Obstetrics & Gynecology:
Prognostic Factors for Uterine Cancer in Reproductive-Aged Women
Lee, Nita Karnik MD1; Cheung, Michael K.1; Shin, Jacob Y.1; Husain, Amreen MD1; Teng, Nelson N. MD, PhD1; Berek, Jonathan S. MD, MMS1; Kapp, Daniel S. MD, PhD2; Osann, Kathryn PhD3; Chan, John K. MD1
From the 1 Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, Comprehensive Cancer Center, University of California, San Francisco School of Medicine, San Francisco, California; Division of Gynecologic Oncology, 2 Department of Radiation Oncology, Department of Obstetrics and Gynecology, Stanford Cancer Center, Stanford University School of Medicine, Stanford, California; and the 3 Division of Hematology/Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine – Medical Center, Orange, California.
Corresponding author: John K. Chan, MD, University of California, San Francisco School of Medicine, University of California, San Francisco Comprehensive Cancer Center, 1600 Divisadero Street, Box 1702, San Francisco, CA 94143; e-mail: firstname.lastname@example.org.
OBJECTIVE: To determine the prognostic factors that influence the survival of younger women diagnosed with uterine cancer.
METHODS: Demographic and clinico-pathologic data were collected from the National Cancer Institute database between 1988 and 2001. Data were analyzed with Kaplan-Meier methods and Cox proportional hazards regression.
RESULTS: Of the 51,471 women diagnosed with uterine cancer in the study period, 2,076 (4.0%) patients were aged 40 years or younger, and 49,395 (96.0%) were older than 40. The mean age in the younger group was 35.6 years, compared with 65.2 years of the older group. The overall distribution by stage was stage I 75.4%, II 8.1%, III 6.7%, and IV 9.8%. Younger patients were more likely to be nonwhite (42.4% versus 18.3%, P<.001) and have stage I disease (79.2% versus 75.3%, P<.001), grade 1 lesions (47.6% versus 35.6%, P<.001), and sarcomas (15.9% versus 8.2%, P<.001) compared with their older counterparts. The overall 5-year disease-specific survival for younger patients was significantly better than that of older women (93.2% versus 86.4%, P<.001). On multivariable analysis, younger age, earlier stage, lower grade, nonblack race, endometrioid histology, and surgical treatment remained as significant independent prognostic factors for improved survival.
CONCLUSION: This large population-based study demonstrates that patients 40 years and younger have an overall survival advantage compared with women older than 40 years, independent of other clinico-pathologic prognosticators.
LEVEL OF EVIDENCE: III
Although uterine cancer is primarily considered a disease of postmenopausal women, up to 15% of women are premenopausal and under 40 years of age at the time of diagnosis. Prior studies have focused on this younger subset of reproductive-age women and analyzed the demographics, clinico-pathologic prognostic factors, and outcomes based on these prognostic factors. These studies found that younger women, defined as 40 years of age or less, have an improved survival compared with their older counterparts. The improved survival of the younger women may be attributed to the earlier stage and lower grade of disease at presentation.1–6
In contrast, other studies have demonstrated that younger patients have more adverse pathologic and prognostic factors. Gitsch et al7 demonstrated that a proportion of younger patients have advanced disease as well as a higher rate of lymph node metastasis and synchronous ovarian primaries. Evans-Metcalf et al8 found that, although younger women had lower-grade disease, there was no overall difference between their age cohorts in terms of stage, high-risk histologies, or survival. Similarly, Tran et al9 found no difference in stage, grade, histology, or survival between women aged less than 45 and those 45 years of age or older.
After adjusting for these pathologic prognostic features, some studies5,10–13 showed that the significance of age was lost, whereas others claim that it persisted.1,14–20 Thus, it is unclear whether uterine cancer in younger women is intrinsically less aggressive than the disease in an older cohort. Many of these studies were limited by small sample sizes from single academic institutions, clinically staged patients, inconsistent International Federation of Gynecology and Obstetrics (FIGO) staging data, varying histological criteria, and poor reporting of pathologic factors such as myometrial invasion, extrauterine disease, and adjuvant treatment.
