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In Search of the Answerby John LeBas
The advent of hormonal therapies, protein inhibitors, and other drugs that attack specific cancer types has brought new hope to patients with metastatic disease. By acting against the biologic pathways that enable tumors to grow and proliferate, these targeted therapies are extending the survival of late-stage cancer patients. But for some, the promise of targeted therapies can be frustratingly out of reach. That’s because these drugs are most effective when selected for a specific disease type—which isn’t always possible when a patient has the mysterious and puzzling disease presentation known as cancer of unknown primary origin (CUP). CUP often carries a grim outlook. It’s bad enough that the disease has already spread by the time of diagnosis, since metastatic cancer is notoriously difficult to treat. Even worse, CUP patients and their doctors can never be certain what kind of cancer they’re dealing with, so the choice of effective therapy is at best an educated guess. Fewer than 25% of CUP patients remain alive after 1 year. “It’s a diagnosis that patients are, understandably, uneasy about. It’s a diagnosis that their doctors are uneasy about. And that’s why we see so many patients with it here at M. D. Anderson,” said Martin Raber, M.D., a professor of gastrointestinal medical oncology at The University of Texas M. D. Anderson Cancer Center, which treats about 300 CUP patients each year. However, Dr. Raber and other clinicians are slowly taking the guesswork out of CUP therapy, thanks to high-quality imaging, advanced pathology and immunohistochemistry techniques, and the evolving science of genetic profiling. Today, CUP patients have a greater chance of receiving effective, tailored therapy, and the situation will only improve as more is learned about the genetic hallmarks of cancer. “The goal is to understand what the best therapy for every CUP patient is so that we can extend life and improve quality of life,” Dr. Raber said. “I think that over the next decade, we will be able to do that. We will be able to much better choose specific therapies for patients based on the profile of their cancer.” Common, yet enigmatic CUP, largely regarded as a fundamentally unique manifestation of cancer, has long defied the prevailing wisdom of metastasis. Consider the example of a carcinoma found growing in the bone. Carcinomas originate from epithelial cells, so the tumor cannot have originated in the bone—it must be a metastasis that was introduced either through local invasion or via the bloodstream from a distant primary tumor. If no primary carcinoma tumor can be found on physical examination or imaging, the case is considered a CUP.
The exact incidence of CUP in the United States is difficult to determine, though the estimated rate is about 2%–4% of all cancer cases, or several thousand a year, according to the U.S. National Cancer Institute. While most CUP is adenocarcinoma, the cases span the entire spectrum of cancer types. “CUP is a very heterogeneous group of tumors,” said Gauri Varadhachary, M.D., a CUP researcher and associate professor of gastrointestinal medical oncology. “The question we often ask is, what clues can we get from the imaging and laboratory tests to develop a short list of the possible primary cancer profiles, which can then help us treat the disease more specifically? For some cancers, where the treatment is not as effective, the answer isn’t as important. But that is changing because of the emergence of tumor-specific targeted therapies.” Until the past couple of decades, oncologists had few diagnostic tools with the precision, specificity, and sensitivity needed to tackle CUP. Very small primary tumors could escape the view of less sophisticated imaging modalities. Thus, patients were typically treated systemically with a broad spectrum of anticancer agents—a scattergun approach that was less than ideal, given the toxicity and variable effectiveness associated with different chemotherapies. However, as technology caught up, oncologists were able to make more informed treatment decisions. The most valuable advance, according to Dr. Raber, was the development of widely accessible, high-quality imaging modalities, such as the fusion of positron emission and computed tomography known as PET/CT. This technique illuminates active cancer sites in the body at their precise location. Owing to better imaging—and the widespread use of that imaging—more and more CUP patients are eventually diagnosed with a primary tumor, allowing their therapies to be better customized. Quality pathologic examination is also an important element in the hunt for a primary tumor, as well- to moderately differentiated cancers can often be identified. Another key has been the refinement of robust immunohistochemical stains, which detect protein markers known to be associated with specific cancer types. Along with imaging and pathology results, immunohistochemical stains have helped physicians learn to effectively divide patients into subsets according to likely tissue of origin, and from there choose the best-option therapies. Oncologists still don’t fully understand why some primary tumors are undetectable even as their metastases grow. Many possible explanations for this enduring mystery have been proposed over the years, including:
