Low Risk Trophoblastic Neoplasia: Outcome after Initial Treatment with Single Agent Intramuscular Methotrexate and Oral Folinic Acid

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1 Med. J. Cairo Univ., Vol. 82, No. 1, March: , Low Risk Trophoblastic Neoplasia: Outcome after Initial Treatment with Single Agent Intramuscular Methotrexate and Oral Folinic Acid GHADA E. ELADAWEI, M.D. The Department of Clinical Oncology & Nuclear Medicine, Faculty of Medicine, Mansoura University, Egypt Abstract Background: Low risk gestational trophoblastic neoplasia (GTN) is defined as persistent molar pregnancy with a FIGO/ WHO score less than seven. The optimal chemotherapeutic regimen still remains controversial. The aim of this study was to determine the complete response rate and toxicity of single agent methotrexate in low risk GTN, furthermore detection of possible predictors of treatment failure with single agent methotrexate. Patients and Methods: Medical records of patients with low risk gestational trophoblastic neoplasia were reviewed from January 2003 to December Eighty six patients were treated with 2 weekly intramascular methotrexate 50mg four doses days 1,3,5,7 and oral folinic acid 15mg days 2,4,6,8 (MTX/FA). Patient data were collated and correlation between FIGO/WHO risk score and outcome were evaluated. Results: Overall response rate was 74.4% as, 64/86 patients treated with MTX/FA achieved complete biochemical response, while 22 patients (25.6%) developed resistance. Patients with FIGO/WHO score 6 were more likely to develop resistance and require second line chemotherapy than those with score between 0 and 5. Nine patients out of eleven with score 6 (81.8%) developed resistance compared to 13/75 patients (17.3%) scoring 0-5 (p<0.001). Eight patients who had scored FIGO/WHO 6 also had score 4 for hcg level and Seven of these patients (87.5%) developed Methotrexate resistance and required second line chemotherapy. Conclusion: Intramuscular methotrexate with oral folinic acid rescue is an effective, well tolerated and low coast regimen for the treatment of low risk gestational trophoblastic neoplasia. However, patients must be fully informed of the likelihood of requiring salvage chemotherapy to achieve cure. It would be helpful to refine the FIGO/WHO scoring system, as 81.8% of patients with score 6 developed MTX/FA resistance could be identified initially for more intensive therapy. Key Words: Gestational trophoblastic neoplasia Low risk scoring Methotrexate. Correspondence to: Dr. Ghada E. Eladawei, The Department of Clinical Oncology & Nuclear Medicine, Faculty of Medicine, Mansoura University, Egypt Introduction GESTATIONAL trophoblastic disease (GTD) comprises a spectrum of disorders from the premalignant conditions of complete and partial hydatidiform moles through to the malignant invasive mole, choriocarcinoma and very rare placental site trophoblastic tumor/epithelioid trophoblastic tumor. The malignant forms of the disease are also collectively known as gestational trophoblastic tumors or neoplasia (GTN) [1]. Hydatidifrom mole including complete and partial mole are benign expressions of GTN with similar management, surgical evacuation and ßhCG follow-up for six months. An increase or plateau in ßhCG level defines persistent GTN which requires treatment with chemotherapy [2]. All physicians select the most appropriate chemotherapy regimen by utilizing the International Federation of Gynecology and Obstetrics (FIGO 2000) modified prognostic and anatomical staging score (Table 1). A score of 0-6 predicts for a low risk of resistance to single agent chemotherapy, while a score of 7 or more predicts for a high risk and leads to recommendation for combination chemotherapy [3]. MTX was the first agent used and still remains the most prescribed drug in the treatment of low risk GTN. Daily intramuscular injection over the course of 5 days (conventional MTX) has been the earliest regimen [4,5]. High rate of toxic effects in this method of treatment was the reason of introducing alternative schedules with folinic acid (CF) rescue. Eight-day alternating intramuscular MTX-CF regimen is the most widely used regimen in the world. Complete 101

