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New possibilities in chemotherapy for colorectal cancer
Annals of Oncology 10 (Suppl. 6): S105-S111. 1999. © 1999 Klmver Academic Publishers. Printed in the Netherlands.
Review article New possibilities in chemotherapy for colorectal cancer M. Bekradda1 & E. Cvitkovic2 'Cvitkovic & Associes Consultants, Kremlin Bicetre, France; !H6pilal Paul Brousse, ViUejuif, France
Improved diagnostic techniques, such as MRI (magnetic resonance imaging), PET (positron emission tomography), and CEA (Carcino-Embryonic Antigen) scanning, and the introduction of new chemotherapeutic agents, are no less important than improved knowledge about the disease. As a result of such innovations, a new multidisciplinary approach to colorectal cancer treatment has emerged, with new goals that replace those associated with standard treatment.
Local disease (adjuvant setting) Who will be able to benefitfrom adjuvant treatment after complete resection of the primary tumour? Prognosis will mainly depend on the stage of the disease [4]. For most patients with early stage disease (A and B1 according to the Astler-Coller modification of Duke's staging [5, 6]) surgery alone is curative. However, once the tumour has invaded the muscularis propria (stage B2-B3), 5-year survival decreases to 70%. For stages Cl, C2 and C3, 5-year survival is between 25% and 60%. The decreased survival correlates with an increase in the number of invaded proximal lymph nodes [4, 7]. Other anatomical factors that are predictive of relapse include perforation, obstruction and adhesions to and/ or invasion of adjacent organs [8]. Some studies have reported the predictive value of elevated CEA serum levels in preoperative patients with negative lymph nodes [9-14]. Other factors that have been proposed as predictive of relapse include cell cycle (ploidy), DNA synthesising activity (S phase), and cell proliferation [15-18]. Thymidylate synthase (TS), a key target enzyme of 5-FU, has treatment-related prognostic value. In a recent study, Johnston et al. [19] reported a 5-year survival rate of 60% for patients with metastatic disease and low TS levels, compared to 40% for patients with high TS levels. P53 acts as a tumour suppressor gene, located in 17 pi 3. Under normal conditions, it encodes for a 'wild-type' p53 protein which has a very short half-life and is undetectable by immunohistochemistry. Where there is gene mutation, p53 protein is non-functional, has a much longer half-life and becomes detectable by immunohistochemistry. The identification of mutated p53 protein is an independent factor that is
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Colorectal cancer is the second leading cause of cancer death. Approximately 26,000 new cases are diagnosed yearly in France, resulting in more than 10,000 deaths, and 5-year survival remains low, at 40%. This poor prognosis is partly due to the fact that, in 30% of cases, colorectal cancer is metastatic or at a locally advanced stage when discovered. Moreover, visceral metastases complicate the development of the cancer after resection of the primary tumour in 40% to 50% of cases. The liver is the most frequently involved, followed by the abdominal lymph nodes, the peritoneum, the lungs, and far more rarely, the bones, adrenal glands or brain. Metastasis, whether synchronous or metachronous, most frequently occurs in the liver (around 40% of cases), thus exacerbating mortality [1,2]. The prognosis is poor for patients with visceral metastasis, and depends on such factors as the patient's general condition and the number and sites of metastatic disease. Nevertheless, several studies have shown that the prognosis for metastatic disease can be improved if treatment is aimed at 'curing' patients. Surgical resection of metastases, which is the first treatment option, is feasible, either immediately or after chemotherapy in only 10% of cases. The other cases are often candidates for systemic or locoregional chemotherapy treatment. The metastatic potential of colorectal carcinoma seems to correlate with the expression of certain oncoproteins involved in regulating apoptosis and the cell cycle. The presence of the p53 protein in the primary tumour is an indicator of liver and lymph node metastases. Also, overexpression of c-erb B2 in the primary tumour may be an indicator of potential metastasis, particularly in the liver [3]. Once the recently acquired knowledge in the molecular biology of colorectal cancer has been formally recognised as a factor for prognosis/prediction of natural history and/or tumoural response, this will lead to great changes in medical practice. During the last few decades, steady progress has been made in cancer treatment in terms of curability, survival duration and quality of life. This progress has varied according to the type of cancer. Major advances were made in the 1970s in the treatment of breast, testicular and childhood cancer; the end of the century will probably see advances in colorectal cancer treatment also.
106
Systemic treatment:
Pre or perioperative local treatment:
5-FU alone: In the meta-analysis carried out by Buyse in 1988, out of 17 randomised trials comprising 6791 colorectal cancer patients, only treatments with 5-FU-based chemotherapy showed a slight improvement in survival, of around 3% to 5% [23]. This meta-analysis did not consider either administration schedules or 5-FU doses.
In the trial initiated by Sugarbaker et al. [35], intraperitoneal chemotherapy significantly reduced the peritoneal rate of relapse; but had no influence on survival. The small patient cohort number might have limited the chances of obtaining significant results. The first randomised trial to demonstrate the efficacy of intraportal chemotherapy was carried out by Taylor et al [36]. Five-year survival was significantly higher in the experimental arm (117 patients) treated by 5-FU at 1000 mg/day over 7 days, compared with the control arm (127 patients). This difference was particularly significant in patients with Dukes stage B disease. Several trials have attempted to confirm these results. A Swiss group obtained results that seemed to indicate the efficacy of intraportal chemotherapy [37]. A trial by the NSABP in a randomised series of 1158 patients, reported an improvement in overall survival, 76% versus 71%, with no difference in the incidence of liver metastases [38]. One meta-analysis [39] involving 9 randomised trials in 3824 patients demonstrated a significant reduction in risk of death by 13% (p = 0.02). However, the EORTC trial, in 235 patients, showed no advantage in terms of disease-free survival: 56% versus 65% or 5-year survival: 69% versus 71% [40].
Biochemical modulation of 5-FU: The modulation of 5-FU by folinic acid (FA) has proven its efficacy in the palliative treatment of metastatic colorectal carcinoma, leading to several controlled trials in the adjuvant setting. A complete analysis of 1526 patients (1493 eligible), of whom 841 (56%) had stage B disease at diagnosis, showed a 3-year disease-free survival of 71%, which compares favourably with 5-FU alone, compared with 62% in the untreated control group (p = < 0.0001), with a relative reduction in risk of relapse of 35 ± 9% and a 3-year survival of 83% versus 78% (p= 0.03) [26]. A trial by the NSABP (C04) comparing 5-FU/Levamisole, 5-FU/FA (high dose) and 5-FU/Levamisole/FA (high dose) in 2151 patients with stage B and C colon cancers demonstrated no significant difference in disease-free survival (p = 0.12) or in overall survival (p = 0.14) among the three arms [27]. 5-FU in continuous infusion (CI): 5-FU in continuous infusion may be a feasible alternative to biochemical modulation. Phase III trials have demonstrated improved response rates for CI 5-FU compared to bolus 5FU in advanced colorectal cancer [28]. Novel agents: Recently acquired knowledge about the molecular biology of colorectal carcinoma, including the role of p53 protein in the cell cycle and apoptosis [29, 30], the role of deficient mismatch repair [31, 32], and the role of thymidylate synthase activity in 5-FU resistance [33], has encouraged the development of treatment strategies using new agents with novel mechanisms of action. These new anticancer agents include oxaliplatin, a cisplatin analogue of the DACH (diaminocyclohexane) family of platinums, the new thymidylate synthase inhibitors (raltitrexed, Tegafur (UFT), and capecitabine); irinotecan; and immunotherapeutic agents, in particular the monoclonal antibody anti-17-lA. The activity demonstrated by these new chemotherapeutic agents in advanced colorectal carcinoma,
Advanced or metastatic disease The term 'advanced' colorectal cancer denotes very different clinical and prognostic situations which require an adaptive, multidisciplinary approach to their treatment according to the specific clinical settings. Despite progress made in treatment modalities, the prognosis for advanced colorectal cancer remains ominous. Better results could be obtained by targeting patients likely to benefit from a particular treatment modality, by using screening techniques such MRI, PET and CEA scanning, and by improving the identification of prognostic factors, particularly via molecular biology. Advanced disease may be divided into two categories: 1. Potentially 'curable' disease 2. Very advanced disease (purely palliative situation) /. Potentially 'curable'disease Improvements in the treatment of advanced disease, due to the biochemical modulation of 5-FU and the introduction of
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Choosing the adjuvant treatment
pretreated or not by 5-FU, has opened new avenues for their application in the adjuvant setting, with or without 5-FU. As concerns postoperative immunotherapy by the antibody anti-17-lA (Panorex), Riethmuller et al. reported in a randomised trial of 166 patients that overall and disease-free survival were significantly better in the group treated by the antibody, with a reduction in mortality risk of 30% (p =0.04) and a risk of relapse of 27% (p = 0.027) [34].
predictive of poor prognosis in some types of colon carcinoma [21-23]. Lenz et al. [24] reported a > 90% risk of relapse in patients with stage II (B2-B3) colon cancer who had both mutated p53 protein and elevated TS levels.
