Portal vein chemotherapy for colorectal cancer: A meta-analysis of 4000 patients in 10 studies

R. Gray, M. Clarke, R. Collins, R. Peto, P. Piedbois, M. Buyse, B. Gray, H. H. Gruenagel, M. F. De Rodriguez, D. Nitti, T. Sahmoud, L. P. Fielding, J. Fry, R. Hittinger, R. Beart, J. Ingle, M. Kahn, M. O'Connell, H. Rockette

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Background: Systemic delivery of cytotoxic drugs yields relatively low doses in the liver, a major site of recurrence for colorectal cancer. Giving chemotherapy by means of continuous portal vein infusion (PVI) into the liver during the immediate postoperative period may improve therapeutic efficacy. Purpose: We undertook a meta-analysis to assess the effects on recurrence and survival of administering fiuorouracil (5-FU)-based chemotherapy by PVI after colorectal cancer surgery. Methods: Data on mortality and recurrence were sought for all patients enrolled in randomized trials initiated before 1987 in which a few days (range, 5-7 days) of continuous postoperative PVI of cytotoxic drugs was compared with no further treatment. Data from 10 trials (a promising initial study and nine hypothesis-testing trials) involving about 4000 patients were available for analysis. The main cytotoxic drug in each trial was 5-FU (given with heparin); however, mitomycin C was co- administered in two of the trials. Four trials included an additional control group of patients treated with continuous noncytotoxic PVI of either heparin or urokinase alone; one trial included a second control group of patients treated with continuous systemic infusion of 5-FU. Reported P values are two- sided. Results: Among the 3499 patients randomly assigned to receive either cytotoxic PVI or no further treatment, 1557 deaths are known to have occurred. Survival with and without PVI appeared to be the same for the first 2 years; thereafter, it diverged significantly, with the absolute survival difference (i.e., improvement) associated with PVI at 5 years being 4.7% (standard deviation [SD] = 1.2%) (P = .006). When just the nine hypothesis- testing trials were considered, the absolute survival difference was 3.6% (SD = 1.2%) (P = .04). If, ignoring any potential for bias in stage assignment, attention was restricted to patients with Dukes' stage A, B, or C disease (88.3% of the total), the absolute effect on 5-year survival for all 10 trials increased to 6.0% (SD = 1.8%) (P = .001); this estimate remained statistically significant when the initial study was excluded (absolute survival difference = 4.8%; SD = 1.8%; P = .01). In contrast to the highly significant reduction in liver metastases seen in the initial study (79% reduction; SD = 15%; P = .00000007), the reduction found in the nine hypothesis-testing trials was not significant (14% reduction; SD = 10%; P = .2). In the trials with additional control groups, survival appeared to be better with cytotoxic PVI than with noncytotoxic PVI or with systemic cytotoxic drug infusion. Conclusions: PVI of 5-FU (with or without other cytotoxic drugs) for about 1 week after surgery in patients with colorectal cancer may produce an absolute improvement in 5-year survival of a few percent. Although encouraging, this finding is not statistically secure, and additional evidence from randomized trials involving several thousand more patients is needed.

Original languageEnglish (US)
Pages (from-to)497-505
Number of pages9
JournalJournal of the National Cancer Institute
Volume89
Issue number7
DOIs
StatePublished - Apr 2 1997
Externally publishedYes

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Portal Vein
Meta-Analysis
Colorectal Neoplasms
Drug Therapy
Survival
Fluorouracil
Pharmaceutical Preparations
Recurrence
Control Groups
Heparin
Liver
Colorectal Surgery
Urokinase-Type Plasminogen Activator
Mitomycin
Postoperative Period
Therapeutics
Neoplasm Metastasis
Mortality

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Gray, R., Clarke, M., Collins, R., Peto, R., Piedbois, P., Buyse, M., ... Rockette, H. (1997). Portal vein chemotherapy for colorectal cancer: A meta-analysis of 4000 patients in 10 studies. Journal of the National Cancer Institute, 89(7), 497-505. https://doi.org/10.1093/jnci/89.7.497

Portal vein chemotherapy for colorectal cancer : A meta-analysis of 4000 patients in 10 studies. / Gray, R.; Clarke, M.; Collins, R.; Peto, R.; Piedbois, P.; Buyse, M.; Gray, B.; Gruenagel, H. H.; De Rodriguez, M. F.; Nitti, D.; Sahmoud, T.; Fielding, L. P.; Fry, J.; Hittinger, R.; Beart, R.; Ingle, J.; Kahn, M.; O'Connell, M.; Rockette, H.

In: Journal of the National Cancer Institute, Vol. 89, No. 7, 02.04.1997, p. 497-505.

