1. Holt, Chuck

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A study led by researchers at the Florida Hospital Cancer Institute (FHCI) has aimed at improving imaging to detect metastatic disease in pelvic lymph nodes of women with endometrial cancer undergoing robotic-assisted laparoscopic hysterectomy and lymphadenectomy. Through this work, data have shown that, by using isosulfan blue dye (ISB) in combination with indocyanine green dye (ICG) and near infrared (NIR), they detected significantly more sentinel lymph nodes (SLNs) and more lymph node metastasis than ISB-alone.

Excellence in Oncolo... - Click to enlarge in new windowExcellence in Oncology; endometrial cancer. Excellence in Oncology; endometrial cancer

The researchers, led by Robert W. Holloway, MD, FACOG, FACS, and Sarfraz Ahmad, PhD, FAACC, compared two SLN detection technologies, namely fluorescence imaging and ICG, verses standard laparoscopic colorimetric analysis using ISB. Holloway is the Medical Director of the Gynecologic Oncology Program, and Ahmad is Director of Clinical Research at the Gynecologic Oncology Department, both at FHCI in Orlando, Fla.


In the winning entry about the research that Ahmad submitted for the Oncology Times 2018 Excellence in Oncology Award contest, they noted that the single-center, prospective, randomized, controlled, FDA investigational device exempt study enrolled 200 patients with clinical stage I endometrial cancer. Among those patients, 180 received ICG+ISB injections while 20 in the control group received ISB dye only. All the patients received 2 mL of ISB; however, those in the ISB+ICG group also received 2 mL ICG (1 mg/mL) in the cervix and between 3 and 5 mm below mucosa. The investigators completed didactic training for SLN mapping technique and case proctoring with the PI two or more times.


According to the researchers, the SLN detection for ISB+ICG group A (n=180) versus all ISB (n=200) were bilateral, 84 percent versus 39 percent; unilateral, 12 percent versus 37 percent; and none, 4 percent versus 24 percent, (p<0.001). Median SLN per case in group A was two (range 0-4). Positive SLNs were found in 38 (21.1%) group A cases and two (10%) in group B. There was one false-negative SLN (97.5% sensitivity, NPV 99.3%, 2.5% false-negative rate). SLN was the only positive lymph node in 25 out of 41 (61%) node (+) cases. Isolated tumor cells (ITC) were found in 14 out of 38 SLN cases (36.8%) versus four out of 15 (26.7%) non-SLN metastasis. ISB improved the ICG detection of SLNs (bilateral n=0, unilateral n=2, lymph node metastasis n=1). ISB improved the ICG detection of SLNs (bilateral n=0, unilateral n=2, lymph node metastasis n=1). And there were no allergic reactions to either dye.

Robert W. Holloway, ... - Click to enlarge in new windowRobert W. Holloway, MD, FACOG, FACS. WINNING RESEARCHERS: Robert W. Holloway, MD, FACOG, FACS, (left) and Sarfraz Ahmad, PhD, FAACC, aimed at improving imaging to detect metastatic disease in pelvic lymph nodes of women with endometrial cancer.
Sarfraz Ahmad, PhD, ... - Click to enlarge in new windowSarfraz Ahmad, PhD, FAACC. Sarfraz Ahmad, PhD, FAACC

"In this prospective cohort study, we clearly demonstrated that ISB dye in combination with ICG dye and NIR detected significantly more SLN and more lymph node metastasis than ISB alone; the false-negative rate of blue-plus-green dyes for SLN detection of metastasis was 2.5 percent; and the blue dye contributed minimally to ICG detection quantitatively (two unilateral mappings, one positive SLN); however, the qualitative contribution could not be determined (i.e., how the blue dye affected the green dye determinations)," Ahmad wrote in his winning entry.


"Given the excellent results reported for ISB+ICG in our study, we feel that it is reasonable to use the two dye detection methods in combination (at least through a learning curve experience)," added Holloway and Ahmad. "Only another phase III comparison trial of ISB+ICG versus ICG-alone can differentiate the efficacy of these two methods."


The Society of Gynecologic Oncology (SGO) released a position statement on pelvic SLN mapping in November 2015, Ahmad included in his entry. The SGO stated that pelvic lymphadenectomy can be limited or excluded in low-risk histology cases when the surgeon has met metrics with 90 percent mapping efficacy and demonstrate a false-negative rate of <5 percent. As a result, the SGO deemed high-risk histology cases should continue to undergo complete lymphadenectomy with SLN mapping as an "add-on" until more experience and data accrue.


In the Florida Hospital-led study, the authors noted, "we found that 14 (35%) of the SLN metastases were ITC metastases, detected through enhanced pathology methods (ultra-sectioning and immunohistochemistry stains)."


In an interview with Oncology Times, Holloway and Ahmad shared more about the award-winning research, for which additional co-authors included James E. Kendrick, MD, Glenn E. Bigsby, DO, Lorna A. Brudie, DO, Giselle B. Ghurani, MD, Nicole M. Stavitzski, BS, Jasmine L. Gise, BS, Susan B. Ingersoll, PhD, and Julie W. Pepe, PhD.


What inspired you to investigate this research question?

Holloway: The project was proposed out of a need to define the advantages of fluorescent ICG and NIR over standard blue dyes in SLN mapping for endometrial cancer. The inspiration came from observing the obvious advantages of ICG but understanding that its use and that of the imaging system were off-label with the FDA. We needed prospective clinical trial experience to gather legitimate data to define the safety and efficacy of this approach, and therefore filed an IDE with the FDA to conduct this trial.


What are the key takeaways from your study?

Holloway: It was demonstrated in a prospective randomized cohort study that ICG with NIR detected significantly more SLNs than blue dye (96% vs. 76% cases, p<0.001), had more bilateral pelvic mapping (84% vs. 40%, p< 0.001), and there were no safety signals identified in 200 cases.


What, if anything, surprised you about the results?

Holloway: Despite that four of the five surgeons in this study were in their early learning phase, the false-negative rate was only 2.5 percent.


What are the clinical implications, if any, of your research?

Holloway: ISB dye is more expensive and has a higher inherent risk of allergic reactions than ICG. The ICG with NIR was much more efficacious for detecting SLNs in endometrial cancer patients and should be preferentially used.


Is there anything about the study others are likely to get wrong?

Holloway: To reduce the number of study subjects, with approval from the FDA the trial was designed with subjects serving as controls for blue-dye determination. All 200 subjects underwent blue-dye determinations that were recorded in the operation room. A total of 180 cases were randomized to ICG/NIR determinations and these were then recorded. Twenty subjects did not undergo ICG/NIR determinations and served as a control to compare to the other 180 blue-dye determinations (to show no investigator bias). There were no differences in the 20 controls and the other 180 blue-dye determinations. While this was called a prospective cohort study, there was randomization involved in the study design with respect to the blue-dye determinations, and the findings with blue dye mirror that of several retrospective and prospective series in the literature.


What further research needs to be done on this topic?

Holloway: Future research into SLN mapping in endometrial cancers will look at new fluorescent dyes and/or dyes that could tag cancer cells that would detect lymph node metastases, not just sentinel lymph nodes.


What does it mean to you to receive recognition for your work like the Oncology Times 2018 Excellence in Oncology 2018 Award?

Holloway: It is gratifying for me and my co-authors to be recognized for our research efforts in pelvic SLN mapping. It is even more gratifying to help define the contemporary management of patients with endometrial cancer through SLN mapping, by reducing the need for comprehensive lymphadenectomies and the subsequent morbidities.


Chuck Holt is a contributing writer.