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Predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients successfully treated with methotrexate alone Florence Couder; Jérôme Massardier; Benoît You; Fatima Abbas; Touria Hajri; Jean-Pierre Lotz; Anne-Marie Schott; François Golfier

BACKGROUND: Patients with 2000 FIGO low-risk gestational trophoblastic neoplasia are commonly treated with single-agent chemotherapy. Methotrexate is widely used in this indication in Europe. Analysis of relapse after treatment and identification of factors associated with relapse would help understand their potential impacts on 2000 FIGO score evolution and chemotherapy management of gestational trophoblastic neoplasia patients. OBJECTIVE: This retrospective study analyzes the predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients whose hormone chorionic gonadotropin (hCG) normalized with methotrexate alone. STUDY DESIGN: Between 1999 and 2014, 993 patients with gestational trophoblastic neoplasia were identified in the French Trophoblastic Disease Reference Center database, of which 465 were low-risk patients whose hCG normalized with methotrexate alone. Using univariate and multivariate analysis we identified significant predictive factors for relapse after methotrexate. The Kaplan-Meier method was used to plot the outcome of patients. RESULTS: The 5-year recurrence rate of low-risk gestational trophoblastic neoplasia patients whose hCG normalized with methotrexate alone was 5.7% (confidence interval [IC], 3.86e8.46). Univariate analysis identified an antecedent pregnancy resulting in a delivery (HR ¼ 5.96; 95% CI, 1.40e25.4, P ¼ .016), a number of methotrexate courses superior to 5

G

estational trophoblastic neoplasia (GTN) including invasive moles, which arises in any type of pregnancy and typically from a hydatidiform mole, includes the malignant forms of gestational trophoblastic diseases (GTD), namely malignant invasive mole, choriocarcinoma, and, rarely, placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT). After a thorough assessment of the extent of disease, patients are scored/ staged according to the FIGO 2000 Cite this article as: Couder F, Massardier J, You B, et al. Predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients successfully treated with methotrexate alone. Am J Obstet Gynecol 2016;215:80.e1-7. 0002-9378/$36.00 ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2016.01.183

courses (5e8 courses vs 1e4: HR ¼ 6.19; 95% CI, 1.43e26.8, P ¼ .015; 9 courses and more vs 1e4: HR ¼ 6.80; 95% CI, 1.32e35.1, P ¼ .022), and hCG normalization delay centered to the mean as predictive factors of recurrence (HR ¼ 1.27; 95% CI, 1.09e1.49, P ¼ .003). Multivariate analysis confirmed the type of antecedent pregnancy and the number of methotrexate courses as independent predictive factors of recurrence. A low-risk gestational trophoblastic neoplasia arising after a normal delivery had an 8.66 times higher relapse risk than that of a postmole gestational trophoblastic neoplasia (95% CI, 1.98e37.9], P ¼ .0042). A patient who received 5e8 courses of methotrexate had a 6.7 times higher relapse risk than a patient who received 1e4 courses (95% CI, 1.54e29.2, P ¼ .011). A patient who received 9 courses or more had an 8.1 times higher relapse risk than a patient who received 1e4 courses of methotrexate (95% CI, 1.54e42.6, P ¼ .014). CONCLUSION: Low-risk gestational trophoblastic neoplasia following a delivery and patients who need more than 4 courses of methotrexate to normalization are at a higher risk of relapse than other low-risk patients. Allotting a higher score to the “antecedent pregnancy” FIGO item should be considered for postdelivery gestational trophoblastic neoplasia. Further analysis of the need for consolidation courses is warranted. Key words: low-risk gestational trophoblastic neoplasia, methotrexate, predictive factors, relapse

classification system.1,2 Those with a score of 6 or less are classified as having a low risk of resistance to single-agent chemotherapy.2 Different single-agent protocols are available, and methotrexate (MTX) or dactinomycin are used most often. A debate about changing the FIGO score calculation to consider the heterogeneous risk of single-agent failure in low-risk GTN patients is currently underway. We previously published predictive factors for resistance to MTX in 154 low-risk GTN patients and identified choriocarcinoma histology and hormone chorionic gonadotropin (hCG) clearance as the only 2 independent predictive factors for resistance, while existing studies had also identified postdelivery GTN and FIGO score level as factors associated with

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resistance.3-5 Beyond analysis of resistance to single-agent chemotherapy, analysis of relapse after treatment and identification of factors associated with relapse would help to improve our understanding of the disease and bring useful data to the current debate.6-8 Here, we present a cohort of 465 lowrisk GTN patients whose hCG normalized with MTX alone in order to define independent predictive factors for relapse and their potential impact on FIGO 2000 score evolution and chemotherapy management.