Given the limitations of prior reports, a large population-based study was performed to compare the demographics, clinico-pathologic characteristics, and surgical and radiation treatment patterns between young and older patients with uterine cancer. The outcome differences between these two age groups were analyzed to identify potential prognostic factors responsible for the disparities in survival.
MATERIALS AND METHODS
Demographic, clinico-pathological, surgical and radiation treatment, and survival information on over 51,000 women diagnosed with primary uterine cancer during the period from 1988 to 2001 were extracted from the Surveillance, Epidemiology and End Results (SEER) database of the United States National Cancer Institute. Data are reported from 12 population-based registries that represent 14% of the U.S. population, including San Francisco-Oakland, Connecticut, metropolitan Detroit, Hawaii, Iowa, New Mexico, Seattle (Puget Sound), Utah, metropolitan Atlanta, Alaska, San Jose-Monterey, and Los Angeles. This study received exempt status from the Institutional Review Board of Stanford University.
Patients were divided into two age cohorts, a group representing younger women between 16 and 40 years of age and a subset of older women over 40 years of age. We chose the age distributions to focus analysis on reproductive-age women and compare their disease characteristics and survival outcome to that of older women.
Demographic, clinical, histologic, and treatment characteristics were compared by using the χ2 test. Unadjusted Kaplan-Meier models with log-rank tests were used to estimate 5-year disease-specific survivals. Surgical intervention was defined as whether or not primary surgery was administered to the patient. The primary outcome of disease-specific survival was calculated, and time to death was censored in women who died of causes other than uterine cancer. The Cox proportional hazards model was used to identify independent predictors of survival in multivariable analysis. Statistical analysis was performed with Stata 8.0 (Stata Corporation, College Station, TX). All P values reported are two-tailed, and P<.05 was considered to be statistically significant. All factors that were significant in univariate analyses were tested in the multivariable analysis model.
A total of 51,471 women diagnosed with corpus cancer were identified. Of these, 2,076 (4.0%) were between 16 and 40 years of age, while 49,395 (96.0%) were over 40 years of age. The mean age of the younger (40 years or less) group was 35.6 years, compared with 65.2 years for the older cohort. The younger patients were more likely to be nonwhite; 42.4% were classified as either Hispanic, black, Asian, or other, compared with only 18.3% in the over-40 age group (P<.001) (Table 1).
In the overall study group of 51,471 patients, 75.4% had stage I, 8.1% had stage II, 6.7% had stage III, and 9.8% had stage IV cancers. Younger women were less likely to undergo hysterectomy and lymphadenectomy than their older counterparts (91.4% versus 92.9%, P=.011 for primary surgery; 32.5% versus 34.6%, P=.056 for lymphadenectomy). The median numbers of nodes resected from the younger compared with the older patients were 11 and 10, respectively. Adjuvant radiotherapy was employed for 18.1% of the younger patients in contrast to 28.6% of the older women (P<.001). Younger women were more likely to have stage I disease (79.2% versus 75.3%, P<.001) and grade 1 tumors (47.6% versus 35.6%, P<.001) than older patients. Although the majority of both groups had adenocarcinoma histology, younger patients were more likely to have sarcomas than older women; 15.9% of younger patients were diagnosed with uterine sarcoma compared with only 8.2% of patients over 40 years (P<.001). Furthermore, younger patients were less likely to have uterine papillary serous cancers than their older counterparts (1.9% versus 6.8%, P<.001; Table 1).
The overall 5-year disease-specific survival for the younger patients was significantly higher compared with older women (93.2% versus 86.4%, P<.001; Fig. 1). When stratified by stage, this difference remained statistically significant, with younger patients showing an improved survival in those with early (stage I–II) (97.1% versus 93.1%, P<.001) and advanced (stage III–IV) disease (63.8% versus 46.8%, P<.001; Fig. 2).
