Abstracts
PURPOSE:
To compare two single-agent chemotherapy (ChT) regimens evaluating, in first-line treatment, response and side effects and, in final single-agent treatment, the outcomes, among Brazilian patients with low-risk gestational trophoblastic neoplasia (GTN), according to International Federation of Gynecology and Obstetrics (FIGO) 2002.
METHODS:
Retrospective analysis of two concurrent cohorts with 194 low-risk GTN patients: from 1992 to 2012, as first-line treatment, 115 patients received 4 intramuscular doses of methotrexate alternated with 4 oral doses of folinic acid (MTX/FA) repetead every 14 days and, since 1996, 79 patients received an endovenous bolus-dose of actinomycin D (Act-D), biweekly. At GTN diagnosis, patient opinion was taken into consideration when defining the initial single-agent ChT regimen, and when there was resistance or toxicity to one regimen, the other drug was used preferentially. This study was approved by the Irmandade da Santa Casa de Misericórdia de Porto Alegre Ethical Committee.
RESULTS:
Both groups were clinically similar (p>0.05). In first-line treatments, frequency of complete response was similar (75.7% with MTX/FA and 67.1% with bolus Act-D); the number of ChT courses -median 3 (range: 1-10) with MTX/FA and 2 (range: 1-6) with bolus Act-D - and the time to remission -median 9 weeks (range: 2-16) with MTX/FA and 10 weeks (range: 2-16) with bolus Act-D) - were not different between the groups. In both groups, first-line side effects frequency were high but intensity was low; stomatitis was higher with MTX/FA (p<0.01) and nausea and vomit with Act-D (p<0.01). Final single-agent ChT responses were high in both groups (94.8% with MTX/FA and 83.5% with bolus Act-D; p<0.01) and 13% higher in the group initially treated with MTX/FA. Rates of hysterectomy and of GTN recurrence were low and similar. No patient died due to GTN.
CONCLUSION:
The two regimens had similar first-line ChT response. Final single-agent response rates were high and similar in both groups but the final single-agent remission rate was higher in the MTX/FA group.
Methotrexate/administration & dosage; Methotrexate/therapeutic use; Methotrexate/adverse effects; Dactinomycin/administration & dosage; Dactinomycin/therapeutic use; Dactinomycin/adverse effects; Gestational trophoblastic disease/drug therapy
OBJETIVO:
Em mulheres brasileiras com neoplasia trofoblástica gestacional (NTG) de baixo-risco, de acordo com a Federação Internacional de Ginecologia e Obstetrícia (FIGO) 2002, comparar dois regimes de quimioterapia (Qt) por agente único avaliando resposta e efeitos colaterais no tratamento de primeira linha, e a eficácia no tratamento final por agente único de Qt.
MÉTODOS:
Análise retrospectiva de duas coortes concorrentes com 194 pacientes com NTG de baixo risco: de 1992 a 2012; como primeira linha, 115 pacientes receberam 4 doses intramusculares de metotrexato alternado com 4 doses orais de ácido folínico (MTX/FA) repetidos a cada 14 dias e, desde 1996, 79 pacientes receberam quinzenalmente dose em bolo de actinomicina D (Act-D) por via endovenosa. No momento do diagnóstico da NTG, a opinião da paciente foi levada em consideração para definir o regime de Qt por agente único inicial e, quando havia resistência ou toxicidade a um regime, o outro fármaco era usado preferentemente. Este estudo foi aprovado pelo Comitê de Ética da Irmandade da Santa Casa de Misericórdia de Porto Alegre.
RESULTADOS:
Ambos os grupos eram clinicamente semelhantes (p>0,05). Nos tratamentos de primeira linha, a frequência de resposta completa foi semelhante (75,7% com MTX/FA e 67,1% com Act-D em bolo); não houve diferença entre os grupos quanto ao número de séries de Qt - mediana 3 (intervalo: 1-10) com MTX/FA e 2 (intervalo: 1-6) com Act-D em bolo - e ao tempo para remissão - mediana 9 semanas (intervalo: 2-16) com MTX/FA e 10 semanas (intervalo: 2-16) com Act-D em bolo. Em ambos os grupos, foi elevada a frequência de efeitos colaterais no tratamento de primeira linha, mas com intensidade baixa; estomatite foi mais frequente com MTX/FA (p<0.01) e náuseas e vômitos com Act-D (p<0.01). A resposta final à Qt por agente único foi alta nos dois grupos (94,8% com MTX/FA e 83,5% com Act-D em bolo; p<0,01) e 13% maior no grupo inicialmente tratado com MTX/FA. As frequências de histerectomia e de recorrência da NTG foram baixas e semelhantes. Nenhuma paciente morreu devido à NTG.
CONCLUSÃO:
Os dois regimes tiveram resultados semelhantes no tratamento de primeira linha. A resposta final ao tratamento por agente único foi alta e semelhante, mas a taxa final de remissão foi maior no grupo iniciado por MTX/FA.
Metotrexato/administração & dosagem; Metotrexato/uso terapêutico; Metotrexato/efeitos adversos; Dactinomicina/administração & dosagem; Dactinomicina/uso terapêutico; Dactinomicina/efeitos adversos; Doença trofoblástica gestacional/quimioterapia
Introduction
Gestational trophoblastic disease (GTD) describes a rare and highly curable group of
tumors pathologies that arise from tissues of placental origin and results from abnormal
conception caused by aberrant fertilization11 Seckl MJ, Sebire NJ, Fisher RA, Golfier R, Massuger L, Sessa C, et al.
