EDITORIAL
Is Portal-Vein Fluorouracil Hepatic Infusion Effective Colon Cancer Surgical Adjuvant Therapy?
IN
1975, a prospectively randomized trial of adjuvant portal-vein cytotoxic perfusion in colorectal cancer was initiated at the University of Liverpool, United Kingdom, by Taylor et al.' The rationale for this approach as outlined by Taylor et al was straightforward: (1) the liver is a frequent site of failure following potentially curative surgical resection of primary carcinomas of the colon or rectum, and liver metastasis is a prominent cause of death; (2) colorectal liver metastases reach the liver via the portal vein, therefore, administration of a cytotoxic agent using the same route of administration directly into the liver might be more effective than systemic administration; and (3) operative stress has been shown in some experimental systems to improve the survival of malignant cells and to facilitate them to establish growth in the liver; therefore, early perioperative chemotherapy administration might be particularly beneficial destroying suspected tumor cells in the liver before established tumor growth has taken place. The treatment chosen was a generally nontoxic regimen of fluorouracil (5FU)1.0 g (total dose) per day as a continuous infusion during the first 7 postoperative days. Heparin (5,000 U/d) was added to discourage portal-vein thrombosis. The results of this trial, published in 1985,2 were strikingly positive. Twenty-two of 127 control patients (18%) developed liver metastases, in contrast to only five of 117 (4%) who underwent portal-vein 5FU therapy. Survival analyses indicated a major beneficial effect of adjuvant portalvein 5FU with a death rate ratio (controls: treated) of 2.08 (P = .002). Exploratory subset analysis suggested survival benefit only in patients with Dukes' B colon cancer. The median follow-up of patients was 4 years, and only 5% of randomized patients were excluded from analysis, even though randomization occurred prior to surgery. Chemotherapy was generally well tolerated, although one patient died with leukopenia and sepsis. The authors appropriately stated that "it is essential therefore that further studies be performed to confirm this apparent benefit before the treatment is administered to patients outside a clinical trial setting." Indeed, the results of this study have motivated multiple confirmatory trials, 1454
which have reached or are approaching maturity at the present time. In this issue of the Journalof Clinical Oncology, Wolmark et al have presented the preliminary results of the National Surgical Breast and Bowel Project (NSABP) confirmatory trial of portal-vein 5FU (plus heparin) hepatic infusion.3 The authors are to be commended for their ability to rapidly accrue such a large number of patients for their trial. The results in 1,158 patients with Dukes' A, B, and C colon cancer suggest an improvement in disease-free survival (one-sided P = .02) and a borderline improvement in overall survival (one-sided P = .07) for patients treated with portal-vein 5FU. Forty patients (3.5%) were ineligible. Chemotherapy produced little or no toxicity for most patients, although four episodes of small-bowel infarction (one fatal) were observed due to catheterinduced thrombosis. Preoperative randomization was also used in this study. However, in contradistinction to the experience of Tayor et al,' 18.7% of patients randomized were excluded from analysis either because they did not have cancer at all (5.2%) or were found to have distant metastasis (13.2%) at the time of surgery. Although the identification of this larger proportion of patients with occult distant metastasis may reflect particularly careful surgical staging, one can only speculate on what impact the exclusion of these 217 randomized patients could have on the analyses of therapeutic outcome. Also troubling from a methodologic standpoint was the inclusion of 210 patients with Dukes' A colon cancer. Since patients with this early stage of colon cancer have such an excellent prognosis with surgery alone, paralleling the survival experience of agematched controls without cancer, it is not clear why they were included in the study. It is even more perplexing that when the Dukes' A patients were excluded from the statistical analysis, the advantage for patients treated with portal-vein infusion 5FU for both disease-free and overall survival lost its statistical significance. A final comment on methodology relates to the preliminary nature of the results. As the authors point out, 3 follow-up information is complete for more than half the patients at the 3-year point,
Journal of Clinical Oncology, Vol 8, No 9 (September), 1990: pp 1454-1456
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 20, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1455
EDITORIAL
