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Therapeutic strategy in unresectable metastatic colorectal cancer:

Therapeutic strategy in unresectable metastatic colorectal cancer: 431592 TAM421758834011431592B Chibaudel, C TournigandTherapeutic Advances in Medical Oncology Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Therapeutic strategy in unresectable (2012) 4(2) 75 –89 DOI: 10.1177/ metastatic colorectal cancer 1758834011431592 © The Author(s), 2011. Reprints and permissions: Benoist Chibaudel, Christophe Tournigand, Thierry André and Aimery de Gramont http://www.sagepub.co.uk/ journalsPermissions.nav Abstract: While surgery is the cornerstone treatment for early-stage colorectal cancer, chemotherapy is the first treatment option for metastatic disease when tumor lesions are frequently not fully resectable at presentation. Mortality from colon cancer has decreased over the past 30 years, but there is still a huge heterogeneity in survival rates that can be mainly explained by patient and tumor characteristics, host response factors, and treatment modalities. The management of unresectable metastatic colorectal cancer is a global treatment strategy, which applies several lines of therapy, salvage surgery, maintenance, and treatment-free intervals. The individualization of cancer treatment is based on the evaluation of prognostic factors for survival (serum lactate dehydrogenase level, performance status), and predictive factors for treatment efficacy [Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status]. The available treatment modalities for metastatic colorectal cancer are chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic agents (e.g. bevacizumab), and anti-epidermal growth factor agents (cetuximab, panitumumab). The increasing number of active compounds dictates the strategy of trials evaluating these treatments either in combination or sequentially. Alternative outcomes that can be measured earlier than overall survival are needed to shorten the duration and reduce the size and cost of clinical trials. Keywords: chemotherapy, clinical trial, colorectal cancer, molecular targeted therapy Correspondence to: Introduction This review focuses on the management of unre- Benoist Chibaudel, MD Colorectal cancer is the third most common can- sectable MCRC. Trial acronyms are used for Division of Medical Oncology, Hôpital cer and the third cause of cancer death in western brevity: readers may refer to the cited references Saint-Antoine, Assistance countries [Globocan, 2008]. The main parameter for full study names and details. Publique des Hôpitaux de Paris, 184 rue du faubourg to predict survival or relapse is tumor staging Saint-Antoine, 75571, [American Cancer Society, 2010]. While surgery Paris Cedex 12, France benoist.chibaudel is the cornerstone treatment for early-stage cancer Prognostic factors @sat.aphp.fr (stage I–III), chemotherapy is the first treatment Several parameters have been found to be inde- Christophe Tournigand, option for metastatic disease (stage IV) when pendent prognostic factors for MCRC. These MD Thierry André, MD tumor lesions are frequently not fully resectable at are patient characteristics such as World Health Aimery de Gramont, MD presentation. Approximately one third of patients Organization (WHO) performance status (PS), Division of Medical Oncology, Hôpital Saint- with metastatic colorectal cancer (MCRC) have age, sex, weight loss, biological variables such as Antoine, Assistance metachronous disease, which is currently defined white blood cell (WBC) count, serum alkaline Publique des Hôpitaux de Paris, Paris, France as more than 1 year between the occurrence of the phosphatase (ALP) level, serum lactate dehydroge- primitive tumor and metastasis. Mortality from nase (LDH) level, serum carcino-embryonic anti- colon cancer has decreased over the past 30 years, gen (CEA) level, or tumor characteristics like the partly due to better treatment modalities. Hetero- number of metastatic sites, or liver involvement. geneity in survival rates can be mainly explained by patient and tumor characteristics, host response Three risk groups for death were recognized in factors, and treatment strategy (drugs, regimen, patients receiving 5-fluorouracil (5-FU)-based and surgery of metastasis). chemotherapy for MCRC, depending on four http://tam.sagepub.com 75 Therapeutic Advances in Medical Oncology 4 (2) baseline prognostic parameters: PS, WBC count, dependent. A reversible posterior leukoencepha- ALP, and number of metastatic sites [Köhne et al. lopathy syndrome has been reported in rare cases. 2002]. Aflibercept (Zaltrap, Sanofi-Aventis, Paris, France; The Groupe Coopérateur Multidisciplinaire en Regeneron, Tarrytown, NY) is an investigational Oncologie (France) (GERCOR) prognostic score (i.e. it has not been approved by the US Food and was recently developed and validated in patients Drug Administration) fusion protein for the treat- treated with oxaliplatin- or irinotecan-based ment of cancer (colorectal, lung, prostate) and wet chemotherapy. This model was based on the two macular degeneration. This drug is designed to most important prognostic factors, LDH level bind to circulating VEGF-A, VEGF-B, and pla- and WHO PS, before starting first-line chemo- cental growth factor in the bloodstream and in the therapy. The median survival in patients having extravascular space with higher affinity than their PS0 and normal LDH value was twofold higher native receptors. than in patients with poor prognosis (PS1 and LDH>1N, or PS2) [Chibaudel et al. 2011b]. Anti-epidermal growth factor agents. Cetuximab (Erbitux, Merck, Darmastadt, Germany) is a chi- meric human mouse anti-epidermal growth fac- Antitumor drugs tor receptor (EGFR) monoclonal antibody. Panitumumab (Vectibix, Amgen, Thousand Oaks, Chemotherapy CA) is a fully human anti-EGFR monoclonal Three cytotoxic drugs are available for the treat- antibody. These two drugs have been studied as ment of MCRC: fluoropyrimidines, oxaliplatin, monotherapy and in combination with oxalipla- and irinotecan. These drugs can be administered tin- or irinotecan-based therapy in a palliative set- either in combination (doublets: fluoropyrimidine/ ting. It has been shown that only patients with oxaliplatin [de Gramont et al. 2000; Goldberg wild-type Kirsten rat sarcoma viral oncogene et al. 2006; Diaz-Rubio et al. 2007], 5-FU/ homolog (KRAS) tumors respond to anti-EGF irinotecan [Tournigand et al. 2004; Douillard agents and have a prolongation of progression- et al. 2000; Fuchs et al. 2007]; triplet: 5-FU/ free survival (PFS) [Lièvre et al. 2008]. Thus, the oxaliplatin/irinotecan [Falcone et al. 2007]); or as KRAS tumor gene has been validated as a nega- monotherapy (fluoropyrimidine alone) [de Gramont tive predictive marker for anti-EGF agent activity, et al. 1997; Van Cutsem et al. 2001]. but additional testing for tumor genes such as ser- ine/threonine-protein kinase B-Raf (BRAF) or neuroblastoma N-Rras (NRAS) could be useful Molecular-targeted agents to identify patients who might benefit the most Anti-angiogenic agents. Angiogenesis, the for- from anti-EGF agents [Di Nicolantonio et al. mation of new blood vessels, takes part in tumor 2008; Laurent-Puig et al. 2009; Khambata-Ford cell proliferation and thus is a target for antitumor et al. 2007]. In contrast to anti-angiogenic agents, therapy. Vascular endothelial growth factor the benefit of anti-EGF agents is maintained or (VEGF), a diffusible glycoprotein produced by even amplified in second- or third-line therapy normal and neoplastic cells, is an important regu- when a survival benefit is observed. This suggests lator of physiological and pathological angiogen- that if the goal is survival, it might be better to use esis. Increased levels of VEGF expression have anti-EGF drugs as salvage therapy. been found in most human malignancies. Bevacizumab (Avastin, Roche, Bale, Switzerland) First-line therapy is a recombinant humanized monoclonal immu- noglobulin G1 antibody targeting VEGF. Adding Irinotecan- or oxaliplatin-based regimens bevacizumab to commonly used chemotherapy as first-line chemotherapy? regimens improves outcomes in patients with The choice of oxaliplatin- or irinotecan-based MCRC. Infrequent specific bevacizumab-related regimens is a matter of debate. The C97-3 study side effects are bleeding, hypertension, fistulae, was the first direct comparison between the gastrointestinal perforation, arterial thromboem- addition of oxaliplatin or irinotecan with a sim- bolic events, and proteinuria. The occurrence of plified leucovorin/5-FU (LV5FU2) regimen hypertension and proteinuria is likely to be dose [Tournigand et al. 2004]. The final results did 76 http://tam.sagepub.com B Chibaudel, C Tournigand et al. not show any difference between FOLFIRI patients in the bevacizumab-containing arms and (leucovorin/5-FU/irinotecan regimen) and in 47% of patients in the placebo-containing FOLFOX6 (leucovorin/5-FU/oxaliplatin regi- arms. The benefit of bevacizumab was larger in men) in first-line therapy in terms of response the predefined on-treatment PFS analysis (HR = rate (RR 54% and 56%) and PFS (8.4 and 8.0 0.63): if events occurred more than 28 days months). These results were confirmed in another after stopping study medication, the patient was trial [Colucci et al. 2005]. The main difference censored back to the date of last known between these two combinations is mainly in the nonprogression. toxicity profile. Grade 3–4 gastrointestinal toxici- ties (nausea, vomiting, mucitis) and alopecia were Adding bevacizumab to fluoropyrimidine alone significantly more frequent with the FOLFIRI also achieved a highly significant improvement in regimen, whereas grade 3–4 neutropenia and PFS. The AVF2192g study provided further sup- neuropathy were significantly more frequent with port for combination with 5-FU/ leucovorin, the FOLFOX regimen. although the patient population was different than that for the AVF2107g study (only patients Arguments favoring FOLFIRI first line were less who were not candidates for first-line irinotecan grade 3–4 toxicity and better activity of FOLFOX treatment were eligible for the trial) [Kabbinavar second line (RR 15% versus 4%; PFS 4.9 versus et al. 2005]. Median PFS was increased from 5.5 2.3 months) while arguments in favor of FOLFOX to 9.2 months (HR = 0.50), and median overall first line were fewer patients with serious adverse survival (OS) was increased from 12.9 to 16.6 events, more patients amenable to surgery of months (HR = 0.79). In the MAX study, bevaci- metastases, and fewer chemotherapy cycles to zumab was added to capecitabine [Tebbutt et al. achieve the same results. The main reason for 2010]. Median PFS was increased from 5.7 to 8.5 stopping oxaliplatin was the cumulative drug neu- months (HR = 0.63), but median OS was similar rosensory toxicity in patients free of progression. in the two treatment groups (HR = 0.87). Thus, the potential of FOLFOX could be improved by the management of oxaliplatin- Vatalanib and cediranib, two recent oral VEGF induced neuropathy. Moreover, the difference in receptor-2 (KDR) tyrosine kinase inhibitors the incidence of grade 3–4 toxicity is due to neu- (TKIs), have been evaluated in first-line MCRC tropenia, which in most cases is not clinically therapy. In the CONFIRM1 trial, 1168 patients relevant. with previously untreated MCRC were randomly assigned to receive FOLFOX4 plus vatalanib or placebo [Hecht et al. 2011]. Response rate, PFS Anti-angiogenic agents or anti-epidermal (HR = 0.88), and OS (HR = 1.08) were not growth factor agents in combination as improved with