INTRODUCTION — The majority of patients with metastatic colon or rectal cancer cannot be cured, although a subset with liver and/or lung-isolated disease is potentially curable with surgery. For other patients with metastatic colorectal cancer (CRC), treatment is palliative and generally consists of systemic chemotherapy. (See "Management of potentially resectable colorectal cancer liver metastases" and "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)
For decades, fluorouracil (FU) was the sole active agent. This has changed markedly since the year 2000, with the approval of irinotecan, oxaliplatin, three humanized monoclonal antibodies (MoAbs) that target the vascular endothelial growth factor (VEGF; bevacizumab) and epidermal growth factor receptor (EGFR; cetuximab and panitumumab), intravenous aflibercept, a recombinant fusion protein consisting of VEGF binding portions from the human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1, regorafenib, an orally active inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1, 2, and 3) as well as several other membrane-bound and intracellular kinases that are involved in normal cellular function and in pathologic processes, and trifluridine-tipiracil (TAS-102), an oral cytotoxic agent that consists of the nucleoside analog trifluridine (a cytotoxic antimetabolite that inhibits thymidylate synthetase and, after modification within tumor cells, is incorporated into DNA causing strand breaks) and tipiracil, a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well. The best way to combine and sequence these agents is still not established. Most recently, the immune checkpoint inhibitors pembrolizumab and nivolumab have been approved for advanced microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) CRC that has progressed following conventional chemotherapy.
The best way to combine and sequence all of these agents is not known. Increasingly, biomarker expression is driving therapeutic decision-making. However, the biologic targets for most of the agents that are active against metastatic CRC are unknown, with the exception of agents targeting the EGFR and immunotherapy with immune checkpoint inhibitors:
●Benefit from MoAbs targeting the EGFR is restricted to patients whose tumors do not contain mutated RAS genes or a mutation in the BRAF gene at the 600 codon (V600E mutation).
●Benefit from immunotherapy with immune checkpoint inhibitors appears to be limited to the subset of tumors that are MSI-H or dMMR.
This topic review will cover the data from clinical trials evaluating systemic chemotherapy for nonresectable metastatic CRC. General principles of treatment and specific treatment recommendations, including the use of biomarkers to select therapy and a compilation of treatment protocols, are presented elsewhere, as is the use of systemic therapy for the purpose of downstaging potentially resectable CRC liver metastases. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles" and "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations" and "Treatment protocols for small and large bowel cancer" and "Management of potentially resectable colorectal cancer liver metastases", section on 'Therapy after resection of liver metastases'.)
FLUOROPYRIMIDINES — Until the development of combination regimens of leucovorin (LV)-modulated fluorouracil (FU) with either irinotecan or oxaliplatin, FU/LV was the standard first-line therapy for metastatic colorectal cancer (mCRC), and it is still used in patients who cannot tolerate these triple-drug regimens. If it is to be used alone, because of the more favorable toxicity profile, we recommend short-duration infusional FU/LV (ie, the de Gramont regimen)  rather than the Mayo regimen of treatment for five consecutive days once per month. An acceptable alternative is weekly FU (500 mg/m2) plus LV (500 mg/m2) for six of every eight weeks .
Oral capecitabine is a more convenient (but not necessarily less toxic ) alternative to LV-modulated FU in clinical settings where fluoropyrimidines alone are indicated (ie, in patients who are not considered appropriate candidates for intensive therapy using a first-line oxaliplatin or irinotecan-based combination regimen). The approved dose is 1250 mg/m2 twice daily for 14 of every 21 days, although most United States oncologists begin at a lower dose (1000 mg/m2 twice daily).
Fluoropyrimidines such as fluorouracil (FU) have been used for mCRC for over 40 years. The primary mechanism of cytotoxicity is thought to be impaired DNA synthesis via inhibition of thymidylate synthase (TS). Inhibition of RNA synthesis may further contribute to cytotoxicity of bolus regimens .
FU is rapidly metabolized to inactive compounds. Interpatient variation in the activity of the critical metabolizing enzyme dihydropyrimidine dehydrogenase (DPD) may account for toxicity differences . Individuals who lack DPD develop severe, potentially fatal side effects. (See "Enterotoxicity of chemotherapeutic agents".)
Bolus FU monotherapy has limited activity; only 10 percent achieve an objective response. Higher response rates can be achieved with infusional regimens, but the survival impact is minimal [6,7]. The toxicity profile differs with bolus and infusional FU. While rates of GI toxicity are similar, grade 3/4 neutropenia is more common with bolus FU (31 versus 4 percent), while hand-foot syndrome is more frequent with infusional regimens (34 versus 13 percent) . (See "Cutaneous side effects of conventional chemotherapy agents" and "Enterotoxicity of chemotherapeutic agents".)
Leucovorin plus FU — Leucovorin (LV) enhances FU cytotoxicity by interacting with thymidylate synthase to form a stable ternary complex, prolonging inhibition of the enzyme by FU . Compared to bolus FU alone, FU/LV is associated with a twofold higher response rate (21 versus 11 percent in two meta-analyses [10,11]), which, in one, translated into a small but statistically significant 10 percent improvement in one-year survival (47 versus 37 percent ).
Until the development of combination regimens of FU/LV with either irinotecan or oxaliplatin, FU/LV was the standard first-line therapy for mCRC; it is still used in patients who cannot tolerate these triple drug regimens (see below).
Most American patients receive a racemic mixture of d,l-leucovorin. However, the l-isomer is the biologically active moiety, and a preparation of l-leucovorin is now commercially available in the United States (LEVOleucovorin, Fusilev). It is dosed at one-half that of d,l-leucovorin (table 1), and is similarly effective as the racemic mixture .
Optimizing the schedule and dose — Several dose and schedules of FU and LV are in clinical use.
●Bolus regimens – There are two widely used bolus regimens:
•The Mayo regimen: FU (425 mg/m2) plus low-dose LV (20 mg/m2), both given on days one to five, every four to five weeks. A modification consists of FU (370 mg/m2) plus high-dose LV (200 mg/m2) each given on days one to five, every four to five weeks .
•The Roswell Park Memorial Institute (RPMI) regimen: weekly FU (500 mg/m2) plus LV (500 mg/m2) for six of every eight weeks . The initial RPMI regimen, containing 600 mg/m2 FU weekly, was too toxic .
At least three trials have directly compared both approaches [14-16]. The monthly schedule causes more neutropenia and stomatitis, while the weekly schedule causes more diarrhea. Furthermore, five-day bolus regimen appears to be more toxic in women than in men. Given the lower rates of neutropenia and stomatitis and the ability to stop or modify therapy if toxicity occurs, the weekly RPMI regimen is generally preferred. (See "Enterotoxicity of chemotherapeutic agents".)
The equivalence of low-dose (ie, 20 mg/m2 per dose) versus high-dose (ie, 500 mg/m2 per dose) LV for the weekly schedule has not yet been firmly established, although at least one trial suggests similar outcomes and a more favorable toxicity profile for the lower dose regimen . Many clinicians use the lower dose regimen because of cost issues .
●Short-term infusional FU/LV – Response rates with FU/LV have been further improved by the use of short-term infusional schedules of FU. This was demonstrated in a trial of 448 patients who were randomly assigned to a monthly regimen of LV (20 mg/m2) plus bolus FU (425 mg/m2) on days one to five every four weeks or a bimonthly regimen (the de Gramont regimen, (table 2)) of LV (200 mg/m2 over two hours) followed by bolus FU (400 mg/m2) and a 22-hour infusion of FU (600 mg/m2); both drugs are given daily for two consecutive days every two weeks . The infusional regimen was associated with a significantly better response rate (33 versus 14 percent) and median progression-free survival (28 versus 22 weeks), and a trend toward longer median survival (62 versus 57 weeks, p = 0.067).
Infusional therapy also caused less hematologic and GI toxicity. For these reasons, the majority of regimens incorporating FU into irinotecan and oxaliplatin-based regimens now use short-term infusional schedules.
Chronomodulated FU — Chronomodulation, a method where drug administration varies over a 24-hour period, is based upon the following principles :
●Drug absorption, transport, metabolism, and/or elimination usually show diurnal changes.
●Most cellular detoxification rhythms appear to be coupled to the rest-activity cycle.
●These variations in target cell exposure to drugs and the diurnal rhythms that modulate cellular detoxification functions may impact the pharmacology of administered drugs, including FU .
Chronomodulated administration schedules of FU with or without LV generally improve response rates and lessen toxicity as compared to nonchronomodulated schedules [18,20]. However, the true value of this approach has not been fully established, and it remains experimental.
Orally active fluoropyrimidines — Orally active FU analogs provide response rates that are comparable to IV FU/LV, with the convenience of oral delivery [21,22]. The available agents include capecitabine (Xeloda) and ftorafur (tegafur) plus uracil (UFT).
Capecitabine — Capecitabine is a fluoropyrimidine carbamate that is absorbed intact through the intestinal wall and then converted to FU in three sequential enzymatic reactions. The final requisite enzyme, thymidine phosphorylase, is present at consistently higher levels in tumor compared to normal tissue, thereby providing the basis for enhanced selectivity for tumor cells and better tolerability .
Two identically designed randomized trials (602 and 605 patients, respectively) have shown similar efficacy for capecitabine monotherapy (1250 mg/m2 twice daily for 14 of every 21 days) compared to IV FU/LV (the Mayo regimen, see above) for the first-line treatment of mCRC [24,25].
In one of the trials, capecitabine was associated with a modestly but significantly higher response rate than FU/LV (25 versus 16 percent), but similar median time to tumor progression (TTP, 4.3 versus 4.7 months) and overall survival (12.5 versus 13.3 months) . The incidence of grade 3 or 4 diarrhea, stomatitis, nausea, and neutropenic sepsis were significantly less in the capecitabine group; only hyperbilirubinemia and hand-foot syndrome were more common compared to FU/LV.
In contrast to these data, objective response rates with second-line capecitabine monotherapy are quite low in patients with FU/LV-refractory disease [26,27]. Capecitabine alone is an inappropriate treatment strategy for patients who have failed FU-based regimens.
Capecitabine is approved in the United States for first-line treatment of mCRC, when fluoropyrimidines alone are indicated. The approved dose is 1250 mg/m2 twice daily for 14 of every 21 days. Some have suggested that lower doses (beginning at 1000 mg/m2 twice daily for 14 of every 21 days) improve the therapeutic index . However, randomized trials have not established the comparative efficacy of these lower capecitabine doses. In at least one study using 1250 mg/m2 twice daily in 51 elderly patients with advanced CRC, treatment was well tolerated, and only six (12 percent) experienced grade 3 or 4 adverse events .
Some data suggest that the incidence and severity of capecitabine-associated toxicity are substantially higher when it is given after FU/LV . The mechanism underlying this sequence-specific exacerbation of toxicity is unclear. The potential for excess toxicity is a consideration for patients who are being considered for crossover from FU/LV to capecitabine. However, this information is based on a relatively small number of patients and needs confirmation.
Combinations of capecitabine with irinotecan and oxaliplatin are discussed below, and hand-foot syndrome due to capecitabine is discussed elsewhere. (See 'Irinotecan plus capecitabine or S-1' below and 'Capecitabine plus oxaliplatin' below and "Cutaneous side effects of conventional chemotherapy agents".)
S-1 — S-1 is an oral fluoropyrimidine that includes three different agents: ftorafur (tegafur), gimeracil (5-chloro-2,4 dihydropyridine, a potent inhibitor of DPD), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea). It is available in some countries outside of the United States.