Across all races, reproductive-age patients had similar survival rates of 93.3%, 91.4%, and 93.4% in whites, blacks, and Asians, respectively (P<.001). On the other hand, black women over the age of 40 had the worst survival rate of only 68.6%, compared with survival rates of 87.3% and 86.9% in white and Asian women, respectively (P<.001). Analysis of histology demonstrated that younger patients with adenocarcinoma, uterine papillary serous cancer, and sarcoma also showed significantly improved survival compared with older counterparts with the same histology (Table 2). A subset analysis was also performed in the patients with stage I–II compared with those with stage III–IV uterine papillary serous cancer and sarcoma, which showed that younger patients with early-stage uterine papillary serous cancer had a statistically significant improved survival compared with the older cohorts (96.7% versus 80.7%, P=.012). For advanced-stage uterine papillary serous cancer, there was a trend toward improved survival compared with the older cohorts, although this result was not statistically significant given the small numbers (62.5% versus 32.4%, P=.118). Younger patients with early-stage sarcoma had a statistically significant improved survival compared with the older cohorts (85.4% versus 74.3%, P<.001). These findings were similar in those with advanced-stage sarcoma (61.1% versus 37.0%, P=.002).
To determine whether young age is an independent prognostic factor for improved survival or whether the survival advantage is due to more aggressive surgery or adjuvant therapy in this younger cohort, a comparison was made of the outcomes of these two groups of patients, controlling for surgery or radiation therapy and adjusting for stage of disease. There were no statistical differences between the two patient groups with respect to surgical intervention. However, younger women did undergo a more extensive lymphadenectomy than the older women. The younger cohort had a statistically significant greater median number of lymph nodes removed than the older group (11 versus 10, P<.001). Furthermore, younger patients were more likely to undergo surgical intervention alone and less likely to receive radiation. Among patients 40 years of age or less, 18.1% of patients received radiation therapy, whereas 28.6% of patients over 40 years of age received radiation (P<.001). Of the women with stage I–II disease who underwent adjuvant radiotherapy, the 5-year disease-specific survival of the younger group was 94.5%, compared with 87.6% in the older cohort (P=.01). Furthermore, for patients with stage III–IV disease who received radiation, the 5-year disease-specific survival of the young women was 69.9%, compared with only 53.8% in the older group (P=.008). Multivariable analysis revealed that younger age at diagnosis, earlier stage disease, lower grade of disease, nonblack race, endometrioid histology, and surgical treatment were all independent prognostic factors associated with improved survival (Table 3).
Uterine cancer remains the most common gynecologic malignancy diagnosed in the United States. This investigation confirms that age is an important prognostic factor for survival in uterine cancer. Several prior studies have shown that younger patients have a better survival than older patients. Many prior studies have also linked younger age to lower-risk clinico-pathologic prognostic factors.1–6 However, these results concerning uterine cancer in reproductive-age women have been challenged in recent studies.8,9 In fact, some studies have shown that younger women may have more poor prognostic tumors with a worse outcome. Many prior reports have been limited by small sample sizes, from single academic institutions, clinically staged patients, inconsistent FIGO staging data, varying histological criteria, and poor reporting of pathologic factors, such as myometrial invasion and extrauterine disease and adjuvant treatment. In addition, given that it is relatively uncommon to find uterine cancer in reproductive-age females, studies on younger women and uterine cancer have been limited because of the small sample size of the patients in the younger age groups. In fact, four of five studies that were unable to show a difference by age consisted of 65 patients or fewer.21–24 This current report is a large series, consisting of over 2,000 reproductive-age patients, showing a survival benefit for younger patients.
This analysis also showed that younger women are more likely to present with earlier-stage disease and lower-grade tumors. Furthermore, the younger women were less likely to have uterine papillary serous histology than the older patients. These findings support those of Soliman et al,25 who found that young premenopausal patients have more endometrial hyperplasia and well-differentiated tumors. They also showed that the majority of the young patients were nulliparous, obese, and had menstrual irregularities. This profile suggests a plausible biological explanation of unopposed endogenous estrogen excess leading to earlier-stage and lower-grade tumors associated with an improved survival. However, it is important to note that this current report showed a survival advantage for younger patients after controlling for grade and stage of disease, suggesting that the improved survival cannot be simply explained by the pathologic characteristics alone.