2 102 Low Risk Trophoblastic Neoplasia response rate for methotrexate as first line therapy for low risk GTN with different chemotherapy regimens including 5 day regimen of MTX (conventional MTX), and 5 day regimen of Actinomycin-D (conventional Act-D), 8-day alternating intramuscular MTX-folinic acid (MTX-CF) every 2 weeks, high dose intravenous MTX and weekly intramuscular MTX have ranged from 49% to 92.3% [6,7]. Previous studies have shown that ostensibly low risk patients with a FIGO/WHO score of 6 and/or high hcg levels are highly likely to develop resistance and need salvage treatment [8]. This study is a retrospective analysis of all low risk patients with a FIGO/WHO score of 0-6 treated in Clinical Oncology and Nuclear Medicine Department Mansoura University Hospital. The aim of this study was to determine the complete response rate and toxicity of single agent methotrexate in low risk GTN, furthermore detection of possible predictors of treatment failure with single agent methotrexate. Patients and Methods A retrospective review of all patients treated with single-agent weekly intramuscular MTX and oral folinic acid for low risk GTN was conducted between January 2003 and December A diagnosis of GTN was made based on a history of molar pregnancy confirmed by pathological study of curettage specimen and a plateau (less than 10% fall) of hcg over 3 weeks or more or a rise of hcg (more than 10%) over 2 weeks or more according to the FIGO criteria. Medical records of the patients included clinical and obstetric history and staging information used to determine total and hcg specific FIGO/WHO scores. In addition, information on primary, secondary and subsequent treatments as well as clinical responses to each was recorded. Initial clinical workup included a complete history and physical examination, baseline pretreatment serum hcg level, complete blood count, liver function tests and renal function tests. Radiological examination included chest X-ray, abdominal and pelvic ultrasound, followed by a computerized tomographic scan if chest X-ray or abdominal and pelvic ultrasound revealed evidence of disease. Eighty six of low risk patients with a FIGO/ WHO score of 0-6 started to receive A total of four doses of intramuscular methotrexate 50mg every other day (days 1,3,5 and 7) alternating with four doses of 15mg oral folinic acid on days 2,4,6 and 8 (MTX/FA). Then one week rest, another cycle was restarted on day 15 and repeated. hcg was measured every 2 weeks prior to each cycle of methotrexate. CBC, LFTs and RFTs were obtained before each treatment cycle. All patients received this agent until remission or non-response (methotrexate resistance) condition occurred, where remission was defined as hcg <5IU/litre and non-response condition was defined as less than 10% decrease of hcg titer over two consecutive weeks or the appearance of a new metastatic disease or an abnormal hcg level after dropping to normal. After initial normalization of hcg titer, two additional cycles was administered as consolidation therapy. All women were treated on an outpatient basis. Hematologic, hepatic, renal and gastrointestinal toxicities were evaluated at each weekly visit during treatment by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 3.0. After treatment, follow-up of the Patients was continued with monthly hcg titers for 12 months. Thereafter urine hcg is measured periodically every 3 months for 2 years and then every 6 months. Disease relapse was defined as a confirmed rise in hcg in the absence of pregnancy. Second line chemotherapy for MTX resistant cases was required. According to hcg level, if hcg levels were less than 150iu/I, single agent intravenous dactinomycin (Act-D) 1.25mg/m 2, as short infusion every 2 weeks, was administered. If hcg levels were above this threshold, combination chemotherapy was given using Etoposide, Methotrexate, Actinomycin-D, Cyclophosphamide and vincristine (EMA-CO). Statistical analysis: Data was analyzed using SPSS (Statistical Package for Social Science) version 15. Qualitative data was presented as number and percent. Chisquare test was used for comparison between groups. Non parametric data was presented as min-max and median. Mann-Whitney test was used for comparison between groups. p-value is considered significant if it is <0.05. Results Eighty six low risk GTN patients were identified from medical records between January 2003 and December They were treated with singleagent weekly intramuscular MTX and oral folinic acid for low risk GTN.

