Feasibility of central co-ordinated EMA/CO for gestational trophoblastic disease in the Netherlands

Transcription

1 BJOG: an International Journal of Obstetrics and Gynaecology February 2004, Vol. 111, pp DOI: /j x Feasibility of central co-ordinated EMA/CO for gestational trophoblastic disease in the Netherlands Clasien van der Houwen a, *, Ron C. Rietbroek b, Christianne A.R. Lok c, Marianne J. Ten Kate-Booij d, Frits B. Lammes c, Anca C. Ansink e Objective In the Netherlands, high risk gestational trophoblastic disease (GTD) patients are treated in different referral hospitals with a national working party on trophoblastic tumours having a co-ordinating function. Our purpose was to evaluate whether this policy is a satisfactory alternative to complete centralisation. Design A retrospective study of all etoposide, methotrexate, actomycin D, cyclophosphamide and vincristine (EMA/CO)-treated women in the Netherlands between 1986 and Data regarding risk factors, treatment results and toxicity were collected. Setting Ten hospitals; 2 general, 6 academical and 2 oncology centres. Population Fifty EMA/CO-treated women registered by the central registration unit of the Dutch Working Party on Trophoblastic Disease. Methods Patients files and quarterly reports of the Dutch Working Party. Main outcome measures Cure rate and consistency of treatment in different hospitals. Results EMA/CO treatment was administered in 10 different hospitals. All patients were discussed during the meetings of the Dutch Working Party and overall, 86% of patients were cured. Consistency in treatment was good. Conclusions Cure rates were comparable with results of single institution series. We conclude that treatment of high risk GTD patients in different referral hospitals with concentration of expertise in a working party is a good alternative to centralisation of treatment in GTD specialised hospitals. INTRODUCTION Multi-agent chemotherapy is the optimal treatment for patients with high risk gestational trophoblastic disease (GTD). Newlands and Bagshawe developed the etoposide, methotrexate, actomycin D, cyclophosphamide and vincristine (EMA/CO) schedule in They reported a survival rate of 84% in high risk patients treated primarily with EMA/CO. These results were comparable with other multi-agent chemotherapy schedules (e.g. CHAMOCA), but a Department of Obstetrics and Gynaecology, De Tjongerschans Hospital, Heerenveen, The Netherlands b Department of Internal Medicine, Rode Kruis Hospital, Beverwijk, The Netherlands c Department of Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, The Netherlands d Department of Obstetrics and Gynaecology, Amphia Hospital, Breda, The Netherlands e Department of Gynaecology, Erasmus MC Daniel den Hoed Oncology Center, Rotterdam, The Netherlands * Correspondence: Dr C. van der Houwen, Department of Obstetrics and Gynaecology, Tjongerschans Hospital, Thialfweg 44, 8441 PW Heerenveen, The Netherlands. D RCOG 2004 BJOG: an International Journal of Obstetrics and Gynaecology EMA/CO was considerably less toxic, easier to administer and well tolerated. 1 It was introduced in the Netherlands in Patients with high risk GTD in the Netherlands are treated in referral hospitals and not in one central specialised institution. Each referral hospital is represented on the Working Party on Trophoblastic Disease, a multidisciplinary group of gynaecologists, oncologists, pathologists and biochemists, and management of all patients with high risk GTD is discussed at quarterly meetings. The purpose is to evaluate, record and resolve therapeutic problems by experts. Because prompt decision-making is important in high risk GTD, the members of the Dutch Working Party are frequently consulted between the meetings. Our experience is unique. Previous literature on EMA/ CO in high risk GTD is based solely on single institution experience. 2 6 We present the results of all patients treated with EMA/CO in the Netherlands between 1986 and METHODS We identified all patients treated with EMA/CO between 1986 and 1997, registered by the central registration unit of the Dutch Working Party on Trophoblastic Disease. All patients with GTD in the Netherlands are registered.

