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There is no validated system to identify prognostically distinct cohorts of women with uterine leiomyosarcoma (ULMS). Using an independent, pooled, multi-institutional, international patient cohort, we validated a recently proposed ULMS nomogram.
The ULMS nomogram incorporates 7 clinical characteristics (age, size, grade, cervical involvement, locoregional metastases, distant metastases, and mitotic index (per 10 HPF) to predict overall survival (OS) following primary surgery. Independent cohorts from two sarcoma centers were included. Eligible women underwent at minimum a hysterectomy for primary, locally advanced, or metastatic ULMS and received part of their care at one of the centers between 1994 and 2010.
We identified 187 women with ULMS who met the above criteria (median age, 51 years; median tumor size, 9 cm; median mitotic index, 20). Tumors were generally high grade (88%), FIGO stage I-II (61%) without cervical involvement (93%) and without locoregional (77%) or distant metastases (83%). Median OS and the 5-year OS rate were 4.5 years (95% CI 3.2–5.3) and 46%, respectively; 65 women (35%) were alive at last follow-up. The nomogram concordance index was 0.67(SE=0.02), which was as high as the concordance index from the initial cohort used for nomogram development. The concordance between actual OS and nomogram predictions suggests excellent calibration since predictions were within 1% of actual 5-year OS rates for patients with a predicted 5-year OS of less than 0.68.
The ULMS nomogram was externally validated using independent cohorts. These findings support the international use of the ULMS nomogram prognostic of OS in ULMS.
Uterine leiomyosarcoma (ULMS) is a rare malignancy with an annual incidence of 0.64 per 100,000 women.1 It accounts for less than 5% of all uterine malignancies and approximately 30% of all uterine sarcomas.2 Although most frequently diagnosed while still confined to the uterus, the clinical course of the disease is difficult to predict and the overall prognosis is poor. Current staging systems fail to identify which patients are at highest risk for death, and thus it is difficult to select patients in whom to test potentially beneficial adjuvant strategies.3–6 Neither the International Federation of Gynecology and Obstetrics (FIGO) nor the American Joint Committee on Cancer (AJCC) staging systems for uterine cancer accurately distinguish patients with ULMS into prognostically distinct groups.7,8 To address this, FIGO recently developed a new classification system specifically for ULMS to include variables, such as tumor size, extra-uterine spread, and invasion of abdominal tissues.9
Nomograms are prognostic models that provide a score or a probability of a patient being without disease or alive within a specific time frame.10 Nomograms have been increasingly used in the clinical setting to provide patient counseling.11,12 Given that there is still confusion around ULMS staging systems,7,8 Memorial Sloan-Kettering Cancer Center (MSKCC) recently developed a novel ULMS-specific nomogram prognostic of post-resection 5-year overall survival (OS) using seven clinico-pathologic characteristics.13 The utility of the nomogram is that it can more accurately distinguish groups of patients in terms of prognosis, compared to either staging system alone. It may be used to provide patients with reasonable expectations. In addition, it may serve as a tool for discussing potential treatments, for identifying similar risk patients for more uniform cohorts within any future study and in particular for identifying high grade tumor patients who could benefit from enrollment in clinical trials.
The purpose of this study was to validate the MSKCC ULMS-specific nomogram prognostic of post-resection 5-year OS using an external, independent, international cohort.
The ULMS nomogram incorporates seven clinical characteristics: age at diagnosis, tumor size, tumor grade, involvement of cervix, locoregional metastases (including direct extrauterine spread or locoregional lymph node), distant metastases (including omentum, peritoneum, bowel serosa, lung, or liver), and mitotic index (per 10 high power fields [HPF]) to predict OS following primary surgery. Independent cohorts from two international sarcoma centers (Brigham and Women's Hospital/Dana-Farber Cancer Institute [BWH/DFCI] in Boston, MA, USA, and European Institute of Oncology [EIO], Milan, Italy) were included as the “validation cohort.” Eligible women were those treated with hysterectomy at the institutions between 1994 and 2010. Women with locally advanced or metastatic disease who underwent more extensive surgery were included if the primary tumor (uterus) was also resected, although they did not have to be rendered disease-free. Women who previously underwent resection of the primary tumor or recurrences at other institutions were included if they received follow-up care at one of the two sarcoma centers. Women who presented with unresectable disease who never underwent surgery and those with insufficient information on any of the nomogram variables were excluded. The cohort included patients from BWH/DFCI previously reported in a study evaluating the predictive value of FIGO and AJCC staging systems.7 Institutional review board approval was obtained from each institution for this retrospective data collection.