Materials and Methods We identified 465 low-risk GTN patients whose hCG normalized with MTX alone, registered to the French Trophoblastic Disease Reference Center (FTDRC) between November 1999 and

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FIGURE 1

Patient identification methods

Flow chart illustrates study inclusion/exclusion criteria. Couder et al. Predicting relapse in low-risk gestational trophoblastic neoplasia patients. Am J Obstet Gynecol 2016.

May 2014. Among 992 total GTN cases, high-risk GTN, PSTT, and ETT patients were excluded (n ¼ 184). Low-risk patients who received treatments other than MTX were excluded, namely those with hysterectomy, MTX-resistant disease requiring second-line chemotherapy, and spontaneous normalization of hCG levels (n ¼ 322). Twenty-one low-risk patients still under MTX treatment at the time of data extraction were not included. One patient had 2 GTN events and we decided to keep the first event in the analysis (Figure 1). The FTDRC’s functioning has already been described elsewhere.9 Patients are reported to the FTDRC as molar pregnancy or GTN. They receive the

treatment by their physician in their own region according to national guidelines. The FTDRC currently uses MTX in an 8-day MTX regimen10 with 1 mg/kg intramuscular MTX on days 1, 3, 5, and 7 with 10 mg of folinic acid on days 2, 4, 6, and 8.9,11,12 Day 1 of each course is repeated every 14 days until hCG levels normalize; 2 additional consolidation courses of chemotherapy are given after the first hCG normalization. As patients receive the treatment in different centers, hCG concentrations are determined by different laboratories using various immunoassay kits that could impact interpretation of data. GTN diagnosis and FIGO score/stage were established according to 2000

Original Research

FIGO oncology committee recommendations.2 Twenty-one patients (4.5%) did not complete MTX treatment either owing to poor tolerance or because of nonobservance of the treatment. They were maintained in the study population, as hCG normalized without further treatment. Disease relapse was defined as a rise in hCG levels following the completion of MTX treatment in the absence of a new pregnancy. The following potential predictive factors were investigated using survival log-rank tests: parameters included in the FIGO score except for location of metastasis item because no metastasis other than pulmonary were present; previous chemotherapy item because all patients were chemonaïve; age; and other potential predictive covariates except for tumor pathology (which was not available for the vast majority of postmolar GTN patients), including FIGO score (0e4 compared to 5e6), premature interruption of MTX (defined as patients who stopped the treatment before normalization or consolidation courses because of poor tolerance), delay in hCG normalization centered to the mean 1.9, number of whole MTX courses, and number of MTX consolidation courses. For the determination of independent predictive factors for relapse, variables found to be statistically significant in univariate analysis were included in multivariate analysis using the Cox proportional hazards model with backward elimination. A P value of .05 was considered statistically significant. Median follow-up was calculated using a reverse Kaplan-Meier estimate. The Kaplan-Meier method estimated a 5year survival rate without relapse. The analyses were carried out by SAS V9.3 software (SAS Institute, Cary, NC).

Results Four hundred and sixty-five patients with low-risk gestational trophoblastic neoplasia normalized their hCG with MTX alone. The mean follow-up period was 56.2 months (range, 1.7e171 months; standard deviation [SD], 40.0). The antecedent pregnancy was a mole in 440 patients (94.6%) and a delivery in

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TABLE 1

Patient characteristics at baseline Patient characteristics

All patients (n ¼ 465) n (%)a

Age <40 years

384 (82.6)

40 years

81 (17.4)

Age, mean (SD)

32.3 (8.1)

Interval between end of previous pregnancy and start of chemotherapy Missing data

3 (0.7)

<4 months

392 (84.3)

4e6 months (<7 mo)

63 (13.5)

7e12 months (<13 mo)

5 (1.1)

13 months

2 (0.4)

Pregnancy history Post mole

440 (94.6)

Post term

8 (1.7)

Post ectopic or termination

17 (3.7)

Serum Hcg before start MTX (IU/L) 1000

155 (33.3)

1000e10,000

150 (32.3)

10,000e100,000

145 (31.2)

