193 EOC patients from Peking University First Hospital were enrolled into the training group. The characteristics of these patients, including age, FIGO stage, histological grade, histological type, lymph node metastasis, residual lesion size, serum CA125 level and molecular markers of tumor tissues were summarized in Table 1. 106 cases (54.9%) had recurrence. The RFI ranged from 1.8 months to 173.2 months, with a median of 46.7 months. 77 cases had no recurrence; 10 cases had censored data, 9 cases had lost follow-up, 1 case died of other disease, the rate of lost follow-up was 4.7%. The results of Kaplan Meier survival analysis and log rank test are summarized in Table 1.
Table 1
Kaplan-Meier single factor survival analysis of patients in training group
Factors | Stratification factor | Number(%) | Median RFI(months) | P value |
Age | ≤ 50 years old | 68(35.2%) | 53.0 | 0.778 |
> 50 years old | 125(64.8%) | 48.0 |
FIGO stage | I | 55(28.5%) | NA | < 0.001 |
II | 26(13.5%) | NA |
III | 92(47.7%) | 18.0 |
IV | 20(10.4%) | 10.1 |
Histological grade | G1 | 37(19.2%) | NA | < 0.001 |
G2 | 45(23.3%) | 27.6 |
G3 | 111(57.5%) | 26.4 |
Histological type | Serous carcinoma | 117(60.6%) | 24.0 | < 0.001 |
Non-serous carcinoma༊ | 76(39.4%) | NA |
Postoperative residual size | 0 | 78(40.4%) | NA | < 0.001 |
< 1 cm | 88(45.6%) | 26.8 |
≥ 1 cm | 27(14.0%) | 18.0 |
Lymph node status | No metastasis | 53(27.5%) | NA | < 0.001 |
Metastasis | 17(8.8%) | 10.1 |
No Lymphonectomy | 123(63.7%) | 27.3 |
Pretreatment CA125 level | < 35U/mL | 30(15.5%) | NA | < 0.001 |
≥ 35 and < 1000 U/mL | 118(61.1%) | 53.0 |
≥ 1000 U/mL | 45(23.3%) | 16.1 |
Expression of ER in tumor tissues | Negative | 70(36.3%) | NA | 0.008 |
Positive | 123(63.7%) | 32.5 |
Expression of PR in tumor tissues | Negative | 81(42.0%) | 27.6 | 0.192 |
Positive | 112(58.0%) | 94.5 |
༊ Non-serous cancers include endometrioid, clear cell, mucinous, undifferentiated and mixed epithelial tumors. |
༊ NA: Not available. |
Cox regression univariate analysis showed that FIGO staging, histological grade, histological type, size of residual lesions after surgery, lymph node metastasis, pre-treatment CA125 level, ER expression in tumor tissue had significant differences in the impact of internal stratification on recurrence. Cox regression multivariate analysis showed that advanced EOC, histological grade and histological type were independent risk factors for recurrence of epithelial ovarian cancer. The results of specific stratification factor were shown in Table 2.