vatalanib in the whole population. first-line chemotherapy? Of note, PFS was longer with vatalanib in patients Anti-angiogenic agents as first-line therapy. The with high serum LDH level at baseline (HR = addition of bevacizumab to oxaliplatin-based 0.67) [Schmoll et al. 2010]. In the HORIZON III (N016966) or irinotecan-based (AVF2107g) che- study (1422 patients), the direct comparison of motherapy improved survival [Saltz et al. 2008; cediranib and bevacizumab in combination with a Hurwitz et al. 2004]. Of note, this improvement modified FOLFOX6 regimen did not show any was effective in wild-type and mutated KRAS difference between the two regimens in terms of MCRC [Rosen et al. 2008]. Thus, KRAS testing efficacy (RR, odds ratio = 0.96; HR = 1.10; PFS is not warranted in the selection of patients for HR = 0.94). Moreover, the bevacizumab-based OS bevacizumab-based therapy in MCRC. The mag- therapy had a more favorable toxicity profile with nitude of benefit was higher with irinotecan [haz- less severe diarrhea and neutropenia. ard ratio (HR) = 0.54] than with oxaliplatin (HR = 0.83). This might be due to a better synergy Anti-epidermal growth factor agents as first-line between irinotecan and bevacizumab, or to more therapy. In patients with KRAS wild-type prolonged administration of bevacizumab in the tumors, the addition of cetuximab to either FOL- irinotecan trial (AVF2107g). In the oxaliplatin- FIRI (CRYSTAL) or FOLFOX (OPUS) pro- based trial (N016966), a large proportion of duced an improvement in median PFS (HR = patients stopped treatment earlier than allowed 0.68 and 0.54) [Van Cutsem et al. 2009; Boke- by the study protocol. The treatment was discon- meyer et al. 2009]. Similarly, the addition of pani- tinued because of progression in only 29% of tumumab to FOLFOX (PRIME) was superior to http://tam.sagepub.com 77 Therapeutic Advances in Medical Oncology 4 (2) Table 1. Randomized trials in metastatic colorectal cancer first-line therapy: results in a wild-type KRAS population. Study E Regimen N KRAS RR (%) PFS OS testing (%) (∆) (months) (months) Bev trials AVF2107g (Hurwitz OS IFL ± bev 67/85 28 37/60 7.4/13.5 17.6/22.7 et al., 2004) (+23%) (HR = 0.44) (HR = 0.58) PACCE (Hecht PFS Oxali based + bev 203 82 56 12.5 19.8 et al., 2008) Irinotecan based 58 48 13.5 27.7 CAIRO2 PFS XELOX + bev 156 71 50 10.6 22.4 (Tol et al., 2009) EGF trials CRYSTAL (Van PFS FOLFIRI ± CTX 350/316 89 40/57 8.4/9.9 20.0/23.5 Cutsem et al., (+17%) (HR = 0.70) (HR = 0.80) 2009) OPUS (Bokemeyer RR FOLFOX ± CTX 73/61 69 37/61 7.2/7.7 18.5/22.8 et al., 2009) (+24%) (HR = 0.57) (HR = 0.85) PRIME (Douillard PFS FOLFOX ± Pmab 331/325 93 48/55 8.0/9.6 19.7/23.9 et al., 2010) (+7%) (HR = 0.80) (HR = 0.83) COIN (Maughan OS Oxali based ± CTX 367/362 81 57/64 8.6/8.6 17.9/17.0 et al., 2011) (+7%) (HR = 0.96) (HR = 1.38) NORDIC VII PFS FLOX ± CTX 97/97 88 47/46 8.7/7.9 22.0/20.1 (Tveit et al., 2011) (–1%) (HR = 1.07) (HR = 1.14) bev, bevacizumab; CTX, cetuximab; E, primary endpoint; EGF, epidermal growth factor; HR, hazard ratio; KRAS, Kirsten rat sarcoma viral oncogene homolog; N, number of patients; OS, overall survival; PFS, progression-free survival; Pmab, panitumumab; RR, response rate. FOLFOX alone in terms of PFS (HR = 0.83) (leucovorin/5-FU/oxaliplatin regimen) until [Douillard et al. 2010]. In this study, the improve- progression or limiting toxicity, or the same ment in OS was not statistically significant (HR = chemotherapy in combination with cetuximab. 0.83; p = 0.07). The only significant improvement A third arm received intermittent FLOX chemo- in OS (median increased by 3.5 months) in a therapy with continuous cetuximab. In these two first-line trial has been reported in the CRYSTAL trials, PFS and OS did not differ among treat- trial. Unfortunately, the positive results came ment groups in patients with wild-type KRAS from a retrospective analysis and the proportion tumors (COIN: HR = 0.96, HR = 1.04; PFS OS of patients who received cetuximab after first line NORDIC VII: HR = 1.07; HR = 1.14). PFS OS in the control arm was not reported. A limited Unexpectedly the KRAS status did not affect the number of crossover patients (cetuximab in sec- efficacy of cetuximab in the NORDIC VII trial. ond or third line) in the control arm may explain Of note, cetuximab did not improve PFS and OS, this survival advantage for cetuximab in first-line even in patients with wild-type KRAS tumor. therapy (Table 1). Based on these data, it is too early to recommend Two first-line phase III trials contrasted with the systematic use of an anti-EGFR antibody in these results [Maughan et al. 2011; Tveit et al. combination with oxaliplatin as first-line therapy 2011]. In the COIN trial, 1630 patients were in patients with wild-type KRAS unresectable randomized to receive either oxaliplatin-based metastases. chemotherapy [FOLFOX or XELOX (cape- citabine plus oxaliplatin regimen)] alone or in The addition of both an anti-angiogenic agent combination with cetuximab. A third arm and an anti-EGF agent to chemotherapy had a received intermittent chemotherapy. In the negative impact on survival in comparison to NORDIC VII trial, 571 patients were rand- chemotherapy with bevacizumab [Hecht et al. omized to receive either continuous FLOX 2008; Tol et al. 2009]. 78 http://tam.sagepub.com B Chibaudel, C Tournigand et al. Second-line therapy Anti-epidermal growth factor agents. In the EPIC Most patients should be offered second-line ther- trial, cetuximab added to irinotecan after 5-FU/ apy when tumor progression or unacceptable tox- oxaliplatin failure significantly improved PFS (4.0 icity stops first-line therapy. Effective second-line versus 2.6 months; HR = 0.70) and RR (16.4% therapies are available. Knowledge of the most versus 4.2%) [Sobrero et al. 2008]. The absence of active second-line regimens must not lead to using survival advantage can be partly due to crossover: a suboptimal first-line regimen. It has been half of the control patients received cetuximab as reported that exposure to all available agents could post-trial therapy. KRAS mutation status was ret- be more important than the number of lines rospectively obtained for only 23% of randomized [Grothey et al. 2004]. However, based on the cor- patients. In the small subset of patients with wild- relation between the percentage of patients who type KRAS tumor (15% of the whole population), received all the available drugs and median sur- PFS was longer when cetuximab was added to iri- vival, if all eligible patients receive all the drugs, notecan, but RR and OS were similar. [Langer et the median survival would still be limited to 22 al. 2008]. The combination of panitumumab and months. New strategies using targeted agents or FOLFIRI (181 study) was superior to the same the oxaliplatin stop-and-go strategy have already chemotherapy in terms of RR and PFS, but not achieved median survival well over 22 months and OS [Peeters et al. 2010]. The magnitude of the argue against this basic approach. In the C97-3 PFS benefit remains modest and consistently study, the FOLFIRI regimen was less active in below 3 months. One acceptable hypothesis to second-line therapy in patients whose condition explain the discrepancy between PFS and OS is failed to respond to FOLFOX6 than FOLFOX6 crossover in the chemotherapy-alone arms. after progression on FOLFIRI. Of note, more than 70% of patients received second-line therapy and 13% of patients had R0 surgery of metastases Second-line therapy after irinotecan- on FOLFOX and 7% on FOLFIRI. based first-line chemotherapy Chemotherapy regimen. An oxaliplatin-based chemotherapy regimen is the cornerstone treat- Second-line therapy after oxaliplatin- ment after failure of an irinotecan-based therapy. based first-line chemotherapy The expected overall RR and median PFS with Chemotherapy regimen. Irinotecan-based che- FOLFOX as second-line therapy are 9–15% and motherapy is the treatment of choice after oxalipl- 4.2–4.7 months, respectively [Tournigand et al. atin-based therapy failure. The expected overall 2004; Giantonio et al. 2007]. response rate and median PFS of the standard FOLFIRI regimen are 4–12% and 2.5–4.7 Anti-angiogenic agents. The addition of bevaci- months, respectively [Tournigand et al. 2004; Van zumab to FOLFOX (E3200) after 5-FU/irinote- Cutsem et al. 2011; Peeters et al. 2010]. This regi- can failure led to an improvement in RR, PFS men was enhanced based on a positive interaction (4.7–7.3 months, HR = 0.61), and OS (10.8–12.9 between irinotecan and 5-FU given after 5-FU months, HR = 0.75) [Giantonio et al. 2007]. Con- infusion [Inoue et al. 2006]. Indeed, the FOL- tinuing bevacizumab after progression on first-line FIRI3 regimen has shown a RR of 20–25% and a therapy may also prolong survival and is being median PFS of 3.7–4.7 months without any tar- evaluated in prospective trials [Grothey et al. geted agents in several studies [Mabro et al. 2006; 2008]. In the CONFIRM2 trial (855 patients), Bidard et al. 2009]. However, these results have vatalanib in combination with FOLFOX after not been evaluated in randomized trials. 5-FU/irinotecan failure has demonstrated signifi- cant prolongation of PFS (4.1–5.5 months, HR = Anti-angiogenic agents. In the EFC10262- 0.83) but not OS (HR = 0.94) [Köhne et al. 2007]. VELOUR trial, the addition of aflibercept to the standard FOLFIRI regimen was evaluated in Anti-epidermal growth factor agents. No data 1226 patients after failure of oxaliplatin-based from phase III trials are available for anti-EGF chemotherapy. The new combination significantly agents in this setting. improved both PFS (4.7–6.9 months, HR = 0.76) and OS (12.1–13.5 months, HR = 0.82). This Finally, a benefit in OS in second-line therapy was effect was seen whether or not patients had observed only in trials using an anti-angiogenic received prior bevacizumab therapy [Van Cutsem agent in combination with FOLFIRI or FOLFOX et al. 2011]. [Van Cutsem et al. 2011; Giantonio et al. 2007]. http://tam.sagepub.com 79 Therapeutic Advances in Medical Oncology 4 (2) Third-line therapy The concept of maintenance therapy with fluoro- After exposure to oxaliplatin- and irinotecan- pyrimidine alone, referred to as oxaliplatin stop- based treatment, a significant number of patients and-go strategy [de Gramont, 2008], was evaluated are still able and willing to receive therapy. in the OPTIMOX1 study, in which 620 patients with unresectable MCRC were randomized to The BOND trial, in which a significant either FOLFOX4 until progression or the oxalipl- proportion of patients were not only refractory atin stop-and-go strategy [Tournigand et al. 2006]. to irinotecan-based chemotherapy but also to This strategy consisted of six cycles of FOLFOX7 oxaliplatin-based chemotherapy, demonstrated chemotherapy [Maindrault-Goebel et al. 2001] a synergy between irinotecan and cetuximab followed by maintenance therapy with the simpli- [Cunningham et al. 2004]. The response rate for fied LV5FU2 regimen without oxaliplatin. After 12 irinotecan plus cetuximab was superior to the cycles of LV5FU2 chemotherapy, FOLFOX7 was response rate for the monoclonal antibody alone reintroduced in patients with controlled disease. (23% versus 11%), and the HR for disease pro- This study demonstrated that a short induction gression in the combination therapy group com- with oxaliplatin followed by maintenance therapy pared with the monotherapy group was 0.54 with 5-FU alone was better tolerated than and (median PFS 4.1 versus 1.5 months). Later stud- achieved a similar efficacy as continuous adminis- ies demonstrated that the anti-EGFR monoclonal tration of the drug until progression or the occur- antibodies cetuximab and panitumumab were rence of cumulative neurotoxicity. also active alone as third-line treatment versus best supportive care, and the results were ampli- Maintenance therapy with fluoropyrimidine fied in the wild-type KRAS population [Jonker and bevacizumab was evaluated in the Com- et al. 2007; Van Cutsem et al. 2007]. Thus, there is bined Oxaliplatin Neuropathy Prevention Trial an unquestionable survival advantage for anti- (CONcePT). This trial compared continuous EGFR monoclonal antibodies in third-line ther- administration of FOLFOX with intermittent apy in the wild-type KRAS population. administration of eight cycles of FOLFOX plus bevacizumab followed by eight cycles of mainte- Knowing that bevacizumab is not active in nance LV/5FU plus bevacizumab, and FOLFOX third-line therapy [Chen et al. 2006; Kang et al. reintroduction plus bevacizumab for eight cycles 2009] the only active third-line therapies are [Grothey et al. 2008]. PFS with continuous based on anti-EGFR monoclonal antibodies, administration was 7.3 months compared with which are only active in wild-type KRAS tumors. 