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Abstract
Objective To evaluate the prognosis and recurrence in patients with residual lesions of pulmonary metastasis from gestational trophoblastic neoplasia after initial treatment, and to explore the clinical significance of pulmonary resection.
Methods A retrospective analysis was performed on 606 patients with residual lesions from pulmonary metastasis after receiving standardized chemotherapy as initial treatment in Peking Union Medical College Hospital from January 2002 to December 2018. Patients were divided into surgery (51 patients) and non-surgery (555 patients) groups. The prognosis of these patients was compared. Risk factors affecting recurrence were analyzed to explore the effect of pulmonary resection.
Results Among low risk patients, complete remission rate was 100% and recurrence rate was <1% in both groups. Among high risk patients, complete remission and recurrence rates were 93.5% and 10.3% in the surgery group and 94.7% and 14.3% in the non-surgery group, respectively. There was no significant difference in prognostic features between the two groups (all p>0.05). No significant difference was found in recurrence rates based on recurrence risk factors (≥3.2 cm residual lung lesions, prognosis score ≥9.0, and drug resistance) between the two groups (all p>0.05).
Conclusion After standardized chemotherapy, pulmonary resection was not necessary for initially treated stage III gestational trophoblastic neoplasia patients whose blood β human chorionic gonadotropin levels normalized and residual lung lesions remained stable. These patients should be closely monitored during follow-up, regardless of the size of the residual lung lesions or high/low risk score, especially within a year after complete remission.
- surgical oncology
Data availability statement
The data are available from the corresponding author on reasonable request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Pulmonary resection is recommended for patients who relapse and develop drug resistance during treatment.
Minimal work has been done to directly evaluate the effects of surgery for initially treated patients with residual lung lesions after standard chemotherapy and hence further studies and direct evidence are needed for the indication of pulmonary surgery in these patients.
WHAT THIS STUDY ADDS
Close follow-up should be adopted for stage III patients with normal human chorionic gonadotropin levels and stable lung lesions after standard initial treatment, regardless of the lesion size or prognosis score.
Requirements for surgery can be relaxed for those with recurrence risk factors so as to improve complete remission rates and reduce recurrence rates.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study may guide gynecological oncologists to more accurately grasp the pulmonary surgical indications for initially treated patients with residual lesions after standard chemotherapy, which is helpful to improve the cure rate, reduce the recurrence rate, and avoid excessive medical treatment.
Introduction
Gestational trophoblastic neoplasia is a rare malignancy occurring in trophoblastic tissue. Pathologically, it includes invasive hydatidiform mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic neoplasia.1 It is highly invasive and prone to hematogenous metastasis, which can be transferred to different parts of the body as the tumor progresses. The most common target of extrauterine metastasis is the lung. Research has revealed that metastasis to the lung is found on chest X-ray or chest computed tomography (CT) in 60–70% of patients with gestational trophoblastic neoplasia2 3 (intermediate gestational trophoblastic tumors are excluded). Gestational trophoblastic neoplasia is sensitive to chemotherapy and can be cured if treated properly.1
Some studies have highlighted the correlation between lung metastasis and poor prognosis. For example, Jiang et al found4 that the size of lung metastases ≥1.8 cm significantly affected the outcome of first line multidrug chemotherapy and the likelihood of recurrence. Vree et al5 highlighted that the presence of lung metastases was a risk factor for an unfavorable course, such as a high recurrence rate and probability of death. Therefore, the standard treatment for patients initially treated for lung metastases should be further improved. In this study, we investigated the significance of pulmonary resection in the prognosis of patients with residual lung lesions after standard initial chemotherapy.
Methods
Gestational trophoblastic neoplasia patients with pulmonary metastasis who received initial treatment in Peking Union Medical College Hospital from January 2002 to December 2018 were included. Patients were divided into surgery and non-surgery groups according to whether or not they had undergone pulmonary lesion resection.
