Obstetrics & Gynecology:
Fertility-Conserving Surgery for Young Women With Stage IA1 Cervical Cancer: Safety and Access
Wright, Jason D. MD; Nathavithrana, Ruvandhi MD; Lewin, Sharyn N. MD; Sun, Xuming; Deutsch, Israel MD; Burke, William M. MD; Herzog, Thomas J. MD
From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, and Department of Radiation Oncology, Columbia University College of Physicians and Surgeons, New York, New York; and Herbert Irving Comprehensive Cancer Center, New York, New York.
Corresponding author: Jason D. Wright, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 161 Fort Washington Avenue, 8th Floor, New York, NY 10032; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To estimate the safety of fertility-conserving surgery for stage IA1 cervical cancer and to analyze predictors of access to conization.
METHODS: We analyzed women with stage IA1 cervical cancer aged 40 years or younger who were diagnosed between 1988 and 2005 and recorded in the Surveillance, Epidemiology, and End Results database. The outcomes of hysterectomy were compared with fertility-conserving conization. Clinical and demographic characteristics were compared using χ2. Multivariable logistic regression models were constructed to examine predictors of conization. Survival was examined using multivariable Cox proportional hazards models and the Kaplan-Meier method.
RESULTS: A total of 1,409 patients were identified, including 841 (60%) who underwent hysterectomy and 568 (40%) who underwent conization. In a multivariable logistic regression of factors associated with conization, Asian patients, single women, those diagnosed in the later years of the study, and those residing in the eastern United States were more likely to have fertility-conserving surgery. Compared with women younger than 30 years, those older than 35 years were 78% (odds ratio 0.22, 95% confidence interval [CI] 0.16-0.30) less likely to undergo conization. In a Cox proportional hazards model accounting for other prognostic variables, there was no difference in survival (hazard ratio 0.65, 95% CI 0.23-1.47) between conization and hysterectomy. Five-year survival for women who underwent conization was 98% (95% CI 96-99%), compared with 99% (95% CI 97-99%) for those treated with hysterectomy.
CONCLUSION: Fertility-conserving surgery is safe for young women with stage IA1 squamous cell carcinoma of the cervix. Young women with microinvasive cervical tumors should weigh the risks and benefits of conization in the context of individual preferences and tumor characteristics.
LEVEL OF EVIDENCE: II
Despite being a largely preventable disease, 11,270 new cases of cervical cancer will be diagnosed in the United States in 2009 and an estimated 4,070 women will die from the disease.1 Although women with early-stage disease have an excellent prognosis, defining the earliest stages of invasive cancer, microinvasive disease, has proved controversial. In 1994 the Federation Internationale Gynecologica Obstetrica (International Federation of Gynecology and Obstetrics, FIGO) defined stage IA1 cervical cancer as a tumor that invades to a depth of 3 mm or less with a horizontal extension of less than 7 mm. Stage IA2 disease was defined as a tumor that invades to a depth of 3 to 5 mm with less than 7 mm of horizontal spread. Stage IA1 tumors account for 60% to 70% of the cases of microinvasive cervical cancer.2
The diagnosis of cervical cancer in young women represents a difficult management dilemma. Traditional surgical therapy for cervical cancer includes hysterectomy with loss of childbearing potential, whereas radiation therapy often leads to ovarian ablation and the sequelae of premature menopause. Stage IA2 cervical cancer is traditionally managed with a radical or modified radical hysterectomy, whereas stage IA1 cervical cancer is typically treated surgically by a simple hysterectomy. Given the excellent prognosis of patients with stage IA1 cervical cancer, fertility-conserving therapy with conization has been proposed as an alternative to hysterectomy for young women.2–10
Although small institutional series and case control studies have suggested that conization is safe, large studies comparing conization and hysterectomy for stage IA1 cervical cancer are largely lacking. The objective of our study was to examine the safety of fertility-conserving conization in a large cohort of young women with stage IA1 squamous cell carcinoma of the cervix. In addition, we sought to analyze the patterns of care for patients with stage IA1 cervical cancer and determine predictors of access to fertility-conserving surgery.