but survival information is available for only 33% of eligible patients at 4 years. It is well known that the results of interim analyses can vacillate markedly over time, and borderline survival advantages such as those seen in the NSABP trial may vanish when mature follow-up is available. Of particular interest in the NSABP trial was the observation that in spite of a putative improvement in disease-free survival, there was no reduction in the incidence of liver metastases among patients receiving portal-vein infusion 5FU. The same lack of suppression of hepatic metastases by portal-vein 5FU 4 or 5FU plus mitomycin 5 has also recently been reported in two other prospectively randomized clinical trials. These negative findings challenge the initial rationale for regional chemotherapy administration into the hepatic circulation. The authors of the NSABP trial raise the issue of whether the apparent benefit of portal-vein 5FU may be due to a systemic (rather than regional) effect of the chemotherapy. Although this possibility cannot be denied, if in fact there is a true benefit from portal-vein 5FU at all, it is not clear why the lower systemic concentrations of 5FU would be effective in supressing distant metastases when presumably higher regional drug concentrations were ineffective in eradicating microscopic disease within the liver. It is also of interest in this regard that perioperative systemic adjuvant chemotherapy with the related fluorinated pyrimidine 5-fluorodeoxyuridine, albeit given by a different schedule of administration, was not effective in an early study conducted by the Veterans Administration Surgical Adjuvant Group. 6 What about results from other confirmatory studies of portal-vein infusion 5FU? The Mayo/ North Central Cancer Treatment Group trial4 randomized 224 patients with Dukes' B2 or C colorectal cancer based on intraoperative surgical findings and frozen section pathology to either portal-vein 5FU (500 mg/m 2 plus 5,000 U heparin/d x 7 days) or control. The number of ineligible patients was 2.2%, and median follow-up was 51/2 years. There was no reduction in the incidence of liver metastases, and an adequate number of patients was treated to exclude a 30% reduction in the death rate (P < .05). A limitation of this trial was that not enough patients were studied to confidently exclude a
smaller degree of therapeutic effect, although the clinical relevance of such a small degree of benefit can be questioned based upon recent advances in systemic adjuvant chemotherapy with 5FU plus levamisole (see below). Metzger et al recently updated the results of their trial of portal-vein infusion 5FU plus mitomycin. 5'7 Five hundred thirty-three patients were preoperatively randomized to surgery alone or surgery followed by portal-vein infusion 5FU (500 mg/m 2/d x 7 days) plus a single dose of mitomycin 10 mg/m 2. Sixty-eight patients (12.8%) were excluded based on operative findings. With a median follow-up of 54.3 months, the incidence of liver metastases has not been decreased in patients receiving portal-vein 5FU plus mitomycin. However, survival appears to be superior in patients receiving adjuvant chemotherapy (P = .03). Five-year survival estimates were 71% for treated patients and 57% for controls. The Swiss group is currently comparing surgery alone, perioperative portal-vein infusion 5FU plus mitomycin, and systemic 5FU plus mitomycin to confirm their results and directly assess the importance of route of chemotherapy administration. Wereldsma et al recently published the results of a Dutch trial8 comparing portal-vein infusion 5FU plus heparin, portal-vein infusion of urokinase, or control. Three hundred seventeen patients were randomized intraoperatively. The incidence of liver metastases was decreased from 23% in controls to 7% with 5FU plus heparin (18% of urokinase-treated patients developed liver metastases). However, there was no significant improvement in the death rate associated with portal-vein 5FU therapy. In addition to these trials, the mature results of several other portal-vein 5FU studies,9,t" including those reviewed by Metzger et al," are awaited with interest. It is important to place the results of portalvein 5FU therapy into some perspective with respect to other available surgical adjuvant regimens for patients with colon cancer. The recently reported intergroup trial 12 has unequivocally established the efficacy of systemic 5FU plus levamisole in patients with Dukes' C colon cancer-a 41% reduction in the recurrence rate (two-sided P < .0001), and a 33% reduction in the death rate (P = .006 by two-sided test). The
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 20, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1456
MICHAEL J. O'CONNELL
final results of 5FU plus levamisole are not yet available for patients with Dukes' B2 colon cancer. This regimen has been endorsed by a National Institutes of Health Consensus Development Conference as a new standard for comparison for patients with Dukes' C colon cancer in clinical trials, and a treatment to be recommended in clinical practice for individuals with Dukes' C colon cancer who are unable to participate in a clinical trial. In conclusion, in 1990 the value of portal-vein infusion 5FU as adjuvant therapy for colon
cancer remains controversial and unproven. However, there is a general consensus that is shared by the authors of the individual published clinical trials and this editorialist: Portal-vein infusion 5FU is not recommended in clinical practice based on all available information at the present time.
