Vol. 14, Issue 2 Mar 2014

Case Management: Improving Outcomes for Early-Stage Cervical Cancer

Contributing Author: Emma Rossi, MD

ACCREDITATION STATEMENT
Indiana University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

DESIGNATION STATEMENT
Indiana University School of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

COMMITTEE AND AUTHOR DISCLOSURE
Statements of Disclosure of Relevant Financial Relationships have been obtained from Emma Rossi, MD. Dr. Rossi has disclosed that she has no relevant financial relationships with any commercial interests.

FACULTY DISCLOSURE STATEMENT
In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial Support, educational programs sponsored by Indiana University School of Medicine (IUSM) must demonstrate balance, independence, objectivity, and scientific rigor. All faculty, authors, editors, and planning committee members participating in an IUSM-sponsored activity are required to disclose any relevant financial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services that are discussed in an educational activity.

OBJECTIVES
After reading this article, the reader should be able to:

  • Identify the major risk factor for and the most common type of cervical cancer.
  • Describe the surgical management of early-stage cervical cancer.
  • Summarize the complications associated with bilateral retroperitoneal lymphadenectomy.
  • Compare and contrast traditional and fluorescence-guided sentinel lymph node mapping of gynecologic malignancies.
  • Discuss the potential implications of the FIRES clinical trial on the management of early-stage cervical cancer.

Date of original release: March 2014
Date of expiration: March 2015


Note: While it offers CME credits, this activity is not intended to provide extensive training or certification in the field.

Overview of Cervical Cancer

The widespread use of the Papanicolaou test for cervical cancer screening and human papillomavirus (HPV) vaccination have dramatically reduced the incidence and mortality of cervical cancer in developed countries. Despite these advances in care, cervical cancer remains the second most common malignancy in women worldwide, with an estimated 500,000 new cases annually, and it is the third leading cause of cancer deaths in the United States.1

One-half of all cervical cancer diagnoses are made in women aged 35 to 55 years,2 with squamous cell carcinoma accounting for 80 to 85 percent of all cases.3 The major risk factor for the development of cervical malignancy is HPV infection, in particular, infection with serotypes 16 and 18 (Table 1).2 The disease is often asymptomatic in its early stages. Postcoital bleeding in a young patient is a specific symptom of possible cervical cancer; intermenstrual bleeding and postmenopausal bleeding are common nonspecific symptoms of this gynecologic malignancy.

Case Study

A 46-year-old woman with a history of human papillomavirus infection presents to her gynecologist with the complaint of intermenstrual bleeding. A cone biopsy is performed and reveals a 2.5 cm cervical cancer lesion. She is diagnosed with stage IB1 squamous cell carcinoma of the cervix and referred to the Indiana University Health Simon Cancer Center for treatment. Positron-emission tomography/computed tomography (PET/CT) is ordered, and the scan shows no obvious metastatic disease. A radical hysterectomy is planned.

Managing Early-Stage Cervical Cancer

Initial staging for cervical cancer is achieved with integrated data from physical examination and PET/CT or magnetic resonance imaging. In North America, approximately 60 percent of cases are identified at stage I (Table 2).4

Radical Hysterectomy

“Radical hysterectomy, the en bloc excision of the uterus with the parametrium, upper one-third to one-half of the vagina, and bilateral pelvic lymph node (LN) dissection, is the gold standard for the treatment of early-stage (stage IA2-IB1) cervical cancer,"* says Emma Rossi, MD, former staff physician with IU Health Physicians Women's Health and former assistant professor of obstetrics and gynecology at Indiana University School of Medicine. “Surgery—which is performed as an open abdominal procedure, laparoscopically, or laparoscopically with robotic assistance— removes the primary disease and provides maximum tissue for histologic analysis and accurate assessment of the extent of disease, which aids in planning adjunctive therapy and determining prognosis."

*Radical trachelectomy, where the uterus is left in place, may be an option for selected younger patients who wish to preserve fertility.

Sentinel Lymph Node Mapping

Retroperitoneal lymphadenectomy is an essential component of the surgical management of cervical cancer, with LN status the primary prognosticator of earlystage disease. Women with positive LNs at the time of surgery—approximately 16 to 20 percent of those with early-stage cervical cancer—typically receive postoperative radiation and chemotherapy to improve progression-free and overall survival. Owing to the extensive nature of LN dissections, which involves removing approximately 10 cm of lymph node-containing tissue on either side of the pelvis (Figure 1), complications may occur and include lower extremity lymphedema, genitofemoral nerve injury, and lymphocyst formation.