Gestational trophoblastic disease: ESMO clinical practice guidelines for diagnosis,
treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:vi39-50..
Most GTD cases include the two types of hydatidiform moles (HM) that have a variable
potential to progress into the rare malignant dis ease, called gestational trophoblastic
neoplasia (GTN)22 May T, Goldstein DP, Berkowitz RS. Current chemotherapeutic management
of patients with gestational trophoblastic neoplasia. Chemother Res Pract.
2011;2011:806256.
,
33 Froeling FE, Seckl MJ. Gestational trophoblastic tumours: an update for
2014. Curr Oncol Rep. 2014;16(11):408.. GTN has become a highly curable tumor, with an
overall 90% of patient survival, due to the possibility of early diagnosis and treatment
monitoring, ideally in Reference Centers (RC), and the individualized chemotherapy (ChT)
based on prognostic factors, according scoring system of the International Federation of
Gynecology and Obstetrics (FIGO) 200211 Seckl MJ, Sebire NJ, Fisher RA, Golfier R, Massuger L, Sessa C, et al.
Gestational trophoblastic disease: ESMO clinical practice guidelines for diagnosis,
treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:vi39-50.
2 May T, Goldstein DP, Berkowitz RS. Current chemotherapeutic management
of patients with gestational trophoblastic neoplasia. Chemother Res Pract.
2011;2011:806256.
3 Froeling FE, Seckl MJ. Gestational trophoblastic tumours: an update for
2014. Curr Oncol Rep. 2014;16(11):408.
4 Biscaro A, Braga A, Berkowitz RS. Diagnosis, classification and
treatment of gestational trophoblastic neoplasia. Rev Bras Ginecol Obstet.
2015;37(1):42-51.
5 Lurain JR. Gestational trophoblastic disease II: classification and
management of gestational trophoblastic neoplasia. Am J Obstet Gynecol.
2011;204(1):11-8.
6 FIGO Oncology Committee. FIGO staging for gestational trophoblastic
neoplasia 2000. Int J Gynaecol Obstet. 2002;77(3):285-7.
-
77 Ngan HY, Kohorn EI, Cole LA, Kurman RJ, Kim SJ, Lurain JR, et al. FIGO
report 2012: trophoblastic disease. Int J Gynaecol Obstet. 2012;119 Suppl
2:S130-6..
The FIGO 2002 defined that low-risk GTN could be treated with single-agent ChT,
resulting in final survival rates approaching 100%33 Froeling FE, Seckl MJ. Gestational trophoblastic tumours: an update for
2014. Curr Oncol Rep. 2014;16(11):408.
,
77 Ngan HY, Kohorn EI, Cole LA, Kurman RJ, Kim SJ, Lurain JR, et al. FIGO
report 2012: trophoblastic disease. Int J Gynaecol Obstet. 2012;119 Suppl
2:S130-6.. Several studies with Methotrexate (MTX) and
Actinomycin D (Act-D) protocols have been used for treatment of low-risk GTN88 Chapman-Davis E, Hoekstra AV, Rademaker AW, Schink JC, Lurain JR.
Treatment of nonmetastatic and metastatic low-risk gestational neoplasia: factors
associated with resistance to single-agent methotrexate chemotherapy. Gynecol Oncol.
2012;125(3):572-5.
9 Growdon WB, Wolfberg AJ, Goldstein DP, Feltmate CM, Chinchilla ME,
Lieberman ES, et al. Evaluating methotrexate treatment in patients with low-risk
postmolar gestational trophoblastic neoplasia. Gynecol Oncol.
2009;112(2):353-7.
10 Covens A, Filiaci VL, Burger RA, Osborne R, Chen MD; Gynecologic
Oncology Group. Phase II trial of pulse dactinomycin as salvage therapy for failed
low-risk gestational trophoblastic neoplasia: a Gynecologic Oncology Group study.
Cancer. 2006;107(6):1280-6.
11 Lurain JR, Chapman-Davis E, Hoekstra AV, Schink JC. Actinomycin D for
methotrexate-failed low-risk gestational trophoblastic neoplasia. J Reprod Med.
2012;57(7-8):283-7.
-
1212 Petrilli ES, Twiggs LB, Blessing JA, Teng NH, Curry S. Single-dose
actinomycin D treatment for nonmetastatic gestational trophoblastic disease. A
prospective phase II trial of the Gynecologic Oncology Group. Cancer.
1987;60(9):2173-6.; nevertheless, few studies compared these two
drugs in the management of low-risk GTN1313 Lertkhachonsuk AA, Israngura N, Wilailak S, Tangtrakul S. Actinomycin d
versus methotrexate-folinic acid as the treatment of stage I, low-risk gestational
trophoblastic neoplasia: a randomized controlled trial. Int J Gynecol Cancer.
2009;19(5):985-8.
14 Abrão RA, de Andrade JM, Tiezzi DG, Marana HR, Candido dos Reis FJ,
Clagnan WS. Treatment for low-risk gestational trophoblastic disease: comparison of
single-agent methotrexate, dactinomycin and combination regimens. Gynecol Oncol.
2008;108(1):149-53.
15 Mousavi A, Cheraghi F, Yarandi F, Gilani MM, Shojaei H. Comparison of
pulsed actinomycin-D versus 5-day methotrexate for the treatment of low-risk
gestational trophoblastic neoplasia. Int J Gynecol Obstet.