Histologic tumor grade was determined by microscopic analysis and was based on the assessment of three key histologic parameters in the primary uterine tumor: significant cytologic atypia, mitotic rate, and presence of coagulative tumor cell necrosis. Cytologic atypia, in the form of nuclear enlargement, variation in nuclear shape, and prominent hyperchromasia, was considered significant if it could be discernible at low power magnification (10× objective). Morphologically high-grade tumors had moderate to marked cytologic atypia, tumor cell necrosis, and mitotic rates in excess of 10 per 10 HPF. Intermediate-grade tumors lacked necrosis, but had moderate cytologic atypia and mitotic rates greater than 10 per 10 HPF. Low-grade tumors had no to minimal cytologic atypia, but had coagulative tumor cell necrosis and a variable mitotic rate.14
The ULMS nomogram is designed to be prognostic of 5-year OS rate. Overall survival was calculated from the date of surgery to either the date of last follow-up or the date of death. In order to compare the predictions of the nomogram with the actual outcome, OS probabilities were estimated using the Kaplan-Meier method and were compared with the nomogram’s calculated probabilities.
The performance of the nomogram in the validation cohort was assessed through estimates of discrimination and calibration. The nomogram’s predictive accuracy and its ability to separate patients with different outcomes were measured via the concordance probability estimate (CPE).15 CPE quantifies the level of concordance between predicted probabilities and the actual chance of having the event of interest. The CPE denotes the probability that of two randomly selected patients, the patient who survives longer will have a higher survival probability obtained from the nomogram than the patient with shorter survival. Calibration assesses how far predictions are from actual outcomes. The calibration of the nomogram was assessed via a calibration plot by plotting the nomogram’s predicted 5-year survival probability against the patient observed or actual probability as calculated by the Kaplan-Meier method for four sub-cohorts. Each sub-cohort was obtained by ranking patients based on their predicted probabilities and dividing the entire validation cohort into quartiles. A perfectly accurate nomogram would result in a plot where the observed and predicted probabilities for given groups fall along the 45-degree line. The distance between the pairs and the line of unity (along the 45-degree line) is a measure of how far the nomogram’s predictions are from actual outcomes. The seven nomogram factors described in the original paper proposing the nomogram were collected and grouped in the same way. Patients’ baseline characteristics were compared using the Wilcoxon test for continuous variables and the Chi-square test for categorical variables. All tests were two-sided. Statistical analyses were performed using SAS and SPlus software S-Plus (Version 2000 Professional, Redmond, Washington) with the Design and Hmisc libraries16 and library PHCPE in R version 2.12.2.
One-hundred eighty-seven eligible patients were included in this study in the validation cohort (129 patients from BWH/DFCI and 58 patients from EIO). Patient characteristics of the original cohort from MSKCC used to construct the nomogram (“model development cohort”) and the validation cohort are provided in Table 1. The median age for the validation cohort was 51 years, median tumor size was 9 cm, and median mitotic index was 20 (per 10 HPF). Tumors were generally morphologically high grade (88%), FIGO stage I–II (61%) without cervical involvement (93%) and without locoregional (77%) or distant metastases (83%) at initial presentation. The validation and model development cohorts were very similar in terms of patient and pathologic characteristics. Mitotic index had a wider range although a smaller median in the model development cohort compared to the validation cohort. The model development and validation cohorts were similar in terms of stage and number of patients with metastatic disease. However, a two-way comparison of patient characteristics showed significant differences between patients from EIO versus MSKCC and EIO versus BWH/DFCI (Table 2). Patients from EIO were younger (median age, 45 years), had smaller tumors (median size, 7 cm), and had lower mitotic indices (median, 11.5). Fewer patients from EIO had high-grade tumors (76% vs. 91%) or locoregional metastasis (14% vs. 28%) compared to the MSKCC or BWH/DFCI subsets.
For the validation cohort, median survival was 4.5 years (95% CI, 3.2–5.3 years), and the 5-year OS rate was 46% (Figure 1). Sixty-five women (35%) were alive at last follow-up. Median follow-up was 6.6 years (0.25–19 years). Figure 2 shows the published ULMS nomogram. The nomogram includes age at diagnosis, tumor size, grade, involvement of cervix, locoregional metastases (direct extrauterine spread, locoregional lymph node), distant metastases, and mitotic index (per 10 HPF).
The nomogram concordance index was 0.67 (95% CI, 0.62–0.72), which was as high as the concordance index from the model development cohort (0.67; 95% CI, 0.63–0.72). The concordance between actual OS and nomogram predictions suggests excellent calibration of the nomogram in the validation cohort. The calibration plot illustrates how the nomogram predictions compare with the actual outcomes of the validation cohort (Figure 3). Predictions were within 1% of actual 5-year OS rates, except for the patients with a 5-year OS predicted probability greater than 0.68. For this favorable prognostic group, the nomogram prediction was on average 0.69, whereas the actual proportion of patients who were alive at 5 years was 0.80.
Figure 4 shows the nomogram-predicted 5-year OS probability presented separately within each FIGO stage. Across all four FIGO stages, there is a wide range of predictions as illustrated from the histograms, indicating heterogeneity within each stage. Patients with FIGO stage I ULMS have a nomogram-predicted 5-year OS probability ranging from 0.2 to 0.9 when taking into account the nomogram characteristics, whereas patients with FIGO stage IV ULMS have a nomogram predicted 5-year OS probability ranging from 0 to 0.75.
