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Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas
Pilot study for the upcoming European Rhabdomyosarcoma Protocol
Article first published online: 18 AUG 2004
Copyright © 2004 American Cancer Society
Volume 101, Issue 7, pages 1664–1671, 1 October 2004
How to Cite
Casanova, M., Ferrari, A., Bisogno, G., Merks, J. H. M., De Salvo, G. L., Meazza, C., Tettoni, K., Provenzi, M., Mazzarino, I. and Carli, M. (2004), Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas. Cancer, 101: 1664–1671. doi: 10.1002/cncr.20544
- Issue published online: 17 SEP 2004
- Article first published online: 18 AUG 2004
- Manuscript Revised: 23 JUN 2004
- Manuscript Accepted: 23 JUN 2004
- Manuscript Received: 29 FEB 2004
Following their previous report on the activity of vinorelbine in the treatment of rhabdomyosarcoma, the authors report the results of a pilot study aimed at defining the optimal dose of vinorelbine when this agent is used in conjunction with continuous, orally administered low-dose cyclophosphamide to treat patients with refractory or recurrent sarcoma. It is hoped that the combination of vinorelbine and low-dose cyclophosphamide can be used as a maintenance regimen in an upcoming European trial involving high-risk patients with rhabdomyosarcoma.
In the current pilot study, the cyclophosphamide dose was fixed at 25 mg/m2 per day for 28 days. Vinorelbine was administered intravenously on Days 1, 8, and 15, with trial doses escalated from an initial level of 15 mg/m2 in steps of 5 mg/m2; intrapatient dose escalation was not allowed.
Between April 2002 and November 2003, 18 patients ages 2–23 years were treated with the study regimen after having received 1–4 (median, 2) other regimens previously. Ninety cycles were administered in total (median, 5 cycles per patient; range, 1–10 cycles per patient). Two cases of dose-limiting toxicity (Grade 4 neutropenia in both cases) were observed among the 5 patients who received vinorelbine at a dose of 30 mg/m2. Of the 41 cycles in which vinorelbine was administered at a dose of 25 mg/m2, Grade ≥ 3 neutropenia was observed in 15 (37%); no other major toxicity was documented in association with these cycles. One complete remission and 6 partial remissions were noted among the 17 patients who had measurable disease. Three of the eight assessable patients with rhabdomyosarcoma (which was embryonal in two cases and alveolar in one) had responses to treatment.
Combination therapy involving vinorelbine and low-dose cyclophosphamide was found to be feasible and to possess activity against recurrent sarcomas. The maintenance therapy doses recommended for use in the upcoming European trial are cyclophosphamide 25 mg/m2 per day for 28 days and vinorelbine 25 mg/m2 on Days 1, 8, and 15. Cancer 2004. © 2004 American Cancer Society.
Rhabdomyosarcoma (RMS) is one of the most common childhood malignancies, accounting for more than half of all soft tissue sarcomas. The outcome for patients with RMS has improved dramatically in the last 3 decades, due to the development of a risk-adapted multimodality treatment approach that involves surgery, multiagent chemotherapy, and radiotherapy. In addition, chemotherapy regimens have grown more intense over time, and this intensification has led to improved survival rates for patients with localized disease and to an increase (from 30% to 70%) in the observed cure rate.1, 2 Nonetheless, the prognosis for patients with high-risk characteristics has not changed significantly. An attempt to further increase chemotherapy doses in patients with metastases at the onset of disease failed to bring about a significant improvement in outcome, despite the high complete response rate that was documented3; this finding suggests that once complete remission has been achieved, residual disease that is resistant to short-term high-dose treatment represents the primary obstacle to cure. In light of this consideration, the addition of a maintenance regimen to the end of conventional chemotherapy may serve as an alternative method for improving cure rates. This hypothesis is one of the foundations of an upcoming cooperative European randomized trial in which maintenance therapy will be evaluated in patients with RMS who have high-risk characteristics.
