Timmer-Bonte, J.N., Punt, C.J., vd Heijden, H.F., van Die, C.E., Bussink, J., Beijnen, J.H., . . . Tjan-Heijnen, V.C. (2008). Prophylactic G-CSF and antibiotics enable a significant dose-escalation of triplet-chemotherapy in non-small cell lung cancer. Lung Cancer, 60, 222–230.

The purpose of the study was to establish the maximum-tolerated dose of paclitaxel and investigate whether prophylactic G-CSF and antibiotics would allow further dose escalation of paclitaxel in treatment-naïve patients.

Doses were given in increasing increments to groups of three patients to determine dose-limiting toxicity (DLT). Part A: Paclitaxel escalation without prophylactic G-CSF (unless DLT from neuropathy). Part B: Level 7 etoposide administered with G-CSF. Part C: Same as part B plus prophylactic antibiotics (ciprofloxacin and roxithromycin). With a hematologic toxicity recovery to CTC less than 3, a subsequent cycle was allowable with a max delay of two weeks. Dose reduction was given if grade 2 CTC hematologic toxicity persisted after a two-week delay and/or there was a greater than grade 2 nephro- or neurotoxicity.

• 47 participants were included in the study.
• Age range was 32–74 years.
• 31.9% were women; 68.1% were men
• Non-small cell lung cancer: squamous cell carcinoma (n = 20), adenocarcinoma (n = 18), other (n = 9)
• World Health Organization performance status 0 (n = 13), 1 (n = 29), 2 (n = 3), unknown (n = 2)
• Stage IIIA (n = 13), IIIB (n = 9), and IV (n = 25).

Single-site outpatient setting in the Netherlands.

Active treatment

Prospective dose-finding study.

• Dose-limiting toxicity: defined as granulocytes less than 0.5×10⁹/L lasting for seven days or more, granulocytes less than 0.5×10⁹/L, fever of 38.5ºC or higher, platelet count less than 25×10⁹/L, and any toxicity higher than grade 2 (with the exception of nausea/vomiting responsive to treatment) occurring during the first cycle
• Blood cell counts: WBC, ANC, platelets, hemoglobin
• Adverse events: fever, polyneuropathy, anorexia, nausea, vomiting, diarrhea, cardiac, asthenia, hemorrhage, electrolyte disorder, hematologic toxicity
• Infections
   

In total, 189 cycles of chemotherapy were administered. Forty-three of the 47 patients enrolled survived treatments. Thirty-four completed the full protocol (febrile neutropenia or dose delays from toxicity were the main reasons for incomplete cycles).

The use of G-CSF and antibiotics allows for higher chemotherapy doses in patients with stage IIIA, IIIB, and IV non-small cell lung cancer, which could increases survival.

• Small sample (less than 100 participants)
• The findings circumvent details about survival time in the patients who received G-CSF and prophylactic antibiotics allowing for higher chemotherapy doses; therefore, it is unknown if the patients who survived the longest were the recipients of the higher chemotherapy doses with G-CSF and antibiotics, which was the goal of the study.
   

The administration of G-CSF and prophylactic antibiotics may reduce neutropenia and infections increasing the DLT, allowing for higher doses of chemotherapy for better chance of prolonged survival. However, research in this area needs further exploration.