On the DOT: Combining Optical Imaging and Ultrasound to Better Diagnose and Treat Women's Cancers
By Beth W. Orenstein
Radiology Today
Vol. 18 No. 9 P. 14

When a woman or her physician feels a lump in her breast and/or doctors see the abnormality on a mammogram, they often turn to ultrasound to determine whether it is a fluid-filled cyst or a solid lesion. If it is a solid lesion, the ultrasound can't determine whether it is malignant or benign. The next step is often to send the woman for a needle biopsy. A professor of biomedical engineering at Washington University in St. Louis, Quing Zhu, PhD, is hoping to change this practice.

Zhu, who has a secondary appointment as a professor of radiology at Washington University's School of Medicine, is hoping to make it easier for doctors to use ultrasound to get an accurate understanding of the patient's tumor and how to best treat it. To help further that goal, she has been awarded a grant from the National Institutes of Health to study the addition of an optical imaging component—diffused near infrared light—to ultrasound so doctors can better diagnose and treat breast cancer. In addition, she has a similar project underway—pairing photoacoustic technology with ultrasound—to allow physicians to better characterize ovarian masses and distinguish benign from malignant ovarian tissue.

Improved Detection
Zhu started working on her advanced imaging techniques in 2002 while at the University of Connecticut in Storrs. "We were driven by the clinical problem that so many women underwent biopsies of suspicious findings on mammograms that turned out to be benign," Zhu says. She adds that 70% to 80% of biopsies performed in current clinical practice show lesions to be benign. "That leads to unnecessary cost and anxiety for many women."

Zhu's idea was to combine ultrasound with diffuse optical tomography (DOT) to lower the rate at which women undergo breast biopsies for suspicious lesions. DOT measures light absorption within tissue to quantify blood content—hemoglobin level—and blood oxygen levels. Hemoglobin levels can help distinguish early-stage cancers from benign lesions because cancerous lesions have many more small blood vessels than normal tissue, Zhu explains.

Zhu's device consists of a commercial ultrasound transducer surrounded by an optical source and detector fibers. The ultrasound probe locates the lesion. DOT is then performed by shining infrared light into the area and measuring light absorption at optical wavelengths. Infrared light penetrates deep into the tissue, up to 4 cm, Zhu says.

Zhu led a study at the University of Connecticut Health Center and Hartford Hospital in Hartford in which she tested the device on 178 women who had mammograms and ultrasound that identified lesions and were followed by biopsy. The study of women between the ages of 21 and 89 was conducted between 2004 and 2008. The researchers computed total hemoglobin levels from the light absorption measured at two wavelengths and correlated the measurements with biopsy results. Laboratory examination of tissue samples revealed two in situ carcinomas, 35 carcinomas that measured less than 2 cm, 24 carcinomas greater than 2 cm, and 114 benign lesions.

The malignant group had a significantly higher maximum and average total hemoglobin level than the benign group, Zhu says. The sensitivity and specificity of the technique (92% and 93%, respectively) were the greatest when the researchers were evaluating cancers that were less than 2 cm, she notes. The researchers published their results in the August 2010 issue of Radiology.

Zhu and colleagues published a follow-up study in the August 2016 issue of Radiology, which involved 288 women who underwent ultrasound with Zhu's handheld ultrasound and optical probe. Two radiologists evaluated the combined diagnosis of ultrasound and DOT. The biopsies identified 59 cancers and 233 benign lesions. Again, the mean maximum hemoglobin levels were significantly higher for those whose biopsies showed malignancy. The combined sensitivity and negative predictive value reached 97% to 100% and 99% to 100%, respectively.

"Based on our results, we believe ultrasound-guided diffuse optical tomography holds promise as an adjunct to diagnostic mammography and ultrasound for distinguishing breast cancers from benign lesions," Zhu says. She also expects that the technology will be able to help radiologists evaluate small to intermediate-sized lesions that are harder to diagnose with conventional imaging technologies.

Treatment Monitoring
Zhu is also researching whether the combination of ultrasound and optical imaging can be used to monitor breast cancer treatment. "We are focusing on monitoring neoadjuvant chemotherapy, as this is another problem," Zhu says. Women with cancers may be treated with six to eight cycles of neoadjuvant chemotherapy over a period of several months without knowing whether the treatment is working because oncologists do not have a good way to monitor response. X-ray and ultrasound are not sensitive to treatment changes, and MRI and nuclear imaging are too expensive to use repeatedly.

Breast cancer is a highly heterogeneous disease with different biomarkers, subtypes, and metabolic rates, and the patients' treatment response rates vary. Knowing early whether an individual patient is responding to a given treatment regimen is important because oncologists can change treatment regimens or suggest surgery to avoid ineffective chemotherapies with their associated toxicities, Zhu says. Her ultrasound optical imaging probe can see which tumors are getting smaller and whether the vasculature level is getting lower with each treatment cycle. Lower vasculature levels indicate a response.

"When cancer cells are killed due to treatment, the blood vessels also are being killed, and then we see much less vascular content," Zhu says. It is a good sign if the regimen works, and it is not a good sign if there is little or no change, she says.