Vinorelbine (VNR) was considered for use in this upcoming international trial on the basis of our previous single-institution report of its activity in heavily pretreated patients with RMS.4 The combination of VNR with continuous low-dose chemotherapy was found to be especially intriguing, particularly in view of the unique antitumor mechanisms that can be induced by the ‘metronomic’ administration of chemotherapy.5–8
Cyclophosphamide (CTX) was assumed to be the ideal agent for use in combination with VNR. This assumption was based on the following considerations: 1) CTX is one of the most active known agents against RMS; 2) the overall bioavailability of orally administered CTX makes this agent particularly suitable for continuous low-dose administration on an outpatient basis; 3) CTX already has been used at low doses (2.5 mg/kg per day for up to 2 years [maximum total dose, 25 g/m2]) in the first two Intergroup Rhabdomyosarcoma Study (IRS) trials9, 10; and 4) CTX can easily be included in the upcoming European protocol, in which various agents will be used during the initial intensive treatment phase.
The current pilot study was conducted to determine the optimal VNR dose for use in combination with continuous, orally administered low-dose CTX in patients with refractory or recurrent sarcomas and to qualitatively and quantitatively assess the toxic effects associated with this combination chemotherapy regimen.
MATERIALS AND METHODS
Eligible patients had histologically confirmed sarcoma that had progressed or recurred and was not amenable to surgical treatment with curative intent following conventional chemotherapy. Additional eligibility requirements included age ≤ 21 years at diagnosis of the tumor that was to be treated in the current study; life expectancy ≥ 8 weeks; Lansky score ≥ 50; and normal hepatic, renal, and bone marrow function (defined by an absolute neutrophil count > 1.0 × 109 per liter; a platelet count > 100 × 109 per liter; a serum creatinine concentration < 1.5 × the upper limit of normal or a creatinine clearance or radioisotope glomerular filtration rate > 70 mL/min per 1.73 m2; a total bilirubin concentration < 1.5 × the upper limit of normal; an aspartate aminotransferase concentration < 2.5 × the upper limit of normal; and an alanine aminotransferase concentration < 2.5 × the upper limit of normal). Patients were excluded if they had received chemotherapy or radiotherapy < 4 weeks before study enrollment (or < 6 weeks before enrollment if chemotherapy involved nitrosourea use) or if psychologic status, familial or sociologic circumstances, or geographic location was determined to be a potential barrier to study compliance. Finally, in accordance with institutional and national guidelines, participants were required to sign an informed consent statement indicating that they were aware of the investigational nature of the current study.
Pretreatment evaluation included acquisition of a complete medical history, physical examination, and tumor assessment. The tumor assessment process involved chest X-ray and computed tomographic/magnetic resonance imaging of disease sites, with evaluation of all measurable tumor parameters (although measurability of disease was not an eligibility requirement). Complete blood cell counts (including differential counts) and blood chemistry assays were performed at baseline and before each treatment cycle, and additional blood cell counts were obtained weekly. Furthermore, all patients were evaluated for toxicity once weekly during the study period; toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (Version 2.0).
In the current regimen, CTX was administered orally at a fixed dose of 25 mg/m2 per day for 28 days. VNR was administered intravenously on Days 1, 8, and 15, with trial doses escalated from an initial level of 15 mg/m2 in steps of 5 mg/m2 (Fig. 1); intrapatient dose escalation was not allowed. All treatment was administered on an outpatient basis.
CTX was administered as early in the day as possible to minimize the amount that remained in the bladder overnight. During treatment, adequate fluid intake (at least 1 L/m2) was recommended as a measure for curtailing damage to the transitional epithelium. CTX was administered in the form of 50 mg tablets; to avoid any unpredictable variability in terms of drug absorption, these tablets were not split under any circumstances. Appropriate dosing was achieved by using the established daily dose to generate an administration schedule that required only whole tablets. For example, in the case of a patient whose body surface area is 1.3 m2, a daily CTX dose of 32.5 mg is called for; because this dose corresponds to approximately 100 mg every 3 days, for such a patient, treatment would consist of repeated 3-day periods in which 1 whole tablet (50 mg) was administered only on each of the first 2 days. In the current cohort, body surface areas ranged from 0.51 m2 to 1.97 m2 (median, 1.15 m2); thus, the child with the smallest body surface area received 1 tablet every 4 days (12.5 mg per day), whereas the child with the largest body surface area received 1 tablet daily (50 mg per day).
