ORIGINAL ARTICLE. Summary. Introduction

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1 Journal of BUON 11: , Zerbinis Medical Publications. Printed in Greece ORIGINAL ARTICLE Myeloablative chemotherapy with autologous peripheral blood stem cell transplantation in patients with poor-prognosis solid tumors Bulgarian experience B. Avramova 1, M. Jordanova 1, G. Michailov 2, D. Konstantinov 1, I. Christosova 1, Dr. Bobev 1 1 Specialized Hospital for Pediatric Oncohematology and Bone Marrow Transplantation, Sofi a; 2 National Center for Hematology and Transfusion Medicine, Sofi a, Bulgaria Summary Purpose: To assess the outcome of patients with refractory or relapsed solid tumors treated with myeloablative chemotherapy followed by autologous peripheral blood stem cell transplantation. Patients and methods: From October 1997 to March 2006, 38 transplantations were performed in 32 patients (19 children and 13 adults, 20 men and 12 women, median age 18.5 years, range 3-59). Six patients underwent 2 transplantations. The diagnoses were: rhabdomyosarcoma 4; Ewing s sarcoma 7; lymphoepithelioma epipharyngis 7; germ-cell tumors 6; neuroblastoma 4; pulmonary blastoma 1; breast cancer -3. The indication for high-dose chemotherapy was sensitive relapse in 17 and refractory disease in 15 patients. At the time of transplantation the state of remission was: complete remission (CR) in 10 patients; partial remission (PR) in 16 and disease progression in 6. The median number of transplanted CD34+ cells was /kg of patient s body weight. High-dose chemo- therapy regimens were: thiotepa, carboplatin 1; thiotepa, cyclophosphamide 5; ifosfamide, carboplatin, etoposide (ICE) 18; etoposide, carboplatin 2; etoposide, cyclophosphamide, melphalan 2; melphalan, fl udarabine 1; melphalan, busulfan 3; etoposide, carboplatin, ifosfamide/ thiotepa, cyclophosphamide (EBDIS) - 4. Results: Twenty-nine patients were engrafted and 3 died from graft failure. Transplantation-related mortality was 9%. The most important transplantation-related toxicities included mucositis (90% of the patients), fever (85%) and diarrhea (75%). With a median follow-up of 32 months (range 1-95), the median overall survival (OS) and the eventfree survival (EFS) were 62 and 36 months, respectively. Conclusion: High-dose chemotherapy with autologous stem cell transplantation was curative for many of our patients with poor-prognosis solid tumors. Key words: autologous transplantation, high-dose chemotherapy, relapse, resistance, stem cells, solid tumors Introduction The use of high-dose chemotherapy with hemopoietic stem cells transplantation for the treatment of both hematological malignancies and solid tumors has Received ; Accepted Author and address for correspondence: Dr. Boryana Avramova Specialized Hospital for Pediatric Oncohematology and Bone Marrow Transplantation 8, Bjalo More Street 1527 Sofia Bulgaria Tel: Fax: bavramova65@yahoo.co.uk, b.avramova@sbaldohz.com increased dramatically over the past several years [1]. Now this therapy is standard for several pediatric and adult malignancies, including solid tumors. In patients with poor-prognosis solid tumors (resistant or relapsed) high-dose chemotherapy with autologous hemopoietic stem cells transplantation (ahsct) is an alternative to conventional therapy. The use of allogeneic stem cells transplantation in this patient s group is limited because of high transplantation - related morbidity and mortality, despite graft versus tumor (GvT) effect. Recently introduced allogeneic nonmyeloablative regimens have greatly decreased morbidity and mortality, which retain a powerful GvT effect [2]. Annually in Europe around 1800 hemopoietic stem cells transplantations are carried out in patients