In this population-based study, women of reproductive age had a better overall 5-year disease-specific survival than their older counterparts, controlling for race, stage, grade of tumor, type of surgical intervention, and radiation treatment. Age remained as a significant independent prognostic factor even when analyzed as a continuous variable. On the other hand, a recent study by Mundt et al20 found that age was not an independent prognostic factor for recurrence after controlling for the imbalances in the pathologic factors and less aggressive therapy. However, the patients in their study were dichotomized at age 60 years, with only 156 patients less than 60 years old.20 In this current report, there were 2,076 women, 40 years of age or less, showing that younger patients with uterine cancer have intrinsically better survival. Similarly, Alektiar et al26 studied 405 women with FIGO stage IB–II uterine cancer treated with postoperative radiotherapy and found that older age, presence of lymphovascular invasion, aggressive histology, and cervical involvement remained as independent predictors for poorer disease-specific and overall survival.
Clearly, more research is needed to evaluate the molecular prognostic factors associated with improved survival of the younger cohort. Chan and colleagues27 investigated the differences in molecular markers in tumors of women 45 years of age or younger compared with those over 45 who were diagnosed with ovarian cancers to explain the better prognosis of the younger cohort. Based on CD34 expression, tumors from women over 45 had lower microvessel density compared those of younger women. Lower microvessel density also predicted a worse prognosis than higher microvessel density in the overall study group (P=.001) and within the older subgroup (P=.03). Beyond conventional pathologic prognostic factors, other important molecular markers, including p53 expression,28 Her2neu,29 and DNA ploidy,30,31 can also help elucidate the survival differences between younger and older women. Perhaps there are subgroups of younger women who may not require aggressive surgery or adjuvant therapy given their overall favorable prognosis.
It is possible that that the improved outcome of the younger patient could be attributed to more aggressive adjuvant therapy offered to the younger patients. Other studies have shown that elderly patients were less likely to receive lymphadenectomy and undergo adjuvant radiation.32–34 Although the extent of surgery may have partially contributed to the better survival of the younger women, the differences in the outcome persist after multivariable analyses. Furthermore, the therapeutic role of lymphadenectomy remains controversial.35–37 Nevertheless, up to 20% of younger patients had disease beyond the uterus, emphasizing the importance of thorough staging procedures in all women diagnosed with uterine cancer to guide appropriate postoperative treatment. Moreover, the proportion of young patients who underwent radiotherapy was less than that of the older cohort (18.1% versus 28.6%, P<.001). However, the survival of younger patients was superior after controlling for adjuvant radiotherapy. Jolly et al37 analyzed the outcome of 243 patients with stage I and occult stage II cancer and controlled for radiotherapy with respect to doses, fields employed, duration of treatment, and treatment breaks for acute treatment-related toxicity. These authors found that radiation treatment cannot account for the lower failure rates in the younger age group.
The results of this population-based study confirm those found in two recent randomized controlled trials. Both of these phase III trials showed a strong correlation between age and failure rates, and age contributed to defining patients with significant risks for recurrence after surgery. In the Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) study, the authors found that age over 60 years, grade 3 disease, and outer 50% myometrial invasion were poor prognostic factors. In their study, those with 2 of 3 risk factors had a high risk for failure.36 Similarly, the Gynecologic Oncology Group (GOG) protocol 99 also found that age at diagnosis was an important prognosticator. The study, a clinical trial of stage I–II endometrioid uterine cancer, randomized patients to surgery alone compared with surgery with adjuvant pelvic radiation treatment. In this analysis, these authors also found that younger patients had an improved outcome compared with their older counterparts.39 Furthermore, they found that grade 2 and 3 disease, lymphovascular space invasion, and outer myometrial invasion were three additional poor prognostic factors. Highlighting the importance of age, the GOG defined a high-intermediate risk group that included three subsets of patients: 1) any age women with all three of the above pathologic risk factors, 2) those between 50 and 70 years of age with two additional risk factors, and 3) women over 70 years of age with only one risk factor. Patients meeting these criteria had a 4-year recurrence after surgery of 27%, which was reduced to 13% with adjuvant pelvic radiation therapy.39 Thus, the significance of age is not only an important prognosticator but can be used to formulate treatment recommendations.
