Journal of Surgical Oncology Supplement 2:112-115 (1991)
Advanced Colorectal Cancer: Impact of Chemotherapy on Survival ENRICO CORTESI, MD, A U G U S T 0 PADOVANI, MD, ALESSANDRA ALOE, MD, VlNCENZO PICECE, MD, PATRlZlA PELLEGRINI, MD, AND A. PELLEGRINI, MD From the Chair of Medical Oncology, Department of Experimental Medicine, The University of Rome “ l a Sapienza,” Rome, ltaly
KEYWORDS:colorectal carcinoma, lymph node involvement, metastatic disease, chemotherapy, survival
INTRODUCTION Colorectal carcinoma is the second most frequent cancer in the western world. In 1991, an estimated 155,000 cases of colorectal cancer will be diagnosed in the United States and at least 40% of them will die of the disease. In Italy more than 11,000 colorectal cancer patients will die each year. At the time of pathological diagnosis almost 50% of the patients will have lymph node involvement, and 10-25% will present with hepatic metastases. The 5-year relative survival rate for colon cancer increased from 41% in 1950 to 54% in 1980: that for rectal cancer increased from 40% to 5 1.5% in the same period [ 11. This trend might be due in part to improved diagnostic and screening techniques, leading to earlier detection and surgical treatment, with a better control of micrometastatic disease. In fact, such a survival improvement is not shown for the most advanced states and progress in the medical treatment of metastatic disease is very difficult to evaluate.
SYSTEMIC CHEMOTHERAPY The role of chemotherapy, single agents or combinations, regional and adjuvant therapy, in the management of colorectal cancer has to be established regarding its impact on survival. This article will describe whether chemotherapy given in any of its settings, locoregional or systemic, has any role in prolonging the life of colorectal cancer patients. Fluorouracil and folinic acid (FA) since the introduction by Heidelberger [13] in 1956 of 5-fluorouracil, (5-FU) has been employed as the standard treatment in colorectal cancer. There is no systemic chemotherapy, using either single agents or combiantions of cytotoxic drugs, which has been shown to modify the natural history of colorectal carcinoma. To date the fluorinated pyrimidines, with 5-FU being the most widely employed, 0 1991 Wiley-Liss, Inc.
have yielded a mean response rate (RR) of approximately 20% with no improvement in survival. The optimal method of administration of 5-FU is still controversial although the average RR is lower than the reported overall rate of 20%. In fact, in studies where the response measurements are clearly defined, the average RR is 15% [2].
5-FU
+ FA
Numerous clinical studies have been conducted in an attempt to improve the efficacy of this treatment: combinations of 5-FU with other drugs have failed to demonstrate better results; biochemical modulation of 5-FU with methotrexate, allopurinol, and other agents has had limited success. Biochemical studies of the mechanism of action of 5-FU have demonstrated that the intracellular level of CH-2-FH-4 were insufficient to allow optimal binding between FdUMP and TS: however, the addition of leucovorin to culture medium enhanced the cytotoxicity of 5-FU. A variety of phase I and I1 clinical trials using different schedules and doses of 5-FU and leucovorin have shown RR ranging from 12-50%; furthermore, they have indicated that this combination is more active in patients who have not received prior chemotherapy. The optimal dose of FA required to enhance the activity of 5-FU is not clearly defined; considering that concentrations greater than 10 mM are required for maximal potentiation of fluoropyrimidines in cell culture, doses of 200-500 mg/m2 intravenous (i.v.) of FA seem to be adequate to obtain a maximum effect. As shown in Tables I and I1 the combination of 5-FU and Citrovorum Factor increases 5-FU activity leading to a higher rate of response, particularly when higher doses Accepted for publication May 30, 1991. Address reprint requests to Professor Enrico Cortesi, Chair of Medical Oncology, Department of Experimental Medicine, The University of Rome “La Sapienza,” Viale del Policlinico 155, 00161, Rome, Italy.
