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Journal of Clinical Oncology, Vol 18, Issue 13 (July), 2000: 2576-2581
© 2000 American Society for Clinical Oncology

Fractionated Cyclophosphamide and Etoposide for Children With Advanced or Refractory Solid Tumors: A Phase II Window Study

By Elpis Mantadakis, Larry Herrera, Patrick J. Leavey, Robert O. Bash, Naomi J. Winick, Barton A. Kamen

From the Department of Pediatrics, Division of Hematology/Oncology, and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX.

Address reprint requests to Barton A. Kamen, MD, PhD, Departments of Pediatrics and Pharmacology, Cancer Institute of New Jersey, 195 Little Albany St, PO Box 2681, New Brunswick, NJ 08903-2681; email kamenba{at}umdnj.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Cyclophosphamide (CPA) has a broad spectrum of activity against solid tumors. Hepatic self-induction of the active metabolite 4-hydroxycyclophosphamide occurs after repeated administration. We evaluated the clinical efficacy of a window regimen that administers fractionated CPA in conjunction with etoposide (VP16) in children with advanced or refractory solid tumors.

PATIENTS AND METHODS: Seventeen children with advanced (n = 12) or refractory (n = 5) solid tumors were entered onto this phase II window study. The treatment regimen consisted of intravenous (IV) CPA 500 mg/m2/d and IV VP16 100 mg/m2/d. Both drugs were administered daily by short infusions for 5 consecutive days.

RESULTS: A total of 34 courses were administered, with a median of two courses per patient. The median interval between chemotherapy courses was 21 days (range, 17 to 35 days). Thirty-three courses were assessable for toxicity, and all patients were assessable for response. No life-threatening toxicities were observed. The incidence of grade 3 or 4 neutropenia was 94% and of fever and neutropenia 38%. Fever and neutropenia occurred after 12 of 26 courses without recombinant human granulocyte colony-stimulating factor (rhG-CSF) and after one of eight courses with rhG-CSF (P = .09). Grade 3 or 4 thrombocytopenia occurred after 10 courses (29%). There were no positive blood cultures. One heavily pretreated patient developed a localized perirectal abscess that required drainage. There were 10 patients (59%) with partial responses, four (23.5%) with stable disease, and three with progressive disease.

CONCLUSION: Fractionated IV CPA and VP16 over 5 days can be safely administered in children with advanced or refractory solid tumors and has notable antineoplastic activity.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
CHILDREN WITH metastatic, unresectable, or recurrent solid tumors continue to have a poor prognosis. Cyclophosphamide (CPA), an oxazaphosphorine, is active against pediatric malignant solid tumors and has been incorporated into most primary chemotherapy regimens used for the treatment of these diseases.1-4

CPA is a prodrug that must be oxidized to 4-hydroxycyclophosphamide (4-OHCPA) in the liver.5,6 4-OHCPA then enters cells and is ultimately converted to the DNA alkylator phosphoramide mustard and acrolein.5-7 Phosphoramide mustard is a polar molecule and enters cells poorly. Therefore, the antitumor activity of CPA depends on the readily diffusible and nonpolar 4-OHCPA.5,6 Many reports describe a significant increase in 4-OHCPA area under the plasma-time curve after repeated doses of CPA because of autoinduction of its metabolism.6,8-10 In addition, fractionated CPA has decreased renal elimination compared with high-dose CPA, which increases the amount of drug available for bioactivation.9,10 Finally, fractionated CPA has a better therapeutic index (cytotoxicity against tumor cells v bone marrow precursors) compared with a single intravenous (IV) injection.11

