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Lack of guidelines, clinical data complicate treatment of rare cancers
Limited research funding, preference toward addressing more common tumors often stymie innovation.
The Rare Diseases Act of 2002 defines rare diseases as those that affect fewer than 200,000 people per year in the United States. By definition, this includes all cancers except for breast, lung, prostate and colon cancers.
However, many cancers affect considerably smaller populations each year — from a few hundred to a few thousand — making the definition of ‘rare’ that much more difficult to define.
“I would define a rare cancer as a cancer that is infrequently seen by practitioners, one that an oncologist may see only three or four times every few years,” George J. Bosl, MD, chair of the department of medicine and the Patrick M. Byrne Chair in Clinical Oncology at Memorial Sloan-Kettering Cancer Center, told HemOnc Today.
The lack of treatment guidelines and published research often leave oncologists with no clear way to treat patients who present with those diseases. Questions often arise about whether insurance will cover treatments that are considered experimental, and in some cases, there may be a lack of interest in learning more about cancers that affect so few people.
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Photo courtesy of George J. Bosl, MD reprinted with persmission |
“One of the major challenges is the ability to conduct clinical trials to determine what the best therapy is,” Robert Dreicer, MD, chairman of the department of solid tumor oncology at the Cleveland Clinic, said in an interview. “All of those things that lead to improvement in the treatment paradigms and outcomes for patients are inherently problematic in rare cancers.”
HemOnc Today spoke with several leaders in oncology to find out about the challenges that surround rare cancers, how oncologists should approach these tumors, and what must be done to draw more attention to them to trigger innovations in research and treatment.
Lack of experience, evidence
Treatments for any medical condition are the product of extensive clinical research. With rare cancers, however, a lack of clinical data translates to no known ideal treatment, and determining a course of action is not as simple as looking at published guidelines that are backed by ample research.
“When you have a cancer that is so uncommon, it is difficult for a general oncologist to gain experience and expertise with that cancer,” said Keith C. Bible, MD, PhD, associate professor of oncology and chair of the Endocrine Malignancies Disease Oriented Group at the Mayo Clinic in Rochester, Minn. “Their infrequency limits the ability of oncologists to have the critical knowledge needed to treat the cancer. This is different from the common cancers that we see consistently, for which we have the knowledge and experience to treat.”
Consequently, oncologists charged with targeting a rare cancer often are left to draw from case reports or anecdotal evidence.
“The treatment side is where we have the problem because we don’t know a lot about these rare cancers and don’t know what treatments to use,” Michael J. Overman, MD, assistant professor in the department of gastrointestinal oncology at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “There is no compendium. There are no [National Comprehensive Cancer Network] guidelines. There is no database to go to find treatment standards.
“Deciding treatments is empiric,” Overman said. “People try different things and either they work or they don’t work. In a rare cancer, you never get further than that. That’s one of the frustrations.”
Clinicians in larger academic medical centers may have more experience with a particular rare tumor. That, in turn, may help to guide treatment. Oncologists in community centers or rural areas often are more likely to face challenges when presented with rare tumors.
“Community oncologists have to rely on calling a larger center for advice or interpreting what the medical literature says, which consists of isolated cases or retrospective experience,” Dreicer said. “They basically need to use the best clinical judgment to apply limited knowledge. This is a major issue that, unfortunately, doesn’t have easy solutions.”
Even in an academic center, physicians who have more experience dealing with a particular rare tumor may be biased by the experience he or she had with a previous patient, Bible said. A treatment that worked for one patient will not necessarily work for others.
“When a treatment works once, that can give a false impression that the experience is generalizable, when it’s not,” Bible said. “It’s easy to be misled and not realize that anecdotal evidence is not necessarily relevant to other patients. The random experience can affect decision-making inappropriately.”
Determination of treatment
The designation of rare cancer does not simply apply only to specific cancers. It also applies to rare subtypes of otherwise more common cancers.
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“As we get more sophisticated in learning about the genetics of individual diseases, we’re finding that a leukemia is not a leukemia and a lymphoma is not a lymphoma, and even a lung cancer is not a lung cancer,” said Patrick Stiff, MD, Coleman Professor of Oncology Medicine and director of the Cardinal Bernardin Cancer Center at Loyola University. “As time goes by, we find that there are certain rare forms of any particular disease.”
To decide on a treatment, Stiff said to first divide tumors into those that are potentially curative and those that are not. That would determine whether the goal is palliation or treating the tumor.
“If the decision is to treat, you make a rational decision without trying to injure or harm the patient,” he said. “For example, you would not give high doses of chemotherapy to a patient with a widely metastatic unusual tumor that, as best you can tell, nobody has an idea of how to treat.”