2 434 with solid tumors and 93% of them are autologous. The most common indications for this treatment are neuroblastoma (21%), germ-cell tumors (17%), Ewing s family tumors (14%) and breast cancer (11%). In the last years there is an increase in ahsct for neuroblastoma, glioma, soft tissue sarcoma, germ-cell cancer and Ewing s sarcoma and a decrease for breast cancer, lung cancer and ovarian cancer [3]. As a key element of a therapeutic strategy in patients with solid tumors, myeloablative chemotherapy with ahsct is carried out in Bulgaria from The purpose of this retrospective study was to assess the outcome of patients with solid tumors, treated with high-dose chemotherapy followed by ahsct in our hospital. Patients and methods Patient characteristics Thirty-two patients received 38 high-dose chemotherapy courses followed by ahsct between October 1997 and March 2006 at the Transplantation Unit in the Specialized Hospital for Pediatric Oncohematology and Bone Marrow Transplantation in Sofia. Six patients received double transplantations. The patients were 19 children and 13 adults. Their age ranged from 3 to 59 years (median 18.5). The main patient characteristics are shown in Table 1. All patients were with a variety of different solid tumors. The main indications for myeloablative chemotherapy with Table 1. Main patient characteristics Characteristic Patients,n Age (years), median 18.5 range 3-59 Malignancy Ewing s sarcoma 7 Lymphoepithelioma epipharyngis 7 Germ-cell tumors 6 Rhabdomyosarcoma 4 Neuroblastoma 4 Breast cancer 4 Pulmonary blastoma 1 Status of remission before transplantation Complete remission 10 Partial remission 16 Progression 6 Indications for high-dose chemotherapy Sensitive relapse 17 Refractory disease 15 ahsct were chemosensitive relapse and refractory disease. The previous treatment of the patients was according to the protocols approved by our hospital for the respective disease. Stem cell harvest Peripheral blood stem cells (PBSC) were mobilized with cyclophosphamide 2 g/m 2 /d for 2 days plus etoposide 100 mg/m 2 /d for 3 days and G-CSF 5 μg/kg/ d s.c. until the last day of collection. PBSC collections were carried out using a Fresenius Hemo Care -Com. Tech. cell separator through a double lumen apheresis catheter on the day after mobilization with leukocyte count over 1500/mm 3, platelet count over 50000/mm 3 and CD34+ count over 40/μl blood. No purging was done in all cases. The median collected amount of CD34+ cells were /kg (range /kg) with median number of aphereses 2 (range 1-3). Conditioning regimens Patients were conditioned with a variety of preparative regimens (Table 2). These regimens included one or combination of several cytotoxic drugs without total body irradiation (TBI). For patients with neuroblastoma, the following drug combinations were used: etoposide (60 mg/m 2-1 day) with carboplatin (500 mg/m 2 /d - 3 days); etoposide (60 mg/m 2-1 day) with carboplatin (500 mg/m 2 /d - 3 days) and melphalan (180 mg/m 2-1 day); and melphalan (80 mg/m 2-1 day) with fludarabine (25 mg/m 2 /d - 5 days). For patients with rhabdomyosarcoma and for relapsed or high-risk solid tumors thiotepa (200 mg/m 2 /d - 3 days) with carboplatin (500 mg/m 2 /d - 3 days) or with cyclophosphamide (1500 mg/m 2 /d - 3 days) were given. The conditioning regimen for patients with lymphoepithelioma epipharyngis, rhabdomyosarcoma and germ-cell tumors was ICE (ifosfamide 2 Table 2. Types of conditioning regimens Conditioning regimen Patients, n Thiotepa + Carboplatin 1 Thiotepa + Cyclophosphamide 5 ICE 18 Etoposide + Carboplatin 2 Etoposide + Carboplatin + Melphalan 2 Melphalan + Busulfan 3 Melphalan 2 Melphalan + Fludarabine 1 EBDIS 4

