Cancers of Unknown Primary: A Neglected Disease Attracts Attention

While more common cancers garner the lion’s share of attention, a relatively unfamiliar entity is responsible for a staggering number of cancer deaths.

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.

Dr. Fowell agrees that CUP tumors behave differently from known primary tumors and said that many CUP patients present late when their performance score is already quite poor. “We saw that as a really important factor that people need to make an early decision as to whether we should be pursuing invasive investigations when at the end of the day they may not be fit for treatment anyway,” he said, noting that data suggests that as few as 8% of CUP patients go to chemotherapy.

The NICE guidelines recommend that investigations be performed only if they affect a treatment decision; and the patient understands why the investigation is being done, the potential benefits and risks of the investigation and treatment, and is prepared to accept treatment.

The NCCN guidelines recommend that chemotherapy for patients with disseminated disease should be limited to symptomatic patients with a performance score of 1-2 or asymptomatic patients with aggressive disease.

NICE, which calls CUP a “neglected disease” contends that patients with CUP are largely denied the medical and other benefits afforded those with site-specific cancers because of a lack of specific, dedicated clinical services, a lack of understanding and information about the disease, and the absence of a formal research structure. The guidelines call on every hospital with a cancer center or unit to establish a CUP team, comprising an oncologist, palliative care physician, and a CUP specialist nurse or key worker as a minimum, said Dr. Fowell, a consultant in palliative medicine at Bangor Hospital in North Wales.

NICE also suggests that a clinical studies group be established for CUP at the National Cancer Research Network level to coordinate and direct clinical trials. There has been a paucity of research, but new studies are in the works. The open-label, phase II UNKPRI 21 trial, also based in Nashville, compares carboplatin/paclitaxel with carboplatin/paclitaxel plus the histone deacetylase inhibitor PXD101 (belinostat) in patients with previously untreated CUP. The United Kingdom’s CUP-ONE trial is prospectively validating three molecular classification techniques and assessing the feasibility of combining the established chemotherapy regimen epirubicin (Ellence), cisplatin and capecitabine (Xeloda) with erlotinib.

Dr. Fowell and Dr. Pavlidis disclosed no conflicts of interest. Dr. Ettinger disclosed relationships with 11 companies including Genentech, which markets bevacizumab and erlotinib.

While more common cancers garner the lion’s share of attention, a relatively unfamiliar entity is responsible for a staggering number of cancer deaths.

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.

Dr. Fowell agrees that CUP tumors behave differently from known primary tumors and said that many CUP patients present late when their performance score is already quite poor. “We saw that as a really important factor that people need to make an early decision as to whether we should be pursuing invasive investigations when at the end of the day they may not be fit for treatment anyway,” he said, noting that data suggests that as few as 8% of CUP patients go to chemotherapy.

The NICE guidelines recommend that investigations be performed only if they affect a treatment decision; and the patient understands why the investigation is being done, the potential benefits and risks of the investigation and treatment, and is prepared to accept treatment.

The NCCN guidelines recommend that chemotherapy for patients with disseminated disease should be limited to symptomatic patients with a performance score of 1-2 or asymptomatic patients with aggressive disease.

NICE, which calls CUP a “neglected disease” contends that patients with CUP are largely denied the medical and other benefits afforded those with site-specific cancers because of a lack of specific, dedicated clinical services, a lack of understanding and information about the disease, and the absence of a formal research structure. The guidelines call on every hospital with a cancer center or unit to establish a CUP team, comprising an oncologist, palliative care physician, and a CUP specialist nurse or key worker as a minimum, said Dr. Fowell, a consultant in palliative medicine at Bangor Hospital in North Wales.

NICE also suggests that a clinical studies group be established for CUP at the National Cancer Research Network level to coordinate and direct clinical trials. There has been a paucity of research, but new studies are in the works. The open-label, phase II UNKPRI 21 trial, also based in Nashville, compares carboplatin/paclitaxel with carboplatin/paclitaxel plus the histone deacetylase inhibitor PXD101 (belinostat) in patients with previously untreated CUP. The United Kingdom’s CUP-ONE trial is prospectively validating three molecular classification techniques and assessing the feasibility of combining the established chemotherapy regimen epirubicin (Ellence), cisplatin and capecitabine (Xeloda) with erlotinib.

Dr. Fowell and Dr. Pavlidis disclosed no conflicts of interest. Dr. Ettinger disclosed relationships with 11 companies including Genentech, which markets bevacizumab and erlotinib.

While more common cancers garner the lion’s share of attention, a relatively unfamiliar entity is responsible for a staggering number of cancer deaths.

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.

Dr. Fowell agrees that CUP tumors behave differently from known primary tumors and said that many CUP patients present late when their performance score is already quite poor. “We saw that as a really important factor that people need to make an early decision as to whether we should be pursuing invasive investigations when at the end of the day they may not be fit for treatment anyway,” he said, noting that data suggests that as few as 8% of CUP patients go to chemotherapy.

The NICE guidelines recommend that investigations be performed only if they affect a treatment decision; and the patient understands why the investigation is being done, the potential benefits and risks of the investigation and treatment, and is prepared to accept treatment.

The NCCN guidelines recommend that chemotherapy for patients with disseminated disease should be limited to symptomatic patients with a performance score of 1-2 or asymptomatic patients with aggressive disease.

NICE, which calls CUP a “neglected disease” contends that patients with CUP are largely denied the medical and other benefits afforded those with site-specific cancers because of a lack of specific, dedicated clinical services, a lack of understanding and information about the disease, and the absence of a formal research structure. The guidelines call on every hospital with a cancer center or unit to establish a CUP team, comprising an oncologist, palliative care physician, and a CUP specialist nurse or key worker as a minimum, said Dr. Fowell, a consultant in palliative medicine at Bangor Hospital in North Wales.

NICE also suggests that a clinical studies group be established for CUP at the National Cancer Research Network level to coordinate and direct clinical trials. There has been a paucity of research, but new studies are in the works. The open-label, phase II UNKPRI 21 trial, also based in Nashville, compares carboplatin/paclitaxel with carboplatin/paclitaxel plus the histone deacetylase inhibitor PXD101 (belinostat) in patients with previously untreated CUP. The United Kingdom’s CUP-ONE trial is prospectively validating three molecular classification techniques and assessing the feasibility of combining the established chemotherapy regimen epirubicin (Ellence), cisplatin and capecitabine (Xeloda) with erlotinib.

Dr. Fowell and Dr. Pavlidis disclosed no conflicts of interest. Dr. Ettinger disclosed relationships with 11 companies including Genentech, which markets bevacizumab and erlotinib.