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© 2000 American Society for Clinical Oncology LMCE3 Treatment Strategy: Results in 99 Consecutively Diagnosed Stage 4 Neuroblastomas in Children Older Than 1 Year at DiagnosisFrom the Centre L. Bérard, Lyon; Institut Curie, Paris; Hôpital de la Timone, Marseille; Hôpital Nord, Saint Etienne; and Centre Hospitalo-Universitaire, Besançon, France. Address reprint requests to D. Frappaz, MD, Centre Léon Bérard, 28 rue Laënnec 69373, Lyon Cédex 08, France; email frappaz{at}lyon fnclcc.fr.
PURPOSE: To tailor postinduction therapy for stage 4 neuroblastoma in children who are older than 1 year at diagnosis according to status after induction. PATIENTS AND METHODS: From March 1987 to December 1992, 99 patients who were consecutively admitted were included in the Lyon-Marseille-Curie East of France (LMCE)3 strategy. After induction with the French Society of Pediatric Oncology NB87 regimen and surgery, patients who were in complete remission immediately proceeded to consolidation therapy with vincristine, melphalan, and fractionated total-body irradiation (VMT). All other patients underwent a postinduction strategy before VMT, either an additional megatherapy regimen or further chemotherapy with etoposide/carboplatin. RESULTS: The progression-free survival (PFS) is 29% at 7 years from diagnosis, which compares favorably with that of a similar cohort of 72 patients previously reported by our group (LMCE1; PFS of 20% at 5 years and 8% at 14 years, P = .004). In the multivariate analysis, only age younger than 3 years at diagnosis (P = .0085) and achievement of complete or very good partial remission after NB87 and surgery (P = .00024) remained significant. The PFS of the 87 patients who were included in the postinduction strategy was significantly better than that of the comparable 62 patients on the LMCE1 study (32% v 11% at 7 years; P = .005). CONCLUSION: The progressive improvements in the LMCE results over the last 10 years suggest that improvements in supportive care measures and increases in each component of this strategy (induction, postinduction, consolidation) may all contribute to increased survival rates.
THE SURVIVAL RATE of children with metastatic neuroblastoma (NB) who are older than 1 year of age at diagnosis has progressively increased within the past 20 years.1-3 Only series that report on unselected groups of newly diagnosed patients may give an insight into the reasons for this improvement, as increased dose-effect during induction chemotherapy and/or megatherapy consolidation may both account for this improvement. The Lyon-Marseille-Curie East of France (LMCE) group previously published the LMCE1 study, which involved an unselected cohort of children who were successively diagnosed with metastatic NB.4,5 It used a single strategy: all patients received similar induction chemotherapy followed by surgery, in addition to a consolidation regimen of vincristine, melphalan, and total-body irradiation (VMT) in chemotherapy-sensitive patients. At 5 years after diagnosis, the progression-free survival (PFS) was 20% in the total cohort of 72 patients (v 10% for historical controls; P < .05), but the toxic death rate was 22%. This study and the report of the European Bone Marrow Transplantation Group (EBMT)6 demonstrated that clearance of skeletal uptake on bone scan after induction therapy defines a good prognosis subgroup that comprises 40% of the population and has a PFS at 5 years of 40% (v 10% for historical controls). The use of a higher dose-intensity during induction7 may increase the proportion of patients who clear their metastases. For those who are not in remission, postinduction chemotherapy may be proposed on the basis of encouraging results obtained in phase II trials conducted by LMCE and/or French Society of Pediatric Oncology (SFOP) groups.8,9 The LMCE3 strategy reported here was thus designed to fulfill these requirements. Its major aims were as follows: (1) to find an induction regimen that would improve both the response rate and its quality, (2) to tailor the postinduction therapy according to the response to induction, and (3) to limit levels of toxicity during consolidation. Seven years after the presentation of the preliminary results in 40 patients with a median follow-up period of 24 months,10 we report the ultimate results in a cohort of 99 patients treated consecutively with this strategy.
