of patients at previously known sites; in three cases new metastatic sites were observed. Patients with primary

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1 Bone Marrow Transplantation, (17) 1, Stockton Press All rights reserved /7 $12.00 Do patients with metastatic and recurrent rhabdomyosarcoma benefit from high-dose therapy with hematopoietic rescue? Report of the German/Austrian Pediatric Bone Marrow Transplantation Group. E Koscielniak 1, TH Klingebiel 2, C Peters 3, J Hermann, ST Burdach 5, C Bender-Götze 6, ST Müller-Weihrich 6 and J Treuner 1 1 Department of Pediatric Oncology, Olga Hospital, Stuttgart; 2 University of Tübingen, Germany; 3 St Anna Kinderspital, Vienna, Austria; University of Jena; 5 University of Düsseldorf; and 6 University of München, Germany Summary: of patients at previously known sites; in three cases new metastatic sites were observed. Patients with primary Patients with primary metastatic or recurrent rhabdomyosarcoma localized tumors who had been treated with HDC (RMS) have a very poor prognosis. Since because of relapse did slightly better (four of nine alive high-dose chemotherapy (HDC) TBI was thought to with NED) than patients with primary metastatic dis- improve survival, many centers performed this ther- ease (five of 27 alive with NED). HDC is still of uncertain apy using different types of hematopoietic rescue (auto value in the therapy of poor-risk rhabdomyosarapy BM or PBSC, allo BM). This is a retrospective, multi- coma and should be performed only as part of center analysis of the results of treatment in 36 patients controlled clinical trials. with primary metastatic or relapsed RMS who were Keywords: rhabdomyosarcoma; high-dose therapy; soft given HDC TBI and hematopoietic rescue between tissue sarcoma 186 and 1. The median age was 6 years ( 1 22 years). Primary therapy was given according to either one of the Cooperative German Soft Tissue Sarcoma Studies CWS-81, -86, -1 or the European Study for Rhabdomyosarcoma (RMS) is the commonest, highly Stage IV Malignant Mesenchymal Tumors in Childof malignant soft tissue sarcoma of childhood. The prognosis hood. There were 22 alveolar RMS, 13 embryonal patients with localized rhabdomyosarcoma has improved RMS and one undifferentiated sarcoma. The indication in the last 20 years, with an EFS rate of approximately for HDC was primary metastatic disease (27 patients) 70%. 1 3 In contrast, the chance of cure in primary meta- or a relapse of a primary localized tumor (nine static or relapsed tumors is very poor. The 5 year survival patients). Thirty-two patients were in 1st or 2nd CR rates of patients with primary disseminated tumors in the when given HDC and four in VGPR. The median time Intergroup Rhabdomyosarcoma Studies IRS I, II and III from last event to HDC was weeks (21 110). HDC were between 20 and 30%. In the German Soft Tissue Sar- consisted of fractionated melphalan (( 30 coma Study CWS-81 it was 1% and in the European Study 5 mg/m 2 ), VP mg/kg, carboplatin 3 00 for Stage IV Malignant Mesenchymal Tumors in Childhood 500 mg/m 2 ) in 26 patients, 10 of whom received (MMT Stage IV) the survival rate at 3 years was 2.7%. 1 6 additional FTBI. Seven patients were treated with melchanged It is interesting to note that the results of treatment have phalan alone or in combination with carboplatin. Two little over the last 20 years. The chance of being patients received cyclophosphamide/busulphan with cured after relapse of primary localized RMS depends on TLI (total lymphoid irradiation) and one cyclophoscal the intensity of the primary chemotherapy, on the histologiphamide with FTBI. Thirty-one patients were given subtype and whether radiotherapy was given. In the autologous BM or PBSC as hematopoietic rescue and German Cooperative Soft Tissue Sarcoma Studies CWS-81 five allogeneic bone marrow from HLA-identical sibcoma and CWS-86 only patients with embryonal rhabdomyosar- lings. Fourteen patients received GM-CSF or G-CSF who relapsed locally and in whom local irradiation after hematopoietic stem cell transfusion (HSCT). Ten was still feasible had a slightly better chance of survival patients received adjuvant IL-2. There was one toxic with a survival rate at 3 years of 62% (data not published). HDC-related death. Nine patients are alive and free of For the remaining patients the EFS rate at 2 years did not disease with a median observation time of 57 months exceed 20%. 7 Since RMS is a chemosensitive tumor a (32 108). The median time from HDC to relapse was further escalation of dose intensity seemed to be the best months (1 17). The tumor recurred in the majority way of improving results. Many centers in Europe and USA have performed high-dose chemotherapy with hematopoietic stem cell transfusion (HSCT) as a late consolidation of therapy in patients with metastatic and relapsed solid Correspondence: Dr E Koscielniak, Department of Pediatric Oncology and Hematology, Olga Hospital, Bismarckstr. 8, Stuttgart, Germany tumors. 8 However, the prognostic benefit of this procedure Received 21 March 16; accepted September 16 is still unproven. 8 1