107 the approach be extended to the postoperative setting? (After resection of liver metastases?) One advantage of these new strategies for advanced colorectal cancer patients is that they result in improved response rates which enable more patients to receive curative surgery [51, 53]. Even in first line treatment, the improved knowledge of molecular targets permits the identification of patients who might benefit from the new strategies. 2. Very advanced disease (palliative setting) The treatment consists of optimising treatment choices in first line as well as in second line after failure with standard treatment. 5-FU has been the reference treatment since the 1950s. However, response rates rarely reach 15% with single agent 5-FU [54, 55] and a consensus has not yet been reached regarding dose, schedule and mode of administration. The 5-FU/FA combination has been shown to be more active in terms of objective response rates [56, 57], but is barely superior in terms of survival [57, 58]. Although continuous infusion 5-FU has demonstrated a statistically significant survival advantage of about one month over short infusion [47], this finding has no major clinical relevance. As a result, clinical research efforts have focussed on the development of other anticancer agents, to be used as single agents or in combination with 5-FU or its analogues. The introduction of new agents has led to a redefinition of the whole approach to the treatment of metastatic colorectal cancer allowing the optimisation of combinations, schedules and sequences of administration. Raltitrexed, irinotecan and oxaliplatin have been intensively developed in the last few years. Thymidylate synthase inhibitors •
•
Raltitrexed (Tomudex) has been tested in phase II trials at the recommended dose of 3 mg/m2 in the United States, Europe and Australia [58], in 177 patients with non pretreated advanced colorectal carcinoma. The response rate was 26% with a median survival of 9.6 months. In a randomised phase III European trial of raltitrexed versus weekly 5-Fu/FA bolus 5D q4w (Mayo clinic), there was no statistically significant difference in objective response and median survival [60]. Other thymidylate synthase inhibitors are currently being developed: LY 231514, BW 18431189, Thymitaq.
New 5-FU analogues •
Orally administered tegafur (UFT) showed a response rate of 25%, with a median survival of 7.5 months in 56 patients evaluable in first and second line in a multicentric phase II trial in Japan [60]. Another similar trial in the United Kingdom showed a response rate of 16.6 %, with a median survival of 7.8 months in 36 patients [62]. Three American trials testing the combination of UFT with folinic acid per os showed response rates of 25%, 30% and 42.2% [63-65].
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new combination agents should produce a higher rate of quicker and better responses. In addition, the multidisciplinary approach combining surgical resection of liver metastases with chemotherapy could provide hope of a cure to some patients with metastatic disease. One of the main goals of future studies should be to distinguish those patients with advanced disease who are potential subjects for curative treatment from those who are not immediate candidates for curative surgery. Surgery provides the only hope of a cure in advanced colorectal cancer. Liver metastasis resection can increase 5year survival by 30% [41-43]. Similarly, lung metastases resection can be curative and increase survival [44]. Many patients present with liver metastases that are considered inoperable because of their sise, site and/or number, or have extrahepatic metastatic invasion. One recent technique, cryosurgery, reduces liver metastases that are often considered inoperable, thus increasing the number of patients with potentially 'curable' metastatic disease [45]. A recent randomised trial involving 123 patients demonstrated a better 5-year survival rate in patients treated by liver cryosurgery (44%) than in patients treated by standard metastatic surgery (36%) [46]. For patients with inoperable metastatic disease, the treatment option is often chemotherapy that is referred to as 'palliative.' The goals of this chemotherapeutic option should be two-fold: adequate tumour control and acceptable safety. Tumour control is assessed by response rate and disease-free survival. An optimal response rate increases tumour operability and facilitates curative surgery. The experience of randomised trials in metastatic colorectal carcinoma has given cause to doubt the value of bolus 5-FU/ FA as standard treatment. All the schedules including 5-FU as continuous infusion have shown superior tumour control, and, for the most part, less toxicity [47]. Although 5-FU remains the reference chemotherapy treatment for colorectal cancer, its efficacy is limited by resistance that is either spontaneous (in over 50% of cases) or secondary (in almost all cases). This resistance is partly related to an overexpression or a modification in thymidylate synthase activity. Several new anticancer agents with novel mechanisms of action (oxaliplatin, irinotecan, raltitrexed and other thymidylate synthase inhibitors) have opened avenues that were, until now, unimaginable - it is now possible to propose second-line treatment to patients progressing under 5-FU, and to envisage chemotherapy treatment combining several cytotoxic agents [48-50]. One interesting approach is the sequential treatment of advanced colorectal carcinoma by intrahepatic chemotherapy combined with systemic chemotherapy. In one published trial, the Mayo Clinic team reported 62% of objective responses with a median survival of 18 months but there was no impact on median time to progression in 40 patients with inoperable liver metastases, treated by hepatic intra-arterial fluorodeoxyuridine (FUDR) combined with systemic chemotherapy by bolus 5-FU-FA [52]. Should this approach be optimised by using new agents in systemic treatment? Should
108 Capecitabine (Xeloda), a promising oral analogue already registered in the United States for breast cancer treatment, has been tested in phase II randomised trials in a two weeks out of three schedule, with or without folinic acid. The latter regimen, having obtained objective responses of 28%, was used in later phase III trials [66]. It will soon be available for colorectal cancer patients. Other 5-FU analogues, such as SI, B0FA2, and 776C85 (dihydropyrimidine dehydrogenase inhibitor) are currently undergoing clinical development.
Local disease
Topoisomerase I inhibitors: Irinotecan (CPT-11) Like oxaliplatin, the most interesting property of CPT-11 is its lack of cross-resistance with 5-FU. Phase II studies have reported response rates of 18.8% to 29% in non pretreated patients, and 17% in those progressing under 5-FU [72, 73]. Other agents belonging to the metalloprotein family are currently undergoing preclinical and clinical development.
High risk of relapse Stage B2 / C. > 4 N+, Perforation
Conclusion Treatment regimens which combine new agents with novel mechanisms of action will probably result in an improved prognosis for colorectal cancer. Several possibilities are feasible in the 'palliative' setting: tritherapy consisting of three active agents, (oxaliplatin/irinotecan/5-FU; capecitabine/ oxaliplatin/irinotecan), alternated chemotherapy allowing several agents to be administered, and, possibly, sequential treatments combining systemic and locoregional chemotherapy treatment. Some details still require clarification, such as optimal dose, route of administration and administration schedule. The potential role of these new agents needs to be assessed in adjuvant and palliative settings. Recently acquired knowledge in the molecular biology of colorectal carcinoma may
L-OHP/5-FU±FA? or CPT-11/ 5-FU ± FA? or UFT/L-OHP ou CPT-11 "> or Capecitabine ? or New TS inhibitors or anti-17-lA or sequential chemotherapy ? (locoregional + systemic)
5-FU + FA or New oral 5-FU analogues 4-
Antibody ami 17-1A
Figure I. Treatment algorithm for localised colorectal cancers.
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enable patients who could benefit from these new agents in adjuvant and palliative settings to be identified [74, 75]. These new treatment approaches are based on two phenomena: the development of a multidisciplinary strategy in which chemotherapy is combined with tumour resection, either before or after chemotherapy, and the appearance of adjuvant treatments. Colorectal cancer should no longer be considered a homogenous, infrequently curable disease, and it is difficult, and possibly unnecessary, to propose any kind of inflexible 'decision-making tree,' to guide oncologists in their choice of treatment. It is important, however, to be very familiar with Platinum analogues: Oxaliplatin the treatment options based on recently acquired knowledge in the biological, diagnostic and therapeutic fields, which can The efficacy of single agent oxaliplatin has been proven in be adapted to every clinical situation and which should be first line treatment, with a 27% of objective response rate in prospectively validated (see Figures 1 and 2). 38 treated patients [67]. Under the guidance or 'dictation' of the pharmaceutical The recent combination of oxaliplatin with 5-FU/FA has industry, progress in the clinical development of new agents shown objective response rates exceeding 40%, even after in France, particularly for advanced colorectal carcinoma, has treatment failure with 5-FU [68, 69]. led to the registration and marketing of major anticancer agents Extensive research with the chronomodulated combina- such as oxaliplatin and irinotecan. This progress is likely to tion of oxaliplatin/5-FU-FA has been carried out by Levi et be applied to the postoperative phase. Two randomised trials al., treating more than 500 patients with a 5 day q3w, or 4 day are currently ongoing in France using standard 5-FU/FA verq2w schedule. This combination obtained response rates of sus 5-FU/FA combined with the new agents (5-FU/FA +iriabout 50%, including second line, with median survival ex- notecan and 5-FU/FA + oxaliplatin) in localised colorectal ceeding one year and reaching 17 months in first line [69- cancer with a high risk of relapse. The new thymidylate syn71]. thase inhibitors are among the agents that could feasibly be De Gramont also administered oxaliplatin in combination used in the adjuvant setting. with his biweekly FU/FA schedule and obtained objective responses of 45% and a median survival of 17 months in 46 pretreated patients [68].