12.0 months with the stop-and-go strategy. Consequently, there is no standard third-line therapy for patients with mutated KRAS tumors and for patients with wild-type KRAS tumors Maintenance therapy with targeted agents who receive anti-EGFR treatment as first- or sec- Recent studies have evaluated maintenance ther- ond-line therapy. apy without chemotherapy. Targeted therapies blocking a critical pathway for tumor growth can delay tumor progression with fewer side effects Strategies than chemotherapy. To date, treatment until progression or unaccep- table toxicity, and allowing the administration of Maintenance therapy with cetuximab alone. Main- all available drugs sequentially or in combination tenance therapy with cetuximab alone was evalu- has been the standard practice for advanced colo- ated in the NORDIC VII study [Tveit et al. 2011]. rectal cancer. Various treatment strategies are OS for patients treated with continuous cetuximab depicted in Figures 1 and 2. and a chemotherapy-free interval (FLOX) was similar to that for patients with continuous chemo- therapy (FLOX) with or without cetuximab. Stop-and-go strategy Stop-and-go strategies especially fit with therapies Maintenance therapy with bevacizumab alone. inducing cumulative toxicity, such as oxaliplatin, Maintenance therapy with bevacizumab alone which have to be stopped before disease progres- was compared with continuous XELOX plus bev- sion. In cases of reversible toxicity (e.g. sensory acizumab therapy in the Spanish MACRO trial neuropathy) reintroduction of the same therapy [Tabernero et al. 2010]. The primary endpoint can be proposed at progression. was median PFS with a noninferiority limit of 80 http://tam.sagepub.com B Chibaudel, C Tournigand et al. Figure 1. Examples of treatment strategies for metastatic colorectal cancer. CFI, chemotherapy-free interval; chemo, chemotherapy; PD, progression disease. 7.6 months (i.e. HR = 1.32), assuming 10 months (4.2–5.9 months, HR = 0.81; p = 0.24), but this as median PFS in the control arm. Median PFS study lacked sufficient statistical power to detect was 10.4 months in the continuous arm (control) the effects of interest [Johnsonn et al. 2011]. and 9.7 months in the maintenance arm (investi- gational), with a HR of 1.11 (0.89–1.37). The authors concluded that noninferiority was not Treatment-free interval strictly demonstrated, but a detriment in PFS of The evolution of treatment for colorectal carci- more than 3 weeks could be excluded. Moreover, noma resulted in approximately 12 months of there was no statistically significant difference in median OS with 5-FU alone, 20 months in the OS (22.4 versus 21.7 months) between the two oxaliplatin and irinotecan era, and more than 20 groups (HR = 1.04). months when patients were exposed to all availa- ble drugs. Chemotherapy-free intervals (CFIs) are Maintenance therapy with double pathway inhibi- frequently used in patients with advanced colorec- tion. In the ACT-1 study, 159 patients were ran- tal cancer, for several reasons, including lengthy domized to receive either maintenance therapy sustained responses or stabilization, toxicity, and with bevacizumab alone or a combination of the patient’s decision to discontinue treatment. bevacizumab and erlotinib, an oral EGFR TKI, The gradual prolongation of median survival in after 4.5 months of oxaliplatin- or irinotecan- patients with metastatic disease and the difficulty based induction chemotherapy with bevacizumab in keeping patients on therapy for a long time have (investigator’s discretion). There was a trend for led to the evaluation of chemotherapy discontinu- longer maintenance PFS in the combination arm ation in prospective trials. http://tam.sagepub.com 81 Therapeutic Advances in Medical Oncology 4 (2) Figure 2. Treatment options in unresectable wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) metastatic colorectal cancer. CT, chemotherapy; EGF, epidermal growth factor. Study acronyms are used for brevity: readers may refer to the cited references in the text for full details of study names and details. OPTIMOX (Tournigand et al., 2006); CONcePT (Grothey et al., 2008); AVF2107g (Hurwitz et al., 2004); PRIME (Douillard et al., 2010); CRYSTAL (Van Cutsem et al., 2009); 181 (Peeters et al., 2010); FOLFIRI3 (Mabro et al., 2006); E3200 (Giantonio et al., 2007); BRITE (Grothey et al., 2008); VELOUR (Van Cutsem et al., 2011); BOND (Cunningham et al., 2004). Two recent studies evaluated completely stopping fewer visits to the hospital. The small difference in therapy in patients receiving combination chemo- OS in favor of continuous therapy should be therapy. The OPTIMOX2 study compared the weighed against the significantly reduced toxicity oxaliplatin stop-and-go strategy with completely associated with intermittent treatment. stopping chemotherapy after 3 months of induc- tion FOLFOX7 chemotherapy in the first-line An important methodology limitation of these two treatment of MCRC [Chibaudel et al. 2009]. The studies (OPTIMOX2, COIN) was the randomiza- results were in favor of maintenance therapy. The tion of patients before induction therapy, including median duration of disease control (DDC), the patients in the intermittent arm who were not eli- primary endpoint, was significantly longer in the gible for this strategy. Patients with progressive dis- maintenance arm than in the CFI arm (13.1 versus ease on induction therapy or amenable to salvage 9.2 months, HR = 0.71). Median PFS and median surgery biased the results. We now believe that OS were also longer in the maintenance arm. The decisions about chemotherapy holidays cannot be MRC COIN study (815 patients per arm) com- made before starting therapy. Despite these results, pared continuous oxaliplatin-based chemotherapy a significant number of patients can benefit from until disease progression with a complete stop- chemotherapy discontinuation. New criteria for and-go strategy after 3 months of oxaliplatin-based chemotherapy discontinuation were defined from treatment, followed by reintroduction on progres- the findings for patients in the OPTIMOX1 and sion of disease [Adams et al. 2011]. Intermittent OPTIMOX2 studies who had a successful CFI chemotherapy was associated with improved qual- and prolonged survival: a normal CEA level after ity of life, reduced time on chemotherapy, and 3 months of chemotherapy and chemotherapy 82 http://tam.sagepub.com B Chibaudel, C Tournigand et al. lasting 6 months before CFI [Perez-Staub et al. measured without bias. However, OS has several 2008]. In the COIN trial, patients with normal drawbacks. First, death occurs after a relatively platelet counts at baseline were found to signifi- long time for most patients. Second, clinical trials cantly benefit from a CFI [Adams et al. 2011]. using OS as the primary endpoint require a large number of patients and several years of follow up to demonstrate a statistically significant difference Reintroduction and the concept of between the new treatment and the standard treat- residual sensitivity ment, increasing the cost and duration of these tri- In the investigational arm of the OPTIMOX1 als. Finally, the effects of a drug on OS are diluted study, oxaliplatin was reintroduced in only 40% of by the effects of crossover and subsequent thera- patients and achieved a disease control rate of pies. Of note, OS represents the overall effect of 69%. Despite the fact that a large number of several treatment lines. Therefore, OS may not be a patients did not receive the planned oxaliplatin sensitive endpoint to evaluate the effect of a new reintroduction or received oxaliplatin after second- first-line therapy, or a new therapeutic strategy. line therapy, both oxaliplatin reintroduction and the percentage of patients with oxaliplatin reintro- duction per center had an independent and signifi- Alternative endpoints cant impact on OS [de Gramont et al. 2007]. Alternative outcomes that can be measured ear- Centers in which oxaliplatin was reintroduced in lier are needed to shorten the duration and reduce more than 40% of patients had an adjusted HR for the size and cost of clinical trials. OS of 0.59 compared with centers in which oxali- platin was not reintroduced in any patients. PFS evaluates the time to first progression or death from any cause if disease progression did not occur. Defining oxaliplatin sensitivity is important for the This definition limits PFS to the direct measure of therapeutic strategy when oxaliplatin reintroduc- a single sequence of treatment until the occurrence tion is feasible. As with platinum compounds in of the first event. PFS is unconfounded by crosso- ovarian cancer, a prolonged interval (>6 months) ver but cannot evaluate a treatment strategy beyond between two periods of FOLFOX therapy and first progression. In MCRC it has been shown that efficacy of first-line FOLFOX both predicted the the treatment effects on OS, based on the effects efficacy of oxaliplatin reintroduction. Thus, rein- on PFS, are predicted extremely well when patients troduction of oxaliplatin should be considered in receive no effective second-line therapy [Buyse et patients who have an initial benefit from FOLFOX al. 2007]. However, the prediction may not be as and who can tolerate it [de Gramont et al. 2009]. good when patients receive subsequent active lines of treatment. Indeed, the benefit in PFS will be lost in OS when the median survival post progression Intermittent chemotherapy (SSP) is large. This is particularly the case for In the GISCAD study, 337 patients with previ- MCRC because subsequent therapies are available ously untreated MCRC were randomized to after the first sequence of therapy (reintroduction, receive irinotecan-based chemotherapy, either second- and third-line therapy). continuously until progression or intermittently (2 months on treatment, 2 months off) [Labianca Thus, considering that PFS and OS are not reli- et al. 2011]. There were no differences in PFS able endpoints to evaluate therapeutic strategies, (HR = 0.88) or OS (HR = 1.03). new composite endpoints have been proposed to evaluate a chemotherapy strategy in MCRC: DDC, time to failure of strategy (TFS), and strat- Endpoints in strategy trials egy failure-free survival (SFFS). DDC may be The increasing number of active compounds seen as a direct measure of the treatment effect of available for MCRC therapy dictates the strategy a therapeutic strategy by excluding uncontrolled of trials evaluating these treatments either