Advanced Colorectal Cancer
113
TABLE I. Advanced Colorectal Carcinoma Phase 111 Clinical Trials: 5-FU Vs. 5-FU FA Weekly*
+
Trial IST-GE [ 141 (1988) GITSG [15) (1989) RPMI [ 161 (1987)
No. patients
5-FU
RR (%)
82
600
5
318
500
12
44
450
11
+ FA 600 + 500 600 + 500 600 + 500
5-FU
RR (%)
Survival
16
N.S.
30
46 vs. 55
48
N.S.
*The year in parentheses refers to the year the study was carried out. Reference numbers are in brackets.
TABLE 11. Advanced Colorectal Carcinoma Phase 111 Clinical Trials: 5-FU Vs. 5-FU f FA 5-Day Schedule* Trial NCOG [ 171 (1989) GOIRC [ 181 (1 989) GISTAD [19] (1989) N C C T G [20] (1989) C O H [21] (1987) PMH [22] (1988)
No. patients
5-FU
RR (%)
153
600
17
181
540
16
182
400
10
208
500
10
74
370
13
124
370
7
5-FU
+ FA
+ 200 400 + 200 400 + 200 370 + 200 370 + 20 370 + 200 370 + 200 400
RR (%)
Survival
19
20 vs. 24
15
21 vs. 24
22
44 vs.44
26 43 44
34 vs. 53 vs. 52
33
41 vs. 54
55 vs. 62
*The year in parentheses refers to the year the study was carried out. Reference numbers are in brackets.
of leucovorin are administered. Improvement in survival is only marginal if not significant at all, with both low and high doses of leucovorin. These data show that more investigations are needed to point out when it might be justified to add to the cost of treatment also the expense of Citrovorum Factor and the higher systemic toxicity.
In fact, the reasons for the bolus scheL.de of chemotherapy are both tradition and practical logistics. Many investigations have demonstrated that with the availability of safe central venous access and or portable infusion devices, continuous infusion is both practical, at least as active as the bolus delivery, and less toxic. The issue of the impact on survival was studied by Lockich et al. with a prospective randomized study comparing protracted continuous infusion fluorouracil and conventional bolus schedule. Although tumor RR differed greatly (7% for the bolus arm vs. 30% for the infusion arm), overall survival for the two groups was comparable. Lockich et al. confirmed that a protracted continuous infusion schedule yields a RR similar to that reported for 5-FU-leucovorin, but without its peculiar gastrointestinal tract toxicity pattern [8].
Other Combinations Methyl-CCNU, 5-FU, and vincristine (MOF) was the first combination that appeared to increase the RR in colorectal cancer (-20% RP). However, in those studies where MOF regime was randomly compared with 5-FU alone there was no significant improvement in the median survival [3,4]. The addition of streptozotocin to the MOF combination showed an increased RR, compared with MOF (-27%), but a small randomized study comparing 5-FU with MOF-strept did not confirm any increase in LIVER METASTASES survival [ 5 ] .Cisplatin and 5-FU show a synergistic effect The diagnosis of liver metastases yields to different in tumor cell lines and a 23% cumulative RR in nine treatment options: surgery, systemic, or locoregional clinical studies [ 6 ] . A recent randomized study of continuous infusion chemotherapy. The latter, although theoretically attracfluorouracil vs. 5-FU plus cisplatin on 122 chemotherapy tive, is far from being an ideal treatment: limitations and naive patients confirmed a higher partial RR for the failures of locoregional chemotherapy are due to systemic combination CDDP + FU (25% vs. 3%), but did not progressive disease, toxicity, and unclear advantages show any significant difference in survival (median 10 over systemic application. and 12 months for CDDP + FU and FU groups, respecThere are now six randomized trials demonstrating a tively) [7]. A different direction for improving the significantly higher RR with intrahepatic vs. systemic effectiveness of 5-FU is the investigation of the optimal infusion in the treatment of hepatic metastases from colorectal cancer. Unfortunately, the impact of the loschedule of its delivery.