UFT — UFT is a 1:4 molar combination of ftorafur (tegafur) with uracil, which competitively inhibits the degradation of FU, resulting in sustained plasma and intratumoral concentrations . Response rates are approximately 25 percent with UFT monotherapy and 40 percent in combination with oral LV (150 mg daily) . In phase III studies, UFT plus LV has comparable efficacy and better tolerability as compared to IV bolus FU [33,34]. The dose limiting toxicity is diarrhea. Myelosuppression and hand-foot syndrome are infrequent. Combinations of UFT with irinotecan (TEGAFIRI) and oxaliplatin (TEGAFOX, UFOX) appear to be effective and well tolerated, with similar efficacy and tolerability to the corresponding FU- and capecitabine-based regimens [35-39].
UFT is not available in the United States.
Raltitrexed — Raltitrexed (Tomudex), a folate analog, is a pure thymidylate synthase inhibitor . It is not more active than FU and is not approved in the United States [41-43]. In at least one randomized trial that assigned 905 patients with mCRC to raltitrexed, infusional FU, or bolus plus short-term infusional FU/LV (the de Gramont regimen), raltitrexed was associated with the greatest toxicity and worst health-related quality of life .
Raltitrexed, which is not available in the United States, may be a useful substitute for FU in patients with dihydropyrimidine dehydrogenase deficiency (which markedly increases FU toxicity), or possibly as a component of second-line therapy in patients failing irinotecan or oxaliplatin [44-47]. (See "Enterotoxicity of chemotherapeutic agents".)
IRINOTECAN — Irinotecan, a topoisomerase I inhibitor, is active as monotherapy in advanced colorectal cancer (CRC); it is more active in combination with fluorouracil (FU) as well as with the targeted agents bevacizumab and cetuximab. The combination of irinotecan with FU/leucovorin (LV) is more effective than FU/LV alone, and the doublet combination represents a standard option for first-line therapy of metastatic CRC (mCRC). At present, most American oncologists use irinotecan-based regimens in the second-line setting, after failure of initial oxaliplatin-based therapy. However, an irinotecan-based regimen could be considered initially in a patient with a relative contraindication to oxaliplatin (eg, pre-existing neuropathy or prior exposure to oxaliplatin in the adjuvant setting).
For patients receiving irinotecan plus FU/LV, the weekly bolus regimen (the irinotecan/FU/LV [IFL] or "Saltz" regimen) should no longer be considered an appropriate administration schedule for doublet therapy. Regimens that contain short-term infusional FU (FOLFIRI (table 3) or the Douillard regimen) (table 1) are preferred because of their more favorable toxicity profile . (See 'Irinotecan plus FU' below and "Treatment protocols for small and large bowel cancer".)
Concerns have been raised about potentially inferior efficacy and greater toxicity using the combination of capecitabine plus irinotecan for patients who wish to avoid short-term infusional FU (which requires a central venous catheter and an ambulatory infusion pump). This approach has not been widely adopted. (See 'Irinotecan plus capecitabine or S-1' below.)
Individuals who inherit a genetic polymorphism in the drug-metabolizing enzyme UGT1A1 (the UGT1A1*28 allele) may have more severe irinotecan-related neutropenia and diarrhea; the available data are conflicting. While testing for the presence of this allele is available (the Invader UGT1A1 Molecular Assay), whether its use is warranted for all patients who are to receive irinotecan is unclear. Whether initial dose reduction is needed for UGT1A1*28 homozygotes and the precise dose reduction that is warranted in this patient population remain controversial areas. (See 'UGT1A1 polymorphisms' below.)
Irinotecan alone — As a single agent, irinotecan has demonstrated clinical benefit after FU failure in patients with mCRC [49-52]. This was illustrated in a trial of 279 patients with FU-refractory disease who were randomly assigned to best supportive care with or without irinotecan . The irinotecan group had superior one-year survival (36 versus 14 percent) and quality of life .
Different administration schedules (weekly, every two, or every three weeks) appear to result in similar therapeutic outcomes, although in one report, the every-three-week schedule was associated with significantly less grade 3 diarrhea (36 versus 19 percent) than a weekly regimen . Diarrhea is the dose-limiting side effect of irinotecan and may be severe; early use of loperamide decreases its severity and is essential to prevent treatment-related mortality. (See "Enterotoxicity of chemotherapeutic agents".)
●In a European trial, 387 previously untreated patients were randomly assigned to FU/LV with or without irinotecan . Triple therapy could be administered either weekly (irinotecan 80 mg/m2, FU 2300 mg/m2 over 24 hours, LV 500 mg/m2) or every other week (irinotecan 180 mg/m2 on day 1, FU 400 mg/m2 bolus followed by 600 mg/m2 over 22 hours, both on days one and two, and LV 200 mg/m2 on days one and two [the Douillard FOLFIRI regimen], (table 1)). The control arm allowed weekly (FU 2600 mg/m2 over 24 hours plus LV 500 mg/m2) or every other week regimens (FU 400 mg/m2 bolus followed by 600 mg/m2 over 22 hours, both on days one and two, and LV 200 mg/m2 on days one and two).
Triple therapy was associated with a significantly higher response rate (49 versus 31 percent), as well as longer time to tumor progression (TTP, 6.7 versus 4.4 months) and median survival (17.4 versus 14.1 months). Although some toxicities were more common with irinotecan (ie, grade 3/4 diarrhea [44 versus 27 percent] and neutropenia [29 versus 2 to 4 percent]), they were manageable, reversible, and noncumulative.
●Nearly identical results were found in another European trial comparing weekly infusional FU/LV with and without irinotecan in 430 patients with mCRC . As with the prior trial, the addition irinotecan was associated with significantly higher response rates and progression-free survival, but the difference in median survival (20.1 versus 16.9 months) did not reach the level of statistical significance.
●In contrast to the European trials, American studies focused on more convenient triple combination regimens that include bolus FU/LV (eg, the Saltz regimen or IFL). Although the benefit of IFL over FU/leucovorin was shown in an American randomized trial , the IFL regimen causes more toxicity than infusion FU-based regimens such as FOLFIRI (table 3) [54,56-60]. As a result, bolus FU-based irinotecan combinations such as IFL should no longer be considered an appropriate choice for irinotecan/FU/LV therapy. (See "Enterotoxicity of chemotherapeutic agents", section on 'Irinotecan plus FU' and "Treatment protocols for small and large bowel cancer".)
Drug sequence and administration — Drug sequencing and method of administration influence toxicity. As noted above, infusional FU-based irinotecan regimens (eg, FOLFIRI, including the originally published Douillard regimen) (table 1) appear to be associated with less GI toxicity than bolus FU-based regimens such as IFL . In addition, in one report, the area under the concentration x time curve (AUC) for the irinotecan metabolite SN-38 was 40 percent lower when irinotecan preceded FU, and this sequence of administration was associated with fewer side effects .
Pharmacokinetic variability — A major issue with irinotecan is the marked interpatient variability in pharmacodynamics and pharmacokinetics that correlates poorly with body surface area-based dosing [62-65]. Pharmacokinetic variability has been related to biliary excretion [66-68]. Even modest elevations in serum bilirubin increase the risk for severe neutropenia and diarrhea . Lower starting doses are appropriate in such patients, particularly those receiving weekly therapy. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease", section on 'Irinotecan and liposomal irinotecan'.)
Pharmacokinetic variability has also been linked to inherited alterations in the hepatic metabolic pathways that control irinotecan disposition . The best studied of these pharmacogenetic factors are inherited polymorphisms in uridine diphospho glucuronosyltransferase 1A1 (UGT1A1). (See "Overview of pharmacogenomics".)
UGT1A1 polymorphisms — The active form of irinotecan (SN-38) is metabolized by the polymorphic enzyme UGT1A1. Intratumoral enzymatic activity is reduced in individuals who inherit genetic polymorphisms such as the UGT1A1*28 allele (also known as TA indel or UGT1A1 7/7). Approximately 10 percent of the North American population is homozygous for the UGT1A1*28 allele (which is responsible for Gilbert's syndrome); an additional 40 percent are heterozygotes. (See "Dosing of anticancer agents in adults", section on 'UGT1A1 polymorphisms and irinotecan' and "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction", section on 'Pathogenesis'.)
Initial reports suggested that UGT1A1*28 homozygotes (and heterozygotes to a lesser degree) were at high risk for irinotecan-related gastrointestinal (GI) toxicity and neutropenia. However, more data indicate that the magnitude of the problem (particularly the association with worse diarrhea) was not as great as initially suspected.
In 2005, the US Food and Drug Administration (FDA) recommended modification of the irinotecan drug labeling to specify that individuals who are homozygous for the UGT1A1 *28 allele are at increased risk for severe neutropenia following treatment with irinotecan. The FDA-approved label recommends testing for the presence of the UGT1A1 *28 allele, and reducing the initial irinotecan dose in those who are homozygous for UGT 1A1*28 to reduce the likelihood of dose-limiting neutropenia.
However, routine use of this assay to select the appropriate dose of the drug in all patients who are to receive irinotecan for treatment of metastatic disease has not been widely accepted. Whether initial dose reduction improves outcomes for UGT1A1*28 homozygotes and the precise dose reduction that is warranted in this patient population remain controversial areas; in addition, inheritance of UGT1A1*28 polymorphisms seems to account for only a fraction of the observed variability in irinotecan toxicity. (See "Dosing of anticancer agents in adults", section on 'UGT1A1 polymorphisms and irinotecan'.)
Emerging work suggests that hepatic functional imaging (HFI) might represent a promising approach for assessing hepatic irinotecan handling . However, whether those patients at risk for irinotecan-related toxicity are best identified by HFI or a combined approach of HFI plus drug response gene polymorphisms remains to be seen.
Irinotecan plus capecitabine or S-1 — Capecitabine and irinotecan have partially overlapping toxicity profiles, particularly with regard to diarrhea. The potential for greater toxicity reduces the therapeutic advantage of an irinotecan/capecitabine combination. (See "Enterotoxicity of chemotherapeutic agents".)
Six trials have compared the safety and efficacy of CAPIRI and FOLFIRI regimens, either with or without bevacizumab [56,70-74]; the irinotecan doses in the XELIRI arms ranged from 200 to 250 mg/m2 on day 1 of each 21-day cycle, and all trials used capecitabine 1000 mg/m2 twice daily on days 1 to 14. A meta-analysis of all six trials concluded that both regimens had similar efficacy and similar adverse event profiles .
Unfortunately, regional differences in capecitabine tolerability  make it difficult to translate toxicity and efficacy findings generated in trials conducted outside of the United States  into American patients. This problem was particularly apparent in the phase III BICC-C trial, which compared three different approaches to combining irinotecan with a fluoropyrimidine (infusional FU [FOLFIRI], bolus FU [modified IFL], or capecitabine [XELIRI] using the standard European doses of irinotecan [250 mg/m2 day 1] and capecitabine [1000 mg/m2 twice daily, on days 1 to 14 of every three-week cycle]) . No prespecified dose reduction for irinotecan and capecitabine for elderly patients (as suggested by other authors ) was implemented. FOLFIRI emerged as the undisputed winner of the head-to-head comparison of all three regimens in terms of efficacy and tolerability. XELIRI was associated with a higher rate of grade 3/4 adverse events, in particular, diarrhea (48 versus 14 percent), nausea (18 versus 9 percent), vomiting (16 9 percent), and dehydration (19 versus 6 percent). Higher rates of grade 3 and 4 diarrhea with XELIRI as compared to FOLFIRI have been seen in other trials as well [70,74].
Despite the conclusions of the meta-analysis , in our view, XELIRI cannot be routinely recommended, at least for American patients, and this regimen should not be regarded as a valid substitute for FOLFIRI. The question of whether dose reductions of both drugs can make XELIRI more tolerable, and perhaps more effective, particularly in elderly patients, will have to be explored in future clinical trials.