Research output: Contribution to journalArticle

Gray, R, Clarke, M, Collins, R, Peto, R, Piedbois, P, Buyse, M, Gray, B, Gruenagel, HH, De Rodriguez, MF, Nitti, D, Sahmoud, T, Fielding, LP, Fry, J, Hittinger, R, Beart, R, Ingle, J, Kahn, M, O'Connell, M & Rockette, H 1997, 'Portal vein chemotherapy for colorectal cancer: A meta-analysis of 4000 patients in 10 studies', Journal of the National Cancer Institute, vol. 89, no. 7, pp. 497-505. https://doi.org/10.1093/jnci/89.7.497
Gray, R. ; Clarke, M. ; Collins, R. ; Peto, R. ; Piedbois, P. ; Buyse, M. ; Gray, B. ; Gruenagel, H. H. ; De Rodriguez, M. F. ; Nitti, D. ; Sahmoud, T. ; Fielding, L. P. ; Fry, J. ; Hittinger, R. ; Beart, R. ; Ingle, J. ; Kahn, M. ; O'Connell, M. ; Rockette, H. / Portal vein chemotherapy for colorectal cancer : A meta-analysis of 4000 patients in 10 studies. In: Journal of the National Cancer Institute. 1997 ; Vol. 89, No. 7. pp. 497-505.
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title = "Portal vein chemotherapy for colorectal cancer: A meta-analysis of 4000 patients in 10 studies",
abstract = "Background: Systemic delivery of cytotoxic drugs yields relatively low doses in the liver, a major site of recurrence for colorectal cancer. Giving chemotherapy by means of continuous portal vein infusion (PVI) into the liver during the immediate postoperative period may improve therapeutic efficacy. Purpose: We undertook a meta-analysis to assess the effects on recurrence and survival of administering fiuorouracil (5-FU)-based chemotherapy by PVI after colorectal cancer surgery. Methods: Data on mortality and recurrence were sought for all patients enrolled in randomized trials initiated before 1987 in which a few days (range, 5-7 days) of continuous postoperative PVI of cytotoxic drugs was compared with no further treatment. Data from 10 trials (a promising initial study and nine hypothesis-testing trials) involving about 4000 patients were available for analysis. The main cytotoxic drug in each trial was 5-FU (given with heparin); however, mitomycin C was co- administered in two of the trials. Four trials included an additional control group of patients treated with continuous noncytotoxic PVI of either heparin or urokinase alone; one trial included a second control group of patients treated with continuous systemic infusion of 5-FU. Reported P values are two- sided. Results: Among the 3499 patients randomly assigned to receive either cytotoxic PVI or no further treatment, 1557 deaths are known to have occurred. Survival with and without PVI appeared to be the same for the first 2 years; thereafter, it diverged significantly, with the absolute survival difference (i.e., improvement) associated with PVI at 5 years being 4.7{\%} (standard deviation [SD] = 1.2{\%}) (P = .006). When just the nine hypothesis- testing trials were considered, the absolute survival difference was 3.6{\%} (SD = 1.2{\%}) (P = .04). If, ignoring any potential for bias in stage assignment, attention was restricted to patients with Dukes' stage A, B, or C disease (88.3{\%} of the total), the absolute effect on 5-year survival for all 10 trials increased to 6.0{\%} (SD = 1.8{\%}) (P = .001); this estimate remained statistically significant when the initial study was excluded (absolute survival difference = 4.8{\%}; SD = 1.8{\%}; P = .01). In contrast to the highly significant reduction in liver metastases seen in the initial study (79{\%} reduction; SD = 15{\%}; P = .00000007), the reduction found in the nine hypothesis-testing trials was not significant (14{\%} reduction; SD = 10{\%}; P = .2). In the trials with additional control groups, survival appeared to be better with cytotoxic PVI than with noncytotoxic PVI or with systemic cytotoxic drug infusion. Conclusions: PVI of 5-FU (with or without other cytotoxic drugs) for about 1 week after surgery in patients with colorectal cancer may produce an absolute improvement in 5-year survival of a few percent. Although encouraging, this finding is not statistically secure, and additional evidence from randomized trials involving several thousand more patients is needed.",
author = "R. Gray and M. Clarke and R. Collins and R. Peto and P. Piedbois and M. Buyse and B. Gray and Gruenagel, {H. H.} and {De Rodriguez}, {M. F.} and D. Nitti and T. Sahmoud and Fielding, {L. P.} and J. Fry and R. Hittinger and R. Beart and J. Ingle and M. Kahn and M. O'Connell and H. Rockette",
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TY - JOUR

T1 - Portal vein chemotherapy for colorectal cancer

T2 - A meta-analysis of 4000 patients in 10 studies

AU - Gray, R.

AU - Clarke, M.

AU - Collins, R.

AU - Peto, R.

AU - Piedbois, P.

AU - Buyse, M.

AU - Gray, B.

AU - Gruenagel, H. H.

AU - De Rodriguez, M. F.

AU - Nitti, D.

AU - Sahmoud, T.

AU - Fielding, L. P.

AU - Fry, J.

AU - Hittinger, R.

AU - Beart, R.

AU - Ingle, J.

AU - Kahn, M.

AU - O'Connell, M.

AU - Rockette, H.