From March 1987 to December 1992, every patient older than 1 year with stage 4 NB who was admitted to the LMCE institutions of Lyon (Centre Léon Bérard), Marseille (Hôpital de la Timone), Paris (Curie Institute), Besançon (Centre Hospitalo-Universitaire), and St. Etienne, France, (Hôpital Nord) was entered onto the LMCE3 study (n = 103). Staging at diagnosis and during follow-up was performed according to International Neuroblastoma Staging System (INSS) recommendations.11
Patients Response rate and remission status were evaluated after each step of the strategy (induction, postinduction, and megatherapy). The International Neuroblastoma Response Criteria was used to define response as follows: complete response (CR) was defined as the disappearance of signs of tumor in both primary and metastatic sites. Continuous complete remission (CCR) is the term used to describe patients who remained in CR. A very good partial remission (VGPR) was defined as a nearly CR locally and a CR elsewhere. A partial response (PR) was defined as a greater than 50% reduction in both the size of the primary tumor and the number of metastatic lesions. All regressions of tumor less than 50% were considered as no response (NR). Progressive disease (PD) was defined as a more than 25% increase in the size of measurable lesions at any involved site and/or the appearance of new lesions. A mixture of CR and/or PR and NR without progression was defined as mixed response (MR). The response rate was defined as the percentage of CRs plus VGPRs plus PRs among assessable patients. Toxicity was assessed at each step and during the 100 days after consolidation therapy according to World Health Organization criteria.13
Treatment Patients with PD during induction were excluded from further treatment with the LMCE3 strategy. All other patients underwent surgery. Local radiotherapy was not to be given in this protocol. Most patients underwent an autologous bone marrow harvest with immunologic immunobead purging.14 The postinduction strategy was tailored according to remission status. The patients in CR and VGPR received no postinduction therapy but immediately proceeded to consolidation therapy (LMCE3A) after surgery. All other patients underwent a postinduction therapy that varied with time: either a first megatherapy followed by a second marrow harvest (LMCE3B1) or additional chemotherapy (LMCE3B2). The first megatherapy regimen of LMCE3B1 consisted of teniposide, carmustine, and carboplatin as previously published.8 Because this regimen was associated with high hematologic toxicity, it was replaced with alternative chemotherapy. This chemotherapy regimen (LMCE3B2) consisted of two courses of etoposide-carboplatin as previously published.9 The megatherapy regimen proposed for consolidation was similar for all patients and included vincristine (1.5 mg/m2 push at day 1 followed by 0.5 mg/m2/d on days 1 to 5 in continuous infusion), melphalan (180 mg/m2 on day 6), and fractionated total-body irradiation (TBI; days 2 to 4, in two daily fractions of 2 Gy each for a total dose of 12 Gy), followed by marrow rescue (autologous marrow purged with immunobead, allogeneic, or syngenic bone marrow reinfusion). For patients whose parents or physician refused this treatment, an alternative non–TBI-containing LMCE4 regimen was designed, which included high-dose carboplatin (days 1 to 4, either a total standard dose of 1,750 mg/m2 or a dose that was calculated according to creatinine clearance) and melphalan (day 5, 180 mg/m2).
Statistical Analysis
From March 1987 to December 1992, 103 patients older than 1 year were admitted for untreated stage 4 NB in the LMCE participating institutions. No stage 3 patients were included. Four patients were excluded from study: two for socioeconomic reasons, one for esthesioneuroblastoma, and one for undifferentiated tumor. Thus 99 patients could be included in the study of the LMCE3 treatment strategy. The sex ratio was 38 female and 61 male patients. Median age at diagnosis was 42 months (range, 12 to 136 months). Primary tumor was in retroperitoneum (lateral in 74 patients, median in 18), thorax (five patients), or pelvis (two patients). Its size using INSS criteria was T1 (12 patients), T2 (49), T3 (37), and T4 (one). Serum levels of LDH were raised in 93% of patients (median, 1,522 U/L; range, 540 to 14,500 U/L), ferritin in 85% of patients (median, 360 mg/mL; range 125 to 1,700 mg/mL), and neuron-specific enolase in 98% of patients (median, 161 mg/mL; range, 15 to 1,000 mg/mL). Urinary levels of catecholamine were raised in 62% of patients, with homovanillic acid (median, 91 mmol/mmol of creatinine; range, 36 to 538 mmol/mmol of creatinine), vanillylmandelic acid (median, 99 mmol/mmol of creatinine; range, 28 to 478 mmol/mmol of creatinine), and dopamine (median, 7,035 mmol/mmol of creatinine; range, 591 to 271,300 mmol/mmol of creatinine). Shimada classification was not determined because chemotherapy was delivered before surgery. MYCN was amplified in 26 of 74 tested patients (all with > 10 copies). Eight of 90 patients with complete interpretable initial marrow staging had no bone marrow invasion. There was a local uptake on MIBG scan in 97 of 98 tested patients. One patient had uptake neither in the primary tumor nor in the skeleton, but numerous skeletal lesions were observed on plain x-ray. Twelve had MIBG uptake in the primary tumor but no skeletal uptake (for one patient, skeletal spots appeared postsurgery; this patient is considered to be initially assessable for skeletal lesions). Of these 12 patients, nine had marrow invasion and three had neither skeletal nor bone marrow metastases. Other metastatic sites included liver (five patients), thorax (21), distant lymph nodes (27), CNS (one), and skin metastases (one).