114
Cortesi et al.
coregional chemotherapy on survival is difficult to evaluate in these studies because patients in the systemic arm were allowed to receive intrahepatic therapy after failure on systemic therapy. These studies however demonstrate a survival difference between groups who never received intrahepatic treatment and those who did [ 121. A longer survival, close to statistical significance, has been observed for those who received intrahepatic therapy, whether originally or after systemic failure. From this data it is still debated if locoregional chemotherapy should be indicated only after failure of systemic treatment, or at the first diagnosis of unresectable liver metastases. Studies are ongoing on the use of new drug combinations to increase both the RR and the survival. It should soon be possible to define whether there is a clear survival advantage with the intraarterial chemotherapy when compared with systemic therapy. The randomized studies so far available are pointing to that direction, but stronger evidence is going to be needed in order to consider intraarterial hepatic chemotherapy as a standard treatment for liver colorectal metastases.
Best Supportive Care Although survival should be the debated endpoint of clinical trials in advanced colorectal cancer, very few studies considered the best supportive care (BSC) as one of the optional treatments. Scheithauer et al., in Austria, in a small but randomized trial (36 patients) compared 5-FU + CDDP vs. BSC: The median survival was 8.0 months vs. 5.5, and the quality of life evaluation (FLIC) showed a benefit from chemotherapeutic treatment [9]. The impact on survival of intrahepatic chemotherapy vs. standard palliative treatment was analyzed in France from Rougier et al. in a recent prospective multicenter trial. Median survival of the 81 patients treated with intrahepatic FuDR was 14 months, vs. 10 months for the 82 patients of the palliative treatment arm [lo]. A very interesting study is from Palmer et al. at Roswell Park Memorial Institute: they showed that the overall mean survival of 30 patients who chose to have no treatments for their unresectable liver metastases, was 16 months [ 1 11.
CONCLUSIONS The impact of chemotherapy on survival of patients affected by metastatic colorectal cancer must be considered unproved. As for other neoplastic diseases such as the non small cell lung cancer, melanoma, renal cancer, etc., the endpoint of survival improvement in the treatment of colorectal cancer patients should be the main objective of present and future clinical trials. In particular, combination chemotherapy does show better palliative results when compared with the single agent 5-FU, but yields higher toxicity, and prospective randomized trials failed to show a survival improvement.
Continuous infusion chemotherapy with 5-FU showed a RR at least as good as combination chemotherapy but with a different and more acceptable toxicity pattern. Still, randomized trials failed to demonstrate any improvement in survival with 5-FU protracted infusion. Locoregional chemotherapy for colorectal liver metastases is tolerable, shows a higher RR compared with systemic treatment, and might have a positive impact on patient survival. It is still controversial the timing of locoregional chemotherapy: before any systemic treatment or after its failure? Future prospective studies should point to the evaluation of survival and quality of life for patients affected by metastatic colorectal cancer. Of particular interest are clinical trials on continuous infusion, with both protracted or circadian chemotherapy, on the modulation of response with interferons, and treatment vs. best supportive care. Quality of life evaluation should be part of every prospective randomized clinical trial as one of the main objectives of the study.
