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of the study, and this probably explains why no treatment differences were seen. Was this also true of the present study? What were the received dose intensities in the three arms? William M. Hryniuk Hamilton Regional CancerCentre Hamilton, Canada REFERENCES 1. French Epirubicin Study Group: A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. J Clin Oncol 9:305-312, 1991 2. Hryniuk WM, Goodyear M: The calculation of received dose intensity. J Clin Oncol 8:1935-1937, 1990 (editorial) 3. Hortobagyi GN, Bodey GP, Buzdar AU, et al: Evaluation of high-dose versus standard FAC chemotherapy for advanced breast cancer in protected environment units: A prospective randomized study. J Clin Oncol 5:354-364, 1987 4. Hortobagyi GN, Hryniuk WM, Frye D, et al: Doseintensity (DI) analysis of high-dose (HD) chemotherapy for metastatic breast cancer (MBB). Proc Am Assoc Can Res 30:252, 1989 (abstr)
Reply To the Editor: We appreciate the comments of Dr Hryniuk about our study.' The mean epirubicin dose intensity actually received by the patients had been calculated and was 15.06, 22.06, and 23.23 mg/m2/wk in the FEC-50, the FEC-75, and epirubicin-alone groups, respectively. The calculation accounted for both possible dose reductions and/or treatment delays. The dose intensity was clearly higher in the two groups with the high epirubicin dose. Patients in the FEC-75 group had a 46.7% higher epirubicin dose intensity than in the FEC-50 group; patients in the epirubicin-alone group had a 54.2% higher dose intensity than in the FEC-50 group. The statement in the text (p 310) was probably not clear; 90.4%, 88.3%, and 92.9% were refering to the ratio of the actually received epirubicin dose intensity to the theoretical one calculated as a mean in each treatment arm. For example, in the FEC-75 group: 88.3% = 100 x Epirubicin Mean Dose Intensity Received Epirubicin Theoretical Dose Intensity Planned 22.06 = 100 x 25 We were not aware of the reanalysis2 of the study by Hortobagyi et al. 3 It is interesting to note that, in that study, dose intensity was not different in the two arms. This clearly was not the case in our study. J. Bonneterre for the French Epirubicin Study Group Centre OscarLambret Lille, France
REFERENCES 1. French Epirubicin Study Group: A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. J Clin Oncol 9:305-312, 1991 2. Hortobagyi GN, Hryniuk WM, Frye D, et al: Doseintensity (DI) analysis of high-dose (HD) chemotherapy for metastatic breast cancer (MBB). Proc Am Assoc Can Res 30:252, 1989 (abstr) 3. Hortobagyi GN, Bodey GP, Buzdar AU, et al: Evaluation of high-dose versus standard FAC chemotherapy for advanced breast cancer in protected environment units: A prospective randomized study. J Clin Oncol 5:354-364, 1987
What is the Value of Methotrexate in the Treatment ofAdvanced Colorectal Cancer? To the Editor: We read the recent article by Marsh et al' with interest but remain uncertain regarding the role of methotrexate in the treatment of advanced colorectal cancer. This prospectively randomized trial suggests that sequential methotrexate (with leucovorin rescue) followed by fluorouracil (FU) 24 hours later is superior to the same drug combination with FU given 1 hour after methotrexate. In the Discussion section of the paper, the authors quote data from a Mayo/North Central Cancer Treatment Group clinical trial' in support of increased efficacy of the methotrexate/FU combination when a 24-hour interval between drugs is used instead of a 7-hour interval. We question this interpretation of our data. We found no significant difference in objective tumor response rate among patients treated with these two regimens (26% v 21%). More importantly, the major end point in our trial was patient survival, for which all randomized patients were evaluable regardless of whether or not they had a measurable indicator lesion. Using this measure of treatment effect, the median survival was 7.7 months for FU alone versus 8.7 months for the combination regimen containing FU at hour 24 (P = .25, one-sided log-rank test). The methotrexate regimen giving FU at hour 7 yielded a somewhat longer median survival of 10.5 months (P = .21 compared with single-agent FU). According to study design, we dropped the 24-hour regimen entirely from our