3 Ghada E. Eladawei 103 Table (2) summarizes patient characteristics. The median age of patients was 29 years (range, 19-46). The majority of the patients (95.3%) diagnosed with complete mole. Sixty five patients (75.6%) had non metastatic disease and 21 (24.4%) had metastasis (19/21 lung, 2/21 vagina). Pretreatment hcg level ranged from 1980iu/l to iu/l with median level of 25150iu/l. Table (1): FIGO/WHO scoring system for gestational trophoblastic neoplasia (FIGO2000). Prognostic factor Score Age (years) <40 40 Antecedent pregnancy (AP) Mole Abortion Term Interval (end of AP to chemotherapy in months) < >12 hcg (IU/l) < ,000 10, ,000 >100,000 Number of metastases >8 Site of metastases Lung Spleen and kideny Gastro-intestinal Liver, Brian Largest tumor mass 3-5 cm >5 cm Prior chemotherapy Single drug 2 drugs hcg is human chorionic gonadotrophin. The total score for a patient is obtained by adding the individual scores for each prognostic factor. The total score is classified as low risk of resistance if 0-6 and high risk if more than 7. Table (2): Patients characteristics. Table (3): Comparison of groups by outcome. Characteristics Number (N=86) % Characteristics Methotrexate Methotrexate p Age: (N=86) response resistant value Range years Age: Median 29 years <40 (N=77) Gravidity: >40 (N=9) 7 2 Primigravida Muligravida Gravidity: Primigravida Type of antecedent pregnancy: Complete mole (N=39) Partial mole Multigravida (N=47) Stage: I Pretreatment II-III hcg level: Pretreatment BHCG level (iu/l): Range iu/l < Range Median Median Stage: FIGO/WHO score: 0 1 I (N=65) II-III (N=21) FIGO/WHO score: (N=75) < (N=11) Efficacy of MTX/FA regimen: Overall response rate was 74.4% as, 64/86 patients treated with MTX/FA achieved complete biochemical response, while 22 patients (25.6%) developed resistance. Fig. (1) displays rate of complete response and Methotrexate resistance for each individual low risk score. Patients with FIGO/ WHO score 6 were more likely to develop resistance and require second line chemotherapy than those with score between 0 and 5. Nine patients out of eleven with score 6 (81.8%) developed resistance compared to 13/75 patients (17.3%) scoring 0-5 (p<0.001). Eight patients who had scored FIGO/WHO 6 also had score 4 for hcg level and Seven of these patients (87.5%) developed Methotrexate resistance and required second line chemotherapy. Toxicity: MTX/FA regimen well tolerated. Most of the adverse events were mild to moderate. There were only 2/86 patients (2.3%) with slight liver enzymes elevation (grade 1 hepatic toxicity). They improved with supportive measures and do not need to discontinue MTX/FA. Grade 1-2 Gastrointestinal toxicity occurred in 15 (17.4%). Only 2 patients (2.3%) had Grade 1 stomatitis and 3 patients (3.5%) had Grade 1-2 neutropenia.

4 104 Low Risk Trophoblastic Neoplasia Univariate analysis: Characteristics of the patients are compared between two groups of MTX/FA response and resistance. There was significant correlation between patient response and pretreatment level of hcg and FIGO/WHO score (p-value = <0.0001, <0.001 respectively), but correlation with age, gravidity and stage were non-significant ( p=0.807, 0.991, respectively). Second line chemotherapy: Twenty two patients (25.6%) who were classified as resistant to MTX/FA, all received second line chemotherapy. Most of patients (18/22) changed to EMA-CO regimen (Etoposide, Methotrexate, Actinomycin-D, Cyclophosphomide and vincristine). Only 4 cases received Dactinomycin (Act-D). Overall response to second line chemotherapy was 91% (20/22). Only 2 patients (9%) developed resistance and required additional treatment. Hysterectomy successfully salvaged the two patients. Number of patients Methorexate response Methorexate resistance Fig. (1): Total FIGO/WHO score. Discussion In 2000 the FIGO produced a new staging and scoring system [3]. This combined and simplified the previous staging and scoring system from 1992 [9] and the original WHO scoring system [10]. Consequently, for nearly all low risk GTN patients, single agent chemotherapy with either MTX or ActD is the preferred treatment. Studies demonstrated a 50% to 90% chance of inducing remission [11]. This variability reflects differences in dose, frequency and route of administration as well as criteria used to select patients for therapy [2]. In this study, 86 patients defined by FIGO/WHO score as low risk (score 0-6). 