100,000e1,000,000 >1,000,000

15 (3.2) 0 (0)

FIGO score 0e4

431 (92.7)

5e6

34 (7.3)

FIGO stage Stage I

387 (83.2)

Stage II

17 (3.7)

Stage III

60 (12.9)

Stage IV

1 (0.2)

Site of metastases None or lung

464 (99.8)

Spleen or kidney

1 (0.2)

Alimentary canal

0 (0)

Brain or liver

0 (0)

Premature interruption of MTX No

444 (95.5)

Yes

21 (4.52)

Couder et al. Predicting relapse in low-risk gestational trophoblastic neoplasia patients. Am J Obstet Gynecol 2016. (continued)

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8 patients (1.7%). The mean number of MTX courses was 5.8 (range, 1e18): 166 patients (35.8%) received 1e4 MTX courses, 236 patients (50.7%) received 5e8 courses, and 63 patients (13.5%) received more than 9 courses. No patient died of the disease. The characteristics of the patients are summarized in Table 1. Twenty-four patients relapsed at a mean interval of 10.9 months (range, 1.7e37.7 months). The 5-year KaplanMeier recurrence rate was 5.7% (CI, 3.86e8.46). Among the 8 patients with low-risk GTN after delivery, 25% relapsed. Figure 2A displays the Kaplan-Meier curve for relapse-free survival according to antecedent pregnancy type. Relapse rate was significantly higher for low-risk GTN occurring after a delivery than after any other type of antecedent pregnancy (P ¼ .0095). Relapse rate was also significantly higher for patients who had 5e8 courses or more than 9 courses of MTX: 1.2% for patients with 1e4 courses, and 7.2% and 7.9% for 5e8 courses and 9 courses, respectively (P ¼ .016). Figure 2B displays the Kaplan-Meier curve for relapse-free survival according to number of MTX courses (P ¼ .0158). Univariate analysis did not reveal premature interruption of MTX or number of consolidation courses to be risk factors for relapse (Table 2). Further, FIGO score, time interval between last pregnancy and beginning of GTN treatment, hCG level before treatment, and presence of metastasis were not found to be risk factors of relapse for low-risk GTN patients treated with MTX only (Table 2). Three factors were identified as predictive factors of relapse: low-risk GTN after delivery (P ¼ .016), the overall number of MTX courses (P ¼ .015 for 5e8 courses vs 1e4; P ¼ .022 for 9 courses or more vs 1e4), and the hCG normalization delay centered to the mean (1.9 months) (P ¼ .003). Multivariate analysis was performed after backward elimination of nonsignificant predictive factors from univariate analysis (Table 3). Owing to a positive correlation and collinearity between number of MTX courses and

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relapse risk than a patient who received 1e4 courses (95% CI, 1.54e42.6, P ¼ .014).

TABLE 1

Patient characteristics at baseline (continued) All patients (n ¼ 465) n (%)a

Patient characteristics Number of whole courses of MTX 1e4

166 (35.8)

5e8

236 (50.7)

9

63 (13.5)

Number of whole courses of MTX, mean (SD)

5.8 (2.6)

Number of consolidation courses 0

37 (8)

1e1.5b

45 (9.7)

2

343 (73.8)

3

40 (8.6)

Number of consolidation courses of MTX, mean (SD)

1.9 (0.7)

HCG normalization delay (mo), mean (SD)

1.9 (1.4)

Relapse No

441 (94.8)

Yes

24 (5.2)

a

Number and percent of patients, unless stated otherwise; b 1.5 courses: patients who did not complete the second course of MTX because of bad tolerance. Couder et al. Predicting relapse in low-risk gestational trophoblastic neoplasia patients. Am J Obstet Gynecol 2016.

hCG normalization delay (Pearson’s rho ¼ 0.78; P < .0001), we also eliminated time to hCG normalization. We identified 2 independent predictive factors of relapse in low-risk GTN patients whose hCG normalized with MTX alone: (1) a postdelivery low-risk GTN had an 8.66 times higher relapse

Original Research

risk than a postmole low-risk GTN (95% CI, 1.98e37.9, P ¼ .0042); and (2) a patient who received 5e8 courses of MTX had a 6.7 times higher relapse risk than a patient who received 1e4 courses (95% CI, 1.54e29.2, P ¼ .011). A patient who received 9 courses or more of MTX had an 8.1 times higher

FIGURE 2

Kaplan-Meier survival estimates

Kaplan-Meier relapse-free survival according to A, antecedent pregnancy outcome and B, number of MTX courses. Couder et al. Predicting relapse in low-risk gestational trophoblastic neoplasia patients. Am J Obstet Gynecol 2016.

