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BALKAN MCO 2011 - P. Stefanovski - Treatment of advanced disease
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  • This updated analysis demonstrates, on a large data set, that FU-LV improves both response rate and overall survival compared with FU alone and that this benefit is consistent across various prognostic factors. (JCO 2004;22:3766-3775) In a recent meta-analysis of 3,300 patients randomized in 19 trials, the response rate was twofold greater in patients receiving FU/LV than in those receiving FU alone (21% versus 11%, respectively; p < .0001) [5]. There also was a slightly, but significantly, longer survival time in those receiving FU/LV [5]. Biomodulation of FU with LV also has, however, been associated with higher incidences of grade 3 and 4 diarrhea, stomatitis, and hematologic toxicities than either bolus or infusional FU [6]. (Oncologist 2005;10:250-261)
  • In a recent meta-analysis of 3,300 patients randomized in 19 trials, the response rate was twofold greater in patients receiving FU/LV than in those receiving FU alone (21% versus 11%, respectively; p < .0001) [5]. There also was a slightly, but significantly, longer survival time in those receiving FU/LV [5]. Biomodulation of FU with LV also has, however, been associated with higher incidences of grade 3 and 4 diarrhea, stomatitis, and hematologic toxicities than either bolus or infusional FU [6]. (Oncologist 2005;10:250-261)
  • A pooled analysis, incorporating data from six randomized trials, showed that FU administered as a continuous i.v. infusion led to a significantly higher response rate than bolus i.v. FU (Mayo Clinic protocol) (22% versus 14%, respectively; odds ratio, 0.55; p = .0002), although the median survival times were similar (infusional FU 12.1 months versus bolus FU 11.3 months; hazards ratio, 0.88; p = .04) [2]. FU administered by continuous infusion allows for the delivery of more drug than bolus FU and shifts the dose-limiting toxicity from myelosuppression to hand-foot syndrome, which results in a more favorable toxicity profile [2, 3]. The change in toxicity profile is a result of a higher concentration of FU in the bone marrow following bolus administration versus continuous infusion (Oncologist 2005;10:250-261)
  • In two pivotal phase III trials, therapy with single-agent irinotecan resulted in a longer survival time than best supportive care or infusional FU/LV therapy in FU-refractory patients [10, 11] (Table 1). Therefore, based on these data, irinotecan was approved for patients with mCRC who had failed treatment with FU/LV (Table 2). (Oncologist 2005;10:250-261)
  • Researchers then evaluated the addition of irinotecan to FU/LV as first-line treatment for mCRC. Saltz and colleagues showed that combining irinotecan with bolus FU/LV (IFL) resulted in a higher response rate, longer progression-free survival (PFS) time, and longer overall survival time in first-line mCRC treatment compared with bolus FU/LV alone [12] (Table 1). As expected, the incidence of grade 3 diarrhea was more common with irinotecan-based therapy than with bolus FU/LV alone. Similarly, in a European trial, Douillard and colleagues also showed that adding irinotecan to weekly or every-2-weeks regimens of FU/LV by infusion (FOLFIRI) improved the response rate and increased the PFS and survival times [13] (Table 1). Based on data from these trials, the U.S. Food and Drug Administration (FDA) and European regulatory authorities approved irinotecan in combination with both bolus and infusional FU/LV as first-line therapy for mCRC, replacing FU/LV as the standard of care (Table 2). (Oncologist 2005;10:250-261)
  • Oxaliplatin is a cisplatin derivative with a similar mechanism of action to other platinum compounds, although its antitumor profile differs from those of cisplatin (PlatinolR; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and carboplatin (ParaplatinR; Bristol-Myers Squibb, http://www.bms.com) [15]. Indeed, experimental studies have shown that oxaliplatin inhibits colorectal cancer tumor cell lines that are resistant to cisplatin and carboplatin [16]. (Oncologist 2005;10:250-261)
  • A phase III trial demonstrated the efficacy of oxaliplatin-based therapy as second-line treatment for mCRC [18]. Rothenberg and colleagues showed a higher response rate and longer time to progression (TTP) with oxaliplatin plus infusional plus bolus FU than with oxaliplatin monotherapy and infusional FU/LV alone, although single-agent oxaliplatin and FU/LV had no meaningful activity (Table 1). These data led to the approval of oxaliplatin in combination with infusional FU/LV as second-line therapy following irinotecan and FU/LV for mCRC in the U.S. (Table 2). (Oncologist 2005;10:250-261)
  • IROX is an effective treatment for metastatic CRC that has progressed after first-line fluoropyrimidine therapy. IROX improves efficacy compared with irinotecan alone, providing an additional option in the postadjuvant or second-line treatment setting for patients who experience treatment failure with single-agent fluoropyrimidine therapy. (Haller D.G. et al. JCO 2008;26:4544-4550.)
  • In a phase III trial, oxaliplatin was evaluated in combination with infusional FULV2 (FOLFOX regimen) as first-line therapy for patients with mCRC. The findings showed a higher response rate, longer median PFS time, and longer survival than those observed with FU/LV alone, although the survival difference was not statistically significant (Table 1) [17]. The lack of difference in survival benefit between the two groups may be explained by the small sample and crossover treatments that might have obscured any difference in survival [17]. Toxicities of oxaliplatin in combination with FU/LV2 also were mild, although dose-dependent and mostly reversible sensory neuropathy was a cumulative dose-limiting toxicity in the oxaliplatin arm. (Oncologist 2005;10:250-261)
  • A phase III trial recently suggested that FOLFOX first-line therapy is superior in efficacy and safety to IFL [19]. Goldberg and colleagues showed that FOLFOX produced a higher response rate (45%) and longer median survival time (19.5 months) than IFL (31% and 15 months, respectively) and than irinotecan and oxaliplatin given every 3 weeks (IROX; 35% and 17.4% months, respectively) (Table 1). With the exception of peripheral neuropathy, the toxicity profile for FOLFOX also was more favorable than that of either IFL or IROX. The conclusion that the FOLFOX regimen is more effective than IFL or IROX for first-line mCRC therapy must be tempered by several nuances in the trial design. Notably, that an infusional FU-based combination regimen was compared with a bolus FU-based combination regimen, and therefore the individual contributions of irinotecan and oxaliplatin to an Fu based regimen cannot be determined. Also, crossover to second- line therapy was imbalanced because oxaliplatin was not readily available in the U.S. at the time of the trial, and therefore, most patients who received FOLFOX initially, as firstline therapy, received irinotecan at progression, whereas only a few patients who received first-line IFL received oxaliplatin at progression. (Oncologist 2005;10:250-261)
  • Tournigand and colleagues also evaluated the FOLFOX and FOLFIRI regimens to find the best sequence for treating patients with mCRC [22]. Those authors showed that a sequence of first-line FOLFOX followed by second-line FOLFIRI resulted in a similar survival time to that produced by the reverse sequence (Table 1). However, as at least 30% of patients did not receive second-line therapy, the authors highlighted the importance of choosing the most appropriate first-line therapy. Although both first-line therapies achieved similar response rates (FOLFIRI 56% versus FOLFOX 54%), second-line FOLFIRI achieved a significantly lower response rate than did FOLFOX (4% versus 15%). (Oncologist 2005;10:250-261)
  • The toxicity profiles for the two regimens were also different. As expected from previous studies, grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more common with FOLFIRI, whereas grade 3/4 neutropenia and neurosensory toxicity were more common with FOLFOX. (Oncologist 2005;10:250-261)
  • FOLFOX and FOLFIRI appear to be the most effective in terms of efficacy and tolerability. In a recent randomized trial, Colucci and colleagues showed that the two regimens were comparable. (Oncologist 2005;10:250-261)
  • 3. Enzymatic activation of Xeloda ® Xeloda and its intermediate metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR) are cytotoxic only after conversion to 5-FU and its cytotoxic anabolites via a three-step enzymatic cascade. 1 Following rapid and almost complete absorption of the intact molecule, Xeloda is hydrolysed by carboxylesterase in the liver to 5'-DFCR. The next step occurs in the liver and/or tumour tissue, where cytidine deaminase converts 5'-DFCR to 5'-DFUR. The third and final stage of conversion to 5-FU involves TP, which is highly active in tumour tissue compared with healthy tissue. This results in the tumour-selective activation of Xeloda. 2 1. Miwa M, Ura M, Nishida M et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue.Eur J Cancer 1998;34:1274–81. 2. Schüller J, Cassidy J, Dumont E et al. Preferential activation of capecitabine in tumor following oral administration in colorectal cancer patients. Cancer Chemother Pharmacol 2000;45:291–7.
  • In two randomized trials, the efficacy and toxicity of capecitabine as first-line treatment in patients with mCRC were evaluated [26, 27] (Table 1). Those trials showed that capecitabine had an efficacy that was at least equivalent to that of i.v. FU/LV. (Oncologist 2005;10:250-261) Subsequently, two phase III randomized trials have compared oral capecitabine with the Mayo Clinic regimen in patients with metastatic CRC(table I).[11,12] In both trials, the equivalence of capecitabine with the Mayo Clinic regimen was demonstrated, and in one of them capecitabine actually produced a significantly superior RR.[11] (Drugs 2008;68:949-961)
  • Grade 3 handfoot syndrome was reported more frequently with capecitabine, although the condition was tolerated with a reduced dose. A higher incidence of grade 3/4 hyperbilirubinemia also was reported, but all cases were reversible. Against this background, capecitabine appears to offer equivalent efficacy and a better toxicity profile than the Mayo regimen, with the added convenience of an oral agent. (Oncologist 2005;10:250-261)
  • From all these data, it can be concluded that the combination of capecitebine with irinotecan can be problematic because both these drugs may cause diarrhoea and dehydration. The occurrence of such adverse effects, which may be life-threatening especially in older patients, is without doubt greater than that reported when combining irinotecan with infusional 5FU plus folinic acid, and also, by an indirect comparison, much higher tha that usually observed with capecitabine plus oxaliplatin. (Drugs 2008;68:949-961)
  • In a phase II trial, patients were randomized to treatment every 3 weeks with the XELOX regimen or with oxaliplatin on day 1 plus 5FU 250 mg/m2/day as a consecutive intravenous infusion for 3 weeks. The RR was similar for the two regimens; however, the XELOX regimen caused less severe diarrhoea and a significantly lower occurrence of severe stomatitis.( FOCA TRIAL) In the TREE (Three Regimens of Eloxatin Evaluation)-1 study, patients were randomly allocated to receive either (i) the mFOLFOX regimen (oxaliplatin 85 mg/m2, folinic acid 350 mg/m2, 5FU 400 mg/m2 bolus and 2400 mg/m2 46-hour infusion on day 1) every 2 weeks; (ii) the bFOL regimen (oxaliplatin 85 mg/m2 on day 1 and 5FU 500 mg/m2 plus folinic acid 20 mg/m2 intravenously on days 1 and 8, every 2 weeks); or (iii) the XELOX regimen every 3 weeks. Efficacy was similar across the three arms. (TREE-1 Trial) (Drugs 2008;68:949-961)
  • The German Arbeitsgemeinschaft InternistischeOnkologie (AIO) Colorectal Study Group compared the FUFOX regimen (5FU 2000 mg/m2 infused over 24 hours, folinic acid 500 mg/m2 and oxaliplatin 50 mg/m2 infused over 2 hours) given weekly for 4 weeks and 2 weeks of rest, with the CAPOX regimen (oxaliplatin 70 mg/m2 on days 1 and 8, and capecitabine 2000 mg/m2/day for 2 weeks, recycling every 3 weeks). No significant difference in RR,median PFS or median OS were reported for the two arms of the study. The non-inferiority of the CAPOX regimen compared with the FUFOX regimen was claimed on the basis of a hazard ratio (HR) for progression of 1.17. However, it should noted that the 95% CI of the HR ranged from 0.96 to 1.43. This means that patients treated with CAPOX may have a risk of a substantially shorter PFS. In addition, no safety advantage has been reported for CAPOX and patients treated with this regimen had a significantly greater occurrence of grade 2–3 hand- foot syndrome. (German Trial) A Spanish trial has been carried out with the aim of proving the non-inferiority of the XELOX regimen compared with a regimen including a 48-hour infusion of 5FU 2250 mg/m2 once a week plus oxaliplatin 85 mg/m2 given twice a week. Although patients treated with the XELOX regimen had a lower RR, the median PFS and OS were not significantly different. It should also be noted that the HR for PFS was 1.18 (95% CI 0.9, 1.5) in favour of the infusional regimen. Significantly fewer patients receiving the XELOX regimen experienced severe diarrhoea and grade 1–2 mucositis. However, capecitabine treatment was associated with more hand-foot syndrome. (Spanish Trial) (Drugs 2008;68:949-961)
  • A French phase III trial randomly compared the XELOX and FOLFOX6 regimens in terms of RR. The non-inferiority of the XELOX was accepted because the 95% upper limit of the difference in RR (39% vs 46%) was below the non-inferiority margin; median PFS was 8.8 versus 9.3 months and median OS was 19.9 versus 20.5 months. XELOX significantly reduced the occurrence of neutropenia, febrile neutropenia and neuropathy. (Franch trial) The Southern Italy Cooperative Oncology Group randomly compared the OXXEL regimen[33] with a combination of oxaliplatin 85mg/m2 on day 1 and folinic acid 250 mg/m2 (2-hour intravenous infu sion) plus intravenous 5FU 850 mg/m2 bolus on day 2, repeated every 2 weeks. RR, PFS and OS were similar in the two arms of the study. Less neutropenia and febrile neutropenia, but more gastrointestinal disturbance, were reported with OXXEL. (COFFEE Trial) (Drugs 2008;68:949-961)
  • XELOX is noninferior to FOLFOX-4 when administered as second-line treatment in patients with metastatic colorectal cancer.
  • The NO16966 trial was initially aimed at demonstrating the non-inferiority in terms of PFS of the XELOX in comparison with the FOLFOX4 (see table IV) regimen. This endpoint has been demonstrated because the PFS was 8.0 months versus 8.5 months, with an HR of 1.05 (97.5% CI 0.94, 1.18). Moreover, XELOX reduced the risk of severe neutropenia but produced more severe diarrhoea than the FOLFOX4 regimen.[39] When bevacizumab became available for clinical use, the trial design was modified and new patients entering the trail were also randomized to receive either bevacizumab (5 mg/kg twice a week or 7.5 mg/kg three times a week)or placebo in addition to chemotherapy. Bevacizumab added to either XELOX or FOLFOX4 did not increase the RR of these regimens (47% vs 49%) but did significantly prolong the median PFS from 8.0 to 9.4 months (HR = 0.83; p = 0.0023). Excluding the occurrence of severe hypertension, addition of bevacizumab did not significantly increase the toxicity in comparison with placebo. (Drugs 2008;68:949-961)
  • Two phase III studies comparing oxaliplatin–irinotecan–5-fluorouracil/leucovorin (FOLFOXIRI) and FOLFIRI have been published with conflicting results: the Italian study [16]showed superiority of the triplet in terms of OS, PFS, RR and resectability rate of liver metastases; the Greek study [17]failed to report these differences. The major difference in outcome between these studies was the median OS in the control arm (19.5 months versus 16.7 months, respectively), while the median OS in the triplet arm was comparable (21.5 months versus 22.6 months, respectively). The fact that one of these studies failed to demonstrate a survival benefit, as well as the fact that a median OS of 21 months has been achieved in several other studies with less toxic chemotherapy do not provide support for triplet therapy with FOLFOXIRI as a general rule. FOLFOXIRI, despite its toxicity, could be considered in the occasional patient who is perfectly fit, young and with potentially resectable liver metastases. (Sobrero ESMO 2010)
  • In general, a doublet, oxaliplatin–5-fluorouracil/leucovorin (FOLFOX) or irinotecan–5-fluorouracil/leucovorin (FOLFIRI) is superior to FU alone in terms of OS, PFS and response rate (RR) [3–6]. However, they are also more toxic. And the superiority was demonstrated mainly when treatment with the doublets after FU failure was not commercially available. When the doublets became widely available on the market, the question arose of whether the doublets used in second line after FU could provide the benefit lost when they are not used in first line. The British FOCUS and LIFE studies, the Dutch CAIRO study and the French FFCD 05 trial [7–10] provide an answer to this issue. A staged approach of single-agent fluoropyrimidine (either FU–LV or capecitabine) followed by a classical doublet chemotherapy [FOLFOX–FOLFIRI–capecitabine + oxaliplatin (XELOX)– capecitabine + irinotecan (XELIRI)] is as good as starting with the doublets in first line whenever scenario 1 and 2 patients are excluded (potentially resectable and symptomatic). These studies demonstrated superiority of the doublets over the staged approach in terms of RR and sometimes PFS, but there was no substantial loss in OS. Despite these results, the staged approach is somehow underutilized, probably because of the emphasis on RR and PFS given by oncologists and their patients. . (Sobrero ESMO 2010)
  • Addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival. ( JCO 2005;23:3697-3705) Bevacizumab has also been added to the IFL regimen [3]. A total of 813 patients received the IFL regimen either alone or in combination with bevacizumab (Table 1). The response rate of 45% versus 35% (P = 0.004) and the PFS of 6.2 versus 10.6 months (P < 0.001) and the median OS of 15.6 versus 20.3 months (P < 0.001) all indicated a substantial improvement in favour of the bevacizumab combination. (Kohne ESMO 2010)
  • When intravenous bevacizumab (5 mg/kg twice weekly or 7.5 mg/kg three times a week) was added to these same regimens in the second part of this trial (TREE-2), the capecitabine dose in combination with oxaliplatin was reduced to 1750 mg/m2/day. All the efficacy parameters of the TREE-2 trial compared with the TREE-1 trial were improved by the addition of bevacizumab, while the occurrence of severe dehydration caused by the modified XELOX plus bevacizumab regimen in this cohort of patients was significantly reduced. (Drugs 2008;68:949-961) Saltz and coworkers [5] reported on a randomized trial including 401 patients who received either capecitabine plus oxaliplatin (XELOX) or infusional 5FU plus oxaliplatin (FOLFOX regimen). In a 2 · 2 factorial design bevacizumab or placebo was added to the XELOX or the FOLFOX regimen. When the regimens without or with bevacizumab were compared, there was no difference in the objective response rate, which was 38% in both arms. A moderate increase in PFS from 8.0 to 9.4 months was noted (P = 0.0023), while the OS was not significantly different (19.9 versus 21.3 months). The picture is different if all four arms of these studies are analysed separately. Here bevacizumab appeared to improve the XELOX regimen [hazard ratio (HR) 0.77, P = 0.0026] while there was no difference for the FOLFOX regimen (HR 0.89; P = 0.187). Indeed, XELOX plus bevacizumab had a similar PFS to the FOLFOX regimen alone. It is for this reason that FOLFOX plus bevacizumab has not gained broad acceptance as a first-line combination in Europe as it has in the USA. One may speculate that bevacizumab has best activity when added to suboptimal chemotherapy (5FU/FA, capecitabine or IFL). (Kohne ESMO 2010)
  • Strong data for second-line use of bevacizumab in combination with the FOLFOX4 regimen were reported in the E3200 study from the Eastern Cooperative Oncology Group [10] (see Table 5). A total of 829 patients were randomized to receive bevacizumab alone, FOLFOX or FOLFOX plus bevacizumab. In this study the dose of bevacizumab was twice the dose usually used in first-line studies (10 instead of 5 mg/kg). The response rate in patients receiving bevacizumab alone was only 3%, but was 9% and 23%, respectively, for patients receiving FOLFOX or FOLFOX plus bevacizumab (P < 0.0001). Also, the median PFS was higher in the FOLFOX plus bevacizumab than in the FOLFOX-alone arm (7.3 compared with 4.7 months) and only 2.7 months in the bevacizumab-alone arm (P > 0.0001). This difference translated into an OS benefit only for those patients receiving FOLFOX plus bevacizumab (12.9 months versus 10.8 and 10.2 months; P = 0.001). Why bevacizumab plus FOLFOX resulted in a different outcome in the first-line setting as compared with second-line treatment is unknown. (Kohne ESMO 2010)
  • To determine whether adding bevacizumab, with or without mitomycin, to capecitabine monotherapy improves progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) in an open-label, three-arm randomized trial. Adding bevacizumab to capecitabine, with or without mitomycin, significantly improves PFS without major additional toxicity or impairment of QOL. (JCO 2010;28:3191-3198)
  • In the landmark Bowel Oncology With Cetuximab Antibody (BOND) study [16] patients refractory to irinotecan were randomized to receive cetuximab alone or in combination with irinotecan (the drug they had been refractory to!). The response rate was significantly higher in the combination arm (22% versus 11%; P = 0.007) and the median time to progression was also prolonged (1.5 to 4.1 months; P < 0.001). Cetuximab was further studied [NCIC CO-17] in patients who had progressed after receiving a fluoropyrimidine, irinotecan and oxaliplatin and was compared with best supportive care alone. This study demonstrated a significant prolongation of OS for the cetuximab combination (4.6 to 6.1 months; HR 0.68; P <0.001). (Kohne ESMO 2010)
  • In the erbitux plus irinotecan for metastatic colorectal cancer (EPIC) study [20] 1298 patients who had failed first-line fluoropyrimidine plus oxaliplatin treatment were randomized to receive cetuximab and irinotecan or irinotecan alone. The response rate was significantly higher (16% versus 4%) and the PFS (4.0 versus 2.6 months) significantly prolonged in favour of cetuximab, but the OS times were comparable between the two regimens (10.7 and 10.0 months, respectively), probably because nearly 50% of patients assigned to irinotecan monotherapy later received cetuximab as well. Cetuximab was also studied in combination with the FOLFOX regimen in the smaller OPUS study. Patients with KRAS wild-type tumours receiving FOLFOX alone had on objective response rate of 34% and a median PFS of 7.2 months as compared with a response rate of 57% and an 8.3-month PFS for patients receiving FOLFOX plus cetuximab (P < 0.001 and P = 0.028, respectively). (Kohne ESMO 2010)
  • Based on these promising results in pretreated patients EGFR antibodies were tested in first line. In the cetuximab combined with irinotecan in first-line therapy for metastatic colorectal cancer (CRYSTAL) study [12] 1217 patients were randomly assigned to receive either cetuximab plus FOLFIRI or FOLFIRI alone. When the analysis was restricted to KRAS wild-type patients (n = 666) the response rate was significantly higher for those patients also receiving cetuximab (57 versus 40%; P < 0.0001) and the PFS (9.9 versus 8.4 months; P = 0.0012) and the median OS (20.0 versus 23.5 months; P = 0.0093) were both longer. This was actually the first report that a targeted agent, when added to an active and optimal chemotherapy backbone, was able to prolong survival in colorectal cancer. (Kohne ESMO 2010)
  • We compared the activity of panitumumab plus best supportive care (BSC) to that of BSC alone in patients with metastatic colorectal cancer who had progressed after standard chemotherapy. We randomly assigned 463 patients with 1% or more EGFR tumor cell membrane staining, measurable disease, and radiologic documentation of disease progression during or within 6 months of most recent chemotherapy to panitumumab 6 mg/kg every 2 weeks plus BSC (n 231) or BSC alone (n 232). Panitumumab significantly improved PFS with manageable toxicity in patients with chemorefractory colorectal cancer. (JCO 2007;25:1658-1664)
  • Based on these promising results in pretreated patients EGFR antibodies were tested in first line. In the cetuximab combined with irinotecan in first-line therapy for metastatic colorectal cancer (CRYSTAL) study [12] 1217 patients were randomly assigned to receive either cetuximab plus FOLFIRI or FOLFIRI alone. When the analysis was restricted to KRAS wild-type patients (n = 666) the response rate was significantly higher for those patients also receiving cetuximab (57 versus 40%; P < 0.0001) and the PFS (9.9 versus 8.4 months; P = 0.0012) and the median OS (20.0 versus 23.5 months; P = 0.0093) were both longer. This was actually the first report that a targeted agent, when added to an active and optimal chemotherapy backbone, was able to prolong survival in colorectal cancer. (Kohne ESMO 2010)
  • Cetuximab was also studied in combination with the FOLFOX regimen in the smaller OPUS study [13]. Patients with KRAS wild-type tumours receiving FOLFOX alone had on objective response rate of 34% and a median PFS of 7.2 months as compared with a response rate of 57% and an 8.3-month PFS for patients receiving FOLFOX plus cetuximab (P < 0.001 and P = 0.028, respectively). (Kohne ESMO 2010)
  • KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy. (JCO 2008;26:1626-1634)
  • Panitumumab is a fully human anti–epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS) in chemotherapy-refractory metastatic colorectal cancer (mCRC). This trial evaluated the efficacy and safety of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone after failure of initial treatment for mCRC by tumor KRAS status. Patients with mCRC, one prior chemotherapy regimen for mCRC, Eastern Cooperative Oncology Group performance status 0 to 2, and available tumor tissue for biomarker testing were randomly assigned 1:1 to panitumumab 6.0 mg/kg plus FOLFIRI versus FOLFIRI every 2 weeks. The coprimary end points of PFS and overall survival (OS) were independently tested and prospectively analyzed by KRAS status. Panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT KRAS mCRC. (J CO 2010;28:4706-4713)
  • In the larger PRIME study [15] previously untreated patients received either FOLFOX alone or FOLFOX in combination with panitumumab. The progressions free survival (primary end point) was longer for the combination treatment (8.0 versus 9.5 months, HR 0.8; P = 0.02). The higher objective response rate for the combination chemotherapy of 55% versus 48% was not statistically significant. The OS was in favour of the combination treatment (23.9 versus 19.7 months; HR 0.83; P = 0.07). Although failing to achieve a stastically difference in the OS this study supports the results observed in the CRYSTAL study. (Kohne ESMO 2010)
  • We evaluated the safety and efficacy of concurrent administration of two monoclonal antibodies, cetuximab and bevacizumab, in patients with metastatic colorectal cancer. This was a randomized phase II study in patients with irinotecan-refractory colorectal cancer. All patients were naı¨ve to both bevacizumab and cetuximab. Patients in arm A received irinotecan at the same dose and schedule as last received before study entry, plus cetuximab 400 mg/m2 loading dose, then weekly cetuximab 250 mg/m2, plus bevacizumab 5 mg/kg administered every other week. Patients in arm B received the same cetuximab and bevacizumab as those in arm A but without irinotecan. Cetuximab and bevacizumab can be administered concurrently, with a toxicity pattern that seems to be similar to that which would be expected from the two agents alone. This combination plus irinotecan also seems to be feasible. The activity seen with the addition of bevacizumab to cetuximab, or to cetuximab plus irinotecan, seems to be favorable when compared with historical controls of cetuximab or cetuximab/irinotecan in patients who are naı¨ve to bevacizumab. ( JCO 2007;25:4557-4561)
  • In the CAIRO2 study [22] patients received CAPOX plus bevacizumab alone or in combination with cetuximab. In KRAS wild-type patients there was no increase in the objective response rate (50% versus 61%; P = 0.06) and no prolongation of the progression free (10.6 versus 10.5 months; P = 0.30) or OS (22.4 versus 21.8 months; P = 0.64). For KRAS mutant tumours a stastically significant detrimental effect was observed when cetuximab was added to the oxaliplatin regimens with a lower objective response rate, a shorter PFS and shorter median OS (Table 3) (Kohne ESMO 2010)
  • This was also observed in the PACCE study [23] in which patients received either FOLFOX or FOLFIRI according to the physicians’ choice in combination with bevacizumab, and panitumumab was added in the experimental arm. In patients with KRAS wild-type tumours the response rate, median progression free and OS were all not statistically significant while there was a shorter PFS for those patients treated with FOLFOX, bevacizumab and panitumumab as compared with patients receiving the FOLFOX regimen plus bevacizumab alone (Table 4). (Kohne ESMO 2010)

BALKAN MCO 2011 - P. Stefanovski - Treatment of advanced disease Presentation Transcript

  • 1. Colorectal Cancer Treatment of advanced disease Petar Stefanovski M.D., Ph.D. Clinical Hospital - Bitola
  • 2. Medical treatment of mCRC in 2011
    • The efficacy of therapy
    • Availability of four active chemotherapy agents and three biologics
    • The efficacy of several lines of therapy
    • Real chance to cure some patients with combined use of chemotherapy and surgery
  • 3. Frequency of mCRC
    • 25% of patients have metastatic disease at the time of diagnosis
    • Another 25% will develop metastasis in the first 2 years of diagnosis
    Proc ASCO 2004;22:3502 ~ 40%
  • 4. Decision making process in mCRC
    • Patient’s preferences
    • Age
    • PS
    • Resectability (potentially resectable/never resectable)
    • Symptoms (symptomatic/asymptomatic)
    • Tumor burden (bulky/non-bulky disease)
    • Clinical course of disease (rapid progression/indolent)
  • 5. The aim of treatment in mCRC
    • Symptom relief – better quality of live
    • To prolong the time of disease progression ( TTP)
    • To prolong survival
    • Individual patient decision
      • To obtain response of disease
      • To achieve disease control
      • With the least toxic regimen available
  • 6. Treatment priority in mCRC
    • Tumor shrinkage (40%)
    • potentially resectable, symptomatic, bulky, rapid progression
    • vs.
    • Delaying progression (60%)
    • never resectable, asymptomatic, non-bulky disease, indolent
  • 7. Treatment ?
    • AGGRESSIVE
    • VS
    • NON AGGRESSIVE
  • 8. Medical treatment of mCRC
    • CHEMOTHERAPY
    • 5-Fluorouracil
    • Leucovorin
    • Capecitabin е
    • Irinotecan
    • Oxaliplatin
    • BIOLOGICAL THERAPY
    • Bevacizumab
    • Cetuximab
    • Panitumumab
  • 9. 0 1 2 3 4 5 6 7 1960 1965 1970 1975 1980 1985 1990 1995 2000 2006 Year Cetuximab Bevacizumab Oxaliplatin Capecitabine Irinotecan/CPT-11 Leucovorin 5-fluorouracil Treatment options in mCRC Panitumumab 8
  • 10. Irinotecan Oxaliplatin 5-FU Capecitabine
  • 11. 5-FU
    • In clinics more than 40 years
    • Pyrimidine analog
    • Inhibition of tymidylate synthase ( TS)
    • Typically administered with Leucovorin which stabilize connection with TS
  • 12.
    • 19 randomized trials
    • 3300 patients
    • 5-FU – 11% RR
    • 5-FU/LV – 20% RR
    • 5-FU – OS 6 months
    • 5-FU /LV – OS 12 months
  • 13.
    • 5-FU/LV vs. 5-FU
    • > G3-4 diarrhea
    • > stomatitis
    • > haematotoxicity
  • 14. 5-FU/LV bolus i.v. vs. 5-FU/LV c.i.v.
    • Meta-analysis
    • 6 randomized trials
    • RR 14% vs. 22% (p=0.0002)
    • MOS 11.3 months vs. 12.1 months (p=0.04)
    • > Myelosupresion vs. HFSy
    JCO 1998;16:301-308
  • 15.
    • topoisomerase 1 inhibitor
    Irinotecan (CPT-11)
  • 16. Irinotecan – second line chemotherapy in mCRC Cunningam D. et al. Lancet 1998;352:1413-1418 Rougier P. et al. Lancet 1998;352:1407-1412 N RR (%) MPFS (months) OS (months) Irinotecan 189 NA NA 9.2 BSC 90 NA NA 6.5 Irinotecan 133 NA 4.2 10.8 5-FU 134 NA 2.9 8.5
  • 17. Irinotecan – first line chemotherapy in mCRC Saltz LB et al. NEJM 2000;343:905-914 Douillard et al. Lancet 2000;355:1041-1047 N RR (%) MPFS (months) OS (months) IFL 231 39 p<0.001 7.0 p<0.004 14.8 p<0.04 5-FU/LV bolus 226 21 4.3 12.6 Irinotecan 226 18 4.2 12.0 FOLFIRI 198 34.8 p<0.005 6.7 p<0.001 17.4 p=0.031 5-FU/LV 187 21.9 4.4 14.1
  • 18. TTP OS Lancet 2000;355:1041-1047. p<0.001 p=0.031
  • 19.
    • Combination of Irinotecan + 5FU/LV replace 5FU/LV as a standard first line treatment in mCRC
    • Diarrhea G3 is more frequent in Irinotecan combination
    • IFL is generally more toxic than FOLFIRI
  • 20.
    • Inhibition of DNA synthesis
    Oxaliplatin
  • 21. Oxaliplatin – second line chemotherapy in mCRC Rothenberg ML et al. JCO 2003;21:2059-2069 N RR (%) MPFS (months) OS (months) FOLFOX 152 9.9 4.6 NA 5-FU/LV 151 0 2.7 NA Oxaliplatin 156 1.3 1.6 NA
  • 22. Haller D.G. et al. JCO 2008;26:4544-4550. PFS OS p<0.0001 p=0.0072 Oxaliplatin – second line chemotherapy in mCRC N RR (%) MPFS (months) OS (months) IROX 317 22 5.3 13.4 Irinotecan 310 7 2.8 11.1
  • 23. Oxaliplatin – first line chemotherapy in mCRC De Gramont et al. JCO 2000;18:2938-2947 Coldberg et al. (N9741 Study) JCO 2004;22:23-30 N RR (%) MPFS (months) OS (months) FOLFOX 210 50.7 9.0 16.2 (ns) 5-FU/LV 210 22.3 6.2 14.7 FOLFOX 267 45 8.7 19.5 IFL 264 31 6.9 15.0 IROX 264 35 6.5 17.4
  • 24.  
  • 25. Efficacy data from N9741 study - update Goldberg RM et al. JCO 2004;22:23-30. Sanoff HK et al. JCO 2008;26:5721-5727. Endpoint IFL FOLFOX IROX FOLFOX vs. IFL ORR, % 31 45 35 p = 0.002 OS, months 15 19.5 17.4 p = 0.0001 5-year survival (updated 2008) 14.6 20.2 17.3 p < 0.001 TTP, months 6.9 8.7 6.5 p = 0.0014 TTP, months (updated 2008) 6.1 8.9 6.7 p < 0.001
  • 26.  
  • 27. FOLFIRI FOLFOX6 (GERCOR Study) Tournigand C et al. JCO 2004;22:229-237
  • 28. GERCOR Study Progression –free survival Time to second progression Overall survival Tournigand C et al. JCO 2004;22:229-237
  • 29. Tournigand C et al. JCO 2004;22:229-237 FOLFIRI FOLFOX6 (GERCOR Study) N RR (%) MPFS (months) OS (months) FOLFIRI 1 st line 109 56 8.5 21.5 FOLFOX6 1 st line 111 54 8.0 20.6 FOLFIRI 2 nd line 69 4 2.5 NA FOLFOX6 2 nd line 81 15 p=0.05 4.2 p=0.003 NA
  • 30.
    • FOLFIRI
      • G 3-4 mucositis
      • Nausea/vomiting
      • Alopecia G2
    • FOLFOX6
      • G 3-4 neutropenia
      • neurotoxicity
    GERCOR Study Toxicity Tournigand C et al. JCO 2004;22:229-237
  • 31. Progression –free survival Overall survival Colucci G. et al. JCO 2005;23:4866-4875.
  • 32. Observed Toxicities for Both Treatment Arms Colucci G. et al. JCO 2005;23:4866-4875.
  • 33. Capecitabine
  • 34. Enzymatic activation of Capecitabine Intestine Liver Capecitabine 5 ' -DFCR 5 ' -DFUR CyD 5 ' -DFCR 5 ' -DFUR 5-FU Tumour Capecitabine Thymidine phosphorylase (TP) CyD CE 5 ' -DFCR = 5 ' -deoxy-5-fluorocytidine; 5 ' -DFUR = 5 ' -deoxy-5-fluorouridine; CyD = cytidine deaminase; CE = carboxylesterase
  • 35. Capecitabine – first line chemotherapy in mCRC Hoff PM et al. JCO 2001;19:2282-2292 Van Cutsem E et al. JCO 2001;19:4097-4106 N RR (%) MPFS (months) OS (months) 5-FU/LV bolus 303 11.6 4.7 13.3 CPCT 302 25.8 p=0.005 4.3 12.5 5-FU/LV bolus 301 15 4.7 12.1 CPCT 301 18.9 5.2 13.2
  • 36. Capecitabine – first line chemotherapy in mCRC TOXICITY Hoff PM et al. JCO 2001;19:2282-2292 Van Cutsem E et al. JCO 2001;19:4097-4106 N STOMATITIS Hand-Foot Syndrome 5-FU/LV 303 16% 1% CPCT 302 3% 18% 5-FU/LV 301 13.3% 0.3% CPCT 301 1.3% 16.2%
  • 37.
    • More toxicity than usual
    • 19-48% diarrhea and dehydration
    • Particularly problematic in older patients
    • In some studies mortality in the first 60 days up to 6.6%
    Capecitabine + Irinotecan in mCRC Bajetta et al. Cancer 2004;15:279-287 Borner et al. Ann Oncol 2005;16:282-288 Fuchs et al. JCO 2007;25:4779-4786 Kohne et al. Ann Oncol 2007doi1093/annonc/mdm544:10
  • 38. Capecitabine + Oxaliplatin in mCRC FOCA trial (Phase II)- Martoni et al. EJC 2006;42:3161-3168 US TREE-1 trial - Hochster et al. JCO 2006;24:18S N RR (%) MPFS (months) OS (months) XELOX 62 43 7 NA pviFOX 56 48 9 NA XELOX 48 27 5.9 17.2 bFOL 50 20 6.9 17.9 mFOLFOX 49 41 8.7 17.6
  • 39. Capecitabine + Oxaliplatin in mCRC German trial - Porschen et al. JCO 2007;25:4217-4223 Spanish trial – Diaz-Rubio et al. JCO 2007;25:4224-4230 N RR (%) MPFS (months) OS (months) CAPOX 241 48 7.1 16.8 FUFOX 233 54 8.0 18.8 XELOX 171 37 8.9 18.1 FUOX 171 46 9.5 20.8
  • 40. Capecitabine + Oxaliplatin in mCRC French trial (Phase III)- Ducreux et al. JCO 2007;25:18S COFFEE trial – Comella et al. ASCO GI Cancer Syposium 2008 N RR (%) MPFS (months) OS (months) XELOX 156 39 8.8 19.9 FOLFOX6 150 46 9.3 20.5 OXXEL 158 34 6.2 16.0 OXAFAFU 164 33 6.3 17.1
  • 41. Progression –free survival Overall survival Rothenberg M.L. et al. Ann Oncol 2008;19:1720-1726.
  • 42.  
  • 43. XELOX-1/NO16966, a randomized Phase III trial of first-line XELOX compared with FOLFOX4 for patients with metastatic colorectal cancer: updated survival and tolerability results Cassidy et al. ASCO GI 2009: Abstract 382
  • 44. NO16966 study: updated survival results (additional 26 months follow-up) XELOX + placebo (n=350) FOLFOX4 + placebo (n=351) XELOX + bevacizumab (n=350) FOLFOX4 + bevacizumab (n=349) XELOX (n=317) FOLFOX4 (n=317) Initial two-arm open-label study (n=634) Protocol amended to 2x2 placebo-controlled design after bevacizumab Phase III data became available (n=1400) Recruitment Feb 2004–Feb 2005 Cassidy et al. ASCO GI 2009
  • 45. NO16966: XELOX primary objective met Non-inferior PFS HR=1.01 (97.5% CI: 0.91–1.12) Upper limit <1.23 (non-inferiority margin) 0.0 0.2 0.4 0.6 0.8 1.0 Months Estimated probability 8.0 8.5 42 36 30 24 18 12 6 0 ITT population XELOX/XELOX + placebo/ XELOX + bevacizumab (n=1017) 48% FOLFOX/FOLFOX + placebo/ FOLFOX + bevacizumab (n=1017) 47% RR Cassidy et al. J Clin Oncol 2008 Cassidy et al. ASCO GI 2009
  • 46. Updated NO16966: overall survival in treatment subgroup comparisons* *ITT population Cassidy et al. ASCO GI 2009 No. of events Median time to event (months) HR [97.5% CI] FOLFOX4/FOLFOX4 + placebo/ FOLFOX4 + bevacizumab 847 19.5 0.95 [0.85–1.06] XELOX/XELOX + placebo/ XELOX + bevacizumab 820 19.8 FOLFOX 4 + bevacizumab 274 21.0 0.95 [0.78–1.15] XELOX + bevacizumab 274 21.6 FOLFOX4/FOLFOX4 + placebo 573 18.9 0.95 [0.83–1.09] XELOX/XELOX + placebo 546 19.0 FOLFOX4 284 17.7 0.87 [0.72–1.05] XELOX 266 18.8
  • 47. Updated NO16966: equivalent overall survival* Cassidy et al. ASCO GI 2009 *ITT population Estimated probability Months 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 Overall study population FOLFOX4/FOLFOX4 + placebo/FOLFOX4 + bevacizumab (n=1017) XELOX/XELOX + placebo/XELOX + bevacizumab (n=1017) HR=0.95 [97.5% CI: 0.85  1.06] (ITT) HR=0.96 [97.5% CI: 0.86  1.08] (EPP)
  • 48. Updated NO16966: equivalent overall survival* Cassidy et al. ASCO GI 2009 *ITT population Estimated probability Months 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 Initial two-arm study FOLFOX4 (n=317) XELOX (n=317) HR=0.87 [97.5% CI: 0.72–1.05] (ITT) HR=0.89 [97.5% CI: 0.73–1.08] (EPP )
  • 49. Updated NO16966: equivalent overall survival* Cassidy et al. ASCO GI 2009 *ITT population Estimated probability Months 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 Combination with bevacizumab FOLFOX4 + bevacizumab (n=351) XELOX + bevacizumab (n=350) HR=0.95 [97.5% CI:0.78–1.15] (ITT) HR=0.95 [97.5% CI: 0.78–1.16] (EPP)
  • 50. Updated NO16966: equivalent overall survival* Cassidy et al. ASCO GI 2009 *ITT population Estimated probability Months 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 Patients not receiving bevacizumab FOLFOX4/FOLFOX4 + placebo (n=668) XELOX/XELOX + placebo (n=667) HR=0.95 [97.5% CI: 0.83–1.09] (ITT) HR=0.97 [97.5% CI: 0.84–1.11] (EPP)
  • 51. Updated NO16966: most common grade 3/4 treatment-related AEs* 0 20 40 60 Patients (%) Diarrhoea Neurosensory Venous thromboembolic Hand-foot syndrome Cardiac disorders Neutropenia Febrile neutropenia XELOX/XELOX + placebo (n=655) FOLFOX4/FOLFOX4 + placebo (n=649) *Safety population Cassidy et al. ASCO GI 2009
  • 52.  
  • 53. Hendric – Tobias et al. JCO 2008;26:5910-5917
  • 54. Overall Response Rates Hendric – Tobias et al. JCO 2008;26:5910-5917
  • 55. Progression Free Survival Hendric – Tobias et al. JCO 2008;26:5910-5917
  • 56. Overall Survival Hendric – Tobias et al. JCO 2008;26:5910-5917
  • 57. Hendric – Tobias et al. JCO 2008;26:5910-5917
  • 58. Hendric – Tobias et al. JCO 2008;26:5910-5917
  • 59. Triplet Chemotherapy Combination vs. Doublet Chemotherapy Combination
  • 60. BJC 2006;94:798-805.
  • 61. JCO 2007;25:1670-1676.
  • 62. Planned Drug Sequences FOCUS CAIRO LIFE Seymour MT et al. Lancet 2007;370:143-152. Koopman M et al. Lancet 2007;370:135-142. Cunningham D et al. Ann Oncol 2009;20:244-250.
  • 63.  
  • 64.
    • Doublets better than single agent 5-FU
    • FOLFIRI = FOLFOX
    • Capecitabine is equal with 5-FU in doublets
    • FOLFOXIRI is an option (perfectly fit, young, potentially resectable liver metastasis)
    • XELIRI ( High rate of G3-4 diarrhea and mortality)
    First line chemotherapy in mCRC
  • 65. Treatment of mCRC
    • AGGRESSIVE
    • Tumour shrinkage (40%)
    • potentially resectable, symptomatic, bulky, rapid progression
    • FOLFOX or XELOX or FOLFIRI
    • FOLFOXIRI (in selected patients)
  • 66. Treatment of mCRC
    • NON AGGRESSIVE
    • Delaying progression (60%)
    • never resectable, asymptomatic, non-bulky disease, indolent
    • 5-FU/CPCT
    • OXALIPLATIN combination
    • IRINOTECAN combination
  • 67. Bevacizumab Humanized monoclonal antibody Binds to vascular endothelial growth factor A (VEGF-A)
  • 68. Chemotherapy + Bevacizumab in mCRC Kabinavar et al. JCO 2005;23:3697-3705. (Phase II First line) Hurwitz et al. NEJM 2004;350:2335-2342. (Phase III First line) N RR (%) MPFS (months) OS (months) 5-FU/LV + Placebo 105 15.2 5.5 12.9 5-FU/LV + Bevacizumab 104 26.0 9.2 16.6 IFL + Placebo 411 34.8 6.2 15.6 IFL + Bevacizumab 402 44.8 10.6 20.3
  • 69. Chemotherapy + Bevacizumab in mCRC Hochster et al. JCO 2008;26:3523-3529. (Phase II First line) TREE-1 and TREE-2 Saltz et al. JCO 2008;26:2013-2019. (Phase III First line) N016966 N RR (%) MPFS (months) OS (months) FOLFOX6, bFOL, or CAPOX 150 - - 18.2 FOLFOX6, bFOL, or CAPOX + Bevacizumab 223 - - 23.7 FOLFOX4 or XELOX + Placebo 701 49 8.0 19.9 FOLFOX4 or XELOX + Bevacizumab 699 47 9.4 21.3
  • 70. Chemotherapy + Bevacizumab in mCRC Giantonio BJ et al. JCO 2007;25:1539-1544. E3200 (second line) N RR (%) MPFS (months) OS (months) FOLFOX + Bevacizumab (Arm A) 291 22.7 7.3 12.9 FOLFOX (Arm B) 286 8.6 4.7 10.8 Bevacizumab (Arm C) 243 3.3 2.7 10.2
  • 71. Chemotherapy + Bevacizumab in mCRC Tebbutt NC et al. JCO 2010;28:3191-3198. N RR (%) MPFS (months) OS (months) Capecitabine (C) 156 30.3 5.7 18.9 Capecitabine + Bevacizumab (CB) 157 38.1 8.5 18.9 CB + mitomycin (CBM) 158 45.9 8.4 16.4
  • 72. Incidence (%) of grade 3-4 toxicities in studies of bevacizumab Hypertension Bleeding GI perforation Venous TEE Arterial TEE Proteinuria Hurwitz NEJM 2004 11.0 3.1 1.5 19.4 - <1 Kabbinavar JCO 2005 16 5 2 13 - 1 Hochster JCO 2008 16.4 - - 3.8 - - Saltz JCO 2008 4 2 <1 8 2 <1 Giantonio JCO 2007 7 <1 1 - - - Tebbutt JCO 2010 3.8 1.3 1.9 8.9 3.2 3.2
  • 73.
    • IFL + Bevacizumab (consistent results regarding RR, PFS, OS) in first line
    • FOLFOX/XELOX + Bevacizumab (only PFS improvement) (XELOX+Bevacizumab = FOLFOX) in first line
    • Capecitabine + Bevacizumab > Capecitabine (PFS) in first line
    • FOLFOX + Bevacizumab > FOLFOX (consistent results regarding RR, PFS, OS) in second line
  • 74. Cetuximab cetuximab Chimeric (mouse/human) monoclonal antibody A n epidermal growth factor receptor (EGFR) inhibitor
  • 75. Chemotherapy + Cetuximab in mCRC Cunningham et al. NEJM 2004;351:337-345. (BOND PhaseII Second line) Jonker et al. NEJM 2007;357:2040-2048. (NCIC CO-17 Phase III More lines) N RR (%) MPFS (months) OS (months) Cetuximab 111 10.8 1.5 6.9 Irinotecan + Cetuximab 218 22.9 4.1 8.6 BSC 285 0 NR 4.6 BSC + Cetuximab 287 8.0 NR 6.1
  • 76. Chemotherapy + Cetuximab in mCRC Bokemeyer et al. JCO 2009;27:663-671. ( OPUS Phase II First line) Sobrero et al. JCO 2008;26:2311-2319. (EPIC Phase III Second line) N RR (%) MPFS (months) OS (months) Irinotecan 650 4.2 2.6 10.0 Irinotecan + Cetuximab 648 16.4 4.0 10.7 FOLFOX 168 36 7.2 - FOLFOX + Cetuximab 169 46 7.2 -
  • 77. Chemotherapy + Cetuximab in mCRC Van Cutsem et al. NEJM 2009;360:1408-1417. (CRYSTAL Phase III First line) N RR (%) MPFS (months) OS (months) FOLFIRI 599 38.7 8.0 18.6 FOLFIRI + Cetuximab 599 46.9 8.9 19.9
  • 78. Panitumumab Fully human monoclonal antibody B ind to the extracellular domain of the EGFR preventing its activation
  • 79. Panitumumab in mCRC Van Cutsem et al. JCO 2007;25:1658-1664. ( Phase III More lines) N RR (%) MPFS OS (months) BSC 232 0 7.3 wk BSC + Panitumumab 231 10 8.0 wk NS
  • 80. Incidence (%) of toxicities in studies of cetuximab and panitumumab * Cetuximab; ** Panitumumab Rash Diarrhea Low Mg Infusion reaction All Grades G3 G3-G4 All Grades G3 G3-G4 Cunningham* NEJM 2004 78.0 9.4 21.2 - - 3.5 Jonker * NEJM 2007 88.5 11.8 - 47.9 5.2 4.5 Sobrero* JCO 2008 76.3 8.2 28.4 33.8 3.3 - Bokemeyer* JCO 2009 90 11 8 - - 5 Van Cutsem* NEJM 2009 - 16.2 15.7 - - 2.5 Van Cutsem** JCO 2007 62 3.1 <1.0 - - -
  • 81. Cancer Res 2006;66:3992-3995.
  • 82. Chemotherapy + Cetuximab in mCRC by KRAS genotype Van Cutsem et al. NEJM 2009;360:1408-1417. (CRYSTAL Phase III First line) P=0.02 KRAS N RR (%) MPFS (months) OS (months) FOLFIRI WT 176 43.2 8.7 21.0 MT 87 40.2 8.1 17.7 FOLFIRI + WT 172 59.3 9.9 24.9 Cetuximab MT 105 36.2 7.6 17.5
  • 83. Chemotherapy + Cetuximab in mCRC by KRAS genotype Bokemeyer et al. JCO 2009;27:663-671. ( OPUS Phase II First line) KRAS N RR (%) MPFS (months) OS (months) FOLFOX WT 73 37 7.2 - MT 47 49 8.6 - FOLFOX + WT 61 61 7.7 - Cetuximab MT 52 33 5.5 -
  • 84. Cetuximab with chemotherapy as first-line treatment for mCRC: Analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status Bokemeyer et al. JCO 2010;28:(Suppl.) 3506 N RR (%) MPFS (months) OS (months) KRAS WT CT 447 38.5 7.6 19.5 Cetuximab + CT 398 57.3 p<0.0001 9.6 p<0.0001 23.5 p=0.0062 KRAS WT/ CT 381 40.9 7.7 21.1 BRAF WT Cetuximab + CT 349 60.7 p<0.001 10.9 p<0.0001 24.8 p=0.0479 KRAS WT/ CT 38 13.2 3.7 9.9 BRAF MT Cetuximab + CT 32 21.9 p=0.4606 7.1 p=0.2301 14.1 P=0.0764
  • 85. Panitumumab in mCRC by KRAS genotype Amado et al. JCO 2008;26:1626-1634. ( Phase III More lines) Progression –free survival – KRAS Mutant Progression –free survival – KRAS WT KRAS N RR (%) MPFS (weeks) OS (months) BSC WT 119 0 7.3 7.6 MT 100 0 7.3 4.4 BSC + WT 124 17 12.3 8.1 Panitumumab MT 84 0 7.4 4.9
  • 86. Chemotherapy + Panitumumab in mCRC by KRAS genotype Peeters et al. JCO 2010;28:4706-4713. (181 Study Phase III Second line) P=0.004 KRAS N RR (%) MPFS (weeks) OS (months) FOLFIRI WT 294 10 3.9 12.5 MT 248 14 4.9 11.1 FOLFIRI + WT 303 35 5.9 14.5 Panitumumab MT 238 13 5.0 11.8
  • 87. Chemotherapy + Panitumumab in mCRC by KRAS genotype Douillard et al. JCO 2010;28:4697-4705. ( PRIME Phase III First line) WT MT KRAS N RR (%) MPFS (weeks) OS (months) FOLFOX WT 331 48 8.0 19.7 MT 219 40 8.8 19.3 FOLFOX + WT 325 55 9.6 23.9 Panitumumab MT 221 40 7.3 15.5
  • 88.
    • The EGF receptor antibodies are active only in KRAS WT CRC
    • FOLFIRI/FOLFOX + Cetuximab > FOLFIRI/FOLFOX (consistent results regarding RR,PFS,OS) in first line KRAS WT mCRC
    • FOLFOX + Panitumumab > FOLFOX (PFS) in first line KRAS WT mCRC
    • FOLFIRI + Panitumumab > FOLFIRI (PFS) in second line KRAS WT mCRC
  • 89. Combination of Anti-VEGF and Anti-EGFR Treatment
  • 90. Saltz et al. JCO 2007;25:4557-4561. N RR (%) MPFS (months) OS (months) Cetuximab + Bevacizumab 40 23 4.9 11.4 Cetuximab + Bevacizumab +Irinotecan 43 37 7.3 14.5
  • 91. Saltz et al. JCO 2007;25:4557-4561.
  • 92. Chemotherapy + Bevacizumab +Cetuximab mCRC Tol J. et al. NEJM 2009;360:563-572. CAIRO 2 N RR (%) MPFS (months) OS (months) CAPOX + Bevacizumab 368 50.0 10.7 20.3 CAPOX + Bevacizumab + Cetuximab 368 52.7 9.4 19.4
  • 93. Hecht et al. JCO 2009;27:672-680. PACCE
  • 94. Incidence (%) of grade 3-4 toxicities in studies of bevacizumab combined with cetuximab or panitumumab and chemotherapy in mCRC Rash Diarrhea GI perforation Hypertension Any Toxicity Saltz BOND-2 JCO 2007 21.0 28.0 2.3 - - Tol CAIRO 2 NEJM 2009 25.4 26.0 1.6 9.3 81.7 Hecht PACCE JCO 2009 35.6 23.8 0 5.3 90.0
  • 95.
    • Simultaneous use of the two
    • antibodies out of clinical trials
    • should be avoided!
  • 96. Treatment of mCRC
    • AGGRESSIVE
    • Tumor shrinkage (40%)
    • potentially resectable, symptomatic, bulky, rapid progression
    • FOLFOX or XELOX or FOLFIRI
    • FOLFOX/FOLFIRI + Cetuximab KRAS WT (PS 2?)
  • 97. Treatment of mCRC
    • NON AGGRESSIVE
    • Delaying progression (60%)
    • never resectable, asymptomatic, non-bulky disease, indolent
    • 5-FU/CPCT + Bevacizumab
    • OXALIPLATIN combination (+Bevacizumab)
    • IRINOTECAN combination
    • FILFIRI/FOLFOX + Cetuximab (KRAS WT)
  • 98. Dis Colon Rectum 2011;54:214-219