Irinotecan after oxaliplatin failure — As oxaliplatin-based regimens are increasingly used as first-line therapy of mCRC, the efficacy of salvage irinotecan is emerging as an important issue. Although limited, the most mature data from three series suggest response rates between 4 and 20 percent, and PFS of 2.5 to 7.1 months, respectively, for patients receiving a FOLFIRI-like regimen after progression on FOLFOX [80-82].
The optimal sequence of oxaliplatin and irinotecan-containing chemotherapy remains unresolved, and may differ between patients based on tumor-related heterogeneity and pharmacogenetic issues. Exposure to all active agents is probably more important than the specific sequence of administration [83,84]. Nevertheless, most American oncologists initiate chemotherapy for mCRC with FOLFOX, using irinotecan alone  or irinotecan-based regimens such as FOLFIRI as second-line therapy after the failure of FOLFOX.
Oxaliplatin alone — Early phase II data suggested activity for oxaliplatin alone for first-line therapy (20 to 25 percent response rate in two separate studies [87,88]). However, subsequent randomized data (albeit for second-line therapy) have shown a fairly low level of activity . As a result, most clinicians consider single agent oxaliplatin to be an inappropriate choice for first-line therapy.
First-line oxaliplatin plus FU/LV — The combination of oxaliplatin, short-term infusional fluorouracil (FU), and leucovorin (LV) is a standard treatment option for first-line treatment of mCRC. Most American oncologists use a modification of the FOLFOX6 regimen in which the oxaliplatin dose is the same as in FOLFOX4 (modified FOLFOX6 (table 4)). The available data support the view that efficacy of first-line FOLFOX is similar to that of FOLFIRI. The choice of which regimen to use should be based upon the expected toxicities of each regimen in the context of coexisting conditions for any given patient. (See "Treatment protocols for small and large bowel cancer".)
As noted previously, oxaliplatin synergizes with FU. At least three trials show significantly greater response rates and progression-free survival (PFS) but similar overall survival with oxaliplatin plus short-term infusional FU and leucovorin (FOLFOX) compared to FU plus leucovorin (LV) alone in the first-line setting [90-92]. FOLFOX has comparable activity to irinotecan plus FU/LV given as a short-term infusion (FOLFIRI) for patients with mCRC [80,93]. (See "Treatment protocols for small and large bowel cancer".)
Oxaliplatin/FU/LV versus FU/LV — The benefit of adding oxaliplatin to FU/LV was initially shown in a trial in which 420 patients with previously untreated mCRC were randomly assigned to LV (200 mg/m2 daily over two hours) followed by a FU bolus (400 mg/m2 daily) and a 22-hour infusion of FU (600 mg/m2 daily) for two consecutive days every two weeks (the de Gramont regimen), either alone or with oxaliplatin (85 mg/m2 on day one over two hours), a regimen termed FOLFOX4 (table 1) . Patients treated with FOLFOX4 had a significantly higher objective response rate (51 versus 22 percent) and longer PFS (9 versus 6.2 months) but similar median overall survival (16.2 versus 14.7 months). Grade 3/4 neutropenia (42 versus 5 percent) and diarrhea (12 versus 5 percent) were more common with oxaliplatin.
Results were similar in a second multicenter study, in which 410 patients were randomly assigned to short-term infusional LV-modulated FU or FOLFOX6 (table 1) . Initial combination treatment was associated with a significantly better objective response rate (58 versus 24 percent) and PFS (7.6 versus 5.3 months), but median overall survival (16.2 versus 16.4 months) was similar.
Oxaliplatin/FU/LV versus irinotecan/FU/LV — The available data from head to head comparisons suggest that outcomes with first-line oxaliplatin/FU/LV and irinotecan/FU/LV are similar. While a survival benefit for the oxaliplatin-containing regimen compared to bolus irinotecan/FU/LV (IFL) was suggested in a United States Cooperative Group trial , two smaller (ie, not statistically powered for a noninferiority comparison) European trials that used short-term infusional FU/LV (ie, FOLFIRI) as the comparator did not [80,93]. (See 'Irinotecan plus FU' above.)
●INT 9741 – Intergroup (INT) 9741 randomly assigned patients to IFL, oxaliplatin/FU/LV using the FOLFOX4 regimen (table 1), or irinotecan plus oxaliplatin (IROX; oxaliplatin 85 mg/m2 plus irinotecan 200 mg/m2, both administered on day one every three weeks). The trial was unblinded early by the Data Safety Monitoring Committee because FOLFOX proved more effective and less toxic than IFL .
The initial analysis included 795 patients who were assigned to IFL, FOLFOX4, or IROX . FOLFOX4 was significantly superior to IFL in terms of objective response rate (45 versus 31 percent), time to tumor progression (TTP, 8.7 versus 6.9 months), and median overall survival (20 versus 15 months). Patients receiving IFL had significantly higher rates of alopecia, diarrhea, nausea, vomiting, and febrile neutropenia, but significantly fewer paresthesias than those receiving FOLFOX4. More patients discontinued FOLFOX for reasons other than disease progression (60 versus 25 percent of the IFL group), presumably reflecting cumulative neuropathy.
In a later update, FOLFOX was also superior to IROX in terms of response rate (43 versus 36 percent), TTP (9.2 versus 6.7 months), and overall survival (19.5 versus 17.3 months) . Patients over the age of 70 receiving IROX had significantly higher rates of grade 3 or worse hematologic toxicity.
●European/Asian trials – In contrast to the results from Intergroup trial N9741, in which irinotecan was given in combination with bolus FU/LV, two European trials and a Japanese trial of first-line bevacizumab plus either FOLFOX or FOLFIRI suggest similar efficacy for combinations of irinotecan or oxaliplatin with short-term infusional LV-modulated FU [80,93,96].
One trial compared a different schedule of FOLFOX (every two weeks oxaliplatin 100 mg/m2, plus LV 200 mg/m2 and FU bolus 400 mg/m2, followed by FU 2.4 to 3.0 g/m2 over 46 hours by continuous infusion, termed FOLFOX6 [(table 1)]) versus FOLFIRI, the same de Gramont FU/LV regimen plus irinotecan (180 mg/m2 on day one every two weeks) in 226 previously untreated patients . Patients were allowed to crossover to the alternative regimen at progression. Response rates were similar (54 and 56 percent for FOLFOX6 and FOLFIRI, respectively), and the PFS (8 versus 8.5 months) and median survival (20.6 and 21.5 months, respectively) rates were similar.
A lack of superiority for FOLFOX was also noted in an Italian trial, which randomly assigned 360 patients with previously untreated mCRC to one of the following groups :
•Every other week irinotecan (180 mg/m2 day one), LV (100 mg/m2 over two hours in days one and two) with each dose of LV followed by FU (400 mg/m2 bolus and 600 mg/m2 over 22 hours), a regimen termed the Douillard regimen (table 1).
•Overall response rates were similar (31 and 34 percent, respectively), as were PFS, median survival (14 versus 15 months), and toxicity profiles.
Noninferiority of FOLFIRI plus bevacizumab as compared with FOLFOX/bevacizumab for first-line therapy of mCRC was also noted in the West Japan Oncology Group study 4407G; median progression-free survival was 12.1 versus 10.7 months for FOLFIRI/FOLFOX, respectively, median overall survival was 31.4 versus 30.1 months, and the objective response rate was 64 versus 62 percent .
Differences in trial design may provide at least part of the explanation for these disparate results. In INT 9741, FU was delivered differently (bolus or infusion) in the two arms containing oxaliplatin, whereas it was given by bolus alone with irinotecan; delivery of FU and LV was the same on both arms of the two European studies and the Japanese study.
The need for infusional FU in oxaliplatin combination regimens is unclear. At least one phase II study reports comparable results with a less complex bolus regimen . However, at present, administration with short-term infusional FU/LV is considered a standard approach.
Capecitabine plus oxaliplatin — A combination of capecitabine plus oxaliplatin (XELOX; also called CAPOX) is a reasonable alternative for first-line therapy of mCRC in patients for whom ambulatory infusional FU therapy using a pump is not feasible or desired. The available data suggest that XELOX has approximately similar antitumor efficacy, but there is a possibility of more toxicity (especially thrombocytopenia and hand-foot syndrome, possibly diarrhea) as compared with infusional FU/oxaliplatin combinations.
For American patients, we consider the standard regimen to be capecitabine 850 mg/m2 twice daily for 14 of every 21 days (as was used in the TREE-2 trial) plus oxaliplatin 130 mg/m2 on day 1 over two hours (table 5) [98,99]. Oncologists in Europe and Asia more commonly start with capecitabine 1000 mg/m2 twice daily, as was used in TREE-1 . (See "Treatment protocols for small and large bowel cancer".)
A lower oxaliplatin dose (eg, 85 mg/m2 over two hours on day 1) with capecitabine (850 or 1000 mg/m2 twice daily on days 2 to 15) could be considered for older adult patients . More intensive regimens (eg, week on, week off therapy with both capecitabine and oxaliplatin ) may be more active, but direct comparisons with standard doses are not yet available.
The efficacy and tolerability of the XELOX (also called CAPOX) combination has been explored extensively for both first- and second-line therapy [98-106].
The best regimen is uncertain. In three separate phase II studies in previously untreated patients, objective response rates using oxaliplatin (130 mg/m2 day one) followed by capecitabine (1000 mg/m2 twice daily for 14 of every 21 days) were 36, 42, and 55 percent, respectively [101-103], and the median survival in one of these trials was 19.5 months . Tolerability was better in two studies (one of which focused on patient over the age of 70 [102,103]) than in the third .
On the other hand, lower initial doses of oxaliplatin (85 mg/m2 every three weeks) were combined with capecitabine (1000 mg orally twice daily for 14 of every 21 days) in a trial that focused on first-line treatment of patients 70 years of age or older . If tolerated, the oxaliplatin dose could be increased to 110 mg/m2 and then to 130 mg/m2 for the second and third cycles. The objective response rate was 41 percent and the median overall survival 14.4 months (nearly identical to results with higher dose oxaliplatin in a separate phase II trial conducted in an elderly population ). Treatment was well tolerated with only 5 percent of patients developing grade 3 or 4 hematologic toxicity, 8 percent peripheral neuropathy, and 13 percent severe hand-foot syndrome.
First-line XELOX versus FOLFOX — Multiple randomized trials have explored whether XELOX provides similar efficacy and tolerability as other fluoropyrimidine/oxaliplatin combinations [98,99,106-108]; all suggest comparable efficacy, but a different toxicity profile. As examples:
●The phase II TREE-1 trial randomly assigned 150 patients to modified FOLFOX6 (table 4), CAPOX (capecitabine 1000 mg twice daily for 14 of every 21 days plus oxaliplatin 130 mg/m2 on day one), or bFOL (bolus FU 500 mg/m2, and LV 20 mg/m2 weekly for three of every four weeks plus oxaliplatin 85 mg/m2 on days 1 and 15) . The differences between FOLFOX and CAPOX in response rates, TTP and median survival were not significant (table 6).
Patients in the CAPOX group had the highest rates of hand-foot syndrome, grade 3 or 4 nausea/vomiting and neuropathy (38 and 21 percent), and more often discontinued therapy because of toxicity. The FOLFOX6 group had the highest rate of grade 3 or 4 neutropenia (53 versus 15 percent with CAPOX). Rates of grade 3 or 4 diarrhea were the same (31 percent) in both groups.