3 435 g/m 2 /d - 6 days; carboplatin 200 mg/m 2 /d - 6 days; etoposide 250 mg/m 2 /d - 6 days). Ewing s sarcoma patients received melphalan (140 mg/ m 2-1 day) with busulphan (4 mg/kg/d - 4 days). Patients with breast cancer were conditioned according to the EBDIS protocol (Regimen I: etoposide 400 mg/m 2 /d 3 days; carboplatin 800 mg/m 2 /d - 3 days; ifosfamide 4 g/m 2 /d - 3 days. Regimen II: thiotepa 200 mg/m 2 /d - 4 days; cyclophosphamide 1.5 g/m 2 /d - 4 days, with 2-month interval between the two conditioning regimens). The transplantation was carried on day 0 after high-dose chemotherapy through central venous catheter. The median CD34+ cells transplanted were /kg of patient s body weight. Supportive care All patients were nursed in special single rooms in the Transplantation Unit. CMV- and HSV-positive patients received prophylactically acyclovir i.v. Orally non-absorbable antibiotics (for intestinal decontamination) were given to all patients. Broad-spectrum antibiotics were administered if fever developed during aplasia and fluconazole (diflucan) i.v. was added if fever persisted despite the initial antibiotic therapy. Blood component therapy was used to maintain the hemoglobin level above 8 g/dl and platelets above 20000/mm 3 ; all cellular products were irradiated with 25 cgy. All patients received G-CSF 10 μg/kg, starting from day +3. Statistical analysis Kaplan-Meier curves were used to compute time to relapse or death. In each case, intervals were calculated from the date of transplantation until the date of relapse/death or the date of last follow-up. Results Twenty-nine patients were engrafted with median engraftment time for neutrophils >500/mm 3 10 days and for platelets >20000/mm 3 13 days. Three patients died in the Transplantation Unit without engraftment due to severe hemorrhagic complications during aplasia. The transplantation - related mortality was 9%. Twenty-six (81%) patients were in CR (10 patients) or PR (16 patients) before transplantation and 6 (9%) were with disease progression. After transplantation 19 (59.3%) patients achieved disease-free status. No patient with disease progression achieved CR; only 2 (33.3%) patients achieved PR (lymphoepithelioma epipharyngis and neuroblastoma) (Tables 3,4). With a median follow-up time of 32 months (range 1-95), the median OS is 62 months and the median event-free survival (EFS) 36 months (Figures 1, 2). All relapsed patients were treated with second line chemotherapy and 6 of them received a second highdose therapy with ahsct. One (16.6%) of them died of transplant toxicity, 4 (66.8%) of disease progression Table 3. Results of the transplantations according to tumor type Diagnosis Remission status after TRM PRM PTR PTS PRS Transplant toxicity transplantation (Gr. I-II) Pts, n (%) Pts, n (%) Pts, n (%) Pts, n (%) Pts, n (%) Pts, n (%) Ewing s sarcoma (n=7) CR 4 (57.1) 1 (14.2) 3 (42.8) 3 (42.8) 3 (42.8) 0 (0) 5 (71.4) SD 1 (14.3) PD 2 (28.6 Lymphoepithelioma epipharyngis (n=7) CR 5 (71.4) 0 (0) 1 (14.2) 2 (28.5) 6 (85.7) 1 (14.2) 5 (83.3) PR 2 (28.6) Germ-cell tumors (n=6) CR 3 (50) 1 (16.6) 2 (33.3) 2 (33.3) 3 (50) 0 (0) 6 (85.7) SD 3 (50) Rhabdomyosarcoma (n=4) CR 3 (75) 1 (25) 1 (25) 2 (50) 2 (50) 1 (25) 3 (75) SD 1 (25) Neuroblastoma (n=4) CR 3 (75) 0(0) 2 (50) 2 (50) 2 (50) 0 (0) 3 (75) SD 1 (25) Breast cancer (n=3) PR 1 (33.3) 0 (0) 1 (33.3) 2(66.6) 2 (66.6) 1 (33.3) 3 (100) SD 2 (66.7) Pulmonary blastoma (n=1) CR 1 (100) 0 (0) 0 (0) 0 (0) 1 (100) 0 (0) 0 (0) TRM: transplant-related mortality, PRM: progression-related mortality, PTR: post-transplant relapse, PTS: post-transplant survivors, PRS: post-relapse survivors

4 436 Table 4. Results of the transplantations according to cancer type and state of remission before transplantation State of remission TRM PRM PTR Overall PRS Transplant toxicity before transplantation survival (Gr. I-II) Pts, n (%) Pts, n (%) Pts, n (%) Pts, n (%) Pts, n (%) Pts, n (%) Complete remission (n=10) Ewing s sarcoma (n=2) 1 (10) 2 (20) 1 (10) Lymphoepithelioma 3 (30) 2 (20) epipharyngis (n=2) Germ-cell tumors (n=2) 1 (10) 1 (10) 2 (20) 0 (0) Rhabdomyosarcoma (n=2) 1 (10) 1 (10) Neuroblastoma (n=1) 1 (10) 1 (10) Pulmonary blastoma (n=1) 1 (10) Partial remission (n=16) Ewing s sarcoma (n=3) 1 (6.2) 2 (12.5) 1 (6.2) 2 (12.5) Lymphoepithelioma 1 (6.2) 3 (18.8) 1 (6.2) 3 (18.8) epipharyngis (n=3) Germ-cell tumors (n=2) 1 (6.2) 1 (6.2) 