VNR was diluted to yield an isotonic solution with a concentration of 1.5–3 mg/dL, and this solution was infused into a large central vein over a period of 6–10 minutes. Serotonin receptor 3 antagonists were administered intravenously before the start of VNR infusion. On Days 8 and 15, VNR was administered only to patients who had neutrophil counts > 0.5 × 109 per liter, platelet counts > 75 × 109 per liter, and Grade < 2 nonhematologic toxicity. Treatment cycles were repeated every 4 weeks, provided that all organ function–related eligibility criteria were met.
Subsequent doses were reduced by 5 mg/m2 in the event that dose-limiting toxicity (DLT) developed as a result of VNR treatment. DLT was defined as the occurrence within the first two treatment cycles of Grade 4 neutropenia, Grade 4 thrombocytopenia, or any Grade 3 or 4 nonhematologic toxicity. In addition, patients who were unable to recover to the eligibility threshold for the second treatment course within 6 weeks of the start of the first course and patients for whom treatment was withheld on Day 8 or 15 due to toxicity were considered to have DLTs. The use of granulocyte–colony-stimulating factor in concurrence with the interruption of CTX treatment was permitted for patients with Grade 4 neutropenia.
At least three patients who were evaluable for toxicity were treated at each dose level. Each patient received at least 2 cycles of treatment and thus was assessed for response and toxicity for a minimum of 8 weeks. If none of the first three patients treated at a given dose level experienced DLT, then the next dose level was opened to subsequent patients; in contrast, if one of these first three patients did experience DLT, then three more patients were treated at the same dose level.
The maximum tolerated dose (MTD) was defined as the first dose level at which two patients in a cohort of three or more experienced DLT within the first two treatment cycles. The dose level that was one step below the MTD was to be recommended for use in future maintenance therapy trials, provided that the feasibility and tolerability of repeated treatment cycles at that level could be demonstrated in additional patients.
Objective responses were documented according to the guidelines set forth by the Response Evaluation Criteria in Solid Tumors.11 Tumor imaging was repeated every two treatment cycles for patients who were found to have measurable disease at baseline. Treatment was administered until the onset of disease progression or unacceptably severe toxicity or until the patient (or the patient's guardian) declined further treatment. When disease progression was clearly apparent before the first assessment of response (which took place after two treatment cycles), therapy was discontinued and the response to treatment was classified as early progression.
Between April 2002 and November 2003, 18 patients were enrolled in the current study. Their characteristics are summarized in Table 1. Ten patients were male, and the median age of the cohort as a whole was 12 years (range, 2–23 years). Among the 18 participants in the current trial, there were 9 cases of RMS (embryonal [n = 7], alveolar [n = 1], or not otherwise specified [n = 1]), 2 malignant peripheral nerve sheath tumors (1 of which was associated with neurofibromatosis type 1), 2 synovial sarcomas, 2 desmoplastic small round cell tumors, 1 clear cell sarcoma, 1 osteosarcoma, and 1 soft tissue primitive neuroectodermal tumor.
|Characteristic||No. of patients|
|No. of previous chemotherapy regimens|
|Prior hdCT with PBSC rescue|
Patients had received a total of 1–4 (median, 2) other chemotherapy regimens before being treated with the current study regimen. Five of the six patients who had previously received only one other chemotherapy regimen (three with RMS, one with a desmoplastic small round cell tumor, and one with a soft tissue primitive neuroectodermal tumor) had been treated with high-dose chemotherapy accompanied by stem cell support. All 18 patients had previous exposure to vincristine-containing chemotherapy. Regarding the use of alkylating agents, it is noteworthy that all 18 patients had received ifosfamide (total cumulative dose, 36–108 g/m2; median, 54 g/m2) at some point in the past; 9 of these 18 patients had previously received CTX as well (total cumulative dose, 4.0–11.2 g/m2; median, 7.2 g/m2). Finally, 12 of the 18 patients in the current study had received radiotherapy as part of a previous treatment regimen.
Dose Escalation and Exposure to Treatment
DLT was not observed in any of the three patients who were treated in Step 1 of the dose escalation process. For one patient with parameningeal RMS (who had completed radiotherapy 8 weeks before the start of treatment), prolonged Grade 2 mucositis caused the administration of the second treatment cycle to be delayed for 12 days; mucositis was not observed in any of the 5 cycles that subsequently were administered to this patient.