2012;116(1):39-42.
-
1616 Osborne RJ, Filiaci V, Schink JC, Mannel RS, Alvarez Secord A, Kelley
JL, et al. Phase III trial of weekly methotrexate or pulsed dactinomycin for low risk
gestational trophoblastic neoplasia: a gynecologic oncology group study. J Clin
Oncol. 2011;29(7):825-31.. Osborne et al.1616 Osborne RJ, Filiaci V, Schink JC, Mannel RS, Alvarez Secord A, Kelley
JL, et al. Phase III trial of weekly methotrexate or pulsed dactinomycin for low risk
gestational trophoblastic neoplasia: a gynecologic oncology group study. J Clin
Oncol. 2011;29(7):825-31. has recently published a randomized study that suggests that the use of a
bolus dose of Act-D every 15 days might be more effective than the administration of a
weekly dose of MTX1616 Osborne RJ, Filiaci V, Schink JC, Mannel RS, Alvarez Secord A, Kelley
JL, et al. Phase III trial of weekly methotrexate or pulsed dactinomycin for low risk
gestational trophoblastic neoplasia: a gynecologic oncology group study. J Clin
Oncol. 2011;29(7):825-31.. A randomized multi-center
trial (GOG0275) is underway to compare pulsed Act-D with other MTX administration
schemes1717 Schink J. Methotrexate or dactinomycin in treating patients with
low-risk gestational trophoblastic neoplasia [Internet]. 2015 [cited 2015 Jan 15].
Available from:
<http://www.cancer.gov/about-cancer/treatment/clinical-trials/search/view?cdrid=725211&version=HealthProfessional>
http://www.cancer.gov/about-cancer/treat...
. To our knowledge, no study has
evaluated the use of biweekly 8-day MTX alternated with folinic acid (MTX/FA) and
bolus-dose Act-D. This retrospective study compared the results of these regimens,
administered as first-line and as total single-agent ChT, to two concurrent cohorts of
Brazilian patients with FIGO 2002 low-risk GTN.
Methods
From March 1985 to September 2012, from 1,678 cases with GTD and after excluding 70 patients (4.2%) due to pre-remission loss to follow-up (45 cases - 2.7%) and due to transfers to other RC (25 cases - 1.5%), 300 GTN patients (17.9 %) were retrospectively analysed in the Trophoblastic Disease Center of Irmandade da Santa Casa de Misericórdia de Porto Alegre (ISCMPA), in Southern Brazil.
The GTN patients met FIGO 2002 criteria and had an hCG plateau of ±10% for at least 3 consecutive weeks, a rise of hCG >10% for 2 consecutive weeks, a high hCG for 6 months or longer77 Ngan HY, Kohorn EI, Cole LA, Kurman RJ, Kim SJ, Lurain JR, et al. FIGO report 2012: trophoblastic disease. Int J Gynaecol Obstet. 2012;119 Suppl 2:S130-6. , 1818 Uberti EMH, Diestel MCF, Guimarães FE, Lacerda ME, Rosa MW, Nápoli G, et al. Conduta no Tumor Trofoblástico Gestacional (TTG): experiência de 10 anos de um centro de referência. Acta Oncol Bras. 2000;20(2):53-62., or other Charing Cross Hospital indications for ChT in GTD11 Seckl MJ, Sebire NJ, Fisher RA, Golfier R, Massuger L, Sessa C, et al. Gestational trophoblastic disease: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:vi39-50. , 33 Froeling FE, Seckl MJ. Gestational trophoblastic tumours: an update for 2014. Curr Oncol Rep. 2014;16(11):408.. After the diagnosis of GTN was established, a staging evaluation was performed, using clinical, laboratorial and radiology resources, as recommended by FIGO 2002. Then, patients with GTN were categorized according to the FIGO 2002 criteria into a low (≤6) or high-risk (≥7) group. FIGO stage and score were retrospectively determined in patients treated prior to 2002. Complete response or remission was diagnosed after 3 consecutive weekly hCG levels were within normal range (<5 mIU/mL) and sustained remission, when the hCG level remained at that same level for 1 year11 Seckl MJ, Sebire NJ, Fisher RA, Golfier R, Massuger L, Sessa C, et al. Gestational trophoblastic disease: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:vi39-50. , 22 May T, Goldstein DP, Berkowitz RS. Current chemotherapeutic management of patients with gestational trophoblastic neoplasia. Chemother Res Pract. 2011;2011:806256. , 44 Biscaro A, Braga A, Berkowitz RS. Diagnosis, classification and treatment of gestational trophoblastic neoplasia. Rev Bras Ginecol Obstet. 2015;37(1):42-51. , 55 Lurain JR. Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol. 2011;204(1):11-8. , 77 Ngan HY, Kohorn EI, Cole LA, Kurman RJ, Kim SJ, Lurain JR, et al. FIGO report 2012: trophoblastic disease. Int J Gynaecol Obstet. 2012;119 Suppl 2:S130-6. , 1818 Uberti EMH, Diestel MCF, Guimarães FE, Lacerda ME, Rosa MW, Nápoli G, et al. Conduta no Tumor Trofoblástico Gestacional (TTG): experiência de 10 anos de um centro de referência. Acta Oncol Bras. 2000;20(2):53-62..