REFERENCES I . Cohen A, Shank B, Friedman M: Colorectal cancer. In DeVita V, Hellman S, Rosenberg S (eds): “Cancer.” Philadelphia: J.B. Lippincott, 1989, p895. 2. Kemeny N: The systemic chemotherapy of hepatic metastases. Semin Oncol 10:148-158, 1983. 3 . Falkson G , Falkson H: Fluorouracil, methyl-CCNU and vincristine in cancer of the colon. Cancer 38:468, 1976. 4. Baker LH, Talley RW, Maiter R, Lehame DE, Ruffner BW, Jones SE, Morrison FS, Stephens RL, Gehan EA, Vaitkevicius VK: Phase 111 comparison of the treatment of advanced gastrointestinal cancer with bolus weekly 5-Fu vs methyl-CCNU plus bolus weekly 5-FU. Cancer 38:l-7, 1976. 5. Buroken TR, Moertel CG, Fleming TR, Everson LK, Cullinam SA, Kroof JE, Maillard JA, Marschke RF, Klaassen DD, Laurie JA, Moon M: A controlled evaluation of recent approaches to biochemical modulation a enhancement of 5 4uorouracil therapy in colorectal carcinoma. J Clin Oncol 3: 1624-163 I , 1985. 6. Kemeny N: Role of chemotherapy in the treatment of colorectal carcinoma. Semin Surg Oncol 3:19&214, 1987. 7. Kemeny N, Israel K , Niedzwiecki D, Chapman D, Botet J, Minsky B, Vinciguerra V, Rosembluth R, Bosselli B, Cochram C: Randomized study of continuous infusion fluorouracil versus fluorouracil plus cisplatin in patients with metastatic colorectal cancer. J Clin Oncol 8:313-318, 1990. 8. Lockich JI, Ahlgren J, Gullo J, Philips J, Fryer J: A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol 7:425432, 1989. 9. Scheithauer W, Depisch D, Schiessel R, Rosen H, Sebesta C, Ludwig H: Proc Am SOCClin Oncol 9:A1176, 1990. 10. Rougier P, Hay JM, Olivier JM, Escat J, Laplanche A, Elias D, Lasser P, Hugier M: A controlled multicenter trial of intrahepatic chemotherapy vs standard palliative treatment for colorectal liver metastases. Proc Am SOCClin Oncol 9:A403, 1990. 11. Palmer M, Petrelli MJ, Herrera L: No treatment option for liver metastase from colorectal carcinoma. Dis Colon Rectum 32:698701, 1989. 12. Kemeny N, Cortesi E: Regional chemotherapy of colorectal carcinoma. In Fegiz G, Ramacciato G (eds): “Current Topics in Surgical Oncology.” Milan: Masson Publishers, 1991, in press.
Advanced Colorectal Cancer 13. Heidelberger C, Chandary NK, Dannemberg P: Fluorinated
14.
15. 16.
17.
pyrimidines: A new class of tumor inhibitory compounds. Nature 170:663466, 1957. Nobile MT, Vidili MG, Sobrero A: 5-fluorouracil alone or combined with high dose folinica acid in advanced colorectal cancer patients: A randomized trial. Proc Am SOCClin Oncol 7: 97, 1988. Petrelli N, Douglas HD, Herrera L: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma. A perspective randomized phase 111 trial. J Clin Orcol7: 1419, 1989. Petrelli N, Herrera L, Rustum Y: A perspective randomized trial of 5-fluorouracil versus 5-fluorouracil and leucovorin in previously untreated patients with advanced colorectal carcinoma. J Clin Orcol 5: 1559, 1987. Valone FH, Friedman MA, Wittlinger PS: Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high dose leucovorin plus fluorouracil or sequential methotrexate, fluorouracil, leucovorin: A randomized trial of the Northern California Oncology Group. J Clin Oncol 7: 1427, 1989.
115
18. Di Costanzo F, Bartolucci R, Sofra M: 5-fluorouracil alone versus high dose folinic acid and 5FU in advanced colorectal cancer. A randomized trial of the Italian Oncology Group for Clinical Research. Proc Am SOCClin Oncol 8: 410, 1989. 19. Labianca R , Pancera G, Beretta G : A randomized study of intravenous 5-fluorouracil plus or minus folinic advanced metastatic colorectal carcinoma. Proc Am Soc Clin Oncol 8: 457, 1989. 20. Poon MA, O’Connell MJ, Moertel CG: 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, 1989. 21. Doroshow JA, Bertrand M, Multhauf P: Prospective randomized trial comparing 5-FU versus 5FU and high dose folinic acid for treatment of advanced colorectal cancer. Proc Am SOCClin Oncol 6: 96, 1987. 22. Erlichman C, Fine S , Wong A: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 6: 469, 1988.