in com- disease intervals (time from disease progression to bination or sequentially. reinitiation of chemotherapy) and an inactive sec- ond course of treatment, defined as documented disease progression at the first tumor evaluation Overall survival after reinitiation of full therapy. TFS, however, OS is the final accepted ‘true’ clinical outcome aims to evaluate a global treatment strategy. DDC in cancer trials. OS is simple to measure and and TFS were found to be strongly correlated with http://tam.sagepub.com 83 Therapeutic Advances in Medical Oncology 4 (2) OS [Chibaudel et al. 2011a]. SFFS, which looks with bevacizumab [Hegewisch-Becker, 2011]. The like TFS, was recently evaluated in the MRC primary endpoint is time to failure of maintenance COIN trial. In the intermittent treatment group, a and a reintroduction treatment strategy. In SWS- SFFS event occurred when a patient had progres- SaKK-41/06, patients are randomized after first- sive disease during a planned treatment period or line therapy to maintenance with bevacizumab or within 8 weeks of starting a chemotherapy-free completely stopping antitumor therapy [Koeberle, interval. In the continuous treatment group, SFFS 2011]. The primary endpoint is time to progres- was similar to PFS [Adams et al. 2011]. Contrary sion. In the CAIRO-3 study, patients are randomly to PFS, these endpoints enable the duration of the assigned to bevacizumab plus capecitabine or therapeutic effect to be assessed before and after observation after 4.5 months of induction therapy the first disease progression. with oxaliplatin, capecitabine, and bevacizumab [Punt, 2011]. The primary endpoint is PFS after reintroduction of chemotherapy and bevacizumab. Ongoing strategy trials These are summarized in Table 2. Maintenance: interest in double pathway inhibition? Optimal timing for the use of Ongoing studies are further evaluating the role of anti-angiogenic and anti-epidermal targeted therapies alone during CFI. Both growth factor agents DREAM and ACT-2 studies are comparing main- An important practical question for the majority tenance therapy with bevacizumab alone or in of patients who have an unresectable tumor, even combination with erlotinib. In the GERCOR- in the case of tumor shrinkage, is when to use DREAM trial, patients are randomized after 3–6 anti-angiogenic agents and anti-EGF agents. months of induction chemotherapy (oxaliplatin based or irinotecan based) with bevacizumab, only Three ongoing first-line phase III trials (CALBG in the case of controlled disease or when metasta- 80405, FIRE-3, ML25686) are performing a sis resection is not appropriate, whatever the comparison of a standard chemotherapy regimen KRAS mutation status [Tournigand, 2011]. In the in combination with either bevacizumab or cetuxi- ACT-2 study, the comparison is restricted to mab [Venook and Blanke, 2011; Heinemann, 2011; patients with wild-type KRAS tumors. The activity Hoffman-La Roche, 2011a]. Primary endpoints of bevacizumab and low-dose metronomic capecit- are OS in the CALGB trial, RR in the FIRE-3 trial, abine is being explored in a third arm in patients and PFS in the ML25686 trial. Of note, subse- with KRAS-mutated tumors [Johnsson, 2011]. quent lines of treatment are not part of the trials. The multiline GISCAD trial (second and third Anti-angiogenic agent beyond progression lines) is comparing two different treatment Should VEGF inhibition be carried over from sequences (FOLFOX4 followed, after progres- first- to second-line therapy, meaning beyond sion, by irinotecan/cetuximab or the reverse progression? This question will be answered by sequence) after failure of FOLFIRI/bevacizumab the European ML18147 and the Italian GONO first-line therapy [Labianca, 2011]. The primary trials, which are investigating the use of bevaci- endpoint is OS. zumab beyond progression added to a sequential chemotherapy backbone in advanced colorectal cancer [Hoffman-La Roche, 2011b; Falcone, Maintenance or chemotherapy-free interval? 2011]. The results of the ML18147 study should Three trials are comparing bevacizumab- be available by the end of 2012. based maintenance therapy, either alone (AIO- KRK-0207, SWS-SAKK-41/06) or in combina- tion with fluoropyrimidine (AIO-KRK-0207, Conclusions CAIRO-3) to completely stopping therapy. In the The management of MCRC is a global treatment AIO trial, patients are randomly allocated to one strategy, which applies several lines of therapy, of three arms: bevacizumab with fluoropyrimi- salvage surgery, maintenance, and treatment-free dine (arm 1), bevacizumab alone (arm 2), or intervals. Our knowledge is based on clinical trials observation (arm 3) after 6 months of induction performed in selected populations, of younger therapy with oxaliplatin-based chemotherapy age, and with fewer comorbidities than the 84 http://tam.sagepub.com B Chibaudel, C Tournigand et al. Table 2. Ongoing phase III strategy trials in metastatic colorectal cancer. NCT No. Study name Sponsor N Control arm Investigational Reference Bev versus CTX first line 00265850 C80405 CALGB 760 Chemo+bev Chemo+CTX (Venook & Blanke, 2011) 00433927 FIRE-3 LM-UM 568 FOLFIRI+bev FOLFIRI+CTX (Heinemann, 2011) 01338558 ML25686 Roche 825 mFOLFOX6+CTX mFOLFOX6+bev (Hoffman-La Roche, 2011a) CTX second or third line 01030042 COMETS GISCAD 350 L2: FOLFOX4 L2: irinotecan+CTX (Labianca, L3: irinotecan+CTX L3: FOLFOX4 2011) Maintenance and/or observation 00544700 SWS- SGCCR 238 Bev Therapy-free interval (Koeberle, SAKK-41/06 2011) 00442637 CAIRO3 DCCG 635 Cap+bev Therapy-free interval (Punt, 2011) 00973609 AIO-KRK-0207 AIO 760 Fluoropyrimidine+bev Therapy-free interval or (Hegewish- bev monotherapy Becker, 2011) 00265824 DREAM GERCOR 700 Bev Bev+erlotinib (Tournigand, 2011) 01229813 ACT-2 LUH 181 Bev WT-KRAS: Bev+erlotinib (Johnsson, Mut-KRAS: Cap-Bev 2011) Bev beyond progression 00700102 ML18147 Roche 822 Chemo (no bev) Chemo+bev (Hoffman-La Roche, 2011b) 00720512 GONO-BEBYP- GONO 262 Chemo (no bev) Chemo+bev (Falcone, ASL607LIOM03 2011) AIO, Arbeitsgemeinschaft Internistische Onkologie (Germany); Bev, bevacizumab; CALBG: Cancer and Leukemia Group (US); CTX, cetuximab; DCCG, Dutch Colorectal Cancer Group (Netherlands); FOLFIRI, 5-fluorouracil/leucovorin/irinote- can regimen; FOLFOX, 5-fluorouracil/leucovorin/oxaliplatin regimen; GERCOR, Groupe Coopérateur Multidisciplinaire en Oncologie (France); GISCAD, Gruppo Italiano per lo studio dei Carcinomi dell’Apparato Digerente (Italy); GONO, Gruppo Oncologico del Nord-Ovest (Italy); LM-UM, Ludwig-Maximilians – University of Munich (Germany); LUH, Lund University Hospital (Sweden); Mut, mutant; N, estimated enrollment; NCT No., ClinicalTrials.gov Identifier; SGCCR, Swiss Group for Clinical Cancer Research (Swiss); WT, wild-type. Study acronyms are used for brevity: readers may refer to the cited refer- ences for full details of study names and details. References general MCRC population. Thus, formal conclu- Adams, R.A., Meade, A.M., Seymour, M.T., Wilson, sions should be formulated carefully. R.H., Madi, A., Fisher, D. et al. (2011) Intermittent versus continuous oxaliplatin and fluoropyrimidine The treatment options available in clinical prac- combination chemotherapy for first-line treatment of tice for patients with initially unresectable wild- advanced colorectal cancer: results of the randomised type KRAS MCRC are shown in Figure 2. phase 3 MRC COIN trial. Lancet Oncol 12: 642–653. Randomized strategy trials (i.e. beyond first line) American Cancer Society (2010) American Joint comparing these different options are needed to Committee on Cancer (AJCC): Colon and Rectum formally recommend the best strategy. Cancer Staging, 7th edition. Available at: http://www. cancerstaging.org/staging/index.html (accessed 12 Funding September 2011). This research received no specific grant from any Bidard, F.C., Tournigand, C., André, T., Mabro, funding agency in the public, commercial, or not- M., Figer, A., Cervantes, A. et al. (2009) Efficacy for-profit sectors. of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan based regimens in Conflict of interest statement oxaliplatin-pretreated metastatic colorectal cancer The authors declare no conflicts of interest in in the GERCOR OPTIMOX1 study. Ann Oncol 20: preparing this article. 1042–1047. http://tam.sagepub.com 85 Therapeutic Advances in Medical Oncology 4 (2) Bokemeyer, C., Bondarenko, I., Makhson, A., de Gramont, A., Buyse, M., Abrahantes, J.C., Hartmann, J.T., Aparicio, J., de Braud, F. et al. Buzykowski, T., Quinaux, E., Cervantes, A. et al. 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(2008) Who can leucovorin with oxaliplatin (FOLFOX-4) vs benefit from chemotherapy holidays after first-line FOLFOX-4 followed by irinotecan/cetuximab) in therapy for advanced colorectal cancer? A GERCOR metastatic colorectal patients treated with fluorouracil/ study. J Clin Oncol 26 (Suppl.): 4037. leucovorin with irinotecan FOLFIRI/bevacizumab as first line chemotherapy (COMETS). http:// Punt, C. (2011) Maintenance treatment with clinicaltrials.gov/ct2/show/NCT01030042 capecitabine and bevacizumab versus observation (accessed 12 September 2011). after induction treatment with chemotherapy and 88 http://tam.sagepub.com B Chibaudel, C Tournigand et al. bevacizumab as first-line treatment in patients with metastatic colorectal adenocarcinoma. http:// advanced colorectal carcinoma (CAIRO3). http:// clinicaltrials.gov/ct2/show/NCT00265824 (accessed clinicaltrials.gov/ct2/show/NCT00442637 (accessed 12 September 2011). 12 September 2011). Tournigand, C., Andre, T., Achille, E., Lledo, G., Rosen, O., Yi, J., Hurwitz, H., Ince, W., Novotny, Flesh, M., Mery-Mignard, D. et al. (2004) FOLFIRI W. and Holmgren, E. (2008) Clinical benefit of followed by FOLFOX6 or the reverse sequence in bevacizumab in metastatic colorectal cancer is advanced colorectal cancer: a randomized GERCOR independent of K-RAS mutation status: analysis of a study. J Clin Oncol 22: 229–237. phase III study of bevacizumab with chemotherapy in Tournigand, C., Cervantes, A., Figer, A., Lledo, G., previously untreated metastatic colorectal cancer. Ann Flesch, M., Buyse, M. et al. (2006) OPTIMOX1: Oncol 19(Suppl. 6): vi19; abstract 0-035. a randomized study of FOLFOX4 or FOLFOX7 Saltz, L.B., Clarke, S., Diaz-Rubio, E., Scheitauer, W., with oxaliplatin in a stop-and-go fashion in advanced Figer, A., Wong, R. et al. (2008) Bevacizumab in colorectal cancer – a GERCOR study. J Clin Oncol combination with oxaliplatin-based chemotherapy as 24: 394–400. first-line therapy in metastatic colorectal cancer: Tveit, K., Guren, T., Glimelius, B., Pfeiffer, P., a randomized phase III study. J Clin Oncol Sorbye, H., Pyrhonen, S. et al. (2011) Randomized 26: 2013–2019. phase III study of 5-flurouracil/folinate/oxaliplatin Schmoll, H.J., Cunningham, D., Sobrero, A., given continuously or intermittently with or without Karapetis, C.S., Rougier, P., Koski, S.L. et al. cetuximab, as first-line therapy of metastatic colorectal (2010) mFOLFOX6 + cediranib vs mFOLFOX6 cancer: the NORDIC VII study (NCT0014314), by + bevacizumab in previously untreated metastatic the Nordic Colorectal Cancer Biomodulation Group. colorectal cancer (mCRC): a randomized, double- J Clin Oncol 29(Suppl. 4): abstract 365. blind, phase II/III study (HORIZON III). Ann Oncol Van Cutsem, E., Köhne, C.H., Hitre, E., Zaluski, J., 21(Suppl. 