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Pre- and Post-operative FOLFOX Based Therapy for Patients With Colorectal Cancer With Liver Involvement

27. oktober 2016 oppdatert av: Washington University School of Medicine

Effect of Short-duration Preoperative Neoadjuvant Therapy With FOLFOX Based Therapy on Morbidity After Liver Resection for Colorectal Cancer Metastases

The purpose of this study is to determine the effect of short-duration pre-operative FOLFOX based therapy on postoperative problems after liver surgery for patients with metastatic colorectal cancer.

Studieoversikt

Status

Avsluttet

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

Although early stage, localized colon and rectal cancers are associated with 5 year survival rates of nearly 90%, only a minority of patients present with localized disease. Unfortunately, at the time of their initial presentation, approximately 35% of patients with colon or rectal cancer have metastatic disease. Nearly two thirds of these patients with stage IV disease have evidence of extrahepatic spread and have a median overall survival rate of 8-10 months in the absence of further treatment. Even with the most intensive chemotherapeutic regimens, the median overall survival for these patients ranges from 12 months to 20 months. However, a small subset of patients with stage IV disease has isolated hepatic metastatic disease and can undergo resection. The patients with completely resected liver metastases enjoy a significantly higher overall five-year survival, which is as high as 58% in carefully selected patients. Ten-year overall survival has been reported in 22% of patients. Despite this improvement, the five-year disease-free survival for these patients is at best 35%, with hepatic recurrences occurring in 46%.

The fact that adjuvant chemotherapy improves the three-year survival rate for stage II disease and five-year survival rates for stage III disease implies that it can treat micrometastatic disease in some fraction of patients. Because micrometastatic disease is likely the cause of the high recurrence rate in patients who undergo liver resection, there is a clear biologic rationale for using postoperative adjuvant chemotherapy after liver resection. Although this strategy is a common practice in many centers, no convincing data that this improves survival have been reported. A large randomized phase III trial (EORTC 40983) examining this question is currently ongoing and effect on survival has not yet been reported. Given that systemic chemotherapy after liver resection remains of unproven benefit at the present time, many have wondered if preoperative treatment might have more promise in improving recurrence rates.

Studietype

Intervensjonell

Registrering (Faktiske)

9

Fase

  • Fase 2

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiesteder

  • Forente stater
    • Missouri
      • St. Louis, Missouri, Forente stater, 63110
        • Washington University School of Medicine

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

18 år og eldre (Voksen, Eldre voksen)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

Inclusion Criteria:

  • Synchronous or metachronous colorectal metastases

  • Technically resectable liver metastases

    • Four or fewer metastases
    • No tumors in porta hepatis
    • Resection of no more than 70% of liver needed
  • Medically suitable candidate for major liver resection
  • FDG-PET scan without metastatic disease outside the liver

Exclusion Criteria:

  • Near-obstructing or obstructing colon lesions in patients in whom combined resection is planned (as delay for preoperative chemotherapy would be medially impossible)
  • Treatment with FOLFOX or cetuximab within 12 months
  • Treatment with irinotecan within 12 months
  • Abnormal liver function (ALT or AST > 5x ULN, bilirubin > 3x ULN)
  • Body mass index >/= 35 kg/m² (as the risk for steatohepatitis is increased)
  • Renal insufficiency (Cr > 2.5mg/dL)
  • Interstitial lung disease (because cetuximab has been rarely associated with development of interstitial lung disease)
  • ECOG performance score >/= 3
  • Patients unable to give informed consent
  • Pregnant patient (as cetuximab is a Class C drug)
  • Peripheral neuropathy >/= grade II (as oxaliplatin causes neuropathy to worsen)

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Behandling
  • Tildeling: Ikke-randomisert
  • Intervensjonsmodell: Parallell tildeling
  • Masking: Ingen (Open Label)

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: Arm 1 - Wildtype

Neoadjuvant therapy

Week 1

  • Leucovorin 400 mg/m^2 IV
  • Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m2 IV
  • 5FU bolus 400 mg/m^2
  • 5FU CIVI 1200 mg/m^2/day over 46 hours

Weeks 2, 4, 6, 8 *Cetuximab 250 mg/m^2 IV weekly

Weeks 3, 5, 7

  • Leucovorin 400 mg/m^2 IV
  • Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m^2 IV
  • 5FU bolus 400 mg/m^2
  • 5FU CIVI 1200 mg/m^2/day over 46 hours

Wait 3-8 weeks after completion of therapy

Liver resection

Wait 4 weeks or until clinical status allows

Adjuvant Therapy

Week 1, 3, 5, 7, 9, 11, 13, 15

  • Leucovorin 400 mg/m^2 IV
  • Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m^2 IV
  • 5FU bolus 400 mg/m^2
  • 5FU CIVI 1200 mg/m^2/day over 46 hours