Advanced Colorectal Cancer: Impact of Chemotherapy on Survival ENRICO CORTESI, MD, A U G U S T 0 PADOVANI, MD, ALESSANDRA ALOE, MD, VlNCENZO PICECE, MD, PATRlZlA PELLEGRINI, MD, AND A. PELLEGRINI, MD From the Chair of Medical Oncology, Department of Experimental Medicine, The University of Rome “ l a Sapienza,” Rome, ltaly
KEYWORDS:colorectal carcinoma, lymph node involvement, metastatic disease, chemotherapy, survival
INTRODUCTION Colorectal carcinoma is the second most frequent cancer in the western world. In 1991, an estimated 155,000 cases of colorectal cancer will be diagnosed in the United States and at least 40% of them will die of the disease. In Italy more than 11,000 colorectal cancer patients will die each year. At the time of pathological diagnosis almost 50% of the patients will have lymph node involvement, and 10-25% will present with hepatic metastases. The 5-year relative survival rate for colon cancer increased from 41% in 1950 to 54% in 1980: that for rectal cancer increased from 40% to 5 1.5% in the same period [ 11. This trend might be due in part to improved diagnostic and screening techniques, leading to earlier detection and surgical treatment, with a better control of micrometastatic disease. In fact, such a survival improvement is not shown for the most advanced states and progress in the medical treatment of metastatic disease is very difficult to evaluate.
SYSTEMIC CHEMOTHERAPY The role of chemotherapy, single agents or combinations, regional and adjuvant therapy, in the management of colorectal cancer has to be established regarding its impact on survival. This article will describe whether chemotherapy given in any of its settings, locoregional or systemic, has any role in prolonging the life of colorectal cancer patients. Fluorouracil and folinic acid (FA) since the introduction by Heidelberger [13] in 1956 of 5-fluorouracil, (5-FU) has been employed as the standard treatment in colorectal cancer. There is no systemic chemotherapy, using either single agents or combiantions of cytotoxic drugs, which has been shown to modify the natural history of colorectal carcinoma. To date the fluorinated pyrimidines, with 5-FU being the most widely employed, 0 1991 Wiley-Liss, Inc.
have yielded a mean response rate (RR) of approximately 20% with no improvement in survival. The optimal method of administration of 5-FU is still controversial although the average RR is lower than the reported overall rate of 20%. In fact, in studies where the response measurements are clearly defined, the average RR is 15% [2].
5-FU
+ FA
Numerous clinical studies have been conducted in an attempt to improve the efficacy of this treatment: combinations of 5-FU with other drugs have failed to demonstrate better results; biochemical modulation of 5-FU with methotrexate, allopurinol, and other agents has had limited success. Biochemical studies of the mechanism of action of 5-FU have demonstrated that the intracellular level of CH-2-FH-4 were insufficient to allow optimal binding between FdUMP and TS: however, the addition of leucovorin to culture medium enhanced the cytotoxicity of 5-FU. A variety of phase I and I1 clinical trials using different schedules and doses of 5-FU and leucovorin have shown RR ranging from 12-50%; furthermore, they have indicated that this combination is more active in patients who have not received prior chemotherapy. The optimal dose of FA required to enhance the activity of 5-FU is not clearly defined; considering that concentrations greater than 10 mM are required for maximal potentiation of fluoropyrimidines in cell culture, doses of 200-500 mg/m2 intravenous (i.v.) of FA seem to be adequate to obtain a maximum effect. As shown in Tables I and I1 the combination of 5-FU and Citrovorum Factor increases 5-FU activity leading to a higher rate of response, particularly when higher doses Accepted for publication May 30, 1991. Address reprint requests to Professor Enrico Cortesi, Chair of Medical Oncology, Department of Experimental Medicine, The University of Rome “La Sapienza,” Viale del Policlinico 155, 00161, Rome, Italy.
