From OncoLog, July 2012, Vol. 57, No. 7
Compass: 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.
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 |
Michael Frumovitz, M.D., M.P.H. |
Anuja Jhingran, M.D. |
| 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.
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.
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