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Neuro Oncol 2006 8(1):53-59; DOI:10.1215/S1522851705000463
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Duke University Press

Clinical Therapy Trials—Drug

Efficacy of vincristine and etoposide with escalating cyclophosphamide in poor-prognosis pediatric brain tumors1

David S. Ziegler, Richard J. Cohn2, Geoffrey McCowage, Frank Alvaro, Cecilia Oswald, Robert Mrongovius, Les White for the Australian and New Zealand Children's Cancer Study Group

Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Randwick, New South Wales 2031 (D.S.Z., R.J.C., C.O., L.W.); School of Women's and Children's Health, University of New South Wales, Kensington, New South Wales (D.S.Z., R.J.C., L.W.); Oncology Unit, Children's Hospital at Westmead, Westmead, New South Wales (G.M.); Haematology and Oncology Department, John Hunter Hospital, New South Wales (F.A.); and Amgen Australia, Pty. Ltd., Melbourne, Victoria 3122 (R.M.); Australia

2 Address correspondence to Richard J. Cohn, Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, High St., Randwick, NSW 2031, Australia (r.cohn{at}unsw.edu.au).


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children's Cancer Study Group—VETOPEC I, Baby Brain 91, and VETOPEC II—have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed support further development of this chemotherapy regimen.

Key Words: brain tumor • childhood • cyclophosphamide • high-dose chemotherapy • stem cell transplant


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 References
 
Infants with brain tumors and older children with relapsed or progressive brain tumors have a particularly poor prognosis. High-dose chemotherapy, with or without stem cell rescue, has increasingly been used in an attempt to improve their outcomes (Finlay et al., 1996; Gururangan et al., 1998; Mason et al., 1998a, b). Many treatment protocols have been limited by excessive treatment-related mortality and poor response rates (Dunkel and Finlay, 2002).

Cyclophosphamide (CPA)3 has proven activity against many childhood solid tumors and malignant brain tumors (Allen and Helson, 1981; Friedman et al., 1986; Mitchell and D'Angio, 1986) and has a steep dose-response curve, suggesting that higher doses result in a greater tumor-cell kill (Strother et al., 2001). It is also significantly less toxic than other alkylating agents such as ifosfamide. In addition, unlike other alkylating agents, CPA has been shown to be more effective when given in a fractionated schedule (Teicher et al., 1989). The combination of etoposide (VP-16) and CPA may be synergistic (Lilley et al., 1990) and has been found to be effective in a variety of settings (Kalwinsky et al., 1985; Saleh et al., 1990; Spitzer et al., 1989). A pilot study conducted by the Australia and New Zealand Children's Cancer Study Group (ANZCCSG) showed that a specific regimen of vincristine (VCR), VP-16, and escalating CPA (VETOPEC) produced high response rates in patients with refractory or recurrent solid tumors, including two patients with brain tumors (White et al., 1994). As a result of this finding, since 1991, the ANZCCSG has conducted three studies utilizing the VETOPEC regimen in high-risk pediatric solid tumors. The three sequential studies are the subjects of separate manuscripts. We compile here the analysis of this regimen of chemotherapy in the specific subset of patients with high-risk brain tumors treated in these three studies. The primary aim was to assess the response rates, survival data, and major toxic events observed in this cohort of patients. A secondary aim was to compare the response rates and toxicity in patients treated with very high doses of CPA plus peripheral blood stem cell (PBSC) support with those in patients who received relatively lower doses without PBSC support.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 References
 
The data collected in three consecutive ANZCCSG studies was analyzed, and cases of patients with brain tumors were extracted. All studies were conducted in ANZCCSG institutions. Patients from six ANZCCSG centers were enrolled in the VETOPEC I study between May 1991 and May 1994 (Carpenter et al., 1997). All patients had high-risk solid tumors, which were either progressive or recurrent following conventional chemotherapy, or had newly diagnosed tumors for which there were no adequate conventional treatment options available. All children with brain tumors included in this study had relapsed or progressive disease. Chemotherapy consisted of VCR, VP-16, and CPA escalating from 90 mg/kg per cycle to 165 mg/kg per cycle over six successive cycles (Fig. 1). Tumor status was reevaluated after every two to three cycles of chemotherapy.