●The 474-patient AIO trial compared XELOX using a unique oxaliplatin schedule (capecitabine 1000 mg/m2 twice daily for 14 of every 21 days plus oxaliplatin 70 mg/m2 on day 1 and day 8) versus FUFOX (FU 2000 mg/m2 over 22 hours, LV 500 mg/m2, and oxaliplatin 50 mg/m2 on days 1, 8, 15, and 22, with cycles repeated every 36 days) . As with TREE 1, the differences between FUFOX and CAPOX in response rates (54 versus 48 percent), PFS (8 versus 7.1 months), and median survival (18.8 versus 16.8 months) were not statistically significant.
A systematic review of eight trials comparing first-line CAPOX with oxaliplatin plus infusional FU/LV concluded that CAPOX was associated with similar response rates and overall survival . Thrombocytopenia, diarrhea, and hand-foot syndrome were consistently more prominent with CAPOX, but neutropenia was worse with FOLFOX.
S-1 plus oxaliplatin — S-1 is an oral fluoropyrimidine that includes three different agents: ftorafur (tegafur), gimeracil (5-chloro-2,4 dihydropyridine, a potent inhibitor of DPD [dihydropyrimidine dehydrogenase]), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea). It is available in most countries outside of the United States. The combination of S-1 plus oxaliplatin (SOX) was directly compared to XELOX in a multicenter randomized Korean phase III trial of 340 patients with previously untreated mCRC . The design was characterized as a noninferiority trial with an upper boundary of the PFS hazard ratio of 1.43 (meaning that a 43 percent detriment in PFS would have been considered acceptable to define noninferiority). SOX was statistically noninferior to standard CAPOX in terms of PFS (HR 0.79, 95% CI 0.6-1.04), and demonstrated a significantly higher response rate (48 versus 36 percent), but more grade 3 or 4 neutropenia, thrombocytopenia, and diarrhea.
S-1 plus oxaliplatin (SOX) in combination with bevacizumab was compared to mFOLFOX6 plus bevacizumab (table 7) in the randomized SOFT study of 512 Japanese patients with previously untreated mCRC. SOX plus bevacizumab was noninferior to FOLFOX/bevacizumab (median PFS 11.5 versus 11.7 months) and objective response rates were similar (61 versus 62 percent) .
Taken together, these data support the view that SOX represents an acceptable first-line chemotherapy regimen for mCRC, at least for Asian patients.
Oxaliplatin after irinotecan failure — The benefit of oxaliplatin-based therapy in patients failing an initial irinotecan-based regimen was addressed in four multicenter trials:
●In an early crossover trial, the response rate with FOLFOX6 in patients failing initial FOLFIRI was 15 percent, and the PFS was 4.2 months .
●The largest trial, conducted in the United States and Canada, randomly allocated 812 irinotecan-refractory patients to one of three different treatment groups [89,112]:
•Oxaliplatin alone (85 mg/m2 every two weeks).
•The de Gramont FU/LV regimen (leucovorin 200 mg/m2 over two hours, followed by FU [bolus 400 mg/m2 and a 22-hour infusion of 600 mg/m2 per day], days one and two every two weeks
•The combination (FOLFOX4) (table 1).
In the latest report, the objective response rate with FOLFOX4 was significantly higher than with either oxaliplatin alone or FU/LV (9.6 versus 1.1 and 0.7 percent, respectively) . Median TTP was also significantly longer with FOLFOX4 as compared to FU/LV (4.2 versus 2.1 months), and more patients had symptomatic benefit (28 versus 15 percent). Median overall survival was similar (9.8 versus 8.7 months). The higher frequency of grade 3 or 4 toxicity with FOLFOX4 (ie, diarrhea, nausea, vomiting, neutropenia) did not translate into a higher rate of treatment discontinuation or mortality [89,112].
●Similar results were noted in a United States trial, in which 214 patients failing sequential FU and irinotecan monotherapy were randomized to the de Gramont regimen of FU/LV or FOLFOX4 . Patients treated with FOLFOX4 had a higher response rate (13 versus 2 percent) and TTP (4.8 versus 2.4 months), but similar survival.
●Second-line FOLFOX4 was directly compared to XELOX (oxaliplatin 130 mg/m2 over 30 minutes on day one every three weeks plus capecitabine 1000 mg/m2 orally twice daily on days 1 to 14) in a phase III trial of 627 patients failing initial FU/irinotecan . Results with XELOX were not inferior to FOLFOX4 in terms of response rates, TTP, or median overall survival (12.5 and 11.9 months for FOLFOX and XELOX). Toxicity profiles were also comparable, with the exception of fewer grade 3 or 4 neutropenia (5 versus 35 percent), and more grade 3 or 4 diarrhea (19 versus 5 percent) and hand-foot syndrome (4 versus <1 percent) with XELOX. (See 'Capecitabine plus oxaliplatin' above.)
In the United States, oxaliplatin is approved in combination with infusional FU/LV (FOLFOX4) for patients who recur or progress during or within six months of completion of first-line irinotecan-based therapy. Capecitabine/oxaliplatin could be considered in patients who desire to avoid a central venous line ambulatory infusion pump, although increasingly, oxaliplatin is being administered through a central line because of pain with peripheral vein administration. The contribution of bevacizumab to the efficacy of oxaliplatin/fluoropyrimidine regimens is discussed below.
Toxicity — The toxicity of oxaliplatin and FU-based combination regimens is dependent both on the oxaliplatin dose and the schedule of FU/LV. As previously noted, in the INT 9741 trial, treatment-related toxicity rates were acceptable in the group treated with FOLFOX4 (85 mg/m2 oxaliplatin), while they were unacceptable with oxaliplatin 130 mg/m2 plus bolus FU/LV. (See 'First-line oxaliplatin plus FU/LV' above.) .
Others report less toxicity when smaller doses of biweekly oxaliplatin (85 mg/m2) are combined with weekly bolus FU/LV . However, a randomized trial comparing this regimen to FOLFOX4 has not been performed.
The relationship between oxaliplatin dose, efficacy, and toxicity was evaluated in a pooled summary of phase II studies in which different oxaliplatin doses (80 to 100 mg/m2) were added to every two week FU plus LV . A total of 47 patients received low-dose intensity oxaliplatin (≤85 mg/m2 per two weeks) while 79 received high-dose intensity (>85 mg/m2 every two weeks) therapy. Higher doses were associated with a higher objective response rate (39 versus 19 percent), and a greater chance of six-month PFS (52 versus 36 percent). The higher-dose intensity was not associated with an increase in severe neurotoxicity or GI toxicity.
However, these were retrospective comparisons that did not take into account the heterogeneity of patients treated with the different regimens, leaving open the question of whether dose intensity does make a difference in efficacy when oxaliplatin is combined with FU and LV. A role for intensifying the oxaliplatin dose above 85 mg/m2 every two weeks has not been established in prospective studies.
Neurotoxicity — The major dose-limiting toxicity with oxaliplatin is neurotoxicity. There are two distinct syndromes (see "Overview of neurologic complications of platinum-based chemotherapy", section on 'Clinical manifestations'):
●A reversible cumulative sensory neuropathy, with distal sensory loss and dysesthesias. The incidence of grade 3 neuropathy with cumulative doses of 850 mg/m2 is 10 to 15 percent, and rises thereafter.
●An acute neurosensory complex, which consists of striking paresthesias and dysesthesias of the hands, feet, and perioral region, jaw tightness, and unusual pharyngo-laryngo-dysesthesias. Patients need to be warned not to drink cold fluids in the days around their oxaliplatin infusions. Lengthening the infusion duration from two to six hours can prevent recurrence of the pseudolaryngospasm. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Lengthened infusion duration'.)
Whether long-term neurotoxicity can be mitigated by intermittent oxaliplatin-free intervals has been addressed in multiple randomized trials. Taken together, the results suggest that in responding patients, a full break in therapy is associated with inferior outcomes and it is not routinely recommended. On the other hand, when FOLFOX with or without bevacizumab is used for first-line therapy, the available data suggest that it is reasonable to discontinue oxaliplatin temporarily while maintaining a fluoropyrimidine plus bevacizumab. Options for prevention of oxaliplatin-induced peripheral neuropathy and the design and results of trials of intermittent oxaliplatin-free therapy are discussed in more detail elsewhere. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Patients treated with oxaliplatin' and "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Oxaliplatin'.)
Infusion reactions — Acute infusion reactions, characterized by rash, fever, and ocular and respiratory symptoms of varying severity, have been reported in up to 25 percent of patients treated with oxaliplatin. Patients with mild reactions can continue to be treated with oxaliplatin by premedication with diphenhydramine and steroids, and by lengthening the infusion duration and/or decreasing the dose. (See "Infusion reactions to systemic chemotherapy", section on 'Oxaliplatin'.)
OXALIPLATIN PLUS IRINOTECAN — In an attempt to improve on current therapy, combinations of oxaliplatin and irinotecan with and without fluorouracil/leucovorin (FU/LV) have been studied, both as first-line and second-line therapy. Regimens that contain both irinotecan and oxaliplatin with or without bevacizumab have not yet replaced standard doublet regimens, such as FOLFOX or FOLFIRI with or without bevacizumab, as a standard approach for first-line therapy or salvage treatment after failure of an irinotecan- or oxaliplatin-based regimen. Toxicity is greater than with a two-drug chemotherapy backbone with or without bevacizumab, and similar and slightly better survival durations have been reported with FOLFOX and FOLFIRI when two chemotherapy drugs were paired with a biologic. (See 'Bevacizumab versus an EGFR agent with first-line chemotherapy backbone' below.)
However, a first-line triplet regimen, such as FOLFOXIRI (table 8), with or without bevacizumab may be considered for selected patients for whom a more aggressive first-line approach is chosen (eg, younger age, high tumor burden, particularly if symptomatic, RAS mutation, BRAF mutation). There are, as yet, no data on the efficacy of FOLFOXIRI plus an anti-epidermal growth factor receptor (EGFR) agent. Irinotecan plus oxaliplatin (IROX) could also be considered in the unusual case of a patient with severe dihydropyrimidine dehydrogenase (DPD) deficiency. This approach should be used cautiously in older patients . (See "Enterotoxicity of chemotherapeutic agents".)
First-line IROX and FOLFOXIRI — A number of trials are evaluating the best method of combining irinotecan and oxaliplatin, with or without FU/LV for first-line therapy [60,117-123]; however, few data are available to answer the question as to whether this approach is superior to other irinotecan or oxaliplatin-based regimens.
The irinotecan plus oxaliplatin (IROX) regimen was inferior to first-line FOLFOX4 in United States Intergroup (INT) trial 9741, and it was more toxic in elderly individuals . (See 'Oxaliplatin/FU/LV versus irinotecan/FU/LV' above.)
Similarly, a report of the FIRE trial (IROX versus FOLFIRI as first-line treatment of colorectal [CRC]) suggested that the regimens had similar efficacy (objective response rate 41 percent with both regimens, median survival 22 and 19 months for FOLFIRI and IROX, respectively) .
High rates of successful resection and favorable long-term survival rates for patients with initially unresectable liver metastases have been reported for the FOLFOXIRI (leucovorin, FU, oxaliplatin, and irinotecan, (table 8)) regimen with and without bevacizumab [125-128]. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Conversion therapy for initially unresectable metastases' and "Treatment protocols for small and large bowel cancer".)
However, whether results with FOLFOXIRI are better than can be achieved with irinotecan/FU/LV or FOLFOX alone is unclear; the following data are available:
●Two phase III trials comparing FOLFOXIRI with the Douillard irinotecan/FU/LV regimen (table 1) have come to opposite conclusions, while a third phase III trial comparing FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab suggests superiority for FOLFOXIRI in terms of response rate and progression-free survival (PFS), but comparable rates of subsequent complete resection of liver metastases:
•An Italian trial comparing a six-month course of FOLFOXIRI versus FOLFIRI suggests significantly better outcomes with FOLFOXIRI [121,123]. Benefits of a six-month course of FOLFOXIRI included a significantly higher response rate (the primary end point, 66 versus 41 percent), and a greater number of patients able to undergo complete secondary surgical resection of liver metastases (36 versus 12 percent) . In the latest report, at a median follow-up of over 60 months, FOLFOXIRI was associated with significantly longer median PFS (9.8 versus 6.8 months), and overall survival (23.4 versus 16.7 months), with a five-year survival rate of 15 versus 8 percent .