2 228 We present a retrospective analysis of the results of was treated according to the German Cooperative Study for treatment in patients with metastatic or relapsed rhabdomyosarcoma relapsed sarcomas (CWS/CESS Relapse-Study). Treatment who were given HDC with HSCT as a con- regimens used included: VACA (vincristine, dactinomycin, solidation of CR or very good PR. Patients were registered cyclophosphamide and doxorubicin), VAIA (vincristine, in the German/Austrian Pediatric Bone Marrow Trans- dactinomycin, ifosfamide and doxorubicin), EVAIA plantation Register in Tübingen and were treated between (additional VP16), CEVAIE (carboplatin, epiadriamycin, 186 and 1 in several centers in Germany and Austria vincristine, ifosfamide, dactinomycin and VP16). The recommended (Appendix 1). The endpoint for the analysis was 31 chemotherapy duration for metastatic patients December 15. in the CWS studies was 56 (CWS-81) or 6 weeks (CWS- 86). In the MMT Stage IV study it was 26 weeks. Since local therapy (irradiation or surgery on primary tumor metastases) was also given, the complete duration of therapy Materials and methods before HDC was even longer than 56 weeks in sev- eral patients. The clinical characteristics of the 36 patients are given in The median interval between the last event that led to Table 1. The median age at diagnosis was 6 years ( 1 eligibility for HDC and the HDC itself was weeks (21 22). Alveolar rhabdomyosarcoma was the predominant histological 110). The latest event before HDC was defined either as a subtype, occurring in 22 (61%) patients. Primary relapse or a diagnosis of primary metastatic RMS. Thirty- metastatic disease was the indication for HDC in 27 (75%) two patients were in first or second CR before HDC and patients. Nine patients received HDC because of relapse four in VGPR. High-dose therapy in 26 patients consisted (four systemic, four lymph nodes and one local relapse) of of fractionated melphalan ( 30 5 mg/m 2 ), VP16 (0 their primary localized tumors. 60 mg/kg) and carboplatin (3 00 mg/m 2 ), the so-called The treatment received before high-dose therapy was MEC schema, developed in Vienna and Düsseldorf.,13 Ten according to the protocols of the German Cooperative Soft of 26 patients given MEC therapy received fractionated Tissue Sarcoma Studies (CWS-81, CWS-86 and CWS-1) total body irradiation (FTBI), administered to a total dose or the European Study for Stage IV Malignant Mesenchy- of 12 Gy (2 1.5 Gy/day), parallel to melphalan application. mal Tumors in Childhood (MMT Stage IV). One patient Five patients received melphalan only ( mg/m 2 ), two patients melphalan in combination with carboplatin and one patient received MEC with BCNU. Two of five patients who were given allogeneic bone mar- Table 1 Patients characteristics and outcome (n 36) row from related donors received cyclophosphamide with busulphan and total lymphoid irradiation (TLI). One patient Median age (at diagnosis) years 6( 1 22) received cyclophosphamide with FTBI. The hematopoietic Histology rescue consisted of autologous BM or peripheral hemato- RMS alveolar 22 poietic stem cells in 31 patients (86%), 1 of whom were RMS embryonal 13 Undifferentiated sarcoma 1 given G-CSF or GM-CSF support. In five patients allo- Indication for HDC geneic BM from related HLA-identical donors was trans- Primary metastatic 27 fused. Ten of 33 patients who were given autologous HSCT Relapsed received immunologic modulation for 2 3 months with Tumor status at HDC 1CR 27 recombinant DNA-derived interleukin 2 (Proleukin; Euro- 2CR 5 Cetus, Frankfurt, Germany). Three cycles were adminis- VGPR tered at increasing doses from 6 (day 1), (day 2), to 12 Therapy before HDC (days 3 to 5) 10 6 IU/kg with a 2 3 week interval CWS-81, CWS-86, CWS-1 23 between cycles. MMT Stage IV 12 CWS/CESS relapse protocol 1 HDC MEC TBI 26 Melphalan 5 Melphalan Carboplatin (ME) 2 Results MEC BCNU 1 CY-BU TLI 2 Nine patients are alive with no evidence of disease (NED) Interval