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  		Fig. 1. Schema showing drug dosages and escalation strategy of the VETOPEC I study.

 

In the Baby Brain '91 study, patients less than four years of age from 10 institutions were enrolled between May 1991 and October 1995 (White et al., 1998). All patients had newly diagnosed malignant brain tumors and were treated postoperatively with a VETOPEC-based protocol without radiotherapy. The protocol consisted of VCR, VP-16, and CPA at 120 mg/kg per cycle (Fig. 2). Tumor status was reevaluated after each two courses of the initial therapy and after each complete cycle of the continuation therapy.



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  		Fig. 2. Schema of initial chemotherapy in the Baby Brain '91 cohort.

 
The VETOPEC II study included patients aged 0 to 22 years with relapsed or progressive solid tumors or newly diagnosed patients with diseases considered at high risk of treatment failure with conventional therapies (Lal et al., 1999). Brain tumor patients from both categories were treated with this protocol. Study treatment consisted of mobilization therapy, harvesting of PBSCs, and then intensive chemotherapy cycles supported by reinfusion of autologous PBSCs and filgrastim. Mobilization chemotherapy used a lower dose VETOPEC regimen: VCR at 0.05 mg/kg on days 1 and 8 together with VP-16 at 2.5 mg per day and standard dose CPA at 40 mg/kg per day on days 1, 2, and 3. Filgrastim at 10 µg/kg per day was given from day 4. Following PBSC collection, intensive chemotherapy cycles were administered consisting of VCR at 0.05 mg/kg on days 1 and 15; VP-16 at 2.5 mg/kg per dose twice a day on days 1, 2, and 3; and CPA on days 1, 2, and 3 (Fig. 3). The dose of CPA was escalated in cohorts of at least five patients starting at 180 mg/kg per cycle and increasing to 270 mg/kg per cycle, in increments of 15 mg/kg per cycle. Autologous PBSCs were reinfused on day 4, and filgrastim at 10 µg/kg per day was given from day 4 until neutrophil counts exceeded 10 x 109 per liter.



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  		Fig. 3. Schema showing drug dosages and escalation strategy of the VETOPEC II study.

 

Following treatment with the different VETOPEC regimens, the treating physicians were permitted to proceed with other treatment options at their own discretion.

Response rates and toxicity were measured consistently across all three studies. A complete response (CR) was defined as the complete disappearance of all radiologically and clinically detectable disease. A partial response (PR) was defined as a 50% or greater reduction in tumor mass as measured by the products of the largest perpendicular diameters, with no evidence of new lesions. Stable disease was a reduction of less than 50% in size or an increase of up to 25% in size of the original mass. Progressive disease was an increase in tumor size of at least 25%. Major toxic events leading to death or withdrawal from the study were analyzed in each cohort of patients.

We compared the response rates and toxicities among patients receiving different dosages of CPA, as well as those among patients in different diagnostic categories, by using the chi-squared or Fisher exact probability test. The Wilson procedure was used to calculate 95% CIs for response rates. Survival of patients within each study cohort was calculated by the Kaplan and Meier method.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 References
 
Seventy-two brain tumor patients aged 3 months to 14 years were enrolled in the three studies. One patient experienced a severe neurologic deterioration prior to commencement of therapy and did not proceed. The 71 remaining patients were treated with the VETOPEC-based protocols. Forty-two newly diagnosed patients less than four years of age were treated with the Baby Brain '91 protocol, and 11 patients with relapsed or progressive brain tumors were treated with the VETOPEC I protocol. Eighteen brain tumor patients were treated with the VETOPEC II protocol, of whom six had newly diagnosed high-risk tumors. The diagnoses in the 71 patients were medulloblastoma in 29, primitive neuroectodermal tumors (PNETs) in 11, grade 3 or 4 astrocytoma in 13, and ependymoma in 15. Two patients had choroid plexus tumors, and another had a primary cerebral neuroblastoma. The disease status according to diagnostic category is summarized in Table 1.


