and individual offices.
Knowing that it’s not always feasible to conduct late-phase clinical trials in only one institution, Ashraful Hoque, M.D., Ph.D., and others turn to the Southwest Oncology Group for help with patient accrual.
Although SWOG’s member institutions were concentrated in the Southwestern United States when the group was established in the late 1950s, today the group’s research trials are conducted by investigators at more than 550 institutions across the country, including 17 of NCI’s 61 designated cancer centers. Approximately 120 SWOG clinical trials are under way at any given time.
SWOG estimates that over the last 25 years, more than 170,000 patients have directly benefited from the group’s trials, while millions more have received improved care as new standards of treatment and prevention have been developed by the group.
SWOG enables its members to participate in clinical trials that probably couldn’t be conducted at just one institution, according to Ashraful Hoque, M.D., Ph.D., assistant professor in the Department of Clinical Cancer Prevention. Hoque is co-principal investigator on M. D. Anderson’s SWOG grant and Scott Lippman, M.D., chair of the Department of Thoracic/Head and Neck Medical Oncology, serves as principal investigator.
“Although M. D. Anderson is a big institution, it’s still difficult to do Phase III studies here because it can take years to accrue enough patients to conduct the trials,” Hoque says.
Hundreds or even thousands of patients may be needed to conduct a Phase III trial in which researchers track whether a new treatment is better than, the same as or less effective than the standard treatment.
“The cooperative group mechanism represents a key strategic method for rapidly accruing patients,” adds Robert Coleman, M.D., professor in the Department of Gynecologic Oncology, who serves as M. D. Anderson’s institutional principal investigator to NCI’s Gynecologic Oncology Group.
“If I have a clinical study concept that merits investigation, I can develop it locally. But accrual may take several years to reach its primary objectives. Alternatively, if I can develop it through the GOG, the accrual window can be significantly shortened,” Coleman says.
Like other NCI cooperative groups, GOG offers opportunities for junior faculty to progress in their clinical research careers.
“Within the GOG, there’s no hierarchical structure in terms of who may submit a concept, and there’s a concerted effort within GOG to engage junior investigators,” Coleman says.
“Currently, the process governing concept submission to open a clinical study involves oversight by several procedural committees. Opportunities for participation in this process come annually with phased roster rotation.”
Making a difference
The cooperative group setting is of particular value when conducting research on uncommon cancers, such as cancers in children, according to Joann Ater, M.D., professor in the Department of Pediatrics and the chair of NCI’s Children’s Oncology Group at M. D. Anderson. COG grew out of several cooperative groups established by NCI in the 1950s and is now the world’s largest childhood cancer research organization.
“To conduct a Phase III study where you need to randomize patients between two different therapies to find out which one is best, you need several hundred patients. Childhood cancer is rare, so you really can’t do that at a single institution,” Ater explains.
In addition to its research projects, COG offers educational resources for patients and families. It also advocates for childhood cancer research funding.
“A lot of our progress in childhood cancer has been made thanks to COG and its predecessors,” Ater says. “For instance, childhood cancer mortality has decreased by 25% just in the last 10 years.”
Since the 1950s, Ater adds, cooperative research has helped improve the overall survival rates for childhood cancer from less than 10% to more than 77%.
“Cooperative group research also has established the standard of care for childhood leukemia,” she says. “In fact, it has established the proven best therapy for many childhood cancers.”
Scientists who approach cooperative groups with an idea for a protocol have no guarantees that their project will be accepted. This is especially true in today’s climate of tight federal funding for medical research. A proposed research protocol must be backed by solid preliminary data from smaller studies and go through a rigorous evaluation process before it’s allowed into an NCI cooperative group. Once a study is approved and opened, group members must follow strict criteria as they conduct their research.
“M. D. Anderson has to accrue a minimum of 50 patients in SWOG trials each year. And we follow every patient for life,” Hoque says. “We have to submit regular progress reports on each project, and SWOG also conducts regular audits of patient charts. If they find violations, they can shut down the program.”
After an investigational drug shows promise in early phase studies, James Abbruzzese, M.D., takes it to the Southwest Oncology Group where the results can be tested in a larger patient population.