Michael J. O'Connell Mayo Clinic Rochester, MN
REFERENCES 1. Taylor I, Rowling J, West C: Adjuvant cytotoxic liver perfusion for colorectal cancer. Br J Surg 66:833-837, 1979 2. Taylor I, Machin D, Mullee M, et al: A randomized controlled trial of adjuvant portal vein cytotoxic perfusion in colorectal cancer. Br J Surg 72:359-363, 1985 3. Wolmark N, Rockette H, Wickerham DL, et al: Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: Preliminary results of National Surgical Adjuvant Breast and Bowel Project protocol C-02. J Clin Oncol 8:1466-1475, 1990 4. Beart RW Jr, Moertel CG, Wieand HS, et al: A randomized trial of 5-fluorouracil by portal vein infusion as surgical adjuvant therapy for colorectal cancer. Presented at the 42nd Annual Cancer Symposium of the Society of Surgical Oncology and the 35th Annual Meeting of the Society of Head and Neck Surgeons, San Francisco, CA, May 21-24, 1989 (abstr 204) 5. Metzger U, Laffer U, Castiglione M, et al: Randomized multi-center trial of adjuvant intraportal 5FU + mitomycin C chemotherapy for colorectal cancer (SAKK 40/81). NIH Consensus Development Conference on Adjuvant Therapy for Patients With Colon and Rectum Cancer. April 16-18, 1990 (abstr) 6. Dwight RW, Humphrey EW, Higgins GA, et al: FUDR
as an adjuvant to surgery in cancer of the large bowel. J Surg Oncol 5:243-249, 1973 7. Metzger U, Laffer U, Casteglione M, et al: Adjuvant intraportal chemotherapy for colorectal cancer-4-year results of the randomized Swiss study (SAKK 40/81). Proc Am Soc Clin Oncol 8:407, 1989 (abstr) 8. Wereldsma JCJ, Bruggink EMD, Meijer WS, et al: Adjuvant portal liver infusion in colorectal cancer with 5-fluorouracil/heparin vs urokinase vs control. Cancer 65:425432, 1990 9. Gray BN, DeZwart J, Fisher R, et al: The Australia and New Zealand trial of adjuvant chemotherapy in colon cancer, in Salmon S (ed): Adjuvant Therapy of Cancer vol 5. Philadelphia, PA, Grune & Stratton, 1987, pp 537-546 10. Ryan J, Weiden P, Crowley J, et al: Adjuvant portal vein infusion for colorectal cancer: A 3-arm randomized trial. Proc Am Soc Clin Oncol 7:361, 1988 (abstr) 11. Metzger U, Mermillod B, Aeberhard E, et al: Intraportal chemotherapy in colorectal carcinoma as an adjuvant modality. World J Surg 11:452-458, 1987 12. Moertel CG, Fleming TR, MacDonald JS, et al: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352-358, 1990
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 20, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
Is Portal-Vein Fluorouracil Hepatic Infusion Effective Colon Cancer Surgical Adjuvant Therapy?
IN
1975, a prospectively randomized trial of adjuvant portal-vein cytotoxic perfusion in colorectal cancer was initiated at the University of Liverpool, United Kingdom, by Taylor et al.' The rationale for this approach as outlined by Taylor et al was straightforward: (1) the liver is a frequent site of failure following potentially curative surgical resection of primary carcinomas of the colon or rectum, and liver metastasis is a prominent cause of death; (2) colorectal liver metastases reach the liver via the portal vein, therefore, administration of a cytotoxic agent using the same route of administration directly into the liver might be more effective than systemic administration; and (3) operative stress has been shown in some experimental systems to improve the survival of malignant cells and to facilitate them to establish growth in the liver; therefore, early perioperative chemotherapy administration might be particularly beneficial destroying suspected tumor cells in the liver before established tumor growth has taken place. The treatment chosen was a generally nontoxic regimen of fluorouracil (5FU)1.0 g (total dose) per day as a continuous infusion during the first 7 postoperative days. Heparin (5,000 U/d) was added to discourage portal-vein thrombosis. The results of this trial, published in 1985,2 were strikingly positive. Twenty-two of 127 control patients (18%) developed liver metastases, in contrast to only five of 117 (4%) who underwent portal-vein 5FU therapy. Survival analyses indicated a major beneficial effect of adjuvant portalvein 5FU with a death rate ratio (controls: treated) of 2.08 (P = .002). Exploratory subset analysis suggested survival benefit only in patients with Dukes' B colon cancer. The median follow-up of patients was 4 years, and only 5% of randomized patients were excluded from analysis, even though randomization occurred prior to surgery. Chemotherapy was generally well tolerated, although one patient died with leukopenia and sepsis. The authors appropriately stated that "it is essential therefore that further studies be performed to confirm this apparent benefit before the treatment is administered to patients outside a clinical trial setting." Indeed, the results of this study have motivated multiple confirmatory trials, 1454