Our management protocol is shown in Figure 1. We excluded 106 patients: 35/300 patients (11.7%), due to high-risk GTN; 38/300 patients (12.7%), due to hysterectomy before ChT; 10/300 patients (3.3%), due to emergency treatment with bolus Act-D, immediately followed by 8-day MTX/FA; 23/300 patients (7.7%), due to other therapy than the studied ChT regimens.
Management and outcome of patients with low-risk gestational trophoblastic neoplasia treated with single-agent high-dose Methotrexate alternated with folinic acid or bolus dose of Actinomycin D, repeated each two weeks
A final cohort population with 194 low-risk GTN patients was included in the study. All patients were primarily treated as outpatient with one of the two single-agent ChT regimens described here, and, at GTN diagnosis, patient opinion was taken into consideration when defining the initial single-agent ChT regimen: Group A (GA): from October 1992 to September 2012; for 115 patients (59.3%), the first-line single-agent ChT was the 8-day MTX/FA regimen, which consisted of 4 intramuscular doses of 1 mg/kg MTX every other day plus 0.1 mg/kg to 15 mg of oral folinic acid in the intervening day, recycled every 14 days until hCG remission and then, after one normal hCG value (<5 mUI/mL), treatment was maintained for 6 weeks post-remission. Group B (GB): from September 1996 to September 2012; for 79 patients (40.7%), the first-line single-agent ChT was the pulsed Act-D regimen, which consisted of administration of intravenous Act-D (1.25 mg/m2; maximum dose: 2.0 mg), recycled every 14 days until hCG remission and then, after one normal hCG value, ChT treatment was maintained for more 6 weeks post-remission. When there was resistance or toxicity to one regimen, the other drug was used preferentially.
GTN surveillance during treatment included bi-weekly measurements of serum hCG levels on the first day of each course of treatment. The regression hCG curve for each patient was compared with the standard curve established by Schlaerth et al.1919 Schlaerth JB, Morrow CP, Kletzky AO, Nalick RH, D'Ablaing GA. Prognostic characteristics of serum human chorionic gonadotropin titer regression following molar pregnancy. Obstet Gynecol. 1981;58(4):478-82.. Regardless of hCG serum levels, when evidence of resistance or toxicity to first-single-agent ChT was identified, patients received the other single-agent ChT regimen. All patients required advice about pregnancy prevention and they generally received contraceptive pills every month. After the first normal hCG, the patients received two to three cycles of the last ChT regimen as treatment consolidation1818 Uberti EMH, Diestel MCF, Guimarães FE, Lacerda ME, Rosa MW, Nápoli G, et al. Conduta no Tumor Trofoblástico Gestacional (TTG): experiência de 10 anos de um centro de referência. Acta Oncol Bras. 2000;20(2):53-62. , 2020 Bagshawe KD. Choriocarcinoma: a model for tumour markers. Acta Oncol. 1992;31(1):99-106.. After ChT completion, the patients underwent clinical examination and hCG measurements as recommended by Bagshawe2020 Bagshawe KD. Choriocarcinoma: a model for tumour markers. Acta Oncol. 1992;31(1):99-106.. One year after ChT completion, the patients were released to become pregnant11 Seckl MJ, Sebire NJ, Fisher RA, Golfier R, Massuger L, Sessa C, et al. Gestational trophoblastic disease: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:vi39-50. , 22 May T, Goldstein DP, Berkowitz RS. Current chemotherapeutic management of patients with gestational trophoblastic neoplasia. Chemother Res Pract. 2011;2011:806256. , 55 Lurain JR. Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol. 2011;204(1):11-8. , 77 Ngan HY, Kohorn EI, Cole LA, Kurman RJ, Kim SJ, Lurain JR, et al. FIGO report 2012: trophoblastic disease. Int J Gynaecol Obstet. 2012;119 Suppl 2:S130-6. , 1818 Uberti EMH, Diestel MCF, Guimarães FE, Lacerda ME, Rosa MW, Nápoli G, et al. Conduta no Tumor Trofoblástico Gestacional (TTG): experiência de 10 anos de um centro de referência. Acta Oncol Bras. 2000;20(2):53-62..
When a third-line GTN treatment was necessary, most patients received the EMA/CO multi-agent ChT regimen (etoposide + MTX/FA + Act-D + vincristine + cyclophosphamide)11 Seckl MJ, Sebire NJ, Fisher RA, Golfier R, Massuger L, Sessa C, et al. Gestational trophoblastic disease: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:vi39-50. , 22 May T, Goldstein DP, Berkowitz RS. Current chemotherapeutic management of patients with gestational trophoblastic neoplasia. Chemother Res Pract. 2011;2011:806256. , 55 Lurain JR. Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol. 2011;204(1):11-8. , 77 Ngan HY, Kohorn EI, Cole LA, Kurman RJ, Kim SJ, Lurain JR, et al. FIGO report 2012: trophoblastic disease. Int J Gynaecol Obstet. 2012;119 Suppl 2:S130-6., but a few patients chose to undergo secondary hysterectomy associated with single-agent ChT1818 Uberti EMH, Diestel MCF, Guimarães FE, Lacerda ME, Rosa MW, Nápoli G, et al. Conduta no Tumor Trofoblástico Gestacional (TTG): experiência de 10 anos de um centro de referência. Acta Oncol Bras. 2000;20(2):53-62. , 2121 Pires LV, Uberti EM, Fajardo MC, da Cunha AG, Rosa MW, Ayub AC, et al. Role of hysterectomy in the management of patients with gestational trophoblastic neoplasia: importance of receiving treatment in reference centers. J Reprod Med. 2012;57(7-8):359-68..
