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Major dose-limiting factors of high-dose thiotepa. (TEPA) and melphalan are life-threatening mucositis and neurotoxicity. To administer a maximum dose of.
Bone Marrow Transplantation, (1998) 22, 7–12  1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt

Double-conditioning regimens consisting of thiotepa, melphalan and busulfan with stem cell rescue for the treatment of pediatric solid tumors J Hara1, Y Osugi1, H Ohta1, Y Matsuda1, K Nakanishi1, K Takai1, H Fujisaki1, S Tokimasa1, M Fukuzawa2, A Okada2 and S Okada1 Departments of 1Pediatrics and 2Pediatric Surgery, Osaka University School of Medicine, Osaka, Japan

Summary: Major dose-limiting factors of high-dose thiotepa (TEPA) and melphalan are life-threatening mucositis and neurotoxicity. To administer a maximum dose of these drugs safely and to obtain a maximum anti-cancer effect, a double-conditioning regimen with a single grafting, two cycles of administration of a combination of TEPA (300–600 mg/m2) plus melphalan (70– 150 mg/m2) with a 1-week interval was attempted in 20 patients with pediatric advanced or chemotherapyresistant solid tumors (seven rhabdomyosarcoma, four hepatoblastoma, three neuroblastoma and four other malignancy). Combinations of TEPA plus melphalan/busulfan (Bu) (8–10 mg/kg) and TEPA plus Bu were given to four and two patients with brain tumors, respectively. In an additional two patients, three cycles of drug administration were performed. According to the results of the dose-escalating study, the maximum tolerable doses of TEPA and melphalan for children aged 2 years old or older were 1000 mg/m2 and 280 mg/m2, respectively. Mucositis was dose-limiting. Renal toxicity was also dose-limiting in young children (⬍2 years old). There were two treatment-related deaths (7%) (fungal pneumonia and renal tubular acidosis). Among 13 patients who received high-dose chemotherapy during CR, 10 are alive with no evidence of disease (15–59 months, median: 35 months) and in 13 evaluable patients without CR, six are alive without regrowth of the disease (14–59 months, median: 39 months). Thus, these novel conditioning regimens allowed us to increase the dose intensity to nearly the maximum for each drug and seemed to reduce adverse effects compared to previously reported regimens with these drugs. With regard to the effect on outcome, the results of this study seem to be encouraging, but a further study on a larger number of patients is required. Keywords: high-dose chemotherapy; thiotepa; melphalan; busulfan; stem cell

Correspondence: J Hara at his present address: Department of Pediatrics, Suita City Hospital, 2-13-20, Katayamacho, Suita, Osaka, 564 Japan Received 4 October 1997; accepted 14 February 1998

High-dose chemotherapy (HDC) requiring autologous stem cell rescue has been increasingly utilized to treat a variety of pediatric solid tumors. However, an appropriate preconditioning regimen is unidentified and the contribution of HDC to survival rate improvement is still not established. In previous reports, etoposide and carboplatin in addition to an alkylating agent have been frequently used as key drugs in preconditioning regimens.1 However, tumor cells are supposedly at least partially resistant to these drugs, since they were repeatedly used in previous chemotherapy at standard doses before HDC. In contrast, alkylating agents such as thiotepa (TEPA), melphalan and busulfan (Bu) are not used in chemotherapy administered prior to HDC and are therefore expected to retain considerable anti-tumor activity. Alkylating agents have several suitable characteristics for HDC including: (1) a logarithmic cytotoxic activity in proportion to the doses; (2) less cross resistance; and (3) no specific adverse effects other than myelosuppression and mucositis.2 In addition, the ratios of maximum amounts of TEPA and Bu for HDC with stem cell rescue in conventional chemotherapy are much higher (five- and 20-fold) than other agents including etoposide and carboplatin.3 Nevertheless, combinations of these drugs were anticipated to cause severe mucositis and neurotoxicity.4–7 Therefore, to administer a maximum dose of these drugs safely, a double-conditioning regimen (two cycles of drug combinations with a 1-week interval) was attempted in 26 children with pediatric solid tumors. In two patients, three cycles were given.