Comment Our results demonstrate that in a very homogeneous population of 2000 FIGO-defined low-risk GTN patients whose hCG normalized with MTX alone, the relapse rate is very low. The 5year Kaplan-Meier relapse rate of 5.7% is in the range of relapse rates (2%e8.1%) from previously published series6,9,13-15 where the FIGO scoring system was not uniformly used. Although the relevance of comparison with these studies is poor, such reported low rates of relapse associated with the quasi-absence of fatal cases confirm the overall excellent prognosis of MTX-treated low-risk GTN patients. Despite such low relapse rates, demonstration in our study of antecedent pregnancy type as an independent predictive factor for relapse after MTX alone reveals heterogeneity within the low-risk GTN group. The 8.66times-higher relapse risk associated with an antecedent delivery should question the relevance of treating all low-risk GTN with MTX and considering them as real low-risk patients.3 Indeed, beside this higher risk of relapse after treatment, the risk of MTX resistance while under treatment has also been shown to differ in low-risk patients with antecedent delivery. Postdelivery choriocarcinoma, almost the exclusive histologic form of GTN after such a pregnancy (when excluding the rare PSTT and ETT), where most fatal cases occur,16 has also been identified as an independent predictive factor for resistance to MTX in low-risk GTN patients.4,14 This raises the question again of considering them as low risk. The existing and likely poorly reported tendency to shift toward treatment of postdelivery low-risk GTN as high-risk3 could lead to an overestimation of cure rate of low-risk GTN patients.13,14,17,18 Consequently, considering revision of the 2000 FIGO scoring system by increasing the weight allocated to antecedent, socalled “term” pregnancy would allow

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TABLE 2

Univariate analyses of risk factors in relapsing patients Risk Factors

Crude hazard ratio

95% CI HR

P

Age (y) centered at 10

0.96

0.57e1.59

.863

2e3 months

1.43

0.54e3.82

.473

4 months

1.88

0.57e6.17

.296

Delivery

5.96

1.40e25.4

.016

Abortion or unknown

1.18

0.16e8.78

.871

1000e10,000

1.42

0.49e4.10

.513

10,000e100,000

1.44

0.50e4.16

.496

100,000e1,000,000

3.43

0.69e17.0

.131

1.79

0.53e5.99

.348

3.87

0.52e28.7

.185

1.11

0.15e8.25

.916

1.27

1.09e1.49

.003

Time interval from antecedent pregnancy

Versus <2 months Last pregnancy outcome

Versus mole hCG level before treatment (IU/L)

Versus <1000 FIGO score 5e6 Versus 0e4 Number of metastases 0 Versus 1 Premature MTX interruption Versus complete regimen HCG normalization delay (mo) centered at mean (1.9 mo) Number of consolidation courses 0 courses

2.01

0.18e22.2

.569

1e1.5 coursesa

2.48

0.26e23.9

.431

2 courses

2.08

0.28e15.6

.476

5e8 courses

6.19

1.43e26.8

.015

9 courses

6.80

1.32e35.1

.022

1.13

1.00e1.28

.055

Versus 3 courses Number of whole courses of MTX

Versus 1e4 courses Number of whole courses of MTX (continued value) a

1.5 courses: patients who did not complete the second course of MTX because of bad tolerance. Couder et al. Predicting relapse in low-risk gestational trophoblastic neoplasia patients. Am J Obstet Gynecol 2016.

continuing to promote its use by all physicians treating GTN patients.17 Our results also show that the overall number of MTX courses is an

independent predictive factor for relapse after MTX alone. The significantly higher relapse risk associated with patients receiving 5e8 courses or