which have reached or are approaching maturity at the present time. In this issue of the Journalof Clinical Oncology, Wolmark et al have presented the preliminary results of the National Surgical Breast and Bowel Project (NSABP) confirmatory trial of portal-vein 5FU (plus heparin) hepatic infusion.3 The authors are to be commended for their ability to rapidly accrue such a large number of patients for their trial. The results in 1,158 patients with Dukes' A, B, and C colon cancer suggest an improvement in disease-free survival (one-sided P = .02) and a borderline improvement in overall survival (one-sided P = .07) for patients treated with portal-vein 5FU. Forty patients (3.5%) were ineligible. Chemotherapy produced little or no toxicity for most patients, although four episodes of small-bowel infarction (one fatal) were observed due to catheterinduced thrombosis. Preoperative randomization was also used in this study. However, in contradistinction to the experience of Tayor et al,' 18.7% of patients randomized were excluded from analysis either because they did not have cancer at all (5.2%) or were found to have distant metastasis (13.2%) at the time of surgery. Although the identification of this larger proportion of patients with occult distant metastasis may reflect particularly careful surgical staging, one can only speculate on what impact the exclusion of these 217 randomized patients could have on the analyses of therapeutic outcome. Also troubling from a methodologic standpoint was the inclusion of 210 patients with Dukes' A colon cancer. Since patients with this early stage of colon cancer have such an excellent prognosis with surgery alone, paralleling the survival experience of agematched controls without cancer, it is not clear why they were included in the study. It is even more perplexing that when the Dukes' A patients were excluded from the statistical analysis, the advantage for patients treated with portal-vein infusion 5FU for both disease-free and overall survival lost its statistical significance. A final comment on methodology relates to the preliminary nature of the results. As the authors point out, 3 follow-up information is complete for more than half the patients at the 3-year point,
Journal of Clinical Oncology, Vol 8, No 9 (September), 1990: pp 1454-1456
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 20, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1455
EDITORIAL
but survival information is available for only 33% of eligible patients at 4 years. It is well known that the results of interim analyses can vacillate markedly over time, and borderline survival advantages such as those seen in the NSABP trial may vanish when mature follow-up is available. Of particular interest in the NSABP trial was the observation that in spite of a putative improvement in disease-free survival, there was no reduction in the incidence of liver metastases among patients receiving portal-vein infusion 5FU. The same lack of suppression of hepatic metastases by portal-vein 5FU 4 or 5FU plus mitomycin 5 has also recently been reported in two other prospectively randomized clinical trials. These negative findings challenge the initial rationale for regional chemotherapy administration into the hepatic circulation. The authors of the NSABP trial raise the issue of whether the apparent benefit of portal-vein 5FU may be due to a systemic (rather than regional) effect of the chemotherapy. Although this possibility cannot be denied, if in fact there is a true benefit from portal-vein 5FU at all, it is not clear why the lower systemic concentrations of 5FU would be effective in supressing distant metastases when presumably higher regional drug concentrations were ineffective in eradicating microscopic disease within the liver. It is also of interest in this regard that perioperative systemic adjuvant chemotherapy with the related fluorinated pyrimidine 5-fluorodeoxyuridine, albeit given by a different schedule of administration, was not effective in an early study conducted by the Veterans Administration Surgical Adjuvant Group. 6 What about results from other confirmatory studies of portal-vein infusion 5FU? The Mayo/ North Central Cancer Treatment Group trial4 randomized 224 patients with Dukes' B2 or C colorectal cancer based on intraoperative surgical findings and frozen section pathology to either portal-vein 5FU (500 mg/m 2 plus 5,000 U heparin/d x 7 days) or control. The number of ineligible patients was 2.2%, and median follow-up was 51/2 years. There was no reduction in the incidence of liver metastases, and an adequate number of patients was treated to exclude a 30% reduction in the death rate (P < .05). A limitation of this trial was that not enough patients were studied to confidently exclude a
