Abstract
Background: GOLFIG is a chemo-immunotherapy regimen established in preclinical models that combines gemcitabine + FOLFOX (fluoropyrimidine backbone coupled to oxaliplatin) poly-chemotherapy with low-dose s. c. recombinant interleukin-2 (rIL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF). Promising antitumor effects in metastatic colorectal cancer (mCRC) patients were obtained in previous phase II and III trials. Here we report the results of 15 years of follow-up.Methods: This is a multi-institutional retrospective analysis including 179 mCRC patients receiving GOLFIG regimen between June 2002 and June 2018. Sixty-two of them received the treatment as frontline (enrolled in the GOLFIG-2 phase III trial) and 117 as second/third line (49 enrolled in the GOLFIG-1 phase II trial and 68 as compassionate use). One hundred twelve patients showed a primary left side and 67 a primary right side; K/N-ras mutational status was available in 74 cases, and an activating mutation was detected in 33. Kaplan–Meier and Cox regression analyses were carried out to relate PFS and OS with different parameters.Results: Overall, we recorded a mean PFS and OS of 15.28 (95% CI: 10.36–20.20) and 24.6 (95% CI: 19.07–30.14) months, respectively, with 14 patients surviving free of progression for 10 years. This regimen, in our updated survey of the GOLFIG-2 trial, confirmed superiority over FOLFOX in terms of PFS (hazard ratio (HR) = 0.58, p = 0.006) with a trend to a longer OS (HR = 0.69, P = 0.06) in the first line. Our analysis also confirmed significant antitumor activity in pre-treated patients, reporting a mean PFS and OS of 12.55 (95% CI: 7.19–17.9) and 20.28 (95% CI: 14.4–26.13) months, respectively. Immune-related adverse events (irAEs) were recorded in 24% of the cases and were related to a longer survival (HR = 0.36; P = 0.0001). Finally, patients' outcome was not correlated to sex, sidedness, and MT-K/N-ras.Conclusions: The GOLFIG regimen is a reliable underestimated therapeutic option in pre-treated mCRC patients and offers a strong rationale to design further trials.
Highlights
Colorectal carcinoma (CRC) is one of the leading causes of cancer-related deaths worldwide [1]
GOLFIG is a chemo-immunotherapy regimen established in preclinical models that combines gemcitabine + FOLFOX poly-chemotherapy with low-dose s. c. recombinant interleukin-2 and granulocyte-macrophage colony stimulating factor (GM-CSF)
An alternative use of these regimens is recommended in the second line with no real difference in terms of outcome, with the only exception of the regimen of FOLFIRI and aflibercept, an anti-angiogenetic recombinant protein able to trap VEGF A/B and the placental growth factor (PlGF), which showed an advantage over chemotherapy alone in terms of response rate (RR) (19.8 vs. 11.1%; P = 0.0001), PFS [6.90 vs. 4.67 months; hazard ratio (HR) = 0.758; IC95% 0.661–0.869; P < 0.0001], and OS (13.50 vs. 12.06 months; HR = 0.817; IC34% 0.713– 0.937; P = 0.032)
Summary
Colorectal carcinoma (CRC) is one of the leading causes of cancer-related deaths worldwide [1]. An alternative use of these regimens is recommended in the second line with no real difference in terms of outcome, with the only exception of the regimen of FOLFIRI and aflibercept, an anti-angiogenetic recombinant protein able to trap VEGF A/B and the placental growth factor (PlGF), which showed an advantage over chemotherapy alone in terms of response rate (RR) (19.8 vs 11.1%; P = 0.0001), PFS [6.90 vs 4.67 months; hazard ratio (HR) = 0.758; IC95% 0.661–0.869; P < 0.0001], and OS (13.50 vs 12.06 months; HR = 0.817; IC34% 0.713– 0.937; P = 0.032) The latter regimen, is reserved for fit patients since it is associated with potentially severe adverse events including bleeding, hypertension, infections, and gastroenteric and hematological toxicity in almost 30% of the patients who refuse to continue the treatment [6, 7]. We report the results of 15 years of follow-up
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