Advanced disease
(Liver metastases only)
"1
Evaluation of operabilitv (CT Scan and/or echography only)
Clinically operable metastases
Clinically Inoperable metastases
Confirmatory evaluation (CT Scan and/or MR] + CEA scan)
• combination of new agents / 5-FU ±FA (trilherapy, alternated treatment) • sequential chemotherapy (locoregional and systemic)
New agents ± 5-FU ± FA
Treatment?
Figure 2. Treatment algorithm for patients with colorectal cancers metastatic to the liver.
Several trials are presently ongoing in metastatic disease, sessing combinations of new agents with or without 5-FU - FA in first line after failure with fluoropyrimidines. The goal of these trials is to optimise the treatment of adinced colorectal carcinoma, by using new combinations (biid tritherapy), and new administration schedules (alternatg, chronomodulation). Future trials should incorporate not only new anticancer ,ents, but also new treatment modalities, such as sequential lemotherapy (systemic or locoregional), where the operabili of metastases is a criterion of evaluation, and, also progistic factors, including molecular biological parameters. The means at our disposal could enable us to radically insform the natural history of colorectal cancer within the xt few years. It is our responsibility to ensure that these sans reach their full potential.
:knowledgements le authors wish to thank Catherine Benner, William Suthland and Michelle Hughes for assistance in preparation of i manuscript.
Table 1. Ongoing trials in France—end anticancer agents for colorectal carcinoma Indication
Phase Treatm
Local disease (adjuvant)
III III
CPT-11 L-OHP
Advanced disease Non pretreated
II
CPT-11
Pretreated
II
CPT-11 L-OHP OHP(c L-OHP (q3w) 5-FU/F 5-FU/L 5-FU//S L-OHP L-OHP 5-FU/L CPT-11 L-OHP
II III l/II II I I III I
Abbreviations: CPT-11, irinotecan; 5-FU, L-OHP, oxaliplatin. * The list is not exhaustive
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Revaluation of operabilitv (CT Scan and/or MR] + CEA scan)
110
References 1.
2. 3
4.
5. 6. 7.
9.
10. 11.
12.
13.
14.
15.
16. 17.
18.
19.
20.
21.
22. 23.
24.
25.
Downloaded from http://annonc.oxfordjournals.org/ at Gumberg Library on July 9, 2015
8.
Wagner JS, Adson MA, Van Heerden JA et coll. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984; 199: 502-8. Hugh TJ, Kinsella AR, Poston GJ. Management strategies for colorectal liver metastasis - Part I. Surg Oncol 1997; 6: 19-30. Yang J-L, Yu Y, Markovic B et coll. Overexpression of c-erbB-2 mRNA and for c-neu oncoprotein is a predictor for metastasis from colorectal cancer. Anticancer Res 1997; 17: 1023-6. Cohen AM, Shank B, Friedman MA. Colorectal cancer. In De Vital VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice, ed 3 Philadelphia, JB Lippincott, 1989; 929-77. Dukes CE. The classification of cancer of the rectum. J Pathol Bcterioll940; 50: 527-39. Asler WB, Coller FA. The prognostic significance of direct extension of carcinoma of the colon and rectum. Ann Surg 1954; 139: 846-51. Wolmark N, Fisher B, Wei HS. The prognostic value of the modification of the duke's C class of colorectal cancer: an analysis of the NSABP clinical trials. Ann Surg 1986; 203: 115-22. Willet C, Tepper JE, Cohen A et al. Obstructive and perforative colonic carcinoma: patterns of failure. J Clin Oncol 1985; 3: 379-84. Goslin R, Stech G, Mac Intyre I et al The use of preoperative plasma CEA levels for the stratification of patients after curative resection of colorectal cancers. Ann Surg 1980; 192: 747-51. LoGerfo P, Herter F Carcinoembryonic antigen prognosis in patients with colorectal cancer. Ann Surg 1974; 181:81—4. Moertel CG, O'Fallon JR, Go VLW et al. The preoperative carcinoembryonic antigen test in the diagnosis, staging, and prognosis of colorectal cancer. Cancer 1986; 58: 603-10. Steel G, EllenbergS, Ramming Ketal CEA monitoring among patients in multiinstitutional adjuvant GI protocols. Ann Surg 1982; 196: 162— 9. Wanebo HJ, Rao B, Pinsky CM et al. Preoperative carcinoembryonic antigen level as a prognostic indicator in colorectal cancer N Engl J Med 1978; 299: 448-51. Wolmark N, Fisher B, Wieand S et al. The prognostic significance of preoperative carcinoembryonic antigen levels in colorectal cancer. Ann Surg 1984; 199:375-81. Albe X, Vassilakos P, Helfer-Guarnori K et al Independent prognostic value of ploidy in colorectal cancer. A prospective study using image cytometry. Cancer 1990; 66: 1168-75. Kokal WA, Gardine RL, Sheibam K et al. Tumor DNA content in resectable, primary colorectal carcinoma. Ann Surg 1989; 209: 188-93. Scott NA, Wieand HS, Moertel CG et al. Colorectal cancer: Dukes' stage, tumor site, preoperative plasma CEA level and patient prognosis related to tumor DNA ploidy pattern. Arch Surg 1987; 122- 1375-9. Sinicrope F, Hart J, Brasitus T et al Relationship of P-glycoprotein and carcinoembryonic antigen expression in human colon carcinoma to local invasion, DNA ploidy, and disease relapse. Cancer 1994; 74: 2908-17. Moertel CG, Loprinzi CL, Witzig TE et al. The dilemma of stage B2 colon cancer. Is adjuvant therapy justified ? (abstract). Proc Am Soc Clin Oncol 1990; 9:108. Johnston PG, Fisher EF, Rockette HE et al. The role of thymidylate synthase expression in prognosis and outcome to adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol 1994; 12: 2640-7. Yamaguchi A, Nakagawara G, Kurosaka Y et al. p 53 immunoreaction in endoscopic biopsy specimens of colorectal cancer, and its prognostic significance. Br J Cancer 1993; 69: 399-402 Auvinen A, Isola J, Visakorpi T et al. Over expression of p53 and longterm survival in colon carcinoma. Br J Cancer 1994; 70: 293-6. Tomoda H, Kareji Y. Immunohistochemical analysis of p53 in colorectal cancer regarding chemicopathological correlation and prognostic significance. J Surg Oncol 1995; 58: 125-8. Lenz HJ, Danenberg KD, Danenberg P et al. p53 status and thymidylate synthase (TS) expression are associated and predict for recurrence in patients with stage II colon cancer (cc) (abstract). Proc Am Soc Clin Oncol 1996; 15:215. Buyse M, Zeleniuch-Jacquotte A, Chalmers TC. Adjuvant therapy of colorectal cancer.Why we still don't know? JAMA 1988: 259:3571-78.
26. IMPACT Investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 1995; 106: 939-44. 27. Wolmark N, Rochette H, Mamounas EP et al. The relative efficacy of 5FU and Leucovorin (FU-LV), 5-FU and Levamisole (Fu-Lev), and 5FU + Leucovorin and Levamisole (Fu-LV-Lev) in patients with duke's B and C carcinoma of the colon: First report of NSABPC-04 (abstract). Proc Am Soc Clin Oncol 1996; 15: 205. 28. Anderson N, Lokieh JJ. Cancer Chemotherapy and infusional scheduling. Oncology 1994; 8: 99-116. 29. Gottlieb TM, Oren M. p53 in growth control and neoplasia. Biochem BiophysActa 1996; 1287: 77-102. 30. Velculescu VE, El-Deiry WS. Biological and clinical importance of the p53 tumor suppressor gene. Clin Chem 1996; 42: 858-68. 31. Lynch HT, Smyrk T, Lynch JF. Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch syndrome) Int J Cancer 1996; 69. 38-43. 32. Marra G, Boland CR. Hereditary non polyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J. Nat Cancer Inst 1995; 87: 1114-25. 33. Johnston PG, Lenz HJ, Leichman CG et al. Thymidylate synthase gene and protein expression correlate and are associated with response to 5fluorouracil in human colorectal and gastric tumors. Cancer Res 1995; 55: 1407-12. 34. Riethmuller G, Schneider-Gadicke E, Schhmok G et al. Randomised trial of onoclonal antibody for adjuvant therapy of resected Dukes C colorectal carcinoma. Lancet 1994; 343: 1177-83. 35. Sugarbaker PH, Gianola FJ, Speyer JL et al. Prospective randomised trial of intravenous vs intraperitoneal 5-FU in patients with advanced primary colon or rectal cancer. Sem Oncol 1985; 12: 101-11. 36. Taylor I, Machin D, Muller M et al. A randomised controlled trial of adjuvant portal vein cytotoxic perfusion in colorectal cancer. Br J Surg 1985; 72: 359-63. 37. SAKX- Swiss Group for Clinical Cancer Research Long term results of single course of adjuvant intraportal chemotherapy for colorectal cancer. Lancet 1995; 345: 349-53. 38. Wolmark N, Rockette H, Petrelli N et al. Long-term results of the efficacy of perioperative portal vein infusion of 5-FU for treatment of colon cancer. NSABP C-02. Proc Am Soc Clin Oncol 1994; 13- 194. 39. Piedbois P, Bruyse M, Gray R et al. Portal vein infusion is an effective adjuvant treatment for patients with colorectal cancer. Proc Am Soc Clin Oncol 1995; 14: 192. 40. Nitti D et al. Final results of phase III clinical trial on adjuvant intraportal infusion with heparin and 5-fluorouracil (5-FU) in resectable colon cancer (EORTC GITTCCG 1983-1987). Eur J Cancer 1997; 33(8): 1209-15. 41. Burke D, Allen-Mersh TG. Colorectal liver metastases. Postgrad Med J 1996; 72. 464-9 42. VanderMeer TJ, Callery MP, Meyers WC et al. The approach to the patient with single and multiple liver metastases, pulmonary metastases, and intra-abdominal metastases from colorectal carcinoma. Hematol Oncol Clin North Am 1997; 11: 759-77. 43. Blumgart L, Fong Y. Surgical options in the treatment of hepatic metastasis from colorectal cancer. Curr Probl Surg 1995; 32: 333-421. 44. McAfee MIC, Allen MS, Trastek VF et al. Colorectal lung metastasis: results of surgical excision. Ann Thorac Surg 1992; 53: 780-6. 45. Weaver M, Atkinson D, Zemel R. Hepatic cryosurgery in treating colorectal metastases. Cancer 1995; 76: 210-4. 46. Korpan N. Hepatic cryosurgery for liver metastases. Long-term followup. Ann Surg 1997; 225: 193-201. 47. The Meta-analysis Group In Cancer. Efficacy of intravenous continuous infusion offluorouracilcompared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16: 301-8. 48. Cvitkovic E. New anticancer agents in current clinical development (abstract). Eight Mediterranean Congress on Chemotherapy - May 1992 49. Haller D. An overview of adjuvant therapy for colorectal cancer. European J Cancer 1995; 31: App. 50. Cassidy J, Kaye S. New drugs in clinical development in Europe. Hematol Oncol Clin North America 1994; 8: 289-303. 51. Giacchetti S, Zidani R, Perpoint B et al. Phase III trial of 5-fluorouracil (5-FU), folinic acid (FA), with or without oxaliplatin (OXA) in
Ill
52.
53.
54. 55.
56. 57
58.
60.
61.
62. 63.
64.
65.
66. Findlay M, Van Custem E, Kocha W et coll. A randomised phase II Xeloda, (Capecitabine) in patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 1997; 16: 227a, (abstract). 67. Becouarn Y, Ychou M, Ducreux M et coll. Oxaliplatin (L-OHP) as first line chemotherapy in metastatic colorectal cancer (MCRC) patients: preliminary activity / toxicity report. Proc Am Soc Clin Oncol 1997; 16:229a, (abstract 804). 68. de Gramont A, Vignoud J, Tournigand C et coll. Oxaliplatin with highdose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 1997; 33: 214-9. 69. Berthault-Cvitkovic F, Jami A, Ithzaki M et al. Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil and leucovorin in patients with metastatic colorectal cancer. J Clin Oncol 1996; 14: 2950-8. 70. Levi FA, Zidani R, Vannetzel JM et coll. Chronomodulated versus fixedinfusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and fohnic acid (leucovorin) in patients with colorectal cancer metastasis: a randomised multi-institutional trial. J Natl Cancer Inst 1994; 86: 1608-17. 71. Levi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil and folinic acid in metastatic colorectal cancer. For the International Organisation for Cancer chronotherapy. Lancet 1997; 350: 681-6. 72. Rougier P, Culine S, Bugat R et al. Multicentric phase II study of first line CPT-11 (irinotecan) in advanced colorectal cancer (CRC). Preliminary results (abstract). Proc Am Soc Clin Oncol 1994; 13: 200. 73. Bugat R, Rougier P, Douillard JY et al. Efficacy of irinotecan HCI (CPT11) in patients with metastatic colorectal cancer after progression while receiving a 5-FU based chemotherapy (abstract) . Proc Am Soc Clin Oncol 1995; 14: 122 74. Johnston PG, Allegra CJ. Colorectal cancer biology: clinical implications. Sem Oncol 1995; 22: 418-32. 75. O'Connel MJ, Schaid DJ, Ganju V et al. Current status of adjuvant chemotherapy for colorectal cancer: can molecular markers play a role in predicting prognosis? Cancer 1992; 70 (suppl): 1732-9. Correspondence to: Esteban Cvitkovic F.S.M.S.I.T. Hopital Paul Brousse 12, avenue Paul Vaillant Couturier 94800 Villejuif France
Downloaded from http://annonc.oxfordjournals.org/ at Gumberg Library on July 9, 2015
59.
previously untreated patients (pts) with metastatic colorectal cancer (MCC) (abstract). Proc Am Soc Clin Oncolg 1997, 17:A985. O'Connel MJ, Nagorney DM, Bernath AM et coll. Sequential intrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver. J Clin Oncol 1998; 16 / 2528-33. Bismuth H, Adam R, Levi F et al. Resection of non resectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann surg 1996; 224: 509-22. Bleiberg H Role of chemotherapy for advanced colorectal cancer: new opportunities Sem Oncol 1996; 23: 42-50. Schmoll HJ. Development of treatment for advanced colorectal cancer: Infusional 5-FU and the role of new agents. Eur J Cancer 1996 (suppl 5);32A/S18-S22. Kemeny N. Current approaches to metastatic colorectal cancer. Semin Oncol 1994 (suppl 7); 21: 67-75. Piedbois P, Bryse M, Rustum Y et al. Meta-analysis of 5-FU and Leucovorin in patients with advanced colorectal cancer (abstract). Ann Oncol 1992 (suppl 5); 3 205. Advanced colorectal Cancer meta-analysis Project. Modulation of fluorouracil by Leucovorin in patients with advanced colorectal cancer, evidence in terms of response rate J Clin Oncol 1992; 10 896-903. Cunningham D, Zalcerg J, Smith I et al. Tomudex (ZD 1694): a novel thymidylate synthase inhibitor with clinical antitumor activity in a range of solid tumors Ann Oncol 1996; 7: 179-82. Seitz JF, Cunningham D Rath U et al. Final results and survival data of a large randomised trial of Tomudex in advanced colorectal cancer (ACC) confirm comparable efficacy to 5-fluorouracil plus leucovorin (5-Fu+LV) (abstract)Proc Am Soc Clin Oncol 1996; 15. 201. Ota K, Taguchi T, Kimura K. Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer in chemoth Pharmacol 1988; 22: 333-8. Malk STA, Talbot D, Clarke PI et al Phase II trial of UFT in advanced colorectal and gastric cancer. Br J Cancer 1990; 62: 1023-5. Nogue M, Segui MA, Batiste E et al. Phase II study of oral tegafur (TF) and low-dose oral leucovorin (LV) in advanced colorectal cancer (ACC) (abstract). Proc Am Soc Clin Oncol 1996; 15: 200 Pazdur R, Lassere Y, Rhodes V et al. Phase II trial of uracil and tegafur plus oral Leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma. J Clin Oncol 1994; 12: 2296-2300. Saltz LB, Leichman CG, Young CW et al. A fixed-ratio combination of uracil and florafur (UFT) with low-dose leucovorin. an active oral regimen for advanced colorectal cancer Cancer 1995; 75: 782-5.