Table 2
The result of Cox multi-regression survival analysis
Factors | Stratification factor | HR | 95%CI | P |
FIGO stage | I | 1 | | |
II | 2.3 | 0.8–6.4 | 0.102 |
III | 5.9 | 2.1–16.4 | 0.001 |
IV | 6.3 | 2.0–20.0 | 0.002 |
Histological grade | G1 | 1 | | |
G2 | 6.4 | 1.4–28.4 | 0.015 |
G3 | 6.9 | 1.6–31.1 | 0.011 |
Histological type | Serous carcinoma | 1 | | |
Non-serous carcinoma༊ | 1.8 | 1.1–2.9 | 0.027 |
Postoperative residual size | 0 | 1 | | |
< 1 cm | 0.6 | 0.3–1.1 | 0.099 |
≥ 1 cm | 0.7 | 0.4–1.5 | 0.392 |
Lymph node status | No metastasis | 1 | | |
Metastasis | 2.0 | 0.8–4.8 | 0.114 |
Not available | 1.6 | 0.8–3.3 | 0.158 |
Pretreatment CA125 level | < 35U/mL | 1 | | |
≥ 35 and < 1000 U/mL | 1.7 | 0.6-5.0 | 0.304 |
≥ 1000 U/mL | 2.0 | 0.7–6.2 | 0.210 |
Expression of ER in tumor tissues | Negative | 1 | | |
Positive | 1.0 | 0.6–1.6 | 0.942 |
LASSO regression was used to screen the best influencing factors for the establishment of the model. The optimal number of factors used to establish the contour map prediction model was 5. The final selected model included the following 5 variables: FIGO staging, histological grade, histological type, lymph node metastasis and serum CA125 level before treatment. Each stratification factor is assigned with a specific grading value (see Table 3 for details). When the grading values of the five influencing factors are determined, the total score can be obtained by adding them together. Figure 1 showed the nomogram for predicting 3-year recurrence risks of patients with EOC. The mathematical formulas between the total score and the recurrence rate for 3 years are as follows:
Table 3
Scores for Recurrence related Factors
Recurrence related Factors | Stratification factor | Score |
FIGO stage | I | 0 |
II | 29 |
III | 65 |
IV | 71 |
Histological grade | G1 | 0 |
G2 | 96 |
G3 | 100 |
Histological type | Serous carcinoma | 0 |
Non-serous carcinoma | 26 |
Lymph node status | No metastasis | 0 |
Metastasis | 41 |
Not available | 27 |
Pretreatment CA125 level | < 35U/mL | 0 |
≥ 35 and < 1000 U/mL | 21 |
≥ 1000 U/mL | 28 |
3-year recurrence rate = 1 - [1.51e-07 * total score ^ 3 + (-0.000101727) * total score ^ 2 + 0.016191444 * total score + 0.144929485]
For example, a patient with EOC had a serum CA125 level of 600 U/ml (21 points) underwent the initial cytoreductive surgery. Pathology result showed that she was stage IIIC (65 points), serous carcinoma (26 points), grade G3 (100 points), lymph node metastasis (41 points) and she has reached CCR after 6 cycles of standardized chemotherapy. According to the above-mentioned contour map model, the total score of the patient was 253. The relatively overall 3-year predicted recurrence rate for this patient was 82.01%.
The ROC curve of the monogram was shown in Fig. 2. The Area under ROC curve (C statistics) was 0.828 (95% CI, 0.764–0.884). When the threshold value was set at 198, the sensitivity, specificity, positive predictive value, negative predictive value and correct index were 88.8%, 67.0%, 71.8%, 86.3% and 0.558 respectively. Patients with total score higher than 198 were identified with high-risk recurrence and those with total score lower than 198 were identified with low-risk recurrence. Hosmer-Lemeshow test for evaluation of calibration showed that the Chi-square value is 3.6 (P = 0.731 > 0.05), As the calibration curve shown in Fig. 3, if the 3-year predicted recurrence rate calculated by the model is within the range of 15–30%, the predicted value is basically consistent with the actual recurrence rate; if the predicted value is below 15% or above 30%, the predicted value is less than the actual recurrence rate, indicating that the recurrence risk is underestimated.
The medical data of 187 EOC patients from in Peking University Third Hospital and Beijing Obstetrics and Gynecology Hospital were enrolled into the external validation group. The ROC curve of the contour map model was shown in Fig. 4. The AUC (C statistics) for the validation data group was 0.803 (95% CI, 0.738–0.867). When using the threshold value of 198, the sensitivity, specificity, positive predictive value, negative predictive value and correct index were 75.7%, 77.0%, 83.2%, 67.9%, and 0.52 respectively. Hosmer-Lemeshow test for evaluation of calibration showed that the Chi-square value is11.074 (P = 0.135 > 0.05),