Evaluation and management of brain metastatic patients with high-risk gestational trophoblastic tumors

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1 Int J Gynecol Cancer 2004, 14, Evaluation and management of brain metastatic patients with high-risk gestational trophoblastic tumors F. GHAEMMAGHAMI*, N. BEHTASH*, N. MEMARPOUR*, K. SOLEIMANI*, P. HANJANI & F. A. HASHEMI *Department of Gynecology and Oncology, Tehran University of Medical Sciences, Tehran, Iran; Rosenfeld Cancer Center, Abington Memorial Hospital, Abington, PA, USA; and Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran Abstract. Ghaemmaghami F, Behtash N, Memarpour N, Soleimani K, Hanjani P, Hashemi FA. Evaluation and management of brain metastatic patients with high-risk gestational trophoblastic tumors. Int J Gynecol Cancer 2004;14: A retrospective study to evaluate the characteristics of brain metastatic patients with gestational trophoblastic tumors (GTT) and to analyze the results of treatment has been performed. During , 40 patients with metastatic GTT were diagnosed at Vali-e-Asr Hospital, Tehran, Iran. Of them, nine with brain metastases, which were documented with the help of computed tomography scan, were evaluated retrospectively. Eight patients received EMA-EP regimen (etoposide, methotrexate, actinomycin, etoposide, and cisplatinum) and one received EMA-CO (etoposide, methotrexate, actinomycin, cyclophosphamide, and vincristin). All cases received whole brain irradiation therapy concurrently. The median age of the patients at diagnosis was 30 years (range: 17 53). Six of them were of early group (five with symptoms of central nervous system and one was detected during workup) and three were of late group (relapsed group). Five (56%) patients responded to treatment and four (44%) were deceased (three of them belonged to late group). It seems that multi-agent chemotherapy (EMA-EP) concurrently with whole brain irradiation results in acceptable survival rates in GTT patients with brain metastases. KEYWORDS: brain metastatic GTT, choriocarcinoma, EMA-EP regimen, multi-agent chemotherapy. Gestational trophoblastic tumor (GTT) is a rare malignancy of human beings, which is extremely responsive to chemotherapy even with metastatic forms (1). Therefore, prognosis of GTT has been substantially improved by the introduction of chemotherapic Address correspondence and reprint requests to: Fatemeh Ghaemmaghami, MD, Department of Gynecology and Oncology, Vali-e-Asr Hospital, Imam Khomeini Hospital Complex, Keshavarz Blvd, Tehran 14194, Iran. ftghaemmagh@yahoo.com agents. The major contributing factors to this are the effective use of b-hcg assay, therapy for individualizing the identified risk factors, the aggressive use of multi-agent chemotherapy (MAC) and irradiation, and surgical intervention. It is known that about 80% of GTT have remote metastatic lesions, and brain metastases occur in about 10% of patients with metastatic GTT, the incidence of which is the second highest, next to that of lung metastases (2). Two-thirds of patients, who died of advanced metastatic GTT, showed autopsy evidence of cerebral # 2004 IGCS

2 Management of brain metastatic patients with GTT 967 involvement. Brain metastases place patients at high risk of treatment failure (3). GTT has long been known to be a radiosensitive tumor (4). The risk of spontaneous cerebral hemorrhage may be lessened by the concurrent use of the combination of chemotherapy and brain irradiation, because irradiation may be both hemostatic and tumoricidal (5). However, when MAC and whole brain radiotherapy (WBRT) have been used concurrently, overall 50 80% of patients with brain metastases can be expected to be cured (2,6,7). Computed tomography (CT) or magnetic resonance imaging of the head has facilitated the early diagnosis of a symptomatic involvement in most of the cases (8,9). Ayhan et al. reported poor prognosis for patients, who present initially with neurologic symptoms similar to late central nervous system (CNS) group (10) in contrast to other data, indicating a favorable survival in the early neurological symptom group (3). Schechter et al. concluded that the prognosis of patients with brain metastatic GTT is excellent, if extracranial disease can be controlled (4). This study presents the characteristics of brain metastatic patients with GTT and analyzes the results of their treatment. Materials and methods During , 40 patients with metastatic GTT were diagnosed at Vali-e-Asr Hospital, Tehran, Iran. Among them, nine patients with brain metastases, which were documented with the help of CT scan, were evaluated retrospectively as a case series. Eight patients received high dose of EMA-EP (etoposide, methotrexate, actinomycin, etoposide, and cisplatinum) and one received high dose of EMA-CO (etoposide, methotrexate, actinomycin, cyclophosphamide, and vincristin). All these patients received concurrent whole brain irradiation (with 3000 cgy; 300 cgy for 10 consecutive days). Response was defined as three consecutive weekly normal b-hcg titers (<5 miu/ml). Four additional courses of chemotherapy were administered after the first normal b-hcg. Patients were divided into two categories (i) early group (individuals, who had presented with brain metastases before chemotherapy; six