Response Surgery. Of 96 patients who underwent surgery, the tumor was completely removed in 17 patients, partially removed with a microscopic residue in 41 patients, partially removed with a macroscopic residue in 28 patients, only partially resected in nine patients, or not reported in one patient. A nephrectomy was required in 24% of patients with abdominal primary tumor. The response rate after NB87 and surgery was 57%, with 23 CRs, eight VGPRs, 26 PRs (16 had persistent skeletal uptake), 32 MR-NR (28 had persistent skeletal uptake but one was not evaluated), and nine cases of PD (six had persistent skeletal uptake). Postinduction strategy (Table 1). Twelve patients did not meet the requirements for inclusion in the postinduction strategy. One patient died early as a result of tumor bleeding. Two had no response, and nine experienced PD that was local (one patient), intracranial (one), skeletal (six), or multifocal (one). One of the nonresponders underwent surgery (metastatic vipoma) and received etoposide and carboplatin after induction and no further therapy, and two received a megatherapy regimen. All of the patients ultimately died of disease, except the patient with metastatic vipoma, who is alive with stable disease. Thus 87 patients were considered to comply with the requirements for the postinduction strategy.
Immediate consolidation (LMCE3A) was delivered to 32 patients. Status before consolidation was as follows: CR (25 patients), VGPR (two), PR (two), and NR-MR (three, of whom two had persistent skeletal uptake on MIBG). The conditioning regimen included VMT followed by purged autograft (31 patients) or LMCE4 with allograft (one patient). One patient died at day 10 as a result of CNS hemorrhage. Status after consolidation was as follows: CCR (24 patients), CR (two), VGPR (three), PR (one), and NR-MR (one with persistent skeletal uptake on MIBG). Thirteen patients eventually experienced PD and died of disease; 17 patients are alive and disease-free. The intended treatment for the 55 remaining patients was LMCE3B1 (25 patients) and LMCE3B2 (30 patients). In 25 patients, the intended treatment was the double-graft LMCE3B1 strategy. Status before the first megatherapy regimen was CR (one patient), PR (10 patients, of whom six had persistent skeletal uptake on MIBG), and MR-NR (14 patients, of whom 11 had persistent skeletal uptake on MIBG). Five patients did not receive both megatherapies because of toxic death (two patients), PD (two), or poor harvest (one). Status after the LMCE3B1 strategy was as follows: CCR (one patient), CR (10), PR (three), NR-MR (four), PD (five), and not assessable (two). The toxic death rate of the double-graft program was two of 25 patients, or 8%. A pilot study of interleukin-2 administered after grafting for poor-risk patients who were not in CR or VGPR was initiated in 1990. One of the LMCE3B patients was included; this patient suffered a toxic death. Fourteen patients died of disease, one is alive with disease, and six are alive disease-free. One of these patients has developed a femoral osteosarcoma. The intended treatment for 30 patients was postinduction therapy with LMCE3B2. Status before postinduction therapy was as follows: CR (one patient), VGPR (two patients), PR (15 patients, of whom 11 had persistent skeletal uptake on MIBG), and MR-NR (12 patients, all with persistent skeletal uptake on MIBG). Two patients did not respond to etoposide/carboplatin and received two additional courses of high-dose cyclophosphamide/etoposide before consolidation. One patient experienced PD after etoposide/carboplatin and thus received no megatherapy. The consolidation regimen was VMT (24 patients) or LMCE4 (five patients). The marrow rescue was purged autologous (26 patients), allogeneic (two patients), or syngenic (one patient). Status after grafting was as follows: CCR (one patient), CR (11), VGPR (four), PR (seven), NR-MR (one), PD (one), and not assessable (five). The toxic death rate was four of 29 patients (13%); all deaths occurred during megatherapy. One additional patient experienced a late (day 270) and unexplained sudden death. Finally, 18 patients died of disease, and seven are disease-free. All together, the site of relapse was exclusively primary in only 12% of these patients. Among long-term survivors, there was only one patient without bone and bone marrow invasion and without MYCN amplification at diagnosis and two patients with MYCN amplification. There were 14 with bone marrow and/or bone invasion and no MYCN amplification and six patients with MYCN amplification. The hematologic toxicity of consolidation with VMT was greatest among patients in the double-graft program: among patients who underwent consolidation with the LMCE3A, LMCE3B1, and LMCE3B2 regimens, the mean (extremes) number of days on which patients had less than 500 neutrophils was 31 (range, 2 to 67 days), 42 (range, 21 to 80 days), and 22 (range, 11 to 52 days), respectively, and the number of days on which patients had less than 50,000 platelets was 53 (range, 25 to 155 days), 69 (range, 26 to 253 days), and 51 (range, 21 to 167 days), respectively.