8): viii188; abstract 580O. Chang Chien, C.R., Makhson, A. et al. (2009) Sobrero, A.F., Maurel, J., Fehrenbacher, L., Cetuximab and chemotherapy as initial treatment Scheitauer, W., Abubakr, Y.A., Lutz, M.P. et al. for metastatic colorectal cancer. N Engl J Med 360: (2008) EPIC: phase III trial of cetuximab plus 1408–1417. irinotecan after fluoropyrimidine and oxaliplatin Van Cutsem, E., Peeters, M., Siena, S., Humblet, Y., failure in patients with metastatic colorectal cancer. Hendlisz, A., Neyns, B. et al. (2007) Open-label phase J Clin Oncol 26: 2311–2319. III trial of panitumumab plus best supportive care Tabernero, J., Aranda, E., Gomez, A., Massuti, B., compared with best supportive care alone in patients Sastre, J., Abad, A. et al. (2010) Phase III study with chemotherapy-refractory metastatic colorectal of first-line XELOX plus bevacizumab (BEV) for cancer. J Clin Oncol 25: 1658–1664. 6 cycles followed by XELOX plus BEV or single- Van Cutsem, E., Tabernero, J., Lakomy, R., agent BEV as maintenance therapy in patients with Prausova, J., Ruff, P., Van Hazel, P. et al. (2011) metastatic colorectal cancer: the MACRO trial Intravenous (IV) aflibercept versus placebo in (Spanish Cooperative Group for the Treatment of combination with irinotecan/5-FU (FOLFIRI) for Digestive Tumors). J Clin Oncol 28(Suppl. 15): 3501. second-line treatment of metastatic colorectal cancer Tebbutt, N.C., Wilson, K., Gebski, V.J., Cummins, (MCRC): results of a multinational phase III trial M.M., Zannino, D., van Hazel, G.A. et al. (2010) (EFC10262- VELOUR). Ann Oncol 22(Suppl. 5): Capecitabine, bevacizumab, and mitomycin in first- v10–v18. line treatment of metastatic colorectal cancer: results Van Cutsem, E., Twelves, C., Cassidy, J., Allman, of the Australasian Gastrointestinal Trials Group D., Bajetta, E., Bayer, M. et al. (2001) Oral Randomized Phase III MAX Study. J Clin Oncol 28: capecitabine compared with intravenous fluorouracil 3191–3198. plus leucovorin in patients with metastatic colorectal Tol, J., Koopman, M., Cats, A., Rodenburg, C.J., cancer: results of a large phase III study. J Clin Oncol Creemers, G.J.M., Schrama, J.G. et al. (2009) 19: 4097–4106. Chemotherapy, bevacizumab, and cetuximab in Venook, A.P. and Blanke, C.D. (2011) Randomized metastatic colorectal cancer. N Engl J Med 360: phase III study of cetuximab and/or bevacizumab 563–572. in combination with either oxaliplatin, fluorouracil, Tournigand, C. (2011) Randomized phase III and leucovorin calcium (FOLFOX) or irinotecan study of combination chemotherapy comprising hydrochloride, fluorouracil and leucovorin calcium oxaliplatin, leucovorin calcium, and fluorouracil (FOLFIRI) in patients with previously untreated Visit SAGE journals online http://tam.sagepub.com (modified FOLFOX) or oxaliplatin and capecitabine locally advanced or metastatic adenocarcinoma of (XELOX) in combination with bevacizumab with the colon or rectum. http://clinicaltrials.gov/ct2/show/ SAGE JOURNALS versus without erlotinib in patients with unresectable NCT00265850 (accessed 12 September 2011). Online http://tam.sagepub.com 89 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Therapeutic Advances in Medical Oncology SAGE

Therapeutic strategy in unresectable metastatic colorectal cancer:

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431592 TAM421758834011431592B Chibaudel, C TournigandTherapeutic Advances in Medical Oncology Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Therapeutic strategy in unresectable (2012) 4(2) 75 –89 DOI: 10.1177/ metastatic colorectal cancer 1758834011431592 © The Author(s), 2011. Reprints and permissions: Benoist Chibaudel, Christophe Tournigand, Thierry André and Aimery de Gramont http://www.sagepub.co.uk/ journalsPermissions.nav Abstract: While surgery is the cornerstone treatment for early-stage colorectal cancer, chemotherapy is the first treatment option for metastatic disease when tumor lesions are frequently not fully resectable at presentation. Mortality from colon cancer has decreased over the past 30 years, but there is still a huge heterogeneity in survival rates that can be mainly explained by patient and tumor characteristics, host response factors, and treatment modalities. The management of unresectable metastatic colorectal cancer is a global treatment strategy, which applies several lines of therapy, salvage surgery, maintenance, and treatment-free intervals. The individualization of cancer treatment is based on the evaluation of prognostic factors for survival (serum lactate dehydrogenase level, performance status), and predictive factors for treatment efficacy [Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status]. The available treatment modalities for metastatic colorectal cancer are chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic agents (e.g. bevacizumab), and anti-epidermal growth factor agents (cetuximab, panitumumab). The increasing number of active compounds dictates the strategy of trials evaluating these treatments either in combination or sequentially. Alternative outcomes that can be measured earlier than overall survival are needed to shorten the duration and reduce the size and cost of clinical trials. Keywords: chemotherapy, clinical trial, colorectal cancer, molecular targeted therapy Correspondence to: Introduction This review focuses on the management of unre- Benoist Chibaudel, MD Colorectal cancer is the third most common can- sectable MCRC. Trial acronyms are used for Division of Medical Oncology, Hôpital cer and the third cause of cancer death in western brevity: readers may refer to the cited references Saint-Antoine, Assistance countries [Globocan, 2008]. The main parameter for full study names and details. Publique des Hôpitaux de Paris, 184 rue du faubourg to predict survival or relapse is tumor staging Saint-Antoine, 75571, [American Cancer Society, 2010]. While surgery Paris Cedex 12, France benoist.chibaudel is the cornerstone treatment for early-stage cancer Prognostic factors @sat.aphp.fr (stage I–III), chemotherapy is the first treatment Several parameters have been found to be inde- Christophe Tournigand, option for metastatic disease (stage IV) when pendent prognostic factors for MCRC. These MD Thierry André, MD tumor lesions are frequently not fully resectable at are patient characteristics such as World Health Aimery de Gramont, MD presentation. Approximately one third of patients Organization (WHO) performance status (PS), Division of Medical Oncology, Hôpital Saint- with metastatic colorectal cancer (MCRC) have age, sex, weight loss, biological variables such as Antoine, Assistance metachronous disease, which is currently defined white blood cell (WBC) count, serum alkaline Publique des Hôpitaux de Paris, Paris, France as more than 1 year between the occurrence of the phosphatase (ALP) level, serum lactate dehydroge- primitive tumor and metastasis. Mortality from nase (LDH) level, serum carcino-embryonic anti- colon cancer has decreased over the past 30 years, gen (CEA) level, or tumor characteristics like the partly due to better treatment modalities. Hetero- number of metastatic sites, or liver involvement. geneity in survival rates can be mainly explained by patient and tumor characteristics, host response Three risk groups for death were recognized in factors, and treatment strategy (drugs, regimen, patients receiving 5-fluorouracil (5-FU)-based and surgery of metastasis). chemotherapy for MCRC, depending on four http://tam.sagepub.com 75 Therapeutic Advances in Medical Oncology 4 (2) baseline prognostic parameters: PS, WBC count, dependent. A reversible posterior leukoencepha- ALP, and number of metastatic sites [Köhne et al. lopathy syndrome has been reported in rare cases. 2002]. Aflibercept (Zaltrap, Sanofi-Aventis, Paris, France; The Groupe Coopérateur Multidisciplinaire en Regeneron, Tarrytown, NY) is an investigational Oncologie (France) (GERCOR) prognostic score (i.e. it has not been approved by the US Food and was recently developed and validated in patients Drug Administration) fusion protein for the treat- treated with oxaliplatin- or irinotecan-based ment of cancer (colorectal, lung, prostate) and wet chemotherapy. This model was based on the two macular degeneration. This drug is designed to most important prognostic factors, LDH level bind to circulating VEGF-A, VEGF-B, and pla- and WHO PS, before starting first-line chemo- cental growth factor in the bloodstream and in the therapy. The median survival in patients having extravascular space with higher affinity than their PS0 and normal LDH value was twofold higher native receptors. than in patients with poor prognosis (PS1 and LDH>1N, or PS2) [Chibaudel et al. 2011b]. Anti-epidermal growth factor agents. Cetuximab (Erbitux, Merck, Darmastadt, Germany) is a chi- meric human mouse anti-epidermal growth fac- Antitumor drugs tor receptor (EGFR) monoclonal antibody. Panitumumab (Vectibix, Amgen, Thousand Oaks, Chemotherapy CA) is a fully human anti-EGFR monoclonal Three cytotoxic drugs are available for the treat- antibody. These two drugs have been studied as ment of MCRC: fluoropyrimidines, oxaliplatin, monotherapy and in combination with oxalipla- and irinotecan. These drugs can be administered tin- or irinotecan-based therapy in a palliative set- either in combination (doublets: fluoropyrimidine/ ting. It has been shown that only patients with oxaliplatin [de Gramont et al. 2000; Goldberg wild-type Kirsten rat sarcoma viral oncogene et al. 2006; Diaz-Rubio et al. 2007], 5-FU/ homolog (KRAS) tumors respond to anti-EGF irinotecan [Tournigand et al. 2004; Douillard agents and have a prolongation of progression- et al. 2000; Fuchs et al. 2007]; triplet: 5-FU/ free survival (PFS) [Lièvre et al. 2008]. Thus, the oxaliplatin/irinotecan [Falcone et al. 2007]); or as KRAS tumor gene has been validated as a nega- monotherapy (fluoropyrimidine alone) [de Gramont tive predictive marker for anti-EGF agent activity, et al. 1997; Van Cutsem et al. 2001]. but additional testing for tumor genes such as ser- ine/threonine-protein kinase B-Raf (BRAF) or neuroblastoma N-Rras (NRAS) could be useful Molecular-targeted agents to identify patients who might benefit the most Anti-angiogenic agents. Angiogenesis, the for- from anti-EGF agents [Di Nicolantonio et al. mation of new blood vessels, takes part in tumor 2008; Laurent-Puig et al. 2009; Khambata-Ford cell proliferation and thus is a target for antitumor et al. 2007]. In contrast to anti-angiogenic agents, therapy. Vascular endothelial growth factor the benefit of anti-EGF agents is maintained or (VEGF), a diffusible glycoprotein produced by even amplified in second- or third-line therapy normal and neoplastic cells, is an important regu- when a survival benefit is observed. This suggests lator of physiological and pathological angiogen- that if the goal is survival, it might be better to use esis. Increased levels of VEGF expression have anti-EGF drugs as salvage therapy. been found in most human malignancies. Bevacizumab (Avastin, Roche, Bale, Switzerland) First-line therapy is a recombinant humanized monoclonal immu- noglobulin G1 antibody targeting VEGF. Adding Irinotecan- or oxaliplatin-based regimens bevacizumab to commonly used chemotherapy as first-line chemotherapy? regimens improves outcomes in patients with The choice of oxaliplatin- or irinotecan-based MCRC. Infrequent specific bevacizumab-related regimens is a matter of debate. The C97-3 study side effects are bleeding, hypertension, fistulae, was the first direct comparison between the gastrointestinal perforation, arterial thromboem- addition of oxaliplatin or irinotecan with a sim- bolic events, and proteinuria. The occurrence of plified leucovorin/5-FU (LV5FU2) regimen hypertension and proteinuria is likely to be dose [Tournigand et al. 2004]. The final results did 76 http://tam.sagepub.com B Chibaudel, C Tournigand et al. not show