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Rare Tumors: Finding Common GroundBy Joe Munch To combat common cancers, oncologists can draw from a wealth of resources, including readily available screening methods, a large body of literature to help guide treatment, and funding for preclinical and clinical studies.
Rare cancers, on the other hand, can be much more difficult. Patients with rare cancers often present with indistinct symptoms attributable to any number of other diseases, leading to misdiagnoses that can delay appropriate treatment and thus reduce the chance of cure. Finding enough patients to enroll in clinical trials can be an adventure in futility, making it difficult to learn more about the disease and effective treatments; literature that can be used to guide treatment is often scarce, if not nonexistent; and funding is not always easy to secure. Yet despite such obstacles, physicians at The University of Texas M. D. Anderson Cancer Center are working together every day to improve the diagnosis and treatment of rare tumors. The institution treats a variety of very uncommon cancers, from tumor types that occur in only a few hundred patients in the United States per year (such as chordoma) to those that occur in a few thousand (such as mesothelioma). As those physicians can attest, what is learned from rare tumors—including the examples described below—advances the fight against not only uncommon cancers but all forms of the disease. Rare tumors at M. D. Anderson: A snapshot Pseudomyxoma peritonei Because patients with an MTA exhibit typically vague symptoms, such as weight gain or abdominal pain, MTAs are usually discovered incidentally on computed tomography (CT) studies or during an unrelated surgery, such as a hernia repair or laparoscopic cholecystectomy. When an MTA is discovered, the path of treatment is not always clear, especially for physicians who are unfamiliar with the disease. For that reason, M. D. Anderson specialists recommend that patients with an MTA—and, in fact, most rare tumors—receive their initial treatment at a cancer center where uncommon cancers are seen with some regularity. In general, MTA does not require urgent treatment; in fact, some patients can be treated with a “watch and wait” approach with close follow-up and surgical intervention only when the disease progresses. If surgery is required, Dr. Mansfield said, it can be “formidable”—and it is not a guarantee that the disease won’t recur, depending on the nature of the tumor. “Some patients describe it as the ‘mother of all surgeries,’” Dr. Mansfield said. “It is both physically and emotionally demanding for a patient—not just the operation, but also the recovery, which can take many months.” During the surgery, an incision is made from the base of the sternum to the pubic bone. The mucin-producing tumor and mucin are removed, as are any organs adversely affected by the mucin, which may include the omentum, spleen, gallbladder, uterus, ovaries, right colon with the appendix, and other portions of the intestines. If the tumor is completely resected, surgeons wash the abdomen with a heated chemotherapy solution to kill residual cancer cells and lower the risk of recurrence. The entire operation usually takes 8–12 hours, and recovery can take 3 months or longer. According to Dr. Mansfield, the operation has a steep learning curve. At most centers that have limited experience with the operation, the operative mortality rate is substantially higher because some complications may not be identified and managed as quickly as in centers that have substantial experience. “I think that in general, if you’re managed at a center that sees a lot of a certain type of disease, particularly those requiring a high-end surgery, the survival outcomes are better,” Dr. Mansfield said. Malignant thymoma “There will be medical oncology fellows in my clinic who will rotate for a month and see three or four thymomas, and that will be more than they see for the rest of their careers,” said Edward Kim, M.D., an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology.