2 144 C. VAN DER HOUWEN ET AL. In the study period, two different schedules were used, EMA/CO and another schedule containing etoposide, methotrexate, actomycin D, cyclophosphamide and cisplatin. This platinum-containing schedule is repeated every 3 weeks and it had been applied since 1982, before the introduction of EMA/CO, and in view of favourable outcomes, some centres preferred to continue this platinumcontaining schedule. In 1986, both treatment schedules were considered acceptable although in late years, the Dutch Working Party recommended EMA/CO as first choice, to conform with international guidelines and because of increased toxicity of the platinum-containing schedule. In the present study, we focus on the patients receiving EMA/CO to make a valid comparison with other studies of high risk GTD patients. The definition of high risk GTD according to the Dutch Working Party is shown in Table 1. The applied criteria are largely based on the clinical classification of Hammond et al., 7 which is used by the majority of gynaecologic oncologists in the United States (NCI risk score). 8 An important difference from the American system is that we also recommended EMA/CO in all patients with methotrexate resistance and in patients with an antecedent term pregnancy, even in the absence of metastases. An analysis of a Dutch population with GTD (Kate ten-booij s thesis) 9 had revealed that 25% of post-term choriocarcinoma patients had a score <8. Only 15% of these patients with a WHO risk score of <8 achieved remission with methotrexate, 43% were methotrexate-resistant and achieved remission with multi-agent chemotherapy and the other 43% died of disease. Based on these results, we consider all patients with GTD after a term pregnancy as high risk and they all are primarily treated with multi-agent chemotherapy. All patients were evaluated by history and physical examination, haematology and chemistry profile, including h-hcg serum level, chest X-ray and abdominal ultrasound. A computed tomography of the chest was obtained for further evaluation of chest radiograph findings or clinical symptoms. When clinical suspicion of brain metastases existed or pulmonary metastases were present, a cerebrospinal fluid analysis and/or brain-computed tomography and/or magnetic resonance imaging were performed. Quantitative h-hcg values were obtained using different assays, depending on availability in the individual hospitals. The EMA/CO schedule was given according to the schedule of Newlands. 1 When brain metastases were present, patients received Table 1. High risk GTD according to the Dutch Working Party on trophoblastic tumours. 1. Metastases in one or more of the next organs: liver, brain, spleen, kidney, intestines, bone or 2. Antecedent term pregnancy or 3. Resistance to prior chemotherapy or 4. More than 12 months interval between antecedent pregnancy and start of chemotherapy either intrathecal methotrexate or a high dose intravenous methotrexate. The Dutch Working Party initially recommended six consolidation EMA/CO treatment cycles. In later years, four consolidation cycles were advised in patients with serum h-hcg normalisation within 8 weeks. Salvage chemotherapy or adjuvant surgical procedures including hysterectomy and thoracotomy for excision of resistant tumour foci were performed in selected patients when considered necessary. Hospital and outpatient records were reviewed to determine patient age, antecedent pregnancy, pretreatment h-hcg value and dissemination. The WHO risk scores were reviewed and recorded. Because the paternal data were usually not available, we used the modified WHO risk score without the ABO blood groups. 10 An assessment was made whether patients were high risk according to the Dutch Working Party (Table 1). For each cycle, the administered dose of EMA/CO was noted. The reason for dose reduction or postponement of the schedule was noted. Once serum h-hcg remained within normal limits for three consecutive weeks, the patient was considered to be in remission. The number of treatment cycles to achieve remission and the number of consolidation cycles were noted. Toxicity was graded by using WHO criteria. 11 RESULTS In the study period, patients with GTD were registered annually, 15% with persistent trophoblastic disease. Among the patients with low risk persistent trophoblastic disease, 80% showed complete response leaving 20% with resistance to methotrexate. From 1986 until 1997, we also registered 43 patients with non-molar trophoblastic disease, most of them post term. Ninety-four patients were treated with multi-agent chemotherapy. Fifty patients received EMA/CO, whereas 44 patients received the platinum-containing schedule. In the group receiving platinum, three patients died. Treatment reduction was more often necessary than in the EMA/CO group because of increased toxicity. In the EMA/CO group, 51 patients were registered but one patient was late excluded because revision of histology revealed a placental site trophoblastic tumour and EMA/CO was cancelled in the first week of treatment. A hysterectomy resulted in complete remission. EMA/CO treatment was administered in 10 different hospitals (Table 2). The mean age of patients was 32 years (range: years). The type of antecedent pregnancy is shown in Table 3. The interval between the antecedent pregnancy and treatment was over 1 year in 12 patients (24%). All patients were classified as high risk on either a score of > 7 according to the WHO, methotrexate resistance or a GTD following a term pregnancy. Twenty-two patients were resistant to methotrexate treatment. Three of the 21 patients with an antecedent term pregnancy would have