1 (6.2) 2 (12.5) Rhabdomyosarcoma (n=2) 2 (12.5) 1 (6.2) 1 (6.2) 2 (12.5) Neuroblastoma (n=3) 1 (6.2) 1 (6.2) 1 (6.2) 1 (6.2) 2 (12.5) Breast cancer (n=3) 1 (6.2) 2 (12.5) 2 (12.5) 1 (6.2) 3 (18.8) Progression (n=6) Ewing s sarcoma (n=2) 2 (33.3) 1 (6.2) 0 (0) 0 (0) 2 (33.3) Lymphoepithelioma 1 (16.6) 1 (16.6) 0 (0) 0 (0) 2 (33.3) epipharyngis (n=2) Germ-cell tumors (n=2) 1 (16.6) 1 (16.6) 1 (16.6) 0 (0) 0 (0) 2 (33.3) For abbreviations see footnote of Table 3 after a median of 15.5 months (range 2-24) after the second transplantation, and one (16.6%) is in CR up to date. Seventy-one percent of the relapsed patients died after a median of 9.4 months (range 1-17). The main toxic manifestations from the conditioning regimens were grade I and II mucositis in 85% of the patients, fever in 78% and grade I diarrhea in 75% of them. All toxic complications except the 3 fatal hemorrhagic events were not severe and recovery was complete after engraftment. Figure 1. Overall survival. Figure 2. Event-free survival.

5 437 Discussion Most of the described tumors treated in our hospital with high-dose chemotherapy and ahsct were chemosensitive [4]. On the other hand, patients with metastatic disease generally have a poor prognosis despite intensive front-line chemotherapy and an initially responsive disease [5]. Use of aggressive chemotherapy is limited by both hematological and non-hematological toxicities. Therefore, high-dose chemotherapy is followed by ahsct to overcome hematological toxicity. Germ-cell tumors are among the cancers most successfully treated with ahsct, both in children and adults [6,7]. In germ-cell tumors myeloablative chemotherapy is used in high-risk patients (highvolume metastatic disease, very high elevations of serum tumor markers, extragonadal primary tumors, tumors resistant/refractory to conventional-dose chemotherapy, some types of relapse etc). Using the same conditioning regimen (ICE) like other European transplantation centres, our results for disease control in this patient group are similar [8-10]. The University Hospital in Indiana had the following results: after conditioning with ICE, 25% of the patients achieved CR and 20% PR, for an overall response rate 45%. Half of the patients with PR achieved CR after second transplantation. Sixty-two percent of the patients were disease-free for more than 18 months [6]. The results of European studies are similar [7,8,10,11]. The other solid tumor in which high - dose chemo therapy with ahsct is applied is neuroblastoma, the most common extracranial solid tumor in children. Sixty percent of the patients are high risks in whom conventional chemotherapy is not sufficient for long-term survival. According to many studies [12-15] these patients must be treated with induction conventional chemotherapy and consolidation with myeloablative chemotherapy with ahsct. Most of the conditioning regimens include melphalan, cisplatin or carboplatin, and etoposide, and in recent years fludarabine [12]. Disputable is the question for the time of transplantation - after first remission or after progression of the disease. In eighty percent of the patients who are transplanted in first remission the therapeutic response is very good with 5-year diseasefree survival (DFS) 25-50%. In patients treated after disease progression the 2-year DFS is 7-25% [14,15]. Stram and colleagues [13] reported 40% 4-year DFS in patients treated with high-dose chemotherapy and 19% in those treated conventionally. All of our patients with neuroblastoma transplanted in progression or in PR (4 patients) relapsed between 3 and 9 months after transplantation. Those transplanted in CR or in very good PR achieved very good long-term CR lasting for a median of months. Ewing s sarcoma and other Ewing s family tumors are considered chemosensitive malignancies, which provided a rationale for high-dose chemotherapy as initial treatment of metastatic disease or more often as