any difference between FOLFIRI patients in the bevacizumab-containing arms and (leucovorin/5-FU/irinotecan regimen) and in 47% of patients in the placebo-containing FOLFOX6 (leucovorin/5-FU/oxaliplatin regi- arms. The benefit of bevacizumab was larger in men) in first-line therapy in terms of response the predefined on-treatment PFS analysis (HR = rate (RR 54% and 56%) and PFS (8.4 and 8.0 0.63): if events occurred more than 28 days months). These results were confirmed in another after stopping study medication, the patient was trial [Colucci et al. 2005]. The main difference censored back to the date of last known between these two combinations is mainly in the nonprogression. toxicity profile. Grade 3–4 gastrointestinal toxici- ties (nausea, vomiting, mucitis) and alopecia were Adding bevacizumab to fluoropyrimidine alone significantly more frequent with the FOLFIRI also achieved a highly significant improvement in regimen, whereas grade 3–4 neutropenia and PFS. The AVF2192g study provided further sup- neuropathy were significantly more frequent with port for combination with 5-FU/ leucovorin, the FOLFOX regimen. although the patient population was different than that for the AVF2107g study (only patients Arguments favoring FOLFIRI first line were less who were not candidates for first-line irinotecan grade 3–4 toxicity and better activity of FOLFOX treatment were eligible for the trial) [Kabbinavar second line (RR 15% versus 4%; PFS 4.9 versus et al. 2005]. Median PFS was increased from 5.5 2.3 months) while arguments in favor of FOLFOX to 9.2 months (HR = 0.50), and median overall first line were fewer patients with serious adverse survival (OS) was increased from 12.9 to 16.6 events, more patients amenable to surgery of months (HR = 0.79). In the MAX study, bevaci- metastases, and fewer chemotherapy cycles to zumab was added to capecitabine [Tebbutt et al. achieve the same results. The main reason for 2010]. Median PFS was increased from 5.7 to 8.5 stopping oxaliplatin was the cumulative drug neu- months (HR = 0.63), but median OS was similar rosensory toxicity in patients free of progression. in the two treatment groups (HR = 0.87). Thus, the potential of FOLFOX could be improved by the management of oxaliplatin- Vatalanib and cediranib, two recent oral VEGF induced neuropathy. Moreover, the difference in receptor-2 (KDR) tyrosine kinase inhibitors the incidence of grade 3–4 toxicity is due to neu- (TKIs), have been evaluated in first-line MCRC tropenia, which in most cases is not clinically therapy. In the CONFIRM1 trial, 1168 patients relevant. with previously untreated MCRC were randomly assigned to receive FOLFOX4 plus vatalanib or placebo [Hecht et al. 2011]. Response rate, PFS Anti-angiogenic agents or anti-epidermal (HR = 0.88), and OS (HR = 1.08) were not growth factor agents in combination as improved with vatalanib in the whole population. first-line chemotherapy? Of note, PFS was longer with vatalanib in patients Anti-angiogenic agents as first-line therapy. The with high serum LDH level at baseline (HR = addition of bevacizumab to oxaliplatin-based 0.67) [Schmoll et al. 2010]. In the HORIZON III (N016966) or irinotecan-based (AVF2107g) che- study (1422 patients), the direct comparison of motherapy improved survival [Saltz et al. 2008; cediranib and bevacizumab in combination with a Hurwitz et al. 2004]. Of note, this improvement modified FOLFOX6 regimen did not show any was effective in wild-type and mutated KRAS difference between the two regimens in terms of MCRC [Rosen et al. 2008]. Thus, KRAS testing efficacy (RR, odds ratio = 0.96; HR = 1.10; PFS is not warranted in the selection of patients for HR = 0.94). Moreover, the bevacizumab-based OS bevacizumab-based therapy in MCRC. The mag- therapy had a more favorable toxicity profile with nitude of benefit was higher with irinotecan [haz- less severe diarrhea and neutropenia. ard ratio (HR) = 0.54] than with oxaliplatin (HR = 0.83). This might be due to a better synergy Anti-epidermal growth factor agents as first-line between irinotecan and bevacizumab, or to more therapy. In patients with KRAS wild-type prolonged administration of bevacizumab in the tumors, the addition of cetuximab to either FOL- irinotecan trial (AVF2107g). In the oxaliplatin- FIRI (CRYSTAL) or FOLFOX (OPUS) pro- based trial (N016966), a large proportion of duced an improvement in median PFS (HR = patients stopped treatment earlier than allowed 0.68 and 0.54) [Van Cutsem et al. 2009; Boke- by the study protocol. The treatment was discon- meyer et al. 2009]. Similarly, the addition of pani- tinued because of progression in only 29% of tumumab to FOLFOX (PRIME) was superior to http://tam.sagepub.com 77 Therapeutic Advances in Medical Oncology 4 (2) Table 1. Randomized trials in metastatic colorectal cancer first-line therapy: results in a wild-type KRAS population. Study E Regimen N KRAS RR (%) PFS OS testing (%) (∆) (months) (months) Bev trials AVF2107g (Hurwitz OS IFL ± bev 67/85 28 37/60 7.4/13.5 17.6/22.7 et al., 2004) (+23%) (HR = 0.44) (HR = 0.58) PACCE (Hecht PFS Oxali based + bev 203 82 56 12.5 19.8 et al., 2008) Irinotecan based 58 48 13.5 27.7 CAIRO2 PFS XELOX + bev 156 71 50 10.6 22.4 (Tol et al., 2009) EGF trials CRYSTAL (Van PFS FOLFIRI ± CTX 350/316 89 40/57 8.4/9.9 20.0/23.5 Cutsem et al., (+17%) (HR = 0.70) (HR = 0.80) 2009) OPUS (Bokemeyer RR FOLFOX ± CTX 73/61 69 37/61 7.2/7.7 18.5/22.8 et al., 2009) (+24%) (HR = 0.57) (HR = 0.85) PRIME (Douillard PFS FOLFOX ± Pmab 331/325 93 48/55 8.0/9.6 19.7/23.9 et al., 2010) (+7%) (HR = 0.80) (HR = 0.83) COIN (Maughan OS Oxali based ± CTX 367/362 81 57/64 8.6/8.6 17.9/17.0 et al., 2011) (+7%) (HR = 0.96) (HR = 1.38) NORDIC VII PFS FLOX ± CTX 97/97 88 47/46 8.7/7.9 22.0/20.1 (Tveit et al., 2011) (–1%) (HR = 1.07) (HR = 1.14) bev, bevacizumab; CTX, cetuximab; E, primary endpoint; EGF, epidermal growth factor; HR, hazard ratio; KRAS, Kirsten rat sarcoma viral oncogene homolog; N, number of patients; OS, overall survival; PFS, progression-free survival; Pmab, panitumumab; RR, response rate. FOLFOX alone in terms of PFS (HR = 0.83) (leucovorin/5-FU/oxaliplatin regimen) until [Douillard et al. 2010]. In this study, the improve- progression or limiting toxicity, or the same ment in OS was not statistically significant (HR = chemotherapy in combination with cetuximab. 0.83; p = 0.07). The only significant improvement A third arm received intermittent FLOX chemo- in OS (median increased by 3.5 months) in a therapy with continuous cetuximab. In these two first-line trial has been reported in the CRYSTAL trials, PFS and OS did not differ among treat- trial. Unfortunately, the positive results came ment groups in patients with wild-type KRAS from a retrospective analysis and the proportion tumors (COIN: HR = 0.96, HR = 1.04; PFS OS of patients who received cetuximab after first line NORDIC VII: HR = 1.07; HR = 1.14). PFS OS in the control arm was not reported. A limited Unexpectedly the KRAS status did not affect the number of crossover patients (cetuximab in sec- efficacy of cetuximab in the NORDIC VII trial. ond or third line) in the control arm may explain Of note, cetuximab did not improve PFS and OS, this survival advantage for cetuximab in first-line even in patients with wild-type KRAS tumor. therapy (Table 1). Based on these data, it is too early to recommend Two first-line phase III trials contrasted with the systematic use of an anti-EGFR antibody in these results [Maughan et al. 2011; Tveit et al. combination with oxaliplatin as first-line therapy 2011]. In the COIN trial, 1630 patients were in patients with wild-type KRAS unresectable randomized to receive either oxaliplatin-based metastases. chemotherapy [FOLFOX or XELOX (cape- citabine plus oxaliplatin regimen)] alone or in The addition of both an anti-angiogenic agent combination with cetuximab. A third arm and an anti-EGF agent to chemotherapy had a received intermittent chemotherapy. In the negative impact on survival in comparison to NORDIC VII trial, 571 patients were rand- chemotherapy with bevacizumab [Hecht et al. omized to receive either continuous FLOX 2008; Tol et al. 2009]. 78 http://tam.sagepub.com B Chibaudel, C Tournigand et al. Second-line therapy Anti-epidermal growth factor agents. In the EPIC Most patients should be offered second-line ther- trial, cetuximab added to irinotecan after 5-FU/ apy when tumor progression or unacceptable tox- oxaliplatin failure significantly improved PFS (4.0 icity stops first-line therapy. Effective second-line versus 2.6 months; HR = 0.70) and RR (16.4% therapies are available. Knowledge of the most versus 4.2%) [Sobrero et al. 2008]. The absence of active second-line regimens must not lead to using survival advantage can be partly due to crossover: a suboptimal first-line regimen. It has been half of the control patients received cetuximab as reported that exposure to all available agents could post-trial therapy. KRAS mutation status was ret- be more important than the number of lines rospectively obtained for only 23% of randomized [Grothey et al. 2004]. However, based on the cor- patients. In the small subset of patients with wild- relation between the percentage of patients who type KRAS tumor (15% of the whole population), received all the available drugs and median sur- PFS was longer when cetuximab was added to iri- vival, if all eligible patients receive all the drugs, notecan, but RR and OS were similar. [Langer et the median survival would still be limited to 22 al. 2008]. The combination of panitumumab and months. New strategies using targeted agents or FOLFIRI (181 study) was superior to the same the oxaliplatin stop-and-go strategy have already chemotherapy in terms of RR and PFS, but not achieved median survival well over 22 months and OS [Peeters et al. 2010]. The magnitude of the argue against this basic approach. In the C97-3 PFS benefit remains modest and consistently study, the FOLFIRI regimen was less active in below 3 months. One acceptable hypothesis to second-line therapy in patients whose condition explain the discrepancy between PFS and OS is failed to respond to FOLFOX6 than FOLFOX6 crossover in the chemotherapy-alone arms. after progression on FOLFIRI. Of note, more than 70% of patients received second-line therapy and 13% of patients had R0 surgery of metastases Second-line therapy after irinotecan- on FOLFOX and 7% on FOLFIRI. based first-line chemotherapy Chemotherapy regimen. An oxaliplatin-based chemotherapy regimen is the cornerstone treat- Second-line therapy after oxaliplatin- ment after failure of an irinotecan-based therapy. based first-line chemotherapy The expected overall RR and median PFS with Chemotherapy regimen. Irinotecan-based che- FOLFOX as second-line therapy are 9–15% and motherapy is the treatment of choice after oxalipl- 4.2–4.7 months, respectively [Tournigand et al. atin-based therapy failure. The expected overall 2004; Giantonio et al. 2007]. response rate and median PFS of the standard FOLFIRI regimen are 4–12% and 2.5–4.7 Anti-angiogenic agents. The addition of bevaci- months, respectively [Tournigand et al. 2004; Van zumab to FOLFOX (E3200) after 5-FU/irinote- Cutsem et al. 2011; Peeters et al. 2010]. This regi- can failure led to an improvement in RR, PFS men was enhanced based on a positive interaction (4.7–7.3 months, HR = 0.61), and OS (10.8–12.9 between irinotecan and 5-FU given after 5-FU months, HR = 0.75) [Giantonio et al. 2007]. Con- infusion [Inoue et al. 2006]. Indeed, the FOL- tinuing bevacizumab after progression on first-line FIRI3 regimen has shown a RR of 20–25% and a therapy may also prolong survival and is being median PFS of 3.7–4.7 months without any tar- evaluated in prospective trials [Grothey et al. geted agents in several studies [Mabro et al. 2006; 2008]. In the CONFIRM2 trial (855 patients), Bidard et al. 2009]. However, these results have vatalanib in combination with FOLFOX after not been evaluated in randomized trials. 