Compared with FOLFIRI, FOLFOXIRI was associated with significantly higher rates of grade 2 or 3 peripheral neuropathy (19 versus 0 percent) and of grade 3 or 4 neutropenia (50 versus 28 percent), but the incidence of febrile neutropenia (5 versus 3 percent) and of grade 3 or 4 diarrhea (20 versus 12 percent) were not significantly different . The initial administration of FOLFOXIRI did not have a negative impact on outcomes of treatment after disease progression (a second objective response to FOLFOXIRI was seen in 22 percent of patients initially treated with FOLFOXIRI ), underscoring the importance of rechallenging patients who responded to first-line treatment with the same agents used first-line. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Subsequent treatment and the continuum of care model'.)
•A second phase III trial comparing bevacizumab plus either FOLFOXIRI or FOLFIRI (the TRIBE trial) did not confirm these high rates of secondary surgical resection of liver metastases with FOLFOXIRI plus bevacizumab, although it did confirm higher response rates and a significantly longer PFS with this regimen as compared with FOLFIRI plus bevacizumab . At a median follow-up of 32.2 months, FOLFOXIRI-bevacizumab was associated with a significantly better overall response rate (65 versus 53 percent) and PFS rate (median 12.1 versus 9.7 months). In the most recent update, at 48-month median follow-up, median overall survival was significantly better with FOLFOXIRI-bevacizumab (29.8 versus 25.8 months), and estimated five-year overall survival rates were twice as high (24.9 versus 12.5 percent) . However, the rate of secondary complete (R0) resections in patients with liver metastases was not higher with FOLFOXIRI (15 versus 12 percent) . Grade 3 to 4 toxic effects that were more common with FOLFOXIRI included diarrhea (19 versus 11 percent), stomatitis (9 versus 4 percent), neutropenia (50 versus 21 percent), and peripheral neurotoxicity (5 versus 0 percent) . (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Neoadjuvant chemotherapy'.)
•In contrast to these two trials, an Hellenic Oncology group trial of 283 patients with previously untreated mCRC noted no significant benefit for FOLFOXIRI over the Douillard regimen of FU/LV/irinotecan (table 1) in terms of median overall survival (21.5 versus 19.5 months), time to tumor progression (TTP, 8.4 versus 6.9 months), or objective response rate (43 versus 34 percent) . However, the FOLFOXIRI regimen used in this trial contained smaller doses of irinotecan, oxaliplatin, and FU.
●More limited data are available comparing FOLFOXIRI to standard FOLFOX with or without bevacizumab:
•The phase III STEAM trial randomly assigned 280 patients with previously untreated mCRC to bevacizumab plus FOLFOX, or concurrent FOLFOXIRI or sequential FOLFOXIRI, which consisted of alternating courses of FOLFOX and FOLFIRI every four weeks . In a preliminary report presented at the 2016 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, the objective response rates were higher for concurrent FOLFOXIRI/bevacizumab (60 versus 47 percent for FOLFOX), median PFS was modestly but significantly better (11.7 versus 9.3, hazard ratio [HR] 0.672, 95% CI 0.489-0.922), and twice as many patients were able to undergo secondary liver resection (15.1 versus 7.4 percent). Results did not differ significantly for sequential administration of alternating FOLFOX and FOLFIRI compared to concurrent FOLFOXIRI.
•The phase II OLIVIA trial randomly assigned 80 patients with initially unresectable liver metastases from mCRC to bevacizumab plus either FOLFOX or FOLFOXIRI . Bevacizumab plus FOLFOXIRI was associated with higher objective response rates (81 versus 62 percent), higher overall and complete (R0) resection rates (61 versus 49 and 49 versus 23 percent, respectively), and a significantly longer PFS (18.6 versus 11.5 months). (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Neoadjuvant chemotherapy'.)
Second-line IROX — The utility of second-line irinotecan plus oxaliplatin (IROX) was studied in a randomized phase II trial that assigned 62 patients with FU-refractory disease to IROX or a triple regimen of FU/LV plus alternating irinotecan and oxaliplatin (FC/FO) . The IROX regimen was associated with a higher response rate (23 versus 6 percent), slightly longer median survival (12.3 versus 9.8 months), and a more favorable toxicity profile.
The clinical significance of these findings is limited in that most patients receive an oxaliplatin or irinotecan-containing regimen as first-line therapy. Others report a 39 percent response rate with oxaliplatin plus irinotecan/FU/LV (IFL) in patients failing first-line IFL . Whether these results are better than can be achieved by FOLFOX alone in this setting is unclear since randomized trials are not available.
AGENTS TARGETING VEGF — The development of a blood supply is a necessary prerequisite for tumor growth. The dominant factor controlling angiogenesis is vascular endothelial growth factor (VEGF). Inhibition of VEGF by a variety of methods produces a marked antitumor response.
First-line use — Bevacizumab (Avastin) is a humanized monoclonal antibody (MoAb) targeting VEGF. Adding bevacizumab to a variety of first-line regimens used for metastatic colorectal cancer (mCRC) improves outcomes, although only modestly. As an example, in a pooled analysis of trials comparing chemotherapy with and without bevacizumab in the first-line setting, the addition of bevacizumab was associated with a significant 19 percent reduction in the risk of death (hazard ratio [HR] for death 0.81, 95% CI 0.70-0.93), but this translated into a median overall survival advantage of only two months (19.8 versus 17.6 months) . Progression-free survival was also significantly improved (HR 0.58, 95% CI 0.46-0.73) but the advantage was also limited to approximately two months (median progression-free survival [PFS] 9.1 versus 6.9 months). These modest advances come at a cost of treatment-related side effects, including bleeding, hypertension, bowel perforation, and thromboembolic events. However, although there are these potentially serious outcomes, they are not common. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)
Irinotecan regimens — The benefit of adding bevacizumab to irinotecan was initially shown in a trial of 813 patients who were randomly assigned to irinotecan/fluorouracil (FU)/leucovorin (LV; IFL) with or without bevacizumab . Bevacizumab improved the objective response rate (45 versus 35 percent), and significantly improved time to tumor progression (TTP; 11 versus 6 months) and median survival (20 versus 16 months). Following publication of these data, bevacizumab received broad approval in the United States in combination with FU for first-line treatment of mCRC.
The above trial combined bevacizumab with bolus IFL, a regimen that has fallen out of favor due to the more favorable GI toxicity profile of regimens that contain short-term infusional FU/LV (eg, FOLFIRI) (table 1). The available data on bevacizumab plus FOLFIRI are limited and conflicting:
●In the complex BICC-C trial, patients with previously untreated mCRC were assigned to FOLFIRI, modified IFL, or capecitabine/irinotecan, all arms with or without celecoxib; a later amendment added bevacizumab to patients on the FOLFIRI and IFL arms . The median PFS was 11.2 months in the small group of 61 patients receiving bevacizumab/FOLFIRI (8.3 months for bevacizumab/IFL), and the objective response rate was 58 percent (53 percent with bevacizumab/IFL). In a later report, at a median follow-up of 34 months, median survival in the group receiving FOLFIRI/bevacizumab was 28 months while it was 19.2 months with bevacizumab/IFL .
Oxaliplatin regimens — The benefit of adding bevacizumab to a first-line oxaliplatin-based regimen is even less clear; results from randomized trials are conflicting:
●In the phase II randomized TREE-2 trial, 223 previously untreated patients were randomly assigned to bevacizumab (5 mg/kg every two weeks) and one of the three different oxaliplatin and FU-containing regimens used in the TREE 1 trial . Bevacizumab substantially improved the response rates of all of the regimens (table 6).
Median overall survival was 23.7 months for the combined groups receiving bevacizumab (versus 18.2 months for the combined non-bevacizumab-treated groups). This is one of the highest median survival values ever reported. However, bevacizumab also increased rates of grade 3 or 4 hypertension (table 6), bowel perforation (2 percent overall), impaired wound healing (n = 3) and bleeding events (45 versus 22 percent in the groups treated with FOLFOX with and without bevacizumab).
●A modest benefit for the addition of oxaliplatin was also suggested in the ECOG 3200 trial, which randomly assigned 829 patients with previously treated (with FU or irinotecan) mCRC to FOLFOX4, bevacizumab alone (10 mg/kg every two weeks) or FOLFOX4 plus bevacizumab . The bevacizumab/FOLFOX4 group had a significantly better PFS (7.3 versus 4.7 months) and median overall survival (12.9 versus 10.8 months) compared to FOLFOX4 alone, and the bevacizumab alone arm was inferior to both.
●Modest benefit for the addition of bevacizumab was also suggested in the NO 16966 trial of FOLFOX or XELOX with and without bevacizumab . There was a significant progression-free survival for the addition of bevacizumab; however, the magnitude of benefit was smaller than expected, and neither median overall survival nor response rates were significantly higher in patients who received bevacizumab (table 9). Bevacizumab-treated patients discontinued treatment more often because of toxicity than disease progression; the authors postulated that failure to continue therapy until disease progression offset the benefit of adding bevacizumab.
●On the other hand, neither a PFS nor an overall survival benefit for the addition of bevacizumab to FOLFOX4 could be shown in the phase III ITACa randomized trial . However, in our view, the results of this trial are problematic, given the heterogeneous patient populations, a second randomization after disease progression, a change in the statistical assumptions mid-trial, and the lack of information on duration of chemotherapy.
Fluoropyrimidines alone — Bevacizumab also adds benefit to first-line FU/LV and capecitabine [142-147]. In two randomized phase II trials in which previously untreated patients were assigned to bolus FU/LV with or without bevacizumab (5 or 10 mg/kg every two weeks), response rates were approximately twofold higher with bevacizumab, and median survival was extended by 7.7 and 3.7 months for the two doses, respectively [142,143].
Thus, bevacizumab is active in first-line combination with fluoropyrimidines for mCRC beyond combinations with irinotecan or oxaliplatin. For patients in whom either oxaliplatin or irinotecan need to be held because of toxicity, it is reasonable to continue the fluoropyrimidine plus bevacizumab, or even bevacizumab alone. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Duration of initial chemotherapy'.)
Second-line bevacizumab — For patients treated with a first-line bevacizumab-containing chemotherapy regimen, the use of bevacizumab beyond progression in conjunction with a second-line fluoropyrimidine-based chemotherapy regimen can be considered a standard approach. However, for patients with RAS wild-type tumors who are receiving irinotecan-based second line regimens, bevacizumab should not be used in conjunction with an anti-epidermal growth factor receptor (EGFR) antibody. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Agents targeting the EGFR' and 'Dual antibody therapy' below.)
In view of the increasing use of bevacizumab in first-line regimens, an important clinical issue is whether it should be continued in patients who switch to an alternative regimen after failing first-line bevacizumab-containing therapy. An association between survival and exposure to bevacizumab beyond first progression was suggested in an analysis of the observational BRiTE registry of 1953 patients who progressed after receiving a first-line bevacizumab-containing regimen , in a preliminary report from the ARIES observational cohort study , and from a retrospective analysis of 573 patients treated with and without second-line bevacizumab from community-based United States Oncology practices .