In Step 2 of the dose escalation process, one patient had clinically evident early progression during the second treatment cycle; as a consequence, therapy was interrupted, and only one cycle was fully evaluable for toxic effects. This patient was deemed ineligible for dose escalation, and thus a fourth patient entered the study at Step 2. DLT was not observed in any of the patients treated at this dose level or in any of the three participants who subsequently entered the study at Step 3, and as a result, Step 4 was initiated. Two of the five patients who entered the study at Step 4 experienced a DLT, which was Grade 4 neutropenia in both cases and was associated with pulmonary infection in one case. Thus, 30 mg/m2 emerged as the maximum tolerated VNR dose. To expand the cohort of patients treated at the dose level that was to be recommended for use in future trials, three more patients were entered into the study at Step 3; DLT was not observed in any of these three additional patients.
For each step of the dose escalation process, the number of patients treated and the number of cycles administered are listed in Table 2. Ninety cycles were administered in total. The median number of cycles administered per patient was 5 (range, 1–10), and 7 patients (40%) received at least 6 treatment cycles. No patient had treatment discontinued on account of toxicity. At the time of the current report, treatment was still being administered to 4 patients, who had already received 6, 6, 8, and 10 cycles, respectively. For two patients, therapy was halted at the investigators' discretion after six treatment cycles. One of these patients, who had embryonal RMS, currently is without evidence of disease. The other, who was affected by parameningeal RMS, had chemotherapy halted after biopsy of the stable lesion revealed fibrosis with no evidence of active disease; 8 months after the discontinuation of treatment, this patient is alive with stable radiologic findings that are consistent with the presence of fibrosis. Treatment was halted at the parents' request in one other case; in this case, a patient with a soft tissue primitive neuroectodermal tumor had stable disease after 5 cycles and experienced disease progression 2 months after the discontinuation of treatment. For all other participants, including the patient who experienced early progression, treatment was discontinued upon diagnosis of progressive disease.
|Step no.||VNR dose (mg/m2)||CTX dose (mg/m2)||No. of patients||No. of cycles administered||No. of cycles with documented Grade 3–4 neutropenia||No. of cycles with documented nonhematologic toxicity|
|1||15||25||3||11||5||1 (Grade 2 mucositis)|
|2||20||25||4||17||6||2 (Grade 2 bilirubin toxicity)|
|4||30||25||5||21||17||1 (Grade 2 allergy)|
Toxicity was evaluated in all 18 patients and for all 90 treatment cycles. Neutropenia was the only documented DLT and was the most frequently observed adverse event. Grade 3 or 4 neutropenia occurred in 13 patients (72%) and was noted in a total of 43 treatment cycles (48%). Grade 3 neutropenia was observed in 5 of 11 cycles in Step 1 and in 6 of 17 cycles in Step 2, and Grade 3 or 4 neutropenia was documented in 15 of 41 cycles (37%) in Step 3 and in 17 of 21 cycles (81%) in Step 4. Aside from the two cases of DLT that occurred during dose escalation, all episodes of Grade 4 neutropenia (two during Step 3 and eight during Step 4) were observed after the third treatment cycle. Four patients (22%) received granulocyte–colony-stimulating factor for a period of 3–6 days (median, 4 days). Among these four patients were the two who experienced DLT, one other patient who entered the study at Step 4, and one patient who entered the study at Step 3. The only participant who required hospitalization for the management of neutropenia was the patient who had an associated pulmonary infection. The two patients who experienced DLT subsequently received VNR at a dose of 25 mg/m2, and the VNR dose ultimately was reduced to 20 mg/m2 for one of these two.
Grade 3 or 4 thrombocytopenia and anemia were not observed in the current study. Nonhematologic toxicities included Grade 2 mucositis (which occurred during Step 1 in a patient who had undergone irradiation at a parameningeal site 8 weeks before the start of treatment), Grade 2 elevation of bilirubin levels (which was documented in 2 of 6 cycles received by a patient who entered the study at Step 2), and Grade 2 allergy (asymptomatic bronchospasm, which was documented during the first treatment cycle received by a patient who entered the study at Step 4, and which was prevented in subsequent cycles via premedication).
For 12 patients, the interval between the first and second treatment cycles was 28 days, as scheduled, whereas 5 patients (one in Step 2, two in Step 3, and two in Step 4) had the start of their second cycle delayed by ≤ 3 days due to neutropenia. Only one trial participant (the patient who entered the study at Step 1 and developed a prolonged case of Grade 2 mucositis) experienced a major delay in the start of the second treatment cycle.
