Special fluorescent dyes may be able to improve survival after cancer surgery, The Guardian has reported.
In tests using the dyes, surgeons were able to identify and remove very small areas of cancerous cells in women with advanced ovarian cancer.
In their study, doctors examined 10 women with suspected ovarian cancer and injected them with a fluorescent “tagging” dye that would make cancerous ovarian cells glow under special lights, but leave healthy cells untagged. In photos taken from one woman’s surgery, the fluorescent images helped surgeons identify more areas of cancerous tissue than they could identify by looking at colour photos of the tissue alone. It is hoped that better identification of cancerous tissue would lead to improved staging (telling how advanced the cancer is) and may help surgeons remove a higher proportion of cancerous cells in later surgery aimed at treating the cancer. As with current therapies, women could then be given chemotherapy to try to kill any remaining cancer cells.
This technique is promising, but will need to be tested in larger numbers of women with different stages of ovarian cancer. Longer-term studies will also be needed to test whether using this technique (either as an aid to diagnosis and staging, or to guide therapeutic surgery) reduces the chance of relapse and improves women’s survival.
Where did the story come from?
The study was carried out by researchers from the University of Groningen in the Netherlands, and other universities in Germany and the US. No funding sources were reported. The study was published in the peer-reviewed journal Nature Medicine.
The Guardian and Daily Mail both provided good coverage of this study.
What kind of research was this?
This uncontrolled trial developed and tested a fluorescent “tagging” system to help surgeons identify ovarian cancer tissue in humans.
The researchers say that ovarian cancer does not initially cause very distinctive symptoms, meaning that it is often diagnosed at an advanced stage. The outlook for women with advanced-stage ovarian cancer is currently poor, and it is reported that only 20-25% of women with stages III and IV ovarian cancer survive for five years. At this stage of the disease, ovarian cancer is treated with surgery, plus a course of chemotherapy after surgery. However, if the surgeon thinks it may be hard to remove all the cancer, chemotherapy may also be given before surgery to shrink the tumour. If two courses of chemotherapy are given in this way, the operation is called “interval debulking surgery”. The greater the amount of cancerous tissue removed, the better the outlook will be for the woman.
The researchers wanted to develop a technique that would make the cancerous tissue glow fluorescently but leave normal tissue unchanged. They hoped that the ability to visually highlight cancerous tissue would help surgeons remove all the cancerous tissue. The researchers hope that this will improve women’s outcomes after surgery.
This study provides the sort of early, small-scale testing of a new technique that must be performed before it can be more widely used.
What did the research involve?
The most common form of ovarian cancer is called epithelial ovarian cancer. The researchers knew that in 90-95% of cases of this type of cancer, there will be high levels of a protein called folate receptor alpha on the surface of the cancerous cells. This protein is not present on healthy cells. Therefore, it was selected as a good target to which a fluorescent marker would be attached. This would allow the researchers to identify the cancer cells. The researchers took folate, the chemical that naturally binds to the folate receptor, and attached a fluorescent dye called FITC.
The researchers enrolled 10 women who were having exploratory keyhole surgery (laparoscopy) for suspected ovarian cancer. Four of these women were found to have a malignant ovarian tumour (cancer), one had a borderline tumour, and five had benign (non-cancerous) tumours.
The women were injected with the fluorescently labelled folate shortly before their surgery. Videos were then taken of their ovarian and surrounding abdominal tissue under a special light to identify any fluorescent tissue. Taking these videos took about ten minutes on average and did not disrupt the normal surgical procedures.
The surgical team removed samples of suspicious tissue and researchers examined it under a microscope to see if it was malignant, and if there was any fluorescence. The researchers also tested the tissue to see if the folate receptor was present.
The researchers also took images, both with and without fluorescence shown, of three different regions of the abdominal cavity of one woman who had extensive small areas of cancerous tissue spread throughout this region. They then asked five surgeons who were not involved in the surgery and unaware of the tissue examination results to look at these images and identify any areas of cancerous tissue. They looked first at the standard colour images without fluorescence shown, and then at the fluorescent images. The researchers compared how well the surgeons were able to identify the cancerous tissue using the normal images and the fluorescent images.
What were the basic results?
The researchers found that after injection of the fluorescent dye, the cancerous tissue fluoresced in three out of the four women with malignant tumours. In one of these women, fluorescent tissue was found spotted throughout the abdominal cavity, and this fluorescence aided removal of areas of tissue smaller than a millimetre in size. Samples of these areas of tissue were confirmed to be malignant when examined under the microscope. The fluorescence of these deposits lasted up to eight hours after the fluorescently labelled folate had been injected.
One woman’s malignant tumour did not fluoresce as it did not produce the folate receptor protein (around 5-10% of epithelial ovarian cancers are thought not to produce the receptor). The benign and borderline tumours did not fluoresce, nor did the healthy ovarian tissue.
All fluorescent tissue samples taken during the surgeries were found to be cancerous, and all non-fluorescent tissue samples were non-cancerous. The folate receptor was found at high levels in the three malignant tumours that fluoresced, but not in the one malignant tumour that did not fluoresce, or in the benign tumours.
The researchers found that surgeons were able to identify more tumour deposits using fluorescent photos than with normal colour photos. On average (median) they could identify seven areas of cancerous tissue from the colour photos but 34 using the fluorescent images.
How did the researchers interpret the results?
The researchers concluded that their trial “showcased the potential applications” for using fluorescent imaging with fluorescently tagged folate during surgery in patients with ovarian cancer.
This research has illustrated that fluorescent tagging of ovarian cancer cells during diagnostic keyhole surgery is not only possible, but it can also help surgeons identify small areas of cancerous tissue that they cannot see by regular visual inspection alone. This potentially allows surgeons to better identify cancerous tissue when assessing the stage of the cancer by laparoscopy, a technique which is often used alongside other diagnostic imaging procedures such as CT and MRI scanning. It may also help surgeons ensure that they remove all cancerous tissue during therapeutic surgery, which will usually be quite a major operation. In particular, the authors consider that it may guide surgeons when performing debulking surgery, and so improve the likely efficiency of the chemotherapy that follows this.
More research is needed before use of this technique becomes widespread. For example, the researchers mainly looked at stage III cancers in this study. They will want to look at whether the technique is also useful for less advanced cancers. In addition, the researchers say that the fluorescent dye used in this study could be improved on by developing new dyes that can fluoresce from deeper down in the tissue. Finally, this study looked at how the technique aided diagnostic surgery but not the women’s long-term outcomes. The researchers will want to look at whether these outcomes, particularly survival, are improved in women who have fluorescently guided diagnostic or therapeutic surgery.
This study has provided “proof of concept” that this technique could have a practical application in ovarian cancer surgery. Further work will be needed to test the technique more widely. Importantly, this technique would not be expected to identify all malignant ovarian tumours, as a minority do not produce the protein (the folate receptor) that is targeted by the fluorescent marker. Therefore, this marker would not be useful in all cases of advanced ovarian cancer, and further studies would help to identify exactly what proportion of cancers this marker might identify. However, the researchers may be able to identify other proteins in these ovarian cancers and other types of cancer that could be tagged in this way, although obviously these would also need to be tested.
Women with advanced-stage ovarian cancer generally have a poor outlook, and research that aims to improve this is important.
- van Dam GM, Themelis G, Crane LMA et al. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results. Nature Medicine, September 18