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  		Table 1. Disease status at treatment commencement according to diagnosis

 

Response Rates
Fifty-four patients were evaluable for their response to treatment. Of these, 17 had a CR and 20 a PR, which equated to an overall response rate of 69% (95% CI, 54%-80%). The CR + PR for medulloblastomas was 83% (19/23; 95% CI, 60%-94%), for PNETs was 56% (5/9; 95% CI, 23%-85%), for grade 3 or 4 astrocytomas was 54% (6/11; 95% CI, 26%-82%), and for ependymomas was 80% (6/8; 95% CI, 36%-95%). The two patients with choroid plexus tumors did not respond, and the patient with the cerebral neuroblastoma had a very good PR (>90% reduction in tumor size). A comparison of the response rates for the three different protocols is summarized in Table 2.


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  		Table 2. Response rates according to treatment protocol

 

The total response rate in the 20 previously treated patients was equally as high as in the 34 patients with newly diagnosed tumors (65% [95% CI, 43%-82%] vs. 71% [95% CI, 54%-83%], P = 0.89; Table 3). Although the rate of CRs was higher in previously untreated patients, this difference was not statistically significant (41% [95% CI, 26%-58%] vs. 25% [95% CI, 11%-47%], P = 0.76).


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  		Table 3. Response rates according to histology and disease status at study commencement

 

The response rates were compared according to dose of CPA administered per cycle. The response rate (CR + PR) in the 35 evaluable patients who received doses of up to 165 mg/kg per cycle was 69% (95% CI, 52%-81%), and among the 17 who received higher doses with stem cell support it was 71% (95% CI, 47%-87%). Thus, higher escalation of CPA given with stem cell support did not further improve the response rate in these heterogeneous cohorts of patients.

Toxicity
The major regimen-related toxicity was myelosuppression. Overall there were four deaths attributable to the hematologic toxicity of the prescribed regimens. One patient had sepsis combined with acute respiratory distress syndrome, one had transfusion-related graft-versus-host disease and subsequent sepsis combined with disease progression, and two patients died of sepsis alone. These four toxic deaths occurred in patients who received up to 165 mg/kg per cycle of CPA but did not receive stem cell support. Despite the very high doses of CPA used in the VETOPEC II patients, there were no toxic deaths in this cohort. The overall treatment-related mortality of 7% (95% CI, 2%-17%) for non-PBSC-supported patients versus 0% (95% CI, 0%-22%) for PBSC-supported patients did not reach statistical significance.

Two patients died from nontumor-related causes that were not directly attributable to the VETOPEC-based regimens. One patient died of cisplatin toxicity following an accidental overdose later in the course of disease management, and another died of respiratory failure during a subsequent autologous stem cell transplant using busulfan and thiotepa.

Surprisingly few patients experienced nonhematologic toxicities. One patient developed veno-occlusive disease, which led to the early cessation of therapy. Another two patients were withdrawn from therapy because of the development of hemorrhagic cystitis, in one case in association with echocardiographic changes. There was no apparent correlation between dose of CPA used and the incidence of nonhematological toxicity.

The maximal tolerated dose of CPA was defined as a key study end point in the VETOPEC II cohort of patients but was not reached.