MATERIALS AND METHODS
Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Surveillance, Epidemiology, and End Results is a population-based cancer registry that includes approximately 26% of the U.S. population. It is composed of several geographically distinct tumor registries. The demographic characteristics of the SEER registries have previously been characterized and are representative of the general population within the United States. Data from SEER 17 registries were used.11,12 Exemption from the Columbia University institutional review board review was obtained.
Women aged 40 years or younger with stage IA1 squamous cell cervical carcinoma diagnosed between 1988 and 2005 were included in our analysis. Clinical and pathologic data including age at diagnosis (younger than 30, 30-35, or older than 35 years), race (white, African American, Asian, or other), marital status, and tumor grade were collected. Year of diagnosis was stratified as 1988 to 1993, 1994 to 1999, or 2000 to 2005. Patients were categorized based on the geographic area of residence within the United States at the time of diagnosis: central (Detroit, Iowa, Kentucky, Louisiana, Utah), eastern (Connecticut, NJ, Atlanta, rural Georgia), or western (Alaska, California, Hawaii, Los Angeles, New Mexico, San Francisco, San Jose, Seattle).
The vital status of each patient was recorded. Survival was calculated as the number of months from cancer diagnosis to date of death. Patients who were alive at last follow-up were censored. Both overall and cancer-specific survivals were calculated.
Frequency distributions between categorical variables and clinical and demographic characteristics were compared using the χ2 test. Logistic regression models were developed to describe predictors of receipt of fertility-conserving surgery. Multivariable logistic regression models were constructed to examine predictors of conization. In the logistic regression analysis, we modeled all the categories of each variable, controlling for all other variables in the model. Cox proportional hazards models were developed to examine survival. In Cox proportional hazards analysis, we modeled the overall mortality hazard ratios comparing patients who underwent fertility-sparing surgery with those who had a hysterectomy, controlling for the other predictor variables. Kaplan-Meier curves were generated to examine overall and cancer-specific survival and compared using the log-rank test. All hypothesis tests were two-sided. Statistical analysis was conducted with SAS 9.2 (SAS Institute Inc., Cary, NC).
A total of 1,409 women aged 40 years or younger with stage IA1 squamous cell carcinoma of the cervix were identified. The cohort included 841 women (60%) who underwent hysterectomy and 568 (40%) who underwent fertility-conserving conization. The demographic characteristics of the study population are displayed in Table 1. Fifty-nine percent of women younger than 30 years had a conization, compared with 25% of those older than 35 years (P<.001). Hysterectomy was performed in 61% of white women, 55% of African-American women, and 53% percent of Asian women (P=.09). Of those who were single, 44% underwent conization, compared with 34% of married patients (P<.001).
A logistic regression model of factors associated with fertility-conserving surgery is shown in Table 2. Asian women, single women, those diagnosed in the later years of the study, and those residing in the eastern United States were more likely to have fertility-sparing surgery. Asian women were 94% (odds ratio [OR] 1.94, 95% confidence interval [CI] 1.15-3.26) more likely to have fertility-sparing surgery than white women. Compared with women younger than 30 years, those older than 35 years were 78% (OR 0.22, 95% CI 0.16-0.30) less likely to undergo conization. Women residing in the eastern United States were 41% (OR 1.41, 95% CI 1.03-1.93) more likely to have a conization than those in the western United States.
Survival was then examined in a Cox proportional hazards model (Table 3). Accounting for other prognostic variables, there was no difference in survival (hazard ratio 0.65, 95% CI 0.23-1.47) between conization and hysterectomy for young women with stage IA1 cervical cancer. Similar findings were noted in a Kaplan-Meier analysis; there was no difference in either cancer-specific (P=.98) or overall (P=.54) survival between hysterectomy and conization (Figs. 1 and 2). Five-year survival is displayed in Table 4. At 5 years, 98% (95% CI 96-99%) of patients who underwent hysterectomy and 99% (95% CI 97-99%) of those who underwent conization were alive.
Our findings suggest that fertility-conserving surgery is safe for young women with stage IA1, microinvasive squamous cell carcinomas of the cervix. In our cohort, there was no difference in survival for women with stage IA1 tumors whether treatment consisted of hysterectomy or conization. Overall, 40% of women aged 40 years or younger were treated with uterine-sparing conization.