3 GESTATIONAL TROPHOBLASTIC DISEASE AND EMA/CO 145 Table 2. Number of patients treated per hospital (N ¼ 50). Hospital Academic Medical Center, Amsterdam 24 Utrecht University Medical Center 7 Netherlands Cancer Institute, Amsterdam 5 University Hospital Rotterdam 3 University Hospital Groningen 3 Daniel den Hoed Oncology Center, Rotterdam 3 Leiden University Medical Center 2 Eemland Hospital, Amersfoort 1 Free University Hospital, Amsterdam 1 Amphia Hospital, Breda 1 n Table patients with GTD treated with EMA/CO in the Netherlands Metastases n (%) Total metastases 28 (56) Lung 25 (50) Brain 9 (18) Liver 8 (16) been classified as medium risk according to the WHO. These three patients were treated with EMA/CO and all three were cured without further treatment. Central nerve system metastases were present in nine patients and liver metastases in eight patients as shown in Table 4. Four patients received other multi-agent chemotherapy prior to EMA/CO. The minimum and median follow up were 24 and 54 months, respectively. One patient was lost to follow up. Response to EMA/CO was usually prompt and satisfactory (Table 5). Thirty-eight (76%) patients achieved a complete remission to EMA/CO with normalisation of h-hcg in 2 18 weeks (median of 5 weeks). In this group, there were four relapses, three patients died of disease and one was cured by further therapy. Twelve patients (24%) did not achieve a complete remission. Three of these 12 patients died within 2 weeks before adequate treatment could be given as a result of widespread disease and nine patients appeared to be resistant to EMA/CO. With chemotherapy containing platinum, eight of these nine patients were cured. Overall, 86% of patients were cured. The survival in the AMC group was 88% and in the other hospitals 85%. Three hospitals treated only one patient and all three were cured without recurrence. Toxicity profiles of EMA/CO treatment were obtained in 42 out of 50 patients. Three patients died within 2 weeks making toxicity assessment impossible and four patients were excluded from the toxicity study because they received other multi-agent chemotherapy prior to EMA/CO. One patient was excluded because she started with two cycles of EMA with adjusted doses. Anaemia was a common complication of treatment. Seven patients had a WHO toxicity grade 3 and none had grade 4. Twenty-three (54%) patients received transfusions. Leukopaenia was a common complication. Twenty-four (57%) patients had a WHO toxicity grade of 3 or 4. Treatment cycles had to be postponed in 15 (36%) patients because of leukopaenia. Four patients developed thromboembolic disease with subsequent thrombocytopaenia. In the other patients, there was no thrombocytopaenia of WHO toxicity grade 3 or more. Vincristine was reduced or stopped in 11 patients because of neuropathy. In 16 (38%) patients, neuropathy WHO grade 1 or 2 was recorded. Gastrointestinal symptoms and alopecia were not systematically documented for all patients. One patient developed an acute myeloid leukaemia 1 year after the trophoblastic tumour was cured. Genetic analysis showed a translocation, which may be related to chemotherapy-induced leukaemia. She achieved a complete remission after multi-agent chemotherapy, and currently, she has a disease-free interval of 3 years. Consistency of management Two patients received EMA/CO although they had no high-risk disease according to the criteria of the Dutch Working Party. They both had multiple lung metastases and additional risk factors as age and unusual localisation of the tumour, and both decisions were well documented. Two other patients with term pregnancies received methotrexate prior to EMA/CO, although the Dutch Working Party recommended EMA/CO as first-line therapy. Their disease was resistant to methotrexate and EMA/CO was administered as second-line treatment. All patients had adequate pretreatment work up. Table 5. Outcome in 50 patients with GTD treated with EMA/CO in the Netherlands Table patients with GTD treated with EMA/CO in the Netherlands Type of antecedent pregnancy n (%) Hydatidiform mole 22 (44) Abortion/ectopic pregnancy 5 (10) Term delivery 21 (42) Unknown 2 (4)