Because malignant thymoma can microscopically infiltrate surrounding structures such as the pleura and pericardium, completely resecting the tumor can be difficult, especially in patients with late-stage disease. Several years ago, Dr. Kim reported a study aimed at improving tumor resectability in malignant thymoma patients. In the study, patients were treated with induction chemotherapy (cyclophosphamide, doxorubicin, cisplatin, and prednisone) before undergoing thymoma resection and subsequent radiation therapy and consolidation chemotherapy. (Owing to the rarity of the disease, it took 10 years to enroll 22 patients in the study.) While rates of response to the induction chemotherapy were in line with those of previous studies, 5- and 7-year overall survival rates exceeded 90% and 70%, respectively, and were far higher than those previously reported for patients undergoing chemotherapy followed by tumor resection. Dr. Kim attributes the higher survival rates to the complete surgical resection of the disease. Now, in part because of the study’s findings, Dr. Kim believes that more physicians are treating their thymoma patients with chemotherapy before trying to resect the tumor. “Even if you do a surgery up front that removes 99.9% of the thymoma, it’s still not a complete resection. If you can do anything to shrink the tumor before surgery—or at least loosen its grip—the tumor comes off more like a glossy sticker than like a price tag.” That’s not to say that resecting thymomas, even after effective chemotherapy, is easy. And unfortunately, malignant thymomas are commonly mistaken for lymphomas, which are treated with different methods. Lymphomas, often found at multiple sites throughout the body, tend to respond well to chemotherapy and radiation therapy but are not treated with surgical resection. According to Dr. Kim, obtaining enough biopsy tissue to pathologically confirm the tumor type is the key to avoiding this mix-up. Dr. Kim believes that the route to better treatment is developing therapies that are effective against early-stage disease. He contrasts this with the strategy for lung cancer; because lung cancer patients typically present with metastatic, incurable disease, drug development has focused on advanced lung cancer. “For thymoma,” Dr. Kim said, “we should be thinking the opposite: How can we optimize treatment for those people who potentially have curable disease? And that requires a multidisciplinary approach.” Small bowel adenocarcinoma Dr. Overman, an assistant professor in the Department of Gastrointestinal Medical Oncology, became interested in treating SBA when he was a fellow at M. D. Anderson. Frustrated by the lack of data available to help guide therapy for his patients, he decided to initiate studies of various chemotherapy combinations that could be used to treat SBA. The findings from one of Dr. Overman’s retrospective studies, for example, indicated that 5-fluorouracil combined with a platinum analogue is a promising therapy for SBA—not a conclusion easily reached, given the infrequency of the disease. “Most people who come to M. D. Anderson have been diagnosed with a cancer and have an idea of what they’re in for,” Dr. Overman said. “But for rare cancers, such as SBA, patients may not have as much information because their doctors have told them that they’ve never seen anything like this disease.” Unfortunately, most patients with SBA do not find out they have the disease until it has metastasized, making long-term survival unlikely. (The mean overall survival duration with the optimal aggressive regimen for patients with advanced SBA is a little over 20 months.) Patients with SBA often have nonspecific symptoms such as abdominal discomfort, cramping, weight loss, and nausea, which often lead to SBA’s being misdiagnosed as more common gastrointestinal conditions, such as irritable bowel syndrome. “Whenever someone has abdominal discomfort or nausea, the last thing a physician suspects is small bowel cancer,” Dr. Overman said. SBA is usually suspected only after symptoms persist and progress for months despite treatment for other potential causes. In addition, evaluating the small intestine for disease is difficult. Even when SBA is present, gastrointestinal x-ray series or CT may not detect it. Capsule endoscopy (in which the patient swallows a tiny camera that photographs the small bowel as the capsule moves through the digestive tract) is a recent technology that has markedly aided the detection of tumors in the small bowel. Furthermore, treatment options for SBA are limited—while chemotherapy can be used to shrink the tumor, and intestinal bypass surgery can be performed after the involved bowel is surgically removed, resection of the tumor itself is difficult. According to Dr. Overman, the key to improving treatment for SBA patients is collaboration among many different centers. Even so, Dr. Overman said, “The problem is that it’s a rare cancer, so not every institution is going to have somebody who is interested in that cancer.” Making strides through quicksand
“The reason we make big strides in certain types of cancers is that we have a good understanding of the disease’s mechanisms,” Dr. Overman said. “So clearly, to make inroads into a cancer, we really need to do more laboratory-based research, but lab-based research requires funding.” Obtaining funding for rare tumors can be a problem—“horrendous,” as one researcher put it. Government agencies like the U.S. National Institutes of Health tend to fund research that will have the biggest effect across the population, and so common cancers tend to receive the most funding. Pharmaceutical companies tend to fund research only if it is likely to be profitable; if only a few hundred cases of a disease are identified each year, interest in funding research for that disease is generally nonexistent. Researchers of rare tumor types often must rely on donations, which can be few and far between. The lack of funding can