This issue was directly studied in two trials:
●In the European TML (ML18147) study, 820 patients with unresectable mCRC progressing within three months of receiving first-line chemotherapy with bevacizumab were randomly assigned to fluoropyrimidine-based chemotherapy with or without bevacizumab (2.5 mg/kg/week) . Continuation of bevacizumab with the second line chemotherapy regimen was associated with a significant improvement in progression-free (median 5.7 versus 4.1 months) and overall survival (median 11.2 versus 9.8 months), and bevacizumab-related adverse events were not increased compared with historical data of first-line bevacizumab treatment. Although significantly more patients achieved disease control in the bevacizumab group (68 versus 54 percent), objective response rates in both arms were low (5.4 versus 3.9 percent for bevacizumab and no bevacizumab, respectively). Based upon these results, in January 2013, the US Food and Drug Administration (FDA) approved bevacizumab for use in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin-based chemotherapy for treatment of patients with mCRC whose disease has progressed on a first-line bevacizumab-containing regimen.
●A second trial, the BEBYP trial, randomly assigned 185 patients undergoing first-line fluoropyrimidine-based chemotherapy with bevacizumab to receive second line FOLFOX or FOLFIRI with or without bevacizumab . Accrual to the trial was prematurely stopped when the results of the TML trial became known. Median PFS was significantly improved by continuation of bevacizumab with the second-line regimen (median 6.8 versus 5 months), although the differences in objective response rates to the second-line regimen (17 versus 21 percent) and disease control rates overall (58 versus 70 percent) were not statistically significant.
A different question, whether to switch to cetuximab or continue with second-line bevacizumab in patients with RAS wild-type tumors progressing on first-line bevacizumab, was addressed in the phase II PRODIGE 18 trial . In a preliminary report presented at the 2016 annual American Society of Clinical Oncology (ASCO) meeting, continuation with bevacizumab was associated with a numerically higher but not statistically significant PFS rate at four months (79 versus 67 percent, p = 0.09) and overall survival (15.9 versus 10.6 months, p = 0.08) compared to cetuximab plus chemotherapy.
Adverse effects — The benefits of bevacizumab are counterbalanced by its side effect profile, which includes serious and potentially fatal adverse events . Potentially serious side effects include proteinuria and the nephrotic syndrome, hypertension, bleeding, GI tract perforation, and arterial and possibly venous thromboembolic events:
●Intermittent urinalysis is recommended during therapy because of the risk of proteinuria and nephrotic syndrome, although elevated proteinuria only infrequently affects treatment decisions (2 percent of cases in one series ). (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Proteinuria/nephrotic syndrome'.)
●Guidelines for pretreatment assessment, monitoring, and management of elevated blood pressure in patients receiving bevacizumab are available (table 10A-B) . This subject is discussed elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Hypertension'.)
●The risk of major bleeding is approximately 2 to 3 percent. This subject is discussed in detail elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Bevacizumab and aflibercept'.)
●Bevacizumab increases the risk of arterial thromboembolic events; whether the risk of venous thromboembolic events is increased is unclear. This subject is discussed in detail elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Bevacizumab and aflibercept'.)
●Other risks are impaired surgical wound healing GI perforation and fistula formation; many cases involve perforation of an in situ bowel primary. However, surgical site complications (both perforation and fistula formation) can also occur at previously resected primary sites, often in the setting of prior irradiation or a prior anastomotic leak. Because of this risk, and the long half-life of bevacizumab (20 days), at least 28 days (preferably six to eight weeks) should elapse between surgery and last dose of bevacizumab, except in emergency situations. This topic is addressed in more detail elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Delayed wound healing' and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Intestinal perforation/fistula formation'.)
●Other rare side effects include reversible posterior leukoencephalopathy, nasal septum perforation, and jaw osteonecrosis. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Osteonecrosis of the jaw' and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Reversible posterior leukoencephalopathy and brain capillary leak syndrome' and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Nasal septal perforation'.)
Aflibercept — Intravenous aflibercept (VEGF Trap, Zaltrap) is a recombinant fusion protein consisting of VEGF binding portions from key domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1. It functions as a decoy receptor that prevents intravascular and extravascular VEGF-A, VEGF-B, and PlGF (placenta growth factor) from binding to their receptors. In cell-free systems, this molecule binds with higher affinity to VEGF-A than does bevacizumab .
Aflibercept is approved in the United States for use in combination with FOLFIRI for the treatment of patients with mCRC that is resistant to or has progressed following an oxaliplatin-containing regimen. Approval was based on the placebo-controlled VELOUR trial, in which 1226 patients with mCRC that had progressed during or within six months of receiving oxaliplatin-containing chemotherapy with or without bevacizumab were randomly assigned to FOLFIRI with aflibercept (4 mg/kg IV) or placebo, every two weeks until progression. The aflibercept was administered over one hour prior to FOLFIRI. Median overall survival was significantly longer in patients treated with aflibercept (13.5 versus 12.1 months) as was median PFS (6.9 versus 4.7 months) . Treatment benefit was similar regardless of prior bevacizumab exposure .
Grade 3 to 4 adverse events were reported in 84 percent of patients treated with aflibercept versus 63 percent of those receiving FOLFIRI alone. Among the grade 3 or 4 toxicities that were more frequent with aflibercept were hypertension (19.3 versus 1.5 percent), proteinuria (7.9 versus 1.2 percent), hemorrhage (2.9 versus 1.7 percent), arterial thromboembolic events (1.8 versus 0.5 percent), and venous thromboembolic events (7.9 versus 6.3 percent). While the side effect profile of aflibercept plus FOLFIRI was consistent with other agents targeting VEGF (bleeding, hypertension, proteinuria, wound infection, arterial thromboembolic events), rates of grade 3 or 4 diarrhea (19.3 versus 7.8 percent), mucositis (13.7 versus 5 percent), complicated neutropenia (5.7 versus 2.8 percent), infection (12.3 versus 6.9 percent), and fatigue/asthenia (16.9 versus 10.6 percent) associated with aflibercept in this trial were higher than usually seen with bevacizumab, as were rates of treatment discontinuation for toxicity (27 versus 12 percent with FOLFIRI alone).
Particularly given the data on benefit from bevacizumab after progression on a first-line bevacizumab-containing regimen, whether aflibercept plus second-line FOLFIRI is the preferred approach after progression on first-line FOLFOX plus bevacizumab is unclear. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Aflibercept'.)
Adding aflibercept to first-line oxaliplatin-containing therapy does not increase efficacy and is associated with higher toxicity. This was shown in the AFFIRM study in which 236 patients with mCRC were randomly assigned to first-line FOLFOX6 with or without aflibercept . Adding aflibercept to FOLFOX was associated with higher rates of grade 3 or 4 diarrhea, neutropenia, hypertension, and deep vein thrombosis and did not prolong median PFS (8.5 versus 8.8 months).
As with bevacizumab, because of the risk of impaired wound healing, bowel perforation, and fistula formation, at least 28 days should elapse between major surgery and administration of aflibercept, except in emergency situations. This recommendation does not apply to minor procedures such as implantation of a venous access device. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Delayed wound healing' and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Aflibercept'.)
Ramucirumab — Ramucirumab is a recombinant monoclonal antibody of the IgG1 class that binds to the VEGFR-2, blocking receptor activation. The efficacy of ramucirumab for second-line treatment of mCRC was addressed in the double blind phase III RAISE trial in which 1072 patients with progressing after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine were randomly assigned to FOLFIRI with ramucirumab (8 mg/kg IV every two weeks) or placebo until disease progression, unacceptable toxicity, or death . Median survival was modestly but significantly greater with ramucirumab (13.3 versus 11.7 months), as was median progression-free survival (5.7 versus 4.5 months). Objective response rates were comparable in the two arms. Grade 3 or worse side effects that were more prominent with ramucirumab included neutropenia (38 versus 23 percent), hypertension (11 versus 3 percent), and fatigue (12 versus 8 percent).
Based upon these results, ramucirumab was approved in April 2015 for use in combination with irinotecan plus leucovorin and short-term infusional fluorouracil (FOLFIRI) for the treatment of metastatic colorectal cancer in patients whose disease has progressed on a first-line bevacizumab, oxaliplatin, and fluoropyrimidine-containing regimen . However, given this modest degree of benefit, the expense of this agent , and the competing data indicating benefit from continuation of second-line bevacizumab in this same setting, we do not consider ramucirumab the agent of choice if continued VEGF inhibition beyond first-line progression is considered. (See 'Second-line bevacizumab' above.)
AGENTS TARGETING THE EGFR — Growth factors such as epidermal growth factor (EGF) and its receptor (EGFR) may be involved in autocrine or paracrine control of colorectal cancer (CRC) cell growth, or in the development of angiogenesis or metastases [164-166]. Two monoclonal antibodies (MoAbs) targeting the EGFR are active for treatment of metastatic CRC (mCRC), cetuximab (Erbitux), and panitumumab (Vectibix).
It is now well-established that biomarker analysis is critical to patient selection for therapy with an EGFR inhibitor. Both cetuximab and panitumumab are only effective in the subset of patients whose tumors have wild-type (WT) and not mutated RAS (NRAS, KRAS) oncogenes (approximately 40 percent of all mCRCs). A Provisional Clinical Opinion issued by the American Society of Clinical Oncology (ASCO) recommends that all patients being considered for anti-EGFR therapy undergo testing of their tumors for mutations in KRAS and NRAS exons 2, 3, and 4, and that treatment with these agents be restricted to those with WT RAS tumors . (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Extended RAS testing'.)
In addition, the BRAF V600E mutation also makes response to panitumumab or cetuximab, as single agents or in combination with cytotoxic chemotherapy, highly unlikely. Whether this resistance can be overcome with concurrent use of a BRAF V600E inhibitor, such as vemurafenib, is an active area of investigation. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'BRAF'.)
Cetuximab — Cetuximab, a mouse/human chimeric MoAb, binds to the EGFR of both tumor and normal cells, competitively inhibiting ligand binding, and inducing receptor dimerization and internalization. It is unclear whether these actions represent the mechanism of antitumor action. Cetuximab is useful in combination with irinotecan for patients with WT RAS tumors who are refractory to irinotecan and as a single agent for those who are intolerant of irinotecan-based chemotherapy. The approved dosing regimen is weekly, although at least some data support the safety and efficacy of every other week dosing. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Are cetuximab and panitumumab interchangeable?'.)
Monotherapy — Cetuximab monotherapy was compared to best supportive care (BSC) in a randomized trial of 572 patients who had failed or were intolerant of all recommended therapies . Median overall survival was significantly better with cetuximab (6.1 versus 4.6 months), as were measures of HR-QOL, including physical function and global health scores.
In a subsequent reanalysis, the benefits of cetuximab were restricted to patients whose tumors lacked a KRAS mutation [169,170]. Among patients with mutated KRAS, there was no significant difference between cetuximab and BSC in terms of overall or progression-free survival (PFS), or quality of life. More data support the view that exclusion of patients with all RAS mutations and not only those limited to exon 2 of KRAS identifies a population that is most likely to benefit from therapy with cetuximab. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Extended RAS testing'.)
Plus irinotecan — The possibility that cetuximab might reverse irinotecan resistance was initially suggested in a study of 138 patients with irinotecan-refractory CRC who received irinotecan at the same schedule as previously administered (350 mg/m2 every three weeks or 125 mg/m2 weekly for four of every six weeks) plus cetuximab . The trial was only reported as an abstract, but 15 percent had a partial response, and the median time to tumor progression (TTP) was 6.5 months.
