The use of myelopoietic growth factors in patients receiving chemotherapy as therapy for solid tumors.

Myelosuppression is a common consequence of anti-cancer chemotherapy as a result, patients treated with chemotherapy often present neutropenia, thrombocytopenia and anemia. These complications are associated with potential mortality, definite morbidity, and decreased levels of quality of life that require expensive supportive care. Therefore, prevention of these complications is essential.

Neutropenia is probably the most common complication of chemotherapy, as a result of dose-intensive treatment, which is required for optimal results. Adequate response is definitely needed when the goal of therapy is cure, significant disease – free survival, or neo-adjuvant and adjuvant situations. In other circumstances, the dose of chemotherapy can be reduced to limit the consequence of neutropenia.
When dose-intensity is to be maintained, neutropenia, and its related infectious complications, can be minimized by the use of granulocyte-colony-stimulating factors (G-CSF or its pegylated form). The initial recommendations from ASCO suggest to use G-CSF when the risk of febrile neutropenia (FN) was 40 % or higher. Practically, this means that most patients treated with chemotherapy for solid tumors would not benefit from G-CSF administration, since most chemotherapeutic regimens for solid tumors lead to FN in less than 40 % of the patients. The more recent NCCR guidelines recommend to used G-CSF in all patients with a 20 % risk of FN, and even in patients with a lower risk, if co-morbid factors that increase the risk of complications during FN are present. They also recommend to used G-CSF to prevent FN if the goal of therapy is cure or significant benefit of chemotherapy in terms of survival. Finally, the NCCR endorses the use of secondary prevention of FN, i.e. prevention with G-CSF of FN in patients who already experienced it, during a previous course of a similar chemotherapy, rather than dose-intensity reduction, especially in patients expected to benefit significantly from chemotherapy.
Prophylactic administration of antibiotics can also reduce the risk of fever and infection during neutropenia. The efficacy seems lower than that of G-CSF administration, and, moreover, there is a definite risk of emergence of multi-resistant strains in those patients receiving prophylactic antibiotics.
Besides C-CSF and prophylactic antibiotics, there are no other evidence-based approaches for reducing the infectious complications resulting from chemotherapy-associated neutropenia.
The administration of G-CSF has been also used therapeutically – in combination with antibiotics – in patients with severe, protracted neutropenia and serious infection. A recent meta-analysis suggests that G-CSF administration may reduced mortality under these circumstances.
The use of G-CSF can also allow to collect significant quantities of neutrophils to be transfused to patients with ;refractory infections although this approach is not often used today, it might become more important as fungal infections, resistant to many agents, emerge in patients with severe and protracted neutropenia.

Thrombocytopenia, and the resulting bleeding, is also the result of dose-intensive chemotherapy. The only recognized prophylaxis of this complication has been – until recently – platelets transfusion. However, it is associated with numerous side effects such as infections (mainly transfusion-mediated viral infections), graft versus host disease and allo-immunization. Therefore, the use of platelets transfusion has been usually restricted to conditions such as very severe thrombocytopenia (less than 10.000 per cu mm) or active bleeding in thrombocytopenic patients.
IL-11 and recombinant thrombopoietin have significant action for preventing thrombocytopenia by stimulating megakaryocytopoiesis and platelets formation. Unfortunately, thrombopoietin has led, in some cases, to refractory immune-thrombocytopenia and is therefore no longer used.
More recently, a new preparation consisting of a megakaryopoiesis protein (AMG 541) has been developed and investigated in phase 1 and 2 trials. This promising molecule might help, in the future, with the prevention and management of thrombocytopenia in intensively treated patients.

Anemia in chemotherapy-treated patients is usually less acute then neutropenia or thrombocytopenia, unless there is brisk bleeding or acute hemolysis.
On the other hand, chronic anemia is very common and causes various symptoms among which fatigue is probably the most frequent. Chronic anemia can result from chemotherapy-induced myelosuppression but other causes are involved as well : iron and folate deficiencies, micoangiopathic anemia, disseminated intravascular coagulation and chronic anemia associated with cancer. Provided the patients has a sufficient reserves of iron, erythropoietin and also its pegylated form, is highly effective to correct chronic anemia associated with cancer. It clearly reduces the need for transfusions and their associated complications. Moreover, it improves very significantly the overall quality of life and significantly diminishes fatigue. The correction of anemia might also improve the results of radiotherapy in patients with lead and neck and cervical carcinomas.

Overall, the use of myelopoietic growth factors has considerably improved the safety of chemotherapy and has been responsible for a very significant improvement in the quality of life in chemotherapy-treated patients.