patients) and (ii) late group (individuals, who had relapsed after an initial complete or partial remission; three patients). The median follow-up was 24 months (range: 9 50) after diagnosis. Results The median age of the patients at diagnosis was 30 years (range: 17 54). The antecedent pregnancy was molar (five patients), aborted (two patients), term pregnancy (one patient), and unknown (one patient). While five patients initially presented with symptoms related to cranial involvement, such as headache, convulsion, decrease in consciousness, parasthesia, anesthesia, visual impairment, and hemiparesis, one was diagnosed during routine investigation for metastases in malignant GTT. Thus, overall six patients presented with brain metastases before chemotherapy (early group). Three patients had relapsed after an initial remission (late group) (Table 1). Besides brain involvement, all patients had lung metastases and there were also adrenal, renal, vaginal, and hepatic metastases in some of the patients. All patients in early group received EMA-EP (highdose regimen). Five of them responded to treatment with 4 11 courses of chemotherapy. One died before the completion of her first course of chemotherapy probably due to brain hemorrhage and herniation (manifestations were altered consciousness, mydriasis, etc.). All three patients in late group were expired. One patient had a history of molar pregnancy and pathological diagnosis of choriocarcinoma. She had a complete remission after TAH and chemotherapy. Four years later, she relapsed in brain and was treated with EMA-CO regimen (10 courses), but died due to cranial herniation. Another patient with a history of term pregnancy and TAH þ BSO, who had histologic report of placental site trophoblastic tumor (PSTT), was controlled for 18 months with negative b-hcg titers. Then, she relapsed in vagina and was treated with EMA-CO (four courses), which was switched to BEP (two courses). After a partial response for 8 months, another relapse occurred in brain, which was treated with EMA-EP (three courses), but she was expired due to toxicity of chemotherapy. The last patient in late group had a history of molar pregnancy. She had undergone TAH þ BSO, after receiving three courses of MTX-CF. Fifteen months later, she had relapse with lung metastases and was treated with EMA-EP (six courses). She responded to treatment successfully. After 7 months, because of rising b-hcg titer, she received six courses of EMA-EP and underwent thoracotomy due to resistance. Because the b-hcg titer was not decreased,

3 968 F. Ghaemmaghami et al. Table 1. Patient Characteristics of gestational trophoblastic tumor (GTT) patients with brain metastases at Vali-e-Asr Hospital, Tehran, Iran Age (years) Antecedent pregnancy Symptoms related to brain metastases Additional sites of metastases Site of brain metastases 1 22 Abortion þ Lung L. & R. occipital 2 33 Molar Lung Unknown Kidney 3 30 Molar þ Lung L. Adrenal Posteroparietal 4 53 Abortion þ Unknown 5 30 Molar Lung Adrenal L. parietal Kidney 6 17 Molar þ Lung L. frontoparietal?? 7 17 Unknown þ Lung L. temporal Liver 8 36 Term pregnancy Lung Unknown Vagina 9 49 Molar Lung Frontal Liver she was treated with EMA-EP (five courses), which then was switched to BEP (four courses). During the therapy, we detected brain metastases; therefore, the chemotherapy regimen was changed to high dose of EMA-EP, but after two courses of high dose of chemotherapy, she died due to respiratory distress (Table 2). Discussion Brain metastases occur in 3 28% of patients with metastatic GTT (3). We found it in 22.5% in our study. Review of literature indicates that when WBRT and MAC are used appropriately and in a timely manner, overall 50 80% of patients with brain metastases can be cured (4,6,7). In our series, 63% of patients responded to MAC (high dose of EMA-EP) and concurrent WBRT, with median of 20-month follow-up (range: 9 31). Although we had only six patients, who presented with early brain metastases, and three patients, who presented with late brain metastases, compared to 33 and 36 patients, respectively, of Athanassiou et al. (3), we agreed with their finding that patients, who develop brain metastases while on treatment or relapse in the brain after an initial complete or partial remission, represent a group of patients with worse prognosis than those who present with brain metastases before treatment. All three patients in late group, in our study, were lost, but only one in early group. Schechter et al. discussed that the survival is similar in early (25%) and late (32%) groups, in their study. Table 2. Presentation, treatment, and outcome in gestational trophoblastic tumor (GTT) patients with brain metastases at Vali-e-Asr Hospital, Tehran, Iran Patient Presentation Prior chemotherapy Surgery Final chemotherapy Courses Outcome 1 Early EMA-EP 4 NED 2 Late MTX, MAC TAH (B)* EMA-CO 10 DoD 3 Early TAH þ BSO (A) EMA-EP 4 NED 4 Early EMA-EP 11 NED 5 Early EMA-EP 5 NED 6 Early EMA-EP 1 DoD 7 Early TAH (A) EMA-EP 8 NED 8 Late EMA-CO, BEP TAH þ BSO (B) EMA-EP 3 DoD 9 Late MTX-CF, TAH þ BSO (A) EMA-EP 2 DoD EMA-EP Thoracotomy (A) A, after chemotherapy; B, before chemotherapy; NED, no evidence of disease; DoD, dead of disease. Placental site trophoblastic tumor (PSTT).