protocol but continued to study the 7-hour regimen in comparison with two FU plus leucovorin regimens without methotrexate.3 The updated results of this comparison indicate unequivocally (P = .01) that FU plus low-dose leucovorin is significantly superior to methotrexate (with leucovorin rescue) and FU at hour 7 with respect to patient survival. The results of the Nordic Gastrointestinal Tumor Adjuvant Therapy Group trial4 are also quoted in support of enhanced efficacy of a long interval between methotrexate and FU. However, since the FU in this study was given in divided doses-one at 3 hours and one at 23 hours after methotrexate-it would seem difficult to rationalize that the 23-hour dose was effective whereas the 3-hour dose was not. In spite of the study reported by Marsh et al,' we are unconvinced that a 24-hour interval represents the optimal timing of methotrexate and FU. One of the coauthors of this
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 7, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
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CORRESPONDENCE report, Dr Bertino, provided in part the basis for our selection of a 7-hour interval. In a literature review,5 Bertino et al found the response rate in colorectal cancer was lowest (10%) with an interval of 1 hour, highest (37%) with an interval of 4 to 7 hours, and intermediate (31%) with an interval of 24 hours. Some investigators6 have seen such low tumor response rates with sequential methotrexate (with leucovorin rescue) plus FU, regardless of treatment interval, that the possibility was raised that methotrexate may actually be inhibitory to the combination of FU and leucovorin. In conclusion, the data reported by Marsh et al certainly suggest that methotrexate followed by FU at a 1-hour interval is an inferior regimen. However, as the authors recognized, further controlled trials will be required to determine if their more active regimen (24-hour interval) offers an advantage over other treatments such as FU plus leucovorin, without any methotrexate at all. Michael J. O'Connell Charles G. Moertel Mayo Clinic Rochester, MN Michael A. Poon Saskatchewan Cancer Foundation Regina, Canada REFERENCES 1. Marsh JC, Bertino JR, Katz KH, et al: The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer. J Clin Oncol 9:371-380, 1991 2. Poon MA, O'Connell MJ, Moertel CG, et al: Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7:1407-1417, 1989 3. O'Connell M, Poon M, Wieand H, et al: Biochemical modulation of 5-fluorouracil (5FU) with leucovorin (LV): Confirmatory evidence of improved therapeutic efficacy in the treatment of advanced colorectal cancer. Proc Am Soc Clin Oncol 9:106, 1990 (abstr) 4. Nordic Gastrointestinal Tumor Adjuvant Therapy Group: Superiority of sequential methotrexate, fluorouracil, and leucovorin to fluorouracil alone in advanced symptomatic colorectal carcinoma: A randomized trial. J Clin Oncol 7:1437-1446, 1989 5. Bertino JR, Mini E, Sobrero A: Sequential methotrexate and 5-fluorouracil in the treatment of solid tumors, in Kimura K (ed): Fluoropyrimidines in Cancer Therapy. Excerpta Medica, 1984, pp 251-260 6. Weinerman B, Maroun J, Stewart D, et al: Sequential methotrexate, 5-fluorouracil, and leucovorin in metastatic measurable colorectal cancer. Does it work? Cancer Invest 8:339-343, 1990
Reply To the Editor:. We appreciate the interest of the North Central Cancer Treatment Group (NCCTG) and Mayo Clinic investigators, who have performed so many valuable trials over the years
in gastrointestinal cancer. We certainly had no intention of misinterpreting their data and do not believe that we did. We did not indicate in our discussion' that the five clinical trials cited even came close to answering the interval question that our study addressed but merely reviewed the relevant controlled clinical trials of the methotrexate (MTX)/ fluorouracil(FU) combination in colorectal cancer. We indicated that where there were trends, they supported the longer interval. We did not state that the response rates of the high-dose MTX, 7-hour FU, and low-dose MTX, 24-hour FU regimens of Poon et al 2 were different from each other (21% v 26%) but that the latter was significantly different from FU alone (P = .04, from their Fig 5), whereas the high-dose, shorter-interval regimen apparently