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Camptothecin Analogues, Combined with Cyclophosphamide, Have Potential Role in Treatment of Resistant Neuroblastoma

The addition of camptothecin analogues to high-dose cyclophosphamide shows modest activity and tolerable morbidity in patients with relapsed or refractory neuroblastoma, according to an American retrospective study. Furthermore, this combination may be a good preparative regimen for passive immunotherapy with monoclonal antibodies.

Camptothecin analogues, such as topotecan and irinotecan, are highly active against resistant neuroblastoma cells in vitro and have a manageable and transient nonhaematological toxicity profile. Studies have also suggested that these agents can be safely given with other anticancer drugs. The use of camptothecin analogues, therefore, has great promise in the treatment of neuroblastoma.

Brian H. Kushner, MD, and colleagues at the Memorial Sloan-Kettering Cancer Centre, New York, United States, evaluated the use of high-dose cyclophosphamide plus topotecan/vincristine (CTV) or irinotecan (C/I) in patients with resistant neuroblastoma.

The study included 55 patients with relapsed or refractory neuroblastoma who had previously received topotecan, a haemopoietic stem-cell transplant, and/or high-dose cyclophosphamide.

All patients were treated with cyclophosphamide (70 mg/kg) on days 1 and 2. Furthermore, 29 patients received topotecan (2 mg/m²) on days 1 to 4 and vincristine (0.067 mg/kg) on day 1; and 26 patients were given irinotecan (50 mg/m²) on days 1 to 5. Mensa (70 mg/kg) and granulocyte colony-stimulating factor were also used.

Both regimens resulted in a similar prolonged duration of grade 4 myelosuppression.

Specifically, the absolute neutrophil count was below 500 cells/µLfor 5-12 days in patients who had not received haemopoietic stem-cell transplants and for 7 to 21 days in post-transplant patients. Furthermore, platelet counts recovered above 75,000 cells/µL for 21 to 28 days and 17 to 40 days in these respective groups.

Blood-borne bacterial infections were identified in 14.5% of patients, and led to death from septic shock in 1 case. Suspected typhlitis occurred in 5.5% of patients. Two other patients showed clinical signs of sepsis and pneumonia, respectively.

One CTV-treated patient had grade 3 generalised pain attributable to vincristine, and 1 C/I-treated patient developed haemorrhagic cystitis. All other toxicities were grade 2 or lower, including 3 cases of grade 2 mucositis that only occurred in CTV-treated patients.

Overall, 15% of CTV-treated patients and 17% of C/I-treated patients with assessable disease achieved a partial response or better. Moreover, bone marrow disease resolved in 28% and 27%, respectively.

Furthermore, passive immunotherapy with the murine anti-GD2 monoclonal antibody 3F8 was possible after chemotherapy in 45% of CTV-treated patients and in 27% of C/I-treated patients. These patients did not develop persistent human anti-mouse antibody, consistent with the desired immunosuppressive effect of high-dose cyclophosphamide.

The authors conclude that "CTV and C/I have modest anti-neuroblastoma activity in heavily treated patients, immunomodulatory effects conducive to antibody-mediated immunotherapy, and modest toxicity to major nonhaematological organs."

Clin Cancer Res 2004 Jan 1;10:1:84-7. "Camptothecin Analogs (Irinotecan or Topotecan) plus High-Dose Cyclophosphamide as Preparative Regimens for Antibody-Based Immunotherapy in Resistant Neuroblastoma"

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