Survival
Sixty-nine patients were eligible for continuing evaluation of tumor status and survival. At a median follow-up of 36 months (range, 4-85 months) overall survival was 34%, with disease-free survival of 13%. Overall survival and disease-free survival for different tumor types were respectively 34% and 17% for medulloblastoma, 36% and 18% for PNETs, 31% and 0% for high-grade gliomas, and 40% and 13% for ependymomas. There was no significant difference in overall or disease-free survival in patients who received stem cell support compared with those who did not.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 References
 
The current analysis demonstrates that the VETOPEC regimen of VCR, VP-16, and high-dose CPA produces high response rates in a poor-prognosis group of patients. The overall response rate of 69% is a notable improvement on much published data. Similar poor-prognosis brain tumor patients were treated with high-dose CPA and melphalan followed by autologous bone marrow rescue (Mahoney et al., 1996). The maximal dose of CPA reached was 6000 mg/m2, equivalent to 200 mg/kg. The response rate was 39%, and toxicity was significant: 22% died of transplant-related complications. The higher response rates demonstrated in our patients may reflect the use of multiple sequential chemotherapy cycles and the specific VETOPEC regimen of CPA combined with VP-16 and VCR rather than CPA plus melphalan. Finlay et al. (1996) used high-dose thiotepa and VP-16 with autologous bone marrow rescue in a similar high-risk group of patients and attained a response rate of 23% with a treatment-related mortality of 16%. Our results are also an improvement on those seen with several newer agents. Paclitaxel has been used in children with recurrent or refractory brain tumors with a response rate of 5% (Hurwitz et al., 2001), and a similar trial of topotecan showed no CRs or PRs (Kadota et al., 1999).

We have also shown that the VETOPEC regimen is effective across a wide range of tumor types, including traditionally less responsive tumors such as high-grade astrocytomas. Most previous studies of chemotherapy for high-grade astrocytomas have shown response rates in the range of 11% to 29% (Galanis and Buckner, 2000), whereas the response rate in our study was 55%. In a previous study, high-dose CPA was administered on its own to 17 patients with malignant gliomas (McCowage et al., 1998). The response rate in that study was 24% (4/17). Similarly, Lachance et al. (1995) had responses in two of 13 glioblastoma multiforme patients treated with high-dose CPA alone in a dose-escalation trial. Together, these results suggest that the combination with VP-16 and VCR in our cohort of patients significantly increased the activity of the regimen. While there were no long-term disease-free survivors in our high-grade astrocytoma cohort, the high response rate demonstrated provides some encouragement. Others have shown high response rates with regimens utilizing stem cell support (Grovas et al., 1999), although their patients experienced significant pulmonary and neurologic toxicities not seen in our patients.

Similarly, the VETOPEC regimen had a high response rate in children with ependymomas. Cisplatin is the only single agent previously shown to have reproducible efficacy with a cumulative response rate of 34% (Grill et al., 2003); we observed responses in six of eight evaluable patients. Trials with high-dose chemotherapy with stem cell rescue have also been conducted previously with poor results. The combination of thiotepa, VP-16, and carboplatin with stem cell rescue showed no CRs or PRs in children with recurrent ependymomas (Mason et al., 1998b).

High-dose CPA has been demonstrated to be effective in newly diagnosed medulloblastoma (Strother et al., 2001). However, for patients with refractory or recurrent tumors, the prognosis remains very poor (Dunkel and Finlay, 2002). Our response rate of 83% is equivalent to or superior to that achieved in other protocols using high-dose chemotherapy in patients who have relapsed. A French group that treated relapsed medulloblastoma patients with busulfan and thiotepa reported a 75% (12/16) response rate (Dupuis-Girod et al., 1996). Similarly, a group of patients treated on the Pediatric Oncology Group protocol with CPA and melphalan had a 50% (4/8) response rate (Mahoney et al., 1996). Patients with recurrent medulloblastoma treated with high-dose carboplatin, thiotepa, and VP-16 with PBSC rescue had a high overall survival and event-free survival of 46% and 34%, respectively, at 36 months. There was, however, significant toxicity with that regimen, with a 14% toxic death rate. The high response rates we have demonstrated in medulloblastoma patients are indicative of the activity of the VETOPEC regimen with minimal associated toxicity.