Survival
In the univariate analysis, patients in CR-VGPR after NB87 and surgery had significantly better prognosis: 52% versus 19% (P = .001) (Fig 2). The complete clearance of skeletal metastases was associated with a trend for increased PFS (37% v 20%; P = .06), although patients with no initial skeletal involvement had the best prognosis (50%) (Fig 3). Thus patients with negative skeletal uptake after induction therapy had significantly better prognosis (40% v 20%; P = .03). In the multivariate analysis, only age (P = .0085) and status after induction (P = .00024) remained significant prognostic factors. The PFS of the 87 patients who were included in the postinduction strategy was 32% at 7 years. This was significantly better than that of the comparable 62 LMCE1 patients (11% at 7 years; P = .005). The PFS was increased for patients in CR-VGPR after NB87 and surgery (50% v 23%; P = .02) and for those who cleared their skeletal metastases (38% v 22%; P = .11). The PFS was significantly higher for the 27 CR-VGPR patients who received immediate consolidation in the LMCE3A group than for a comparable group of 24 patients in the LMCE1 study (48% v 4%; P = .0003).
The PFS at 7 years in the LMCE3A strategy was 50%, compared with 22% (P = .004) for the LMCE3B strategy. PFS was 28% at 7 years for the LMCE3B1 double-graft program and 17% at 6 years for the LMCE3B2 strategy (P = not significant) (Fig 4).
In the 1980s, less than 40% of children with initial stage 4 NB who were older than 1 year at diagnosis achieved a response using conventional combined chemotherapy, and only 5% to 10% of children became long-term survivors.1 Despite the heterogeneity of the series reported, intensified schedules and the addition of cisplatin (or its derivative carboplatin) and epipodophyllotoxins (etoposide or teniposide) to the classical conventional drugs (cyclophosphamide, doxorubicin, and vincristine) have altered these figures, with more than 50% achieving CR/PR after conventional chemotherapy7,15-17 and 30% achieving long-term survival. As shown in this study, induction therapy remains of utmost importance, because status after induction therapy and surgery is the only therapy-related significant prognostic factor in multivariate analysis. However, the gain in survival might be due both to the improvement of induction therapy and/or to introduction of megatherapy.18-30 Preliminary results from a nonrandomized Children’s Cancer Study Group (CCSG) study suggested an advantage for megatherapy only for patients who are older than 2 years at diagnosis, have MYCN amplified tumors, and achieve PR after induction therapy.19 Preliminary results from a nonrandomized study of the German Neuroblastoma Study Group showed no significant advantage of megatherapy over maintenance therapy.24 In a nonrandomized Japanese study, no significant advantage was found for patients in CR after induction who receive megatherapy.25 A prospective CCSG study randomizing megatherapy versus maintenance therapy has recently suggested a significant influence of megatherapy on progression-free survival in patients with stage 3 high-risk NB. However, a trend could only be demonstrated for patients with stage 4 disease.31 Thus the exact place and role of megatherapy remains unclear: It seems that megatherapy might be beneficial, but are type of conditioning, type of rescue, and timing important for definitive cure of NB? The rationale for delivering megatherapy is based on laboratory data indicating that alkylating agents have a steep dose-response curve.32 In a prospectively randomized high-risk group of responding patients, a significant advantage for the group of patients treated with high-dose melphalan was demonstrated.33 Most conditioning regimens that have been proposed since then have combined melphalan with drugs and/or radiation therapy. The LMCE1, LMCE2 double-graft, LMCE3, and LMCE4 strategies have all used melphalan-containing regimens. However, the type of conditioning regimen may not be a key factor, because EBMT data on more than 500 patients failed to demonstrate any difference with the use of any particular conditioning regimen (with or without TBI, with single- or double-graft procedure).6 Our policy was to purge bone marrow harvest or to use allogeneic donors. The extent to which presence of minimal residual disease at the time of harvest, which leads to reinfused tumor cells, may be a limiting factor for cure is unclear. The demonstration that neomycin resistance gene–transfected cells in reinfused marrow may be detected in relapsed disease suggests that contaminated marrow may at least contribute to further relapse.34 Moreover, unusual pulmonary35 or intracranial36 relapses after autologous bone marrow transplantation (ABMT) may suggest that reinfused malignant cells are clonogenic in vivo. However, a retrospective comparison of two groups of patients who received either purged or unpurged marrow failed to show any significant difference in clinical outcome.37 The lack of significant improvement with the use of allogeneic transplantation suggests that reinfusion of malignant cells may not be a crucial problem in autologous transplantation.38,39 However, the rate of toxic death is higher for patients who undergo allogeneic transplantation, and this