Benefit for combined therapy has also been shown in the following trials:
●The EPIC trial randomly assigned 1298 oxaliplatin-refractory patients to irinotecan with or without cetuximab . PFS was significantly higher with combined therapy (median 4 versus 2.6 months), as were rates of objective response (16 versus 4 percent) and overall disease control (61 versus 46 percent). While median survival was not significantly different (10.7 versus 10 months), one-half of the patients receiving irinotecan alone subsequently received cetuximab after progression, potentially obscuring a survival difference. Despite more skin rash (76 versus 5 percent), grade 3 or 4 diarrhea (28 versus 16 percent), and fatigue (8 versus 3 percent), QOL assessments favored combined therapy.
●The BOND trial compared irinotecan (350 mg/m2 every three weeks, 180 mg/m2 every two weeks, or 125 mg/m2 weekly for four of every six weeks) plus weekly cetuximab versus cetuximab alone in 329 patients with irinotecan-refractory mCRC . Combined therapy was associated with a significantly better response rate (23 versus 11 percent) and TTP (4.1 versus 1.5 months) but only a trend towards better median survival (8.6 versus 6.9 months).
●First-line cetuximab was explored in the CRYSTAL trial, in which 1198 patients with previously untreated mCRC were randomly assigned to FOLFIRI (irinotecan plus leucovorin [LV] and short-term infusional fluorouracil [FU]) with or without cetuximab . Median PFS was modestly but significantly better with cetuximab (8.9 versus 8 months), as was the overall response rate (47 versus 39 percent), but this did not translate into a significant overall survival benefit. However, in a later report, among patients with WT KRAS, response rates were significantly higher in those who received cetuximab in conjunction with chemotherapy (57 versus 40 percent), as was median PFS and overall survival (median 23.5 versus 20 months) .
Perhaps more importantly, patients receiving cetuximab had significantly higher rates of surgery for metastases (7 versus 3.7 percent) and a higher rate of complete (R0) resection with curative intent before disease progression (4.8 versus 1.7 percent). (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Choice of regimen'.)
Adverse effects that were more frequent with cetuximab were grade 3 or 4 diarrhea (16 versus 11 percent), skin toxicity (19.7 versus 0.2 percent), and infusion reactions (2.5 versus zero percent). (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Cetuximab'.)
Plus oxaliplatin — Although an early trial suggested that cetuximab also seems to restore sensitivity to oxaliplatin-based chemotherapy regimens that contain an infusional fluoropyrimidine , the results of randomized trials have been mixed [177-181]:
●The multicenter European phase II OPUS trial compared weekly cetuximab plus FOLFOX4 versus FOLFOX 4 alone (table 1) . Combined therapy was associated with a significantly higher response rate (57 versus 34 percent), and a significant 43 percent prolongation in time to disease progression (hazard ratio [HR] 0.57, median 8.3 versus 7.2 months), but only a trend toward improved survival (median 22.8 versus 18.5 months, p = 0.39) when the analysis was restricted to patients with WT KRAS tumors.
As was seen in the CRYSTAL trial, the addition of cetuximab to an oxaliplatin-based regimen in the OPUS trial also resulted in an enhanced ability for patients to undergo R0 surgical resection. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Choice of regimen'.)
●The CALGB 80203 trial of first-line cetuximab plus either FOLFIRI or FOLFOX (oxaliplatin plus short-term infusional FU and LV) was closed early when data on the benefits of bevacizumab became available, with 238 patients accrued to one of four arms (FOLFOX with and without cetuximab, FOLFIRI with and without cetuximab) . In a preliminary report, response rates were similar with FOLFOX and FOLFIRI (40 versus 36 percent), and in each case, they were significantly higher with the addition of cetuximab (60 versus 44 percent). Data were not available regarding the impact of adding cetuximab to either regimen on PFS or overall survival. Results from this trial have not yet been published.
●Similarly, in a preliminary report of CALGB 80405, first-line FOLFOX plus cetuximab was not inferior to FOLFOX plus bevacizumab, and it was, in fact, superior to FOLFOX plus bevacizumab in patients with RAS WT left-sided primary tumors . (See 'Bevacizumab versus an EGFR agent with first-line chemotherapy backbone' below.)
•United Kingdom MRC COIN trial, which compared first-line FOLFOX/CAPOX with or without cetuximab in 1630 patients with mCRC, demonstrated a modest improvement in response rate from the addition of cetuximab in the 729 patients with KRAS WT tumors (64 versus 57 percent), but there was no significant improvement in PFS (8.6 months in both groups) .
•Likewise, the NORDIC VII trial indicated a lack of benefit from the addition of cetuximab to a bolus FU/LV/oxaliplatin (FLOX) regimen in 571 patients with mCRC, even when the 348 patients with KRAS WT tumors were analyzed separately . These and other data support the view that the addition of anti-EGFR antibodies to oxaliplatin-based regimens in which non-infusional fluoropyrimidines were used has not resulted in benefit .
•The randomized New EPOC trial of FOLFOX with or without cetuximab for patients with potentially resectable isolated CRC liver metastases suggested an inferior outcome with the addition of cetuximab .
The advisability of combining cetuximab with an oxaliplatin-based regimen in patients with CRC liver metastases continues to be debated, with disparate results from published trials:
●The randomized phase II CELIM trial of cetuximab plus either FOLFIRI or FOLFOX in patients with initially unresectable CRC liver metastases showed that the chemotherapy backbone did not matter .
●On the other hand, as noted above, the randomized New EPOC trial of FOLFOX with or without cetuximab for patients with potentially resectable isolated CRC liver metastases suggested an inferior outcome with the addition of cetuximab .
One possible explanation might be the influence of primary tumor location on benefit from an anti-EGFR agent in patients with RAS/BRAF WT tumors, as was suggested in CALGB 80405 and by others . This subject is discussed in detail below and elsewhere. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Regimen choice' and "Management of potentially resectable colorectal cancer liver metastases", section on 'Choice of regimen'.)
Thus, in contrast to irinotecan-based regimens, the benefit of adding cetuximab to a first-line oxaliplatin-based regimen is less certain. However, in our view, it is reasonable to combine cetuximab with an oxaliplatin-based regimen given the totality of the evidence of benefit, particularly for left-sided tumors that are WT for RAS and BRAF. (See 'Bevacizumab versus an EGFR agent with first-line chemotherapy backbone' below.)
Panitumumab — Panitumumab (Vectibix) is a fully human MoAb specific for the extracellular domain of EGFR. The benefit of panitumumab monotherapy was initially shown in a multicenter trial in which 463 patients refractory to FU, irinotecan, and oxaliplatin were randomly assigned to best supportive care (BSC) with or without panitumumab (6 mg/kg every two weeks) . The objective response rate with panitumumab was 10 percent, and 27 percent had stable disease; the corresponding rates with BSC alone were 0 and 10 percent. Patients receiving panitumumab were significantly more likely to be alive and progression-free at eight weeks (49 versus 30 percent). The lack of a survival difference was likely due to panitumumab use after crossover in the BSC group .
In a later reanalysis, efficacy was limited to patients whose tumors were WT for KRAS exon 2 (partial response and stable disease in 17 and 34 percent, respectively, versus zero and 12 percent with mutated KRAS) . Adverse effects that were significantly more frequent with panitumumab were skin toxicity (90 versus 9 percent in the BSC group), diarrhea (21 versus 11 percent), abdominal pain (23 versus 17 percent), fatigue (24 versus 15 percent), and nausea (22 versus 15 percent).
Others have confirmed a more pronounced effect in patients with WT RAS tumors beyond KRAS exon 2 . (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Extended RAS testing'.)
Based upon the phase III ASPECCT trial, efficacy appears to be similar to cetuximab monotherapy [192,193], and the two drugs might be interchangeable as single agents in this setting. Whether panitumumab is of benefit in patients who are refractory to cetuximab is unclear; this subject is addressed elsewhere. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Panitumumab after failure of cetuximab'.)
Panitumumab combinations — There are increasing data supporting the efficacy of first, second, and third-line panitumumab in combination with oxaliplatin- or irinotecan-based regimens in patients with WT RAS tumors [194-202].
A progression-free survival benefit for adding panitumumab to a first-line oxaliplatin-based regimen (FOLFOX) was shown in the phase III PRIME trial (median PFS 9.6 versus 8 months) ; the overall survival benefit, while potentially clinically meaningful, was not statistically significant with median follow-up of 55 weeks (23.9 versus 19.7 months, HR 0.88, 95% CI 0.73-1.06) but the difference achieved statistical significance in a later exploratory analysis of updated survival at median follow-up 80 weeks (HR for death 0.83, 95% CI 0.70-0.98) . Survival was impaired in patients with exon 2 KRAS mutant mCRC who were treated with panitumumab plus FOLFOX, a finding that has been noted in other trials testing the addition of panitumumab (and cetuximab) to oxaliplatin-containing chemotherapy. Furthermore, a later analysis of data from this trial, 108 patients (17 percent) without KRAS mutations in exon 2 had other RAS mutations in KRAS exons 3 and 4 and in NRAS exons 2, 3, and 4 . These additional mutations predicted a lack of response to panitumumab, and in fact, their presence was associated with inferior progression-free and overall survival in patients receiving panitumumab plus FOLFOX compared with FOLFOX alone. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Extended RAS testing'.)
In the US Food and Drug Administration (FDA)-approved manufacturer's product labeling, panitumumab is indicated as a first-line therapy in combination with FOLFOX, but not with irinotecan-containing or bevacizumab-containing regimens. We consider that combinations of panitumumab with either an irinotecan or oxaliplatin-based regimen are acceptable and safe for patients with RAS WT tumors. However, we avoid combining either cetuximab or panitumumab with a bevacizumab-containing regimen, an approach that is supported by NCCN guidelines. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Benefit of cetuximab and panitumumab' and 'Dual antibody therapy' below.)
Influence of tumor sidedness — Accumulating data suggest that among patients with RAS WT mCRC, the site of the primary tumor might be prognostic as well as predictive of benefit from EGFR-targeted therapies [183,186,205,206]. The following data are available:
●A survival advantage of first-line cetuximab over bevacizumab could not be shown in the large United States Intergroup trial 80405, in which 1137 patients with KRAS exon 2 WT mCRC were randomly assigned to cetuximab or bevacizumab with either FOLFOX or FOLFIRI (dealer's choice) . An intriguing retrospective re-analysis of data from this trial suggests that the site of the primary tumor may impact benefit from first-line cetuximab versus bevacizumab in patients with RAS WT tumors . Among patients with left-sided tumors, cetuximab provided superior median overall survival, while bevacizumab was superior to cetuximab when the primary tumor was on the right side. A similar result was noted in a retrospective analysis of data from the FIRE-3 and CRYSTAL trials (table 11) .
●A pooled retrospective analysis of data from six randomized trials of patients with RAS WT mCRC treated with chemotherapy and first-line EGFR-directed antibodies showed that a significant benefit for chemotherapy plus an EGFR antibody was observed in patients with left-sided tumors (HR for death 0.75, 95% CI 0.67-0.84) but not right-sided tumors (HR 1.12, 95% CI 0.87-1.45) .
Based upon these data, if a biologic agent is chosen for first-line chemotherapy of RAS/BRAF WT mCRC, we suggest bevacizumab rather than an anti-EGFR agent for patients with a right-sided primary tumor. However, we would allow use of these agents in later lines of therapy. Patients with RAS and BRAF WT right-sided tumors who have a contraindication to bevacizumab might also be considered candidates for anti-EGFR-based rather than bevacizumab-based initial therapy. On the other hand, for first-line therapy of RAS/BRAF WT mCRC with a left-sided primary, an anti-EGFR antibody is preferred over bevacizumab. This subject is discussed in more detail below. (See 'Bevacizumab versus an EGFR agent with first-line chemotherapy backbone' below.)
Adverse effects — The most common adverse effects associated with cetuximab and panitumumab are weakness, malaise, an acneiform rash, nausea, electrolyte disorders, and with cetuximab, infusion reactions.
