Highdose chemotherapy HDC with haematopoietic support

In the clinic, dose escalation within a 'conventional' range has an inconsistent effect on response rates, and with some exceptions, a negligible survival impact. Clinical dose escalation is complicated by a greatly increased toxicity, seen when these relatively non-specific toxins are administered to patients. Substantial advances in haematopoietic support have allowed investigation of very high doses of chemotherapy in the clinic. Autografting, using either autologous marrow or cytokine-mobilized peripheral blood progenitors, is seen to facilitate administration of very high doses of those drugs dose-limited by myelosuppression.

'High-dose chemotherapy' (HDC) is therapy administered in doses clearly outside the standard range and which, with exceptions, require some form of haematopoietic cellular support (some drugs, e.g. cyclophosphamide and etoposide are stem-cell sparing, and it is pos sible to administer them with growth factors as sole support). For drugs primarily dose-limited by myelosuppression, haematopoietic support allows the clinician to mimic the extreme dose escalation studied in the laboratory. Thus, thiotepa can be dose escalated by 30-40-fold, carboplatin by 4-6-fold, etc.

In early studies of HDC with bone marrow autograft support, high rates of objective response were seen in patients with chemotherapy-resistant lymphomas and solid tumours. Toxicity was also formidable, and up to 20% of patients so-treated died from complications of therapy, especially from infections during the prolonged neutropenic phase that inevitably occurred, and also from organ-failure syndromes.

The introduction of the haematopoietic growth factors changed high-dose chemotherapy. Administration of these cytokines following bone marrow re-infusion resulted in a dramatic abbreviation of duration of neutropenia. It was also discovered that administration of these factors, either at steady state or following myelosuppressive chemotherapy, resulted in mobilization of haematopoietic progenitors from the bone marrow into the peripheral blood. These 'peripheral blood progenitors' (PBP) could be harvested by leuco-pheresis, then re-infused as haematopoietic rescue following subsequent HDC. PBP autografting is superior to marrow autografting, with shortened neutropenia and thrombocytopenia, and reduced mortality and morbidity.

Historically, HDC has generally been given as a form of consolidation following conventional chemotherapy. Less frequently, it has been studied as primary treatment. It can be administered in single or in multiple cycles.

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