The outcomes for stage IA1 cervical cancer are favorable.2–10 Although much of the prior literature has included both stage IA1 and IA2 patients, those with stromal invasion of less than 3 mm seem to have a risk of recurrence of less than 2% and a risk of death of only 0.1%.3,4,6,7 Burghardt et al4 analyzed a cohort of 344 patients with stage IA1 cervical cancer and noted only one (0.3%) recurrence that was diagnosed 12 years after treatment with conization. A recent review of the literature suggested that lymphvascular space invasion is an important risk factor for nodal metastases and death for women with IA1 tumors. Nodal disease was noted in 8% of patients with lymphvascular space invasion, compared with only 0.8% without lymphvascular space invasion. Likewise, the risk of recurrence was increased fivefold among IA1 patients with lymphvascular space invasion.2,13 In our cohort, 5-year survival was 98%. Although data on recurrence are not captured by SEER, we identified only five cancer-related deaths in our study population.
Given the favorable prognosis of stage IA1 cervical cancer, conservative, uterine-sparing treatment has often been advocated, particularly for young women.2,7,8,14,15 In a cohort of 494 patients with microinvasive cervical cancer treated by conization, Winter14 noted two cancer-related deaths in patients with stage IA1 disease after a mean follow-up of 14 years. The author concluded that conization was safe for patients with stage IA1 tumors without lymphvascular space invasion.14 Despite the apparent favorable outcomes of conization for stage IA1 cervical cancer, there are no prospective data comparing long-term outcomes of conization and extrafascial hysterectomy. In an analysis of 87 patients who underwent conization, a significant percentage of patients had residual invasive disease at the time of reassessment conization or hysterectomy. Predictors of residual tumor included a positive internal margin or positive postconization endocervical curettage.16 Based on the available literature and our findings, it seems that conization is safe in patients with stage IA1 cervical without lymphvascular space invasion and with negative postconization margins.
Age and race are strong determinants of care for women with cervical cancer.17–19 A prior analysis of SEER data including stage IA1 and IA2 patients found that age and race affected treatment choice. Hysterectomy was performed in 75% of patients aged 35 years or older with stage IA1 tumors, compared with 57% of women younger than 35 years. The investigators also noted that 64% of African-American women with IA1 neoplasms received fertility-conserving surgery, compared with 41% of white women. In our multivariable model, younger women were more likely to undergo conization. Likewise, Asian women were more likely to have uterine-preserving treatment, but there was no difference between African-American and white women.15 We noted that women treated more recently were more likely to have fertility-preserving treatment. Compared with patients treated from 1988 to 1994, women undergoing surgery between 2000 and 2005 were 42% more likely to undergo conization. Finally, we noted significant regional variation in the performance of fertility-conserving surgery. Women residing in the eastern United States were more likely to undergo conization than patients living in the midwest or western United States. Our group has identified similar trends in regional variation of conservative surgery for women with other gynecologic tumors.20,21
Although our study benefits from the inclusion of a large number of patients and represents one of the largest comparisons of hysterectomy and conization for stage IA1 cervical cancer, several limitations must be acknowledged. As with any study of administrative data, central pathology review was not performed. Although patients were selected based on 1994 FIGO criteria of invasion of less than 3 mm, variability in tumor measurements certainly may have occurred based on the experience of individual pathologists and institutions. Important pathologic data, including lymphvascular space invasion, margin status, and data on tumor recurrences, are not captured in SEER. Although we classified patients based on their major cancer-directed surgery, we cannot exclude the possibility that a small number of women who underwent conization followed by a hysterectomy were coded into the conization group. Finally, although we attempted to account for known patient and tumor related characteristics that may have influenced treatment, it is impossible to determine individual patient and physician preferences that impacted treatment planning.
In conclusion, our study suggests that fertility-conserving surgery is safe for young women with stage IA1 squamous cell carcinoma of the cervix. Young women with microinvasive cervical tumors should weigh the risks and benefits of conization in the context of individual preferences and tumor characteristics.
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