last event to graft (weeks) with a median follow-up of 57 months (32 108) after diag- Median nosis and 27 months (20 100) after HDC and one is alive Range in 2nd CR after additional local treatment of relapse occur- Graft source Autologous ring 8 months post-hdc. There was one toxic death as a BM 26 result of sepsis. There were no statistically significant dif- PBSC 5 ferences in the distribution of survivors among different Allogeneic BM 5 subgroups (histological and therapeutic) as shown in Figure Outcome Alive However, some trends did emerge. Patients with primary Therapy-related death 1 localized tumors who had been treated with HDC because Disease-related death 25 of relapse did slightly better (four of nine alive with NED) than patients with primary metastatic disease (five of 27

3 Percentage Total Stage IV 5 Relapse 18 Alv. Embr. 1 TBI 8 No TBI Failure No evidence of disease 2 IL No IL2 Figure 1 Distribution of survivors with no evidence of disease (NED) among different clinical subgroups. given HDC with HSCT as late consolidation of therapy. The patients were registered in the German/Austrian Pediatric Bone Marrow Transplantation Register. They formed a relatively homogenous group with respect to the diagnostic and therapeutic concept prior to HDC since they were all treated either according to the German Cooperative Soft Tissue Sarcoma Studies or the European Study for Metastatic Mesenchymal Tumors. The HDC consisted, in the majority of patients, of fractionated melphalan, carboplatin and VP16. This combination was developed for consolidation of therapy in children with solid tumors in St Anna Children s Hospital in Vienna and was shown to be effective in patients with metastatic Ewing s sarcoma. 13 There are no data about the effectiveness of single agents such as carboplatin and VP16 in rhabdomyosarcoma patients. There is, however, evidence that VP16 combined with carboplatin is effective in relapsed solid tumors in childhood. 17 Melphalan has been proven to have high activity against rhabdomyosarcoma in xenograft models and in vivo. 18 However, there is currently no evidence that high-dose melphalan alone improves the prognosis of children with metastatic RMS. 11 Many centers cooperating in the German/Austrian Pediatric Bone Marrow Transplantation Group have therefore adapted (after 10) the MEC schema as HDC in patients with poor prognosis rhabdomyosarcoma. Nine of 36 patients analyzed in this study are alive with NED with a median follow-up of 57 months after diagnosis. There was a trend for better survival in patients who were treated with HDC because of relapse of localized RMS in comparison to patients with primary metastatic disease. However, the treatment results are no better when com- pared to patients with metastatic or relapsed RMS registered in the German Soft Tissue Sarcoma Studies who were alive with NED). Of the four patients who are alive after receiving HDC after relapse, three had lymph nodes recurrence and one distant metastases. Similarly, those with embryonal RMS had a better chance of disease-free survival than patients with alveolar RMS, but the difference was not significant (four of 13 vs four of 22). There was no trend for a better survival in patients treated after HDC with IL-2. Similarly, there was no difference in prognosis between patients who received FTBI vs no FTBI. None of the five patients who received allogeneic BM are alive. The median interval between the last event that led to eligibility for HDC and the HDC itself was similar for the survivors as compared with the entire group, ie 3 weeks (21 110) vs (21 110). Relapse after HDC occurred early with a not given HDC. 5,6 median interval of months (1 17). Interestingly, most There are many questions concerning dose escalation and relapses (23) were at previously known sites with only three its relevance for cure. It has been shown in the case of acute relapsing in new metastatic sites. The estimated EFS rate myelogenous leukemia that no consistent gain in survival at 2 years after HDC is 36 7%, at 2 years after diagnosis although some improvement in response rate was seen with it is 55 8%. a dose of daunorubicin greater than 30 mg/m 2. 