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New options and old dilemmas in the treatment of patients with advanced colorectal cancer
Annals of Oncology 15: 1453– 1459, 2004 doi:10.1093/annonc/mdh383
Review
New options and old dilemmas in the treatment of patients with advanced colorectal cancer C. J. A. Punt* Department of Medical Oncology, University Medical Center St Radboud, Nijmegen, The Netherlands Received 2 March 2004; revised 27 April 2004; accepted 5 May 2004
Introduction Decades of studying 5-fluorouracil (5-FU) schedules and modulators, from bolus to chronomodulated infusion [1, 2] and from methotrexate to trimetrexate [3,4], have not resulted in a significant survival benefit for patients with advanced colorectal cancer over treatment with 5-FU alone, and a bolus regimen of 5-FU with leucovorin (LV) has remained the standard choice for a long time [5]. However, significant progress has been made in the past 6–7 years by which we can now offer these patients three effective cytotoxic drugs (fluoropyrimidines, irinotecan and oxaliplatin) and two signal transduction inhibitors (cetuximab and bevacizumab). With this ‘abundance’ of choices, the obvious question is how these agents can be optimally used to the benefit of the patient. Although the most urgent question appears to concern the choice of agents (i.e. which combination, which sequence), also the timing and duration of treatment are a matter of debate. With increasing response rates of combination schedules, their use as neo-adjuvant regimens for patients with irresectable liver metastases is becoming more popular. The current data on which these choices may be based are reviewed.
Timing of chemotherapy The most frequently cited study is that of the Nordic Group who have shown a significant survival benefit for immediate versus delayed treatment of chemotherapy in a small cohort of
*Correspondence to: Prof. C. J. A. Punt, Department of Medical Oncology, University Medical Center, St Radboud, PO Box 9010, 6500 HB Nijmegen, The Netherlands. Tel: +31-24-3610353; Fax: +31-24-3540788; E-mail: [email protected] q 2004 European Society for Medical Oncology
183 asymptomatic patients [6]. Based on this result patients are often advised to start chemotherapy even when their disease is still asymptomatic. However, a meta-analysis of 168 patients from two studies with a similar design as the Nordic study failed to reproduce this result, although this has only been presented as an abstract [7]. Whether the results of the Nordic Group can be taken one step further and also apply to patients with only a rise in serum carcinoembryonic antigen (CEA) and without measurable or evaluable disease is unknown. Given the fact that performance status is an important prognostic factor for the outcome of chemotherapy, and that more effective chemotherapy is available nowadays, one obviously does not want to delay chemotherapy until severe symptoms with a concomitant decline in performance status have developed. Based on these data it seems reasonable to start treatment in asymptomatic patients, but watchful waiting in patients with small (unresectable) tumor volume is probably justified as well.
Duration of chemotherapy The optimal duration of treatment has never been rigorously studied. This question is most relevant for regimens that are tolerated for a prolonged period such as fluoropyrimidine therapy. Recently this question was addressed in a randomized fashion [8]. The design of an ongoing Medical Research Council (MRC) study was altered and patients with disease stabilization or better at 3 months were randomized between continuous and intermittent treatment. Patients in the intermittent group were to be offered the initial treatment upon disease progression. As it appeared, many patients refused to be randomized since they did not wish to interrupt a treatment that at that time appeared to be effective, thereby introducing
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With more data on the use of oxaliplatin and irinotecan available, and the recent approval of two signal transduction inhibitors for patients with advanced colorectal cancer, there are now many treatment options to choose from. From the current regimens no straightforward choice can be made that provides any patient with the optimal chance for prolonged survival with the least side-effects. The current data concerning timing and duration of chemotherapy, combination or sequential therapy, preference of agents for first-line treatment, oral fluoropyrimidines, neo-adjuvant chemotherapy for irresectable liver metastases, and the use of signal transduction inhibitors are reviewed. Key words: bevacizumab, capecitabine, cetuximab, colorectal cancer, irinotecan, oxaliplatin
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Oral fluoropyrimidines An important development in the treatment with fluoropyrimidines are oral agents such as capecitabine and uracil-Ftorafur (UFT) –LV. Both agents have shown comparable results in overall and progression-free survival but with improved tolerability to bolus 5-FU– LV [10–13]. The two studies involving
capecitabine were designed to demonstrate an equivalence in response rate, and a pooled analysis of the data showed a significant superior overall response rate, but not response duration, for capecitabine [14,15]. Of the two studies with UFT – LV, one was designed to demonstrate an equivalence in survival, the other an improvement in time to progression. With capecitabine, a significantly lower incidence rate of stomatitis, diarrhea, nausea, alopecia, neutropenic fever/sepsis and treatment-related hospitalisation rate was observed in comparison to bolus 5-FU –LV. Capecitabine treatment was associated with a higher incidence of hand– foot syndrome and uncomplicated hyperbilirubinemia [15]. UFT–LV when compared with 5-FU –LV was associated with less stomatitis, diarrhea, nausea/vomiting, myelosuppression including neutropenic fever and documented infection. As with capecitabine, uncomplicated hyperbilirubinemia was observed with UFT – LV. In a small, randomized crossover study patients preferred UFT–LV over 5-FU –LV [16]. As with 5-FU, cardiac toxicity has been reported for capecitabine and UFT –LV [17,18]. Given its earlier availability as well as its easier dosing schedule (twice versus three times daily), capecitabine is currently being used more frequently in colorectal cancer than UFT– LV. The currently used intermittent schedule of capecitabine has resulted in a higher dose-intensity compared with combination with leucovorin or continuous dosing [19], but alternative dosing schedules have not been rigorously studied. Of several UFT–LV schedules tested in a non-comparative way, the current schedule originated from the largest phase II study performed in colorectal cancer [20]. As with any oral agent when compared with intravenous administration, patient compliance is much more of an issue and this aspect should receive appropriate attention in patient education. Combination studies of capecitabine or UFT–LV with irinotecan or oxaliplatin [21 –25] have shown promising response rates, but data from randomized studies have to be awaited. The ongoing EORTC study 40015 is comparing irinotecan combined with either infusional 5-FU–LV or capecitabine; this study also includes randomisation of celecoxib versus placebo. Lastly, several studies have been performed or are ongoing on the use of capecitabine either alone or as part of combination chemotherapy together with radiotherapy in patients with (locally advanced) rectal cancer [26,27], and randomized studies are being planned.
Sequential or concomitant use of cytotoxics There is no doubt that both irinotecan and oxaliplatin have contributed significantly to a better outcome for patients with advanced colorectal cancer. The value of irinotecan as secondline treatment for 5-FU-refractory patients has been established for several years [28], and recently such data from a randomized study have been published for oxaliplatin as well [29]. The obvious next step was to investigate their use in first-line combinations with 5-FU– LV. Two studies with irinotecan plus either bolus or infusional 5-FU –LV compared to
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a selection bias. A comparison of randomized versus nonrandomized patients did not show a clear survival difference, but obviously such retrospective unplanned subset analysis cannot be taken as solid evidence. Despite the fact that patients were included from outside the original study design, the required number to demonstrate a 10% survival benefit for continuous treatment was not reached and the study was closed prematurely. Further comments on this study include that only 37% of patients in the intermittent group did resume with the scheduled treatment upon progression, no independent review of response was performed while response at 3 months was a pivotal study parameter, and there was very little use of irinotecan or oxaliplatin. Although the authors did conclude that chemotherapy can be safely discontinued at 3 months, one may question the validity of this statement. It is probably more reasonable to state that chemotherapy preferably has to be continued for at least 3 months, and that the continuation of treatment should be based on its toxicity and individual patient preferences. In cases of ongoing remission, many oncologists and patients will prefer to continue treatment, and it seems reasonable to discuss interruption of treatment when no further regression is evident at follow-up evaluation. If progression of disease occurs after a treatment-free period, there are no data from prospective studies available on the minimum progression-free interval that would justify reintroduction of the previous regimen as opposed to starting another regimen, if available in that setting. With more toxic (and expensive!) regimens including irinotecan or oxaliplatin the question regarding treatment duration becomes even more relevant. Some patients may tolerate irinotecan for quite prolonged periods of time without experiencing cumulative toxicity. With oxaliplatin a significant percentage of patients will develop treatment-limiting neurotoxicity, which may justify the limitation of treatment to a fixed number of cycles in order to prevent its occurrence. Whether it is appropriate in that scenario to continue with fluoropyrimidine treatment or to interrupt both drugs altogether is unknown. The randomized OPTIMOX study has been designed in order to overcome two dose-limiting toxicities of the FOLFOX4 regimen: the myelosuppressive effects of bolus 5-FU and the neurotoxicity of oxaliplatin. The experimental arm consists of a simplified 5-FU–LV regimen with high-dose oxaliplatin (FOLFOX7) given for a limited number of cycles in order to allow FOLFOX reintroduction. Preliminary results have shown comparable results on efficacy and a favorable toxicity profile for FOLFOX7 [9].
1455 oxaliplatin. Until we have the results of these two studies, the sequential use of these agents remains a valid option. Phase I studies on the combination of 5-FU –LV plus irinotecan plus oxaliplatin have been published [36 –38]. There are no data on a clear synergistic effect of this combination. The possible disadvantage of such a combination may be that the combined use of these drugs will not allow their administration at full dose and therefore will limit their dose intensity [39]. It may be more relevant that patients are exposed to these drugs at any time during their treatment than that these agents are being administered concomitantly. This is supported by a retrospective analysis that shows that the median overall survival is increased with a higher number of patients who have been exposed to 5-FU –LV, irinotecan and oxaliplatin [40].
Sequence of irinotecan and oxaliplatin Since approximately 30 –40% of patients are not eligible for second-line treatment, one may argue that the best (i.e. most effective and/or least toxic) regimen should be given first (if one wishes to give these agents as first-line treatment at all; see above). In terms of toxicity, it is probably difficult to base this decision on personal experience since the possible toxic effects of these agents are quite divergent and are of different consequence. The small percentage of patients that experience severe toxicity with irinotecan are more likely to be hospitalized, while a larger percentage of patients experiencing dose-limiting toxicity with oxaliplatin in most cases remain outpatients. In a recent study [35], patients were randomized between FOLFOX and FOLFIRI with a crossover upon progression. Indeed, the incidence of serious adverse events was higher in patients treated with FOLFIRI (14% versus 5%), but the overall incidence of grade 3 –4 toxicities as well as the percentage of patients that had to discontinue treatment for reasons of toxicity were greater upon treatment with FOLFOX (74% versus 53%, and 11% versus 6%, respectively). One may question whether this high incidence of severe toxicities is acceptable. Designed to detect a 20% difference in progression-free survival at 15 months, this study did not demonstrate any difference in progression-free or overall survival or first-line response rate. A small difference was noted in second-line response rate in favor of FOLFOX, but this may have been caused by the fact that second-line FOLFIRI after failure on FOLFOX may be inferior to irinotecan monotherapy. Since there is no rationale to combine irinotecan with 5-FU– LV after previous exposure to 5-FU –LV, irinotecan monotherapy may be preferred since this allows a higher irinotecan dose intensity compared with FOLFIRI. Lastly, the preliminary results of a randomized phase II study of capecitabine administered in combination with either irinotecan or oxaliplatin do not suggest a superiority in terms of feasibility or response rate for either regimen [24]. Therefore, the current data suggest that the choice for either irinotecan or oxaliplatin can be made on individual preferences. Promising data have arisen from studies in which pharmacogenomics
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5-FU –LV alone were the first to show a significant benefit in median overall survival of 2.2 and 3.3 months, respectively [30, 31]. However, these studies have been criticized for the fact that effective second-line treatment with irinotecan in the control arm was no prospective part of the study design [32]. Although a lack of cross-over was not identified in a recent assessment of these studies [33], of the patients in the control arm who received any second-line treatment, 20% and 47%, respectively, did not receive irinotecan (or oxaliplatin). The small survival difference in these studies may therefore have been lost when this would have been the case, provided of course that these patients were eligible for irinotecan treatment. Therefore, despite the fact that irinotecan combination treatment was widely accepted as the new standard in first-line treatment at that time, the question of whether to give these drugs concomitantly or sequentially remained unanswered. A combination of infusional 5-FU –LV and oxaliplatin (FOLFOX) was shown in a more recent study to significantly prolong the overall survival compared with a bolus 5-FU – LV–irinotecan regimen (IFL) [34]. These results immediately caused a widespread displacement of IFL by FOLFOX from the number one spot. However, the same criticism also applies to this study, since 60% of patients received second-line irinotecan after failure on FOLFOX, but due to its limited availability at the time of the study, only 24% of patients failing IFL received oxaliplatin. The finding that the difference in median overall survival (4.5 months) was much larger compared to the difference in median time to progression (1.8 months) also suggests that subsequent treatment had a significant impact on survival outcome. Furthermore, the different modes of 5-FU administration between the two treatment arms (continuous versus bolus infusion) may have been responsible for the higher incidence of severe toxicities as well as the decreased efficacy in the IFL arm. This view is supported by the results of another study in which FOLFOX and infusional 5-FU –LV plus irinotecan (FOLFIRI) had comparable results, although this study was not designed with survival as the primary end point [35]. Two important studies will provide a better insight in this ongoing debate. The FOCUS study in the UK is comparing sequential versus concomitant treatment for irinotecan or oxaliplatin with 5-FU–LV (modified de Gramont schedule) in separate treatment arms. In an amendment, patients failing protocol treatment are advised to continue with oxaliplatin after exposure to irinotecan and vice versa, but since this is not a mandatory, integral part of the study design it leaves the door open for other arguments (such as budgetary restraints) not to continue treatment accordingly. The only study that prospectively evaluates the sequential versus the concomitant use of all three effective agents, i.e. a fluoropyrimidine, irinotecan and oxaliplatin, is the CAIRO study of the Dutch Colorectal Cancer Group (DCCG). In this study the treatment with first-line capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin is compared with first-line capecitabine plus irinotecan, and second-line capecitabine plus
1456 are applied to predict the response to chemotherapy [41]. If these results are confirmed in larger prospective series, this would provide us with a valuable tool to tailor the treatment for individual patients.
Neoadjuvant chemotherapy for irresectable liver metastases
Signal transduction inhibitors Two agents of this class of drugs have recently been approved: cetuximab, an antibody against the epidermal growth factor receptor (EGF-R), and bevacizumab, an antibody against the vascular endothelial growth factor (VEGF). Although conflicting data have been presented as to the prognostic significance of the expression of EGF-R and VEGF on colorectal cancer cells, results of the efficacy of their respective inhibitors has been presented. Cetuximab blocks the binding of EGF to its receptor and enhances the effects of chemotherapy by the inhibition of cell proliferation, tumor neoangiogenesis and metastatic potential, and the promotion of apoptosis. Although some activity has been demonstrated when given as a single agent [45], the pivotal data were derived from a trial in which cetuximab alone was randomized versus cetuximab plus irinotecan in 329 irinotecan-refractory patients [46]. Time to progression and response rates were significantly better for the combination, with 4.1 versus 1.5 months, and 23% versus 11%, respectively. Probably due to a design that allowed cross-over, the overall survival did not differ between the two treatment arms. Bevacizumab inhibits tumor neoangiogenesis by blocking VEGF. It was tested versus placebo in combination with the bolus 5-FU –LV–irinotecan (IFL) regimen in 815 previously untreated patients [47]. Median overall survival was significantly improved by almost 5 months from 15.6 to 20.3 months, progression-free survival from 6.2 to 10.6 months and response rates from 35% to 45%. Do these results imply that from now on cetuximab and bevacizumab have to be administered to all patients in the setting in which these trials were positive? Several obvious questions can be raised. . Is one positive trial sufficient for a definite proof of efficacy? . How does the efficacy of these agents relate to the expression of their respective targets on the tumor of the patient?
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The role of radical resection for liver metastases of colorectal cancer is well established, with 5-year overall survival rates of around 20% and in some series (probably due to more stringent selection criteria) up to 40% [42]. However, one should caution against the comparison of these results with the results of chemotherapy in the general population with advanced disease, which of course includes patients with a worse prognosis due to larger liver lesions as well as extrahepatic disease. Secondly, only a few surgical series report on the percentage of patients that received chemotherapy after recurrence. With more effective chemotherapy available nowadays the survival benefit of liver resections might be less spectacular as often stated. In this respect interesting data were provided by a retrospective study that evaluated the results of surgery for recurrent colon cancer [43]. With only 5-FU –LV available at that time, the median overall survival for patients who underwent radical surgery was 33 months, for irradical resection this was only 11 months, which is in line with published results on 5-FU –LV [5]. However, 19 patients were identified who were eligible for radical resection, but for different reasons did not receive this treatment, and their median survival was 26 months, with many of these patients not even receiving chemotherapy at all. Although this number is too small for definite conclusions, it does put liver resections in a somewhat different perspective. There are currently no data to support the use of (neo)adjuvant chemotherapy in patients with resectable liver metastasis. This is being investigated in EORTC study 40983, in which pre- and postoperative chemotherapy with 5-FU –LV–oxaliplatin are compared with surgery alone, and the results are not yet available. With more patients being screened for potential resections upon recurrence, more patients are identified whose intrahepatic disease is too extensive for resection but who are without extrahepatic disease and in a good general condition. Although response rate is a suboptimal surrogate marker for survival, it may be reasoned that if the tumor in these patients responds to chemotherapy to a level that allows radical resection, neoadjuvant chemotherapy in these patients should consist of the regimen that has shown the highest response rates. For this purpose the largest experience has been built with 5-FU – LV–oxaliplatin. The largest series reported so far concerns a cohort of 701 patients with unresectable liver metastases [44]. After chemotherapy 95 patients (13.5%) were found to be resectable and their 5-year overall survival rate after resection was 34%. Although without doubt a positive result by itself, one should, as always, apply the principle of intention-to-treat: these 34% of 95 resected patients form only 4.6% of the initial
cohort of 701 patients. When no data from randomized prospective studies are available, one should at least compare this result with a matched cohort of historical controls. Certainly with current median overall survival rates of 20 months for a less selected population, it may well be that the 5-year survival for a matched group of patients may not be significantly off the mark of 4.6%. For instance, at our institute the 5-year survival for 41 patients with resectable liver metastases during workup who appeared irresectable during laparotomy and who were subsequently treated with chemotherapy was 6% (Ruers T et al., unpublished data). This suggests that the true value of neoadjuvant chemotherapy has still to be established. In this respect it is laudable that a novel experimental local therapy for irresectable liver metastases, radiofrequency ablation (RFA), is now prospectively being evaluated in combination with chemotherapy versus chemotherapy alone in EORTC study 40004 (CLOCC study).
1457 . Will they have comparable efficacy in combination with other chemotherapy regimens? . Are we currently employing their most effective doses and schedules? . May these agents have a role as maintenance treatment in responding patients? . Why should colorectal cancer be a good target for bevacizumab? . What is the correlation between EGF-R expression on (primary? metastatic) tumor tissue and response to cetuximab?
Conclusions New agents have significantly increased the median overall survival in patients with advanced colorectal cancer and survival times of 21 months have been reported in randomized trials with 5-FU, irinotecan and oxaliplatin [35]. Whether one may directly compare this result with the median survival of 8 months from the few data on observation [48], or with the 11 months from randomized trials with 5-FU –LV [5] is questionable, since (i) follow-up procedures are likely to be more intensive nowadays and will therefore present patients with earlier diagnosis, and (ii) patients in whom the diagnosis has been made may be offered chemotherapy at an earlier stage of advanced disease due to a better acceptance of this treatment
References 1. Ko¨hne C-H, Wils J, Lorenz M et al. Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol 2003; 21: 3721–3728.
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Confirmatory data on the efficacy of bevacizumab and cetuximab should become available. Based on the very limited data that we currently have, it is impossible to give any recommendation on their use outside the setting in which they have been developed. Although it is undoubtedly quite promising that a new class of agents have shown efficacy in a relevant tumor type such as colorectal cancer, it can only be hoped that this optimism does not translate into a nihilism towards a critical appraisal of their true value. If anything can be learned from history in cancer drug development, it is that it is quite unusual for a single trial with a drug, however wellconducted it may be, to provide us with the definite proof of its value. As a high official of its manufacturer was quoted on the internet after the FDA approval of bevacizumab: “we are concerned that expectations are getting ahead of us—please don’t get ahead of us”, we as medical oncologists should take this request very seriously! A further concern is that while these agents have been approved, we as medical oncologists at the time that we are expected to start prescribing these drugs to patients have only access to limited data from abstracts and oral presentations and not to peer-reviewed full publications in independent medical journals with accompanying editorials from experts in the field. For bevacizumab and cetuximab, the time between initial presentation and peer-reviewed publication of the results was 1 year. Although the approval by healthcare authorities should be a guarantee of high-quality and independent data analysis, the expected wave of industrydriven introduction symposia can never be expected to make up for such publications when it comes to independent information to professionals.
modality, which is reflected by the inclusion of a higher percentage of patients with good performance status compared to older studies. As an example, the average percentage of patients with a World Health Organization (WHO) performance status of 0 used to be <30% in studies with 5-FU –LV [5], but this percentage is around 50% in more recent randomized studies. With more data available on the use of oxaliplatin and irinotecan, more options are open for the systemic treatment of patients with advanced colorectal cancer. Further results of ongoing studies have to be awaited before any regimen or schedule can be regarded as most optimal in a given situation. Individual preferences or medical conditions of the patient may play an important role in the choice for a particular treatment. The use of pharmacogenomics may prove to be a valuable tool in the selection of patients with the best chance for a response or with a high likelihood of toxicity from a probably ineffective treatment. The promising initial results of targeted therapy will surely lead to the development of many related compounds in this disease. With several lines of treatment now available, new strategies for clinical drug development should be designed which allow testing at an early stage of the disease and not only as fourth- or fifth-line treatment. However, in this scenario it will be quite impossible to evaluate their efficacy based on overall survival as the major end point, since it will not be feasible to evaluate all subsequent effective treatments in a prospective way. Other end points, such as time to progression, appear to be more appropriate for this use and should be further validated. Lastly, although costs of treatment should not play a role in the evaluation of the efficacy of a drug, the expected costs (in the USA estimated at $10 000 for cetuximab and $4400 for bevacizumab per month of treatment) will be serious factors in their general availability to patients. With a steady influx of effective (but expensive) drugs on the positive side, and limitations to healthcare budgets everywhere on the negative side, we are obliged to continuously assess the most efficient way by which these drugs can be administered in order to ensure that cancer patients will receive the treatments with maximal clinical benefits within the dictated financial limits. This goal is unlikely to be reached when clinical research is fully dependent on the support of pharmaceutical industries, since their primary responsibility lies, understandably, not with the benefit of the patient. This can only be achieved if investigator-driven studies performed by industry-independent, collaborative groups continue, and if new legislation does not prevent this [49, 50].
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Review
New options and old dilemmas in the treatment of patients with advanced colorectal cancer C. J. A. Punt* Department of Medical Oncology, University Medical Center St Radboud, Nijmegen, The Netherlands Received 2 March 2004; revised 27 April 2004; accepted 5 May 2004
Introduction Decades of studying 5-fluorouracil (5-FU) schedules and modulators, from bolus to chronomodulated infusion [1, 2] and from methotrexate to trimetrexate [3,4], have not resulted in a significant survival benefit for patients with advanced colorectal cancer over treatment with 5-FU alone, and a bolus regimen of 5-FU with leucovorin (LV) has remained the standard choice for a long time [5]. However, significant progress has been made in the past 6–7 years by which we can now offer these patients three effective cytotoxic drugs (fluoropyrimidines, irinotecan and oxaliplatin) and two signal transduction inhibitors (cetuximab and bevacizumab). With this ‘abundance’ of choices, the obvious question is how these agents can be optimally used to the benefit of the patient. Although the most urgent question appears to concern the choice of agents (i.e. which combination, which sequence), also the timing and duration of treatment are a matter of debate. With increasing response rates of combination schedules, their use as neo-adjuvant regimens for patients with irresectable liver metastases is becoming more popular. The current data on which these choices may be based are reviewed.
Timing of chemotherapy The most frequently cited study is that of the Nordic Group who have shown a significant survival benefit for immediate versus delayed treatment of chemotherapy in a small cohort of
*Correspondence to: Prof. C. J. A. Punt, Department of Medical Oncology, University Medical Center, St Radboud, PO Box 9010, 6500 HB Nijmegen, The Netherlands. Tel: +31-24-3610353; Fax: +31-24-3540788; E-mail: [email protected] q 2004 European Society for Medical Oncology
183 asymptomatic patients [6]. Based on this result patients are often advised to start chemotherapy even when their disease is still asymptomatic. However, a meta-analysis of 168 patients from two studies with a similar design as the Nordic study failed to reproduce this result, although this has only been presented as an abstract [7]. Whether the results of the Nordic Group can be taken one step further and also apply to patients with only a rise in serum carcinoembryonic antigen (CEA) and without measurable or evaluable disease is unknown. Given the fact that performance status is an important prognostic factor for the outcome of chemotherapy, and that more effective chemotherapy is available nowadays, one obviously does not want to delay chemotherapy until severe symptoms with a concomitant decline in performance status have developed. Based on these data it seems reasonable to start treatment in asymptomatic patients, but watchful waiting in patients with small (unresectable) tumor volume is probably justified as well.
Duration of chemotherapy The optimal duration of treatment has never been rigorously studied. This question is most relevant for regimens that are tolerated for a prolonged period such as fluoropyrimidine therapy. Recently this question was addressed in a randomized fashion [8]. The design of an ongoing Medical Research Council (MRC) study was altered and patients with disease stabilization or better at 3 months were randomized between continuous and intermittent treatment. Patients in the intermittent group were to be offered the initial treatment upon disease progression. As it appeared, many patients refused to be randomized since they did not wish to interrupt a treatment that at that time appeared to be effective, thereby introducing
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With more data on the use of oxaliplatin and irinotecan available, and the recent approval of two signal transduction inhibitors for patients with advanced colorectal cancer, there are now many treatment options to choose from. From the current regimens no straightforward choice can be made that provides any patient with the optimal chance for prolonged survival with the least side-effects. The current data concerning timing and duration of chemotherapy, combination or sequential therapy, preference of agents for first-line treatment, oral fluoropyrimidines, neo-adjuvant chemotherapy for irresectable liver metastases, and the use of signal transduction inhibitors are reviewed. Key words: bevacizumab, capecitabine, cetuximab, colorectal cancer, irinotecan, oxaliplatin
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Oral fluoropyrimidines An important development in the treatment with fluoropyrimidines are oral agents such as capecitabine and uracil-Ftorafur (UFT) –LV. Both agents have shown comparable results in overall and progression-free survival but with improved tolerability to bolus 5-FU– LV [10–13]. The two studies involving
capecitabine were designed to demonstrate an equivalence in response rate, and a pooled analysis of the data showed a significant superior overall response rate, but not response duration, for capecitabine [14,15]. Of the two studies with UFT – LV, one was designed to demonstrate an equivalence in survival, the other an improvement in time to progression. With capecitabine, a significantly lower incidence rate of stomatitis, diarrhea, nausea, alopecia, neutropenic fever/sepsis and treatment-related hospitalisation rate was observed in comparison to bolus 5-FU –LV. Capecitabine treatment was associated with a higher incidence of hand– foot syndrome and uncomplicated hyperbilirubinemia [15]. UFT–LV when compared with 5-FU –LV was associated with less stomatitis, diarrhea, nausea/vomiting, myelosuppression including neutropenic fever and documented infection. As with capecitabine, uncomplicated hyperbilirubinemia was observed with UFT – LV. In a small, randomized crossover study patients preferred UFT–LV over 5-FU –LV [16]. As with 5-FU, cardiac toxicity has been reported for capecitabine and UFT –LV [17,18]. Given its earlier availability as well as its easier dosing schedule (twice versus three times daily), capecitabine is currently being used more frequently in colorectal cancer than UFT– LV. The currently used intermittent schedule of capecitabine has resulted in a higher dose-intensity compared with combination with leucovorin or continuous dosing [19], but alternative dosing schedules have not been rigorously studied. Of several UFT–LV schedules tested in a non-comparative way, the current schedule originated from the largest phase II study performed in colorectal cancer [20]. As with any oral agent when compared with intravenous administration, patient compliance is much more of an issue and this aspect should receive appropriate attention in patient education. Combination studies of capecitabine or UFT–LV with irinotecan or oxaliplatin [21 –25] have shown promising response rates, but data from randomized studies have to be awaited. The ongoing EORTC study 40015 is comparing irinotecan combined with either infusional 5-FU–LV or capecitabine; this study also includes randomisation of celecoxib versus placebo. Lastly, several studies have been performed or are ongoing on the use of capecitabine either alone or as part of combination chemotherapy together with radiotherapy in patients with (locally advanced) rectal cancer [26,27], and randomized studies are being planned.
Sequential or concomitant use of cytotoxics There is no doubt that both irinotecan and oxaliplatin have contributed significantly to a better outcome for patients with advanced colorectal cancer. The value of irinotecan as secondline treatment for 5-FU-refractory patients has been established for several years [28], and recently such data from a randomized study have been published for oxaliplatin as well [29]. The obvious next step was to investigate their use in first-line combinations with 5-FU– LV. Two studies with irinotecan plus either bolus or infusional 5-FU –LV compared to
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a selection bias. A comparison of randomized versus nonrandomized patients did not show a clear survival difference, but obviously such retrospective unplanned subset analysis cannot be taken as solid evidence. Despite the fact that patients were included from outside the original study design, the required number to demonstrate a 10% survival benefit for continuous treatment was not reached and the study was closed prematurely. Further comments on this study include that only 37% of patients in the intermittent group did resume with the scheduled treatment upon progression, no independent review of response was performed while response at 3 months was a pivotal study parameter, and there was very little use of irinotecan or oxaliplatin. Although the authors did conclude that chemotherapy can be safely discontinued at 3 months, one may question the validity of this statement. It is probably more reasonable to state that chemotherapy preferably has to be continued for at least 3 months, and that the continuation of treatment should be based on its toxicity and individual patient preferences. In cases of ongoing remission, many oncologists and patients will prefer to continue treatment, and it seems reasonable to discuss interruption of treatment when no further regression is evident at follow-up evaluation. If progression of disease occurs after a treatment-free period, there are no data from prospective studies available on the minimum progression-free interval that would justify reintroduction of the previous regimen as opposed to starting another regimen, if available in that setting. With more toxic (and expensive!) regimens including irinotecan or oxaliplatin the question regarding treatment duration becomes even more relevant. Some patients may tolerate irinotecan for quite prolonged periods of time without experiencing cumulative toxicity. With oxaliplatin a significant percentage of patients will develop treatment-limiting neurotoxicity, which may justify the limitation of treatment to a fixed number of cycles in order to prevent its occurrence. Whether it is appropriate in that scenario to continue with fluoropyrimidine treatment or to interrupt both drugs altogether is unknown. The randomized OPTIMOX study has been designed in order to overcome two dose-limiting toxicities of the FOLFOX4 regimen: the myelosuppressive effects of bolus 5-FU and the neurotoxicity of oxaliplatin. The experimental arm consists of a simplified 5-FU–LV regimen with high-dose oxaliplatin (FOLFOX7) given for a limited number of cycles in order to allow FOLFOX reintroduction. Preliminary results have shown comparable results on efficacy and a favorable toxicity profile for FOLFOX7 [9].
1455 oxaliplatin. Until we have the results of these two studies, the sequential use of these agents remains a valid option. Phase I studies on the combination of 5-FU –LV plus irinotecan plus oxaliplatin have been published [36 –38]. There are no data on a clear synergistic effect of this combination. The possible disadvantage of such a combination may be that the combined use of these drugs will not allow their administration at full dose and therefore will limit their dose intensity [39]. It may be more relevant that patients are exposed to these drugs at any time during their treatment than that these agents are being administered concomitantly. This is supported by a retrospective analysis that shows that the median overall survival is increased with a higher number of patients who have been exposed to 5-FU –LV, irinotecan and oxaliplatin [40].
Sequence of irinotecan and oxaliplatin Since approximately 30 –40% of patients are not eligible for second-line treatment, one may argue that the best (i.e. most effective and/or least toxic) regimen should be given first (if one wishes to give these agents as first-line treatment at all; see above). In terms of toxicity, it is probably difficult to base this decision on personal experience since the possible toxic effects of these agents are quite divergent and are of different consequence. The small percentage of patients that experience severe toxicity with irinotecan are more likely to be hospitalized, while a larger percentage of patients experiencing dose-limiting toxicity with oxaliplatin in most cases remain outpatients. In a recent study [35], patients were randomized between FOLFOX and FOLFIRI with a crossover upon progression. Indeed, the incidence of serious adverse events was higher in patients treated with FOLFIRI (14% versus 5%), but the overall incidence of grade 3 –4 toxicities as well as the percentage of patients that had to discontinue treatment for reasons of toxicity were greater upon treatment with FOLFOX (74% versus 53%, and 11% versus 6%, respectively). One may question whether this high incidence of severe toxicities is acceptable. Designed to detect a 20% difference in progression-free survival at 15 months, this study did not demonstrate any difference in progression-free or overall survival or first-line response rate. A small difference was noted in second-line response rate in favor of FOLFOX, but this may have been caused by the fact that second-line FOLFIRI after failure on FOLFOX may be inferior to irinotecan monotherapy. Since there is no rationale to combine irinotecan with 5-FU– LV after previous exposure to 5-FU –LV, irinotecan monotherapy may be preferred since this allows a higher irinotecan dose intensity compared with FOLFIRI. Lastly, the preliminary results of a randomized phase II study of capecitabine administered in combination with either irinotecan or oxaliplatin do not suggest a superiority in terms of feasibility or response rate for either regimen [24]. Therefore, the current data suggest that the choice for either irinotecan or oxaliplatin can be made on individual preferences. Promising data have arisen from studies in which pharmacogenomics
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5-FU –LV alone were the first to show a significant benefit in median overall survival of 2.2 and 3.3 months, respectively [30, 31]. However, these studies have been criticized for the fact that effective second-line treatment with irinotecan in the control arm was no prospective part of the study design [32]. Although a lack of cross-over was not identified in a recent assessment of these studies [33], of the patients in the control arm who received any second-line treatment, 20% and 47%, respectively, did not receive irinotecan (or oxaliplatin). The small survival difference in these studies may therefore have been lost when this would have been the case, provided of course that these patients were eligible for irinotecan treatment. Therefore, despite the fact that irinotecan combination treatment was widely accepted as the new standard in first-line treatment at that time, the question of whether to give these drugs concomitantly or sequentially remained unanswered. A combination of infusional 5-FU –LV and oxaliplatin (FOLFOX) was shown in a more recent study to significantly prolong the overall survival compared with a bolus 5-FU – LV–irinotecan regimen (IFL) [34]. These results immediately caused a widespread displacement of IFL by FOLFOX from the number one spot. However, the same criticism also applies to this study, since 60% of patients received second-line irinotecan after failure on FOLFOX, but due to its limited availability at the time of the study, only 24% of patients failing IFL received oxaliplatin. The finding that the difference in median overall survival (4.5 months) was much larger compared to the difference in median time to progression (1.8 months) also suggests that subsequent treatment had a significant impact on survival outcome. Furthermore, the different modes of 5-FU administration between the two treatment arms (continuous versus bolus infusion) may have been responsible for the higher incidence of severe toxicities as well as the decreased efficacy in the IFL arm. This view is supported by the results of another study in which FOLFOX and infusional 5-FU –LV plus irinotecan (FOLFIRI) had comparable results, although this study was not designed with survival as the primary end point [35]. Two important studies will provide a better insight in this ongoing debate. The FOCUS study in the UK is comparing sequential versus concomitant treatment for irinotecan or oxaliplatin with 5-FU–LV (modified de Gramont schedule) in separate treatment arms. In an amendment, patients failing protocol treatment are advised to continue with oxaliplatin after exposure to irinotecan and vice versa, but since this is not a mandatory, integral part of the study design it leaves the door open for other arguments (such as budgetary restraints) not to continue treatment accordingly. The only study that prospectively evaluates the sequential versus the concomitant use of all three effective agents, i.e. a fluoropyrimidine, irinotecan and oxaliplatin, is the CAIRO study of the Dutch Colorectal Cancer Group (DCCG). In this study the treatment with first-line capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin is compared with first-line capecitabine plus irinotecan, and second-line capecitabine plus
1456 are applied to predict the response to chemotherapy [41]. If these results are confirmed in larger prospective series, this would provide us with a valuable tool to tailor the treatment for individual patients.
Neoadjuvant chemotherapy for irresectable liver metastases
Signal transduction inhibitors Two agents of this class of drugs have recently been approved: cetuximab, an antibody against the epidermal growth factor receptor (EGF-R), and bevacizumab, an antibody against the vascular endothelial growth factor (VEGF). Although conflicting data have been presented as to the prognostic significance of the expression of EGF-R and VEGF on colorectal cancer cells, results of the efficacy of their respective inhibitors has been presented. Cetuximab blocks the binding of EGF to its receptor and enhances the effects of chemotherapy by the inhibition of cell proliferation, tumor neoangiogenesis and metastatic potential, and the promotion of apoptosis. Although some activity has been demonstrated when given as a single agent [45], the pivotal data were derived from a trial in which cetuximab alone was randomized versus cetuximab plus irinotecan in 329 irinotecan-refractory patients [46]. Time to progression and response rates were significantly better for the combination, with 4.1 versus 1.5 months, and 23% versus 11%, respectively. Probably due to a design that allowed cross-over, the overall survival did not differ between the two treatment arms. Bevacizumab inhibits tumor neoangiogenesis by blocking VEGF. It was tested versus placebo in combination with the bolus 5-FU –LV–irinotecan (IFL) regimen in 815 previously untreated patients [47]. Median overall survival was significantly improved by almost 5 months from 15.6 to 20.3 months, progression-free survival from 6.2 to 10.6 months and response rates from 35% to 45%. Do these results imply that from now on cetuximab and bevacizumab have to be administered to all patients in the setting in which these trials were positive? Several obvious questions can be raised. . Is one positive trial sufficient for a definite proof of efficacy? . How does the efficacy of these agents relate to the expression of their respective targets on the tumor of the patient?
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The role of radical resection for liver metastases of colorectal cancer is well established, with 5-year overall survival rates of around 20% and in some series (probably due to more stringent selection criteria) up to 40% [42]. However, one should caution against the comparison of these results with the results of chemotherapy in the general population with advanced disease, which of course includes patients with a worse prognosis due to larger liver lesions as well as extrahepatic disease. Secondly, only a few surgical series report on the percentage of patients that received chemotherapy after recurrence. With more effective chemotherapy available nowadays the survival benefit of liver resections might be less spectacular as often stated. In this respect interesting data were provided by a retrospective study that evaluated the results of surgery for recurrent colon cancer [43]. With only 5-FU –LV available at that time, the median overall survival for patients who underwent radical surgery was 33 months, for irradical resection this was only 11 months, which is in line with published results on 5-FU –LV [5]. However, 19 patients were identified who were eligible for radical resection, but for different reasons did not receive this treatment, and their median survival was 26 months, with many of these patients not even receiving chemotherapy at all. Although this number is too small for definite conclusions, it does put liver resections in a somewhat different perspective. There are currently no data to support the use of (neo)adjuvant chemotherapy in patients with resectable liver metastasis. This is being investigated in EORTC study 40983, in which pre- and postoperative chemotherapy with 5-FU –LV–oxaliplatin are compared with surgery alone, and the results are not yet available. With more patients being screened for potential resections upon recurrence, more patients are identified whose intrahepatic disease is too extensive for resection but who are without extrahepatic disease and in a good general condition. Although response rate is a suboptimal surrogate marker for survival, it may be reasoned that if the tumor in these patients responds to chemotherapy to a level that allows radical resection, neoadjuvant chemotherapy in these patients should consist of the regimen that has shown the highest response rates. For this purpose the largest experience has been built with 5-FU – LV–oxaliplatin. The largest series reported so far concerns a cohort of 701 patients with unresectable liver metastases [44]. After chemotherapy 95 patients (13.5%) were found to be resectable and their 5-year overall survival rate after resection was 34%. Although without doubt a positive result by itself, one should, as always, apply the principle of intention-to-treat: these 34% of 95 resected patients form only 4.6% of the initial
cohort of 701 patients. When no data from randomized prospective studies are available, one should at least compare this result with a matched cohort of historical controls. Certainly with current median overall survival rates of 20 months for a less selected population, it may well be that the 5-year survival for a matched group of patients may not be significantly off the mark of 4.6%. For instance, at our institute the 5-year survival for 41 patients with resectable liver metastases during workup who appeared irresectable during laparotomy and who were subsequently treated with chemotherapy was 6% (Ruers T et al., unpublished data). This suggests that the true value of neoadjuvant chemotherapy has still to be established. In this respect it is laudable that a novel experimental local therapy for irresectable liver metastases, radiofrequency ablation (RFA), is now prospectively being evaluated in combination with chemotherapy versus chemotherapy alone in EORTC study 40004 (CLOCC study).
1457 . Will they have comparable efficacy in combination with other chemotherapy regimens? . Are we currently employing their most effective doses and schedules? . May these agents have a role as maintenance treatment in responding patients? . Why should colorectal cancer be a good target for bevacizumab? . What is the correlation between EGF-R expression on (primary? metastatic) tumor tissue and response to cetuximab?
Conclusions New agents have significantly increased the median overall survival in patients with advanced colorectal cancer and survival times of 21 months have been reported in randomized trials with 5-FU, irinotecan and oxaliplatin [35]. Whether one may directly compare this result with the median survival of 8 months from the few data on observation [48], or with the 11 months from randomized trials with 5-FU –LV [5] is questionable, since (i) follow-up procedures are likely to be more intensive nowadays and will therefore present patients with earlier diagnosis, and (ii) patients in whom the diagnosis has been made may be offered chemotherapy at an earlier stage of advanced disease due to a better acceptance of this treatment
References 1. Ko¨hne C-H, Wils J, Lorenz M et al. Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol 2003; 21: 3721–3728.
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Confirmatory data on the efficacy of bevacizumab and cetuximab should become available. Based on the very limited data that we currently have, it is impossible to give any recommendation on their use outside the setting in which they have been developed. Although it is undoubtedly quite promising that a new class of agents have shown efficacy in a relevant tumor type such as colorectal cancer, it can only be hoped that this optimism does not translate into a nihilism towards a critical appraisal of their true value. If anything can be learned from history in cancer drug development, it is that it is quite unusual for a single trial with a drug, however wellconducted it may be, to provide us with the definite proof of its value. As a high official of its manufacturer was quoted on the internet after the FDA approval of bevacizumab: “we are concerned that expectations are getting ahead of us—please don’t get ahead of us”, we as medical oncologists should take this request very seriously! A further concern is that while these agents have been approved, we as medical oncologists at the time that we are expected to start prescribing these drugs to patients have only access to limited data from abstracts and oral presentations and not to peer-reviewed full publications in independent medical journals with accompanying editorials from experts in the field. For bevacizumab and cetuximab, the time between initial presentation and peer-reviewed publication of the results was 1 year. Although the approval by healthcare authorities should be a guarantee of high-quality and independent data analysis, the expected wave of industrydriven introduction symposia can never be expected to make up for such publications when it comes to independent information to professionals.
modality, which is reflected by the inclusion of a higher percentage of patients with good performance status compared to older studies. As an example, the average percentage of patients with a World Health Organization (WHO) performance status of 0 used to be <30% in studies with 5-FU –LV [5], but this percentage is around 50% in more recent randomized studies. With more data available on the use of oxaliplatin and irinotecan, more options are open for the systemic treatment of patients with advanced colorectal cancer. Further results of ongoing studies have to be awaited before any regimen or schedule can be regarded as most optimal in a given situation. Individual preferences or medical conditions of the patient may play an important role in the choice for a particular treatment. The use of pharmacogenomics may prove to be a valuable tool in the selection of patients with the best chance for a response or with a high likelihood of toxicity from a probably ineffective treatment. The promising initial results of targeted therapy will surely lead to the development of many related compounds in this disease. With several lines of treatment now available, new strategies for clinical drug development should be designed which allow testing at an early stage of the disease and not only as fourth- or fifth-line treatment. However, in this scenario it will be quite impossible to evaluate their efficacy based on overall survival as the major end point, since it will not be feasible to evaluate all subsequent effective treatments in a prospective way. Other end points, such as time to progression, appear to be more appropriate for this use and should be further validated. Lastly, although costs of treatment should not play a role in the evaluation of the efficacy of a drug, the expected costs (in the USA estimated at $10 000 for cetuximab and $4400 for bevacizumab per month of treatment) will be serious factors in their general availability to patients. With a steady influx of effective (but expensive) drugs on the positive side, and limitations to healthcare budgets everywhere on the negative side, we are obliged to continuously assess the most efficient way by which these drugs can be administered in order to ensure that cancer patients will receive the treatments with maximal clinical benefits within the dictated financial limits. This goal is unlikely to be reached when clinical research is fully dependent on the support of pharmaceutical industries, since their primary responsibility lies, understandably, not with the benefit of the patient. This can only be achieved if investigator-driven studies performed by industry-independent, collaborative groups continue, and if new legislation does not prevent this [49, 50].
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