Advanced Colorectal Cancer
113
TABLE I. Advanced Colorectal Carcinoma Phase 111 Clinical Trials: 5-FU Vs. 5-FU FA Weekly*
+
Trial IST-GE [ 141 (1988) GITSG [15) (1989) RPMI [ 161 (1987)
No. patients
5-FU
RR (%)
82
600
5
318
500
12
44
450
11
+ FA 600 + 500 600 + 500 600 + 500
5-FU
RR (%)
Survival
16
N.S.
30
46 vs. 55
48
N.S.
*The year in parentheses refers to the year the study was carried out. Reference numbers are in brackets.
TABLE 11. Advanced Colorectal Carcinoma Phase 111 Clinical Trials: 5-FU Vs. 5-FU f FA 5-Day Schedule* Trial NCOG [ 171 (1989) GOIRC [ 181 (1 989) GISTAD [19] (1989) N C C T G [20] (1989) C O H [21] (1987) PMH [22] (1988)
No. patients
5-FU
RR (%)
153
600
17
181
540
16
182
400
10
208
500
10
74
370
13
124
370
7
5-FU
+ FA
+ 200 400 + 200 400 + 200 370 + 200 370 + 20 370 + 200 370 + 200 400
RR (%)
Survival
19
20 vs. 24
15
21 vs. 24
22
44 vs.44
26 43 44
34 vs. 53 vs. 52
33
41 vs. 54
55 vs. 62
*The year in parentheses refers to the year the study was carried out. Reference numbers are in brackets.
of leucovorin are administered. Improvement in survival is only marginal if not significant at all, with both low and high doses of leucovorin. These data show that more investigations are needed to point out when it might be justified to add to the cost of treatment also the expense of Citrovorum Factor and the higher systemic toxicity.
In fact, the reasons for the bolus scheL.de of chemotherapy are both tradition and practical logistics. Many investigations have demonstrated that with the availability of safe central venous access and or portable infusion devices, continuous infusion is both practical, at least as active as the bolus delivery, and less toxic. The issue of the impact on survival was studied by Lockich et al. with a prospective randomized study comparing protracted continuous infusion fluorouracil and conventional bolus schedule. Although tumor RR differed greatly (7% for the bolus arm vs. 30% for the infusion arm), overall survival for the two groups was comparable. Lockich et al. confirmed that a protracted continuous infusion schedule yields a RR similar to that reported for 5-FU-leucovorin, but without its peculiar gastrointestinal tract toxicity pattern [8].
Other Combinations Methyl-CCNU, 5-FU, and vincristine (MOF) was the first combination that appeared to increase the RR in colorectal cancer (-20% RP). However, in those studies where MOF regime was randomly compared with 5-FU alone there was no significant improvement in the median survival [3,4]. The addition of streptozotocin to the MOF combination showed an increased RR, compared with MOF (-27%), but a small randomized study comparing 5-FU with MOF-strept did not confirm any increase in LIVER METASTASES survival [ 5 ] .Cisplatin and 5-FU show a synergistic effect The diagnosis of liver metastases yields to different in tumor cell lines and a 23% cumulative RR in nine treatment options: surgery, systemic, or locoregional clinical studies [ 6 ] . A recent randomized study of continuous infusion chemotherapy. The latter, although theoretically attracfluorouracil vs. 5-FU plus cisplatin on 122 chemotherapy tive, is far from being an ideal treatment: limitations and naive patients confirmed a higher partial RR for the failures of locoregional chemotherapy are due to systemic combination CDDP + FU (25% vs. 3%), but did not progressive disease, toxicity, and unclear advantages show any significant difference in survival (median 10 over systemic application. and 12 months for CDDP + FU and FU groups, respecThere are now six randomized trials demonstrating a tively) [7]. A different direction for improving the significantly higher RR with intrahepatic vs. systemic effectiveness of 5-FU is the investigation of the optimal infusion in the treatment of hepatic metastases from colorectal cancer. Unfortunately, the impact of the loschedule of its delivery.