Etoposide (VP16)12 is synergistic with CPA in a xenograft model of rhabdomyosarcoma.13 Moreover, clinical studies have shown the efficacy of various VP16 and CPA or ifosfamide (IFO), a CPA analog, combinations in osteosarcoma and refractory neuroblastoma.1-3,14 For certain tumors, five daily injections of VP16 are more effective and equally toxic compared with a single 24-hour infusion.15 In an effort to exploit the efficacy of fractionated VP16 and of the autoinduction characteristics of CPA, we designed a phase II window clinical trial to administer IV VP16 and CPA for 5 consecutive days in children with recurrent or advanced solid tumors.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
A total of 17 patients aged 4 to 17.8 years with histologically confirmed advanced or recurrent solid tumors treated at Children’s Medical Center of Dallas between December 1991 and December 1998 were enrolled onto this study. All patients and/or their guardians provided informed written consent for administration of chemotherapy according to the local institutional review board guidelines. Sex, age, diagnosis, site of primary tumor, site(s) of metastatic disease (if applicable), and prior therapy (for patients with recurrent disease) are summarized in Table 1. Overall, there were five patients with Ewing’s sarcoma (two skeletal, two extraosseous, and one with a chest-wall Askin’s tumor), four with osteosarcoma, three with rhabdomyosarcoma, two with peripheral-nerve sheath tumors, and one each with synovial sarcoma, epithelioid sarcoma, and undifferentiated sarcoma. Five patients had recurrent disease after intensive frontline therapy, whereas 12 received two cycles of VP16 and CPA as initial therapy. Patients were eligible for the study if they had normal renal and hepatic function, as documented by normal levels of blood urea nitrogen, creatinine, AST, ALT, alkaline phosphatase, and total bilirubin before each course of chemotherapy. A neutrophil count of greater than 750 x 106 cells/L and a platelet count of greater than 100 x 109 cells/L was required before each course of chemotherapy.


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  		Table 1. Demographic and Clinical Characteristics at Diagnosis of Patients With Advanced or Refractory Solid Tumors Who Received VP16 and CPA as an Up-Front Window
 
Chemotherapy Regimen
This phase II window study was designed to administer up front two consecutive courses of VP16 and CPA in newly diagnosed children with advanced solid tumors or in children with recurrent solid tumors. The chemotherapy regimen consisted of VP16 100 mg/m2/d as a 1-hour infusion followed by CPA 500 mg/m2/d by IV infusion over 30 minutes for 5 consecutive days. IV mesna uroprotection was administered at 150 mg/m2 over 15 minutes just before administration of CPA and at 100 mg/m2 3 and 6 hours after the end of CPA infusion. Patients were intravenously hydrated at twice maintenance with 5% dextrose solution in 0.45% normal saline for 2 hours before and for 6 hours after the administration of VP16 and CPA. Chemotherapy courses were repeated every 21 days. Prophylactic cotrimoxazole was administered 3 days per week, whereas recombinant human granulocyte colony-stimulating factor (rhG-CSF; filgrastim) was used according to investigator’s choice. When G-CSF was used, it was administered at 5 µg/kg as a single daily subcutaneous injection, started 24 hours after the end of each course of chemotherapy and discontinued when the neutrophil count was greater than 1,500 x 106 cells/L on 2 consecutive days. Decisions to transfuse packed RBCs were based on individualized clinical assessment. Platelets were transfused only in the case of bleeding and/or if the platelet count was less than 10 x 109 cells/L. No patient received erythropoietin. IV dexamethasone (5 mg/m2) and ondansetron (0.45 mg/kg 30 minutes before the initiation of CPA infusion and 0.15 mg/kg every 6 hours as needed thereafter) were used as antiemetics. Additional IV dexamethasone and promethazine were allowed for breakthrough emesis.

Evaluation of Response and Toxicity
Disease status was evaluated after two courses of VP16 and CPA in 15 patients and after one course in two patients. Patient no. 5 was evaluated twice, after two and four cycles of chemotherapy. Imaging techniques used to evaluate the primary and metastatic sites were computerized tomography, with and without contrast, and magnetic resonance imaging. Complete response was defined as the disappearance of assessable disease and of any symptoms and signs associated with it. Partial response was defined as greater than 50% reduction in the sum of the products of the perpendicular diameters of all measurable lesions with no evidence of new lesions. Stable disease was defined as less than 50% reduction and less than 25% increase in the sum of the products of the perpendicular diameters of all measurable lesions with no radiographic evidence of new lesions. Finally, progressive disease was defined as an increase in the sum of the products of the perpendicular diameters of any measured lesion by greater than 25% from the size present at the time of study entry or the appearance of any new lesions.