When any cancer metastasizes, the sentinel lymph nodes (SLNs), the first nodes in the chain that drain the affected organ or structure, are the most likely to contain malignant cells, according to Dr. Rossi. SLN sampling for early-stage cervical cancer has the potential to preserve the diagnostic and therapeutic benefits of pelvic lymphadenectomy while limiting the extent of the dissection, thereby minimizing lymphatic disruption and reducing the risk for short-term and long-term postoperative complications. Traditional SLN mapping has been shown to reliably detect metastatic disease in patients undergoing surgery for melanoma, breast, and vulvar cancer. Yet the techniques are challenging to master, and the learning curve is substantial, according to Dr. Rossi.

“Traditional SLN mapping consists of the preoperative, peri-tumoral injection of a radioactive tracer, such as technetium (Tc99) or a blue dye (e.g., isosulfan, methylene blue)," she describes. “During surgery, the SLNs are identified using a Geiger counter or by visualizing the blue nodes and are excised.

“Medical dyes that fluoresce and are detected by specialized imagers are a promising alternative for SLN mapping and sampling," Dr. Rossi continues. “Preliminary results in gastric, breast, and rectal cancers5-7 indicate that fluorescence-guided SLN mapping has nodal metastases detection rates comparable to the 88 to 98 percent reported for traditional SLN mapping."

Robotically-Assisted Fluorescence- Guided Lymph Node Mapping

Many medical dyes fluoresce—that is, they emit light of longer wavelength after they absorb light. A few of these substances, such as indocyanine green (ICG), fluoresce in the non-infrared (NIR) portion of the light spectrum. When tissue containing ICG is illuminated with a low-power diode laser at a specific wavelength, it emits a signal that can be captured using a video camera sensitive to NIR light and equipped with appropriate optical filters.* Software associated with the camera converts the signal, allowing the surgeon to see fluorescent green on a background of black and white.

To determine the feasibility of roboticallyassisted, fluorescence-guided LN mapping for gynecologic malignancies, Dr. Rossi conducted a prospective study in 20 women with a preoperative diagnosis of clinical stage I cervical or endometrial cancer who were scheduled to undergo roboticallyassisted laparoscopic radical hysterectomy.8 Each patient received cervical stromal injections totaling 1 mg of ICG, after which the abdomen was insufflated, incisions made, ports placed, and the robot docked. Pelvic and para-aortic SLNs were then identified using a laparoscopic NIR imager (Figures 2 and 3). All patients underwent bilateral pelvic lymphadenectomy (para-aortic LNs were removed in those with endometrial cancer). Data were collected for the number of nodes identified, SLN location, and the pathology characteristics of the SLNs as compared with non-sentinel lymph nodes.

“At least one SLN was identified in 17 patients (85 percent), and 15 of these patients mapped a SLN (Figure 4), for an observed detection rate of 88 percent (95% CI: 64%, 99%)," Dr. Rossi reports. “A median of 4.5 SLNs was identified per patient (range: 0-9). Three patients had lymphatic metastases, one of whom had a positive SLN. No adverse events were observed."

*NIR imagers are available for open, laparoscopic, and robotic surgery.

Case Study (cont.)

The patient consents to undergo SLN mapping as part of an institutional review board-approved protocol. Robotically-assisted type III laparoscopic radical hysterectomy with bilateral pelvic LN dissection is performed using the da Vinci SI® robotic platform fitted with fluorescence imaging. Five incisions are made on the abdomen, each measuring eight to 10 mm, and ICG 1 mg is injected 1 cm into the cervix at the three and nine o'clock positions. Tissues overlying the iliac vessels are exposed to access the lymphatic tissue, and the tissue fluorescence imaging scope is activated, allowing the ICG to be seen as thin channels threading outwards from the cervix and entering the SLNs. The SLNs on the right and left sides of the pelvis are separated from the surrounding lymphatic tissue, removed, and sent for pathologic ultrasectioning,* and the surrounding non-SLN lymphatic tissue is removed. After lymphadenectomy is completed, a radical hysterectomy is performed.

Pathological examination shows no spread of cancer to the sentinel or non-sentinel lymph nodes, and no further treatment is recommended. The patient is discharged the day after surgery with a catheter in the bladder (to allow recovery from inflammation and swelling caused by manipulation of bladder nerves). Her postoperative recovery is uneventful, and after three years of follow-up, she has no evidence of recurrent disease.

*Fine sectioning of the lymph nodes with a duplicate assessment of negative lymph nodes with closer evaluation.