Patient and disease characteristics, including age, parity and hCG serum level before treatment, FIGO 2002 anatomic staging and risk score, response rate with first-line single-agent ChT (time to achieve GTN remission, number of ChT courses, frequency and intensity of toxic treatment effects according to the National Institute of Health standard toxicity criteria), response rate to alternative single-agent ChT in second-line ChT, overall percentage of response to first- and second-line ChT treatment were analysed. Finally, data about secondary hysterectomy rates, discharge conditions, duration of follow-up and compliance to treatment were also collected, as well as GTN recurrence. Patient adherence to follow up was evaluated up to December 2013.
Categorical variables were analyzed and described using frequency rates, followed by the analysis of quantitative variables; results were described as means and standard deviations or medians and inter-quartile ranges. The Pearson χ2 test was used to compare qualitative variables and to identify possible associations between them. The Student's t-test was used to compare means between two independent groups; in case continuous variables had an asymmetric distribution, the Mann-Whitney test was used. The level of significance was set at p<0.05 for all tests. All analyses were conducted using the Statistical Package for the Social Sciences 17.0 (IBM, Armonk, NY, USA). This study was approved by the Institutional Review Board of ISCMPA (Registration number: 3625/11), and an institutional confidentiality term was adopted.
Results
In both groups, most patients were classified as FIGO 2002 stage I (GA=92.2% and GB=91.1%), and risk scores were lower than 5 (GA=95.6% and GB=94.9%). There were no differences between groups in age, parity, weight, histopathology, FIGO 2002 stage/score and serum hCG levels at the beginning of treatment (Table 1). Because in the three cases of FIGO 2002 stage II patients the chosen initial treatment was with bolus-Act-D, the time to diagnosis was significantly shorter in GB than in GA.
Treatment results are shown in Table 2. There were no differences in the comparison of first-line single-agent ChT complete response rate (75.7x67.1%), number of courses (median, 3x2 cycles) and time to GTN remission (median, 9x10 weeks) between GA and GB, respectively. As secondary therapy, the complete response rate was 75% (21/28) in GA (alternatively treated now with Act-D) and 50% (13/26) in GB (now received MTX/FA). However, the overall complete response to sequential single-agent ChT was 94.8% in GA and 83.5% in GB (p=0.02). According to the Poisson regression, after adjustments to the hCG serum levels, time to diagnosis, age and FIGO 2002 stage, a higher response to first + second line remained significantly associated with GA (p=0.02). Patients who begin the GTN treatment with MTX/FA have 13% more probability of response in first + second line (RR=1.1; confidence interval of 95% - 95%CI 1.0-1.2). As a third-line treatment in the total sample, 15/194 patients (7.7%) received the EMA/CO multi-agent ChT regimen as salvage treatment after both single-agent ChT failure and the EMA/CO use rate was higher in GB (2.6% in GA and 15.2% in GB, p<0.01). In both groups, the frequency of surgical treatment with secondary hysterectomy and the GTN recurrence rate - respectively, 2.6% (3 patients) in GA and 1.3% (1 patient) in GB - were low and similar.
The frequency of response to first-line single-agent ChT according to the drug used and FIGO 2002 showed similar response rate between groups when FIGO 2002 score was below 5 (GA=77.3%, GB=69.3%). When second-line response according the hCG serum levels (Table 3) was evaluated, even when these levels were above 300 mIU/mL and although the case numbers were few (GA=7 patients; GB=23 patients), the frequency of response to the alternative single-agent ChT was good and similar (GA=28.6%; GB=43.5%), averting in these cases the use of multi-agent ChT.
Only 3 patients (2.6%) required a change from MTX/FA to pulsed Act-D due to grade 3 mouth ulcers, but no patients required hospital admission for treatment of toxicity. In both groups, total percentage of collateral effects was high, but their intensity was low (grade 1 or 2); they were easy to manage and more frequent in the pulsed Act-D group (p=0.04), especially nausea and vomits (p<0.01). However, in the MTX/FA group, there were higher percentages of mild stomatitis (mouth ulcers) (66.7%; p<0.01), pleuritis (14.8%; p<0.01) and sore eyes (33.3%; p=0.03) (Table 4).
In the total sample, the follow-up duration was high and similar between the groups - median (range): GA=5 years (1.4-16.6) and GB=4.5 years (1.1-11.3). Also, the frequency of medical discharge and of adherence to complete follow-up were elevated and not different among both groups (respectively, 86.9x96.2% and 93.1x96.3%). Almost all patients were alive and healthy (99.5%). The only death occurred in a patient in the Act-D group: it occurred 10 months after GTN remission and was due to adult immunodeficiency syndrome's gastrointestinal complications (bowel hemorrhage).
Discussion
To our knowledge, no study had evaluated the two analysed single-agent ChT regimens in low-risk GTN patients as we did in this concurrent cohort retrospective analysis. In this study, the first-line results for biweekly 8-days MTX/FA and pulsed Act-D among patients with a similar low-risk GTN FIGO 2002 were resemble. The hCG levels normalized in both groups in the same time and the patients received similar number of treatment cycles (p=0.06).