Nomograms have received increased attention within clinical oncology, and many nomograms have been developed and validated for various malignancies.17–20 Recently, a number of nomograms specific for gynecologic malignancies, such as endometrial,11 ovarian,12 and uterine cancers,21,22 have been developed with superior accuracy to staging systems alone. Raut et al7 and Zivanovic et al8 illustrated the poor performance of FIGO and AJCC staging classification in predicting OS for ULMS patients. ULMS is a mesenchymal malignancy with a biology and natural history distinct from epithelial malignancies. Therefore, it is not surprising that staging systems developed for epithelial malignancies, such as endometrial cancer, or other non-leiomyosarcoma uterine sarcomas, were invalid in patients with ULMS. In addition, those studies demonstrated that ULMS patients classified as stage I and II, by either FIGO or AJCC, had quite disparate clinical outcomes amongst patients within each stage. This is in contrast to other disease settings, for example endometrial cancer, in which patients with early-stage disease have similar clinical outcomes and patients with advanced-stage disease have widely differing outcomes.21 Hence, there was a need for an individualized prognostic tool that could be tailored specifically to ULMS patients.
Although a soft tissue sarcoma nomogram that predicts 12-year sarcoma-specific death has been previously developed,23 that nomogram attempts to encompass many histologies and anatomic sites of sarcoma. In addition to being both histology- and location-specific, the ULMS-specific nomogram validated here includes the additional prognostic information of tumor size as a continuous (rather than categorical) variable, extrauterine spread, and mitotic index. The current nomogram predicts 5-year OS rather than 12-year disease-specific death, which is a more commonly utilized endpoint in assessing prognosis both in patient counseling as well as in clinical trial development.
The goal of this nomogram is not to determine response to therapy. Forthcoming molecular diagnostic data will hopefully serve as both a diagnostic tool and a predictor of response to therapy, which are important to individualized patient care. Instead, the goal of the nomogram is to allow the clinician evaluating a particular patient to determine that individual's prognosis, more accurately than existing staging systems. In turn, this allows clinicians to more accurately distinguish low-risk, good prognosis patients who may be followed more conservatively compared to uniformly high-risk, poor prognosis patients who may be included in future clinical trials.
The predictions from the nomogram were within 1% of actual OS outcomes, except for the most favorable prognosis group; in this latter group, those patients with a predicted 5-year OS of greater than 68% were found to have higher variability in the prediction. In evaluating this group further, we noted that patients with low-grade ULMS had a nomogram-predicted 5-year OS of 0.68–0.80, whereas patients with high-grade ULMS had a nomogram-predicted 5-year OS of 0.55–0.66. Thus, the nomogram-predicted 5-year OS for patients with high-grade ULMS may potentially be lower than their actual outcome. Mitotic index and grade have the first and second most significant effect on the nomogram predictions. However, there is subjectivity in assessing both of these covariates, and a comparison of patients’ characteristics indicated differences between the centers in both the proportion of patients with high grade and the range of values for mitotic index. In general, patients in the favorable prognosis group were younger, with low stage, lower mitotic index, smaller tumor size, no cervical involvement or locoregional or distant metastasis; some of these patients lived only 1 year and others lived as long as 10 years. The nomogram could not distinguish these outliers, but it combined a number of covariates to give them individual predictions. If the calibration plot consisted of three groups instead of four (Figure 5), the sample size within each group would become larger and predictions would be within 5% of actual outcomes for all groups, which is reasonable and comparable with published nomograms.24
In the current study, we have externally validated the MSKCC nomogram for ULMS patients using an international, multi-center cohort of patients with ULMS. When applied to this external patient cohort, the nomogram predictions were comparable with the actual observed OS, demonstrating that the nomogram reliably predicts outcome for patients with ULMS. These findings support the international use of this nomogram for predicting OS in patients with ULMS.
A potential concern of the development and validation of postoperative nomograms is that they do not account for the different treatments individual patients may have received. Some patients included in the model development cohort received postoperative treatment either as part of standard or protocol therapy. At primary presentation, all patients of the validation cohort underwent surgery, 61 (33%) patients received chemotherapy, 15 patients (8%) received radiation therapy, 3 (1.6%) patients received neo-adjuvant chemotherapy, and 6 patients (3%) received hormonal therapy. However, post-resection treatment was not included as a covariate in the nomogram development since the goal of this nomogram is to provide prognostic information for patients and physicians at the time of diagnosis when treatment details are not known. In addition, OS did not differ significantly between patients who did or did not receive post-resection treatment in the model development cohort13. Treatment modalities may vary depending on hospital type, location, and different referral patterns. Our observation that the nomogram accurately predicted outcomes in a validation cohort, which includes patients from two, independent academic centers over a 16-year period, further supports the strength and generalizability of this nomogram to patients with resected ULMS.
Grant support: None
Financial Disclosures: None
Presented in part at the annual meeting of the American Society of Clinical Oncology, 2012 (abstract number 5090)