If the tumor is a rare form of a more common cancer, Stiff said it may be possible to treat it similarly to the more common cancer.
Some cancers may be treated based on what is known to work in other similar cancers, according to Barbara Burtness, MD, a member of the HemOnc Today Editorial Board. For example, treatment decisions for duodenal cancer often are based on what oncologists know about pancreatic cancer.
“You might look in the literature and see what is available based on case reports and anecdotal evidence,” Burtness said. “The evidence may lead you to argue by analogy, and sometimes, a case report can be convincing.”
Data from early-phase clinical trials also can lead to hypotheses of possible therapy in rare cancers. Another approach is to look for the underlying mechanisms involved in the pathogenesis of the rare cancer in laboratories and through translational studies.
There are times in which a novel molecular target turns out to be more critical in the pathogenesis of a particular rare cancer, Bible said. That can lead to more detailed laboratory and clinical studies of agents that are directed against those targets.
In some cases, treatment also could be devised using analogy to a more common cancer, Bible said.
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“There are times when a particular rare cancer has a resemblance to a tumor that is more common,” Bible said. “There are times when there is not much to go on except for this analogy. Of course, one will look to find basic data or clinical data to guide the treatment, but sometimes this analogy is all that exists.”
Competition for funding
Research funding, driven by economic conditions around the world, often is a problem for common cancers. The competition for funding for rare cancers is particularly intense.
The consideration of public health is an unavoidable limitation, Bosl said.
“A tumor that is seen in 100 patients a year in the entire country is going to have a much harder time getting funding than a tumor that is common, like lung cancer,” he said.
Funding decisions also may be impeded by reviewer comments that say because the cancer is rare, it is less worthy of study, Bible said. Yet, some argue that understanding rare cancers may provide insight into the more common cancers.
“We could learn more from a rare, more homogenous cancer and actually make more headway from a rare cancer than potentially trying to take on a more common cancer with various homogenous subsets,” Overman said. “For something that is rarer, fewer things go wrong, and there is more focus, unlike with breast cancer where there are various subsets.”
Funding for rare cancer research ideally would come from US cooperative groups, which were the primary source of funding for rare cancers when the economic climate was not so poor, Dreicer said.
“In the old days, when funding was a little more robust, the clinical trials groups in the US were able to conduct phase 2 trials in a rare cancer, like adrenal cancer,” Dreicer said. “It involved multiple groups across multiple centers, prospectively testing a question. But in the funding environment we find ourselves, the cooperative groups are challenged, so when we have rare diseases, it’s difficult to get these trials done.”
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Insurance coverage
Even when a new treatment for a rare cancer is identified, hurdles remain. A significant one is whether insurance companies will pay for the treatment, which often is not indicated by the FDA.
“Most payors stick to formulary drugs and guidelines, which stymies some of the Wild West cowboy-type of trials that include patients who have failed everything and want to try something else,” Stiff said. “We can’t do this because insurance companies won’t approve the drugs, many of which are outrageously expensive. It’s putting a damper on off-label usage for many of these drugs.”
As a result, these patients are going back to less expensive drugs, some of which date to the 1970s.
“In these patients, you’re often left with just trying things to see how they work,” Overman said. “If you want to use an expensive new drug, you can’t. Insurance companies don’t let you use these drugs just to see what it does. This is why, even though oncology is changing and new drugs are available, it’s a challenge to evaluate these new drugs to determine whether they help the patient.”
Besides paying for drugs, insurance companies also are reluctant to support referrals to specialized cancer centers because of the cost, Bosl said.
“I have found in my experience that when something special is necessary, insurance approval can usually be obtained through the usual appeal process with appropriate justification,” he said.
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More experience needed
For oncologists to gain more experience with and expertise on rare cancers, Bible suggests a subspecialty be devoted to rare cancers within the field of medical oncology. In a group of 10 oncologists, for instance, one should be devoted to rare cancers.
Doing so would allow those individuals to focus and develop treatment programs and clinical trials, Bible said.
“There is no question in my mind of the benefit to be attained from assuring that patients afflicted with rare cancers are seen by clinicians with expertise in said rare cancers,” Bible said. “I have several patients whose care was dramatically influenced — with apparently dramatically improved outcomes — resulting from arranging care with experts rather than generalists.”
The benefit often is derived from a collaborative approach encompassing radiation therapy, systemic therapy and surgery, Bible said.
One example is in the treatment of patients with anaplastic thyroid cancer (ATC), which accounts for less than 1.5% of thyroid cancers.
In a study published in Lancet Oncology in 2010, Bible and colleagues investigated the safety and efficacy of pazopanib (Votrient, GlaxoSmithKline) in treatment of patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers.