114
Cortesi et al.
coregional chemotherapy on survival is difficult to evaluate in these studies because patients in the systemic arm were allowed to receive intrahepatic therapy after failure on systemic therapy. These studies however demonstrate a survival difference between groups who never received intrahepatic treatment and those who did [ 121. A longer survival, close to statistical significance, has been observed for those who received intrahepatic therapy, whether originally or after systemic failure. From this data it is still debated if locoregional chemotherapy should be indicated only after failure of systemic treatment, or at the first diagnosis of unresectable liver metastases. Studies are ongoing on the use of new drug combinations to increase both the RR and the survival. It should soon be possible to define whether there is a clear survival advantage with the intraarterial chemotherapy when compared with systemic therapy. The randomized studies so far available are pointing to that direction, but stronger evidence is going to be needed in order to consider intraarterial hepatic chemotherapy as a standard treatment for liver colorectal metastases.
Best Supportive Care Although survival should be the debated endpoint of clinical trials in advanced colorectal cancer, very few studies considered the best supportive care (BSC) as one of the optional treatments. Scheithauer et al., in Austria, in a small but randomized trial (36 patients) compared 5-FU + CDDP vs. BSC: The median survival was 8.0 months vs. 5.5, and the quality of life evaluation (FLIC) showed a benefit from chemotherapeutic treatment [9]. The impact on survival of intrahepatic chemotherapy vs. standard palliative treatment was analyzed in France from Rougier et al. in a recent prospective multicenter trial. Median survival of the 81 patients treated with intrahepatic FuDR was 14 months, vs. 10 months for the 82 patients of the palliative treatment arm [lo]. A very interesting study is from Palmer et al. at Roswell Park Memorial Institute: they showed that the overall mean survival of 30 patients who chose to have no treatments for their unresectable liver metastases, was 16 months [ 1 11.
CONCLUSIONS The impact of chemotherapy on survival of patients affected by metastatic colorectal cancer must be considered unproved. As for other neoplastic diseases such as the non small cell lung cancer, melanoma, renal cancer, etc., the endpoint of survival improvement in the treatment of colorectal cancer patients should be the main objective of present and future clinical trials. In particular, combination chemotherapy does show better palliative results when compared with the single agent 5-FU, but yields higher toxicity, and prospective randomized trials failed to show a survival improvement.
Continuous infusion chemotherapy with 5-FU showed a RR at least as good as combination chemotherapy but with a different and more acceptable toxicity pattern. Still, randomized trials failed to demonstrate any improvement in survival with 5-FU protracted infusion. Locoregional chemotherapy for colorectal liver metastases is tolerable, shows a higher RR compared with systemic treatment, and might have a positive impact on patient survival. It is still controversial the timing of locoregional chemotherapy: before any systemic treatment or after its failure? Future prospective studies should point to the evaluation of survival and quality of life for patients affected by metastatic colorectal cancer. Of particular interest are clinical trials on continuous infusion, with both protracted or circadian chemotherapy, on the modulation of response with interferons, and treatment vs. best supportive care. Quality of life evaluation should be part of every prospective randomized clinical trial as one of the main objectives of the study.