1 No one knows what is more important for primary metastatic RMS: short high-dose intensive therapy or less intensive therapy over a longer duration. Perhaps these two factors should be Discussion considered separately depending on the phase of therapy. Despite the major improvement in prognosis for patients with primary localized rhabdomyosarcoma during the last 20 years, no significant progress has been made in the treatment of patients with primary metastatic or relapsed disease Rhabdomyosarcoma is a chemosensitive tumor and the role of chemotherapy, both adjuvant and preoperative, is well established. The intensification of chemotherapy by escalating the dose and combining more drugs has been shown to improve results, especially in locally advanced, primary non-resectable rhabdomyosarcoma. 1,3,16 The dose response relationship which has been seen in many solid tumors was the theoretical basis for dose escalation beyond the ability of the bone marrow to reconstitute spontaneously within an acceptable period. We have performed a retrospective analysis of patients with primary metastatic and relapsed RMS who have been In the first phase, until a complete remission is achieved, defined as no clinical signs of disease, more intensive therapy is probably warranted. However, by what means should ongoing microscopic disease be eradicated? Intensive short consolidation or low dose but longer therapy? This question has not been answered for poor prognosis RMS. Based on the CWS studies treatment results, one can see that the dose response relationship does not always correlate with better survival. In the first German Soft Tissue Sarcoma Study CWS-81, relative intensive first-line chemotherapy with cyclophosphamide, doxorubicin, dactinomycin and vincristine was recommended for all patients. The treatment results were very good 3 compared to other published series. 1,2,,16 In the CWS-86 Study there was an intensification of first-line chemotherapy by replacing cyclophosphamide by ifosfamide. An improvement in response rate without any change in the overall results was observed. 20 Similarly 22

4 230 the prospective German Italian study comparing ifosfamin 6 Carli M, Pinkerton R, Oberlin O et al. Risk group analysis ide 6 g/m 2 vs g/m 2 in patients with primary localized nonresectable metastatic soft tissue sarcomas (STS) children. European RMS showed a better response for the g/m 2 Intergroup Study MMT 8. Proc ASCO 15; 1:. arm but the overall survival did not differ. 21,22 One can conin soft tissue and Ewing s sarcoma patients. A phase II trial 7 Klingebiel Th, Bode U, Jürgens H et al. Treatment of relapse clude that the dose-response-survival correlation proved (CESS/CWS REZ 1). Med Pediatr Oncol 13; 21: 573 true only for some degree of dose escalation. 1 To our Abstr. knowledge, there are no published data on survival of larger 8 Seeger RC, Reynolds CP. Treatment of high-risk solid tumors series of patients with poor prognosis RMS after HDC. of childhood with intensive therapy and autologous bone mar- Most published series include different soft tissue sarcomas row transplantation. Pediatr Clin North Am 11; 38: 33 or even other solid tumors with different biological 2. behavior. 8,11 The 15 analysis of the European Bone Mar- Emminger W, Emminger-Schmidmeier W, Hawliczek R et al. row Transplantation (EBMT) Solid Tumor Registry showed High-dose melphalan, etoposide carboplatin (MEC) coma 5-year survival rate of 18% for 17 patients with rhabdodren bined with 12-gray fractionated total-body irradiation in chil- with generalized solid tumors. Pediatr Hematol Oncol myosarcoma who received high-dose therapy with HSCT and 28% for those who were grafted in first CR (7 11; 8: Shuster JJ, Cantor AB, McWilliams N et al. The prognostic patients). significance of autologous bone marrow transplant in The survival of children who received IL-2 after HDC advanced neuroblastoma. J Clin Oncol 11; : was no better. Administration of ril-2 during the first 11 Pinkerton CR, Groot-Loonen J, Barret A et al. Rapid VAC, months after HDC was thought to be effective because of high dose melphalan regimen. A novel chemotherapy a relative excess of circulating NK cells with potential approach in childhood soft tissue sarcomas. Br J Cancer 11; lymphokine-activated killer (LAK) activity after ril-2 6: stimulation. 23,2 To date there have been no published data 12 Pinkerton CR. Massive chemotherapy followed by bone marrow showing that the therapeutic concept of immunomodulcer graft in pediatric oncology: arguments against. Bull Canshowing ation with ril-2 or other cytokines after HDC is effective Paris 15; 82: 2 5. in improving the prognosis of children with solid tumors. 