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OS was 70% at 1 year and 60% at 2 years, compared with <20% historical survival at 1 year in analogous patients previously treated with surgery and conventional postoperative radiation, the researchers said.
“The historical prognosis for patients with ATC, even if apparently only locoregionally advanced at diagnosis, has been very poor,” Bible said. “This has led many to be nihilistic about such patients, prompting some providers to recommend no therapy be undertaken, with direct enrollment in hospice recommended from the get-go. In contrast, by taking an aggressive approach when desired by patients, we have been encouraged by outcomes, with patient survival far superior to that expected.”
Increased attention
The efforts to prolong survivorship of patients with rare cancers must extend beyond a devoted subspecialty.
One key element is research funding.
Burtness advocates a greater degree of investment in cancer research across the board. For rare cancers, this requires cooperation between multiple institutions globally.
“You don’t necessarily want to divert resources from cancers that are common and affect numerous people to study rare cancer,” Burtness said. “But to study rare cancers, this is where international collaboration between the NCI and the [European Organisation for Research and Treatment of Cancer] is going to be crucial.”
Some insurance companies have designated certain centers to treat rare and common cancers, Stiff said.
“What that says is that if you have something unusual, these are the centers that have the resources to treat these patients, and these centers have the doctors who are willing to tackle the disease,” Stiff said.
In terms of new drug trials, Stiff said he would like to see a more liberal approach to testing drugs off-label in rare cancers. Insurance companies should welcome single-patient study proposals, provide drugs on a case-by-case basis and collect the data from multiple institutions to propose a formal study.
Consortia and other groups that have interest in rare cancers must be developed to allow investigators and patients to participate in the necessary trials, Bible said. There also is a need for the maintenance and development of trial groups across institutions and across nations.
“It’s interesting to me to work with rare cancers because, in many cases, there has been so little done that there is not only a need, but also a possibility of progress,” Bible said. “There is great potential to make strides and to advance the care in patients with rare cancers.” – by Emily Shafer
Disclosure: Drs. Bible, Bosl, Burtness, Dreicer, Overman and Stiff report no relevant financial disclosures.
For more information:
- Bible KC. Lancet Oncol. 2010;11:962-972.
How should community oncologists handle patients with rare tumors with which they have little experience?
Look for case reports to shed light on possible treatments.
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Community oncologists are likely to face challenges when presented with a rare tumor, both at a diagnostic level and at a treatment level. Often, when a patient presents to an academic center with a rare tumor, there is a multi-disciplinary tumor board discussion, which generates a group consensus on how best to proceed. Patients with rare tumors who originally present to a community oncologist often migrate toward a larger center, especially if there is diagnostic uncertainty or lack of a clear treatment plan.
In addition, oncologists at academic medical centers may have more experience with the particular rare tumor than community oncologists due to an underlying research interest or prior referrals. Many community oncologists may feel uncomfortable initiating therapy for a tumor that they haven’t seen before, especially if there are no evidenced-based guidelines — such as National Comprehensive Cancer Network guidelines — to follow.
Many times, when treating a rare cancer, it’s helpful to search for case studies or case reports to shed some light on possible treatments, although these reports need to be assessed with a critical eye to ensure they accurately represent the case in question. Some rare tumors have biologic characteristics that are similar to more common tumors and, thus, may be sensitive to treatments used for these common tumors. Community oncologists should also be able to reach out to physicians at larger centers for advice when their patients present with rare tumors.
David Cosgrove, MB, BCh, BAO, is assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. Disclosure: Dr. Cosgrove reports no relevant financial disclosures.
Consult with other oncologists at larger centers.
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Community oncologists are faced with more uncertainty and more problems when presented with rare tumors. Often, these are not tumors they are comfortable with, have been exposed to or have any experience with, even if they trained at academic medical centers.
There is a lot of difficulty in getting the correct answer at the academic medical center, and for community oncologists, there may be even more difficulty. My advice is to ask for help, and most of them do. Also, seek help as early as possible. I recently saw a patient with a rare sarcoma who had been treated in a community center a few hundred miles from my center. I wish they had called a little bit earlier. First, because there were still treatments to try, and second, because her management would have been a bit different had we communicated with her team before.
Some may decide to handle a rare tumor themselves rather than reaching out for help, and then find out as much as they can about the tumor. Sometimes, difficult situations are made more difficult by not reaching out to other physicians and seeing if there is anybody who can help. The most important message is to reach out to other centers to see if there is anyone who might have expertise.
Thierry Jahan, MD, is assistant clinical professor in the department of medicine at the University of California, San Francisco. Disclosure: Dr. Jahan reports no relevant financial disclosures.