REFERENCES I . Cohen A, Shank B, Friedman M: Colorectal cancer. In DeVita V, Hellman S, Rosenberg S (eds): “Cancer.” Philadelphia: J.B. Lippincott, 1989, p895. 2. Kemeny N: The systemic chemotherapy of hepatic metastases. Semin Oncol 10:148-158, 1983. 3 . Falkson G , Falkson H: Fluorouracil, methyl-CCNU and vincristine in cancer of the colon. Cancer 38:468, 1976. 4. Baker LH, Talley RW, Maiter R, Lehame DE, Ruffner BW, Jones SE, Morrison FS, Stephens RL, Gehan EA, Vaitkevicius VK: Phase 111 comparison of the treatment of advanced gastrointestinal cancer with bolus weekly 5-Fu vs methyl-CCNU plus bolus weekly 5-FU. Cancer 38:l-7, 1976. 5. Buroken TR, Moertel CG, Fleming TR, Everson LK, Cullinam SA, Kroof JE, Maillard JA, Marschke RF, Klaassen DD, Laurie JA, Moon M: A controlled evaluation of recent approaches to biochemical modulation a enhancement of 5 4uorouracil therapy in colorectal carcinoma. J Clin Oncol 3: 1624-163 I , 1985. 6. Kemeny N: Role of chemotherapy in the treatment of colorectal carcinoma. Semin Surg Oncol 3:19&214, 1987. 7. Kemeny N, Israel K , Niedzwiecki D, Chapman D, Botet J, Minsky B, Vinciguerra V, Rosembluth R, Bosselli B, Cochram C: Randomized study of continuous infusion fluorouracil versus fluorouracil plus cisplatin in patients with metastatic colorectal cancer. J Clin Oncol 8:313-318, 1990. 8. Lockich JI, Ahlgren J, Gullo J, Philips J, Fryer J: A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol 7:425432, 1989. 9. Scheithauer W, Depisch D, Schiessel R, Rosen H, Sebesta C, Ludwig H: Proc Am SOCClin Oncol 9:A1176, 1990. 10. Rougier P, Hay JM, Olivier JM, Escat J, Laplanche A, Elias D, Lasser P, Hugier M: A controlled multicenter trial of intrahepatic chemotherapy vs standard palliative treatment for colorectal liver metastases. Proc Am SOCClin Oncol 9:A403, 1990. 11. Palmer M, Petrelli MJ, Herrera L: No treatment option for liver metastase from colorectal carcinoma. Dis Colon Rectum 32:698701, 1989. 12. Kemeny N, Cortesi E: Regional chemotherapy of colorectal carcinoma. In Fegiz G, Ramacciato G (eds): “Current Topics in Surgical Oncology.” Milan: Masson Publishers, 1991, in press.
Advanced Colorectal Cancer 13. Heidelberger C, Chandary NK, Dannemberg P: Fluorinated
14.
15. 16.
17.
pyrimidines: A new class of tumor inhibitory compounds. Nature 170:663466, 1957. Nobile MT, Vidili MG, Sobrero A: 5-fluorouracil alone or combined with high dose folinica acid in advanced colorectal cancer patients: A randomized trial. Proc Am SOCClin Oncol 7: 97, 1988. Petrelli N, Douglas HD, Herrera L: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma. A perspective randomized phase 111 trial. J Clin Orcol7: 1419, 1989. Petrelli N, Herrera L, Rustum Y: A perspective randomized trial of 5-fluorouracil versus 5-fluorouracil and leucovorin in previously untreated patients with advanced colorectal carcinoma. J Clin Orcol 5: 1559, 1987. Valone FH, Friedman MA, Wittlinger PS: Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high dose leucovorin plus fluorouracil or sequential methotrexate, fluorouracil, leucovorin: A randomized trial of the Northern California Oncology Group. J Clin Oncol 7: 1427, 1989.
115
18. Di Costanzo F, Bartolucci R, Sofra M: 5-fluorouracil alone versus high dose folinic acid and 5FU in advanced colorectal cancer. A randomized trial of the Italian Oncology Group for Clinical Research. Proc Am SOCClin Oncol 8: 410, 1989. 19. Labianca R , Pancera G, Beretta G : A randomized study of intravenous 5-fluorouracil plus or minus folinic advanced metastatic colorectal carcinoma. Proc Am Soc Clin Oncol 8: 457, 1989. 20. Poon MA, O’Connell MJ, Moertel CG: 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, 1989. 21. Doroshow JA, Bertrand M, Multhauf P: Prospective randomized trial comparing 5-FU versus 5FU and high dose folinic acid for treatment of advanced colorectal cancer. Proc Am SOCClin Oncol 6: 96, 1987. 22. Erlichman C, Fine S , Wong A: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 6: 469, 1988.