4 146 C. VAN DER HOUWEN ET AL. Table 6. Number of consolidation cycles of all patients who achieved complete serological remission (n ¼ 38). Cycles Patients Recurrence Nearly all patients received the EMA/CO schedule as recommended by Newlands although four critically ill ones received a modified schedule at the start. Three patients received a high dose methotrexate although no brain metastases were present. Two patients received during one and two treatment cycles, respectively, two-thirds of recommended dose of methotrexate as result of a calculation error. The number of consolidation cycles diverged considerably. Thirty-eight patients achieved a complete serologic remission. The majority of patients received six consolidation EMA/CO treatment cycles (Table 6). One patient did not receive any consolidation therapy because of lifethreatening reactive hepatitis B. She remained disease free for 24 months and gave birth to her second child recently. 12 During the quarterly meetings of the Dutch Working Party, the medical records of all patients were discussed. Most discussion concerned further therapy in case of EMA/ CO resistance and interpretation of inadequate decrease of h-hcg serum levels. The members disagreed with the treatment policy in four patients. One patient with high risk GTD according to the WHO risk score received bleomycine, etoposide and cisplatinum instead of a combination containing EMA/CO. Three EMA/CO-resistant patients received third-line chemotherapy without further consultation. They received the schedules usually given for testis carcinoma. DISCUSSION High risk GTD is relatively uncommon disease, with a high cure rate if adequately treated. Our cure rate was similar to rates in the single institution series 2 6 (Table 7). Although comparison is difficult due to different classification systems. We treated nearly all methotrexate-resistant GTD with EMA/CO where others did not except for the group of Quinn et al. 4 Recently, the group of Newlands advised to give EMA/CO therapy to methotrexate-resistant patients with a h-hcg value above 100 iu/l. 13 There is still no agreement on the best classification system. Tham and Ratnam 14 stated that, compared with the NCI, the WHO risk score may be more predictive of treatment failure and outcome in high risk disease. However, the WHO score is disadvantageous due to complexity with individualised modifications in respective centres. So far, the International Federation of Obstetrics and Gynecology (FIGO) could not overcome this problem. The FIGO staging is anatomically based, whereas the prognostic factors in GTD are only partially anatomically based. Recently, a proposal to combine the revised FIGO staging and modified WHO scoring systems with two risk groupings was made by the Working Committee of the International Society for the Study of Trophoblastic Disease and the International Gynecologic Cancer Society. 15 Multivariate analysis is an important tool in recognising adverse prognostic factors. Kim et al. 16 reported the following as adverse prognostic factors: tumour age over 12 months, metastasis in more than two organs and inadequate previous therapy. Newlands et al. 3 reported liver metastases, prolonged interval from antecedent pregnancy, brain metastases and antecedent term delivery as the most important independent significant risk factors. In older studies, 17 the number of metastases, metastases to sites other than the lung or vagina or previous failed chemotherapy were reported. Azab et al. 18 reported the same factors and nonmolar pregnancy as independent risk factors. In our patient series, central nerve system metastases were present in nine patients, and liver metastases in eight. This is highly comparable with other series as shown in Table 7. In addition, term pregnancies (42%) were highly represented in our group. Three patients died before adequate treatment could be given. Newlands et al. 3 reported early deaths as well (<4 weeks from the start of treatment) in 4% of the high risk GTD patients. Very ill patients will not always be referred to other hospitals, so it is possible that central registration results in a higher percentage of critically ill patients than in single institution registration. Differentiation between a trophoblastic tumour and another hcg-producing tumour is not always possible. Two Table 7. Adverse prognostic factors in high risk GTD patients in different studies. Study Soper Newlands Kim Quinn El-Lamie Houwen n Year of study Cured (%) Term pregnancy (%) Interval >1 year (%) Brain metastases (%) Liver metastases (%)