5-FU/irinotecan failure has demonstrated signifi- cant prolongation of PFS (4.1–5.5 months, HR = Anti-angiogenic agents. In the EFC10262- 0.83) but not OS (HR = 0.94) [Köhne et al. 2007]. VELOUR trial, the addition of aflibercept to the standard FOLFIRI regimen was evaluated in Anti-epidermal growth factor agents. No data 1226 patients after failure of oxaliplatin-based from phase III trials are available for anti-EGF chemotherapy. The new combination significantly agents in this setting. improved both PFS (4.7–6.9 months, HR = 0.76) and OS (12.1–13.5 months, HR = 0.82). This Finally, a benefit in OS in second-line therapy was effect was seen whether or not patients had observed only in trials using an anti-angiogenic received prior bevacizumab therapy [Van Cutsem agent in combination with FOLFIRI or FOLFOX et al. 2011]. [Van Cutsem et al. 2011; Giantonio et al. 2007]. http://tam.sagepub.com 79 Therapeutic Advances in Medical Oncology 4 (2) Third-line therapy The concept of maintenance therapy with fluoro- After exposure to oxaliplatin- and irinotecan- pyrimidine alone, referred to as oxaliplatin stop- based treatment, a significant number of patients and-go strategy [de Gramont, 2008], was evaluated are still able and willing to receive therapy. in the OPTIMOX1 study, in which 620 patients with unresectable MCRC were randomized to The BOND trial, in which a significant either FOLFOX4 until progression or the oxalipl- proportion of patients were not only refractory atin stop-and-go strategy [Tournigand et al. 2006]. to irinotecan-based chemotherapy but also to This strategy consisted of six cycles of FOLFOX7 oxaliplatin-based chemotherapy, demonstrated chemotherapy [Maindrault-Goebel et al. 2001] a synergy between irinotecan and cetuximab followed by maintenance therapy with the simpli- [Cunningham et al. 2004]. The response rate for fied LV5FU2 regimen without oxaliplatin. After 12 irinotecan plus cetuximab was superior to the cycles of LV5FU2 chemotherapy, FOLFOX7 was response rate for the monoclonal antibody alone reintroduced in patients with controlled disease. (23% versus 11%), and the HR for disease pro- This study demonstrated that a short induction gression in the combination therapy group com- with oxaliplatin followed by maintenance therapy pared with the monotherapy group was 0.54 with 5-FU alone was better tolerated than and (median PFS 4.1 versus 1.5 months). Later stud- achieved a similar efficacy as continuous adminis- ies demonstrated that the anti-EGFR monoclonal tration of the drug until progression or the occur- antibodies cetuximab and panitumumab were rence of cumulative neurotoxicity. also active alone as third-line treatment versus best supportive care, and the results were ampli- Maintenance therapy with fluoropyrimidine fied in the wild-type KRAS population [Jonker and bevacizumab was evaluated in the Com- et al. 2007; Van Cutsem et al. 2007]. Thus, there is bined Oxaliplatin Neuropathy Prevention Trial an unquestionable survival advantage for anti- (CONcePT). This trial compared continuous EGFR monoclonal antibodies in third-line ther- administration of FOLFOX with intermittent apy in the wild-type KRAS population. administration of eight cycles of FOLFOX plus bevacizumab followed by eight cycles of mainte- Knowing that bevacizumab is not active in nance LV/5FU plus bevacizumab, and FOLFOX third-line therapy [Chen et al. 2006; Kang et al. reintroduction plus bevacizumab for eight cycles 2009] the only active third-line therapies are [Grothey et al. 2008]. PFS with continuous based on anti-EGFR monoclonal antibodies, administration was 7.3 months compared with which are only active in wild-type KRAS tumors. 12.0 months with the stop-and-go strategy. Consequently, there is no standard third-line therapy for patients with mutated KRAS tumors and for patients with wild-type KRAS tumors Maintenance therapy with targeted agents who receive anti-EGFR treatment as first- or sec- Recent studies have evaluated maintenance ther- ond-line therapy. apy without chemotherapy. Targeted therapies blocking a critical pathway for tumor growth can delay tumor progression with fewer side effects Strategies than chemotherapy. To date, treatment until progression or unaccep- table toxicity, and allowing the administration of Maintenance therapy with cetuximab alone. Main- all available drugs sequentially or in combination tenance therapy with cetuximab alone was evalu- has been the standard practice for advanced colo- ated in the NORDIC VII study [Tveit et al. 2011]. rectal cancer. Various treatment strategies are OS for patients treated with continuous cetuximab depicted in Figures 1 and 2. and a chemotherapy-free interval (FLOX) was similar to that for patients with continuous chemo- therapy (FLOX) with or without cetuximab. Stop-and-go strategy Stop-and-go strategies especially fit with therapies Maintenance therapy with bevacizumab alone. inducing cumulative toxicity, such as oxaliplatin, Maintenance therapy with bevacizumab alone which have to be stopped before disease progres- was compared with continuous XELOX plus bev- sion. In cases of reversible toxicity (e.g. sensory acizumab therapy in the Spanish MACRO trial neuropathy) reintroduction of the same therapy [Tabernero et al. 2010]. The primary endpoint can be proposed at progression. was median PFS with a noninferiority limit of 80 http://tam.sagepub.com B Chibaudel, C Tournigand et al. Figure 1. Examples of treatment strategies for metastatic colorectal cancer. CFI, chemotherapy-free interval; chemo, chemotherapy; PD, progression disease. 7.6 months (i.e. HR = 1.32), assuming 10 months (4.2–5.9 months, HR = 0.81; p = 0.24), but this as median PFS in the control arm. Median PFS study lacked sufficient statistical power to detect was 10.4 months in the continuous arm (control) the effects of interest [Johnsonn et al. 2011]. and 9.7 months in the maintenance arm (investi- gational), with a HR of 1.11 (0.89–1.37). The authors concluded that noninferiority was not Treatment-free interval strictly demonstrated, but a detriment in PFS of The evolution of treatment for colorectal carci- more than 3 weeks could be excluded. Moreover, noma resulted in approximately 12 months of there was no statistically significant difference in median OS with 5-FU alone, 20 months in the OS (22.4 versus 21.7 months) between the two oxaliplatin and irinotecan era, and more than 20 groups (HR = 1.04). months when patients were exposed to all availa- ble drugs. Chemotherapy-free intervals (CFIs) are Maintenance therapy with double pathway inhibi- frequently used in patients with advanced colorec- tion. In the ACT-1 study, 159 patients were ran- tal cancer, for several reasons, including lengthy domized to receive either maintenance therapy sustained responses or stabilization, toxicity, and with bevacizumab alone or a combination of the patient’s decision to discontinue treatment. bevacizumab and erlotinib, an oral EGFR TKI, The gradual prolongation of median survival in after 4.5 months of oxaliplatin- or irinotecan- patients with metastatic disease and the difficulty based induction chemotherapy with bevacizumab in keeping patients on therapy for a long time have (investigator’s discretion). There was a trend for led to the evaluation of chemotherapy discontinu- longer maintenance PFS in the combination arm ation in prospective trials. http://tam.sagepub.com 81 Therapeutic Advances in Medical Oncology 4 (2) Figure 2. Treatment options in unresectable wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) metastatic colorectal cancer. CT, chemotherapy; EGF, epidermal growth factor. Study acronyms are used for brevity: readers may refer to the cited references in the text for full details of study names and details. OPTIMOX (Tournigand et al., 2006); CONcePT (Grothey et al., 2008); AVF2107g (Hurwitz et al., 2004); PRIME (Douillard et al., 2010); CRYSTAL (Van Cutsem et al., 2009); 181 (Peeters et al., 2010); FOLFIRI3 (Mabro et al., 2006); E3200 (Giantonio et al., 2007); BRITE (Grothey et al., 2008); VELOUR (Van Cutsem et al., 2011); BOND (Cunningham et al., 2004). Two recent studies evaluated completely stopping fewer visits to the hospital. The small difference in therapy in patients receiving combination chemo- OS in favor of continuous therapy should be therapy. The OPTIMOX2 study compared the weighed against the significantly reduced toxicity oxaliplatin stop-and-go strategy with completely associated with intermittent treatment. stopping chemotherapy after 3 months of induc- tion FOLFOX7 chemotherapy in the first-line An important methodology limitation of these two treatment of MCRC [Chibaudel et al. 2009]. The studies (OPTIMOX2, COIN) was the randomiza- results were in favor of maintenance therapy. The tion of patients before induction therapy, including median duration of disease control (DDC), the patients in the intermittent arm who were not eli- primary endpoint, was significantly longer in the gible for this strategy. Patients with progressive dis- maintenance arm than in the CFI arm (13.1 versus ease on induction therapy or amenable to salvage 9.2 months, HR = 0.71). Median PFS and median surgery biased the results. We now believe that OS were also longer in the maintenance arm. The decisions about chemotherapy holidays cannot be MRC COIN study (815 patients per arm) com- made before starting therapy. Despite these results, pared continuous oxaliplatin-based chemotherapy a significant number of patients can benefit from until disease progression with a complete stop- chemotherapy discontinuation. New criteria for and-go strategy after 3 months of oxaliplatin-based chemotherapy discontinuation were defined from treatment, followed by reintroduction on progres- the findings for patients in the OPTIMOX1 and sion of disease [Adams et al. 2011]. Intermittent OPTIMOX2 studies who had a successful CFI chemotherapy was associated with improved qual- and prolonged survival: a normal CEA level after ity of life, reduced time on chemotherapy, and 3 months of chemotherapy and chemotherapy 82 http://tam.sagepub.com B Chibaudel, C Tournigand et al. lasting 6 months before CFI [Perez-Staub et al. measured without bias. However, OS has several 2008]. In the COIN trial, patients with normal drawbacks. First, death occurs after a relatively platelet counts at baseline were found to signifi- long time for most patients. Second, clinical trials cantly benefit from a CFI [Adams et al. 2011]. using OS as the primary endpoint require a large number of patients and several years of follow up to demonstrate a statistically significant difference Reintroduction and the concept of between the new treatment and the standard treat- residual sensitivity ment, increasing the cost and duration of these tri- In the investigational arm of the OPTIMOX1 als. Finally, the effects of a drug on OS are diluted study, oxaliplatin was reintroduced in only 40% of by the effects of crossover and subsequent thera- patients and achieved a disease control rate of pies. Of note, OS represents the overall effect of 69%. Despite the fact that a large number of several treatment lines. Therefore, OS may not be a patients did not receive the planned oxaliplatin sensitive endpoint to evaluate the effect of a new reintroduction or received oxaliplatin after