The optimal use of granulocyte macrophage colony stimulating factor in radiation induced mucositis in head and neck squamous cell carcinoma.

OBJECTIVE: Evaluation of response of granulocyte macrophage colony stimulating factor (GM-CSF) on acute radiation toxicity profile in head and neck squamous cell carcinoma. METHODS AND MATERIALS: Thirty three patients with proven stage I or II head &neck carcinoma received conventional external beam radiation therapy. Out of these, six patients received postoperative adjuvant therapy while remaining 27 received definitive RT. Patients were given 100 mcg GM-CSF subcutaneously per day along with radiation after they developed grade 2 mucositis and /or grade 2 dysphagia and / or complained of moderate pain. GM-CSF was administered till there was a subjective relief or objective response. Patients were evaluated for oral ulceration, swallowing status, pain and weight loss. Response to the treatment and patient outcome was assessed. RESULTS: There was a decreased severity of mucositis and dysphagia in the evaluated patients. None of the patients suffered severe pain or required opioids. The mean weight loss was only 1.94%. Minimal side effects were experienced with GM-CSF. CONCLUSIONS: GM-CSF reduces the severity of acute side effects of radiation therapy thereby allowing completion of the treatment without interruption. Its remarkable response needs to be evaluated further in large randomized trials. The time of initiation and cessation of GM-CSF during radiation therapy and the required dose needs to be established.

Increased levels of multiple forms of dihydrofolate reductase in peripheral blood leucocytes of cancer patients receiving haematopoietic colony-stimulating factors: interim analysis

The precise mechanism whereby granulocytes proliferate when haematopoietic colony stimulating factors (CSFs) are used in neutropenic cancer patients is poorly understood. The purpose of this study was to investigate whether these cytokines bring about leucocyte proliferation by increasing the levels of multiple forms of dihydrofolate reductase (DHFR). Blood samples were collected from 36 cancer patients (25 males and 11 females) with chemotherapy-induced neutropenia. One sample of blood from each patient was obtained before therapy either with CSF, such as granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) or with placebo, and another one at the time of resolution of neutropenia. Peripheral blood leucocytes in these blood samples were counted, separated and lysed. From lysates, cytoplasmic samples were prepared and analyzed for active DHFR by a methotrexate-binding assay and for total immunoreactive DHFR by an enzyme linked immunosorbent assay. The increase in total leucocyte count (TLC) was most prominent (P < 0.005) in the CSF group and less so (P < 0.05) in the placebo group. The mean +/- SD concentration values of active DHFR before and after stimulation with GM-CSF found were to be 0.34 +/- 0.4 ng/mg protein and 0.99 +/- 0.82 ng/mg protein, respectively, and in the group treated with G-CSF, 0.24 +/- 0.32 ng/mg protein and 1.18 +/- 2.4 ng/mg protein, respectively. This increase in active DHFR after stimulation with CSF was statistically significant (P <0.05). Similarly, concentration values of immunoreactive but nonfunctional form of DHFR (IRE) were 110 +/- 97 ng/mg protein and 605 +/- 475 ng/mg protein before and after stimulation with GM-CSF, and 115 +/- 165 ng/mg protein and 1,054 +/- 1,095 ng/ mg protein before and after stimulation with G-CSF. This increase in concentration of IRE after stimulation with GM-CSF or G-CSF was statistically significant (P < 0.005). In the control group, there was an increase in the concentration of both active DHFR and IRE after treatment with placebo. However, this was not statistically significant. Resolution of neutropenia was quicker in the groups treated with CSF compared to the control group. Results of this study indicate that colony stimulating factors (G-CSF and GM-CSF) induce white cell proliferation by increasing the levels of multiple forms of DHFR.