Hematologic toxicity was monitored with hemograms performed weekly after the beginning of chemotherapy. Additional hemograms were obtained in case of fever. The interval between successive courses of VP16 and CPA was used to judge the clinical significance of hematologic toxicity. The toxicity was graded as follows: neutropenia grade 1, 1,500 to 1,900 x 106 cells/L, grade 2, 1,000 to 1,499 x 106 cells/L, grade 3, 500 to 999 x 106 cells/L, and grade 4, less than 500 x 106 cells/L; thrombocytopenia grade 1, 75 to 150 x 109 cells/L, grade 2, 50 to 74.9 x 109 cells/L, grade 3, 25 to 49.9 x 109 cells/L, and grade 4, less than 25 x 109 cells/L. Anemia was considered clinically important only if a transfusion was required.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 34 courses of VP16 and CPA were administered in 17 patients. Each patient received between one and four cycles of chemotherapy (median, two courses). Eleven courses were administered on an outpatient basis. All courses except one were assessable for toxicity, and all patients were assessable for response.

Toxicity
Grade 3 or 4 neutropenia occurred after 32 courses (94%). Neutropenia was complicated by fever in 13 cases (38%). There were no positive blood cultures. One heavily pretreated patient (no. 16) with osteosarcoma developed, while neutropenic, a perirectal abscess that required drainage. rhG-CSF was used after eight courses (23.5%). Fever and neutropenia occurred after 12 of 26 courses without rhG-CSF and after one of eight courses with rhG-CSF (P = .09, one-sided Fisher’s exact test). Fever and neutropenia occurred in all five pretreated patients who had recurrent or refractory disease and in eight of 12 previously untreated patients. Grade 3 or 4 thrombocytopenia occurred after 10 courses. No patient required a platelet transfusion, whereas four patients required a transfusion of packed RBCs before courses of chemotherapy. No cases of breakthrough or prolonged nausea/emesis that required additional antiemetics were observed. No patient developed macroscopic hematuria. The median interval between consecutive courses of chemotherapy was 21 days (range, 17 to 35 days). Only four of 34 courses were delayed beyond 28 days after the beginning of the previous cycle of VP16 and CPA, and each of these was in heavily pretreated patients. Twenty-three of 34 courses were administered in the hospital and 11 in an outpatient setting.

Response
Response data and current follow-up, as of October 31, 1999, are summarized in Table 2. No complete responses were observed, 10 patients had partial responses, four had stable disease, and three died of progressive disease without further chemotherapy. Among the 10 patients who had partial responses, seven received additional adjuvant chemotherapy that consisted of alternating courses of vincristine (1.5 mg/m2/dose), doxorubicin (25 mg/m2/d for 3 days), and CPA (1.2 g/m2/dose) with 5 days of IV VP16 and fractionated CPA. Five patients, including patients no. 5 and 10, with widely metastatic disease at diagnosis were alive at the time of this writing, whereas two heavily pretreated patients had died of progressive disease. Among the remaining three patients who had partial responses, patients no. 2 and 3 received high-dose chemotherapy with peripheral stem-cell support for consolidation and died of toxicity. Finally, patient no. 9 was undergoing continued chemotherapy for recurrent synovial cell sarcoma at the time of this writing. Among the four patients who had stable disease for a median of 3 months, three died of progressive disease. Patient no. 13, who had stable disease after two courses of VP16 and CPA, underwent complete surgical resection of his primary tumor (peripheral-nerve sheath tumor) and had no evidence of disease 49 months after diagnosis.