The truth may lie somewhere in the middle of the various theories. For Dr. Raber, the possible reasons for this disease presentation are interesting but not paramount. “Our goal is not to identify the primary tumor,” he said, “but to choose the best therapy that will extend a patient’s life.” Following the clues
Given the complexity and heterogeneity of CUP cases, M. D. Anderson relies on a team approach to treating the disease. Cases are typically routed through the Gastrointestinal Center. First, a pathologist studies previous pathology samples to ensure that no indicators of the primary origin have been overlooked. Then, the patient’s imaging is reviewed for the same purpose. If the primary origin is still considered unknown, the patient will be seen by one of the institution’s CUP specialists. Throughout the treatment process, these lead physicians consult with others whose specialties include diagnostic imaging, pathology, and surgery. One thing the specialists try to determine early on is whether a case fits any of the unique metastatic patterns that have been documented in CUP. “History has taught us that for ‘lookalike’ diseases, we can treat them as a known primary,” Dr. Raber said. For example, if a woman presents with metastatic adenocarcinoma in the axilla, she is given breast cancer therapy. A man with metastatic squamous cell carcinoma above the supraclavicular region is treated as though he has primary squamous cell cancer of the head and neck. These patients can be expected to respond as would patients who have metastatic disease of known origin, Dr. Raber said. Immunohistochemistry If the clinical presentation doesn’t yield any useful clues, the physicians can turn to the increasingly sophisticated array of immunohistochemical stains, which can identify proteins expressed by specific cancer types. “For example, the immunohistochemical marker TTF1 is usually associated with lung cancer, and CUP patients with this marker are treated with a lung cancer regimen,” Dr. Varadhachary said. “Patients with cytokeratin 20–positive and cytokeratin 7–negative cancers are treated with an expanded colon cancer regimen.” But immunohistochemical stains have limitations and are not specific, since different types of cancer can express the same proteins. “Currently, for a majority of CUP patients, the stains give us some direction, but they do not give us the answer. Furthermore, there is no direct validation of the test results unless a latent primary tumor appears, a phenomenon that occurs in only 2%–3% of CUP patients,” Dr. Varadhachary said. One goal for the CUP specialists is to develop a tier system for immunohistochemical stains. With dozens of such tests available, it’s not feasible to perform each one for every case of CUP. However, if the knowledge of common CUP cancers can be translated into immunohistochemical testing guidelines, clinicians could start with the stains most likely to yield useful information, based on the characteristics of a certain case. Genetic profiling What’s now shaping up to be a potential breakthrough for CUP treatment is the use of molecular probe assays to produce a genetic portrait of metastatic tumors. The belief is that genotype analysis will provide a much more specific idea of the originating tissue than immunohistochemistry alone. M. D. Anderson researchers are now testing molecular probe assays in different cancer types by comparing the assay data to immunohistochemistry data. The goal is to see whether genetic profiling can further refine the subsets established through immunohistochemistry. “We need to demonstrate whether these probes can be used to help us determine the primary, and if we use that molecular determinant to decide which chemotherapy to use, is that helpful?” Dr. Raber said. Challenges ahead Despite such promising technology, progress against CUP still faces some of the same basic challenges that it has in the past. There are no large patient associations, as exist for most other prominent cancer types, to apply pressure for greater funding and research. And, by the nature of CUP, there is no way to prove a certain approach is successful, which further limits opportunities for funding. Anecdotal experience indicates CUP patients are living longer, but no recent studies have evaluated the effects of newer technologies on survival, according to Dr. Raber. Additionally, relevant information in the literature can be frustratingly sparse. For example, if a patient presents with a metastatic scalp lesion and no other evidence of disease, it’s unlikely that a body of data on the same presentation will be available, Dr. Varadhachary said. At its core, CUP science remains a process of indirect validation—factoring in all the clues to a cancer’s primary origin, deciding on the best course of action, and hoping for a positive response. “There is still a lot of art in the treatment of unknown primary cases,” Dr. Raber said. “When treating a patient, we need to remain humble and realize that we may be on the wrong track and we may need to change focus. After all, it’s called unknown primary for a reason.”
For more information, call Dr. Varadhachary at 713-792-2828, Dr. Raber at 713-563-2192, or the New Patient Referral Office at 1-877-632-6789. Other articles in OncoLog, March 2008 issue: Home/Current Issue | Previous Issues | Articles by Topic | Patient Education ©2008 The University of Texas M. D. Anderson Cancer Center |
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