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more than 9 courses compared to patients receiving 1e4 courses of MTX reveals additional heterogeneity among low-risk GTN patients. A similar limit of 8 courses of chemotherapy has been reported as a predictive factor for relapse in a more heterogeneous population of low- and high-risk GTN patients.7 In our study, this predictive value was independent of antecedent pregnancy type and other expected prognostic factors, such as FIGO score and other FIGO score components as asserted by the Cox model, suggesting different biological behaviors among low-risk patients whose hCG normalized with MTX. This supports published findings of a proportion of lowrisk GTN patients whose hCG returned to normal in a median 5 weeks, with 1 single course of MTX without any consolidation course together with a crude relapse rate as low as 2%.19 The proportion of patients treated with 1 single course of MTX ranged from 44.8% to 81.5%.19,20 This is also consistent with the outcomes of 2 previous studies, in which the strong predictive value of early hCG-modeled residual production (hCGres) regarding the risk of MTX failure was reported.4,21 Indeed, modeled hCGres is estimated on the basis of hCG values measured during the first 50 days after the start of treatment, thereby suggesting the strong prognostic value of early hCG decline during the first chemotherapy cycles. Together with our inability to identify the number of consolidation courses as an independent predictive factor for relapse, these results could mean that consolidation courses could be critical only for lowrisk GTN patients needing the highest number of chemotherapy courses. Of course, this assumption was not directly raised from the present study and must be further assessed on the basis of previously published data.6,7 The results reported herein should be interpreted with caution, given the small number of patients with relapse or those with low-risk GTN after delivery, although it is the largest study with multivariate analysis of predictive factors for relapse to date. The relatively high

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TABLE 3

Multivariate analyses of risk factors in relapsing patients Adjusted hazard ratio

95% CI HR

P

Post term pregnancy

8.66

1.98e37.9

.0042

Post abortion or ectopic

1.07

0.14e7.98

.95

5e8 courses

6.7

1.54e29.2

.011

9 courses

8.1

1.54e42.6

.014

Parameter Last pregnancy outcome

Versus post mole Number of whole courses of MTX

Versus 1e4 courses Couder et al. Predicting relapse in low-risk gestational trophoblastic neoplasia patients. Am J Obstet Gynecol 2016.

number of patients contributed to the good statistical power of analysis. The results we present relate to our cohort but may not be applicable to another group of patients. The data used in the analysis conformed to “real-life” patient data: treatment in various French hospitals and hCG concentrations determined in different laboratories using various immunoassay kits that may give different results from one patient to another. Despite these limitations, our results are highly statistically significant. In conclusion, the relapse risk of FIGO-defined low-risk GTN patients was significantly higher when occurring after a delivery than after any other type of pregnancy. While promotion of the FIGO scoring/staging system is essential for international comparison, allotting a higher score to the “antecedent pregnancy” FIGO item when occurring after a delivery should be considered. The independent association of relapse risk with the number of whole MTX courses suggests different biological behaviors among low-risk GTN patients. The number of consolidation courses should be further analyzed in light of these new data. Patients needing more courses of MTX should be warned that they are at higher risk of relapse. n References 1. Golfier F, Massardier J, Gustalla J-P, et al. Prise en charge des maladies trophoblastiques

gestationnelles. J Gynecol Obstet Biol Reprod (Paris) 2010;39(3):25-32. 2. Ngan HY, Bender H, Benedet JL, Jones H, Montruccoli GC, Pecorelli S. FIGO Committee on Gynecologic Oncology. Gestational trophoblastic neoplasia, FIGO 2000 staging and classification. Int J Gynaecol Obstet 2003;83(Suppl 1):175-7. 3. Lybol C, Centen DW, Thomas CM, et al. Fatal cases of gestational trophoblastic neoplasia over four decades in the Netherlands: a retrospective cohort study. BJOG 2012;119(12): 1465-72. 4. You B, Pollet-Villard M, Fronton L, et al. Predictive values of hCG clearance for risk of methotrexate resistance in low-risk gestational trophoblastic neoplasias. Ann Oncol 2010;21: 1643-50. 5. Chapman-Davis E, Hoekstra AV, Rademaker AW, Schink JC, Lurain JR. Treatment of nonmetastatic and metastatic low-risk gestational trophoblastic neoplasia: factors associated with resistance to single-agent methotrexate chemotherapy. Gynecol Oncol 2012;125(3):572-5. 6. Lybol C, Sweep FC, Harvey R, et al. Relapse rates after two versus three consolidation courses of methotrexate in the treatment of low-risk gestational trophoblastic neoplasia. Gynecol Oncol 2012;125:576-9. 7. Yang J, Xiang Y, Wan X, Yang X. Recurrent gestational trophoblastic tumor: management and risk factors for recurrence. Gynecol Oncol 2006;103:587-90. 8. Matsui H, Suzuka K, Yamazawa K, et al. Relapse rate of patients with low-risk gestational trophoblastic tumor initially treated with singleagent chemotherapy. Gynecol Oncol 2005;96: 616-20. 9. Chalouhi GE, Golfier F, Soignon P, et al. Methotrexate for 2000 FIGO low-risk gestational trophoblastic neoplasia patients: efficacy and toxicity. Am J Obstet Gynecol 2009;200: 643-6. 10. Bagshawe KD, Dent J, Newlands ES, et al. The role of low-dose methotrexate and