was not, since no P value was given. Incidentally, we apologize for the typographical error in our Table 5, which they graciously do not mention; we cited the response rate for the high-dose MTX, 7-hour interval as 12% instead of the correct 21%. We agree that survival is a more important end point than response rate and, for that reason, indicated in our Table 5 that the response rates reported by Poon et a12 referred to their patients with measurable disease only. Our study shows significant survival differences as well as response rates between the two arms, with all patients having measurable disease. We are pleased to see the median survival data for the two MTX/FU arms from their study. From their Table 3 giving estimated hazards ratios and P values for progression-free and overall survival, we concluded that they are equivalent. The only survival difference for any of the previous trials between FU alone and the FU/MTX combination was seen in the Nordic Gastrointestinal Tumor Adjuvant Therapy Group study,3 which used FU in divided doses, as we noted in our Table 5. We did not rationalize that the 23-hour dose was effective while the 3-hour dose was not but do point out that the only controlled clinical trial to claim a survival advantage for the combination included a 24-hour interval. The issue of optimal timing of MTX-FU certainly cannot be answered definitively from the available data. The review by Bertino et al4 in 1984 was derived from multiple sources and cannot be construed to mean that the 4- to 7-hour interval is superior to a longer interval, without direct comparison, with optimal doses of MTX. The optimal interval is probably tissue- and species-dependent. Although murine tumor cells in vitro have an optimal interval of 3 to 4 hours for synergy,5 the optimum interview was 12 to 24 hours for a human colon cancer cell line.' From such in vitro studies it has become clear that time, dose, and sequence are all important determinants; and inhibitory 7 effects, such as those alluded to, can certainly be seen in 8 vitro as well. Our schedule was chosen on the basis of what we perceived to be the best in vitro interval in colon cancer, with a moderately high dose of MTX and with dose escalation of FU as tolerated every 2 weeks. The NCCTG used high-dose MTX with a 3- to 7-hour interval until FU was given every 3 weeks x 3, then every 4 weeks; the low-dose MTX with a 24-hour interval until FU was given twice at weekly intervals and repeated 3 weeks after the last dose. These regimens may not be optimal for colon cancer, as the frequency of drug administration was less than that in our study.
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 7, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
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CORRESPONDENCE
The fact that the NCCTG has dropped the 24-hour regimen (low-dose MTX) in favor of the 7-hour regimen (high-dose, with leucovorin rescue) and has found the latter "unequivocally" inferior to FU plus low-dose leucovorin does not settle the issue of optimal MTX-FU timing or the role of MTX in this disease. Since our patients all had measurable disease, and the 24-hour group had a median survival of 15.3 months, we think it compares quite favorably to the median survival of 12 months with a substantial (45%) proportion of patients with unmeasurable disease for 2 FU plus low-dose leucovorin reported by Poon et al. Indeed, their Fig 4 and text indicate that the major treatment benefit (survival distribution) for the two FUleucovorin regimens compared with FU alone was seen in patients with nonmeasurable metastatic disease (P = .004, .010) but not in those with measurable metastatic disease (P > .34). We agree with the final paragraph of Drs O'Connell, Poon, and Moertel. Our data suggest, indeed demonstrate, that the 1-hour interval for this regimen is inferior to the 24-hour interval for metastatic colon cancer. We did not find a difference for patients with rectal primary tumors, although the numbers are smaller. We too remain uncertain regarding the role of MTX in colorectal cancer but do not consider that the NCCTG study has eliminated its potential usefulness. We welcome a comparison of the best arm from our study with other promising treatments, including FU plus leucovorin. John C. Marsh Yale University School of Medicine New Haven, CT Joseph R. Bertino Memorial Sloan-KetteringCancer Center New York, NY
