While more common cancers garner the lion’s share of attention, a relatively unfamiliar entity is responsible for a staggering number of cancer deaths.
Dr. David Ettinger
Cancers of unknown primary (CUP), also known as occult primary tumors, are metastatic malignant tumors whose primary site cannot be identified despite pretreatment evaluation. More than 50% of CUP patients present with multiple site involvement. Median overall survival is about 6-9 months, with the primary tumor being found in fewer than 30% of patients who initially present with CUP.
In the United States, CUP represents about 2% of all cancers, said Dr. David S. Ettinger, who chairs the occult primary clinical practice guidelines for the National Comprehensive Cancer Network (NCCN). This number is based on an estimated 30,680 cases in 2010, although the number of deaths from CUP is likely closer to 44,000, as reports of the underlying cause of cancer deaths are not always specific.
CUP is the fourth most common cause of cancer death in England and Wales, even though it constituted just 3% of cancers registered in England in 2006 and 4% of cancers in Wales between 2002 and 2006, according to a recent assessment by England’s National Institute for Health and Clinical Excellence (NICE).
“We found that one in four cancer deaths was due to cancer of unknown primary, which we were quite surprised at and thought was highly significant,” said Dr. Andy Fowell, chair of the guidance development group for the NICE guidelines on metastatic malignant disease of unknown primary origin, published in July.
While CUP might not be recognized as the underlying cause of death in many cases, both men agree it is garnering increased attention. Dr. Fowell suggests this might reflect frustration felt by oncologists at not being able to treat CUP very well, and growing recognition that the management of these patients has not been particularly efficient or effective.
“They are within hospitals for a long period of time, there are a lot of tests being done, which aren’t in any way coordinated and rational, and you still end up with a patient where you don’t know where the cancer came from,” he said.
Gene Profiling
Dr. Ettinger suggests that efforts by several companies to identify the tissue of origin through gene-based expression profiling might be driving the interest in CUP. These tumors have many chromosomal abnormalities and overexpression of several genes, including Ras, HER2, Bcl2, and p53.
In a study involving 104 patients with CUP, the tissue of origin was identified in 61% using a molecular assay evaluating the expression of 10 specific gene markers by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) (J. Clin. Oncol. 2008;26:4442-8). Results of a prospective trial presented at this year’s American Society of Clinical Oncology annual meeting showed that results of a test measuring the expression of 48 microRNAs by RT-PCR were concordant with clinical presentation in 82% of 46 CUP cases (J. Clin. Oncol. 2010;28:15s).
Although gene profiling looks promising, Dr. Ettinger said the 2010 NCCN occult primary guidelines specifically state that genetic profiling is not recommended for standard management at this time. The guidelines cite the need for prospective trials to confirm whether it can be used in choosing treatment options that would impact prognosis. “It’s like screening in a sense; if you have a screening, it has to [affect] survival and, in some fashion, mortality,” he said.
The NICE guideline panel used similar reasoning in making its recommendation that genetic profiling should only be done as part of a research program.
The phase II UNKPRI 20 trial, sponsored by the Sarah Cannon Cancer Center in Nashville, Tenn., in collaboration with Genentech, is prospectively evaluating molecular profile predictions of the primary site for site-directed therapy in patients with CUP.
A Different Animal
While gene profiling can identify the primary site in about 85% of cases, it will not solve the clinical problem of treatment and prognosis, said Dr. Nicholas Pavlidis, who has written extensively on the subject and is a professor of medical oncology at the University of Ioannina, Greece. Patients with poor-risk tumors, which represent 80% of CUP patients, have dismal outcomes, even when gene profiling assigns a tissue of origin. Overall response rates to chemotherapy range from 25% to 50%. Targeted systemic treatments such as bevacizumab (Avastin), erlotinib (Tarceva), and paclitaxel (Taxol)/carboplatin, have not improved results over previous regimens, he said.
While the reasons for this are unclear, CUP tumors might represent a distinct clinical entity, said Dr. Pavlidis. “They have a peculiar clinical picture that is not as we know in the primary tumors,” he said. This includes early dissemination, aggressive disease, resistance to chemotherapy, and an unpredictable metastatic pattern. For example, pancreatic cancer presenting as CUPhas a four- to fivefold higher incidence of bone and lung involvement than does primary pancreatic cancer.