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From OncoLog, July 2012, Vol. 57, No. 7

Graphic: Compass: Quarterly discussion of cancer types for which there is no standard treatment or more than one standard treatment

Early-Stage Cervical Cancer

By Sunni Hosemann

Introduction

This discussion addresses early-stage squamous cell carcinomas and adenocarcinomas of the uterine cervix. Although other histologic types of cervical cancer, including clear cell and glassy cell carcinomas, neuroendocrine carcinomas, and other cancers such as sarcomas, melanomas, or lymphomas may arise in the cervix, these are rare and may require different treatment approaches and considerations; thus, they are not included in this discussion.

Several treatment options have proven to yield equivalent oncologic outcomes in patients whose cervical cancers are discovered in the early stages. However, the effects of the treatments themselves are not equivalent among individual patients, and considerable analysis and discussion are needed to help patients determine their best option for care.

Traditionally, treatment options for early-stage cervical cancers have included surgery and radiation therapy. For both modalities, advances in technology and techniques have given rise to less aggressive treatment options aimed at reducing treatment morbidity and long-term complications while achieving oncologic outcomes that are equivalent to those achieved with more aggressive procedures.

Graphic: Early-stage cervical cancer treatment flowchart

Primary treatment options

Surgery

All treatment options for patients who have stage IA1 cervical cancers are surgical. The decision to use a specific procedure depends on several key factors. The standard treatment is an extrafascial (simple) hysterectomy, in which only the cervix and uterus are removed. If a cone biopsy has been performed and had negative margins, observation is also an acceptable option, particularly if the patient desires to preserve her fertility or is a poor surgical candidate because of medical comorbidities. For certain patients with stage IA1 cancer and high-risk prognostic factors, radical hysterectomy or trachelectomy may be performed as described below.

Radical hysterectomy, in which the uterus, cervix, parametrium, vaginal cuff, and pelvic lymph nodes are removed, is the standard treatment for patients with stage IA2 or IB1 cancer. In patients who desire fertility preservation, a radical trachelectomy, in which the cervix, parametrium, vaginal cuff, and pelvic lymph nodes are removed but the fundus of the uterus is retained, can be performed. A radical trachelectomy is a more complex operation than a radical hysterectomy, and the increased risk is justified only in women who want to preserve their ability to bear children. Because of its complexity, a radical trachelectomy is a surgery best performed by a gynecologic oncologist who sees a high volume of cases.

Candidates for radical trachelectomy are patients who have tumors less than 2 cm in diameter, no high-risk tumor histologies, and no evidence of lymph node or distant metastases, according to Kathleen Schmeler, M.D., an assistant professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center. “The oncologic outcomes of radical trachelectomy are similar to those of radical hysterectomy,” Dr. Schmeler said, “and about 80% of women who have undergone a radical trachelectomy and later attempt pregnancy are successful.” However, compared with pregnancies in the general population, post-trachelectomy pregnancies carry higher risks of miscarriage (particularly during the second trimester) and preterm labor.

Radical hysterectomy and radical trachelectomy can be done as open procedures, laparoscopically, or robotically. According to Michael Frumovitz, M.D., an associate professor in the Department of Gynecologic Oncology and Reproductive Medicine, open surgery for cervical cancer is rare at MD Anderson. He said that for radical hysterectomy, the robotic and laparoscopic approaches are equivalent, and the procedure is usually determined by the surgeon’s preference. For radical trachelectomy, robotic surgery is the only minimally invasive approach performed at MD Anderson.

Most surgeries for cervical cancer are accomplished using minimally invasive means. The exceptions are patients whose uterus is too large to remove intact or whose respiratory reserve would be compromised by the abdominal insufflation necessary for laparoscopic or robotic access. Dr. Frumovitz noted that patients with medical conditions that increase the risk of intraoperative and postoperative complications, such as obesity or diabetes, are the patients most likely to benefit from a minimally invasive procedure. Such patients are also more likely to benefit from the supportive care available at a large center.

Radiation therapy

Although standard treatment guidelines still list radiation therapy as a primary treatment option with oncologic outcomes equivalent to surgery, at MD Anderson, primary radiation therapy is now rarely considered the best choice for patients with early-stage cervical cancer. Anuja Jhingran, M.D., a professor in the Department of Radiation Oncology, said, “There was a time when radiation was the preferred treatment for many older or obese patients with early cervical cancers because it caused less morbidity than surgery. But new surgical techniques have changed the equation.” With the advent of minimally invasive surgeries, which are associated with shorter recovery times than open hysterectomies, an increasing number of patients with cervical cancer undergo surgery. “This is true even for patients with comorbidities—diabetic patients, for example, in whom the preferred treatment was radiation because of the problems they had with postoperative wound healing, are now undergoing surgery,” Dr. Jhingran said.

