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Gemcitabine, Oxaliplatin, Levofolinate, 5-Fluorouracil, Granulocyte-Macrophage Colony-Stimulating Factor, and Interleukin-2 (GOLFIG) Versus FOLFOX Chemotherapy in Metastatic Colorectal Cancer Patients: The GOLFIG-2 Multicentric Open-label Randomized Phase III Trial

Correale, Pierpaolo*; Botta, Cirino; Rotundo, Maria S.; Guglielmo, Annamaria; Conca, Raffaele§; Licchetta, Antonella§; Pastina, Pierpaolo*; Bestoso, Elena*; Ciliberto, Domenico; Cusi, Maria G.; Fioravanti, Antonella; Guidelli, Giacomo M.; Bianco, Maria T.#; Misso, Gabriella**; Martino, Elodia*; Caraglia, Michele**; Tassone, Pierfrancesco†,††; Mini, Enrico‡‡; Mantovani, Giovanni§§; Ridolfi, Ruggero∥∥; Pirtoli, Luigi*; Tagliaferri, Pierosandro

doi: 10.1097/CJI.0000000000000004
Clinical Studies

The GOLFIG-2 phase III trial was designed to compare the immunobiological activity and antitumor efficacy of GOLFIG chemoimmunotherapy regimen with standard FOLFOX-4 chemotherapy in frontline treatment of metastatic colorectal cancer (mCRC) patients. This trial was conceived on the basis of previous evidence of antitumor and immunomodulating activity of the GOLFIG regimen in mCRC. GOLFIG-2 is a multicentric open/label phase III trial (EUDRACT: 2005-003458-81). Chemo-naive mCRC patients were randomized in a 1:1 ratio to receive biweekly standard FOLFOX-4 or GOLFIG [gemcitabine (1000 mg/m2, day 1); oxaliplatin (85 mg/m2, day 2); levofolinate (100 mg/m2, days 1–2), 5-fluorouracil (5-FU) (400 mg/m2 in bolus followed by 24 h infusion at 800 mg/m2,days 1–2), sc. GM-CSF (100 μg, days 3–7); sc. aldesleukin (0·5 MIU bi-daily, days 8–14 and 17–30)] treatments. The study underwent early termination because of poor recruitment in the control arm. After a median follow-up of 43.83 months, GOLFIG regimen showed superiority over FOLFOX in terms of progression-free survival [median 9·23 (95% confidence interval (CI), 6·9–11.5) vs. median 5.70 (95% CI, 3.38–8.02) months; hazard ratio (HR): 0.52 (95% CI, 0.35–0.77), P=0·002] and response rate [66.1% (95% CI, 0.41–0.73) vs. 37·0% (95% CI, 0.28–0.59), P=0.002], with a trend to longer survival [median 21.63 (95% CI, 18.09–25.18) vs. 14.57 mo (95% CI, 9.07–20.07); HR: 0·79 (95% CI, 0.52–1.21); P=0.28]. Patients in the experimental arm showed higher incidence of non-neutropenic fever (18.5%), autoimmunity signs (18.5%), an increase in the number of monocytes, eosinophils, CD4+ T lymphocytes, natural killer cells, and a decrease in immunoregulatory (CD3+CD4+CD25+FoxP3+) T cells. Taken together, these findings provide proof-of-principle that GOLFIG chemoimmunotherapy may represent a novel reliable option for first-line treatment of mCRC.

*Radiotherapy Unit

§Medical Oncology Unit, Department of Oncology, Microbiology Section

Department of Biotechnology

Rheumatology Unit, Department of Medicine

#Pharmacy Unit, Siena University Hospital “Santa Maria alle Scotte”, Istituto Toscano Tumory, Siena

Medical Oncology Unit

Department of Legal, Historical, Economic and Social Sciences-DSGSES, Magna Graecia University of Catanzaro

††Translational Medical Oncology Unit, “Magna Graecia” University and “Tommaso Campanella” Cancer Center, Campus “Salvatore Venuta,” Catanzaro

**Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples

‡‡Chemotherapy Unit, Department of Oncology, Florence University School of Medicine, Florence

§§Medical Oncology Unit, Department of Oncology, Cagliari University School of Medicine, Cagliari

∥∥Medical Oncology Unit, Centro Oncologico Romagnolo, Forlì, Italy

Reprints: Michele Caraglia, Department of Biochemistry and Biophysics, Second University of Naples, Via Costantinopoli 16, Naples 80138, Italy. E-mail: michele.caraglia@unina2.it or michele.caraglia@alice.it.

Received January 17, 2013

Accepted October 3, 2013

© 2014 by Lippincott Williams & Wilkins