5 GESTATIONAL TROPHOBLASTIC DISEASE AND EMA/CO 147 of our patients had not been pregnant before and recent conception was very unlikely. We decided not to exclude those patients from this study as they were treated as high risk GTD. We do not know whether comparable patients are excluded in other studies. Toxicity profiles were comparable with profiles reported by Newlands et al. 1 and El-Lamie et al. 6 In our group, there was less anaemia: 10% WHO grades 3 and 4 versus 40% in the group of Newlands. This was partly due to more blood transfusions in our group: 54% versus 40% in the group of Newlands. Leukopaenia WHO grades 3 and 4 occurred in 57% of our patients compared with 62% in the group of Newlands and 45% in the group of El-Lamie. Granulocyte colony stimulating factor is now available to overcome a major part of the adverse effects of leukopaenia. Rustin et al. 19 found a slight increased risk of second tumours after sequential or combination chemotherapy. In our series, one patient developed acute myeloid leukaemia. There was a remarkable inconsistency in the number of consolidation cycles. In earlier reports, Newlands et al. 1 recommended to continue EMA/CO treatment in the high risk group for approximately 12 weeks after normalisation of serum h-hcg. The Dutch Working Party agreed with this recommendation. In 1998, Newlands advised that consolidation was necessary for only a further 6 8 weeks of therapy. 3 Based on this change of policy, less consolidation cycles were given in recent years in The Netherlands as well. In conclusion, treatment results with EMA/CO in the current series are satisfactory and comparable with prior publications of single institution series. Overall, consistency in treatment was good and all patients were discussed during the meetings of the Dutch Working Party. One may wonder whether treating one high risk GTD patient annually per hospital is sufficient to obtain and maintain adequate expertise on high risk GTD. Centralisation of treatment of rare diseases is commonplace in the Netherlands, just like in most other European countries. We think the concept of the Dutch Working Party is useful and effective in concentrating the expertise on GTD as we showed in this study. Acknowledgements The authors would like to thank Simon Hyde for language corrections. References 1. Newlands ES, Bagshawe KD, Begent RH, Rustin GJ, Holden L, Dent J. Developments in chemotherapy for medium- and high-risk patients with gestational trophoblastic tumours ( ). Br J Obstet Gynaecol 1986;93: Kim SJ, Bae SN, Kim JH, Kim CJ, Jung JK. Risk factors for the prediction of treatment failure in gestational trophoblastic tumors treated with EMA/CO regimen. Gynaecol Oncol 1998;71: Newlands ES, Bower M, Holden L, et al. Management of resistant gestational trophoblastic tumours. J Reprod Med 1998;43: Quinn M, Murray J, Friedlander M, et al. EMACO in high risk gestational trophoblast disease the Australian experience. NZ J Obstet Gynaecol 1994;34: Soper JT, Evans AC, Clarke-Pearson DL, Berchuck A, Rodriguez G, Hammond CB. Alternating weekly chemotherapy with etoposidemethotrexate-dactinomycin/cyclophosphamide vincristine for highrisk gestational trophoblastic disease. Obstet Gynecol 1994;83: El-Lamie IK, Shehata NA, Abou-Loz SK, Ei-Lamie KI. Experience of the Gynecologic Oncology Unit at Ain Shams University in the treatment of gestational trophoblastic tumors. Int J Gynecol Cancer 2000;10: Hammond CB, Borchert LG, Tyrey L, Creasman WT, Parker RT. Treatment of metastatic trophoblastic disease: good and poor prognosis. Am J Obstet Gynecol 1973;115: Goldstein DP, Zanten-Przybysz IV, Bernstein MR, Berkowitz RS. Revised FIGO staging system for gestational trophoblastic tumors. Recommendations regarding therapy. J Reprod Med 1998;43: Ten Kate-Booij MJ. Choriocarcinoom na non-mola zwangerschap. PhD thesis. Dordrecht: ICG Printing, World Health Organization Scientific Group. Gestational Trophoblastic Diseases. WHO Technical Report Series, No. 692, Table 7. Geneva, Switzerland: WHO, World Health Organization Handbook for Reporting Results of Cancer Treatment. WHO Offset Publication No. 48. Geneva, Switzerland: WHO, ter Borg F, Smorenburg S, de Man RA, Rietbroek RC, Chamuleau RA, Jones EA. Recovery from life-threatening, corticosteroidunresponsive, chemotherapy-related reactivation of hepatitis B associated with lamivudine therapy. Dig Dis Sci 1998;43: Kendall A, Gillmore R, Newlands E. Chemotherapy for trophoblastic disease: current standards. Curr Opin Obstet Gynecol 2002;14: Tham KF, Ratnam SS. The classification of gestational trophoblastic disease: a critical review. Int J Gynecol Obstet 1998;60(Suppl 1): S39 S Kohorn EI, Goldstein DP, Hancock BW, et al. Combining the staging system of the International Federation of Gynecology and Obstetrics with the scoring system of the World Health Organization for Trophoblastic Neoplasia. Report of the Working Committee of the International Society for the Study of Trophoblastic Disease and the International Gynecologic Cancer Society. Int J Gynecol Cancer 2000;10: Kim SJ, Bae JH, Kim JH, et al. Effects of multiagent chemotherapy and independent risk factors in the treatment of high-risk GTT 25 years experiences of KRI-TDR. Int J Gynecol Obstet 1998;60(Suppl 1): S85 S Lurain JR, Casanova LA, Miller DS, Rademaker AW. Prognostic factors in gestational trophoblastic tumors: a proposed new scoring system based on multivariate analysis. Am J Obstet Gynecol 1991; 164: Azab MB, Pejovic M, Theodore C, et al. Prognostic factors in gestational trophoblastic tumors, a multivariate analysis. Cancer 1988;62: Rustin GJ, Newlands ES, Lutz JM, et al. Combination but not singleagent methotrexate chemotherapy for gestational trophoblastic tumors increases the incidence of second tumors. JClinOncol1996;14: Accepted 19 September 2003