Cancer of unknown primary (CUP) research

All methods of diagnosis and treatment must be fully researched before they can be adopted as standard for everyone. This is so that

• We can be sure they work
• We can be sure they work better than the methods of diagnosis and treatment that are available at the moment
• They are known to be safe

First of all, treatments are developed and tested in laboratories. For ethical and safety reasons, experimental treatments must be tested in the laboratory before they can be tried in patients. If a treatment described here is said to be at the laboratory stage of research, it is not ready for patients and is not available either within or outside the NHS.

Tests in patients are called clinical trials. The trials and research section describes clinical trials, including the 4 phases of  trials. You can also look at our clinical trials database to find UK trials. If there is a trial you are interested in, you can print off that page and take it to your own specialist. If the trial is suitable for you, your doctor will need to refer you to the research team. The database also has information about closed trials and trial results. There tend to be very few trials specifically for cancer of unknown primary. But some trials for treating different types of advanced cancer are starting to include people who have CUP (UPC or UPT). All the new approaches covered here are the subject of ongoing research.

Until studies are completed and new effective methods of diagnosis and treatment are found, they cannot be used as standard procedures or therapy for cancer of unknown primary.

These tests for cancer are not new but studies are looking at how they can be used to make a more accurate diagnosis when the unknown primary cancer can't be found.

PET scans and PET-CT scans

Several studies have shown that PET scans can identify the primary tumour in 25 to 30% of patients who have a squamous cell type of CUP in the head and neck area. The PET scan can also measure how far the cancer has spread and help doctors to decide on the best treatment. This might mean that radiotherapy can be given to a smaller area which can help to reduce the side effects of radiotherapy. Other studies show that PET scans can detect the primary tumour in 1 in 5 (or 20%) of patients who have CUP in other parts of the body. But even though the scans can find the cancer this does not seem to help people live longer. 

Doctors are using PET-CT scans more often to diagnose CUP. A trial in the USA is looking at whether a PET-CT is better than a PET scan or CT scan alone, for diagnosing CUP.

Biological markers (immunohistochemistry)

Pathologists are often able to see which type of cancer cell they are looking at just by using a microscope. Sometimes this does not give enough information. In some cases it is now possible to find out more about cancer cells by using a process called immunohistochemistry (IHC). This is a way of staining tissue, such as a cancerous tumour, to find particular proteins (antigens). This technique has been in use for some time. For example, it is used to test if breast cancer cells are oestrogen positive or negative.

In the case of CUP, IHC means that it is now sometimes possible to tell what type of cancer you have even if the primary tumour can't be found. IHC includes a large number of different tests and not all of them are needed on each tissue sample. It is likely these will only help to diagnose a certain number of cancers of unknown primary. 

Examining genes or molecules in the cancer tissue

Techniques called gene expression profiling and molecular profiling are now available for research purposes, but are not yet available on the NHS. Molecular profiling looks at genetic material or particular molecules in the biopsy sample. These techniques can be used to find out the type of cancer cell.

In a study of 21 CUP patients in the North London Cancer Network, most of the primary sites were correctly predicted by genetic profiling. As a result, more specific treatment was given and survival rates improved.

A study of tumour tissue from 120 patients used molecular profiling to look for 1 of 6 different tumour types in genetic material in each biopsy of cancer tissue. The tumour type was found in roughly 3 out of 5 (61%) of the samples. The remaining 39% did not match the 6 different tumour types that could be detected by this test. The most common tumour types found in this study were lung cancer, pancreatic cancer and colon cancer. There now need to be larger studies using molecular profiling to decide the most effective treatment. 

A phase 2 study in the USA is using molecular profiling to identify the tumour type of a CUP from the following 7 cancer types – lung, pancreas, colon, breast, renal cell (kidney), prostate or ovarian cancer. If a diagnosis can be made, the usual treatment for the type of cancer is then given. If the cancer cannot be identified, patients have treatment including the cancer drugs paclitaxel, carboplatin, bevacizumab and erlotinib.

Clinical trials mentioned here are mainly for carcinoma of unknown primary. This means that sub groups of unknown primary cancer such as squamous cell or neuroendocrine tumours have been excluded because these already have established treatments. The number of clinical trials of chemotherapy and biological therapies for carcinoma of unknown primary is gradually increasing. Most trials are small phase 2 studies but there are now some larger randomised phase 3 trials. Chemotherapy and biological therapies may be used alone or in combination.

Chemotherapy

A trial called CUP-ONE is looking at chemotherapy for carcinoma of unknown primary in the UK. And testing new ways of finding where the cancer started. The researchers are looking at a combination of 3 chemotherapy drugs called epirubicin, cisplatin and capecitabine to see how much it helps people with cancer of unknown primary. In the USA there is a phase 3 trial comparing carboplatin, paclitaxel and etoposide with gemcitabine and irinotecan. In France another phase 3 trial is comparing cisplatin alone with cisplatin combined with gemcitabine. Results of these trials are not yet available.

Biological therapies

In the USA a phase 2 study of bevacizumab and erlotinib in 51 CUP patients showed improved survival compared with chemotherapy. This has led to a second phase 2 study of 56 patients which combines paclitaxel, carboplatin, bevacizumab and erlotinib. This study shows improved survival rates after a year and patients are still being followed up to measure survival rates at 2 years and 3 years. Another phase 2 study in the USA is looking at adding everolimus to carboplatin and paclitaxel to treat CUP patients.

A phase 1-2 study in the UK has looked at ways of improving the care and support of people who have CUP. The results of this trial are not yet available.

The National Institute for Health and Clinical Excellence (NICE) in the UK produced guidelines for the management and treatment of CUP in July 2010.