second- first-line therapy, or a new therapeutic strategy. line therapy, both oxaliplatin reintroduction and the percentage of patients with oxaliplatin reintro- duction per center had an independent and signifi- Alternative endpoints cant impact on OS [de Gramont et al. 2007]. Alternative outcomes that can be measured ear- Centers in which oxaliplatin was reintroduced in lier are needed to shorten the duration and reduce more than 40% of patients had an adjusted HR for the size and cost of clinical trials. OS of 0.59 compared with centers in which oxali- platin was not reintroduced in any patients. PFS evaluates the time to first progression or death from any cause if disease progression did not occur. Defining oxaliplatin sensitivity is important for the This definition limits PFS to the direct measure of therapeutic strategy when oxaliplatin reintroduc- a single sequence of treatment until the occurrence tion is feasible. As with platinum compounds in of the first event. PFS is unconfounded by crosso- ovarian cancer, a prolonged interval (>6 months) ver but cannot evaluate a treatment strategy beyond between two periods of FOLFOX therapy and first progression. In MCRC it has been shown that efficacy of first-line FOLFOX both predicted the the treatment effects on OS, based on the effects efficacy of oxaliplatin reintroduction. Thus, rein- on PFS, are predicted extremely well when patients troduction of oxaliplatin should be considered in receive no effective second-line therapy [Buyse et patients who have an initial benefit from FOLFOX al. 2007]. However, the prediction may not be as and who can tolerate it [de Gramont et al. 2009]. good when patients receive subsequent active lines of treatment. Indeed, the benefit in PFS will be lost in OS when the median survival post progression Intermittent chemotherapy (SSP) is large. This is particularly the case for In the GISCAD study, 337 patients with previ- MCRC because subsequent therapies are available ously untreated MCRC were randomized to after the first sequence of therapy (reintroduction, receive irinotecan-based chemotherapy, either second- and third-line therapy). continuously until progression or intermittently (2 months on treatment, 2 months off) [Labianca Thus, considering that PFS and OS are not reli- et al. 2011]. There were no differences in PFS able endpoints to evaluate therapeutic strategies, (HR = 0.88) or OS (HR = 1.03). new composite endpoints have been proposed to evaluate a chemotherapy strategy in MCRC: DDC, time to failure of strategy (TFS), and strat- Endpoints in strategy trials egy failure-free survival (SFFS). DDC may be The increasing number of active compounds seen as a direct measure of the treatment effect of available for MCRC therapy dictates the strategy a therapeutic strategy by excluding uncontrolled of trials evaluating these treatments either in com- disease intervals (time from disease progression to bination or sequentially. reinitiation of chemotherapy) and an inactive sec- ond course of treatment, defined as documented disease progression at the first tumor evaluation Overall survival after reinitiation of full therapy. TFS, however, OS is the final accepted ‘true’ clinical outcome aims to evaluate a global treatment strategy. DDC in cancer trials. OS is simple to measure and and TFS were found to be strongly correlated with http://tam.sagepub.com 83 Therapeutic Advances in Medical Oncology 4 (2) OS [Chibaudel et al. 2011a]. SFFS, which looks with bevacizumab [Hegewisch-Becker, 2011]. The like TFS, was recently evaluated in the MRC primary endpoint is time to failure of maintenance COIN trial. In the intermittent treatment group, a and a reintroduction treatment strategy. In SWS- SFFS event occurred when a patient had progres- SaKK-41/06, patients are randomized after first- sive disease during a planned treatment period or line therapy to maintenance with bevacizumab or within 8 weeks of starting a chemotherapy-free completely stopping antitumor therapy [Koeberle, interval. In the continuous treatment group, SFFS 2011]. The primary endpoint is time to progres- was similar to PFS [Adams et al. 2011]. Contrary sion. In the CAIRO-3 study, patients are randomly to PFS, these endpoints enable the duration of the assigned to bevacizumab plus capecitabine or therapeutic effect to be assessed before and after observation after 4.5 months of induction therapy the first disease progression. with oxaliplatin, capecitabine, and bevacizumab [Punt, 2011]. The primary endpoint is PFS after reintroduction of chemotherapy and bevacizumab. Ongoing strategy trials These are summarized in Table 2. Maintenance: interest in double pathway inhibition? Optimal timing for the use of Ongoing studies are further evaluating the role of anti-angiogenic and anti-epidermal targeted therapies alone during CFI. Both growth factor agents DREAM and ACT-2 studies are comparing main- An important practical question for the majority tenance therapy with bevacizumab alone or in of patients who have an unresectable tumor, even combination with erlotinib. In the GERCOR- in the case of tumor shrinkage, is when to use DREAM trial, patients are randomized after 3–6 anti-angiogenic agents and anti-EGF agents. months of induction chemotherapy (oxaliplatin based or irinotecan based) with bevacizumab, only Three ongoing first-line phase III trials (CALBG in the case of controlled disease or when metasta- 80405, FIRE-3, ML25686) are performing a sis resection is not appropriate, whatever the comparison of a standard chemotherapy regimen KRAS mutation status [Tournigand, 2011]. In the in combination with either bevacizumab or cetuxi- ACT-2 study, the comparison is restricted to mab [Venook and Blanke, 2011; Heinemann, 2011; patients with wild-type KRAS tumors. The activity Hoffman-La Roche, 2011a]. Primary endpoints of bevacizumab and low-dose metronomic capecit- are OS in the CALGB trial, RR in the FIRE-3 trial, abine is being explored in a third arm in patients and PFS in the ML25686 trial. Of note, subse- with KRAS-mutated tumors [Johnsson, 2011]. quent lines of treatment are not part of the trials. The multiline GISCAD trial (second and third Anti-angiogenic agent beyond progression lines) is comparing two different treatment Should VEGF inhibition be carried over from sequences (FOLFOX4 followed, after progres- first- to second-line therapy, meaning beyond sion, by irinotecan/cetuximab or the reverse progression? This question will be answered by sequence) after failure of FOLFIRI/bevacizumab the European ML18147 and the Italian GONO first-line therapy [Labianca, 2011]. The primary trials, which are investigating the use of bevaci- endpoint is OS. zumab beyond progression added to a sequential chemotherapy backbone in advanced colorectal cancer [Hoffman-La Roche, 2011b; Falcone, Maintenance or chemotherapy-free interval? 2011]. The results of the ML18147 study should Three trials are comparing bevacizumab- be available by the end of 2012. based maintenance therapy, either alone (AIO- KRK-0207, SWS-SAKK-41/06) or in combina- tion with fluoropyrimidine (AIO-KRK-0207, Conclusions CAIRO-3) to completely stopping therapy. In the The management of MCRC is a global treatment AIO trial, patients are randomly allocated to one strategy, which applies several lines of therapy, of three arms: bevacizumab with fluoropyrimi- salvage surgery, maintenance, and treatment-free dine (arm 1), bevacizumab alone (arm 2), or intervals. Our knowledge is based on clinical trials observation (arm 3) after 6 months of induction performed in selected populations, of younger therapy with oxaliplatin-based chemotherapy age, and with fewer comorbidities than the 84 http://tam.sagepub.com B Chibaudel, C Tournigand et al. Table 2. Ongoing phase III strategy trials in metastatic colorectal cancer. NCT No. Study name Sponsor N Control arm Investigational Reference Bev versus CTX first line 00265850 C80405 CALGB 760 Chemo+bev Chemo+CTX (Venook & Blanke, 2011) 00433927 FIRE-3 LM-UM 568 FOLFIRI+bev FOLFIRI+CTX (Heinemann, 2011) 01338558 ML25686 Roche 825 mFOLFOX6+CTX mFOLFOX6+bev (Hoffman-La Roche, 2011a) CTX second or third line 01030042 COMETS GISCAD 350 L2: FOLFOX4 L2: irinotecan+CTX (Labianca, L3: irinotecan+CTX L3: FOLFOX4 2011) Maintenance and/or observation 00544700 SWS- SGCCR 238 Bev Therapy-free interval (Koeberle, SAKK-41/06 2011) 00442637 CAIRO3 DCCG 635 Cap+bev Therapy-free interval (Punt, 2011) 00973609 AIO-KRK-0207 AIO 760 Fluoropyrimidine+bev Therapy-free interval or (Hegewish- bev monotherapy Becker, 2011) 00265824 DREAM GERCOR 700 Bev Bev+erlotinib (Tournigand, 2011) 01229813 ACT-2 LUH 181 Bev WT-KRAS: Bev+erlotinib (Johnsson, Mut-KRAS: Cap-Bev 2011) Bev beyond progression 00700102 ML18147 Roche 822 Chemo (no bev) Chemo+bev (Hoffman-La Roche, 2011b) 00720512 GONO-BEBYP- GONO 262 Chemo (no bev) Chemo+bev (Falcone, ASL607LIOM03 2011) AIO, Arbeitsgemeinschaft Internistische Onkologie (Germany); Bev, bevacizumab; CALBG: Cancer and Leukemia Group (US); CTX, cetuximab; DCCG, Dutch Colorectal Cancer Group (Netherlands); FOLFIRI, 5-fluorouracil/leucovorin/irinote- can regimen; FOLFOX, 5-fluorouracil/leucovorin/oxaliplatin regimen; GERCOR, Groupe Coopérateur Multidisciplinaire en Oncologie (France); GISCAD, Gruppo Italiano per lo studio dei Carcinomi dell’Apparato Digerente (Italy); GONO, Gruppo Oncologico del Nord-Ovest (Italy); LM-UM, Ludwig-Maximilians – University of Munich (Germany); LUH, Lund University Hospital (Sweden); Mut, mutant; N, estimated enrollment; NCT No., ClinicalTrials.gov Identifier; SGCCR, Swiss Group for Clinical Cancer Research (Swiss); WT, wild-type. Study acronyms are used for brevity: readers may refer to the cited refer- ences for full details of study names and details. References general MCRC population. Thus, formal conclu- Adams, R.A., Meade, A.M., Seymour, M.T., Wilson, sions should be formulated carefully. R.H., Madi, A., Fisher, D. et al. (2011) Intermittent versus continuous oxaliplatin and fluoropyrimidine The treatment options available in clinical prac- combination chemotherapy for first-line treatment of tice for patients with initially unresectable wild- advanced colorectal cancer: results of the randomised type KRAS MCRC are shown in Figure 2. phase 3 MRC COIN trial. Lancet Oncol 12: 642–653. Randomized strategy trials (i.e. beyond first line) American Cancer Society (2010) American Joint comparing these different options are needed to Committee on Cancer (AJCC): Colon and Rectum formally recommend the best strategy. Cancer Staging, 7th edition. Available at: http://www. cancerstaging.org/staging/index.html (accessed 12 Funding September 2011). This research received no specific grant from any Bidard, F.C., Tournigand, C., André, T., Mabro, funding agency in the public, commercial, or not- M., Figer, A., Cervantes, A. et al. (2009) Efficacy for-profit sectors. of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan based regimens in Conflict of interest statement oxaliplatin-pretreated metastatic colorectal cancer The authors declare no conflicts of interest in in the GERCOR OPTIMOX1 study. Ann Oncol 20: preparing this article. 1042–1047. http://tam.sagepub.com 85 Therapeutic Advances in Medical Oncology 4 (2) Bokemeyer, C., Bondarenko, I., Makhson, A., de Gramont, A., Buyse, M., Abrahantes, J.C., Hartmann, J.T., Aparicio, J., de Braud, F. et al. Buzykowski, T., Quinaux, E., Cervantes, A. et al. 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Journal

Therapeutic Advances in Medical OncologySAGE

Published: Dec 14, 2011

Keywords: chemotherapy; clinical trial; colorectal cancer; molecular targeted therapy

References