stifle important research into potentially effective therapies for rare cancers. And medical insurers are not inclined to pay for drugs that have not been proven to work. “So you end up in this catch-22,” Dr. Overman said. “You’re limited in trying to use the new drugs that are effective for other cancers, and then, you’re limited in exploring new drugs for the rare tumor type.” Take bevacizumab (Avastin), for example. Although bevacizumab has been used successfully to treat lung, breast, and colon cancers, among others, few insurance companies will pay for its use in treating SBA. An oncologist like Dr. Overman might point to his positive experience in treating colon cancer patients with bevacizumab to justify its potential use in patients with SBA, but that is not enough to convince an insurance company to pay for an expensive drug whose effectiveness in treating SBA has not been tested in clinical trials. “We may have some experience here with certain drugs that we’ve tried, but convincing insurance companies to do something when there is limited published data is difficult,” Dr. Overman said. “Often, we have to get involved by providing letters to insurance companies explaining our rationale to get them to pay for drugs for a rare tumor type.” M. D. Anderson has mechanisms in place that enable faculty to pursue research without external funding. However, even unfunded clinical studies require patients, and the majority of patients treated for rare tumors at M. D. Anderson live hundreds if not thousands of miles away. For many of these patients, traveling to M. D. Anderson to receive treatment, let alone to participate in a clinical trial, can be difficult and expensive. “Even the people who come to see us in a referral setting may not be able to participate in a clinical trial, because they would have to get the drug here and be here more frequently than they would if they were getting therapy back home,” Dr. Overman said. While some new treatments can be designed to accommodate patients coming from afar—say, by administering a chemotherapy regimen that can be given every 4 weeks instead of one requiring weekly administration, or by working with the patient’s hometown physician to give certain therapies there—for rare tumors, experience matters, especially when making initial decisions about treatment. Multiple ways forward For most oncologists, rare cancers are among the smallest blips on their radar screens. The larger blips—e.g., colon, breast, prostate, and lung cancers—tend to garner the most attention. Yet studying rare cancers may give essential clues about treating more prevalent cancers. “You gain a lot of insight by studying rare cancers, because their biologic mechanisms seem to be more homogeneous than those of the more common cancers,” Dr. Overman said, referring to the opinions put forth by Fadi Braiteh, M.D., a medical oncology and hematology fellow, and Razelle Kurzrock, M.D., chair of the Department of Investigational Cancer Therapeutics. In an editorial published recently in the journal Molecular Cancer Therapeutics, Drs. Braiteh and Kurzrock noted that progress in rare cancer treatment, when it is made, seems to grow by leaps and bounds, while progress against more common cancers tends to happen much more slowly. The authors hypothesized that “the pathophysiologic basis for a tumor being rare is one and the same as the reason that it may ultimately be so treatable.” In other words, if a tumor like SBA—which has many of the same characteristics as colon cancer, yet is nearly 50 times less common—is rare because it arises only from a single genetic aberration, it should be easy to treat with a single therapy. Colon cancer, on the other hand, can arise from many different aberrations and must be approached with many different therapies, making it more difficult to treat than SBA. Dr. Overman said, “If you understand the rare tumor types, if you can focus in and find the abnormality that’s occurring, you can then focus on treating that abnormality in the more common cancers with more heterogeneous processes.” For Dr. Kim’s part, the way forward may include looking to viable cell lines and using mouse models that mimic malignant thymoma to study drugs that could potentially be used to treat malignant thymoma in humans. Dr. Kim’s discovery of a potential mouse model for malignant thymoma was serendipitous. In another laboratory at M. D. Anderson, Renata Pasqualini, Ph.D., and Wadih Arap, M.D., Ph.D., professors in the Department of Genitourinary Medical Oncology, found that the mice they were experimenting on were dying of asphyxiation caused by growing thymuses. Drs. Pasqualini and Arap agreed to let Dr. Kim and his colleagues study the mice to determine whether the mice were developing malignant thymomas. Dr. Kim noted that the enlarged mice thymuses did indeed exhibit some malignant characteristics. While research in the mouse model is still in its infancy, Dr. Kim remains cautiously optimistic and looks forward to the prospect of testing novel chemotherapy agents in the model. “We like to use laboratory science to help guide our clinical science, but when not much laboratory information is available, it is very difficult to choose which drugs will be effective in patients,” Dr. Kim said. “Oftentimes when treating rare tumors, we’re basically guessing which agents are going to work. If we can develop better laboratory models for testing additional drugs, that may help us narrow down what will work in patients.”
For more information, contact Dr. Kim at 713-792-6363, Dr. Mansfield at 713-794-5499, or Dr. Overman at 713-745-4317. M. D. Anderson was recently designated as a Blue Distinction Center for Complex and Rare Cancers by Blue Cross and Blue Shield. Other articles in OncoLog, March 2009 issue: Home/Current Issue | Previous Issues | Articles by Topic | Patient Education ©2009 The University of Texas M. D. Anderson Cancer Center |
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