REFERENCES 1. Marsh JC, Bertino JR, Katz KH, et al: The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer. J Clin Oncol 9:371-380, 1991 2. Poon MA, O'Connell MJ, Moertel CG, et al: Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7:1407-1417, 1989 3. Nordic Gastrointestinal Tumor Adjuvant Therapy Group: Superiority of sequential methotrexate, fluorouracil and leucovorin to fluorouracil alone in advanced symptomatic colorectal carcinoma: A randomized trial. J Clin Oncol 7:1437-1446, 1989 4. Bertino JR, Mini E, Sobrero A: Sequential methotrexate and 5-fluorouracil in the treatment of solid tumors, in Kimura K (ed): Fluoropyrimidines in Cancer Therapy. Excerpta Medica, 1984, pp 251-260 5. Fernandes DJ, Bertino JR: 5-Fluorouracil-methotrexate synergy. Enhancement of 5-fluorodeoxyuridine binding to thymidylate synthetase by dihydropteroyl-polyglutamates. Proc Natl Acad Sci USA 77:5663-5667, 1980 6. Benz C, Cadman E: Modulation of 5-fluorouracil metabolism and cytotoxicity by antimetabolite pretreatment in human colorectal adenocarcinoma, HCT-8. Cancer Res 41:994-999, 1981 7. Weinerman B, Maroun J, Stewart D, et al: Sequential methotrexate, 5-fluorouracil and leucovorin in metastatic measurable colorectal cancer. Does it work? Cancer Invest 8:339-343, 1990 8. Mini E, Moroson BA, Blair OC, et al: Time, dose and sequence relationships for methotrexate, fluorouracil, and their combinations for optimal cell kill in the human T-lymphoid cell line CCRF-CEM. Chemioterapia 2:452453, 1983 (suppl 5)
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 7, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
CORRESPONDENCE
of the study, and this probably explains why no treatment differences were seen. Was this also true of the present study? What were the received dose intensities in the three arms? William M. Hryniuk Hamilton Regional CancerCentre Hamilton, Canada REFERENCES 1. French Epirubicin Study Group: A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. J Clin Oncol 9:305-312, 1991 2. Hryniuk WM, Goodyear M: The calculation of received dose intensity. J Clin Oncol 8:1935-1937, 1990 (editorial) 3. Hortobagyi GN, Bodey GP, Buzdar AU, et al: Evaluation of high-dose versus standard FAC chemotherapy for advanced breast cancer in protected environment units: A prospective randomized study. J Clin Oncol 5:354-364, 1987 4. Hortobagyi GN, Hryniuk WM, Frye D, et al: Doseintensity (DI) analysis of high-dose (HD) chemotherapy for metastatic breast cancer (MBB). Proc Am Assoc Can Res 30:252, 1989 (abstr)
Reply To the Editor: We appreciate the comments of Dr Hryniuk about our study.' The mean epirubicin dose intensity actually received by the patients had been calculated and was 15.06, 22.06, and 23.23 mg/m2/wk in the FEC-50, the FEC-75, and epirubicin-alone groups, respectively. The calculation accounted for both possible dose reductions and/or treatment delays. The dose intensity was clearly higher in the two groups with the high epirubicin dose. Patients in the FEC-75 group had a 46.7% higher epirubicin dose intensity than in the FEC-50 group; patients in the epirubicin-alone group had a 54.2% higher dose intensity than in the FEC-50 group. The statement in the text (p 310) was probably not clear; 90.4%, 88.3%, and 92.9% were refering to the ratio of the actually received epirubicin dose intensity to the theoretical one calculated as a mean in each treatment arm. For example, in the FEC-75 group: 88.3% = 100 x Epirubicin Mean Dose Intensity Received Epirubicin Theoretical Dose Intensity Planned 22.06 = 100 x 25 We were not aware of the reanalysis2 of the study by Hortobagyi et al. 3 It is interesting to note that, in that study, dose intensity was not different in the two arms. This clearly was not the case in our study. J. Bonneterre for the French Epirubicin Study Group Centre OscarLambret Lille, France
REFERENCES 1. French Epirubicin Study Group: A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. J Clin Oncol 9:305-312, 1991 2. Hortobagyi GN, Hryniuk WM, Frye D, et al: Doseintensity (DI) analysis of high-dose (HD) chemotherapy for metastatic breast cancer (MBB). Proc Am Assoc Can Res 30:252, 1989 (abstr) 3. Hortobagyi GN, Bodey GP, Buzdar AU, et al: Evaluation of high-dose versus standard FAC chemotherapy for advanced breast cancer in protected environment units: A prospective randomized study. J Clin Oncol 5:354-364, 1987