Inclusion criteria were: patients diagnosed as stage III gestational trophoblastic neoplasia according to the International Federation of Gynecology and Obstetrics (FIGO) 2000 staging system1 and lung lesions were confirmed by X-ray and CT (none of the patients underwent lung puncture biopsy to obtain a pathological diagnosis); patients had lung lesions >0.5 cm before treatment; and all patients had received standard chemotherapy during initial treatment, and imaging suggested the presence of residual lung lesions
Exclusion criteria were: patients who did not complete the treatment or were lost during the visit; patients with incomplete clinical data, such as disease information or follow-up; and patients with intermediate gestational trophoblastic tumor, non-gestational choriocarcinoma, or mixed choriocarcinoma
Pulmonary metastasis was defined as lung nodules confirmed by chest CT or X-ray before treatment that changed in size as the treatment went on or β human chorionic gonadotropin (β-HCG) levels fluctuated.4 Pulmonary resection was defined as patients with residual lung lesions identified by imaging who underwent pulmonary cuneiform/lobectomy using a thoracoscopic/thoracotomy approach to determine whether the resected lesion was necrotic fibrotic tissue or residual tumor through pathological diagnosis. These patients had received standard chemotherapy and their blood HCG levels had dropped to normal or as close to normal as possible or had reached a plateau. There were four indications for pulmonary resection: (1) size of residual lung lesions ≥1 cm and patients had a strong desire for surgery; (2) chemotherapy regimen had been changed ≥2 times during treatment due to multidrug resistance, and the presence of residual drug resistant lesions was not excluded; (3) HCG levels were close to normal, but the decline was slow or plateaued when patients could not continue to tolerate the side effects of chemotherapy; and (4) pulmonary complications: hemothorax, hemoptysis, respiratory failure, or shock.
Clinical Indicators
Baseline features of all patients were collected. Prognostic indicators were complete remission, progressive disease, mortality, and recurrence. For complete remission, levels of β-HCG remained normal after chemotherapy for at least 1 month. A continuous rise in the levels of β-HCG during treatment, progressive enlargement of primary lesions and metastatic lesions, or new metastatic lesions incurred during treatment was defined as progressive disease.
Drug resistance was assumed if levels of β-HCG decreased by ≤10% or increased after two courses of chemotherapy.6 Tumor recurrence was defined as increased levels of β-HCG when measured twice (at least 1 week apart) over 1 month after complete remission had been achieved and another normal pregnancy was ruled out.7
Statistical Analysis
Patients were stratified into high and low risk patients according to the FIGO 2000 scoring system.8 The prognosis and recurrence of disease in both groups were evaluated with the Statistical Package for Social Sciences (SPSS). Measurement data following a normal distribution were expressed as mean±SD and those not normally distributed as median (quartile), for which the non-parametric test was carried out. Enumeration data were expressed as rate (%), for which the χ2 test or Fisher’s exact test was performed.
Logistic regression analysis was conducted to find risk factors affecting recurrence among high risk patients. A receiver operating characteristic (ROC) curve was plotted to determine the cut-off value for continuous variables of risk factors. Then, a subgroup analysis was performed for stratified high risk patients to determine the effects of surgery on tumor recurrence. The p value presented for a two tailed test, and p<0.05 indicated statistical significance.
Results
A total of 606 patients with gestational trophoblastic neoplasia and pulmonary metastases were examined in this study. There were 51 patients in the surgery group and 555 patients in the non-surgery group. Clinical characteristics of the patients are presented in Table 1.
Clinical characteristics of patients in the surgery and non-surgery groups
To avoid bias in the results due to different levels of risk, patients in the surgery and non-surgery groups were divided into high and low risk patients to evaluate prognosis (Table 2). Among 20 low risk patients in the surgery group, median residual lung lesion was 2.3 cm (range 1–6) before surgery (Online supplemental table S1) and complete remission was achieved in all patients. One of 20 patients relapsed at 6.6 months after initial treatment and achieved complete remission again after chemotherapy. Among 422 low risk patients in the non-surgery group, complete remission was achieved in all patients. One relapsed at 4.5 months after treatment and complete remission was also reached after chemotherapy. There were no deaths in low risk patients in either group. There were no significant differences in recurrence and complete remission rates.
Supplemental material
Comparison of prognosis in patients in the surgery and non-surgery groups
Of 31 high risk patients in the surgery group, median residual lung lesion was 3.5 cm (range 1.5–9) (Online supplemental table S1) and complete remission was achieved in 29 patients (93.5%), but new cerebral metastases developed in 2 (10.9%) patients with progressive disease who later reached remission after chemotherapy combined with radiotherapy or surgery. Among 29 patients with complete remission, three relapsed (10.3%) with a median recurrence time of 4.5 months (range 3.4–7.3). Among the three patients experiencing recurrence, one died of a stroke due to cerebral metastases with overall survival of 30 months, and the other two patients reached remission again after adjuvant chemotherapy.