In addition, Dr. Jhingran noted that ovarian function is lost when the pelvis is irradiated, eliminating the possibility of preserving fertility and hormone production. Long-term effects of hormonal deprivation, such as osteoporosis and pelvic fractures, are especially important because many of the patients who are treated for cervical cancer are young.

Other long-term health considerations factor into treatment decisions. “Losses of bladder and bowel function are concerns in patients who receive radiation therapy and those who undergo surgery for this disease,” Dr. Jhingran said. “It used to be that these complications were less common with radiation, but with newer surgeries, this too has shifted in favor of surgery.”

Radiation therapy remains the treatment of choice in patients with locally advanced cervical cancer (stages IB2–IVA) and those with stage IA2 or IB1 disease who have medical conditions that put them at high risk of surgical complications.

Definitive radiation therapy for cervical cancer includes whole-pelvis external-beam radiation and brachytherapy, which is performed by implanting radioactive pellets into the uterus and/or vagina and is customized according to the size and location of the tumor. “Both treatments are required to give the patient a sufficient radiation dose as a primary treatment,” said Dr. Jhingran. Sensitizing chemotherapy with cisplatin typically is given on a weekly basis during radiation therapy.

Adjuvant treatment

Cervical cancers are initially staged clinically rather than surgically; therefore, surgical findings can indicate the need for additional treatment. Patients should receive adjuvant radiation therapy—and possibly concurrent chemotherapy—if they are found to have disease-positive lymph nodes, positive surgical margins, or parametrial involvement. Patients are also considered for adjuvant treatment if they have a combination of high-risk pathologic features, including poorly differentiated tumors, large tumor size, deep stromal invasion, or lymphovascular space invasion.

Dr. Jhingran said that many factors that would indicate a need for adjuvant radiation therapy often are known in advance of initiating treatment. “For the most part, thanks to advances in imaging, we are able to determine ahead of time whether radiation therapy will be needed,” she said, “If so, it should be given as a definitive treatment instead, so the patient would not have to undergo surgery as well, which may increase long-term complications such as bowel obstruction and lymphedema.”

Incidental diagnosis

Cervical cancer is most often initially detected by a Papanicolaou test, with follow-up colposcopy and biopsies, and occasionally by investigation of symptoms. However, occasionally cervical cancer is discovered incidentally by pathologic analysis after a simple hysterectomy has been performed for unrelated reasons. When that is the case, criteria similar to those described above for adjuvant treatment based on surgical findings—pathologic status of surgical margins and the presence of risk factors—are used to guide further treatment.

Future directions

For many cancers, research aims to find more effective ways of eradicating disease and bringing about cures. For cervical cancer, particularly early-stage cervical cancer, there are already well-established, effective treatments. The emphasis of many current trials is to achieve the best oncologic outcomes with the least invasive treatments. At MD Anderson, such study initiatives consider not only the rigors of treatment a patient must undergo for her cancer but also her future health and quality of life. To that end, most clinical trials in gynecologic oncology have a companion study to evaluate and monitor quality-of-life issues.

Quality of life

According to Dr. Schmeler, all cervical cancer patients enrolled in robotic surgery trials, which assess oncologic and surgical outcomes, are concurrently enrolled in a study by Pamela Soliman, M.D., an assistant professor in the Department of Gynecologic Oncology and Reproductive Medicine, to monitor quality-of-life outcomes. Similarly, patients in prospective trials of radical trachelectomy will be monitored for quality-of-life issues, along with oncologic and fertility results. “We do these procedures to retain fertility, so it is reasonable to try to establish whether women actually do go on to attempt pregnancies, and if so, whether they are successful,” said Dr. Frumovitz. These trials could help establish the value of radical trachelectomy and identify which patients are the most likely to benefit from the procedure.

About Cervical Cancer

According to the World Health Organization, the cervix is the second most common cancer site in women worldwide. Each year, more than 500,000 new cases of cervical cancer are diagnosed, and approximately 250,000 deaths are attributed to cervical cancer. About 80% of cervical cancers occur in low-income countries.

In the United States, where cervical cancer was once one of the deadliest cancers, death rates have declined by 70% since the advent of screening by the Papanicolaou test in 1955 and the test’s subsequent widespread use. Women who are not screened regularly are at higher risk of developing and dying of invasive cervical cancer than are those who undergo regular screening.