may explain why there was no statistical difference in disease outcome. The current study suggests that in vivo purging through the addition of postinduction therapy for poor-risk patients may improve prognosis, because the increase of PFS between LMCE1 and LMCE3 may be explained at least partially by the increase in postinduction therapy in this subgroup of patients. The role of local therapy is likewise not easily determined. Our policy was to systematically operate on patients who showed no signs of disease progression elsewhere. Some series report no significant improvement with surgery.40 As in our cohort, relapses after megatherapy usually occur in multiple areas of previous disease, but they also occur in the primary site alone (10%) or in distant sites only (20%).41,42 This highlights the place of local treatment with surgery or local radiation. It also suggests that the main limiting effect in the use of megatherapy remains the ability of such therapy to completely ablate the malignant cells. The optimal timing of megatherapy is not clearly defined. The actuarial overall survival rate 2 years after megatherapy for relapse is 27% for patients who had previously received conventional-dose primary treatment versus 0% for patients who had previously received dose intensification (P = .02).43 This may open the door to further randomized studies in which megatherapy as first-line elective treatment would be compared with megatherapy as salvage therapy administered after relapse. With improvements in survival curves, it became possible to define prognostic factors. Based on data from more than 500 children who underwent transplantation, the EBMT registry demonstrated that size of the tumor (< 10 cm) and female sex were the initial features associated with favorable outcome.6 In more limited series, the elevation of LDH44 and CD44-positive staining45 proved to be the most discriminating biologic prognostic factors in multivariate analysis. Studies conducted by the CCSG suggest that megatherapy may be more effective for patients with genomic amplification of MYCN.31,46 The LMCE1 study suggested that the lack of skeletal involvement at diagnosis might increase PFS,5 but this was neither confirmed in the multivariate analysis of LMCE3 nor in EBMT data. The response to induction therapy has become the most predictive factor for outcome: the complete disappearance of metastases before ABMT increases the 5-year PFS to 38% versus a PFS of 12% when metastases are present before ABMT. The clearance of bone marrow deposits has no significant value in the EBMT registry. The most significant feature is the disappearance of skeletal metastases on MIBG scintigraphy at the end of induction. In the LMCE1 study, nearly 40% of patients were in such a situation, and their 5-year overall survival was 40% versus 15%. Because this study separated two subgroups with similar numbers of patients, this criteria was used for defining the LMCE3 strategy. As suggested by the present study, one of the keys for cure may be the tailoring of treatment according to chemotherapy sensitivity after induction. For the good responder group, immediate consolidation obtained a 46% PFS rate, and optimization of strategy may include less toxic consolidation and/or postconsolidation treatment. For the poor responder group, the prolongation of chemotherapy (by double-graft ABMT or introduction of carboplatin before consolidation) may explain the better results obtained in LMCE3 as compared with LMCE1. The apparent higher PFS obtained with the double-graft program suggests that increasing the postinduction regimen may be worthwhile. However, the 29% PFS is still relatively low, and alternative strategies are currently being assessed. For example, the use of sequential high-dose chemotherapy using single agents may be one way to increase PFS. Future strategies should also aim at decreasing toxicity. The current use of peripheral-blood stem cells as rescue is clearly a way to decrease hematologic toxicity after megatherapy. Moreover, the long-term sequelae of TBI should be kept in mind. We are currently assessing this toxicity in our long-term survivors.47 Furthermore, postconsolidation therapy with biologic modifiers should be investigated.48 The recent demonstration by the CCSG that postmegatherapy cis-retinoic acid may increase PFS49 should encourage further investigation of this strategy. In conclusion, the results of the LMCE3 strategy suggest that an unselected cohort of children who are older than 1 year at diagnosis of metastatic NB may be best managed according to response to initial chemotherapy. The progressive improvements in the LMCE results over the last 10 years are significant. Whether this is due to improvements in supportive care measures and/or to increases in the dose-intensity of induction therapy, the role of postinduction and consolidation therapy is a matter of continuing debate. The time has come to try to discriminate between each of these components by way of large, international, randomized studies.
Supported in part by grant no. PHRC1994 from the Ministry of Health of France. We thank Prof C.R. Pinkerton for editorial and scientific help and J. Popescu for typing this manuscript.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