What is the Value of Methotrexate in the Treatment ofAdvanced Colorectal Cancer? To the Editor: We read the recent article by Marsh et al' with interest but remain uncertain regarding the role of methotrexate in the treatment of advanced colorectal cancer. This prospectively randomized trial suggests that sequential methotrexate (with leucovorin rescue) followed by fluorouracil (FU) 24 hours later is superior to the same drug combination with FU given 1 hour after methotrexate. In the Discussion section of the paper, the authors quote data from a Mayo/North Central Cancer Treatment Group clinical trial' in support of increased efficacy of the methotrexate/FU combination when a 24-hour interval between drugs is used instead of a 7-hour interval. We question this interpretation of our data. We found no significant difference in objective tumor response rate among patients treated with these two regimens (26% v 21%). More importantly, the major end point in our trial was patient survival, for which all randomized patients were evaluable regardless of whether or not they had a measurable indicator lesion. Using this measure of treatment effect, the median survival was 7.7 months for FU alone versus 8.7 months for the combination regimen containing FU at hour 24 (P = .25, one-sided log-rank test). The methotrexate regimen giving FU at hour 7 yielded a somewhat longer median survival of 10.5 months (P = .21 compared with single-agent FU). According to study design, we dropped the 24-hour regimen entirely from our protocol but continued to study the 7-hour regimen in comparison with two FU plus leucovorin regimens without methotrexate.3 The updated results of this comparison indicate unequivocally (P = .01) that FU plus low-dose leucovorin is significantly superior to methotrexate (with leucovorin rescue) and FU at hour 7 with respect to patient survival. The results of the Nordic Gastrointestinal Tumor Adjuvant Therapy Group trial4 are also quoted in support of enhanced efficacy of a long interval between methotrexate and FU. However, since the FU in this study was given in divided doses-one at 3 hours and one at 23 hours after methotrexate-it would seem difficult to rationalize that the 23-hour dose was effective whereas the 3-hour dose was not. In spite of the study reported by Marsh et al,' we are unconvinced that a 24-hour interval represents the optimal timing of methotrexate and FU. One of the coauthors of this
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 7, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
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CORRESPONDENCE report, Dr Bertino, provided in part the basis for our selection of a 7-hour interval. In a literature review,5 Bertino et al found the response rate in colorectal cancer was lowest (10%) with an interval of 1 hour, highest (37%) with an interval of 4 to 7 hours, and intermediate (31%) with an interval of 24 hours. Some investigators6 have seen such low tumor response rates with sequential methotrexate (with leucovorin rescue) plus FU, regardless of treatment interval, that the possibility was raised that methotrexate may actually be inhibitory to the combination of FU and leucovorin. In conclusion, the data reported by Marsh et al certainly suggest that methotrexate followed by FU at a 1-hour interval is an inferior regimen. However, as the authors recognized, further controlled trials will be required to determine if their more active regimen (24-hour interval) offers an advantage over other treatments such as FU plus leucovorin, without any methotrexate at all. Michael J. O'Connell Charles G. Moertel Mayo Clinic Rochester, MN Michael A. Poon Saskatchewan Cancer Foundation Regina, Canada REFERENCES 1. Marsh JC, Bertino JR, Katz KH, et al: The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer. J Clin Oncol 9:371-380, 1991 2. Poon MA, O'Connell MJ, Moertel CG, et al: Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7:1407-1417, 1989 3. O'Connell M, Poon M, Wieand H, et al: Biochemical modulation of 5-fluorouracil (5FU) with leucovorin (LV): Confirmatory evidence of improved therapeutic efficacy in the treatment of