For nearly all low-risk GTN patients, single-agent ChT with either MTX or Act-D is the
preferred treatment11 Seckl MJ, Sebire NJ, Fisher RA, Golfier R, Massuger L, Sessa C, et al.
Gestational trophoblastic disease: ESMO clinical practice guidelines for diagnosis,
treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:vi39-50.
,
22 May T, Goldstein DP, Berkowitz RS. Current chemotherapeutic management
of patients with gestational trophoblastic neoplasia. Chemother Res Pract.
2011;2011:806256.
,
55 Lurain JR. Gestational trophoblastic disease II: classification and
management of gestational trophoblastic neoplasia. Am J Obstet Gynecol.
2011;204(1):11-8.
,
77 Ngan HY, Kohorn EI, Cole LA, Kurman RJ, Kim SJ, Lurain JR, et al. FIGO
report 2012: trophoblastic disease. Int J Gynaecol Obstet. 2012;119 Suppl
2:S130-6.
,
99 Growdon WB, Wolfberg AJ, Goldstein DP, Feltmate CM, Chinchilla ME,
Lieberman ES, et al. Evaluating methotrexate treatment in patients with low-risk
postmolar gestational trophoblastic neoplasia. Gynecol Oncol.
2009;112(2):353-7.
,
1818 Uberti EMH, Diestel MCF, Guimarães FE, Lacerda ME, Rosa MW, Nápoli G, et
al. Conduta no Tumor Trofoblástico Gestacional (TTG): experiência de 10 anos de um
centro de referência. Acta Oncol Bras. 2000;20(2):53-62.. A variety of regimens have been developed, in
which non-randomized, mostly retrospective studies demonstrate a 50-90% chance of
inducing remission2222 Alazzam M, Tidy J, Hancock BW, Osborne R, Lawrie TA. First-line
chemotherapy in low-risk gestational trophoblastic neoplasia. Cochrane Database Syst
Rev. 2012;7:CD007102.. Osborne et al.1616 Osborne RJ, Filiaci V, Schink JC, Mannel RS, Alvarez Secord A, Kelley
JL, et al. Phase III trial of weekly methotrexate or pulsed dactinomycin for low risk
gestational trophoblastic neoplasia: a gynecologic oncology group study. J Clin
Oncol. 2011;29(7):825-31. have suggested that pulsed Act-D is more likely
to induce remission than weekly MTX but this randomized study has been underpowered. We
are waiting for the results of an larger international trial run by the Gynecology
Oncology Group in the United States, begun in 2013 (NCT01535053), evaluating quality of
life and acceptability of treatment with the objective of helping to define the optimum
single-agent approach1717 Schink J. Methotrexate or dactinomycin in treating patients with
low-risk gestational trophoblastic neoplasia [Internet]. 2015 [cited 2015 Jan 15].
Available from:
<http://www.cancer.gov/about-cancer/treatment/clinical-trials/search/view?cdrid=725211&version=HealthProfessional>
http://www.cancer.gov/about-cancer/treat...
,
2323 Taylor F, Grew T, Everard J, Ellis L, Winter MC, Tidy J, et al. The
outcome of patients with low risk gestational trophoblastic neoplasia treated with
single-agent intramuscular methotrexate and oral folinic acid. Eur J Cancer.
2013;49(15):3184-90.. However, this trial did not include the
chosen MTX regimen as we used in this study.
As the success rates of treating GTN with known agents are high, investigators have
evaluated modified protocols for administering MTX to limit systemic toxicity, to reduce
overall time to remission and costs, with no hospitalization22 May T, Goldstein DP, Berkowitz RS. Current chemotherapeutic management
of patients with gestational trophoblastic neoplasia. Chemother Res Pract.
2011;2011:806256.
3 Froeling FE, Seckl MJ. Gestational trophoblastic tumours: an update for
2014. Curr Oncol Rep. 2014;16(11):408.
4 Biscaro A, Braga A, Berkowitz RS. Diagnosis, classification and
treatment of gestational trophoblastic neoplasia. Rev Bras Ginecol Obstet.
2015;37(1):42-51.
5 Lurain JR. Gestational trophoblastic disease II: classification and
management of gestational trophoblastic neoplasia. Am J Obstet Gynecol.
2011;204(1):11-8.
6 FIGO Oncology Committee. FIGO staging for gestational trophoblastic
neoplasia 2000. Int J Gynaecol Obstet. 2002;77(3):285-7.
-
77 Ngan HY, Kohorn EI, Cole LA, Kurman RJ, Kim SJ, Lurain JR, et al. FIGO
report 2012: trophoblastic disease. Int J Gynaecol Obstet. 2012;119 Suppl
2:S130-6.. According to Osborne and Gerulath2424 Osborne R, Gerulath A. What is the best regimen for low-risk gestational
trophoblastic neoplasia? A review. J Reprod Med. 2004;49(8):602-16., the MTX regimen, most commonly used in Europe
and the rest of the world, excluding North America, is the Charing Cross modified
Bagshawe 8-day regimen: a fixed dose of 50 mg MTX repeated every 14-16 days; on the
results of 10 studies using MTX/FA in 1,238 patients, they reported a primary resistance
in 20.3% (our results, 24.3%); a number of ChT series ranging from 1.4 to 8.0 (our
results, median 3(2)); a toxicity that required a change of ChT regimen in 1% (our
results, 2,6%) and total primary cure of 79.2% (our results, 75.7%).