Virtually all cases of cervical cancer are linked to genital infection with the human papillomavirus (HPV). According to Michael Frumovitz, M.D., an associate professor in the Department of Gynecologic Oncology and Reproductive Medicine, this is of particular note as women become sexually active at early ages. “We believe it takes about 10 years for HPV-related cancers to develop,” he said, “and we are seeing young women—in their 20s and 30s—who have invasive cervical cancers.” The U.S. Preventive Services Task Force recommends that Papanicolaou screening begin at 21 years of age.

Approximately 80% of cervical cancers are squamous cell carcinomas, and the majority of the remainder are adenocarcinomas. Treatment recommendations are currently the same for both types. Recently, despite the decline in the overall incidence of invasive cervical cancer and squamous cell carcinomas, the incidence of adenocarcinoma appears to be increasing, particularly in younger women. One possible reason for this is improved detection techniques. Adenocarcinomas tend to occur higher up in the cervix or in the uterus itself, beyond the transformation zone where squamous cancers arise, and thus are more difficult to sample; newer collection methods for Papanicolaou screening may be better able to detect adenocarcinomas at their earlier stages.

Drs. Schmeler and Jhingran are also conducting a study of long-term sequelae of definitive radiation therapy for cervical cancer. Of particular interest are bone density changes and pelvic fractures.

Is even less aggressive surgery possible?

Although considerable advances have been made in minimally invasive surgery, investigators have begun to explore whether even less aggressive surgical approaches could be used in patients with early-stage cervical cancers. Removal of the parametrium, which is part of both radical hysterectomy and radical trachelectomy, is the cause of many of the undesirable sequelae of these procedures, such as bladder, bowel, and sexual problems. The parametrium contains autonomic nerve fibers that are vital to these functions.

“There may be patients in whom removal of the parametrium is not necessary,” Dr. Schmeler said, citing a recent study conducted by Dr. Frumovitz. The study found no parametrial involvement in pathologic specimens from patients who had favorable pathologic characteristics, specifically patients with negative lymph nodes, no lymphovascular space invasion, and tumors 2 cm or smaller in diameter. “Based on those observations, it’s reasonable to investigate whether conization or a simple hysterectomy with lymph node dissection would be adequate treatment for this group of patients,” Dr. Schmeler said. A prospective multicenter trial is currently under way to find out. For patients whose tumors are larger or have less favorable pathologic characteristics and require a radical hysterectomy, Pedro Ramirez, M.D., a professor and the director of Minimally Invasive Surgical Research and Education in the Department of Gynecologic Oncology and Reproductive Medicine, is conducting a prospective study comparing the surgical, oncologic, and quality-of-life outcomes of minimally invasive and open surgery.

Is clinical staging enough?

A recent MD Anderson study compared surgical findings with pretreatment positron emission tomography findings and found that 24% of patients with locally advanced cervical cancers had disease in the para-aortic lymph nodes that was not detected by preoperative imaging. “This indicates that positron emission tomography analysis may not be enough—it may be leading us to understage and thus undertreat some cervical cancers,” said Dr. Frumovitz. A new trial will use a laparoscopic extraperitoneal approach to examine the para-aortic nodes in patients in whom such involvement is suspected.

Is concurrent chemotherapy enough?

The standard treatment for patients with positive lymph nodes after a hysterectomy is concurrent chemotherapy with pelvic or extended-field radiation therapy. However, the incidence of distant metastasis among patients with more than one positive node is 15%–20%. To address this issue, an international trial is evaluating the addition of four cycles of chemotherapy after the completion of radiation therapy in this group of patients.

Contributing Faculty
The University of Texas MD Anderson Cancer Center

Photo: Dr. Michael Frumovitz

Michael Frumovitz, M.D., M.P.H.
Associate Professor, Gynecologic Oncology and Reproductive Medicine

Photo: Dr. Anuja Jhingran

Anuja Jhingran, M.D.
Professor, Radiation Oncology

Photo: Dr. Kathleen M. Schmeler Kathleen M. Schmeler, M.D.
Assistant Professor, Gynecologic Oncology and Reproductive Medicine

References
American Cancer Society. Cervical Cancer.
Frumovitz M, Sun CC, Schmeler KM, et al. Parametrial involvement in radical hysterectomy specimens for women with early-stage cervical cancer. Obstet Gynecol 2009;114:93–99.
National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology, Cervical Cancer, V1.2012 [subscription only].
Schmeler KM, Frumovitz M, Ramirez PT. Conservative management of early stage cervical cancer: is there a role for less radical surgery? Gynecol Oncol 2011; 120:321–325.
World Health Organization. Sexual and Reproductive Health, Cancer of the Cervix.

For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.

Other articles in OncoLog, July 2012 issue:

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