74.4% of those patients had a complete response to first line treatment with MTX/FA. The overall response rate in this study is comparable with results of other series with MTX/FA, which reported response rates of % [2,6,12]. In the current study, we observed that patients with a total score of 6 or hcg of 100,000iu/I had significantly higher rates of resistance. Nine patients out of eleven with score 6 (81.8%) developed resistance compared to 13/75 patients (17.3%) scoring 0-5 (p<0.001). Eight patients who had scored FIGO/WHO 6 also had score 4 for hcg level and Seven of these patients (87.5%) developed Methotrexate resistance and required second line chemotherapy. This may explain the wide variation in the response of low risk GTN to single agent chemotherapy with either MTX or ActD, As there were variation of patients characteristics subsequently, the response to single agent chemotherapy varies according to FIGO/WHO 0-5 and score 6. Furthermore, rates of future relapse although small were found to be significantly higher in patients with resistance to primary treatment compared to those that attained remission [6]. So, it would be helpful to refine the FIGO/WHO scoring system, as 81.8% of patients with score 6 and those with an hcg level >100,000 developed MTX/FA resistances and could be identified initially for more intense therapy. Similarly, high rate of resistance of FIGO/WHO score 6 and those with an hcg level >1 00,000 are comparable with results from 289 patients with low risk treated with single agent MTX/FA in another retrospective analysis. 29/3 6 (8 1 %) patients with a FIGO/WHO total score of 6 developed resistance to MTX/FA compared with 87/253 (34%) patients with a score of 0-5 (p=0.0001). Significantly higher rates of resistance were found for patients with an hcg level of >100,000iu/l compared to an hcg level of <1 00,000iu/l (84% versus 34% p=0.0001) 13]. Another option to achieve greater rates of primary remission for high score low risk patients would be to consider combination chemotherapy. In the study by McGrath et al., at Charing Cross Hospital London, after counseling, patients with an hcg level of >100,000iu/l were allowed to choose between MTX/FA and EMA/CO regimen. 43.1% of patients chose EMA/CO and of these

5 Ghada E. Eladawei 105 only 7% developed resistance compared to 70% resistance in those that choose MTX/FA [8]. In a phase III trial comparing weekly MTX 30mg/m 2 with pulsed Act-D 1.25mg/m 2 for low risk GTN, used MTX for 107 patients and had a 53% response with this regimen. In Act-D group which were 109 patients response rate was 70%. In the MTX group eight patients had a WHO score of 5 or 6. Only one of these eight patients had complete remission with weekly MTX which showed significant effect of WHO score on prognosis of treatment [14]. Unlike our observation with MTX/FA, in a retrospective analysis of low risk patients treated with methotrexate 0.4mg/kg (max 25mg) IV daily for 5 days every other week. Only 19% patients developed resistance to MTX and required further treatment. Furthermore 89% (n=18) patients with an hcg level of > 100,000iu/l achieved a complete response [16]. Resistance to MTX was significantly associated with increasing FIGO/WHO scores, a higher hcg and presence of metastatic disease as well as diagnosis of choriocarcinoma [15]. Such associations have been replicated in other studies regardless of the chosen single agent and regimen [16-19]. MTX/FA is well tolerated with minimal side effects and has the additional benefit of avoiding intravenous administration. In the current study, only 2-3% of patients suffered mild to moderate gastrointestinal toxicity, stomatitis and neutropenia. These results are similar to what observed in [13]. Importantly, most patients retain fertility [18] and there is a very low risk of second malignancy [20]. A recent cost analysis study conducted to determine the optimal approach to first-line treatment for low-risk gestational trophoblastic neoplasia using a cost analysis of 3 commonly used regimens, accounting for toxicities, response rates and need for second- or third-line therapy. These strategies included 8-day methotrexate (MTX)/folinic acid, weekly MTX, and pulsed actinomycin-d (act-d). Based on similar efficacy and lower societal cost, 8-day MTX/folinic acid was recommended for first-line treatment of low-risk GTN [21]. The minimal side effects of MTX/FA, low social coast and the efficacy of salvage chemotherapy regimens support its utilization despite low response rates in most patients with a FIGO/WHO score of 6. Importantly, despite high rate of resistance in patients with score 6, all patients were eventually cured in this study. Overall survival has been shown not be affected in low risk patients requiring treatment with salvage chemotherapy [17,22]. HCG levels are sensitive measure of disease resistance. Other promising strategies to identify patients with drug resistance at early time-point during initial therapy have employed normograms and hcg kinetic analyses [23,24]. In addition, Doppler pulsatility index to assess tumor vascularity is an independent prognostic factor for resistance to single agent