Patients and methods Patients (Table 1) Between January 1993 and February 1997, 28 consecutive patients with poor prognosis solid tumors aged 1 to 19 years (median age: 3 years) underwent HDC with stem cell transplantation after several courses of chemotherapy. The patients had advanced disease, disease resistant to chemotherapy, relapsed disease, or brain tumors. All patients received HDC after several courses of chemotherapy containing cisplatin, cyclophosphamide and vincristine. Ifosfamide, dactinomycin, etoposide, carboplatin and pirarubicin were also administered in some patients. Twelve and nine patients received autologous bone marrow and peripheral

Double-conditioning regimens J Hara et al

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Table 1 Patient No.

Patient characteristics and outcome Age (year)

Diagnosis

Stage

Pre-HDC Surgery/LRT

Time to Status Response Post HDC at HDC to HDC HDC (months) therapy

−/−

8

9 GCT (HCG)

1st rel (brain, cord) II (brain)

+/+

3

8 GCT (HCG)

II (brain)

4

9 GCT (HCG)

II (brain)

5

3 Medulloblastoma

6

1 Neuroblastoma

1st rel (brain, BM) II (brain)

7a

6 GCT (AFP)

8

19 GCT (HCG)

1

14 GCT (AFP)

2



RRD (2 mo)

dead (2 mo)

8





alive

+/+

7

CR





+(partial)/+

6

CR





−/−

4

PR



+(partial)/−

10

no CR (PD) no CR

NED (34 mo+) NED (37 mo+) NED (47 mo+) REL (4 mo)

MR

4th rel

−/−

5

CR



III

−/−

6

CR

— PR CR



Local SD (14 mo+) radiation — NED (54 mo+) — NED (36 mo+) – REL (3 mo)

3rd rel

−/−

4

10

2 Hepatoblastoma

II

+/−

12

no CR (PD) no CR

11

1 Hepatoblastoma

III

+/−

6

no CR

CR



12

1 Hepatoblastoma

III

+/−

7

no CR

CR



13

3 Neuroblastoma

IV (bone, BM)b

−/−

6

CR





14

2 Neuroblastoma

IV (bone, BM)b

−/−

5

no CR

MR

15

2 Neuroblastoma

IV (bone, BM)b

−/−

4

no CR

MR

16 17 18

1 RMS (alveolar) 18 RMS (alveolar) 1 RMS (alveolar)

III IV IV

−/+ +/− +/+

8 6 6

no CR CR CR

NE — —

19

15 RMS (embryonal)

1st rel

+/−

8

CR



20a

7 RMS (embryonal)

3rd rel (brain)

+/+

5

CR



21

3 RMS (embryonal)

III

+(partial)/+

7

CR



22 23

3 RMS (embryonal) 12 PNET

IV 1st rel

+(partial)/+ −/−

7 5

— MR

24

2 PNET

IV

−/−

5

CR no CR (PD) CR

25

5 Ewing sarcoma

III

−/−

3

no CR

NR

+(partial)/− −/−

6 9

CR PR

−/−

5

no CR no CR (PD) no CR (PD)

3 Pulmonary blastoma III 16 multicentric OS IV 5 MRT

Present status

CR

3 Hepatoblastoma

28

Site of relapse

no CR (PD) CR

9

26 27

Outcome

III



PR

NED (50 mo+) NED (19 mo+) NED (34 mo+) REL (8 mo)

Surgery NED (45 mo+) Surgery NED (59 mo+) — RRD (1 mo) — REL (4 mo) — NED (32 mo+) — NED (21 mo+) — NED (32 mo+) — NED (15 mo+) — REL (3 mo) — REL (2 mo) NED (59 mo+) Chemo- REL (12 mo) therapy — REL (5 mo) — REL (1 mo)

alive alive L,BM dead (5 mo) alive alive alive L

alive alive alive L

REL (1 mo)

dead (13 mo) alive alive

dead (1 mo) lung dead (6 mo) alive alive alive alive L dead (6 mo) L, lung dead (3 mo)





dead (5 mo)

alive L

alive (25 mo+) brain dead (8 mo) L dead (4 mo) L, dead (7 mo) pleura

GCT, germ cell tumor (HCG or AFP producing); RMS, rhabdomyosarcoma; PNET, peripheral neuroectodermal tumor; OS, osteosarcoma; MRT, malignant rhabdoid tumor; REL, relapse; BM, bone marrow; CR, complete response; PD, progressive disease; PR, partial response; MR, minor response; NR, no response; NE, not estimated; NED, no evidence of disease; RRD, regimen-related death; L, local. a Patients who had received HDC previously. b These patients had extensive bone and bone marrow involvement. The N-myc gene was amplified (10 times) in patient 14.

