Toxicity of the high-dose chemotherapy CTC regimen (cyclophosphamide, thiotepa, carboplatin): the Netherlands Cancer Institute experience

Abstract

High-dose chemotherapy (HD-CT) has a role in the potentially curative treatment of several tumours. The relative efficacies of the different regimens have not been studied in comparative trials, but it is clear that toxicities differ significantly between them. We analysed the immediate and long-term toxicity in the first 100 consecutive patients treated with the CTC regimen (cyclophosphamide 6000 mg m À2 , carboplatin 1600 mg m À2 (or 20 mg ml À1 min under the curve (AUC)) both as daily 1 h infusion, thiotepa 480 mg m À2 as twice daily 30 min infusion, all divided over 4 consecutive days) followed by peripheral blood progenitor cell reinfusion (PBPC-Tx). Most patients had high-risk (n ¼ 86) or metastatic (n ¼ 4) breast cancer, or a germ cell tumour (n ¼ 8). Two patients (with a medulloblastoma and an aesthesioneuroblastoma, respectively) received CTC as off-protocol salvage regimen. The main toxicity was bone marrow suppression. Most patients had PBPC-Tx with granulocyte colony-stimulating factor (G-CSF), and the median time to neutrophil count 500 Â 10 6 l À1 and platelet count 420 Â 10 9 l À1 without transfusion independence was 10 (range 8 -25) and 13 (8 -60) days, respectively. The toxic death rate was 1%. Other frequent toxicities were neutropenic fever requiring antibiotics (n ¼ 65), central catheter-related infection (n ¼ 12) or a bleeding episode (n ¼ 48), mostly epistaxis (n ¼ 26). Reversible cardiac toxicity was seen in six patients and pulmonary events occurred in seven patients (infection (n ¼ 6), embolism (n ¼ 1)). Grade 3 -4 gastrointestinal toxicity was frequent: nausea and vomiting 55%, diarrhoea 28% and mild liver toxicity (transaminase elevations) 9%. One patient pretreated with cisplatin had a kidney transplantation 8 years after HD-CT. Late complications included reversible radiation pneumonitis (n ¼ 12) and chronic heart failure (n ¼ 2). We found five second solid malignancies and two myelodysplasias. In conclusion, the CTC regimen is associated with a moderate, mainly reversible, toxicity. Future studies need to compare the efficacy and toxicity of the different HD-CT regimens.

Pegase 03: a prospective randomized phase III trial of FEC with or without high-dose thiotepa, cyclophosphamide and autologous stem cell transplantation in first-line treatment of metastatic breast cancer

“…15 However, although there is evidence that HDC per se is associated with greater mortality and morbidity than are conventional regimens, it seems that the toxicities differ significantly between the various regimens. 22 With regard to DFS and OS, our results are similar to those reported in the other six randomized trials of HDC with PBSC support used for the treatment of metastatic breast cancer. 18,[23][24][25][26][27] These six trials, plus interim results from Pegase 03, have been discussed in reviews.…”

Early reduction in left ventricular contractile reserve detected by dobutamine stress echo predicts high-dose chemotherapy-induced cardiac toxicity

“…It is characterized by increased doses of chemotherapeutic drugs, shorter time intervals between drugs administration, and a combination of different agents. However, HDC positive clinical effects are counterbalanced by an increased risk of acute and long-term toxicity in several organs [1][2][3][4]. While acute bone marrow toxicity can now be largely overcome by hematological growth factors, stem cell infusion, and appropriate supportive care, prevention of long-term toxic effects remains a challenge.…”

Cardiac complications in patients undergoing a reduced-intensity conditioning hematopoietic stem cell transplantation

“…2–6 In spite of restricting HSCT to generally younger and healthier patients some series reported the incidence of cardiac complications as high as 43%, resulting in mortality rates of 9%. 6–9 Cardiovascular events after myeloablative allogeneic HSCT are primarily associated with the use of high-dose CY in the conditioning regimen. 9–13 Dose reductions or replacement of high-dose CY with another immunosuppressive agent in conditioning regimens has led to a lower incidence of cardiac toxicity, but toxic deaths are still being reported.…”

“…6–9 Cardiovascular events after myeloablative allogeneic HSCT are primarily associated with the use of high-dose CY in the conditioning regimen. 9–13 Dose reductions or replacement of high-dose CY with another immunosuppressive agent in conditioning regimens has led to a lower incidence of cardiac toxicity, but toxic deaths are still being reported. 11–14 …”