Act-D is one of the two most used drugs in the treatment of low-risk GTN11 Seckl MJ, Sebire NJ, Fisher RA, Golfier R, Massuger L, Sessa C, et al. Gestational trophoblastic disease: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:vi39-50. , 22 May T, Goldstein DP, Berkowitz RS. Current chemotherapeutic management of patients with gestational trophoblastic neoplasia. Chemother Res Pract. 2011;2011:806256. , 55 Lurain JR. Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol. 2011;204(1):11-8.. Usually, it is administered using a 5-day EV schedule in the cases of MTX resistance or toxicity88 Chapman-Davis E, Hoekstra AV, Rademaker AW, Schink JC, Lurain JR. Treatment of nonmetastatic and metastatic low-risk gestational neoplasia: factors associated with resistance to single-agent methotrexate chemotherapy. Gynecol Oncol. 2012;125(3):572-5. , 1111 Lurain JR, Chapman-Davis E, Hoekstra AV, Schink JC. Actinomycin D for methotrexate-failed low-risk gestational trophoblastic neoplasia. J Reprod Med. 2012;57(7-8):283-7. , 1212 Petrilli ES, Twiggs LB, Blessing JA, Teng NH, Curry S. Single-dose actinomycin D treatment for nonmetastatic gestational trophoblastic disease. A prospective phase II trial of the Gynecologic Oncology Group. Cancer. 1987;60(9):2173-6.. In order to reduce the high rate and intensity of collateral effects with 5-day Act-D schedule, several authors have investigated the use of the so-called pulsed Act-D regimen1515 Mousavi A, Cheraghi F, Yarandi F, Gilani MM, Shojaei H. Comparison of pulsed actinomycin-D versus 5-day methotrexate for the treatment of low-risk gestational trophoblastic neoplasia. Int J Gynecol Obstet. 2012;116(1):39-42. , 1616 Osborne RJ, Filiaci V, Schink JC, Mannel RS, Alvarez Secord A, Kelley JL, et al. Phase III trial of weekly methotrexate or pulsed dactinomycin for low risk gestational trophoblastic neoplasia: a gynecologic oncology group study. J Clin Oncol. 2011;29(7):825-31.. When used as first-line ChT for low-risk GTN patients, pulsed Act-D had the following results in 4 studies: mean number of courses was 4.9 - our results, median 2; resistance was 8-24% - our results, 32.9%; and cure rate ranged from 76% (low-risk metastatic GTN) to 86% (non-metastatic GTN) -our results, 67.1%, with most patients in stage I of FIGO 20021212 Petrilli ES, Twiggs LB, Blessing JA, Teng NH, Curry S. Single-dose actinomycin D treatment for nonmetastatic gestational trophoblastic disease. A prospective phase II trial of the Gynecologic Oncology Group. Cancer. 1987;60(9):2173-6. , 1313 Lertkhachonsuk AA, Israngura N, Wilailak S, Tangtrakul S. Actinomycin d versus methotrexate-folinic acid as the treatment of stage I, low-risk gestational trophoblastic neoplasia: a randomized controlled trial. Int J Gynecol Cancer. 2009;19(5):985-8. , 1616 Osborne RJ, Filiaci V, Schink JC, Mannel RS, Alvarez Secord A, Kelley JL, et al. Phase III trial of weekly methotrexate or pulsed dactinomycin for low risk gestational trophoblastic neoplasia: a gynecologic oncology group study. J Clin Oncol. 2011;29(7):825-31..
Kohorn2525 Kohorn EI. Is lack of response to single-agent chemotherapy in gestational trophoblastic disease associated with dose scheduling or chemotherapy resistance? Gynecol Oncol. 2002;85(1):36-9. and others1010 Covens A, Filiaci VL, Burger RA, Osborne R, Chen MD; Gynecologic Oncology Group. Phase II trial of pulse dactinomycin as salvage therapy for failed low-risk gestational trophoblastic neoplasia: a Gynecologic Oncology Group study. Cancer. 2006;107(6):1280-6. , 1111 Lurain JR, Chapman-Davis E, Hoekstra AV, Schink JC. Actinomycin D for methotrexate-failed low-risk gestational trophoblastic neoplasia. J Reprod Med. 2012;57(7-8):283-7. recommended abandoning the use of combination ChT, as an immediate second-line treatment for primary single-agent failure. We agree with his recommendation and we have tried to use the alternative single-agent ChT regimen, irrespective of the hCG level, before the administration of multi-agent ChT. We had a high overall response rate of 94.8 and 83.5% in patients respectively initially treated with MTX/FA and pulsed Act-D (p=0.019); and patients that begin the GTN treatment with MTX/FA have 13% more probability of response in first + second line (RR=1.1; 95%CI 1.0-1.2).
Although a few patients were submitted to a second-line treatment (respectively, 28 with MTX/FA and 26 with pulsed Act-D), in Act-D group the response to alternative second-line treatment was not different when serum hCG levels were above or below 300 mIU/mL (p=0.2); nevertheless, with this management of second-line treatment, we could avoid the multiagent ChT in 2/7 patients (28.6%) in GA and in 10/23 patients (43.5%) in GB. In our RC, we will continue evaluating the second-line treatment responses to the studied single-agent ChT in low-risk GTN patients1212 Petrilli ES, Twiggs LB, Blessing JA, Teng NH, Curry S. Single-dose actinomycin D treatment for nonmetastatic gestational trophoblastic disease. A prospective phase II trial of the Gynecologic Oncology Group. Cancer. 1987;60(9):2173-6. , 2525 Kohorn EI. Is lack of response to single-agent chemotherapy in gestational trophoblastic disease associated with dose scheduling or chemotherapy resistance? Gynecol Oncol. 2002;85(1):36-9., which may protect some patients against the effects of the more toxic multi-agent ChT.