Seventeen patients had measurable lesions. Overall, there were 7 objective responses to treatment (1 complete remission and 6 partial remissions) and 4 cases of disease stabilization lasting longer than 2 months. The characteristics of patients who had stable disease or experienced an objective response are summarized in Table 3. The median duration of partial remission was 6 months (range, 2.5–10+ months). Also noteworthy was the finding that disease stabilization lasted for 7, 8+, 10, and 14+ months, respectively, in the 4 cases that were encountered in the current study.
|Gender||Age (yrs)||Histology||No. of previous CT regimens||Step no.||Best response||Duration of response (mos)||Status|
|M||9||RMS-E||2||1||SD||14+||Alive at 14 mos with SD and findings consistent with fibrosis|
|F||18||RMS-E||3||2||PR||8||DOD at 12 mos|
|F||12||PNET||1 (HD)||3||SD||7||DOD at 16 mos|
|M||4||CCS||2||3||PR||2.5||DOD at 5 mos|
|M||16||SS||2||3||SD||10||AWD at 14 mos|
|F||12||RMS-E||1 (HD)||3||PR||5||DOD at 10 mos|
|F||19||OS||4||3||PR||3||Died of cardiac complications at 3 mos|
|M||17||DSRCT||1 (HD)||4||PR||6+||Receiving treatment|
Of the eight patients with RMS who were assessable for response, three had objective responses, two experienced disease stabilization, and three experienced disease progression. The lone patient with alveolar RMS experienced complete remission and continues to receive treatment. In addition, 2 patients with embryonal RMS had partial responses to treatment, with these responses lasting 5 and 8 months, respectively.
With regard to histotypes other than RMS, partial responses were documented in the lone patient with clear cell sarcoma, the lone patient with osteosarcoma, one of the two patients with desmoplastic round cell tumors, and one of the two patients with synovial sarcoma. (The other patient with synovial sarcoma experienced disease stabilization for a period of 10 months.) The patient who had osteosarcoma received the trial regimen after the onset of lung and cardiac metastases, and her disease was in partial remission when she died of cardiac complications. In addition, a patient who had a previously unresectable desmoplastic small round cell tumor underwent complete macroscopic resection after receiving four cycles of chemotherapy and experiencing partial disease remission; this patient was without evidence of disease and continued to receive treatment at the time of the current report.
Despite the achievement over the last 3 decades of a generally satisfactory upgrade in treatment outcomes for patients with localized RMS, outcomes for patients with high-risk features still require improvement, and the development of novel agents and therapeutic strategies is therefore warranted. The hypothesis that induction therapy–resistant residual disease might be eradicated by continuous low-dose maintenance therapy has recently been explored in certain types of pediatric solid tumors.12–14 In particular, the German Cooperative Soft Tissue Sarcoma Study Group13 has reported notable preliminary results regarding the role of orally administered maintenance chemotherapy (trofosfamide + etoposide and trofosfamide + idarubicin) in the management of metastatic soft tissue sarcoma; despite the nonrandomized nature of their trial, these investigators found that orally administered maintenance therapy was a more promising option than high-dose chemotherapy.
Several observations suggest that prolonged continuous chemotherapy may possess different mechanisms of action (e.g., antiangiogenic effects) compared with standard and high-dose chemotherapy. The presence of dividing endothelial cells in newly forming tumor blood vessels should make such vessels—unlike their mature, quiescent counterparts in normal tissue—sensitive to cytotoxic antitumor agents, as is the case when dividing bone marrow progenitor cells, gut mucosal cells, or hair follicle cells are present. It is conceivable that this hypothesized mechanism of ‘collateral damage’ to the tumor vasculature could contribute to the in vivo antitumor efficacy of cytotoxic chemotherapy.
CTX has been identified as an agent that may possess antiangiogenic activity when administered continuously at low doses. The potential antiangiogenic effects of CTX may not be realized if this agent is administered in conventional fashion—i.e., at the MTD, with rest periods of up to 2–3 weeks between successive exposures5—because these treatment-free periods provide the endothelial cell compartment of the tumor with the opportunity to repair some of the damage inflicted by chemotherapy. Thus, it has been suggested that this repair process could be partially hindered by the more frequent administration of the chemotherapeutic agent at a lower dose. In practice, such a chemotherapy schedule would be optimized with respect to its effects on the tumor vasculature. Xenograft tumors demonstrating resistance to conventional CTX schedules have been resensitized to this agent by continuous low-dose therapy,6 with the reversal of acquired resistance being attributed to continuously administered CTX's targeting of the accessible and genetically stable endothelial cell compartment of the tumor.