smaller degree of therapeutic effect, although the clinical relevance of such a small degree of benefit can be questioned based upon recent advances in systemic adjuvant chemotherapy with 5FU plus levamisole (see below). Metzger et al recently updated the results of their trial of portal-vein infusion 5FU plus mitomycin. 5'7 Five hundred thirty-three patients were preoperatively randomized to surgery alone or surgery followed by portal-vein infusion 5FU (500 mg/m 2/d x 7 days) plus a single dose of mitomycin 10 mg/m 2. Sixty-eight patients (12.8%) were excluded based on operative findings. With a median follow-up of 54.3 months, the incidence of liver metastases has not been decreased in patients receiving portal-vein 5FU plus mitomycin. However, survival appears to be superior in patients receiving adjuvant chemotherapy (P = .03). Five-year survival estimates were 71% for treated patients and 57% for controls. The Swiss group is currently comparing surgery alone, perioperative portal-vein infusion 5FU plus mitomycin, and systemic 5FU plus mitomycin to confirm their results and directly assess the importance of route of chemotherapy administration. Wereldsma et al recently published the results of a Dutch trial8 comparing portal-vein infusion 5FU plus heparin, portal-vein infusion of urokinase, or control. Three hundred seventeen patients were randomized intraoperatively. The incidence of liver metastases was decreased from 23% in controls to 7% with 5FU plus heparin (18% of urokinase-treated patients developed liver metastases). However, there was no significant improvement in the death rate associated with portal-vein 5FU therapy. In addition to these trials, the mature results of several other portal-vein 5FU studies,9,t" including those reviewed by Metzger et al," are awaited with interest. It is important to place the results of portalvein 5FU therapy into some perspective with respect to other available surgical adjuvant regimens for patients with colon cancer. The recently reported intergroup trial 12 has unequivocally established the efficacy of systemic 5FU plus levamisole in patients with Dukes' C colon cancer-a 41% reduction in the recurrence rate (two-sided P < .0001), and a 33% reduction in the death rate (P = .006 by two-sided test). The
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 20, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1456
MICHAEL J. O'CONNELL
final results of 5FU plus levamisole are not yet available for patients with Dukes' B2 colon cancer. This regimen has been endorsed by a National Institutes of Health Consensus Development Conference as a new standard for comparison for patients with Dukes' C colon cancer in clinical trials, and a treatment to be recommended in clinical practice for individuals with Dukes' C colon cancer who are unable to participate in a clinical trial. In conclusion, in 1990 the value of portal-vein infusion 5FU as adjuvant therapy for colon
cancer remains controversial and unproven. However, there is a general consensus that is shared by the authors of the individual published clinical trials and this editorialist: Portal-vein infusion 5FU is not recommended in clinical practice based on all available information at the present time.
Michael J. O'Connell Mayo Clinic Rochester, MN
REFERENCES 1. Taylor I, Rowling J, West C: Adjuvant cytotoxic liver perfusion for colorectal cancer. Br J Surg 66:833-837, 1979 2. Taylor I, Machin D, Mullee M, et al: A randomized controlled trial of adjuvant portal vein cytotoxic perfusion in colorectal cancer. Br J Surg 72:359-363, 1985 3. Wolmark N, Rockette H, Wickerham DL, et al: Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: Preliminary results of National Surgical Adjuvant Breast and Bowel Project protocol C-02. J Clin Oncol 8:1466-1475, 1990 4. Beart RW Jr, Moertel CG, Wieand HS, et al: A randomized trial of 5-fluorouracil by portal vein infusion as surgical adjuvant therapy for colorectal cancer. Presented at the 42nd Annual Cancer Symposium of the Society of Surgical Oncology and the 35th Annual Meeting of the Society of Head and Neck Surgeons, San Francisco, CA, May 21-24, 1989 (abstr 204) 5. Metzger U, Laffer U, Castiglione M, et al: Randomized multi-center trial of adjuvant intraportal 5FU + mitomycin C chemotherapy for colorectal cancer (SAKK 40/81). NIH Consensus Development Conference on Adjuvant Therapy for Patients With Colon and Rectum Cancer. April 16-18, 1990 (abstr) 6. Dwight RW, Humphrey EW, Higgins GA, et al: FUDR
as an adjuvant to surgery in cancer of the large bowel. J Surg Oncol 5:243-249, 1973 7. Metzger U, Laffer U, Casteglione M, et al: Adjuvant intraportal chemotherapy for colorectal cancer-4-year results of the randomized Swiss study (SAKK 40/81). Proc Am Soc Clin Oncol 8:407, 1989 (abstr) 8. Wereldsma JCJ, Bruggink EMD, Meijer WS, et al: Adjuvant portal liver infusion in colorectal cancer with 5-fluorouracil/heparin vs urokinase vs control. Cancer 65:425432, 1990 9. Gray BN, DeZwart J, Fisher R, et al: The Australia and New Zealand trial of adjuvant chemotherapy in colon cancer, in Salmon S (ed): Adjuvant Therapy of Cancer vol 5. Philadelphia, PA, Grune & Stratton, 1987, pp 537-546 10. Ryan J, Weiden P, Crowley J, et al: Adjuvant portal vein infusion for colorectal cancer: A 3-arm randomized trial. Proc Am Soc Clin Oncol 7:361, 1988 (abstr) 11. Metzger U, Mermillod B, Aeberhard E, et al: Intraportal chemotherapy in colorectal carcinoma as an adjuvant modality. World J Surg 11:452-458, 1987 12. Moertel CG, Fleming TR, MacDonald JS, et al: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352-358, 1990
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