advanced colorectal cancer. Proc Am Soc Clin Oncol 9:106, 1990 (abstr) 4. Nordic Gastrointestinal Tumor Adjuvant Therapy Group: Superiority of sequential methotrexate, fluorouracil, and leucovorin to fluorouracil alone in advanced symptomatic colorectal carcinoma: A randomized trial. J Clin Oncol 7:1437-1446, 1989 5. Bertino JR, Mini E, Sobrero A: Sequential methotrexate and 5-fluorouracil in the treatment of solid tumors, in Kimura K (ed): Fluoropyrimidines in Cancer Therapy. Excerpta Medica, 1984, pp 251-260 6. Weinerman B, Maroun J, Stewart D, et al: Sequential methotrexate, 5-fluorouracil, and leucovorin in metastatic measurable colorectal cancer. Does it work? Cancer Invest 8:339-343, 1990
Reply To the Editor:. We appreciate the interest of the North Central Cancer Treatment Group (NCCTG) and Mayo Clinic investigators, who have performed so many valuable trials over the years
in gastrointestinal cancer. We certainly had no intention of misinterpreting their data and do not believe that we did. We did not indicate in our discussion' that the five clinical trials cited even came close to answering the interval question that our study addressed but merely reviewed the relevant controlled clinical trials of the methotrexate (MTX)/ fluorouracil(FU) combination in colorectal cancer. We indicated that where there were trends, they supported the longer interval. We did not state that the response rates of the high-dose MTX, 7-hour FU, and low-dose MTX, 24-hour FU regimens of Poon et al 2 were different from each other (21% v 26%) but that the latter was significantly different from FU alone (P = .04, from their Fig 5), whereas the high-dose, shorter-interval regimen apparently was not, since no P value was given. Incidentally, we apologize for the typographical error in our Table 5, which they graciously do not mention; we cited the response rate for the high-dose MTX, 7-hour interval as 12% instead of the correct 21%. We agree that survival is a more important end point than response rate and, for that reason, indicated in our Table 5 that the response rates reported by Poon et a12 referred to their patients with measurable disease only. Our study shows significant survival differences as well as response rates between the two arms, with all patients having measurable disease. We are pleased to see the median survival data for the two MTX/FU arms from their study. From their Table 3 giving estimated hazards ratios and P values for progression-free and overall survival, we concluded that they are equivalent. The only survival difference for any of the previous trials between FU alone and the FU/MTX combination was seen in the Nordic Gastrointestinal Tumor Adjuvant Therapy Group study,3 which used FU in divided doses, as we noted in our Table 5. We did not rationalize that the 23-hour dose was effective while the 3-hour dose was not but do point out that the only controlled clinical trial to claim a survival advantage for the combination included a 24-hour interval. The issue of optimal timing of MTX-FU certainly cannot be answered definitively from the available data. The review by Bertino et al4 in 1984 was derived from multiple sources and cannot be construed to mean that the 4- to 7-hour interval is superior to a longer interval, without direct comparison, with optimal doses of MTX. The optimal interval is probably tissue- and species-dependent. Although murine tumor cells in vitro have an optimal interval of 3 to 4 hours for synergy,5 the optimum interview was 12 to 24 hours for a human colon cancer cell line.' From such in vitro studies it has become clear that time, dose, and sequence are all important determinants; and inhibitory 7 effects, such as those alluded to, can certainly be seen in 8 vitro as well. Our schedule was chosen on the basis of what we perceived to be the best in vitro interval in colon cancer, with a moderately high dose of MTX and with dose escalation of FU as tolerated every 2 weeks. The NCCTG used high-dose MTX with a 3- to 7-hour interval until FU was given every 3 weeks x 3, then every 4 weeks; the low-dose MTX with a 24-hour interval until FU was given twice at weekly intervals and repeated 3 weeks after the last dose. These regimens may not be optimal for colon cancer, as the frequency of drug administration was less than that in our study.