PY - 1997/4/2

Y1 - 1997/4/2

N2 - Background: Systemic delivery of cytotoxic drugs yields relatively low doses in the liver, a major site of recurrence for colorectal cancer. Giving chemotherapy by means of continuous portal vein infusion (PVI) into the liver during the immediate postoperative period may improve therapeutic efficacy. Purpose: We undertook a meta-analysis to assess the effects on recurrence and survival of administering fiuorouracil (5-FU)-based chemotherapy by PVI after colorectal cancer surgery. Methods: Data on mortality and recurrence were sought for all patients enrolled in randomized trials initiated before 1987 in which a few days (range, 5-7 days) of continuous postoperative PVI of cytotoxic drugs was compared with no further treatment. Data from 10 trials (a promising initial study and nine hypothesis-testing trials) involving about 4000 patients were available for analysis. The main cytotoxic drug in each trial was 5-FU (given with heparin); however, mitomycin C was co- administered in two of the trials. Four trials included an additional control group of patients treated with continuous noncytotoxic PVI of either heparin or urokinase alone; one trial included a second control group of patients treated with continuous systemic infusion of 5-FU. Reported P values are two- sided. Results: Among the 3499 patients randomly assigned to receive either cytotoxic PVI or no further treatment, 1557 deaths are known to have occurred. Survival with and without PVI appeared to be the same for the first 2 years; thereafter, it diverged significantly, with the absolute survival difference (i.e., improvement) associated with PVI at 5 years being 4.7% (standard deviation [SD] = 1.2%) (P = .006). When just the nine hypothesis- testing trials were considered, the absolute survival difference was 3.6% (SD = 1.2%) (P = .04). If, ignoring any potential for bias in stage assignment, attention was restricted to patients with Dukes' stage A, B, or C disease (88.3% of the total), the absolute effect on 5-year survival for all 10 trials increased to 6.0% (SD = 1.8%) (P = .001); this estimate remained statistically significant when the initial study was excluded (absolute survival difference = 4.8%; SD = 1.8%; P = .01). In contrast to the highly significant reduction in liver metastases seen in the initial study (79% reduction; SD = 15%; P = .00000007), the reduction found in the nine hypothesis-testing trials was not significant (14% reduction; SD = 10%; P = .2). In the trials with additional control groups, survival appeared to be better with cytotoxic PVI than with noncytotoxic PVI or with systemic cytotoxic drug infusion. Conclusions: PVI of 5-FU (with or without other cytotoxic drugs) for about 1 week after surgery in patients with colorectal cancer may produce an absolute improvement in 5-year survival of a few percent. Although encouraging, this finding is not statistically secure, and additional evidence from randomized trials involving several thousand more patients is needed.

AB - Background: Systemic delivery of cytotoxic drugs yields relatively low doses in the liver, a major site of recurrence for colorectal cancer. Giving chemotherapy by means of continuous portal vein infusion (PVI) into the liver during the immediate postoperative period may improve therapeutic efficacy. Purpose: We undertook a meta-analysis to assess the effects on recurrence and survival of administering fiuorouracil (5-FU)-based chemotherapy by PVI after colorectal cancer surgery. Methods: Data on mortality and recurrence were sought for all patients enrolled in randomized trials initiated before 1987 in which a few days (range, 5-7 days) of continuous postoperative PVI of cytotoxic drugs was compared with no further treatment. Data from 10 trials (a promising initial study and nine hypothesis-testing trials) involving about 4000 patients were available for analysis. The main cytotoxic drug in each trial was 5-FU (given with heparin); however, mitomycin C was co- administered in two of the trials. Four trials included an additional control group of patients treated with continuous noncytotoxic PVI of either heparin or urokinase alone; one trial included a second control group of patients treated with continuous systemic infusion of 5-FU. Reported P values are two- sided. Results: Among the 3499 patients randomly assigned to receive either cytotoxic PVI or no further treatment, 1557 deaths are known to have occurred. Survival with and without PVI appeared to be the same for the first 2 years; thereafter, it diverged significantly, with the absolute survival difference (i.e., improvement) associated with PVI at 5 years being 4.7% (standard deviation [SD] = 1.2%) (P = .006). When just the nine hypothesis- testing trials were considered, the absolute survival difference was 3.6% (SD = 1.2%) (P = .04). If, ignoring any potential for bias in stage assignment, attention was restricted to patients with Dukes' stage A, B, or C disease (88.3% of the total), the absolute effect on 5-year survival for all 10 trials increased to 6.0% (SD = 1.8%) (P = .001); this estimate remained statistically significant when the initial study was excluded (absolute survival difference = 4.8%; SD = 1.8%; P = .01). In contrast to the highly significant reduction in liver metastases seen in the initial study (79% reduction; SD = 15%; P = .00000007), the reduction found in the nine hypothesis-testing trials was not significant (14% reduction; SD = 10%; P = .2). In the trials with additional control groups, survival appeared to be better with cytotoxic PVI than with noncytotoxic PVI or with systemic cytotoxic drug infusion. Conclusions: PVI of 5-FU (with or without other cytotoxic drugs) for about 1 week after surgery in patients with colorectal cancer may produce an absolute improvement in 5-year survival of a few percent. Although encouraging, this finding is not statistically secure, and additional evidence from randomized trials involving several thousand more patients is needed.

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