Adverse events were relatively modest on either regimen. There was an observed increase in grades 1 and 2 gastrointestinal adverse effects in patients receiving pulsed Act-D. In patients receiving MTX/FA, there were higher grade 2 stomatitis, pleural pain due to serositis, and sore eyes, especially after the first cycle of ChT. Alopecia was not observed with MTX/FA and was not significant with pulsed Act-D.
To reduce the rate of recurrence, we used a mean of 2-3 consolidation ChT with the last used ChT scheme (respectively, 1.9±0.8 cycles with MTX/FA and 2.1±0.7 cycles with pulsed Act-D; p=0.07), and our recurrence rates (MTX/FA=2.6%, pulsed Act-D=1.3%; p=0.64) were similar to the overall recurrence rate of 4-8% reported in the literature11 Seckl MJ, Sebire NJ, Fisher RA, Golfier R, Massuger L, Sessa C, et al. Gestational trophoblastic disease: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:vi39-50. , 22 May T, Goldstein DP, Berkowitz RS. Current chemotherapeutic management of patients with gestational trophoblastic neoplasia. Chemother Res Pract. 2011;2011:806256. , 44 Biscaro A, Braga A, Berkowitz RS. Diagnosis, classification and treatment of gestational trophoblastic neoplasia. Rev Bras Ginecol Obstet. 2015;37(1):42-51..
In our patients with low-risk GTN, clinical treatments with only ChT, without
hysterectomy, promote excellent healing rates - in final treatment, 97.4% in the MTX/FA
group and 98.7% in the pulsed Act-D (p=0.64). Our results strongly suggest that the
single-agent ChT for low-risk GTN, as studied here, had good and similar first-line
single-agent treatment effectiveness, and final first + second-line single-agent ChT
response rate was high in both groups, but higher in the group of initial MTX/FA. We are
waiting for the GOG0275 randomized trial results1717 Schink J. Methotrexate or dactinomycin in treating patients with
low-risk gestational trophoblastic neoplasia [Internet]. 2015 [cited 2015 Jan 15].
Available from:
<http://www.cancer.gov/about-cancer/treatment/clinical-trials/search/view?cdrid=725211&version=HealthProfessional>
http://www.cancer.gov/about-cancer/treat...
, hoping that the single-agent ChT remission rates be similar or better
than ours results, clarifying this GTN treatment challenge: higher efficiency associated
with lower morbidity.
Acknowledgements
To multidisciplinary team of the Mario Totta Maternity Ward of ISCMPA for their kind and efficient participation in the treatment of patients. We are indebted to Silvia Villa Verde Ribeiro Ferreira, Ceres Oliveira and Anelise Burmeister for their assistance in psychological support, statistical analyses and text translation, respectively.
References
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-
2May T, Goldstein DP, Berkowitz RS. Current chemotherapeutic management of patients with gestational trophoblastic neoplasia. Chemother Res Pract. 2011;2011:806256.
-
3Froeling FE, Seckl MJ. Gestational trophoblastic tumours: an update for 2014. Curr Oncol Rep. 2014;16(11):408.
-
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-
6FIGO Oncology Committee. FIGO staging for gestational trophoblastic neoplasia 2000. Int J Gynaecol Obstet. 2002;77(3):285-7.
-
7Ngan HY, Kohorn EI, Cole LA, Kurman RJ, Kim SJ, Lurain JR, et al. FIGO report 2012: trophoblastic disease. Int J Gynaecol Obstet. 2012;119 Suppl 2:S130-6.
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12Petrilli ES, Twiggs LB, Blessing JA, Teng NH, Curry S. Single-dose actinomycin D treatment for nonmetastatic gestational trophoblastic disease. A prospective phase II trial of the Gynecologic Oncology Group. Cancer. 1987;60(9):2173-6.
-
13Lertkhachonsuk AA, Israngura N, Wilailak S, Tangtrakul S. Actinomycin d versus methotrexate-folinic acid as the treatment of stage I, low-risk gestational trophoblastic neoplasia: a randomized controlled trial. Int J Gynecol Cancer. 2009;19(5):985-8.
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» http://www.cancer.gov/about-cancer/treatment/clinical-trials/search/view?cdrid=725211&version=HealthProfessional -
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23Taylor F, Grew T, Everard J, Ellis L, Winter MC, Tidy J, et al. The outcome of patients with low risk gestational trophoblastic neoplasia treated with single-agent intramuscular methotrexate and oral folinic acid. Eur J Cancer. 2013;49(15):3184-90.
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24Osborne R, Gerulath A. What is the best regimen for low-risk gestational trophoblastic neoplasia? A review. J Reprod Med. 2004;49(8):602-16.
-
25Kohorn EI. Is lack of response to single-agent chemotherapy in gestational trophoblastic disease associated with dose scheduling or chemotherapy resistance? Gynecol Oncol. 2002;85(1):36-9.
Publication Dates
-
Publication in this collection
June 2015
History
-
Received
28 Apr 2015 -
Accepted
15 May 2015