Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08)

for the Swiss Group for Clinical Cancer Research (SAKK)

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background KRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. Methods Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. Results Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3–75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%). Conclusions Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov: NCT00869570.

Original languageEnglish
Pages (from-to)82-89
Number of pages8
JournalEuropean Journal of Cancer
Volume89
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Rectal Neoplasms
Radiotherapy
Chemoradiotherapy
Radiation-Sensitizing Agents
Proctitis
Skin
Maximum Tolerated Dose
Hungary
Switzerland
Protein-Tyrosine Kinases
Fatigue
Diarrhea
Ischemia
Capecitabine
sorafenib
Safety
Pain
Mutation

Keywords

  • Chemoradiotherapy
  • Dose escalation
  • Efficacy
  • Safety
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer : A phase I/II trial (SAKK 41/08). / for the Swiss Group for Clinical Cancer Research (SAKK).

In: European Journal of Cancer, Vol. 89, 01.01.2018, p. 82-89.

Research output: Contribution to journalArticle

@article{5c27ff78eaa14877a7d305c2e66420f4,
title = "Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08)",
abstract = "Background KRAS mutation occurs in ∼40{\%} of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. Methods Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. Results Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100{\%}, capecitabine 98.6{\%}, and sorafenib 100{\%}. The pCR rate (Dworak 3/4) was 60{\%} (95{\%} CI, 43.3–75.1{\%}) by central independent pathologic review. Sphincter preservation was achieved in 89.5{\%}, R0 resection in 94.7{\%}, and downstaging in 81.6{\%}. The most common grade 3 toxicities during phase II included diarrhoea (15.0{\%}), skin toxicity outside radiotherapy field (12.5{\%}), pain (7.5{\%}), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5{\%}). Conclusions Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov: NCT00869570.",
keywords = "Chemoradiotherapy, Dose escalation, Efficacy, Safety, Tyrosine kinase inhibitor",
author = "{for the Swiss Group for Clinical Cancer Research (SAKK)} and {von Moos}, Roger and Dieter Koeberle and Sabina Schacher and Stefanie Hayoz and Winterhalder, {Ralph C.} and Arnaud Roth and G. Bodoky and Panagiotis Samaras and Berger, {Martin D.} and Daniel Rauch and Piercarlo Saletti and Ludwig Plasswilm and Daniel Zwahlen and Meier, {Urs R.} and Pu Yan and Paola Izzo and Dirk Klingbiel and Daniela B{\"a}rtschi and Kathrin Zaugg",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.ejca.2017.11.005",
language = "English",
volume = "89",
pages = "82--89",
journal = "European Journal of Cancer",
issn = "0959-8049",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer

T2 - A phase I/II trial (SAKK 41/08)

AU - for the Swiss Group for Clinical Cancer Research (SAKK)

AU - von Moos, Roger

AU - Koeberle, Dieter

AU - Schacher, Sabina

AU - Hayoz, Stefanie

AU - Winterhalder, Ralph C.

AU - Roth, Arnaud

AU - Bodoky, G.

AU - Samaras, Panagiotis

AU - Berger, Martin D.

AU - Rauch, Daniel

AU - Saletti, Piercarlo

AU - Plasswilm, Ludwig

AU - Zwahlen, Daniel

AU - Meier, Urs R.

AU - Yan, Pu

AU - Izzo, Paola

AU - Klingbiel, Dirk

AU - Bärtschi, Daniela

AU - Zaugg, Kathrin

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background KRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. Methods Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. Results Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3–75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%). Conclusions Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov: NCT00869570.

AB - Background KRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. Methods Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. Results Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3–75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%). Conclusions Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov: NCT00869570.

KW - Chemoradiotherapy

KW - Dose escalation

KW - Efficacy

KW - Safety

KW - Tyrosine kinase inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85037629153&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85037629153&partnerID=8YFLogxK

U2 - 10.1016/j.ejca.2017.11.005

DO - 10.1016/j.ejca.2017.11.005

M3 - Article

C2 - 29241084

AN - SCOPUS:85037629153

VL - 89

SP - 82

EP - 89

JO - European Journal of Cancer

JF - European Journal of Cancer

SN - 0959-8049

ER -