James Abbruzzese, M.D., chair of the Department of Gastrointestinal Medical Oncology, has seen firsthand the value of expanding small studies into the cooperative research group setting. Abbruzzese is a member of the institutional executive committee for M. D. Anderson’s SWOG grant and a former chair of SWOG’s Gastrointestinal Committee.
Abbruzzese cites a small Phase II clinical trial of 40 pancreatic cancer patients that was conducted at M. D. Anderson a few years ago with promising results.
“Based on our findings, we took the trial to SWOG and got them interested in developing a large, randomized Phase III clinical trial of approximately 700 patients. In the study, we compared gemcitabine alone, which is the standard of care for patients with advanced pancreatic cancer, to a combination of gemcitabine plus an epidermal growth factor receptor inhibitor called cetuximab.”
The epidermal growth factor, which instructs cells to grow and multiply, is known to be overexpressesd in pancreatic cancer.
“While the SWOG study didn’t meet its primary goal of significantly extending the survival of patients with advanced pancreatic cancer, it did tell us something important. It suggested that EGFR may not be an optimal target for treatment of pancreas cancer. It may be that we need to target more than one specific molecule to see a major effect,” Abbruzzese says.
He and his colleagues now are continuing this research at M. D. Anderson through the NCI-awarded Specialized Programs of Research Excellence grant in pancreatic cancer.
This study, Abbruzzese notes, demonstrates how conducting research through cooperative groups such as SWOG should be an ongoing process.
“The basic idea is to pilot new studies and ideas here at M. D. Anderson and develop a proof of concept that shows a treatment appears to be useful. Then, to really see if we can alter the standard of care for patients, we can go to SWOG where our results can be tested in a larger patient population,” Abbruzzese explains. “While all this is happening, we can go back and begin to pilot the next concept through our SPORE grant and other institutional avenues.”
Reaching the gatekeepers
The American College of Surgical Oncology Group is different from other NCI cooperative groups because it’s organized and directed by surgeons, many of whom are in private or group practice. This structure and ACOSOG’s individual practitioner membership model enable ACOSOG to reach patients who might not otherwise have the opportunity to participate in multi-institutional clinical trials.
Ritsuko Komaki, M.D., says the quality of radiation treatment has greatly improved nationwide because of the strict review process of Radiation Treatment Oncology Group clinical protocols.
“Many patients with localized forms of cancer enter the cancer care system through their surgeons,” explains Peter Pisters, M.D., professor in the Department of Surgical Oncology and co-chair of ACOSOG’s Gastrointestinal Committee.
Surgeons frequently are the first physicians to see and treat patients with solid tumors that later are found to be cancer. Once patients are diagnosed with cancer and undergo surgery, it’s often their surgeons who counsel them about further treatment options and refer them to medical or radiation oncologists, as needed.
“We formed ACOSOG about 10 years ago, recognizing that a good way to recruit these new patients to clinical trials was to organize the surgeons who are their gatekeepers,” Pisters says.
ACOSOG’s research projects deal primarily with breast, thoracic and gastrointestinal cancers. Because of the group’s surgical focus, ACOSOG members have two particular interests: preoperative therapy and correlative science studies that involve harvesting tumor tissue.
“Since we’re the people who take the tumors out, we’re in a unique position to acquire these resources,” Pisters explains. “For each of our research protocols, we have important correlative science projects that dovetail with the clinical questions.”
To facilitate this research, ACOSOG maintains a centralized, independently funded tumor bank at Washington University in St. Louis that ACOSOG investigators can access when they conduct clinical research trials.
Following the rules
One of M. D. Anderson’s longest cooperative group relationships is with the Radiation Treatment Oncology Group. This group, made up of 250 major research institutions across the United States and Canada, currently is conducting more than 40 active studies that involve radiation therapy, given either alone or in conjunction with surgery, chemotherapy or molecular therapeutics.
Kian Ang, M.D., and his colleagues have been involved in several large Radiation Treatment Oncology Group trials comparing different types of treatment for head and neck cancer against the standard.