salvage therapy of relapsed or refractory disease [16,17]. Most conditioning regimens have focused on melphalan with or without busulfan, which are also used in our hospital. The European Bone Marrow Solid Organ Registry (EBMSOR) reported 27% CR rate and 19% 5-year OS after this treatment [18]. Patients with metastases on diagnosis who received consolidation therapy after surgery in first CR had a 21% 5-year DFS. Those treated in second CR, 84% of whom were diagnosed with localized disease only, had a 5-year DFS of 32% [19]. Our results in patients with Ewing s sarcoma showed very short DFS after transplantation, and the relapses were diagnosed from 3 to 8 months after high-dose chemotherapy. The main reason for this was advanced disease at the time of transplantation in most of the patients. The therapeutic strategy in other solid tumors is similar. In patients with relapsed or resistant rhabdomyosarcoma who received high-dose chemotherapy in either first CR or PR, the 5-year OS was 22% [20]. The 3-year DFS and OS of patients with myeloablative chemotherapy were 29.7% and 40%, respectively, in comparison with 19.2% and 27.7%, respectively, of those with standard chemotherapy [20]. Our results showed 50% 5-year EFS and 63% 3-year DFS in patients treated with high-dose chemotherapy in first CR. In other children s solid tumors (Wilms tumor, lymphoepithelioma epipharyngis, osteosarcoma, retinoblastoma and others), myeloablative chemotherapy is not treatment of choice for different reasons (good results with conventional chemotherapy, no chemosensitivity etc.). We transplanted a relatively large number of patients (children and adults) with lymphoepithelioma epipharyngis, despite the small number of publications for this diagnosis. Our results showed 85.7% 5-year OS and 57.1% DFS. This is a reason to conclude that high-dose chemotherapy with ahsct is a treatment suitable in first CR after standard chemo- and radiotherapy in this patients group. More special is the situation with administration of high-dose chemotherapy and ahsct in patients with metastatic breast cancer. Between 1990 and 2000 there was great enthusiasm for a successful treatment of metastatic breast cancer with myeloablative chemotherapy. The results of the European Group for Blood and Marrow Transplantation, Solid Tumor

6 438 Working Party during this period for 7471 patients who had received high-dose chemotherapy with ahsct were: 5-year DFS and OS 18% and 27% for metastatic disease, respectively, and 42% and 53% for inflammatory breast cancer, respectively [21]. After this period, because of not so good results, the number of ahsct in breast cancer decreased (according to EBMSOR registry ahsct annually in Europe in the last 5 years) and the inclusion/exclusion criteria became more strict. Our results from transplantation of patients with breast cancer are similar to those of other European centers. Multiple factors contribute to transplantationrelated complications after high-dose chemotherapy followed by ahsct, including conditioning regimens, the number of infused stem cells and the clinical characteristics of the patient at transplantation. The results of most European transplantation centers are: transplantrelated mortality (TRM) 3-10% and median engraftment time between 10 and 15 days [22]. Our results were similar: TRM 9%, median engraftment time days for neutrophils and days for platelets, and not very severe transplantation-related toxicity (TRT). We conclude that high-dose chemotherapy with autologous hemopoietic stem cell transplantation was curative for most of the patients with poor-prognosis solid tumors. In our center the OS, EFS, TRM and TRT are comparable with those of other European centers and we should continue to apply this alternative treatment option after appropriate patients selection. References 1. Horowitz MM, Rowlings PA. An update from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry on current activity in hematopoietic stem cell transplantation. Curr Opin Hematol 1997; 4: Carnecale-Schianca F, Ricciardi A, Capaldi A et al. Allogeneic hemopoietic stem cell transplantation in solid tumors. Transplant Proc 2005; 37: EBMT survey on transplant activity 2004 and Robinson LL. General principles of epidemiology of childhood cancer. In: Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology (3rd edn). Philadelphia: Lippincott-Raven Publ, 1997, pp Kung FH, Pratt CB, Vega RA et al. Ifosfamide/etoposide combination in the treatment of recurrent malignant solid tumors of childhood. A Pediatric Oncology Group Phase II study. Cancer 1993; 71: Samaniego F, Bosl G, Geller N, Penenberg D,Golbey R. Identification of prognostic variables in patients with germ cell tumor within the poor risk subgroup. Proc Am Soc Clin Oncol 1988; 7: 132 (abstr). 7. Birch R, Wiliams S, Cone A et al. Prognostic factors for favorable outcome in disseminated germ cell tumors. J Clin Oncol 1986; 4: Hara I, Miyake H, Yamada Y et al. Feasibility and usefulness of high-dose chemotherapy (high-dose ifosfamide, carboplatin and etoposide) combined with peripheral blood stem cell transplantation for male germ cell tumor: a single-institute experience. Anticancer Drugs 2006;17: Shigemura K, Tanaka H, Hara I et al. Clinical study for management of supportive treatment for high-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) for intractable testicular tumor. Hinyokika Kiyo 2006; 52: Muller AM, Ihorst G, Waller CF et al. Intensive chemotherapy with autologous peripheral blood stem cell transplantation during a 10-year period in 64 patients with germ cell tumor. Biol Blood Marrow Transplant 2006;12: Broun E, Nichols C, Kneebone P et al. Long-term outcome of patients with relapsed and refractory germ cell tumors treated with high dose chemotherapy and autologous bone marrow rescue. Ann Intern Med 1992; 117: Kushner BH, Cheung NK. Neuroblastoma. Pediatr Ann 1988; 17: and Stram DO, Matthay KK, O Leary M et al. Consolidation chemoradiotherapy and autologous bone marrow transplantation versus continued chemotherapy for metastatic neuroblastoma: A report of two concurrent Children s Cancer Group Studies. J Clin Oncol 1996; 14: Matthay KK, Seeger RC, Reynolds CP et al. Allogeneic vs autologous purged bone marrow transplantation for neuroblastoma: A report from the Children s Cancer Group. J Clin Oncol 1994; 12: Matthay KK, Perez C, Seeger RC et al. Improved event free survival for autologous bone marrow transplantation vs. chemotherapy in neuroblastoma: A phase III randomized Children s Cancer Group study. Proc Am Soc Clin Oncol 1998; 17: 2018 (abstr). 16. Burdach S, Jurgens H. High-dose chemotherapy (HDC) in the Ewing s family of tumors (EFT). Crit Rev Oncol Hematol 2002; 41: Pinkerton CR, Bataillard A, Guillo S et al. Treatment strategies for metastatic Ewing s sarcoma. Eur J Cancer 2001; 37: Ladenstein R, Gadner H, Hartmann O et al. The impact of megatherapy followed by stem cell reinfusion in Ewing s sarcoma patients with residual disease. Bone Marrow Transplant 1997; 19: S Ladenstein R, Lasset C, Pinkerton R et al. Impact of megatherapy in children with high risks Ewing s tumors in complete remission. A report from the EBMT Solid Tumor Registry. Bone Marrow Transplant 1995; 15: Carli M, Colombatti R, Oberlin O et al. High-dose melphalan with autologous stem cell rescue in metastatic rhabdomyosarcoma. J Clin Oncol 1999; 17: Pedrazzoli P, Ferrante P, Kulekci A et al. Autologous hematopoietic stem cell transplantation for breast cancer in Europe: critical evaluation of data from the European Group for Blood and Marrow Transplantation (EBMT) Registry Bone Marrow Transplant 2003; 32: Martino M, Morabito F, Console G et al. Differences in transplant-related complications between hematologic malignancies and solid tumors receiving high-dose chemotherapy and autologous peripheral blood stem cell transplantation. Tumori 2003; 89: