(Neo-)adjuvant treatments in colorectal cancer

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1 Annals of Oncology 16 (Supplement 2): ii133 ii140, 2005 doi: /annonc/mdi729 (Neo-)adjuvant treatments in colorectal cancer D. Arnold & H.-J. Schmoll Martin Luther University Halle-Wittenberg, Department of Haematology and Oncology, Halle/Saale, Germany Introduction Colorectal cancer (CRC) is one of the most common malignancies in the Western world. In both Europe and the USA, CRC counts for 8 11% of all cancer deaths [1]. Surgery is the only curative modality in patients with localised disease. The goal of adjuvant chemotherapy in colon cancer is to eradicate micrometastasis and therefore to improve survival rate after resection of the primary tumour. In contrast to colon cancer, local relapses occur frequently in rectal cancer, in which adjuvant and neo-adjuvant radiation and chemoradiation remains a primary treatment component. Within the last 2 years, large randomised trials in both rectal and colon cancer have improved patients benefits with respect to both tolerability and efficacy, and therefore led to changes in long-established standards of treatment modalities. Colon cancer: recent developments in adjuvant chemotherapy For more than 40 years, 5-fluorouracil (5-FU) was the only active drug in both metastatic and adjuvant colorectal cancer treatment. Large trials indicated that there was a small survival benefit in patients receiving adjuvant 5-FU after surgery compared with patients undergoing surgery alone. A US metaanalysis with > patients estimated an odds ratio of 0.83 [95% confidence interval (CI) ] [2]. Several developmental steps successfully improved the administration of 5-FU by modulating 5-FU with levamisole [3 5] and leucovorin [6 8]. Consequently, 6 months of bolus 5-FU with leucovorin represented the standard of care in both the USA and Europe [9 11]. However, this standard was limited to stage III patients, whereas the management of stage II patients remained controversial owing to a limited improvement in survival. 5-FU combinations with oxaliplatin and irinotecan In the last decade, the treatment standard of stage IV CRC changed from single-agent 5-FU to combinations of either irinotecan or oxaliplatin with 5-FU and folinic acid (FA), according to advantages in response rate, progression-free survival and survival [12 17]. Consequently, these combination regimens were prospectively evaluated in adjuvant q 2005 European Society for Medical Oncology setting by comparing standard 5-FU regimen with the combinations. All trials finished accrual, and the European MOSAIC trial was the first to be completed [18]. A total of 2246 stage II and III patients were randomly assigned to receive either infusional administration of 5-FU/FA (LV5FU2 schedule) or the FOLFOX-4 regimen. As primary end point, the rate of disease-free survival (DFS) at 3 years was improved to 78.2% versus 72.9% (P = 0.002), leading to a relative risk reduction of 23% for FOLFOX when compared with 5-FU/FA alone for all patients. This advantage was even higher for stage III subgroup patients. Most common grade 3 and 4 toxicities were neutropenia (41%), diarrhoea (10.8%) and nausea/vomiting (5.9%). Oxaliplatin-related peripheral neurotoxicity was reported in 12.4% (grade 3) by time of treatment completion, but decreased to 0.5% of patients after 2 years [19]. The results of another oxaliplatin-containing schedule with bolus administration of 5-FU are awaited (NSABP C07 trial). For irinotecan-based combinations, a first reported trial did not demonstrate a benefit: interim analysis of the US C89003 trial, comparing bolus 5-FU/FA with irinotecan (IFL schedule) with bolus 5-FU/FA alone revealed an unacceptable high 60-day all-cause mortality rate of 2.5% compared with 0.8% for 5-FU/FA alone [20]. These findings underline the known unfavourable toxicity of the IFL regimen in metastatic CRC treatment [21] and do not support the use of this schedule in either setting. However, the infusional administration of 5-FU with irinotecan did not lead to excess of toxicity, and the results of the Pan European Trial of Adjuvant Colon Cancer treatment 3 (PETACC-3) are awaited in Oral fluoropyrimidines replace 5-FU bolus administration Capecitabine and tegafur + uracil (UFT) (with oral leucovorin) are oral fluoropyrimidines that have a proven effect and are registered in metastatic CRC. Capecitabine, the more active drug, had a superior response rate with the same progressionfree and overall survival in metastatic CRC when compared with 5-FU/FA bolus administration. Furthermore, the favourable safety profile made it an attractive drug for testing in adjuvant setting. Within the last year, two large trials comparing capecitabine with Mayo Clinic regimen in stage III patients (X-ACT trial; n = 1987) and UFT/FA with the Roswell Park regimen in stage

2 ii134 II and III patients (NSABP C-06 trial; n = 1608) were presented at the ASCO meeting [22, 23]. The UFT/FA combination showed similar activity in DFS and overall survival at 5 years. In the capecitabine trial, the primary end point not inferior DFS at 3 years was also reached. Furthermore, there was a strong trend towards superiority (hazard ratio 0.87; 95% CI ; P = ) for DFS and also for overall survival (hazard ratio 0.84; 95% CI ; P = ). As in metastatic CRC, the toxicity profile also favoured the oral fluoropyrimidines, with predominantly lower episodes of potentially life-threatening events like neutropenia, febrile neutropenia and sepis (P <0.001). As expected, more patients experienced hand foot syndrome [24]. Taking the results from the MOSAIC trial together with the favourable toxicity and efficacy results from the X-ACT trial, the combination of capecitabine with oxaliplatin (XELOX regimen) was compared with bolus FU/FA administration schedules. This trial recently completed accrual and first safety results at this year s ASCO meeting indicated a favourable toxicity profile (Schmoll et al., ASCO 2005). As a consequence, stage III patients should be candidates for oxaliplatin-based (and perhaps irinotecan-based, as a result of the upcoming PETACC-3 results) combination regimens. However, final conclusions should be made on the basis of more mature data with inclusion of the outstanding results and with a longer follow-up period. Although the recent examinations from Sargent et al. [25] strongly supported the measurement of 3-year DFS as a surrogate for 5-year overall survival, this evaluation was done in the 5-FU only era, and it is unclear how the active drug combinations now used in metastatic disease will influence the estimated benefit of an improved 3-year DFS into survival. However, for patients who are not candidates for a combination regimen it is clear that bolus 5-FU should be substituted by capecitabine for efficacy and safety reasons. Stage II patients benefit from adjuvant chemotherapy Although patients with stage II colon cancer may benefit from adjuvant therapy, this potential benefit has not been clearly displayed in clinical trials. Mostly, benefit of survival with chemotherapy is estimated to be an absolute 2 5% at 5 years. However, the data are quite inconsistent, since data come from trials without sufficient statistical power to detect a significant difference as the pooled analysis of the IMPACT group and the NCCTG study [26 28]. In this year, two more meta-analyses supported the finding that a minor benefit was observed, but this also did not reach statistical significance [29, 30]. On the other hand, some trials showed a statistical significant advantage, but are not acceptable in their design because they compare subgroups of node-positive and nodenegative patients and different treatment arms (but not versus observation, like the four NSABP trials) [31]. However, the hypothesis of a small, but distinct survival advantage is supported by the largest isolated trial for this question so far, which was presented by the UK QUASAR ( Quick and Simple and Reliable ) group [32]. In this study 3238 patients, of whom 91% had Dukes B stage CRC, were randomised to receive either a 5-FU/FA regimen or observation. The 5-year recurrence rate and the overall survival favoured the chemotherapy arm by an absolute increase of 4% and 3%, respectively, leading to a 17% relative risk reduction benefit for overall survival (relapse free: 22.3% versus 26.2%, P = 0.001, hazard ratio 0.78, 95% CI ; survival: 80.3% versus 77.4%; P = 0.02, hazard ratio 0.83, 95% CI ). In conclusion, there is a small benefit for stage II CRC patients and therefore chemotherapy is an option for this patient group, although there is no universal consensus about the indication. Further developmental steps are ongoing: more active combination schedules may enlarge the difference of treatment versus observation only. As an example, out of the MOSAIC trial population, 899 patients had stage II disease. The group receiving FOLFOX had a 20% risk reduction (3-year DFS: hazard ratio 0.80; 95 CI ), which was not statistically significant, but it should be pointed out that the control group received an active regimen (5-FU infusional) owing to the trial s design, and did not receive observation only. Secondly, numerous attempts have been initiated to identify a high-risk relapse population. Previously, this pattern was based on clinical and pathological features like T4 stages, bowel obstruction and/or perforation, poorly differentiated tumours and/or venous invasion, and uncertain N0 stage with <10 nodes examined. However, intensified chemotherapy may offer an additional benefit for this group as was seen in the MOSAIC trial (hazard ratio 0.28; 95% CI ) [19, 33]. Beyond clinical and pathohistological features, molecular prognostic markers have been identified and some of them like microsatelite instability, allelic loss of chromosome 18q (which is related to the DCC gene), microvessel density and thymidylate synthase seem to be powerful markers [34 38]. Ongoing trials such as the PETACC-4 study are prospectively evaluating a broad range of molecular markers and, although so far no prospective randomised trial has proven the use of markers for a therapeutic decision, a first trial of the US Eastern Cooperative Oncology Group is on the way with >3000 node-negative patients to be stratified by favourable chromosome 18q loss to observation, and the rest to be randomised to FOLFOX ± bevacizumab. Rectal cancer: improvement in local control achieved, but urgent need for improved systemic control During the last decade, advances in surgery, specifically the use of meticulous sharp dissection of the mesorectum [total mesorectal excision (TME)], together with pre- or postoperative radiotherapy, have markedly improved local control in patients with rectal cancer. Local relapse rates above 10 15% are now no longer acceptable. Adjuvant radiotherapy with or without chemotherapy has been used widely to

3 improve outcomes in patients with rectal cancer. For locally advanced disease, postoperative chemoradiotherapy significantly improves both local control and overall survival as compared with surgery alone or surgery plus irradiation [39, 40]. This information prompted a National Institutes of Health consensus conference, convened in 1990, to recommend postoperative adjuvant chemoradiotherapy as standard treatment for patients with rectal cancer classified as tumour node metastasis (TNM) stage II (i.e. a tumour penetrating the rectal wall, without regional lymph node involvement) or stage III (i.e. any tumour with regional lymph node involvement) [5]. In most European countries and the USA, adjuvant therapy was to start 4 8 weeks after resection with systemic therapy (bolus administration of 5-FU) as the first step, followed by chemoradiation given as concomitant infusional administration of 5-FU, according to the findings of O Connell et al. [41] Finally, two more courses of bolus 5-FU (without leucovorin) were administered. A further modification was the earlier onset of this schedule, according to the favourable findings of a Korean trial [42]. Preoperative radiotherapy as the novel standard of care Despite the fact that optimal surgery was performed, several randomised studies have found lower rates of local failure with preoperative radiotherapy than with TME surgery alone. However, only the Swedish Rectal Cancer Trial, which evaluated a short course of preoperative irradiation in 1168 patients (25 Gy, delivered in five fractions), found an advantage in overall survival [43]. The authors of a subsequent meta-analysis also concluded that the combination of preoperative radiotherapy and surgery, as compared with surgery alone, significantly improves local control and overall survival [44]. The Dutch Colorectal Cancer Group reported that the addition of short-course preoperative radiotherapy to optimal surgery with TME reduced the rate of local recurrence but did not improve 2-year survival [45]. The major advantage of the preoperative 5 5 Gy radiation is the fast completion of perioperative modalities, allowing radiation from Monday to Friday, followed by resection a week later. However, this short period does not cause significant tumour shrinkage in advanced stages, so that an increase in curative (R0) resection or sphincter preserving surgery cannot result for this patient subgroup [46]. Long time follow-up results indicate that incontinence and stool frequency was higher in the 5 5 arm in randomised trials versus surgery alone [47]. Many patients with locally advanced disease show T4 stages with involvement of adjacent structures where a R0 resection is unlikely, or they present low-lying tumours where sphincter preservation is an issue. For this patient group, preoperative (chemo)radiation is administered frequently. Owing to the modulating effect on tumour cells and therefore enhanced sensitivity for radiation damage, chemoradiotherapy was expected to be superior to radiotherapy alone. This hypothesis is so far supported by a single published trial that showed superiority in local control after chemoradiotherapy [48]. A further large trial of the European Organisation for Research and Treatment of Cancer (EORTC) addressing this question has finished accrual. Interim results indicate that the addition of 5-FU/FA to preoperative radiotherapy significantly reduced tumour size and ptn stage, and significant decreased lymph node invasion rates. Longer follow-up is needed to assess the true impact on local control, and survival and final results will be available after this year s ASCO meeting [49]. Ongoing trials suggest that preoperative chemoradiation is indicated when maximal tumour shrinkage is required prior to surgery, i.e. in locally advanced T4 disease and tumors of the lower part of the rectum when sphincter preservation is attempted. A Polish trial addresses that and in comparison of preoperative 5 5 radiation versus conventional radiation a significant higher tumour downsizing and lower rate of incomplete (R1) resections was yielded. However, sphincter preserving was not improved in this trial [50]. The recently published German AIO/CAO/ARO-94 trial [51] finally addressed the question of whether chemoradiotherapy should be given post- or preoperatively. The findings in 799 patients clearly indicate that preoperative administration is less toxic and enables sphincter preservation in a higher number of patients, although this was not a primary end point. Furthermore, the local failure rate was significant lower (6%) with preoperative chemoradiation when compared with the 13% in the postoperative group (P <0.006). These effects were not limited to the high-risk groups only, but also for T3N0-1 tumours. In conclusion, preoperative radiation is the new standard of care and may be administered as 25 Gy/5 days or as conventional chemoradiotherapy with Gy in more than 25 fractions. The EORTC trial will show whether 45 Gy radiation alone will still play a role. For patients intending sphincter preservation or patients with T4 tumours, preoperative chemoradiation is mandatory. The upcoming role of chemotherapy ii135 The next major steps in rectal cancer treatment should, therefore, aim to enhance systemic control and to improve quality of life by more conservative surgery and by more convenient adjuvant treatment administration. While the routine use of concomitant 5-FU chemotherapy in preoperative radiotherapy schedules for resectable rectal cancer is now standard, chemotherapy has to be improved in two directions. (i) Preoperatively administered combination regimens allow higher complete tumour cell eradication and therefore may lead to a lower local relapse rate. A further positive effect of systemically active schedules on micrometastasis and consecutively systemic control is discussed. (ii) The major concern is to reduce the distant failure rate. As a result of improved surgery and radiation techniques, the local relapse does not exceed 8 12% and therefore is much

4 ii136 lower when compared with distant metastasis rates of 36 38% for UICC II/III stages. Regarding chemotherapy in combination with radiation, while attempts to improve the efficacy of 5-FU-based chemoradiation by incorporation of semustine or 5-FU modulation through the addition of leucovorin and/or levamisol have failed to demonstrate any significant benefit, continuous infusion of 5-FU during radiotherapy has been shown to be superior to bolus 5-FU in terms of DFS and overall survival [42, 52, 53]. Capecitabine mimics the pharmacokinetics of continuous 5-FU infusion while avoiding the potential complications associated with central venous access and reducing the time patients need to spend receiving treatment in infusional centres. Moreover, capecitabine is preferentially converted to the active 5-FU metabolite within tumour cells by exploiting the higher activity of the enzymatic activity in tumour tissue compared with normal tissue [54]. Consequently, capecitabine was evaluated in numerous phase II trials in preoperative chemoradiation. Toxicity was predominantly diarrhoea (grade 3 and 4: maximum 14%) and hand foot syndrome. Not surprisingly, the schedule leads to radiographic downstaging of tumours and pathological complete response (pcr) rates of 4 24% [55 59]. Oxaliplatin and irinotecan are also excellent candidates for inclusion into neo-adjuvant regimens because of their rapid cytoreductive capacity. For oxaliplatin, the lack of acute doselimiting side-effects when added to 5-FU makes it an attractive combination partner. Moreover, recent in vitro and in vivo preclinical and clinical studies have demonstrated oxaliplatin to be a potent radiosensitising agent [60]. Several phase II trials have incorporated oxaliplatin into combinations with 5-FU/FA [61 63], raltitrexed [64, 65] and oral fluoropyrimidines [66 70]. The results indicate that these combinations are feasible and have interesting activity with pcr rates of 15 28%. The same pathological response was seen in 5-FU/irinotecan and capecitabine/irinotecan regimens. As expected, irinotecan-containing regimens seem to be more difficult to handle, with grade 3/4 diarrhoea as limiting toxicity in 10 28% of patients (Table 1). There is no clearly defined standard postoperative adjuvant chemotherapy. Data on adjuvant chemotherapy remain controversial. As mentioned above, in a former postoperative trial the use of continuous infusional versus bolus 5-FU resulted not only in improved relapse-free but also in improved overall survival. For radiation (5 5) only, postoperative chemotherapy has not been evaluated so far. The role of adjuvant chemotherapy after simultaneous chemoradiation was investigated in a German and a Greek trial without showing a clear benefit from therapy versus observation or between 6 versus 12 months administration of 5-FU [77, 78]. On the other hand, older trials demonstrated that only use of chemotherapy improved survival [39, 79, 80]. The ongoing EORTC/FFCD trial is evaluating whether 5-FU/FA should be given as adjuvant chemotherapy after preoperative (chemo)radiation. Results are expected at this year s ASCO meeting. However, the distant recurrence rates for advanced stages (as they are 36% and 38% in the German AIO/ARO/CAO-94 trial) underline the urgent need for a more active regimen than the current standard 5-FU bolus (with or without leucovorin). The maximal improved local control (local failure reduced to 6% in preoperative arm versus 13% in postoperative arm in Table 1. Preoperative chemoradiation in advanced rectal cancer: phase I/II trials of combinations of 5-FU/capecitabine with oxaliplatin/irinotecan Phase I/II trials of combinations of FU/capecitabine with Schedule No. patients Pathological CR (%) Diarrhoea grade 3/4 (%) Oxaliplatin 5-FU Gerard 2003 [61] Oxaliplatin 5-FU Carraro 2002 [62] Oxaliplatin 5-FU Alonso 2004 [63] Oxaliplatin Raltitrexed Gambacorta 2004 [64] Oxaliplatin Raltitrexed Casado 2004 [65] Oxaliplatin UFT/FA (2/11 patients) NA Aschele 2004 [66] Oxaliplatin Capecitabine Rödel 2003 [67] Oxaliplatin Capecitabine Glynne-Jones 2004 [68] Oxaliplatin Capecitabine 31 6 (1/17) 22 Duck 2004 [69] Oxaliplatin Capecitabine Tucci 2004 [70] Irinotecan 5-FU Mehta 2003 [71] Irinotecan 5-FU Mitchell 2003 [72] Irinotecan 5-FU Navarro 2003 [73] Irinotecan 5-FU Levine 2004 [74] Irinotecan Capecitabine Klautke 2004 [75] Irinotecan Capecitabine (1000 mg/day) 43 (1350 mg/day) Hofheinz 2005 [76] Author 5-FU, 5-fluorouracil; CR, complete response; NA, not available.

5 Figure 1. PETACC-6 rectal cancer trial. XRT, radiotherapy; FU, 5-fluorouracil; TME, total mesorectal excision; mos, months. this trial) demonstrated that a survival benefit cannot be achieved by further improvement of local control only, as 5-year survival rates in both arms are 76% and 74%, respectively. The unsolved question so far is whether the benefit of intensified adjuvant treatment like MOSAIC findings is transferable from colon to rectal cancer. The open questions of intensification of preoperative chemoradiation and postoperative adjuvant treatment are addressed by the design of the currently discussed multinational PETACC-6 trial (Figure 1): primary end point is DFS at 3 years as a result of an improved preoperative capecitabine/oxaliplatin modulated chemoradiation, followed by TME and another 18 weeks of adjuvant capecitabine/oxaliplatin versus capecitabine (5-FU?) modulated radiation, followed by TME and adjuvant systemic therapy with capecitabine. Secondary end points are rate of pcr, sphincter preservation and toxicity. New standards, new options and new questions The last year s findings marked a shift in standard of care in adjuvant and neo-adjuvant therapy in both colon and rectal cancer. The survival benefit for stage III colon cancer patients, which was well recognised with 5-FU/FA, is now extended by utilising FOLFOX or other forthcoming combinations (e.g. with irinotecan or capecitabine as a substitute for 5-FU in combinations). Although it still is unclear how large the benefit will be in terms of survival (and not only DFS, which itself represents a clinical relevant end point), which will be influenced by more efficacious palliative therapies. A number of patients will be definitively cured by the use of a combination regimen. For stage II patients, more active combinations offer the change to improve survival in a clinical relevant extent. However, before an individual decision on the use of a combination schedule is made, a detailed and careful discussion with the patient about the risk benefit ratio of each regimen is still necessary. For individuals who are not candidates for a combination regimen, oral fluoropyrimidines are to replace bolus 5-FU administrations. In rectal cancer, preoperative radiation with either 5 5Gy or preoperative chemoradiation (which is preferential for T4 or low-lying tumours with intention of sphincter preservation) have become new standard of care, and further improvement is only to achieve in intensification of the systemic treatment component. The increased understanding of molecular biological characteristics and genetic bases have lead to the development of novel targeted therapies as antibodies against the vascular endothelial growth factor (bevacizumab; Avastine) or the epidermal growth factor receptor (cetuximab; Erbituxe) have been successfully investigated in metastatic colorectal cancer and have just entered the field of (neo-)adjuvant therapies. In colon cancer, several large phase III trials are on the way or designed for stage II and III colon cancer, e.g. FOLFOX and XELOX ± bevacizumab for 6 months, followed by a bevacizumab maintenance (ROCHE), FOLFOX ± bevacizumab (NSABP C-08) or FOLFOX ± cetuximab (MERCK), and the US Intergroup design that includes cetuximab ± FOLFOX, FOLFIRI or a sequence FOLFOX and FOLFIRI. This combinations will probably lead to further improvement in long-time DFS. In rectal cancer, treatment options used for systemic treatment in advanced disease will be investigated in neoadjuvant and adjuvant part in the next generation of trials and probably transfer the benefits from colon to rectal cancer treatment. Furthermore, both antibodies, bevacizumab and cetuximab, have demonstrated promising preclinical activity in combination with chemotherapy and with radiation. Novel preoperative combinations of both drugs with chemotherapy are being tested in ongoing phase I trials. [81] However, the exceeding variety of current and future schedules and the increasing range of therapy options and intensities urgently needs translational research for identification of patient groups, by both clinical pathological features and molecular and genetic markers, that obtain maximal benefit from each therapeutic option. 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