Of the 133 high risk patients in the non-surgery group, complete remission was achieved in 126 (94.7%) patients and progressive disease was documented in 7 (5.3%) patients. Three of the seven patients died with a median overall survival of 33 months (range 28~34). The remaining four patients had a partial response or stable disease after treatment. Of the 126 patients with complete remission, 18 (14.3%) relapsed with a median recurrence time of 3.9 months (range 1.5–7.8). Two of these 18 patients died and overall survival was 45 and 50 months, respectively. One of the 18 patients refused treatment due to the intolerant side effects of chemotherapy after recurrence and one patient discontinued treatment after disease progression. The remaining 14 patients reached remission again after adjuvant chemotherapy combined with surgery. There were no significant differences in complete remission rate, disease progression rate, recurrence rate, or mortality between high risk patients in the surgery and non-surgery groups.
Three patients with high risk disease relapsed in the surgery group and 18 patients relapsed in the non-surgery group. Descriptive analysis of high risk patients experiencing recurrence in both groups revealed the following clinical characteristics which may be considered as risk factors for relapsing (Table 3): maximum diameter of pulmonary lesions ≥3 cm, multiple pulmonary metastases, duration of chemotherapy ≥25 weeks, HCG blood levels ≥103 IU/L before initial treatment, interval from termination of pregnancy to the beginning of chemotherapy >12 months, and chemotherapy resistance.
Characteristics of high risk patients with recurrence in the surgery and non-surgery groups
Based on the clinical characteristics of these patients, a multivariate logistic regression analysis was performed to examine possible factors affecting recurrence. Analysis showed that independent factors affecting recurrence were the diameter of the residual lung lesions (OR 1.5, 95% CI 1.14 to 1.99), prognostic score (OR 1.4, 95% CI 1.08 to 1.9), and drug resistance (OR 21.7, 95% CI 5.69 to 82.72), as shown in Table 4.
Multivariate logistic regression analysis for predicting recurrence
According to the ROC curve for evaluating factors affecting recurrence in high risk patients in the surgery and non-surgery groups, area under the ROC curve (AUC) of the maximum diameter of the lung lesions was 0.704 (95% CI 0.59 to 0.81). With a cut-off value of 3.2 cm, sensitivity was 57.7% and specificity was 70.5%. Regarding the prognostic score to predict relapse, AUC was 0.705 (95% CI 0.59 to 0.82). With a cut-off value of 8.5 points, sensitivity and specificity were 50.3% and 87.5%, respectively (Online supplemental figure S1). Comparison of recurrence among matched patients in the surgery and non-surgery groups regarding the maximum diameter of the lung lesions, prognosis scores, and drug resistance based on corresponding cut-off values showed no significant differences in these three perspectives (all p>0.05), as shown in Table 5.
Supplemental material
Recurrence among high risk patients in the surgery and non-surgery groups
Discussion
Summary of Main Results
Our analyses showed that most low risk patients were sensitive to chemotherapy and had an excellent prognosis, with a cure rate approaching 100% and a recurrence rate of only 0.5% (2/442). Therefore, as long as HCG levels normalize, pulmonary resection is not required for low risk patients, especially those sensitive to chemotherapy, regardless of the size of the residual lung lesions.
No significant differences were observed in the complete remission rate, progressive disease rate, recurrence rate, and mortality between the two groups. Multivariate logistic regression analysis revealed three independent risk factors affecting recurrence in high risk patients after initial treatment. Recurrence rates in targeted patients for the three risk factors were calculated in the surgery and non-surgery groups: maximum diameter of residual lung lesions ≥3.2 cm (14.3% vs 23.7%), prognosis score ≥9 (11.1% vs 26.6%), and chemotherapy resistance (33.3% vs 37.8%). Corresponding tests revealed no significant differences in recurrence among matched patients in the two groups.
Results in the Context of Published Literature
The most common target of extrauterine metastasis is the lung, and chemotherapy is the main method of treatment for gestational trophoblastic neoplasia. However, surgery can still be valuable in certain cases. Previous studies9 have shown that surgery should be performed in patients with pulmonary metastases who experience drug resistance and tumor recurrence. Additionally, research10 has shown that resection can result in a complete remission rate of approximately 90% for stage III patients with drug resistance.