stem cells (PSC), respectively. Six patients received stem cells from both bone marrow and peripheral blood. In the remaining patient (patient 5), because HLA-matched related or unrelated donors were available and neither was an autologous stem cell source, positively selected periph-

eral CD34+ cells from an HLA-mismatched donor (father) were used as stem cells as previously described elsewhere.8 Patient characteristics and clinical stages are shown in Table 1. Patients 7 and 20 received HDC consisting of TEPA and melphalan (single cycle administration) and mel-

Double-conditioning regimens J Hara et al

phalan, etoposide and carboplatin, respectively, prior to the fourth and third relapse. HDC was performed during CR or no CR in 13 and 15 patients, respectively. Bone marrow and PSC harvest Bone marrow was used as the sole stem cell source before 1994. No contamination of the stem cell inoculums with tumor cells was morphologically confirmed. Thereafter, after the second or third course of chemotherapy, PSCs mobilized with G-CSF were harvested and frozen until use. In the case of shortage of CD34+ cells for hematopoietic reconstitution (⬍2.0 × 106/kg), bone marrow was harvested and infused together with PSCs. Conditioning regimen and stem cell infusion (Tables 2 and 3) Nineteen patients received two tandem cycles of HDC consisting of TEPA and melphalan. A combination of TEPA (150–300 mg/m2) and melphalan (35–75 mg/m2) was administered on days −11, −10, −4 and −3. Doses of drugs were gradually escalated as noted in Table 3. After June 1996, the dose was reduced in patients younger than 2 years old (patients 6 and 11) because of the high frequency of renal toxicity. In two patients, because of inadequate responses to two cycles of drug administration, a third cycle of TEPA was added after a 1-week interval, ie TEPA (250 mg/m2) and melphalan (75 mg/m2) was administered on days −18, −17, −11 −10 and 250 mg/m2 of TEPA was added on days −4 and −3. Three patients received TEPA (250 or 300 mg/m2) and Bu (4 or 5 mg/kg) on days −11 and −10, and TEPA (250 or 300 mg/m2) and melphalan (75 mg/m2) on days −4 and −3. Two patients received a combination of TEPA (250 or 300 mg/m2) and Bu (4 or 5 mg/kg) on days −11, −10, −4 and −3. TEPA was given in two equally divided doses on each day and infused over 2 h. After June 1995 TEPA was administered as a 24-h continuous infusion to minimize organ toxicity. Melphalan Table 2

Supportive care All patients were isolated, treated in laminar air flow, and received total parenteral nutrition and nonabsorbable antibiotics. Administration of 5 ␮g/kg of G-CSF (lenograstim) was started on day 1. Definitions of tumor response CR was defined as the disappearance of all evidence of disease, which included return to normal levels of serum tumor markers. For the patients with neuroblastoma, BM samples were obtained from both iliac bones for the determination of CR. PR was defined as a greater than 50% decrease in all measurable tumor lesions. Minor response (MR) was defined as a decrease of between 25% to 50% in all tumor lesions. No response (NR) was defined as no significant change in any tumor lesions, and progressive disease (PD) was defined as the appearance of new lesion(s) or a greater than 25% increase in pre-existing lesion(s). Duration of response was not included in the response definition. Response duration and survival were measured from the date of stem cell infusion to the date of progression and the date of death, respectively.

Preconditioning regimens −18 −17 −11 −10 −4 −3 −2 −1 0

Day Thiotepa Melphalan n = 20a Thiotepa Melphalan n=2 Thiotepa Melphalan Busulfan n = 4b Thiotepa Busulfan n=2

was administered as a 1-h infusion. Patients received Bu 1–1.25 mg/kg orally every 6 h each day. Phenobarbital was orally administered for the prophylaxis of convulsions induced by Bu. In patients 20 and 22, after one cycle of drug administration, convulsions and Candida albicans sepsis occurred on days −10 and −7, respectively. Therefore, TEPA was eliminated from the second cycle of HDC in patient 20 and the second cycle was stopped in patient 22. After 2 days rest, stem cells were infused on day 0. A minimum of 2.2 × 106/kg peripheral CD34+ cells or 2.4 × 107/kg mononuclear bone marrow cells were used. When the number of peripheral CD34+ cells obtained was less than 2 × 106/kg, bone marrow cells were also infused.