13 Burdach St, Jürgens H, Peters C et al. Myeloablative radio- The role of total body irradiation in the eradication of chemotherapy and hematopoietic stem cell rescue in poor residual rhabdomyosarcoma cells is unclear. Some centers prognosis Ewing sarcoma. J Clin Oncol 13; 11: Ladenstein R, Hartmann O, Pinkerton CR. The role of megaused it particularly in patients with multiple bone and/or therapy with autologous bone marrow rescue in solid tumours bone marrow metastases in whom effective local of childhood. Ann Oncol 13; (Suppl. 1): irradiation to all known tumor sites is not feasible. In 15 Treuner J, Flamant F, Carli M. Results of treatment of rhabdopatients with metastatic Ewing s sarcoma TBI has been myosarcoma in the European studies. In: Maurer HM, Ruyshown to produce some prognostic benefit. 13 In five mann FB, Pochedly C (eds). Rhabdomyosarcoma and Related patients, allogeneic BMT had been performed (before Tumors in Children and Adolescents. CRC Press: Boca Raton, 10) because of speculation that the immune function 11, pp of allogeneic BMT may be used as a therapeutic tool in 16 Flamant F, Hill C. The improvement in survival associated producing an anti-tumor effect. At present no benefit from with combined chemotherapy in childhood rhabdomyosar- allogeneic vs autologous BM has been shown in patients coma. Cancer 18; 53: with solid tumors Calaminus G, Jürgens H, Schwamborn D et al. Experience In summary, it can be said that the HDC in poor progtumors. Klin Paediatr 18; 13: with the combination carboplatin/vp16 in recurrent childhood nosis rhabdomyosarcoma cannot be regarded as an estab- 18 Horowitz ME, Etcubanas E, Christensen ML et al. Phase II lished therapy method leading to a better prognosis. In testing of melphalan in children with newly diagnosed rhabdoorder to answer definitively, whether HDC has a place in myosarcoma: a model for anticancer drug development. J Clin the treatment of rhabdomyosarcoma, it should be performed Oncol 188; 6: only within prospective controlled trials. 1 Berman E. Chemotherapy in acute myelogenous leukemia: high-dose, higher expectations? J Clin Oncol 15; 13: Treuner J, Koscielniak E, Keim M. Comparison of the rates of response to ifosfamide and cyclophosphamide in primary References unresectable rhabdomyosarcomas. Cancer Chemother Pharmacol 18; 2 (Suppl. 1): Maurer HM, Beltangady M, Gehan EA et al. The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 188; 61: 21 Koscielniak E, Carli M, Andrello L, Treuner J. Two different regimens with ifosfamide as preoperative chemotherapy in 2 Crist WM, Gehan EA, Ragab AH et al. The third Intergroup children with unresectable rhabdomyosarcoma. A report Rhabdomyosarcoma Study. J Clin Oncol 15; 13: from the German Soft Tissue Sarcoma Study CWS-86 and 3 Koscielniak E, Jürgens H, Winkler K et al. Treatment of soft the Italian Rhabdomaosarcoma Study ICG-88. In: Banzet P, tissue sarcoma in childhood and adolescence. Cancer 12; Holland JF, Khayat D, Weil M (eds). Proceedings of the 70: Third International Congress on Neo-Adjuvant Chemo- Maurer HM, EA Gehan, Beltangady M et al. The Intergroup therapy. Springer Verlag: Paris, Heidelberg, New York, Rhabdomyosarcoma Study-II. Cancer 13; 71: , pp Koscielniak E, Rodary C, Flamant F et al. Metastatic rhabdois 22 Carli M, Treuner J, Koscielniak E et al. Ifosfamide (ifo) more myosarcoma and histologically similar tumors in childhood: a better? 6 g vs 10 g/m 2 in VAIA may influence the tumor retrospective European multi-center analysis. Med Pediatr response rate in childhood rhabdomyosarcoma (RMS)? The Oncol 12; 20: experience of the German (CWS 86) and the Italian (ICS-

5 RMS 88) cooperative studies. Proc ASCO 11; 11: 31 (Abstr). Appendix: Participating centers: 23 Favrot MC, Michon J, Floret D et al. Interleukin 2 immunotherapy in children with neuroblastoma after high dose Olga Hospital, Stuttgart chemotherapy and autologous bone marrow transplantation. University Childrens Hospital, Tübingen Pediatr Hematol Oncol 10; 7: University Childrens Hospital, Munich 2 Laws HJ, Diloo D, Hanenberg H et al. Il2 therapy post auto- University Childrens Hospital, Jena logous stem cell transplantation stimulates the production of University Childrens Hospital, Duesseldorf tumor cytotoxic cytokines in children and adolescents with University Childrens Hospital, Graz solid tumors. Klin Pädiatr 13; 205: University Childrens Hospital, Berlin 25 Ladenstein R, Lasset C, Hartmann O et al. Comparison of auto versus allografting as consolidation of primary treatments University Childrens Hospital, Hannover in advanced neuroblastoma over one year of age at diagnosis. University Childrens Hospital, Hamburg Bone Marrow Transplant 1; 1: St Anna Kinderspital, Vienna 231