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FOLFIRI & Cetuximab

FOLFIRI & Cetuximab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Cetuximab

Regimen

FDA-recommended dose

Study

Dates of enrollment

Evidence

Comparator

Comparative Efficacy

Van Cutsem et al. 2009 (CRYSTAL)

ESMO-MCBS (4)

2004-07 to 2005-11

Phase 3 (E-RT-esc)

FOLFIRI

Superior OS¹ (secondary endpoint)
Median OS: 23.5 vs 19.5 mo
(HR 0.81, 95% CI 0.69-0.94)

Heinemann et al. 2014 (FIRE-3)

2007-2012

Phase 3 (E-switch-ooc)

FOLFIRI & Bevacizumab

Did not meet primary endpoint of ORR

¹Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.

Biomarker eligibility criteria

CRYSTAL: none
FIRE-3: Wild-type KRAS, Wild-type NRAS

Chemotherapy

Leucovorin (Folinic acid) 400 mg/m² IV over 2 hours once on day 1, given second, 1 hour after completion of cetuximab, with irinotecan
Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours, given third (total dose per cycle: 2800 mg/m²)
Irinotecan (Camptosar) 180 mg/m² IV over 30 to 90 minutes once on day 1, given second, 1 hour after completion of cetuximab, with leucovorin

Targeted therapy

Cetuximab (Erbitux) as follows, given first and completed at least 1 hour before FOLFIRI begins:
- Cycle 1: 400 mg/m² IV over 2 hours once on day 1, then 250 mg/m² IV over 60 minutes once on day 8
- Cycle 2 onwards: 250 mg/m² IV over 60 minutes once per day on days 1 & 8

14-day cycles

References

CRYSTAL: Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. link to original article contains dosing details in manuscript PubMed NCT00154102
1. Update: Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. link to original article contains dosing details in manuscript PubMed
2. Pooled update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
3. Biomarker analysis: Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. link to original article PubMed
FIRE-3: Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31. link to original article PubMed NCT00433927

@@ Line 1: / Line 1: @@
-==Thalidomide monotherapy {{#subobject:ff02e1|Regimen=1}}==
+==FOLFIRI & Cetuximab {{#subobject:11cf7b|Regimen=1}}==
-<div class="toccolours" style="background-color:#bebada">
+FOLFIRI & Cetuximab: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Cetuximab
-===Synopsis===
-'''Historical Background of Thalidomide'''
-Originally developed and marketed in the late 1950s as a sedative and remedy for morning sickness in pregnant women, thalidomide led to catastrophic birth defects when taken during pregnancy. Due to these teratogenic effects, its usage was banned in many countries by the early 1960s.
-'''Rediscovery and Anticancer Properties'''
-During the late 1990s, the anti-angiogenic and immunomodulatory effects of thalidomide were explored. Researchers hypothesized that these properties could be harnessed against cancers that rely on angiogenesis.
-Singhal et al., 1999 ([https://pubmed.ncbi.nlm.nih.gov/10564685/] Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. New England Journal of Medicine. 1999;341:1565-71): This seminal study reported the effects of thalidomide in patients with refractory multiple myeloma. Thalidomide showed significant antitumor activity, leading to renewed interest in the drug.
-'''Development of Analogues'''
-The success of thalidomide spurred the development of its analogs, designed to retain its therapeutic benefits while minimizing side effects. Lenalidomide and pomalidomide are two such analogs that have shown significant efficacy in multiple myeloma with a better side effect profile.
-'''Current Role in Therapy'''
-While newer agents and combinations have emerged in the treatment landscape of multiple myeloma, thalidomide and its derivatives remain vital components in various treatment regimens, especially in certain settings and geographies.
-'''Conclusion'''
-The repositioning of thalidomide for multiple myeloma is a testament to the importance of re-evaluating existing drugs for new therapeutic indications. Its successful transition from a notorious drug to a vital component in the multiple myeloma treatment arsenal underscores the ever-evolving nature of drug development and therapy.
-<br><small>''The draft for this synopsis was generated by a large language model and then manually edited by the page editor for accuracy and style. See [[Large language model pilot|this page]] for more information about this pilot project.''</small>
-</div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:43a4e3|Variant=1}}===
+===Regimen {{#subobject:921ac6|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="color:white; background-color:#404040"
-!style="width: 33%"|Study
+|<small>'''FDA-recommended dose'''</small>
-!style="width: 33%"|Dates of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1056/NEJM199911183412102 Singhal et al. 1999]
+|}
-|1997-1998
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|style="background-color:#91cf61"|Non-randomized
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]
+{| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-17-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|-
+|}
+|2004-07 to 2005-11
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[#FOLFIRI_2|FOLFIRI]]
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 23.5 vs 19.5 mo<br>(HR 0.81, 95% CI 0.69-0.94)
+|-
+|[https://doi.org/10.1016/S1470-2045(14)70330-4 Heinemann et al. 2014 (FIRE-3)]
+|2007-2012
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
+|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
 |}
+''<sup>1</sup>Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*CRYSTAL: none
+*FIRE-3: Wild-type KRAS, Wild-type NRAS
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, 1 hour after completion of cetuximab, with irinotecan'''
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given second, 1 hour after completion of cetuximab, with leucovorin'''
 ====Targeted therapy====
-*[[Thalidomide (Thalomid)]] 200 mg PO once per day, increased by 200 mg every two weeks for six weeks, to final dose of 800 mg per day
+*[[Cetuximab (Erbitux)]] as follows, '''given first and completed at least 1 hour before FOLFIRI begins''':
-'''Continued indefinitely'''
+**Cycle 1: 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, then 250 mg/m<sup>2</sup> IV over 60 minutes once on day 8
+**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8
+'''14-day cycles'''
 </div></div>
 ===References===
-# Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeldis J, Siegel D, Crowley J, Barlogie B. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999 Nov 18;341(21):1565-71. Erratum in: N Engl J Med 2000 Feb 3;342(5):364. [https://doi.org/10.1056/NEJM199911183412102 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10564685/ PubMed]
+#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://doi.org/10.1056/NEJMoa0805019 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19339720/ PubMed] [https://clinicaltrials.gov/study/NCT00154102 NCT00154102]
-# Yakoub-Agha I, Mary JY, Hulin C, Doyen C, Marit G, Benboubker L, Voillat L, Moreau P, Berthou C, Stoppa AM, Maloisel F, Rodon P, Dib M, Pegourie B, Casassus P, Slama B, Damaj G, Zerbib R, Harousseau JL, Mohty M, Facon T; Intergroupe Francophone du Myélome (IFM). Low-dose vs. high-dose thalidomide for advanced multiple myeloma: a prospective trial from the Intergroupe Francophone du Myélome. Eur J Haematol. 2012 Mar;88(3):249-59. Epub 2012 Jan 4. [https://doi.org/10.1111/j.1600-0609.2011.01729.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/22023551/ PubMed]
+<!-- ## '''Update: Abstract:''' E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=54429 link to abstract] -->
+##'''Update:''' Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. [https://doi.org/10.1200/jco.2010.33.5091 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21502544/ PubMed]
+##'''Pooled update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://doi.org/10.1016/j.ejca.2012.02.057 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22446022/ PubMed]
+##'''Biomarker analysis:''' Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. [https://doi.org/10.1200/JCO.2014.59.4812 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25605843/ PubMed]
+#'''FIRE-3:''' Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31. [https://doi.org/10.1016/S1470-2045(14)70330-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25088940/ PubMed] [https://clinicaltrials.gov/study/NCT00433927 NCT00433927]