4 Management of brain metastatic patients with GTT 969 They had six patients in early group and 15 in late group. Four of six patients (early group) died. Of them, three died directly of their extracranial diseases. They concluded that the survival of patients with brain metastatic GTT is excellent, if extracranial disease can be controlled (4). Ayhan et al. (10) reported that many of their patients presented initially with neurological symptoms, but their prognosis was poor in contrast to the data of the study by Athanassiou et al. (3). Very late admission of such patients may naturally be the cause of this difference. One patient in our early group died before completion of the first course of her chemotherapy due to brain hemorrhage and herniation. Brain metastases of GTT have been known to cause rapid deterioration and fatalities due to edema, hemorrhage, and associated herniation before completion of the first course of chemotherapy (10). The overall survival rate was 56% in our series, which is comparable with the expected cure rate of 50 80% (4). Altintas and Varder (7) reported 66.6% overall survival rate for their patients that were treated with EMA-CO regimen. Ayhan et al. found 85.7% mortality rate in seven patients in their study, of which five patients were treated with MAC and one with EMA-CO chemotherapy regimens (10). Newlands et al. have found 86% survival rate in 36 patients, who took high dose of EMA-CO with 30-month follow-up (11). In our study, five of eight (63%) patients, who received high dose of EMA-EP, responded to treatment. It must be observed that one of our patients, who died during the study, had PSTT that was resistant to chemotherapy (12). We, usually, use EMA-EP as first-line chemotherapy with high-risk GTT due to other studies and their reported results (13,14,15), in which patients with a lower number of courses of chemotherapy had remissions. Results of this study are similar to those of the study by Weed and Hammond (16). They found the remission rate of 50% (7/14) in patients, who were under treatment with MAC and WBRT. In a study by Yordan et al., 18 of 78 patients with CNS trophoblastic disease received chemotherapy and WBRT, 25 were treated with only chemotherapy, and 35 received neither chemotherapy nor radiation (most of the patients died, before therapy was begun in this group). There were no survivors and 74% of deaths resulted from CNS causes (17). Among the patients, who received only chemotherapy, the survival rate was 24% and 58% of the patients died of CNS problems. In the group of patients, who received chemotherapy and radiation together, the survival rate was about 50% and none of the deaths were of CNS origin. This study demonstrates that radiation has a distinct therapeutic role in the treatment of CNS involvement in GTT. In another study of 42 patients with CNS metastases of GTT, treatment with MAC or etoposide regimen and radiation showed a survival rate of 44%, which is comparable with the rate reported for intrathecal methotrexate regimen (18). Rustin et al. (19) in their study of 25 patients with CNS involvement utilized intensive treatment with EMA-CO chemotherapy without WBRT and reported 72% of 5-year survival. They believe that WBRT is not needed to be used for all of the patients, but a second look at their data shows that 44% of the patients in their study have undergone craniotomy to control hemorrhage and edema. The role of craniotomy in the treatment of the GTT patients with brain metastases is unclear, but is often mandatory in fulminant cases. Schechter NR et al. (4) in a study based on autopsy findings reported that the CNS involvement is multifocal and that craniotomy cannot be an adequate complete treatment. Besides, hemorrhage in the brain metastases may occur at the sites remote from the primary tumor and even in the absence of the mass due to microscopic vascular invasion. Therefore, even though the majority of the patients present with clinical evidence of a solitary mass, WBRT would likely be more effective than craniotomy for definitive treatment. We did not have any complications due to the treatment with the combination of chemotherapy and WBRT. Similarly, Schechter et al. (4) report that the combination of chemotherapy and WBRT (range: cgy) has been utilized in the treatment of 21 patients with brain metastases of GTT. None of our patients had developed radiation-induced dementia, impairment of higher cognitive functioning, or other late neurologic sequela directly attributable to WBRT. In our series, one patient died because of toxicity. This patient had PSTT and had depleted bone marrow due to various combined chemotherapies (four courses of EMA- CO and two courses of BEP) before being referred to us. Conclusion It seems that GTT patients, who present with brain metastases before treatment, do better than those who relapsed in brain after an initial complete or partial response.