쐌 쐌

쐌 쐌

쐌 쐌 쐌 쐌

쐌 쐌

쐌 쐌

쐌 쐌

250 or 300 mg/m2 75 mg/m2 4 or 5 mg/kg









쐌 쐌 쐌 쐌

2

쐌 쐌

쐌 쐌

150–300 mg/m2 35–75 mg/m2 쐌 쐌

250 mg/m2 75 mg/m2

250 or 300 mg/m 4 or 5 mg/kg

쐌 쐌

쐌 쐌 쐌 쐌

Thiotepa in two divided doses (2 h i.v. each) or c.i.v. (24 h); melphalan, i.v. (1 h); busulfan, in four divided doses (p.o.). a In one patient, the second cycle was sustained because of Candida sepsis which occurred after the 1st cycle. b In one patient, the 2nd administration of TEPA was sustained because of convulsion which occurred after the 1st cycle.

Results Toxicity and hematopoietic reconstitution The median duration of granulocytopenia (⬍0.5 × 109/l) was 14 days (range 9–33 days). The duration of granulocytopenia depended on the stem cell source. The duration was shortest after PSCT (9–20 days; median 11 days) and 6 days shorter than after BMT (10–33 days; median, 17 days). Although the cell number was insufficient for hematopoietic reconstitution, the addition of a small number of PSCs to BM cells shortened the period of granulocytopenia (10–25 days; median, 13.5 days). The median duration of thrombocytopenia (⬍20 × 109/l) was 33 days (4–252 days). The duration was shorter after PSCT (14–126 days; median, 23 days) than after transplantation of BM or BM and PSCs (14–252 days; median, 39 days). The addition of a small number of PSCs to BM cells did not shorten the period of thrombocytopenia. The major toxicity observed was on the mucosa of the

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Table 3

Preconditioning regimens and regimen-related toxicity

Patient Age No. (year)

22 25 11a 6a 7 24 10 12a 16a 18a 21 23 26 9 13 14 15 17 19 8 27 28 2 3 20 1 4 5

3 5 1 1 6 2 2 1 1 1 3 12 3 3 3 2 2 18 15 19 16 5 9 8 7 14 9 3

TEPA mg/m2

500b 600 800 800 800 800 800 800 800 800 800 800 800 1000 1000 1000 1000 1000 1000 1200 1500c 1500c 1000 1200 600b 1200 1000 1200

Melphalan mg/m2

140b 300 140 180 200 200 280 280 280 280 280 280 280 280 280 280 300 300 300 300 300 300 150 150 150 150 — —

BU mg/kg

— — — — — — — — — — — — — — — — — — — — — — 8 8 10 10 16 20

Stem cell source

PB PB PB BM BM BM BM BM BM BM PB BM+PB PB BM BM BM BM BM+PB BM+PB PB PB PB BM+PB BM+PB BM+PB PB BM PB

Infused cell dose

Days to Days to PLTC ANC ⬎20 × 109/l 9 ⬎0.5 × 10 /l + PB CD34 BM MNC (×106/kg) (×107/kg) 4.4 10.5 2.5 — — — — — — — 32.0 0.5 2.8 — — — — 0.6 0.7 0.17e 3.3 32.7 56.0d 0.58d 1.1d 2.2 — 4.3

— — — 18.0 8.5 10.1 5.7 9.0 3.5 2.4 — 10.0 — 5.8 4.7 11.0 13.0 12.0 7.5 — — — 4.0 2.5 4.2 — 6.2 —

10 11 14 14 20 21 14 10 17 23 9 25 14 21 33 14 29 10 18 10 20 11 14 10 13 11 13 11

44 15 19 4 39 40 31 23 — 76 14 45 14 24 97 33 57 56 252 35 126 60 14 12 62 19 19 27

Toxicity grade (WHO grade) GI tract 1 2 0 0 0 1 1 1 1 1 0 1 1 1 1 1 4 (HEM) 1 4 (HEM) 3 3 3 0 2 1 3 0 0

