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

27 oktober 2016 uppdaterad 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.

Studieöversikt

Status

Avslutad

Betingelser

Intervention / Behandling

Detaljerad beskrivning

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.

Studietyp

Interventionell

Inskrivning (Faktisk)

9

Fas

  • Fas 2

Kontakter och platser

Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.

Studieorter

  • Förenta staterna
    • Missouri
      • St. Louis, Missouri, Förenta staterna, 63110
        • Washington University School of Medicine

Deltagandekriterier

Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.

Urvalskriterier

Åldrar som är berättigade till studier

18 år och äldre (Vuxen, Äldre vuxen)

Tar emot friska volontärer

Nej

Kön som är behöriga för studier

Allt

Beskrivning

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

Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.

Hur är studien utformad?

Designdetaljer

  • Primärt syfte: Behandling
  • Tilldelning: Icke-randomiserad
  • Interventionsmodell: Parallellt uppdrag
  • Maskning: Ingen (Open Label)

Vapen och interventioner

Deltagargrupp / Arm
Intervention / Behandling
Experimentell: 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
Läkemedel: Oxaliplatin
Läkemedel: Cetuximab
Andra namn:
  • Erbitux
Läkemedel: Leucovorin
Läkemedel: Fluorouracil
Experimentell: 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
Läkemedel: Oxaliplatin
Läkemedel: Leucovorin
Läkemedel: Fluorouracil
Läkemedel: Bevacizumab
Andra namn:
  • Avastin

Vad mäter studien?

Primära resultatmått

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

Sekundära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Postoperative Recurrence Patterns
Tidsram: Up to 5 years
Liver only vs distant disease
Up to 5 years
Histologic Hepatic Toxicity at Surgery
Tidsram: Time of surgery (approximately 11-16 weeks)
Time of surgery (approximately 11-16 weeks)
Nonalcoholic Steatohepatitis Score (0-3)
Tidsram: 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)
Tidsram: Time of surgery (approximately 11-16 weeks)
Time of surgery (approximately 11-16 weeks)
Effect of Preoperative Chemotherapy on Tumor Size
Tidsram: 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
Tidsram: Completion of neoadjuvant therapy (approximately 8 weeks)
-Compare total longest diameter from baseline to preoperative CT scan.
Completion of neoadjuvant therapy (approximately 8 weeks)

Samarbetspartners och utredare

Det är här du hittar personer och organisationer som är involverade i denna studie.

Sponsor

Washington University School of Medicine

Utredare

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

Publikationer och användbara länkar

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Allmänna publikationer

Användbara länkar

Studieavstämningsdatum

Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.

Studera stora datum

Studiestart

1 juni 2007

Primärt slutförande (Faktisk)

1 december 2009

Avslutad studie (Faktisk)

1 juli 2011

Studieregistreringsdatum

Först inskickad

27 september 2007

Först inskickad som uppfyllde QC-kriterierna

30 september 2007

Första postat (Uppskatta)

1 oktober 2007

Uppdateringar av studier

Senaste uppdatering publicerad (Uppskatta)

20 december 2016

Senaste inskickade uppdateringen som uppfyllde QC-kriterierna

27 oktober 2016

Senast verifierad

1 oktober 2016

Mer information

Termer relaterade till denna studie

Nyckelord

Ytterligare relevanta MeSH-villkor

Andra studie-ID-nummer

  • 07-0182

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