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Review article New possibilities in chemotherapy for colorectal cancer M. Bekradda1 & E. Cvitkovic2 'Cvitkovic & Associes Consultants, Kremlin Bicetre, France; !H6pilal Paul Brousse, ViUejuif, France
Improved diagnostic techniques, such as MRI (magnetic resonance imaging), PET (positron emission tomography), and CEA (Carcino-Embryonic Antigen) scanning, and the introduction of new chemotherapeutic agents, are no less important than improved knowledge about the disease. As a result of such innovations, a new multidisciplinary approach to colorectal cancer treatment has emerged, with new goals that replace those associated with standard treatment.
Local disease (adjuvant setting) Who will be able to benefitfrom adjuvant treatment after complete resection of the primary tumour? Prognosis will mainly depend on the stage of the disease [4]. For most patients with early stage disease (A and B1 according to the Astler-Coller modification of Duke's staging [5, 6]) surgery alone is curative. However, once the tumour has invaded the muscularis propria (stage B2-B3), 5-year survival decreases to 70%. For stages Cl, C2 and C3, 5-year survival is between 25% and 60%. The decreased survival correlates with an increase in the number of invaded proximal lymph nodes [4, 7]. Other anatomical factors that are predictive of relapse include perforation, obstruction and adhesions to and/ or invasion of adjacent organs [8]. Some studies have reported the predictive value of elevated CEA serum levels in preoperative patients with negative lymph nodes [9-14]. Other factors that have been proposed as predictive of relapse include cell cycle (ploidy), DNA synthesising activity (S phase), and cell proliferation [15-18]. Thymidylate synthase (TS), a key target enzyme of 5-FU, has treatment-related prognostic value. In a recent study, Johnston et al. [19] reported a 5-year survival rate of 60% for patients with metastatic disease and low TS levels, compared to 40% for patients with high TS levels. P53 acts as a tumour suppressor gene, located in 17 pi 3. Under normal conditions, it encodes for a 'wild-type' p53 protein which has a very short half-life and is undetectable by immunohistochemistry. Where there is gene mutation, p53 protein is non-functional, has a much longer half-life and becomes detectable by immunohistochemistry. The identification of mutated p53 protein is an independent factor that is
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Colorectal cancer is the second leading cause of cancer death. Approximately 26,000 new cases are diagnosed yearly in France, resulting in more than 10,000 deaths, and 5-year survival remains low, at 40%. This poor prognosis is partly due to the fact that, in 30% of cases, colorectal cancer is metastatic or at a locally advanced stage when discovered. Moreover, visceral metastases complicate the development of the cancer after resection of the primary tumour in 40% to 50% of cases. The liver is the most frequently involved, followed by the abdominal lymph nodes, the peritoneum, the lungs, and far more rarely, the bones, adrenal glands or brain. Metastasis, whether synchronous or metachronous, most frequently occurs in the liver (around 40% of cases), thus exacerbating mortality [1,2]. The prognosis is poor for patients with visceral metastasis, and depends on such factors as the patient's general condition and the number and sites of metastatic disease. Nevertheless, several studies have shown that the prognosis for metastatic disease can be improved if treatment is aimed at 'curing' patients. Surgical resection of metastases, which is the first treatment option, is feasible, either immediately or after chemotherapy in only 10% of cases. The other cases are often candidates for systemic or locoregional chemotherapy treatment. The metastatic potential of colorectal carcinoma seems to correlate with the expression of certain oncoproteins involved in regulating apoptosis and the cell cycle. The presence of the p53 protein in the primary tumour is an indicator of liver and lymph node metastases. Also, overexpression of c-erb B2 in the primary tumour may be an indicator of potential metastasis, particularly in the liver [3]. Once the recently acquired knowledge in the molecular biology of colorectal cancer has been formally recognised as a factor for prognosis/prediction of natural history and/or tumoural response, this will lead to great changes in medical practice. During the last few decades, steady progress has been made in cancer treatment in terms of curability, survival duration and quality of life. This progress has varied according to the type of cancer. Major advances were made in the 1970s in the treatment of breast, testicular and childhood cancer; the end of the century will probably see advances in colorectal cancer treatment also.
106
Systemic treatment:
Pre or perioperative local treatment:
5-FU alone: In the meta-analysis carried out by Buyse in 1988, out of 17 randomised trials comprising 6791 colorectal cancer patients, only treatments with 5-FU-based chemotherapy showed a slight improvement in survival, of around 3% to 5% [23]. This meta-analysis did not consider either administration schedules or 5-FU doses.
In the trial initiated by Sugarbaker et al. [35], intraperitoneal chemotherapy significantly reduced the peritoneal rate of relapse; but had no influence on survival. The small patient cohort number might have limited the chances of obtaining significant results. The first randomised trial to demonstrate the efficacy of intraportal chemotherapy was carried out by Taylor et al [36]. Five-year survival was significantly higher in the experimental arm (117 patients) treated by 5-FU at 1000 mg/day over 7 days, compared with the control arm (127 patients). This difference was particularly significant in patients with Dukes stage B disease. Several trials have attempted to confirm these results. A Swiss group obtained results that seemed to indicate the efficacy of intraportal chemotherapy [37]. A trial by the NSABP in a randomised series of 1158 patients, reported an improvement in overall survival, 76% versus 71%, with no difference in the incidence of liver metastases [38]. One meta-analysis [39] involving 9 randomised trials in 3824 patients demonstrated a significant reduction in risk of death by 13% (p = 0.02). However, the EORTC trial, in 235 patients, showed no advantage in terms of disease-free survival: 56% versus 65% or 5-year survival: 69% versus 71% [40].
Biochemical modulation of 5-FU: The modulation of 5-FU by folinic acid (FA) has proven its efficacy in the palliative treatment of metastatic colorectal carcinoma, leading to several controlled trials in the adjuvant setting. A complete analysis of 1526 patients (1493 eligible), of whom 841 (56%) had stage B disease at diagnosis, showed a 3-year disease-free survival of 71%, which compares favourably with 5-FU alone, compared with 62% in the untreated control group (p = < 0.0001), with a relative reduction in risk of relapse of 35 ± 9% and a 3-year survival of 83% versus 78% (p= 0.03) [26]. A trial by the NSABP (C04) comparing 5-FU/Levamisole, 5-FU/FA (high dose) and 5-FU/Levamisole/FA (high dose) in 2151 patients with stage B and C colon cancers demonstrated no significant difference in disease-free survival (p = 0.12) or in overall survival (p = 0.14) among the three arms [27]. 5-FU in continuous infusion (CI): 5-FU in continuous infusion may be a feasible alternative to biochemical modulation. Phase III trials have demonstrated improved response rates for CI 5-FU compared to bolus 5FU in advanced colorectal cancer [28]. Novel agents: Recently acquired knowledge about the molecular biology of colorectal carcinoma, including the role of p53 protein in the cell cycle and apoptosis [29, 30], the role of deficient mismatch repair [31, 32], and the role of thymidylate synthase activity in 5-FU resistance [33], has encouraged the development of treatment strategies using new agents with novel mechanisms of action. These new anticancer agents include oxaliplatin, a cisplatin analogue of the DACH (diaminocyclohexane) family of platinums, the new thymidylate synthase inhibitors (raltitrexed, Tegafur (UFT), and capecitabine); irinotecan; and immunotherapeutic agents, in particular the monoclonal antibody anti-17-lA. The activity demonstrated by these new chemotherapeutic agents in advanced colorectal carcinoma,
Advanced or metastatic disease The term 'advanced' colorectal cancer denotes very different clinical and prognostic situations which require an adaptive, multidisciplinary approach to their treatment according to the specific clinical settings. Despite progress made in treatment modalities, the prognosis for advanced colorectal cancer remains ominous. Better results could be obtained by targeting patients likely to benefit from a particular treatment modality, by using screening techniques such MRI, PET and CEA scanning, and by improving the identification of prognostic factors, particularly via molecular biology. Advanced disease may be divided into two categories: 1. Potentially 'curable' disease 2. Very advanced disease (purely palliative situation) /. Potentially 'curable'disease Improvements in the treatment of advanced disease, due to the biochemical modulation of 5-FU and the introduction of
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Choosing the adjuvant treatment
pretreated or not by 5-FU, has opened new avenues for their application in the adjuvant setting, with or without 5-FU. As concerns postoperative immunotherapy by the antibody anti-17-lA (Panorex), Riethmuller et al. reported in a randomised trial of 166 patients that overall and disease-free survival were significantly better in the group treated by the antibody, with a reduction in mortality risk of 30% (p =0.04) and a risk of relapse of 27% (p = 0.027) [34].
predictive of poor prognosis in some types of colon carcinoma [21-23]. Lenz et al. [24] reported a > 90% risk of relapse in patients with stage II (B2-B3) colon cancer who had both mutated p53 protein and elevated TS levels.
107 the approach be extended to the postoperative setting? (After resection of liver metastases?) One advantage of these new strategies for advanced colorectal cancer patients is that they result in improved response rates which enable more patients to receive curative surgery [51, 53]. Even in first line treatment, the improved knowledge of molecular targets permits the identification of patients who might benefit from the new strategies. 2. Very advanced disease (palliative setting) The treatment consists of optimising treatment choices in first line as well as in second line after failure with standard treatment. 5-FU has been the reference treatment since the 1950s. However, response rates rarely reach 15% with single agent 5-FU [54, 55] and a consensus has not yet been reached regarding dose, schedule and mode of administration. The 5-FU/FA combination has been shown to be more active in terms of objective response rates [56, 57], but is barely superior in terms of survival [57, 58]. Although continuous infusion 5-FU has demonstrated a statistically significant survival advantage of about one month over short infusion [47], this finding has no major clinical relevance. As a result, clinical research efforts have focussed on the development of other anticancer agents, to be used as single agents or in combination with 5-FU or its analogues. The introduction of new agents has led to a redefinition of the whole approach to the treatment of metastatic colorectal cancer allowing the optimisation of combinations, schedules and sequences of administration. Raltitrexed, irinotecan and oxaliplatin have been intensively developed in the last few years. Thymidylate synthase inhibitors •
•
Raltitrexed (Tomudex) has been tested in phase II trials at the recommended dose of 3 mg/m2 in the United States, Europe and Australia [58], in 177 patients with non pretreated advanced colorectal carcinoma. The response rate was 26% with a median survival of 9.6 months. In a randomised phase III European trial of raltitrexed versus weekly 5-Fu/FA bolus 5D q4w (Mayo clinic), there was no statistically significant difference in objective response and median survival [60]. Other thymidylate synthase inhibitors are currently being developed: LY 231514, BW 18431189, Thymitaq.
New 5-FU analogues •
Orally administered tegafur (UFT) showed a response rate of 25%, with a median survival of 7.5 months in 56 patients evaluable in first and second line in a multicentric phase II trial in Japan [60]. Another similar trial in the United Kingdom showed a response rate of 16.6 %, with a median survival of 7.8 months in 36 patients [62]. Three American trials testing the combination of UFT with folinic acid per os showed response rates of 25%, 30% and 42.2% [63-65].
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new combination agents should produce a higher rate of quicker and better responses. In addition, the multidisciplinary approach combining surgical resection of liver metastases with chemotherapy could provide hope of a cure to some patients with metastatic disease. One of the main goals of future studies should be to distinguish those patients with advanced disease who are potential subjects for curative treatment from those who are not immediate candidates for curative surgery. Surgery provides the only hope of a cure in advanced colorectal cancer. Liver metastasis resection can increase 5year survival by 30% [41-43]. Similarly, lung metastases resection can be curative and increase survival [44]. Many patients present with liver metastases that are considered inoperable because of their sise, site and/or number, or have extrahepatic metastatic invasion. One recent technique, cryosurgery, reduces liver metastases that are often considered inoperable, thus increasing the number of patients with potentially 'curable' metastatic disease [45]. A recent randomised trial involving 123 patients demonstrated a better 5-year survival rate in patients treated by liver cryosurgery (44%) than in patients treated by standard metastatic surgery (36%) [46]. For patients with inoperable metastatic disease, the treatment option is often chemotherapy that is referred to as 'palliative.' The goals of this chemotherapeutic option should be two-fold: adequate tumour control and acceptable safety. Tumour control is assessed by response rate and disease-free survival. An optimal response rate increases tumour operability and facilitates curative surgery. The experience of randomised trials in metastatic colorectal carcinoma has given cause to doubt the value of bolus 5-FU/ FA as standard treatment. All the schedules including 5-FU as continuous infusion have shown superior tumour control, and, for the most part, less toxicity [47]. Although 5-FU remains the reference chemotherapy treatment for colorectal cancer, its efficacy is limited by resistance that is either spontaneous (in over 50% of cases) or secondary (in almost all cases). This resistance is partly related to an overexpression or a modification in thymidylate synthase activity. Several new anticancer agents with novel mechanisms of action (oxaliplatin, irinotecan, raltitrexed and other thymidylate synthase inhibitors) have opened avenues that were, until now, unimaginable - it is now possible to propose second-line treatment to patients progressing under 5-FU, and to envisage chemotherapy treatment combining several cytotoxic agents [48-50]. One interesting approach is the sequential treatment of advanced colorectal carcinoma by intrahepatic chemotherapy combined with systemic chemotherapy. In one published trial, the Mayo Clinic team reported 62% of objective responses with a median survival of 18 months but there was no impact on median time to progression in 40 patients with inoperable liver metastases, treated by hepatic intra-arterial fluorodeoxyuridine (FUDR) combined with systemic chemotherapy by bolus 5-FU-FA [52]. Should this approach be optimised by using new agents in systemic treatment? Should
108 Capecitabine (Xeloda), a promising oral analogue already registered in the United States for breast cancer treatment, has been tested in phase II randomised trials in a two weeks out of three schedule, with or without folinic acid. The latter regimen, having obtained objective responses of 28%, was used in later phase III trials [66]. It will soon be available for colorectal cancer patients. Other 5-FU analogues, such as SI, B0FA2, and 776C85 (dihydropyrimidine dehydrogenase inhibitor) are currently undergoing clinical development.
Local disease
Topoisomerase I inhibitors: Irinotecan (CPT-11) Like oxaliplatin, the most interesting property of CPT-11 is its lack of cross-resistance with 5-FU. Phase II studies have reported response rates of 18.8% to 29% in non pretreated patients, and 17% in those progressing under 5-FU [72, 73]. Other agents belonging to the metalloprotein family are currently undergoing preclinical and clinical development.
High risk of relapse Stage B2 / C. > 4 N+, Perforation
Conclusion Treatment regimens which combine new agents with novel mechanisms of action will probably result in an improved prognosis for colorectal cancer. Several possibilities are feasible in the 'palliative' setting: tritherapy consisting of three active agents, (oxaliplatin/irinotecan/5-FU; capecitabine/ oxaliplatin/irinotecan), alternated chemotherapy allowing several agents to be administered, and, possibly, sequential treatments combining systemic and locoregional chemotherapy treatment. Some details still require clarification, such as optimal dose, route of administration and administration schedule. The potential role of these new agents needs to be assessed in adjuvant and palliative settings. Recently acquired knowledge in the molecular biology of colorectal carcinoma may
L-OHP/5-FU±FA? or CPT-11/ 5-FU ± FA? or UFT/L-OHP ou CPT-11 "> or Capecitabine ? or New TS inhibitors or anti-17-lA or sequential chemotherapy ? (locoregional + systemic)
5-FU + FA or New oral 5-FU analogues 4-
Antibody ami 17-1A
Figure I. Treatment algorithm for localised colorectal cancers.
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enable patients who could benefit from these new agents in adjuvant and palliative settings to be identified [74, 75]. These new treatment approaches are based on two phenomena: the development of a multidisciplinary strategy in which chemotherapy is combined with tumour resection, either before or after chemotherapy, and the appearance of adjuvant treatments. Colorectal cancer should no longer be considered a homogenous, infrequently curable disease, and it is difficult, and possibly unnecessary, to propose any kind of inflexible 'decision-making tree,' to guide oncologists in their choice of treatment. It is important, however, to be very familiar with Platinum analogues: Oxaliplatin the treatment options based on recently acquired knowledge in the biological, diagnostic and therapeutic fields, which can The efficacy of single agent oxaliplatin has been proven in be adapted to every clinical situation and which should be first line treatment, with a 27% of objective response rate in prospectively validated (see Figures 1 and 2). 38 treated patients [67]. Under the guidance or 'dictation' of the pharmaceutical The recent combination of oxaliplatin with 5-FU/FA has industry, progress in the clinical development of new agents shown objective response rates exceeding 40%, even after in France, particularly for advanced colorectal carcinoma, has treatment failure with 5-FU [68, 69]. led to the registration and marketing of major anticancer agents Extensive research with the chronomodulated combina- such as oxaliplatin and irinotecan. This progress is likely to tion of oxaliplatin/5-FU-FA has been carried out by Levi et be applied to the postoperative phase. Two randomised trials al., treating more than 500 patients with a 5 day q3w, or 4 day are currently ongoing in France using standard 5-FU/FA verq2w schedule. This combination obtained response rates of sus 5-FU/FA combined with the new agents (5-FU/FA +iriabout 50%, including second line, with median survival ex- notecan and 5-FU/FA + oxaliplatin) in localised colorectal ceeding one year and reaching 17 months in first line [69- cancer with a high risk of relapse. The new thymidylate syn71]. thase inhibitors are among the agents that could feasibly be De Gramont also administered oxaliplatin in combination used in the adjuvant setting. with his biweekly FU/FA schedule and obtained objective responses of 45% and a median survival of 17 months in 46 pretreated patients [68].