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folinic acid in gestational trophoblastic tumors (GTT). Br J Obstet Gynaecol 1989;96: 795-802. 11. Ngan S, Seckl MJ. Gestational trophoblastic neoplasia management: an update. Curr Opin Oncol 2007;19:486-91. 12. Osborne R, Gerulath A. What is the best regimen for low-risk gestational trophoblastic neoplasia? A review. J Reprod Med 2004;49: 602-16. 13. McNeish IA, Strickland S, Holden L, et al. Low-risk persistent gestational trophoblastic disease: outcome after initial treatment with low-dose methotrexate and folinic acid from 1992 to 2000. J Clin Oncol 2002;20(7): 1838-44. 14. Powles T, Savage PM, Stebbing J, et al. A comparison of patients with relapsed and chemo-refractory gestational trophoblastic neoplasia. Br J Cancer 2007;96:732-7. 15. Kerkmeijer LG, Wielsma S, Massuger LF, et al. Recurrent gestational trophoblastic disease after hCG normalization following hydatidiform mole in The Netherlands. Gynecol Oncol 2007;106:142-6. 16. Neubauer NL, Strohl AE, Schink JC, Lurain JR. Fatal gestational trophoblastic neoplasia: an analysis of treatment failures at the Brewer Trophoblastic Disease Center from 1979-2012 compared to 1962-1978. Gynecol Oncol 2015;138(2):339-42. 17. Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet 2010;376: 717-29. 18. Chapman-Davis E, Hoekstra AV, Rademaker AW, Schink JC, Lurain JR. Treatment of nonmetastatic and metastatic low-risk gestational trophoblastic neoplasia: factors associated with resistance to single-agent methotrexate chemotherapy. Gynecol Oncol 2012;125(3):572-5. 19. Chan KK, Huang Y, Tam KF, Tse KY, Ngan HY. Single-dose methotrexate regimen in the treatment of low-risk gestational trophoblastic neoplasia. Am J Obstet Gynecol 2006;195(5):1282-6. 20. Growdon WB, Wolfberg AJ, Goldstein DP, et al. Evaluating methotrexate treatment in patients with low-risk post-molar gestational trophoblastic neoplasia. Gynecol Oncol 2009;112(2):353-7. 21. You B, Harvey R, Henin E, et al. Early prediction of treatment resistance in lowrisk gestational trophoblastic neoplasia using population kinetic modelling of hCG measurements. Br J Cancer 2013;108(9): 1810-6.

Author and article information From the Service de Gyne´cologie-Obste´trique et de Chirurgie Oncologique du Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Faculte´ de Me´decine Lyon Sud, Universite´ Lyon 1 (Drs Couder and Golfier); Centre de Re´fe´rence des Maladies Trophoblastiques

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de Lyon, Faculte´ de Me´decine Lyon Sud, Universite´ Lyon 1 (Drs Massardier, You, Hajri, Lotz, Schott, and Golfier); Service d’Obste´trique, Centre Hospitalier Femme-Me`re-Enfant, Hospices Civils de Lyon, Universite´ Lyon 1 (Dr Massardier); Service d’Oncologie Me´dicale, CITOHL, Service d’He´matologie, Institut de Cance´rologie des Hospices Civils de Lyon (IC-HCL),

Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Faculte´ de Me´decine Lyon Sud, Universite´ Lyon 1 (Dr You); Universite´ de Lyon, Hospices Civils de Lyon, HESPER (Drs Abbas and Schott); and Service d’Oncologie, Centre Hospitalier Tenon, Assistance Publique-Hoˆpitaux de Paris, Universite´ Pierre et Marie Curie (Dr Lotz), France.

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ajog.org Received Sept. 14, 2015; revised Jan. 13, 2016; accepted Jan. 22, 2016. The authors report no conflict of interest. Source of Funding: Institut National du Cancer (INCa), Ligue National Contre le Cancer. Corresponding author: Franc¸ois Golfier, MD, PhD. franc¸[email protected]