M. D. Anderson is a full member of RTOG, which means the institution must enter at least 25 patients on RTOG protocols each year. As with SWOG, RTOG members are followed for life.
“The criteria to be a full RTOG member is very strict,” says Ritsuko Komaki, M.D., professor in the Department of Radiation Oncology. Komaki serves as M. D. Anderson’s principal investigator on RTOG, which is supported by NCI and the American College of Radiology. Smaller institutions that can’t meet the 25 patient annual enrollment requirement join RTOG as affiliate members.
When it comes to patient accrual for RTOG trials, M. D. Anderson usually ranks in the top five nationally and often is either number one or number two, according to Komaki.
“We rank high because our institution is very organized and protocol-oriented. We have shown nationwide that our quality is exceptional and that we can work collaboratively with people from other modalities,” she says.
Like SWOG, ACOSOG and other cooperative group studies, potential and ongoing RTOG trials undergo a stringent NCI review process.
“We have biannual meetings where we go through all the active protocols. Once a trial opens nationwide, the chair of the protocol gets monthly accrual reports. We have to make sure we’re enrolling the expected number of patients and that none of the patients in the trial are violating any of the eligibility requirements,” Komaki explains.
RTOG has strict rules related to all facets of research and conducts biennial audits at participating institutions.
“They check all the details, such as institutional review board approval for newly activated RTOG protocols and amendments, adverse treatment events, radiation treatment fields, dosimetry, dosage documentation for chemotherapy and radiation, treatment facilities and equipment,” Komaki says.
Institutions are given a specific amount of time to fix any problems and then are re-audited. Failure to take the recommended actions will lead to closure of a research trial.
“Nationwide, it’s amazing to see how much radiation treatment quality has improved thanks to RTOG requirements and the quality assurance of RTOG treatment protocols,” says Komaki, noting the leadership role radiation physics professors Michael Gillin, Ph.D., and Geoffery Ibbott, Ph.D., have played in chairing RTOG’s Medical Physics Committee and Radiation Physics Radiological Physics Center, respectively.
“Our treatment quality has improved enormously because of image-guided radiation treatment. We owe the quality assurance of radiation treatment planning and portal imaging to deliver treatment by intensity modulated radiation therapy or three-dimensional conformal radiation therapy to RTOG,” Komaki adds.
Her colleague Kian Ang, M.D., professor in the Department of Radiation Oncology, has been involved in several large RTOG trials comparing different types of treatment for head and neck cancer against the standard.
For example, Ang was co-principal investigator on a Phase III study that looked at more rational distribution of radiation dose over time, known as altered fractionation. Dosage distribution is one of the most important factors in determining the outcome of radiation therapy.
Peter Pisters, M.D., is part of a cooperative group that enables surgeons, many of whom are in private or group practice, to reach patients who might not otherwise have the opportunity to participate in multi-institutional clinical trials.
Investigators compared the standard fractionation schedule, in which radiation is given once a day, to a hyperfractionation regimen, with radiation therapy given more frequently in smaller-than-usual doses, or given at an accelerated fractionation schedule, with radiation administered over a shorter total time period but in more intense doses.
“This was the largest randomized trial ever conducted of altered fractionation in the radiation therapy of locally advanced head and neck cancer,” Ang says.
Investigators found that both hyperfractionation and accelerated fractionation improved local and regional tumor control with no significant increase in long-term complications. This is an important finding since rational modification of a radiation regimen doesn’t cause an appreciable increase in health care expenses, Ang notes.
Ang and his colleagues now are studying the effects of altered fractionation regimens when administered concurrently with chemotherapy and emerging novel agents.
Setting the standard
M. D. Anderson’s internationally recognized experts in areas such as medical oncology, surgery, radiation oncology, biostatistics and prevention are sharing their knowledge on many levels because of the institution’s involvement in cooperative groups.
“These groups aren’t just made up of the major institutions. They also include smaller hospitals and community doctors,” Markman says. “So to the extent that we’re interacting with these people, we’re in fact helping to improve the quality of cancer care that’s being delivered around the country.”
Conquest - Summer 2007