Advanced disease
(Liver metastases only)
"1
Evaluation of operabilitv (CT Scan and/or echography only)
Clinically operable metastases
Clinically Inoperable metastases
Confirmatory evaluation (CT Scan and/or MR] + CEA scan)
• combination of new agents / 5-FU ±FA (trilherapy, alternated treatment) • sequential chemotherapy (locoregional and systemic)
New agents ± 5-FU ± FA
Treatment?
Figure 2. Treatment algorithm for patients with colorectal cancers metastatic to the liver.
Several trials are presently ongoing in metastatic disease, sessing combinations of new agents with or without 5-FU - FA in first line after failure with fluoropyrimidines. The goal of these trials is to optimise the treatment of adinced colorectal carcinoma, by using new combinations (biid tritherapy), and new administration schedules (alternatg, chronomodulation). Future trials should incorporate not only new anticancer ,ents, but also new treatment modalities, such as sequential lemotherapy (systemic or locoregional), where the operabili of metastases is a criterion of evaluation, and, also progistic factors, including molecular biological parameters. The means at our disposal could enable us to radically insform the natural history of colorectal cancer within the xt few years. It is our responsibility to ensure that these sans reach their full potential.
:knowledgements le authors wish to thank Catherine Benner, William Suthland and Michelle Hughes for assistance in preparation of i manuscript.
Table 1. Ongoing trials in France—end anticancer agents for colorectal carcinoma Indication
Phase Treatm
Local disease (adjuvant)
III III
CPT-11 L-OHP
Advanced disease Non pretreated
II
CPT-11
Pretreated
II
CPT-11 L-OHP OHP(c L-OHP (q3w) 5-FU/F 5-FU/L 5-FU//S L-OHP L-OHP 5-FU/L CPT-11 L-OHP
II III l/II II I I III I
Abbreviations: CPT-11, irinotecan; 5-FU, L-OHP, oxaliplatin. * The list is not exhaustive
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Revaluation of operabilitv (CT Scan and/or MR] + CEA scan)
110
References 1.
2. 3
4.
5. 6. 7.
9.
10. 11.
12.
13.
14.
15.
16. 17.
18.
19.
20.
21.
22. 23.
24.
25.
Downloaded from http://annonc.oxfordjournals.org/ at Gumberg Library on July 9, 2015
8.
Wagner JS, Adson MA, Van Heerden JA et coll. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984; 199: 502-8. Hugh TJ, Kinsella AR, Poston GJ. Management strategies for colorectal liver metastasis - Part I. Surg Oncol 1997; 6: 19-30. Yang J-L, Yu Y, Markovic B et coll. Overexpression of c-erbB-2 mRNA and for c-neu oncoprotein is a predictor for metastasis from colorectal cancer. Anticancer Res 1997; 17: 1023-6. Cohen AM, Shank B, Friedman MA. Colorectal cancer. In De Vital VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice, ed 3 Philadelphia, JB Lippincott, 1989; 929-77. Dukes CE. The classification of cancer of the rectum. J Pathol Bcterioll940; 50: 527-39. Asler WB, Coller FA. The prognostic significance of direct extension of carcinoma of the colon and rectum. Ann Surg 1954; 139: 846-51. Wolmark N, Fisher B, Wei HS. The prognostic value of the modification of the duke's C class of colorectal cancer: an analysis of the NSABP clinical trials. Ann Surg 1986; 203: 115-22. Willet C, Tepper JE, Cohen A et al. Obstructive and perforative colonic carcinoma: patterns of failure. J Clin Oncol 1985; 3: 379-84. Goslin R, Stech G, Mac Intyre I et al The use of preoperative plasma CEA levels for the stratification of patients after curative resection of colorectal cancers. Ann Surg 1980; 192: 747-51. LoGerfo P, Herter F Carcinoembryonic antigen prognosis in patients with colorectal cancer. Ann Surg 1974; 181:81—4. Moertel CG, O'Fallon JR, Go VLW et al. The preoperative carcinoembryonic antigen test in the diagnosis, staging, and prognosis of colorectal cancer. Cancer 1986; 58: 603-10. Steel G, EllenbergS, Ramming Ketal CEA monitoring among patients in multiinstitutional adjuvant GI protocols. Ann Surg 1982; 196: 162— 9. Wanebo HJ, Rao B, Pinsky CM et al. Preoperative carcinoembryonic antigen level as a prognostic indicator in colorectal cancer N Engl J Med 1978; 299: 448-51. Wolmark N, Fisher B, Wieand S et al. The prognostic significance of preoperative carcinoembryonic antigen levels in colorectal cancer. Ann Surg 1984; 199:375-81. Albe X, Vassilakos P, Helfer-Guarnori K et al Independent prognostic value of ploidy in colorectal cancer. A prospective study using image cytometry. Cancer 1990; 66: 1168-75. Kokal WA, Gardine RL, Sheibam K et al. Tumor DNA content in resectable, primary colorectal carcinoma. Ann Surg 1989; 209: 188-93. Scott NA, Wieand HS, Moertel CG et al. Colorectal cancer: Dukes' stage, tumor site, preoperative plasma CEA level and patient prognosis related to tumor DNA ploidy pattern. Arch Surg 1987; 122- 1375-9. Sinicrope F, Hart J, Brasitus T et al Relationship of P-glycoprotein and carcinoembryonic antigen expression in human colon carcinoma to local invasion, DNA ploidy, and disease relapse. Cancer 1994; 74: 2908-17. Moertel CG, Loprinzi CL, Witzig TE et al. The dilemma of stage B2 colon cancer. Is adjuvant therapy justified ? (abstract). Proc Am Soc Clin Oncol 1990; 9:108. Johnston PG, Fisher EF, Rockette HE et al. The role of thymidylate synthase expression in prognosis and outcome to adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol 1994; 12: 2640-7. Yamaguchi A, Nakagawara G, Kurosaka Y et al. p 53 immunoreaction in endoscopic biopsy specimens of colorectal cancer, and its prognostic significance. Br J Cancer 1993; 69: 399-402 Auvinen A, Isola J, Visakorpi T et al. Over expression of p53 and longterm survival in colon carcinoma. Br J Cancer 1994; 70: 293-6. Tomoda H, Kareji Y. Immunohistochemical analysis of p53 in colorectal cancer regarding chemicopathological correlation and prognostic significance. J Surg Oncol 1995; 58: 125-8. Lenz HJ, Danenberg KD, Danenberg P et al. p53 status and thymidylate synthase (TS) expression are associated and predict for recurrence in patients with stage II colon cancer (cc) (abstract). Proc Am Soc Clin Oncol 1996; 15:215. Buyse M, Zeleniuch-Jacquotte A, Chalmers TC. Adjuvant therapy of colorectal cancer.Why we still don't know? JAMA 1988: 259:3571-78.