Although our previous study on single-agent VNR was limited in size,4 the response rate documented in that study in patients with recurrent RMS who had already been heavily treated was higher than corresponding response rates associated with other agents known to be active against RMS. Data suggestive of the possible antiangiogenic effects of VNR have been reported elsewhere. In particular, vinca alkaloids have been found to have antivascular effects in murine models,15 and in vitro studies have demonstrated that vincristine and vindesine possess antiangiogenic activity at noncytotoxic doses, whereas the ostensible antiangiogenic effects of vinblastine and VNR appear to be directly related to their cytotoxicity.16 In the clinical setting, VNR has been reported to possess some activity against vascular sarcomas17; furthermore, a noteworthy observation emerging from our previous study was that some patients whose remissions persisted for several months with the continuation of VNR therapy experienced recurrence very soon after the cessation of treatment, a finding that suggests that VNR may control microscopic residual disease via a cytostatic mechanism.4
In recent years, the major European soft tissue sarcoma research groups have joined forces to launch a study on localized RMS. One of the goals of this European cooperative group is to perform a randomized trial investigating the effects of a 6-month maintenance chemotherapy regimen of VNR plus continuous, orally administered low-dose CTX following induction therapy in patients with high-risk features. In the current study, which was performed to determine the recommended doses for use in this maintenance chemotherapy regimen, the maximum tolerated VNR dose was found to be 30 mg/m2, with neutropenia identified as the DLT. At the recommended VNR dose (25 mg/m2), Grade 3 or 4 neutropenia was documented in 37% of all cycles, but no other major toxic events were noted. The overall acceptability and feasibility of the study regimen are supported by the finding that no patient had treatment discontinued on account of toxicity and by the observation that many patients were treated for an extended duration, with 40% of all patients receiving at least 6 cycles of therapy.
Although clinical response was not a primary endpoint of the current study, sufficient activity was observed to warrant further investigation. In particular, three of eight patients with RMS had objective responses; furthermore, four of the six patients overall who received the recommended VNR dose (including two of two patients with RMS) had objective responses, and the remaining two experienced disease stabilization.
One concern regarding the use of the current combination maintenance chemotherapy regimen to treat patients with potentially curable localized RMS is the leukemogenic risk associated with heavy use of alkylating agents. This risk is reportedly correlated with the cumulative dose received, however, which would not be high for patients treated with the proposed low-dose regimen. Nonetheless, larger studies involving patients receiving CTX as a part of adjuvant treatment for breast disease have reported that even a year of treatment with CTX at a cumulative dose of 18 g leads to a minimal increase in leukemia risk.18 In addition, the IRS has reported a combined total of 22 second malignancies in 1770 study participants, with most of these malignancies being bone sarcomas found in patients who received both CTX and radiotherapy and who had findings suggestive of Li–Fraumeni syndrome or had a family history of neurofibromatosis.19
In conclusion, the current study demonstrates that treatment with the combination of CTX administered orally at a dose of 25 mg/m2 per day for 28 days and VNR administered intravenously at a dose of 25 mg/m2 on Days 1, 8, and 15 is feasible and that this combination may possess activity against previously treated pediatric sarcomas. The current regimen's efficacy in eliminating residual disease will be further tested in an upcoming European cooperative trial involving high-risk patients with RMS.
- 2Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of Intergroup Rhabdomyosarcoma Study Group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol. 2001; 23: 215–220., , , et al.
- 11New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000; 92: 205–216., , , et al.
- 13High dose therapy versus oral maintenance: results of HD CWS 96 study for treatment of patients with metastasized soft tissue sarcoma [abstract]. Med Pediatr Oncol. 2003; 41: 278., , , et al.
- 14Stem cell transplantation vs. maintenance chemotherapy in neuroblastoma: a randomized trial of the GPOH Group [abstract]. Med Pediatr Oncol. 2003; 41: 286., , , et al.