Weeks 2, 4, 6, 8, 10, 12, 16

*Cetuximab 250 mg/m^2 IV weekly
Legemiddel: Oksaliplatin
Legemiddel: Cetuximab
Andre navn:
  • Erbitux
Legemiddel: Leucovorin
Legemiddel: Fluorouracil
Eksperimentell: Arm 2 K-Ras 12/13 codon mutation

Neoadjuvant Therapy

Weeks 1, 3, 5

  • Leucovorin 400 mg/m^2 IV
  • Oxaliplatin 85 mg/m^2 IV
  • Bevacizumab 5 mg/kg IV
  • 5FU bolus 400 mg/m^2
  • 5FU CIVI 1200 mg/m^2

Week 7

  • Leucovorin 400 mg/m^2 IV
  • Oxaliplatin 85 mg/m^2 IV
  • 5FU bolus 400 mg/m^2
  • 5FU CIVI 1200 mg/m^2

Wait 3-8 weeks after completion of therapy

Liver resection

Wait 4 weeks or until clinical status allows

Adjuvant Therapy

Weeks 1, 3, 5, 9, 11, 13

  • Leucovorin 400 mg/m^2 IV
  • Oxaliplatin 85 mg/m^2 IV
  • Bevacizumab 5 mg/kg IV
  • 5FU bolus 400 mg/m^2
  • 5FU CIVI 1200 mg/m^2

Week 7, 15

  • Leucovorin 400 mg/m^2 IV
  • Oxaliplatin 85 mg/m^2 IV
  • 5FU bolus 400 mg/m^2
  • 5FU CIVI 1200 mg/m^2
Legemiddel: Oksaliplatin
Legemiddel: Leucovorin
Legemiddel: Fluorouracil
Legemiddel: Bevacizumab
Andre navn:
  • Avastin

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Postoperative Complication Rate
Tidsramme: 30 days following surgery
Fraction of patients with any grade of complication I-V
30 days following surgery
Major Postoperative Complication Rate
Tidsramme: 30 days following surgery
Fraction of patients with any complication grades IV and V
30 days following surgery
All-cause Mortality
Tidsramme: 30 days following surgery
30 days following surgery

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Postoperative Recurrence Patterns
Tidsramme: Up to 5 years
Liver only vs distant disease
Up to 5 years
Histologic Hepatic Toxicity at Surgery
Tidsramme: Time of surgery (approximately 11-16 weeks)
Time of surgery (approximately 11-16 weeks)
Nonalcoholic Steatohepatitis Score (0-3)
Tidsramme: Time of surgery (approximately 11-16 weeks)

  • NASH Scoring

    • Steatosis **<5% = 0

      **5-33%=1

      **>33-66%=2

      **>66%=3

    • Lobular inflammation

      **No foci=0

      **<2 foci per x 200 field=1

      **2-4 foci per x 200 field=2

      **>4 foci per x 200 field=3

    • Hepatocellular ballooning **None=0 **Few balloon cells = 1 **Many cells/prominent ballooning=2
Time of surgery (approximately 11-16 weeks)
Liver Injury Scale Score (0-27)
Tidsramme: Time of surgery (approximately 11-16 weeks)
Time of surgery (approximately 11-16 weeks)
Effect of Preoperative Chemotherapy on Tumor Size
Tidsramme: Upon completion of neoadjuvant chemotherapy (approximately 2 months)
Number of participants whose tumor size decreased from baseline to completion of preoperative chemotherapy.
Upon completion of neoadjuvant chemotherapy (approximately 2 months)
Change in Tumor Size From Pretreatment to Preoperative CT Scan
Tidsramme: Completion of neoadjuvant therapy (approximately 8 weeks)
-Compare total longest diameter from baseline to preoperative CT scan.
Completion of neoadjuvant therapy (approximately 8 weeks)

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Washington University School of Medicine

Etterforskere

  • Hovedetterforsker: David Linehan, M.D., Washington University School of Medicine

Publikasjoner og nyttige lenker

Den som er ansvarlig for å legge inn informasjon om studien leverer frivillig disse publikasjonene. Disse kan handle om alt relatert til studiet.

Generelle publikasjoner

Hjelpsomme linker

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart

1. juni 2007

Primær fullføring (Faktiske)

1. desember 2009

Studiet fullført (Faktiske)

1. juli 2011

Datoer for studieregistrering

Først innsendt

27. september 2007

Først innsendt som oppfylte QC-kriteriene

30. september 2007

Først lagt ut (Anslag)

1. oktober 2007

Oppdateringer av studieposter

Sist oppdatering lagt ut (Anslag)

20. desember 2016

Siste oppdatering sendt inn som oppfylte QC-kriteriene

27. oktober 2016

Sist bekreftet

1. oktober 2016

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • 07-0182

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