Neutrophil recovery time and adverse side effects in acute leukemia patients treated with intensive chemotherapy and concomitant G or GM-CSF

Objetivo. Comparar la velocidad de recuperación de neutrófilos y los efectos secundarios indeseables en dos grupos de pacientes con leucemia aguda con quimioterapia intensiva y factor estimulante de colonias de granulocitos (G-CSF) o de granulocitos y macrófagos (GM-CSF). Pacientes y métodos. Los pacientes fueron asignados de manera aleatoria para recibir, por vía subcutánea y junto con el inicio de la quimioterapia, G-CSF 300 µg en adultos y 150 µg en niños o GM-CSF 400 y 200 µg, respectivamente. Los factores se administraron hasta que la cuenta total de neutrófilos alcanzó 500/µL. Los efectos secundarios fueron atribuidos a los factores sólo cuando no fueron coincidentes con infección, quimioterapia o transfusión de hemoderivados. Resultados. Se incluyeron 34 pacientes con G-CSF y 37 con GM-CSF. La distribución por sexo, edad, tipo de leucemia, tipo de quimioterapia recibida (inducción o postinducción), cifra inicial de leucocitos y plaquetas fue similar entre los dos grupos. El tiempo promedio para alcanzar 500 neutrófilos/µL fue 19 días para el grupo de G-CSF y 16 días para el grupo de GM-CSF (p=0.08). No existieron diferencias estadísticamente significativas entre los efectos secundarios indeseables de los dos grupos. Se registraron dos casos de fiebre asociada a G-CSF y 5 a GM-CSF (p=0.25). Hubo un caso de reacción sistémica en el grupo G-CSF. Veintinueve pacientes de cada grupo presentaron episodios de neutropenia febril (p=0.45). El único factor que mostró influencia significativa en la velocidad de recuperación de neutrófilos fue el tipo de leucemia, siendo más rápido en el caso de leucemia aguda linfoblástica (p=0.04). Conclusiones. No encontramos diferencias significativas entre los dos factores para esta indicación

A Role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in the treatment of neutropenic patients with pneumonia

Pneumonia is a serious, difficult to manage, and often fatal infection in neutropenic patients. The availability of hematopoietic growth factors has made it possible to evaluate the role of reversing the neutropenic state. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used in an investigator-initiated, open-label clinical trial in approximately 1200 patients. Data colleted on each patient was reviewed to identify all patients who had the combination of neutropenia and pneumonia. Sixty-eight patients (5 percent of the patients for whom GM-CSF was requested) met the criteria for having neutropenic peneumonia. In this patient population there were 45 males and 20females (gender was not indicated in 3). Ages ranged from 3 to 83 years (mean 39 ñ 18 years). The underlying diseases included: 7 patients who were receiving chemotherapy for solid malignant tumors, 14 for lymphoma, and 22 for leukemia; 15 post bone marrow transplantation primarily for hematologic malignancy; 3 idiosyncratic drug-induced neutropenia; and 7 with other causes of neutropenia. The type of pneumonia was predominantly fungal in 21 patients, bacterial in 23, viral in 2, protozoal in 1, and uncertain in 21 (presumed to be bacterial in 19 and viral in 2). Patients received a mean of 5µg/kg GM-CSF (range 1.3-12.5µg/kg) daily for a mean of 13 ñ 10 (range 2-57) days. The mean leukocyte count at start of treatment was 600 ñ 500 cells/mmü, and at the end of treatment was 5600 ñ 9200 cells/mmü (P=0.001). The time between start of GM-CSF and a leukocyte level in excess of 1500/mmü was a median of 13 days. Hematopoietic recovery was showm in 46/62 (74 percent), 40/64 (63 percent) showed good clinical and/or radiologic improvement, and 41/68 (60 percent) survived. Four illustrative case reports are provided. By comparing the hematologic responders to non-responders, it is clear that persistent neutropenia contributed significantly to poor clinical outcome and mortality. Only 3/22 (13 percent) of non-responders survived, whereas 38/46 (83 percent) of responders survived. There were 7 adverse events (rash 1, fever/chills 2, malaise 1, myalgia/bone pain 2, increased myeloblasts 1) which were considered to be related to use of the cytokine. Aggravation of the pulmonary inflammation or sepis syndrome was not observed. Tolerability was good or very good in 89 percent of patients. Based on this open-label study, the use of GM-CSF in combination with appropiate antibiotics ...