The prognosis for infants with brain tumors is particularly poor, and the 64% response rate with the VETOPEC-based regimen is demonstrative of its activity. This response rate compares favorably with others. Duffner et al. (1993) reported a 39% response rate in 102 evaluable patients. They described a two-year progression-free survival (PFS) of 39% for patients up to 24 months of age, compared with 11% PFS at 36 months in our cohort of infant patients up to 36 months. Subsequent studies have all shown similar poor survival rates. The "8 in 1" regimen employed by the Children's Cancer Group resulted in a three-year PFS of 22% for infants with medulloblastoma (Geyer et al., 1994). Mason et al. (1998a) used a regimen similar to VETOPEC in the infant population with comparable results. They used a combination of VCR, VP-16, CPA, and cisplatin and reported a three-year overall survival and event-free survival of 40% and 25%, respectively. As a result of these findings, the VETOPEC regimen is being studied further and has been incorporated into the current ANZCCSG infant brain tumor protocol.

Few studies have reached the dose of CPA attained in these patients. Yule et al. (1997) previously treated patients with recurrent brain tumors with escalating cycles of CPA plus PBSC support. They suggested there was a maximal tolerated dose of 3.5 mg/kg per day for two days, equivalent to 210 mg/kg per cycle. However, the cause of death in patients who received the higher doses was not clear. We have shown here that up to 270 mg/kg per cycle of CPA can be safely administered over three days to pediatric brain tumor patients with no significant toxicity and no maximal tolerated dose reached.

Analysis of the subgroup of patients who received stem cell support revealed that it was a safe and effective method of escalating the dose of CPA. We failed to show any increased response with the use of higher doses of CPA, with equivalent CR and PR rates and no improvement in survival. However, there were no toxic deaths among the patients who received stem cell support, as compared with 7% in the remainder. This suggests that the administration of stem cells may have an important protective effect. Similarly, whereas previous studies without PBSC support have shown toxic death rates of 2% to 16%, Strother et al. (2001) found that there were no toxic deaths among their cohort of 50 patients with medulloblastoma who received high-dose CPA with stem cell support.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
References
 
We have shown that the VETOPEC regimen produces high response rates across a heterogeneous group of poor-risk brain tumor patients. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. No toxic deaths were seen in the cohort of patients who were treated with PBSC support. Despite the high activity demonstrated and the lack of toxicity, the overall survival rates remain disappointing. However, the response rates—not only in medulloblastoma and supratentorial PNET but also in high-grade astrocytomas, newly diagnosed ependymomas, and infant brain tumors—are noteworthy. We believe the response rates observed support further development of this chemotherapy regimen. One feasible option to improve the survival may be to combine the VETOPEC chemotherapy regimen with other proven regimens or by alternating it with novel biological agents. We would recommend the further development of the VETOPEC regimen for childhood brain tumors in subsequent clinical trials.


   Acknowledgments
 
We thank Adrian Esterman for his assistance with statistical analysis.


   Footnotes
 
Robert Mrongovius is an employee of Amgen Australia, Pty. Ltd., and a stockholder of Amgen, Inc. Frank Alvaro received a speaking fee in February 2004 at an Amgen-sponsored meeting.

1 This work was supported in part by Schering-Plough, Sydney, Australia, and in part by Amgen Australia. Back

3 Abbreviations used are as follows: ANZCCSG, Australia and New Zealand Children's Cancer Study Group; CPA, cyclophosphamide; CR, complete response; PBSC, peripheral blood stem cell; PFS, progression-free survival; PNET, primitive neuroectodermal tumor; PR, partial response; VETOPEC, vincristine, etoposide, and escalating cyclophosphamide; VP-16, etoposide; VCR, vincristine. Back

Received for publication April 19, 2005. Accepted for publication June 7, 2005.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

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