Renal

2 3

3

2

0 0 0 0 0 0 0 (HUS) (RTA)f 1 0 0 0 0 0 0 0 0 (HUS) 0 0 0 0 0 (HUS) 0 0 0

CNS

Others

0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 1g 1 0 0

Sepsisg

TMA

Heart failure TMA

TMA Fungal pneumoniaf

a

Drug dose was reduced to 75% of indicated doses. 2nd cycles were suspended. c In three cycles. d Total MNCs. e CFU-GM. f Fatal toxicity. g Complication occurred before stem cell transplantation. HEM, hematochezia; HUS, hemolytic uremic syndrome; RTA, renal tubular acidosis; TMA, thrombotic microangiopathy. b

digestive tract. The incidence of severe mucositis (grade 2 or higher) was high in patients who received three alkylating agents (two of four) and patients who had both 1000 mg/m2 of TEPA and 300 mg/m2 of melphalan or greater (five of six). Two (patients 15 and 19) of these seven patients developed severe lower gastrointestinal tract mucositis. Renal toxicity was another concern and was observed in five patients in spite of normal renal function before HDC. There were three life-threatening renal toxicities of which one was acute renal tubular acidosis (RTA) leading to sudden death on day 31 (patient 16) and two required temporary dialysis (patients 12 and 19). Three of five renal toxicities were hemolytic uremic syndrome (HUS) resulting from thrombotic microangiopathy (TMA), and two of these were associated with transient reversible disturbance of consciousness. All three patients with TMA showed erythrocyte fragmentation, hemolytic anemia and sudden decrease in platelet counts. Because all three young children (⬍2 years) who had received 800 mg/m2 of TEPA and 280 mg/m2 of melphalan suffered renal toxicities, the doses of these drugs were reduced in the following two 1year-old patients (patients 6 and 11). There were two treat-

ment-related deaths among the 28 patients (7%) (fungal pneumonia and RTA). Response to HDC Responses to HDC are summarized in Table 1. Among 13 patients who received HDC during CR, 10 patients are alive with no evidence of disease (15–59 months, median: 35). The remaining three patients (two group IV RMS and one stage IV NB), relapsed 3 to 8 months after HDC. In one of these patients (patient 22), the second HDC cycle was not given because of sepsis following the first cycle. Disease recurrence was observed at the original tumor site in two patients. The remaining patient developed a tumor in the lung. In 14 evaluable patients who underwent HDC while not in CR, complete and partial (PR) responses were obtained in five and four patients after HDC. The remaining four and one patients showed minor (MR) and no (NR) responses, respectively. Among the five patients in CR after HDC, three with HB had no measurable tumor, but persistent elevation of the serum AFP level had been documented

Double-conditioning regimens J Hara et al

before HDC. They remain in continuous CR (CCR) to date. In the remaining two patients, brain metastasis appeared in one patient with pulmonary blastoma 5 months post-transplant and the other (patient 1) died of regimen-related toxicity (RRT). Four patients in PR showed regrowth of tumor at the primary site after a short duration with stable disease. Among four patients in MR, the primary tumor was surgically resected in two patients with NB (patients 14 and 15) and a small number of residual viable tumor cells was found in tumors from both patients. Thereafter, both patients are relapse-free to date (45 and 59 months). One patient with brain NB received local irradiation after HDC, and regrowth of the tumor has not been observed to date. The remaining patient in MR and the patients with NR showed disease progression. Altogether, in 13 evaluable patients who underwent HDC not in CR, six are alive without relapse or regrowth of the diseases (14–59 months, median: 39). Discussion The contribution of HDC to the survival improvement of pediatric patients with a variety of tumors is still not established. In this study, we attempted to establish an effective preconditioning regimen and selected three alkylating agents, TEPA, melphalan and Bu for this purpose, which have documented anti-cancer activity in a variety of solid tumors.4–7,9–14 In our experience, a preparative regimen consisting of 800 mg/m2 of TEPA, 140 mg/m2 of melphalan and 16 mg/kg of Bu was safe and tolerable, but severe mucositis was observed and anti-cancer activity was unsatisfactory. Therefore, to administer a maximum dose of these drugs safely and to obtain a maximum anti-cancer effect, a double-conditioning regimen with two cycles of a combination of drugs with a 1-week interval, was designed. According to the results obtained from this study, with the combination of TEPA and melphalan, the maximum tolerable doses were 1000 mg/m2 and 280 mg/m2, respectively, and mucositis was dose-limiting. In patients with brain tumors, Bu was administered together with TEPA with or without melphalan. Although the number of patients studied was small and no conclusion can be drawn, coadministration of three drugs seemed to cause severe mucositis more frequently. The distinctive toxicity of this regimen was renal in young children (⬍2 years). All three patients younger than 2 years old who received 800 mg/m2 of TEPA and 280 mg/m2 of melphalan evidenced renal toxicity including RTA and HUS (TMA).15 Patient 20 with HUS was receiving the second HDC after the third relapse. Thus, high sensitivity of vascular endothelium to these drugs and/or immaturity of renal function leading to high serum level of drugs seems to have resulted in this serious toxicity. In comparison with previous studies on HDC with TEPA reported by others,6,7,16,17 the frequency of severe mucositis was lower. In a phase I study of TEPA, 20 and 15% of patients with 1005–1215 mg/m2 of TEPA exhibited severe (fatal) gastrointestinal toxicity and CNS complications, respectively.6 When other drugs including etoposide, BCNU and carboplatin and/or TBI were added, the fre-