Black women over the age of 40 years had the worst survival: only 68.6% compared with 87.3% and 86.9% of whites and Asians, respectively (P<.001). Others have also found that black women present with more advanced disease and poor prognostic tumors (uterine papillary serous cancers and sarcomas) and undergo less adequate staging procedures. In addition, the tumors of these black patients have more poor prognostic molecular markers, such as p53 mutations.40,41
The current study consists of an unselected group of patients spanning 12 U.S. regions, thus minimizing selection and surveillance biases often associated with clinical trials and studies from single academic institutions. Comparing SEER population with the U.S. census data, there are clearly more urban and foreign-born populations in the SEER population (88.2% versus 79.0% and 17.3% versus 11.1%, respectively). However, the poverty level and education levels are comparable (12.9% versus 12.4% and 20.4% versus 19.6%, respectively). A multivariable analysis using age as a continuous variable was performed and showed that the significance of age still holds true. To provide a means of comparison with previous reports, we chose age 40 as a cutoff based on these prior publications.42–44 Clearly, there is no specific age group that defines young versus older patients. Due to the large numbers of patients, we were able to divide the study cohort and perform subset analyses stratified by various prognostic factors. An additional multivariable analysis on the subgroup of stage I endometrioid patients was performed and found that age remained as a significant prognostic factor for improved survival. These findings have not been reported in other series, perhaps due to their limited sample sizes. In regards to statistical compared with clinical significance, our analytic approach requires that smaller subgroups exhibit a much greater benefit than that experienced by their larger cohorts to attain statistical significance. On the other hand, we showed a +7% disease-specific survival benefit in the young patients. This improvement is relatively small and may not provide a notable clinical benefit. It is important to avoid an overreliance on interpreting the P values and interpret these results with a clinical perspective.
This study was limited by the lack of information on surgeon subspecialty, central pathology review, information of lymphovascular invasion, detailed radiotherapy information, adjuvant hormonal therapy and chemotherapy, site of recurrence, subsequent surgical and medical therapies, and surgical morbidity. Given that 80% of patients in our study had early-stage disease and that there is no evidence that chemotherapy improves the outcome of these early-stage patients, it is unlikely chemotherapy may have affected our results. Thus, the use of chemotherapy is unlikely to bias the results. In addition, the relatively long (14 years) observation period may be another limitation of this study because detection, treatment, and outcome may have changed during this time. However, based on international staging guidelines set forth by the International Federation of Gynecology and Obstetrics, there has been no change in the recommendation for the surgical staging of uterine cancer since 1988. In this population-based registry, we did find that the percentage of patients who underwent lymph node assessment has increased from 22.6% to 29.6% to 40.9% over the study period from 1988 to 1992, 1993 to 1997, and 1998 to 2001.
In addition, this current report demonstrated the excellent survival of patients age under 30 years of age and those 30–40 years of age with endometrioid uterine cancer who underwent primary surgery with 5-year disease-specific survivals of 99.4% and 98.9%, respectively. There may be subsets of reproductive-age women that may not require definitive surgery up front and can undergo conservative management with hormonal agents to preserve their fertility. Ramirez et al45 reviewed the literature on hormonal treatment of grade 1 uterine cancer and found that 62 of the 81 patients (76.5%) responded to treatment. Moreover, 20 patients were able to become pregnant at least once after completing treatment. With a median follow-up of 36 weeks, none of the patients died of their disease. Furthermore, even when an initial response was not achieved or when disease recurred, carcinoma extending beyond the uterus was rare. Clearly, one would need a prospective trial comparing different treatment modalities controlled for other confounding factors such as age, stage, and histology to determine the safety of this conservative approach. Nevertheless, these young patients need to be counseled extensively on the fertility-sparing options and associated risks of the conservative surgery.
In summary, the results of this large population-based study on uterine cancer in the reproductive-age group showed younger patients (40 years of age or less) have an overall survival advantage compared to women over 40 years of age, independent of clinico-pathologic prognostic factors. The use of age and other pathologic prognosticators may help select younger patients who can be offered conservative, fertility-sparing treatment.
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