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  		Table 2. Site(s) of Recurrent Disease, Prior Therapy, Number of Courses Administered, Clinical Response, and Current Status of 17 Patients Who Received VP16 and CPA as an Up-Front Phase II Window
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
CPA is an active drug in the therapy of solid tumors of children. VP16 is also effective against solid tumors, particularly when used in combination with alkylating agents.4,7,10,14,16-29 The effect of this drug is schedule-dependent, with five daily infusions being superior to a 24-hour continuous infusion.15,30 VP16 in combination with fractionated CPA (300 mg/m2 every 12 hours for six doses) produced responses in 15 of 17 patients with newly diagnosed osteosarcomas, including five with metastatic disease.3 Also, VP16 at 75 mg/m2/d in conjunction with vincristine and escalating doses of CPA on 3 consecutive days was effective (95% overall response, including seven complete responses) in 23 patients with recurrent or refractory solid tumors of childhood.4 Finally, VP16 in combination with fractionated IFO, a CPA isomer,31 has been shown to be effective in relapsed or refractory osteosarcomas14 and in other recurrent or refractory solid tumors,21,25 producing overall response rates of 39% to 56%.

IFO has been used as salvage therapy in patients with solid tumors who relapse after primary chemotherapy and, recently, as frontline therapy.16-18 A single clinical trial of adults with soft tissue sarcomas suggested that IFO may be more effective than CPA based on an overall response rate of 18% versus 8%, respectively.32,33 To our knowledge, no randomized pediatric clinical trials have ever compared CPA with IFO in comparable doses and schedules. Despite the lack of evidence-based data, the available literature implies that IFO is superior to CPA on the basis of producing clinical responses in patients with advanced or recurrent solid tumors who received prior CPA therapy.16,19-22 However, CPA is traditionally delivered as a single large dose over 1 to 3 days,34-36 whereas IFO has been administered on a fractionated schedule over 4 to 5 days and at more myelosuppressive doses. It may be that the presumed therapeutic advantage of IFO over CPA is schedule- and dose-dependent.37-39 Like IFO,40,41 repeated administration of CPA leads to autoinduction of its metabolism.7,8 Dividing a single high dose of CPA over 2 days produced more active metabolite through autoinduction and by decreasing the renal elimination of CPA.10,11 Therefore, we designed a phase II window clinical trial of fractionated VP16 and CPA to mimic the 5-day VP16 and IFO regimen that is commonly used as salvage therapy for recurrent pediatric solid tumors.17,21,24,26-28

Our results in 17 patients with recurrent or advanced solid tumors suggest that fractionated VP16 and CPA over 5 days is a myelosuppressive but tolerable regimen. Grade 4 neutropenia was inevitable but rapidly reversible, and no patient developed a life-threatening infection. Although our study was not intended to address this issue, the incidence of fever and neutropenia tended to be lower in patients who received rhG-CSF. Clinically significant anemia and or thrombocytopenia were uncommon. No cases of hemorrhagic cystitis were observed after one to four courses of VP16 and CPA. Based on our experience and that of others,42,43 mesna seems to be effective in preventing hemorrhagic cystitis after various regimens of oxazaphosphorines. Although no complete responses were observed, the overall response rate in 17 patients with recurrent or advanced solid tumors was 59% (10 of 17), which is comparable to the response rates produced with regimens that use VP16 and IFO, with or without carboplatin.14,16-29