quencies of life-threatening mucositis and veno-occlusive disease (VOD) increased even with the lower dose of TEPA.13,18–20 However, patients who received TEPA and substantial doses of melphalan and/or Bu with a doubleconditioning regimen developed mucositis and CNS complications less often and VOD was not observed. The outcome of patients depended strongly on the status of the disease before HDC. While only three of 13 patients, who had been in CR at HDC, relapsed after HDC, seven of 13 evaluable patients, who had been unable to obtain CR before HDC, relapsed after a short duration with stable disease. However, the finding that five patients not in CR at HDC (three with HB and two with NB) and two patients who had relapsed after the first HDC during prior relapses were in CCR was encouraging. Indeed, three of four patients with HB achieved CR and had durable responses. This preconditioning regimen seems to have had potent activity against HB and a further study is warranted. Two patients with NB were in CCR (45 and 59 months) after resection of the primary tumors indicating that HDC eradicated micrometastasis, although HDC was unable to eradicate tumor cells completely. Because of high penetration of the blood–brain barrier with TEPA and Bu, these drugs have been used in various types of brain tumor in phase II studies with limited efficiency.4,14,19 We used the double-conditioning regimen including TEPA and Bu with or without melphalan in seven patients with brain tumors (three with HCG-secreting GCT, one with AFP-secreting GCT, two with medulloblastoma/NB and one with metastatic RMS). All three patients with HCG-secreting GCT and one with RMS were in CCR (32–47 months) and one with AFP-secreting GCT who received HDC with progressive disease died of RRT after achieving CR. One with brain NB who had been resistant to chemotherapy obtained a PR and was in CCR. These patients in CCR received involved field irradiation before or after HDC and had a good performance status without sequelae caused by HDC or radiotherapy. Taken together, a combination of TEPA and Bu, with or without melphalan, seems to be effective on at least intracranial GCT. Although several studies with high-dose melphalan showed some usefulness for chemotherapy-resistant Ewing sarcoma and RMS,14,21,22 the contribution of HDC to the improvement of disease-free survival has not been proved. A recent report of a meta-analysis of HDC mainly consisting of melphalan, etoposide and carboplatin for 36 patients with RMS from a German and Austrian group failed to show the advantage of HDC.23 In our study, of six evaluable patients with RMS, four were alive and disease-free (range 15–32 months). However, because of the short follow-up period and the small number of patients, no conclusions can be drawn. This study showed that the double-conditioning regimens enabled us to safely coadminister TEPA, melphalan and/or Bu at nearly maximum doses in the previously known single-agent setting and these appeared associated with less toxicity than single cycle regimens of drug administration. The major toxicity was mucositis. With regard to the anticancer effect, these regimens resulted in a good response in advanced pediatric malignancies, especially in patients

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with minimal disease. A further study on a larger number of patients is warranted.

11

Acknowledgements This work was supported by a grant from Mr and Mrs Wada. We wish to dedicate this manuscript to their son, Mr Tokiji Wada who died of leukemia in 1995.

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