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 7, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
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CORRESPONDENCE
The fact that the NCCTG has dropped the 24-hour regimen (low-dose MTX) in favor of the 7-hour regimen (high-dose, with leucovorin rescue) and has found the latter "unequivocally" inferior to FU plus low-dose leucovorin does not settle the issue of optimal MTX-FU timing or the role of MTX in this disease. Since our patients all had measurable disease, and the 24-hour group had a median survival of 15.3 months, we think it compares quite favorably to the median survival of 12 months with a substantial (45%) proportion of patients with unmeasurable disease for 2 FU plus low-dose leucovorin reported by Poon et al. Indeed, their Fig 4 and text indicate that the major treatment benefit (survival distribution) for the two FUleucovorin regimens compared with FU alone was seen in patients with nonmeasurable metastatic disease (P = .004, .010) but not in those with measurable metastatic disease (P > .34). We agree with the final paragraph of Drs O'Connell, Poon, and Moertel. Our data suggest, indeed demonstrate, that the 1-hour interval for this regimen is inferior to the 24-hour interval for metastatic colon cancer. We did not find a difference for patients with rectal primary tumors, although the numbers are smaller. We too remain uncertain regarding the role of MTX in colorectal cancer but do not consider that the NCCTG study has eliminated its potential usefulness. We welcome a comparison of the best arm from our study with other promising treatments, including FU plus leucovorin. John C. Marsh Yale University School of Medicine New Haven, CT Joseph R. Bertino Memorial Sloan-KetteringCancer Center New York, NY
REFERENCES 1. Marsh JC, Bertino JR, Katz KH, et al: The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer. J Clin Oncol 9:371-380, 1991 2. Poon MA, O'Connell MJ, Moertel CG, et al: Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7:1407-1417, 1989 3. Nordic Gastrointestinal Tumor Adjuvant Therapy Group: Superiority of sequential methotrexate, fluorouracil and leucovorin to fluorouracil alone in advanced symptomatic colorectal carcinoma: A randomized trial. J Clin Oncol 7:1437-1446, 1989 4. Bertino JR, Mini E, Sobrero A: Sequential methotrexate and 5-fluorouracil in the treatment of solid tumors, in Kimura K (ed): Fluoropyrimidines in Cancer Therapy. Excerpta Medica, 1984, pp 251-260 5. Fernandes DJ, Bertino JR: 5-Fluorouracil-methotrexate synergy. Enhancement of 5-fluorodeoxyuridine binding to thymidylate synthetase by dihydropteroyl-polyglutamates. Proc Natl Acad Sci USA 77:5663-5667, 1980 6. Benz C, Cadman E: Modulation of 5-fluorouracil metabolism and cytotoxicity by antimetabolite pretreatment in human colorectal adenocarcinoma, HCT-8. Cancer Res 41:994-999, 1981 7. Weinerman B, Maroun J, Stewart D, et al: Sequential methotrexate, 5-fluorouracil and leucovorin in metastatic measurable colorectal cancer. Does it work? Cancer Invest 8:339-343, 1990 8. Mini E, Moroson BA, Blair OC, et al: Time, dose and sequence relationships for methotrexate, fluorouracil, and their combinations for optimal cell kill in the human T-lymphoid cell line CCRF-CEM. Chemioterapia 2:452453, 1983 (suppl 5)
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 7, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