methotrexate therapy and is now being evaluated in a prospective trial [25]. In conclusion, intramuscular methotrexate with oral folinic acid rescue is an effective, well tolerated and low coast regimen for the treatment of low risk gestational trophoblastic neoplasia. However, patients must be fully informed of the likelihood of requiring salvage chemotherapy to achieve cure. It would be helpful to refine the FIGO/WHO scoring system, as 81.8% of patients with score 6 developed MTX/FA resistance could be identified initially for more intensive therapy. References 1- SECKL M.J., SEBIRE N.J. and BERKOWLTZ R.S.: Gestational trophoblastic disease. Lancet, 376: , BERKOWITZ R.S. and GOLDSTEIN D.P. Current management of gestational trophoblastic diseases. Gynecol. Oncol., 112: , FIGO Oncology Committee Report: FIGO staging for gestational trophoblastic neoplasia FIGO Oncology Committee. Int. J. Gynecol. Obstet., 77: , SOPER J.T., CLARKE-PEARSON D.L., BERCHUCK A., et al.: 5-day methotrexate for women with metastatic gestational trophoblastic disease. Gynecol. Oncol., 54: 76-9, ABRÃO R.A., de ANDRADE J.M., TIEZZI D.G., et al.: Treatment for low-risk gestational trophoblastic disease: Comparison of single-agent methotrexate, dactinomycin and combination regimens. Gynecol. Oncol., 108: , MATSUI H., SUZUKA K., YAMAZAWA K., et al.: Relapse rate of patients with low-risk gestational trophoblastic tumor initially treated with single-agent chemotherapy. Gynecol. Oncol., 96: , KANG W.D., CHOI H.S. and KIM S.M.: Weekly methotrexate (50mg/m 2 ) without dose escalation as a primary regimen for low-risk gestational trophoblastic neoplasia. Gynecol. Oncol., 117: , McGRATH S., SHORT D., HARVEY R., et al.: The management and outcome of women with post hydatidifrom mole low risk gestational trophoblastic neoplasia, but hcg levels in excess of 100,000 IUL. Br. J. Cancer, 102: , KOHORN E.L.: The new FIGO 2000 staging and risk factor scoring system for gestational trophoblastic disease:

6 106 Low Risk Trophoblastic Neoplasia Description and critical assessment. Int. J. Gynecol. Cancer, 11: 73-77, World Health Organization Scientific Group: Gestational trophoblastic diseases. WHO Tech. Rep. Ser., 692, ALAZZAM M., TIDY J., HANCOCK B.W., et al.: First line chemotherapy in low risk gestational trophoblastic neoplasia. Cochrane Database Syst. Rev. Jan., 21; (1): CD007102, McNEISH I.A., 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 J. Clin. Oncol., 20: , TAYLOR F., GREW T., EVERARD J., et al.: The outcome of patients with low risk gestational trophoblastic neoplasia treated with single agent intramuscular methotrexate and oral folinic acid. E J C, 49: , OSBORNE R.J., FILIACI V., SCHINK J.C., 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., 29: , CHAPMAN-DAVIS E., HOEKSTRA A.V., RADEMAK- ER A.W., et al.: Treatment of nonmetastatic and metastatic low risk gestational trophoblastic neoplasia: Factors associated with resistance to single-agent methotrexate chemotherapy. Gynecol. Oncol., 125: , KHAN F., EVERARD J.E., AHMED S., et al.: Low-risk persistent gestational trophoblastic disease treated with low-dose methotrexate: Efficacy, acute and long term effects. Br. J. Cancer, 89: SITA-LUMSDEN A., SHORT D., LINDSAY I., et al.: Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at the Charing Cross Hospital, , Br. J. Cancer, 107: , CHEN L., LENGYEL E.R. and BETHAN POWELL C.B.: Single-agent pulse dactinomycin has only modest activity for methotrexate-resistant gestational trophoblastic neoplasia. Gynecol. Oncol., 94: , YARANDI F., EFTEKHAR Z., SHOJAEI H., et al.: Pulse methotrexate versus pulse actinomycin D in the treatment of low-risk gestational trophoblastic neoplasia. Int. J. Gynecol. Obstet., 103: 33-37, RUSTIN G., NEWLAND E.S. and LUTZ J.M.: Combination but not single agent methotrexate chemotherapy for gestational trophoblastic tumours increases the incidence of second tumours. J. Clin. Oncol., 14: , SHAH N.T., BARROILHET L., BERKOWITZ R.S., et al.: A coast analysis of first-line chemotherapy for lowrisk gestational trophoblastic neoplasia. J. Repord Med., 57: , OKINES A.F.C., MORRIS R. and HANCOCK B.W.: An evaluation of FIGO 2000: The first five years. J. Reprod Med., 53: , VAN TROMMEL N.E., MASSUGER L.F., SCHIJF C.P., et al.: Early identification of resistance to first-line singleagent methotrexate in patients with persistent trophoblastic disease. J. Clin. Oncol., 24: 52-58, YOU B., HARVEY R., HENIN H., et al.: Early prediction of treatment resistance in low-risk gestational trophoblastic neoplasia using population kinetic modeling of hcg measurement. Br. J. Cancer, 108: , AGARWAL R., HARDING V., SHORT D., et al.: Uterine artery pulsatility index: A predictor of methotrexate resistance in gestational trophoblastic neoplasia. Br. J. Cancer, 106: , 2012.