Steven Poplack, MD, who worked for many years developing optical imaging fusion technologies with engineers at Dartmouth College and is now a professor of radiology and a breast imaging specialist at the Mallinckrodt Institute of Radiology at Washington University School of Medicine, says it's important to stress that Zhu's device is adjunctive technology. "It is in addition to conventional breast imaging with ultrasound and mammography. In particular, it is an adjunct to ultrasound, at this point, and not a standalone technology."

Early Phase
Still, Poplack says, the results have been impressive. "If we can reduce the number of unnecessary biopsies, that would have great clinical impact and be a huge benefit to women," he says. "We're continuing to develop that aim of the technology."

Likewise, he says, the results for its role in treatment response are equally impressive, and he sees a huge potential benefit. "Imagine," Poplack says, "if you knew chemotherapy wasn't working after the end of just one cycle, you could spare the patient toxicity from additional cycles by changing your treatment at that earlier time point."

Poplack says Zhu's technology is easy to incorporate into the clinical workflow. "The interface with the ultrasound transducer is reasonably user friendly," he says. "There are still modifications that need to occur, but, even at this early prototype phase, the exam can be done in just a few minutes." It does not add much more time to the ultrasound exam, he says.

Using ultrasound with optical imaging is inexpensive compared with MRI and nuclear imaging, which are often used for this purpose, and it's nonionizing. "There are no significant health risks from exposure to this technology," Poplack says. The one disadvantage is that conventional imaging for lesion characterization is already highly accurate. "The gold standard of image-guided biopsy provides a definite answer, and the procedure is well tolerated," Poplack says. "Many women would prefer a definite answer to a highly accurate noninvasive test. They want 100% surety, not 95%."

Debra L. Monticciolo, MD, FACR, chair of the ACR's Commission on Breast Imaging and a professor of radiology at Texas A&M University Health Sciences, agrees that the research is very promising and, if successful, would be useful clinically. "Assessing chemotherapy effectiveness is a key component of cancer care," Monticciolo says. "Blood flow to tumor is an important indicator in treatment." Zhu and her colleagues are taking a novel and legitimate imaging approach, Monticciolo says. Because the work is in the early stages, however, "It is difficult to tell how well it will discriminate treatment regimes."

Sound Waves Aid Detection
Zhu is applying similar principles to help better detect ovarian cancers. Ovarian cancer has been dubbed the "silent killer" because many of its early symptoms—bloating, abdominal swelling, upset stomach—are easy to miss or can be mistaken for something else. Often, by the time the cancer is detected, it is not easily treated. Some women who are at high risk for ovarian cancer, such as those with a family history or other risk factors, opt to preemptively have their ovaries removed.

A more effective screening and diagnostic tool that could help physicians determine whether a lesion on the ovaries is cancerous or benign would be a great help, Zhu says. Funded by a National Cancer Institute grant, Zhu is hoping to recruit up to 40 patients to test a noninvasive imaging approach to ovarian cancer diagnosis. Like her device for breast cancer, the device for ovarian cancer could be life changing for many women, Zhu says.

In this case, Zhu has paired ultrasound with photoacoustic technology for real-time assessment of ovarian masses. She has taken a standard transvaginal ultrasound probe usually used for ovarian exams and fit it with a special light delivery channel. Once it is inserted into the vagina, the light is absorbed by the suspected tumor. The absorption generates a slight temperature change that converts to sound waves. The sound waves can be detected and analyzed to determine a lesion's vasculature and oxygen saturation, both of which are potential markers of a cancer, Zhu says.

The photoacoustic images provide valuable information about the vascularity of the lesion. Like breast cancers, ovarian cancers require additional blood vessels to feed them. Current options for imaging ovarian lesions include CT with contrast, MRI with contrast, and FDG/PET. The advantages of Zhu's ultrasound-photoacoustic imaging is that patients aren't exposed to radiation and ultrasound costs far less than the other imaging modalities, says Cary Lynn Siegel, MD, a professor of radiology and chief of genitourinary radiology and gastrointestinal radiology at the Mallinckrodt Institute in St. Louis.

Siegel has been impressed thus far with the preliminary results of the coregistered photoacoustic tomography and ultrasound prototype system. "We have done about five patients using Dr. Zhu's device, but the preliminary data are very exciting," she says. The initial results were published in the April 2016 issue of the Journal of Biomedical Optics.

Siegel's one concern is the range of Zhu's photoacoustic tomography probe. It can go about 5 cm from its end; most ovarian tumors, but not all, can be reached within 5 cm from the end of the probe to the tumor. "We could be dealing with a mass that is so deep it might be beyond the window of our probe," Siegel says.

Siegel believes that if the technology can be developed, it would benefit women worldwide, especially in developing countries where the low cost of ultrasound would boost utilization. Also, she says, by the time ovarian cancer is diagnosed, it has often spread to the pelvis. "So, anything we could use that could help us better detect or specifically diagnose an ovarian tumor's vascularity is important."

— Beth W. Orenstein of Northampton, Pennsylvania, is a freelance medical writer and frequent contributor to Radiology Today.