The FIRES Clinical Trial

With the feasibility study successfully completed, the next step for Dr. Rossi and her colleagues was to design a multicenter clinical trial to further assess the value of SLN mapping with ICG and robotic-assisted NIR imaging for gynecologic malignancies. The Fluorescence Imaging for Robotic Endometrial Cancer Sentinel Nodes (FIRES) clinical trial (NCT01673022), launched in August 2012, is currently underway at six US sites including IU School of Medicine and is open to women with stage I cervical or endometrial cancer scheduled for robotic radical hysterectomy.9

“All SLNs identified in the study patients are removed and sent for ultraprocessing by pathology," says Dr. Rossi. “Non-sentinel pelvic nodes (all patients) and para-aortic nodes (patients with endometrial cancer only) are removed and sent for routine pathologic processing according to standard of care for these surgical procedures. Pathologic results for the sentinel and non-sentinel LNs are evaluated for sensitivity and negative predictive value for their ability to detect metastatic disease."

Target accrual for the FIRES study is 270 patients, a number Dr. Rossi says will be sufficient to test the hypothesis that SLNs contain cancer cells at least 90 percent of the time when a cancer is found in non-sentinel nodes. If the study results validate this theory, she predicts the management of early-stage cervical and endometrial cancer will change, and SLN mapping and sampling will replace bilateral pelvic lymphadenectomy during radical hysterectomy. The impact on practice will translate to a less extensive surgery, a speedier recovery, and a reduced risk for postoperative complications.

“If FIRES continues to proceed on track, we hope to have the efficacy data by 2015 and to submit a manuscript for publication a few months thereafter," Dr. Rossi concludes.

Emma Rossi, MD

Former IU Health Physicians Women's Health
Former Assistant Professor of Obstetrics and Gynecology Indiana University School of Medicine
AdvancedPraxis@IUHealth.org

Dr. Rossi received her medical degree from the University of Queensland in Brisbane, Australia, completed a general surgery internship at the University of Chicago and a residency in obstetrics and gynecology at Northwestern University in Chicago, and did a fellowship in gynecologic oncology at the University of North Carolina in Chapel Hill. Her clinical research interests focus on novel surgical techniques for the treatment of endometrial and cervical cancers, in particular computer-assisted and image-guided surgery.

Dr. Rossi is a fellow of the American Congress of Obstetricians & Gynecologists and a diplomate of the American Board of Obstetricians & Gynecologists. The author of numerous peer-reviewed articles and textbook chapters, she has been an invited lecturer in the United States and abroad and serves as a reviewer for four specialty journals.

Dr. Rossi is the principal investigator for FIRES, the largest clinical trial evaluating the sensitivity and negative predictive value of sentinel notes for endometrial and cervical cancer conducted to date, and for two related IU Health research projects. In 2012, she was named one of the top doctors in obstetrics and gynecology by Indianapolis Monthly.

  1. National Cancer Institute. SEER cancer statistics review, 1975-2008. Available at: http://seer.cancer.gov/archive/csr/1975_2008/; accessed January 20, 2014.

  2. Waggoner SE. Cervical cancer. Lancet. 2003;361(9376):2217-2225.

  3. Chaturvedi AK, Kleinerman RA, Hildesheim A, et al. Second cancers after squamous cell carcinoma and adenocarcinoma of the cervix. J Clin Oncol. 2009;27(6):967-973.

  4. Kanthan R, Senger JL, Diudea D, Kanthan S. A review of duodenal metastases from squamous cell carcinoma of the cervix presenting as an upper gastrointestinal bleed. World J Surg Oncol. 2011;9:113.

  5. Dunn LJ, Robertson AG, Shenfine J, Griffin SM. Indocyanine green fluorescence imaging of sentinel nodes in gastric cancer. Ann Surg. 2009;250(4):653; author reply 653-654.

  6. Hutteman M, Mieog JS, van der Vorst JR, et al. Randomized, double-blind comparison of indocyanine green with or without albumin premixing for near-infrared fluorescence imaging of sentinel lymph nodes in breast cancer patients. Breast Cancer Res Treat. 2011;127(1):163-170.

  7. Noura S, Ohue M, Seki Y, et al. Feasibility of a lateral region sentinel node biopsy of lower rectal cancer guided by indocyanine green using a near-infrared camera system. Ann Surg Oncol. 2010;17(1):144-151.

  8. Rossi EC, Ivanova A, Boggess JF. Robotically assisted fluorescence-guided lymph node mapping with ICG for gynecologic malignancies: a feasibility study. Gynecol Oncol. 2012;124(1):78-82.

  9. ClinicalTrials.gov. Determining the sensitivity of sentinel lymph nodes identified with robotic fluorescence imaging (FIRES). Available at: http://clinicaltrials.gov/ct2/show/NCT01673022?term=FIRES&rank=1; accessed January 17, 2014.

  10. Pecorelli S, Zigliani L, Odicino F. Revised FIGO staging for carcinoma of the cervix. Int J Gynaecol Obstet. 2009;105(2):107-108.