Although Bouchard et al11 showed that residual lung lesions on imaging did not significantly increase the rate of relapse and oncologic outcomes after normalization of HCG levels, a larger dataset would be needed to provide more definitive evidence due to its low number of recurrent events and sample size. Some evidence12 has shown that surgery is not needed for patients with residual lung lesions after HCG remission, but all of the above conclusion were deduced by comparing the recurrence rate of patients with or without residual lesions. Thus far, little work has been done to directly evaluate the effects of surgery for patients with residual lung lesions and no consensus had been reached on whether lung lesion resection is needed for patients with pulmonary metastases, especially those with large residual lesions.
Although our review revealed no significant differences in the prognosis for high risk patients between the two groups, subgroup analyses showed that recurrence rates in the surgery group were lower than those in the non-surgery group for the three risk factors. Therefore, individual conditions should be taken into account for the treatment of targeted patients to better improve prognosis and reduce disease recurrence. For patients who had reached serologic remission after standardized chemotherapy, lobectomy or pulmonary wedge resection can be considered when residual lung lesions are ≥3.2 cm, the prognosis score is ≥9, or there is drug resistance. The results showed that the postoperative complete remission rate of patients with the these high risk factors could reach 89–95% (Online supplemental table S1). Furthermore, pulmonary resection can be used to reduce tumor burden, shorten chemotherapy courses, and improve cure rates for high risk patients whose HCG levels cannot decrease to normal after different chemotherapy regimens, to improve complete remission rates and quality of life.13
Strengths and Weaknesses
Gestational trophoblastic neoplasia is a rare tumor and our center is a large referral institution. To our knowledge, this was the first clinical retrospective analysis to explore the clinical significance of pulmonary resection for stage III patients with residual lung lesions after receiving standard initial treatment. In terms of pulmonary resection, our study included the largest number of cases in a single center. Through multi-angle stratification analysis, this study provides clinical data to support avoidance of unnecessary surgery for certain patients in the future.
Our study had some limitations. The negative analysis result may be attributed to the relatively small sample size for subgroup analyses. Hence research with larger sample sizes is required in the future to verify the significance of surgery for patients with gestational trophoblastic neoplasia. In addition, the findings of this study should be interpreted with caution as patients admitted to only one hospital were reviewed in this study. Thus multicenter prospective research should be done in the future to provide more solid evidence.
Implications for Practice and Future Research
Our study can guide gynecological oncologists to more accurately determine the surgical indications for pulmonary resection to avoid excessive medical treatment. We also showed that requirements for surgery may be avoided for those patients with recurrence risk factors so as to improve complete remission rates and reduce recurrence rates. For surgery, a thorough evaluation of patients is necessary taking into account the following indicators: no other active lesions apart from the lung, levels of HCG below the normal range or as low as possible before lung resection, and lesions confined to the lung.
Conclusion
For stage III gestational trophoblastic neoplasia patients with residual lung lesions after receiving standardized chemotherapy, if their HCG levels have been reduced to normal and metastatic lung lesions remain stable, they can be closely monitored during follow-up, regardless of the level of risk and size of the residual lung lesions. However, we could consider lowering the threshold for surgery for patients with a FIGO score ≥9, residual lung lesions ≥3.2 cm, or who experiencing drug resistance, so as to improve complete remission rates and reduce recurrence rates.
Data availability statement
The data are available from the corresponding author on reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the ethics review committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (ethics review No S-K1881). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We would like thank the researchers and study participants for their contributions.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
WW and YK are joint first authors.
WW and YK contributed equally.
Contributors Conceptualization: WW, JY, and YX. Methodology: WW and YK. Software: TR and YL. Formal analysis: WW, YK, and JY. Investigation: WW and YL. Data curation: XW, FF, and YX. Writing—original draft preparation: WW. Writing—review and editing: JY and YX. Supervision: JY and YX. Project administration: JZ. Funding acquisition: JY and YX. Guarantor:JY .All authors have read and agreed to the published version of the manuscript.
Funding This research was funded by the National Natural Science Foundation of China (No 81972451 and 81971475) and National High Level Hospital Clinical Research Funding (No 2022-PUMCH-B-084).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.