Prophylactic Colony Stimulating Factors: GCSF - GMCSF (Systemic)

Prophylactic Colony Stimulating Factors: GCSF - GMCSF (Systemic)

PEP Topic 
Mucositis
Description 

Granulocyte (G-CSF) and granulocyte-macrophage stimulating factors (GM-CSF) are substances that bind to hematopoietic stem cells, activating them to profliferate and differentiate into granulocytes and macrophages – the specific cell type of interest. Colony-stimulating factors administered systemically have been evaluated and recommended for patients with cancer for the prevention of infection and febrile neutropenia. CSFs may be used for primary or secondary prophylaxis. In primary prophylaxis, CSFs are administered with the first course of chemotherapy in order to prevent neutropenic sequelae. In secondary prophylaxis, CSFs are used for patients who had febrile neutropenia or infections during a prior course of therapy provided without CSF prophylaxis. NCCN, the American Society of Clinical Oncology, and the European Oncology Research and Treatment  groups all have guidelines regarding the use of prophylactic colony-stimulating factors.

Effectiveness Not Established

Research Evidence Summaries

Cawford, J., Tomita, D.K., Mazanet, R., Glaspy, J., & Ozer, H. (1999). Reduction of oral mucositis by filgrastim (r-metHuG-CSF) in patients receiving chemotherapy. Cytokines, Cellular and Molecular Therapy, 5(4), 187–193.

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Intervention Characteristics/Basic Study Process:

G-CSF 230 mcg/m2 given days 4–17 unless the post-nadir neutrophil count exceeded 10x109/1 after day 12. Treatment repeated every 21 days for up to six cycles of chemotherapy (cyclophosphamide, doxorubicin, and etoposide).
Control was placebo injection.
Patients in the placebo group crossed over to G-CSF after episode of febrile neutropenia.

Sample Characteristics:

The study was comprised of 199 patients, of the 211 patients who had enrolled.
G-CSF = 95
Placebo = 101
Small-cell lung cancer

Setting:

Multicenter

Study Design:

Randomized, prospective, control phase III trial

Measurement Instruments/Methods:

Febrile neutropenia was the primary endpoint. Also looked at infectious complications and oral mucositis.
WHO scale
Oral candidiasis included as mucositis incidence, severity, and time to onset.
Duration of mucositis was determined by a combination of patient reporting and clinical examination findings.
 

Results:

54% versus 72% episode of mucositis in G-CSF versus placebo group. Most episodes were grade I–II. Median duration of mucositis was the same for both groups (eight days).
First-cycle mucositis: 28% versus 47% (p = 0.041)
 

Limitations:

Difficult to determine some results because of cross-over nature of study. Also allowed dose reduction in treatment group, which decreased mucositis; confounding results.

Nursing Implications:

Trials with nonmyelosuppressive therapy are needed to determine effect.

McAleese, J.J., Bishop, K.M., A’Hern, R., & Henk, J.M. (2006). Randomized phase II study of GM-CSF to reduce mucositis caused by accelerated radiotherapy of laryngeal cancer. British Journal of Radiology, 79(943), 608–613.

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Intervention Characteristics/Basic Study Process:

GM-CSF 2 mcg/kg (-1) (150 mcg) daily for 14 days starting on day 14 of a 21-day course of RT.

Note: Placebo injections were not given; observer was blinded to treatment.

Sample Characteristics:

The study was comprised of 29 patients (GM-CSF = 14).

Power analysis was completed, but not met (n = 17 in each group).

Patients with proven T1 N0 or T2 N0 glottic carcinoma were being treated with radiotherapy using a 16 fraction 3-week regimen.

Required to have a WHO performance status of grade 0 or higher, no renal or hepatic issues, serious infections requiring antibiotics, or likely need for corticosteroids.
 

Study Design:

Prospective, randomized, observer blind phase II trial

Measurement Instruments/Methods:

  • RTOG
  • Skin erythema
  • Moist and dry desquamation
  • Pain on swallowing
  • Severity of dysphagia
  • Analgesic usage
  • Evidence of candida infection and laryngeal edema
  • Patients weights before and after treatment
     

Results:

Significant difference in the incidence of mucositis p < 0.05, mean time of healing improved but not significant p = 0.25.
No differences in dysphagia, odynophagia, analgesic use, candida infection, of laryngeal edema.
 

Limitations:

  • Study sample size was very small.
  • Only used for early treatment of laryngeal cancer with radiotherapy using 16 fraction 3-week regimen.
  • Frequent side effects related to GMCSF
  • No large trials have been conducted.
     

Rossi, A., Rosati, G., Colarusso, D., & Manzione, L. (2003). Subcutaneous granulocyte–macrophage colony-stimulating factor in mucositis induced by an adjuvant 5-fluorouracil plus leucovorin regimen. Oncology, 64(4), 353–360.

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Intervention Characteristics/Basic Study Process:

GMCSF subcutaneously
(4 mcg/kg) from days 6-10 during cycle following the cycle Grade >2 mucositis was reported.

Also received “standard” anti-mucositis treatment

Sample Characteristics:

The study was comprised of 31 patients, age 39-77 years with a median age of 68.
Three stage phase II trial
Colorectal cancer treated with 5FU plus leucovorin and reporting mucositis > Grade 2.
 

Measurement Instruments/Methods:

Chen design
WHO Mucositis – 3x/wk:

Grade 0 = none

I = painless ulcers, erythema, or mild soreness
2 = painful erythema, edema, or ulcers
3 = can’t eat solids
4 = TPN or enteral support
 

Results:

77 GM-CSF cycles were administered (median/pt = 3).

Success claimed based on reduction of at least one grade of mucositis.

9 of 20 responders mucositis disappeared – 64.5%

45% with mucositis responded, 12.9% failure, 3.2% stopped treatment
3.2 % (1 patient) with mucositis plus diarrhea responded, 3.2% treatment failure, 3.2% stopped treatment

Toxicity in 7 of 20 patients

 

Conclusions:

Claim results are rationale for well-designed trial

Limitations:

No control group
Small N
No P values stated percentages hard to follow.

Ryu, J.K., Swann, S., LeVeque, F., Scarantino, C.W., Johnson, D., Chen, A., et al. (2007). The impact of concurrent granulocyte macrophage-colony stimulating factor on radiation-induced mucositis in head and neck cancer patients: A double-blind placebo-controlled prospective phase III study by Radiation Therapy Oncology Group 9901. International Journal of Radiation Oncology, Biology, Physics, 67(3), 643–650.

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Intervention Characteristics/Basic Study Process:

Subcutaneous GM-CSF (250 mcg/m2) was started one week before radiation and stopped two weeks after completion. GM-CSF was given within two hours after each radiation fraction on Monday, Wednesday, and Friday. Doses were held on days that patients received chemotherapy.

Sample Characteristics:

Patients with head and neck cancer with radiation ports on 50% or more of oral cavity or oropharynx to 60-70 Gy.

GM-CSF: n = 63
Placebo: n = 58

Setting:

October 2000-September 2002
 

Measurement Instruments/Methods:

  • CTC acute toxicity scale
  • Severity and duration of mucositis
  • Quality of life (QOL): University of Washington Head and Neck symptom questionnaire
     

Results:

No statistical differences in mucositis or QOL scores

Limitations:

Some participants discontinued study because of unspecified “toxicity”. Drug supply ended before all patients completed therapy.


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