26. IMPACT Investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 1995; 106: 939-44. 27. Wolmark N, Rochette H, Mamounas EP et al. The relative efficacy of 5FU and Leucovorin (FU-LV), 5-FU and Levamisole (Fu-Lev), and 5FU + Leucovorin and Levamisole (Fu-LV-Lev) in patients with duke's B and C carcinoma of the colon: First report of NSABPC-04 (abstract). Proc Am Soc Clin Oncol 1996; 15: 205. 28. Anderson N, Lokieh JJ. Cancer Chemotherapy and infusional scheduling. Oncology 1994; 8: 99-116. 29. Gottlieb TM, Oren M. p53 in growth control and neoplasia. Biochem BiophysActa 1996; 1287: 77-102. 30. Velculescu VE, El-Deiry WS. Biological and clinical importance of the p53 tumor suppressor gene. Clin Chem 1996; 42: 858-68. 31. Lynch HT, Smyrk T, Lynch JF. Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch syndrome) Int J Cancer 1996; 69. 38-43. 32. Marra G, Boland CR. Hereditary non polyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J. Nat Cancer Inst 1995; 87: 1114-25. 33. Johnston PG, Lenz HJ, Leichman CG et al. Thymidylate synthase gene and protein expression correlate and are associated with response to 5fluorouracil in human colorectal and gastric tumors. Cancer Res 1995; 55: 1407-12. 34. Riethmuller G, Schneider-Gadicke E, Schhmok G et al. Randomised trial of onoclonal antibody for adjuvant therapy of resected Dukes C colorectal carcinoma. Lancet 1994; 343: 1177-83. 35. Sugarbaker PH, Gianola FJ, Speyer JL et al. Prospective randomised trial of intravenous vs intraperitoneal 5-FU in patients with advanced primary colon or rectal cancer. Sem Oncol 1985; 12: 101-11. 36. Taylor I, Machin D, Muller M et al. A randomised controlled trial of adjuvant portal vein cytotoxic perfusion in colorectal cancer. Br J Surg 1985; 72: 359-63. 37. SAKX- Swiss Group for Clinical Cancer Research Long term results of single course of adjuvant intraportal chemotherapy for colorectal cancer. Lancet 1995; 345: 349-53. 38. Wolmark N, Rockette H, Petrelli N et al. Long-term results of the efficacy of perioperative portal vein infusion of 5-FU for treatment of colon cancer. NSABP C-02. Proc Am Soc Clin Oncol 1994; 13- 194. 39. Piedbois P, Bruyse M, Gray R et al. Portal vein infusion is an effective adjuvant treatment for patients with colorectal cancer. Proc Am Soc Clin Oncol 1995; 14: 192. 40. Nitti D et al. Final results of phase III clinical trial on adjuvant intraportal infusion with heparin and 5-fluorouracil (5-FU) in resectable colon cancer (EORTC GITTCCG 1983-1987). Eur J Cancer 1997; 33(8): 1209-15. 41. Burke D, Allen-Mersh TG. Colorectal liver metastases. Postgrad Med J 1996; 72. 464-9 42. VanderMeer TJ, Callery MP, Meyers WC et al. The approach to the patient with single and multiple liver metastases, pulmonary metastases, and intra-abdominal metastases from colorectal carcinoma. Hematol Oncol Clin North Am 1997; 11: 759-77. 43. Blumgart L, Fong Y. Surgical options in the treatment of hepatic metastasis from colorectal cancer. Curr Probl Surg 1995; 32: 333-421. 44. McAfee MIC, Allen MS, Trastek VF et al. Colorectal lung metastasis: results of surgical excision. Ann Thorac Surg 1992; 53: 780-6. 45. Weaver M, Atkinson D, Zemel R. Hepatic cryosurgery in treating colorectal metastases. Cancer 1995; 76: 210-4. 46. Korpan N. Hepatic cryosurgery for liver metastases. Long-term followup. Ann Surg 1997; 225: 193-201. 47. The Meta-analysis Group In Cancer. Efficacy of intravenous continuous infusion offluorouracilcompared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16: 301-8. 48. Cvitkovic E. New anticancer agents in current clinical development (abstract). Eight Mediterranean Congress on Chemotherapy - May 1992 49. Haller D. An overview of adjuvant therapy for colorectal cancer. European J Cancer 1995; 31: App. 50. Cassidy J, Kaye S. New drugs in clinical development in Europe. Hematol Oncol Clin North America 1994; 8: 289-303. 51. Giacchetti S, Zidani R, Perpoint B et al. Phase III trial of 5-fluorouracil (5-FU), folinic acid (FA), with or without oxaliplatin (OXA) in
Ill
52.
53.
54. 55.
56. 57
58.
60.
61.
62. 63.
64.
65.
66. Findlay M, Van Custem E, Kocha W et coll. A randomised phase II Xeloda, (Capecitabine) in patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 1997; 16: 227a, (abstract). 67. Becouarn Y, Ychou M, Ducreux M et coll. Oxaliplatin (L-OHP) as first line chemotherapy in metastatic colorectal cancer (MCRC) patients: preliminary activity / toxicity report. Proc Am Soc Clin Oncol 1997; 16:229a, (abstract 804). 68. de Gramont A, Vignoud J, Tournigand C et coll. Oxaliplatin with highdose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 1997; 33: 214-9. 69. Berthault-Cvitkovic F, Jami A, Ithzaki M et al. Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil and leucovorin in patients with metastatic colorectal cancer. J Clin Oncol 1996; 14: 2950-8. 70. Levi FA, Zidani R, Vannetzel JM et coll. Chronomodulated versus fixedinfusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and fohnic acid (leucovorin) in patients with colorectal cancer metastasis: a randomised multi-institutional trial. J Natl Cancer Inst 1994; 86: 1608-17. 71. Levi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil and folinic acid in metastatic colorectal cancer. For the International Organisation for Cancer chronotherapy. Lancet 1997; 350: 681-6. 72. Rougier P, Culine S, Bugat R et al. Multicentric phase II study of first line CPT-11 (irinotecan) in advanced colorectal cancer (CRC). Preliminary results (abstract). Proc Am Soc Clin Oncol 1994; 13: 200. 73. Bugat R, Rougier P, Douillard JY et al. Efficacy of irinotecan HCI (CPT11) in patients with metastatic colorectal cancer after progression while receiving a 5-FU based chemotherapy (abstract) . Proc Am Soc Clin Oncol 1995; 14: 122 74. Johnston PG, Allegra CJ. Colorectal cancer biology: clinical implications. Sem Oncol 1995; 22: 418-32. 75. O'Connel MJ, Schaid DJ, Ganju V et al. Current status of adjuvant chemotherapy for colorectal cancer: can molecular markers play a role in predicting prognosis? Cancer 1992; 70 (suppl): 1732-9. Correspondence to: Esteban Cvitkovic F.S.M.S.I.T. Hopital Paul Brousse 12, avenue Paul Vaillant Couturier 94800 Villejuif France
Downloaded from http://annonc.oxfordjournals.org/ at Gumberg Library on July 9, 2015
59.
previously untreated patients (pts) with metastatic colorectal cancer (MCC) (abstract). Proc Am Soc Clin Oncolg 1997, 17:A985. O'Connel MJ, Nagorney DM, Bernath AM et coll. Sequential intrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver. J Clin Oncol 1998; 16 / 2528-33. Bismuth H, Adam R, Levi F et al. Resection of non resectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann surg 1996; 224: 509-22. Bleiberg H Role of chemotherapy for advanced colorectal cancer: new opportunities Sem Oncol 1996; 23: 42-50. Schmoll HJ. Development of treatment for advanced colorectal cancer: Infusional 5-FU and the role of new agents. Eur J Cancer 1996 (suppl 5);32A/S18-S22. Kemeny N. Current approaches to metastatic colorectal cancer. Semin Oncol 1994 (suppl 7); 21: 67-75. Piedbois P, Bryse M, Rustum Y et al. Meta-analysis of 5-FU and Leucovorin in patients with advanced colorectal cancer (abstract). Ann Oncol 1992 (suppl 5); 3 205. Advanced colorectal Cancer meta-analysis Project. Modulation of fluorouracil by Leucovorin in patients with advanced colorectal cancer, evidence in terms of response rate J Clin Oncol 1992; 10 896-903. Cunningham D, Zalcerg J, Smith I et al. Tomudex (ZD 1694): a novel thymidylate synthase inhibitor with clinical antitumor activity in a range of solid tumors Ann Oncol 1996; 7: 179-82. Seitz JF, Cunningham D Rath U et al. Final results and survival data of a large randomised trial of Tomudex in advanced colorectal cancer (ACC) confirm comparable efficacy to 5-fluorouracil plus leucovorin (5-Fu+LV) (abstract)Proc Am Soc Clin Oncol 1996; 15. 201. Ota K, Taguchi T, Kimura K. Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer in chemoth Pharmacol 1988; 22: 333-8. Malk STA, Talbot D, Clarke PI et al Phase II trial of UFT in advanced colorectal and gastric cancer. Br J Cancer 1990; 62: 1023-5. Nogue M, Segui MA, Batiste E et al. Phase II study of oral tegafur (TF) and low-dose oral leucovorin (LV) in advanced colorectal cancer (ACC) (abstract). Proc Am Soc Clin Oncol 1996; 15: 200 Pazdur R, Lassere Y, Rhodes V et al. Phase II trial of uracil and tegafur plus oral Leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma. J Clin Oncol 1994; 12: 2296-2300. Saltz LB, Leichman CG, Young CW et al. A fixed-ratio combination of uracil and florafur (UFT) with low-dose leucovorin. an active oral regimen for advanced colorectal cancer Cancer 1995; 75: 782-5.
Downloaded from http://annonc.oxfordjournals.org/ at Gumberg Library on July 9, 2015