CPA has several biochemical and economic advantages over IFO. First, the majority of CPA is metabolized to the active metabolite 4-OHCPA. In contrast, the formation of 4-hydroxyifosfamide, the active metabolite of IFO, occurs at a substantially slower rate.41 Under these circumstances, dechloroethylation, which is not an important inactivating pathway for CPA, becomes prominent for IFO, which leads to the formation of chloracetaldehyde, a metabolite with no antineoplastic activity and homology to acetaldehyde.41 Chloracetaldehyde is likely responsible for the neurotoxicity of IFO.41,44 CPA produces trivial amounts of this compound even after high-dose regimens used for conditioning patients before bone marrow transplantation.41 Second, IFO is nephrotoxic whereas CPA is not. Although mesna is effective in inactivating acrolein, the metabolite mostly responsible for the urotoxicity of oxazaphosphorines,42,43 it is likely that 4-hydroxyifosfamide directly contributes to the nephrotoxicity of IFO.44 In infants and younger children with pre-existent renal dysfunction, especially those who have received high cumulative doses of IFO (greater than 60 g/m2) and/or prior cisplatin therapy, IFO has been associated with renal tubular damage and Fanconi’s syndrome.45-48 The latter has not been associated with CPA. Finally, in today’s cost-conscious era, it is significant that the average wholesale price of 1 g of CPA is approximately $50, versus $936 for 1 gram of IFO with mesna (Alan Lorenzen, RPh, personal communication, November 1999). Considering that higher doses of IFO are required for comparable myelosuppression,36 fractionated IFO regimens can be costly.

Our study has limitations that are inherent to any single-institution phase II pediatric oncology study, such as the small number of patients and the diverse histology of the treated tumors. Thus, the clinical efficacy of fractionated VP16 and CPA for a specific tumor histotype is unclear. Second, we did not treat a comparable group of patients with a regimen that relies on conventional CPA administered over 1 to 3 days. Thus, the most effective way of administering CPA (fractionated v conventional) remains to be seen. Finally, the inpatient administration of CPA over 5 days is more expensive and labor-intensive compared with its conventional administration. However, outpatient chemotherapy, which can safely be given in the case of fractionated IV CPA over 5 days and at substantial savings compared with inpatient administration of the drug, even over only 1 to 3 days, makes the use of fractionated CPA more attractive.

Our study suggests that fractionated VP16 and CPA, as described here, deserves further evaluation in a multicenter clinical trial, along with pharmacokinetic studies of their active metabolites to determine if a correlation exists between their systemic exposure and tumor response. Fractionated IV VP16 and CPA administered over 5 days is tolerable in children with advanced or refractory solid tumors. This regimen can be administered safely on an outpatient basis and is more economical and potentially less toxic than and seems to have comparable efficacy with the more widely used 5-day VP16 and IFO regimen.


   ACKNOWLEDGMENTS
 
Supported by the Children’s Cancer Fund of Dallas, Dallas, TX.


   NOTES
 
B.A.K. is an American Cancer Society Clinical Research Professor.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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14. Gentet JC, Brunat-Mentigny M, Demaille MC, et al: Ifosfamide and etoposide in childhood osteosarcoma: A phase II study of the French Society of Paediatric Oncology. Eur J Cancer 33:232-237, 1997

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36. Ruymann FB, Vietti T, Gehan E, et al: Cyclophosphamide dose escalation in combination with vincristine and actinomycin-D (VAC) in gross residual sarcoma: A pilot study without hematopoietic growth factor support evaluating toxicity and response. J Pediatr Hematol Oncol 17:331-337, 1995[Medline]

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38. Oberlin O, Habrand JL, Zucker JM, et al: No benefit of ifosfamide in Ewing’s sarcoma: A nonrandomized study of the French Society of Pediatric Oncology. J Clin Oncol 10:1407-1412, 1992[Abstract/Free Full Text]

39. Shaw PJ, Eden T: Ifosfamide in paediatric oncology: Tried but not tested? Lancet 335:1022-1023, 1990[Medline]

40. Kurowski V, Wagner T: Comparative pharmacokinetics of ifosfamide, 4-hydroxyifosfamide, chloracetaldehyde, and 2- and 3-dechloroethylifosfamide in patients on fractionated intravenous ifosfamide therapy. Cancer Chemother Pharmacol 33:36-42, 1993[Medline]

41. Wagner T: Ifosfamide clinical pharmacokinetics. Clin Pharmacokinet 26:439-456, 1994[Medline]

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Submitted November 30, 1999; accepted March 3, 2000.


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