5 970 F. Ghaemmaghami et al. Brain metastases place patients at high risk for treatment failure; however, our study shows that MAC (EMA-EP) concurrently with whole brain irradiation can result in acceptable survival rates in GTT patients with brain metastases and is the treatment of choice for all these kinds of patients. References 1 Hoskins WJ, Peres CA, Young RC. Principles and Practice of Gynecologic Oncology, 3rd edn. Philadelphia: Lippencott, Williams & Wilkins, 2000, Kang SB, Lee CM, Kim JW, Park NH, Lee HP. Chemoresistant choriocarcinoma cured by pulmonary lobectomy and craniotomy. Int J Gynecol Cancer 2000;10: Athanassiou A, Begent RH, Newlands ES, Parker D, Rustin GJ, Bagshawe KD. Central nervous system metastases of choriocarcinoma, 23 years experience at Charing Cross Hospital. Cancer 1983;52: Schechter NR, Mychalczak B, Jones W, Sprigg SD. Prognosis of patients treated with whole-brain radiation therapy for metastatic gestational trophoblastic disease. Gynecol Oncol 1998;68: Berkowitz RS, Goldstein DP. Gestational trophoblastic neoplasia. In: Berek JS, Hacker NF, eds. Practical Gynecologic Oncology, 3rd edn. Philadelphia: Lippencott, Williams & Wilkins, 2000, Small WJ, Lurain JR, Shetty RM, Huang CF, Applegate GL, Brand WN. Gestational trophoblastic disease metastatic to the brain. Radiology 1996;200: Altintas A, Varder MA. Central nervous system involvement in getational trophoblastic neoplasia. Int J Gynecol Cancer 1999;9: Kim SJ. Clinical management of benign and malignant trophoblastic disease in North-east Asia. Curr Obstet Gynecol 1995;5: Hammond CB, Weed JC, Currie JL. The role of operation in the current therapy of gestational trophoblastic disease. Am J Obstet Gynecol 1980;136: Ayhan A, Tuncer Z, Selcuk T et al. Central nervous system involvement in gestational trophoblastic neoplasia. Acta Obstet Gynecol Scand 1996;75: Newlands ES, Holden L, Seckl MJ, MacNeish J, Strickland S, Rustin GJ. Management of brain metastases in patients with high risk gestational trophoblastic tumors. J Reprod Med 2002;47: Narita F, Takeuchi K, Hamana S et al. Epitheliod trophoblastic tumor (ETT) initially interpreted on cervical cancer. Int J Gynecol Cancer 2003;13: Surwit EA, Childers JA. High risk metastatic gestational trophoblastic disease. A new dose-intensive, multiagent chemotherapeutic regimen. J Reprod Med 1991;36: Newlands ES, Bagshawe KD, Bergent RH et al. Developments in chemotherapy for medium and high risk patients with gestational trophoblastic tumors Br J Obstet Gynecol 1986;93: Ghaemmaghami F, Modares M, Arab M et al. EMA-EP regimen as first-line multiple agent chemotherapy in high risk GTN. Int J Gynecol Cancer 2004;14: Weed JC Jr, Hammond CB. Cerebral metastatic choriocarcinoma: intensive therapy and prognosis. Obstet Gynecol 1980;55: Yordan EL Jr, Schlaerth JB, Gaddis CP, Morrow CP. Radiation therapy in the management of gestational choriocarcinoma metastatic to the central nervous system. Obstet Gynecol 1987;69: Evans AC, Soper JT, Clarke-Pearson DL et al. Gestational trophoblastic disease metastatic to the central nervous system. Gynecol Oncol 1995;59: Rustin GJS, Newlands EE, Begent RHJ, Dent J, Bagshawe KD. Weekly alternating etoposide, methotrexate, and actinomycin/vincristine and cyclophosphamide chemotherapy for the treatment of CNS metastases of choriocarcinoma. J Clin Oncol 1989;7: Accepted for publication April 12, 2004

6 Management of brain metastatic patients with GTT 971 Appendix Protocol of high dose of EMA-EP chemotherapy for brain metastatic gestational trophoblastic tumor (GTT) EMA-EP protocol Day 1 Etoposide 100 mg/m 2 IV (500 cc N/S in 30 min) Act-D 0.5 mg IV stat MTX 100 mg/m 2 IV stat MTX 1000 mg/m 2 (1000 cc N/S in 12 h) Day 2 Etoposide 100 mg/m 2 IV (500 cc N/S in 30 min) Act-D 0.5 mg IV stat Folinic acid 30 mg IM or PO Q12 h for six doses, start 32 h after MTX was started Day 8 Etoposide 100 mg/m 2 IV (500 cc N/S in 30 min) Cisplatinum mg/m 2 IV (100 cc 1 mg/min) Every 7 days 1, 2, 8,... 15, 16, 22 EMA-CO protocol (high dose) Days 1 and 2 As EMA-EP Day 8 Vincristin 1 mg/m 2 IV Cyclophosphamide 600 mg/m 2 IV Every 7 days 1, 2, 8,... 15, 16, 22