Infusion reactions — Infusion reactions occur in up to 25 percent of patients treated with cetuximab, and rates are highest in some areas of the middle southeastern United States . Most reactions are severe, and 90 percent occur after the first infusion, most within three hours. Premedication with an H1 receptor antagonist is recommended, and drug infusion should not exceed 5 mL/minute. In addition, benefit from premedication with a glucocorticoid in addition to an antihistamine was shown in a report from the MABEL (Monoclonal Antibody Erbitux in A European Pre-Licensure) registry database of over 1000 patients treated with cetuximab plus irinotecan for mCRC . Rates of any infusion reaction were significantly lower among those pretreated with an antihistamine plus a glucocorticoid as compared to an antihistamine alone (7.1 versus 22 percent) and for grade 3 or 4 reactions (1 versus 4.7 percent).
In practice, most patients receiving cetuximab are also receiving irinotecan, for which premedication with both a glucocorticoid and antihistamine is recommended. For patients receiving cetuximab alone, pretreatment with an antihistamine alone is acceptable, although the addition of a glucocorticoid is reasonable for those who reside or have resided in high-risk locations.
For patients who develop a severe reaction despite premedication, and for whom continued use of cetuximab is thought to be clinically important, desensitization can be attempted and protocols have been published. Another alternative is a switch to panitumumab. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Cetuximab'.)
The risk of infusion reactions with panitumumab is lower than with cetuximab (4 percent overall, with 1 percent severe). Given the low rates of infusion reactions, routine premedication is not recommended prior to panitumumab infusion. The lower rate of infusion reactions provides a rationale for choosing panitumumab over cetuximab, particularly in high-risk geographic regions such as the middle southeastern United States. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Panitumumab'.)
The most common side effect is an acneiform type rash (picture 1), which occurs in up to two-thirds of treated patients. (See "Cutaneous side effects of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Acneiform eruption'.)
However, rash severity appears to correlate with better outcomes [210-212]. A report from the EVEREST trial suggests that cetuximab dose escalation (by 50 mg/m2 every two weeks, up to 500 mg/m2 weekly) is safe and increases response rates in patients who have no or a mild skin reaction within three weeks of starting therapy . The response rate among patients with ≤grade 1 skin toxicity (table 13) who were randomized to dose escalation was 30 versus 16 percent in a concurrently randomized group continuing standard dose therapy, and there was also an improvement in disease control rate (70 versus 58 percent), but no indication of improved overall survival. Thus, the clinical benefit of intrapatient cetuximab dose escalation according to grade of early skin reactions remains uncertain.
Grading of the severity of the acneiform eruption that is most typical of this class of agents, management of cutaneous toxicity, and the use of prophylactic systemic antibiotics are addressed in detail elsewhere. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) inhibitors".)
Another common cutaneous adverse effect is pruritus, which is particularly common in patients treated with panitumumab. In a systemic review, the incidence of any grade pruritus was 55 percent with panitumumab (2.6 percent high-grade) and 18 percent with cetuximab (2.1 percent severe) . Management includes patient education and topical agents (emollients, corticosteroids, anesthetics, capsaicin, menthol); for highly symptomatic patients, oral agents such as antihistamines, anticonvulsants, antidepressants, and possibly aprepitant may be helpful. An overview of management of pruritus is presented elsewhere. (See "Pruritus: Overview of management".)
Multiple different ocular toxicities are reported with cetuximab, including corneal erosions, eyelash trichomegaly, and keratitis (inflammation of the cornea). Ocular toxicities associated with panitumumab include conjunctival hyperemia, epiphora (excess tearing), and eyelid irritation. Both drugs can be associated with conjunctivitis, dry eye, corneal epithelial defects, and periocular skin changes, such as edema, erythema, blepharitis, and cicatricial changes (eg, ectropion), which can lead to poor eyelid closure and exposure keratopathy. (See "Ocular side effects of systemically administered chemotherapy", section on 'Epidermal growth factor receptor (EGFR) inhibitor'.)
Electrolyte disorders — Cetuximab and panitumumab cause a magnesium-wasting syndrome, which, in one report, affected 22 percent of 154 patients treated with cetuximab [215,216]. Hypomagnesemia may be more prominent in patients receiving concomitant treatment with oxaliplatin . In addition, hypokalemia is also reported (incidence 8 percent in a meta-analysis of patients treated with cetuximab ). Hypomagnesemia may lead to secondary hypocalcemia. Serum levels of magnesium, potassium, and calcium should be monitored periodically during and for at least eight weeks following therapy. (See "Chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency: Molecularly targeted agents", section on 'Anti-EGFR monoclonal antibodies' and "Clinical manifestations of magnesium depletion", section on 'Calcium metabolism'.)
Venous thromboembolism — A meta-analysis concluded that the use of monoclonal antibodies targeting the EGFR was associated with a statistically significant increase in the risk of venous thromboembolism (VTE; RR 1.34, 95% CI 1.07-1.68), but not arterial thromboembolism (RR 1.38, 95% CI 0.76-2.51) . (See "Drug-induced thrombosis in patients with malignancy", section on 'Antiangiogenic agents and growth factor inhibitors'.)
Other agents — The orally active small molecule EGFR inhibitors erlotinib and gefitinib are inactive by themselves [220,221]. Favorable results have been reported in phase II trials of erlotinib with capecitabine and oxaliplatin in previously treated patients  and with gefitinib plus FOLFOX [223,224]. To know whether these results are better than with oxaliplatin-based therapy alone will require randomized trials.
A preliminary report suggests promise for dual targeting of the EGFR using a combination of cetuximab and erlotinib , but randomized trials will be needed to ascertain whether this represents an advance over cetuximab alone.
Preliminary data on the antitumor efficacy of targeting human epidermal growth factor receptor 2 (HER2) using specific agents that block HER2 in patients with mCRC is presented below.
BEVACIZUMAB VERSUS AN EGFR AGENT WITH FIRST-LINE CHEMOTHERAPY BACKBONE — As noted above, the benefit of adding cetuximab or panitumumab to first-line chemotherapy has been shown in several trials. (See 'Plus irinotecan' above and 'Plus oxaliplatin' above and 'Panitumumab combinations' above.)
Among patients receiving FOLFOX (oxaliplatin plus short-term infusional fluorouracil and leucovorin) or FOLFIRI (irinotecan plus leucovorin and short-term infusional fluorouracil) for first-line therapy who have RAS and BRAF wild type (WT) tumors, a reasonable question is whether it is more beneficial to add bevacizumab or an epidermal growth factor receptor (EGFR)-targeted agent to the chemotherapy backbone. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Extended RAS testing'.)
Accumulating data suggest that the site of the primary tumor might be predictive of benefit from anti-EGFR therapies:
●In the FIRE-3 trial, 735 patients with previously untreated metastatic colorectal cancer (CRC) were randomly assigned to FOLFIRI with either bevacizumab (5 mg/kg every two weeks) or cetuximab (400 mg/m2 on day one followed by a weekly dose of 250 mg/m2). The protocol was amended in 2008 to include only patients with KRAS WT tumors. In a report of the 592 patients with KRAS WT tumors (the intent to treat population), objective response rates were not significantly different when the entire population was considered (62 versus 58 percent with cetuximab and bevacizumab, respectively) . Although median progression-free survival (PFS) was nearly identical (10.0 versus 10.3 months), median overall survival was significantly longer with cetuximab (28.7 versus 25 months, hazard ratio [HR] 0.77, 95% CI 0.62-0.96). There was more grade 1/2 nausea and vomiting, hypertension, abscesses, and bleeding with bevacizumab, and more grade 1/2 hypocalcemia, and grade 3/4 skin toxicity, paronychia, allergic infusion reactions, and hypomagnesemia with cetuximab.
The details of therapy administered to patients beyond the first-line treatment specified in the study have not been elucidated. Since patients were on protocol-specified therapy for five months and the survival curves did not diverge until 24 months, these details are highly important to understanding the difference in overall survival when there was no difference in recurrence rate (RR) or PFS between the treatment arms.
Exclusion of patients with all RAS mutations seems to identify a population that is more likely to benefit from therapy with an anti-EGFR agent. In a later analysis of 400 patients who had WT RAS status in KRAS exons 2, 3, and 4 and NRAS exons 2 and 3, there was an even more pronounced survival benefit from cetuximab over those treated with FOLFIRI plus bevacizumab (median overall survival 33.1 versus 25.0 months, HR for death 0.70, p = 0.01); PFS was still no different (median 10.3 versus 10.2 months) .
●In contrast to these data, a survival advantage of first-line cetuximab over bevacizumab could not be shown in large US Intergroup trial 80405 in which 1137 patients with KRAS exon 2 WT metastatic CRC were randomly assigned to cetuximab or bevacizumab with either FOLFOX or FOLFIRI (dealer's choice) . Overall survival from the time of diagnosis was similar (30 months for cetuximab and 29.9 months for bevacizumab), as was median PFS (10.5 versus 10.6 months). Notably, in this study, more than 70 percent of patients received FOLFOX as the chemotherapy backbone.
An update of these results with expanded RAS analysis (WT in exons 2, 3, and 4 of KRAS and NRAS) was presented at the 2014 European Society for Medical Oncology (ESMO) Congress . Expanded RAS analysis was available for 670 patients, of whom 526 were RAS-WT (256 in the bevacizumab group, 270 in the cetuximab group). Although objective response rates were significantly higher with cetuximab (69 versus 54 percent), median overall survival from the time of diagnosis was similar (32 months for cetuximab and 31.2 months for bevacizumab), as was median PFS (11.4 versus 11.3 months).
An intriguing retrospective reanalysis of data from this trial suggests that the site of the primary tumor may impact benefit from first-line cetuximab versus bevacizumab in patients with RAS WT tumors . The total population with KRAS WT tumors on the left side (n = 732) or the right side (n = 293) was included in this analysis. In a preliminary report presented at the 2016 annual American Society of Clinical Oncology (ASCO) meeting, overall survival was significantly higher for left-sided tumors (median 33.3 versus 19.4 months), a finding that has been noted by others, including in a retrospective analysis of the FIRE-3 trial [229-231]. However, a new finding was that among patients with left-sided tumors, cetuximab provided superior median overall survival (36 versus 31.4 months), while bevacizumab was superior to cetuximab when the primary tumor was on the right side (median 24.2 versus 16.7 months). In contrast, among patients with KRAS-mutant tumors, the location of the primary tumor did not influence outcomes with either biologic agent.
A subsequent meta-analysis of these two trials and a third randomized phase II trial of FOLFOX with either panitumumab or bevacizumab  examining the relationship between primary tumor location and outcomes concluded that patients with RAS WT left-sided colorectal tumors had a significantly greater survival benefit from anti-EGFR treatment compared with anti-vascular endothelial growth factor (VEGF) treatment when added to standard chemotherapy (HR 0.71, 95% CI 0.58-0.85) . In contrast, for patients with right-sided tumors, there was a trend toward longer survival with bevacizumab-based therapy (HR 1.3, 95% CI 0.979-1.74). Unfortunately, this meta-analysis has methodological issues that may compromise the conclusions. The data extraction was not described, and there was no mention of the quality of the follow-up in any of the trials. Furthermore, only 1011 of the 2014 patients included in all three trials were included in the analysis (largely because of the absence of KRAS evaluation in the CALGB and FIRE-3 trials), and there was no analysis performed to compare patients included and excluded in the analysis; these issues introduce the possibility of substantial bias.
A similar relationship between location of the primary tumor and benefit from anti-EGFR agents has been reported by others [186,205,234]. The site of the primary tumor is likely to represent a surrogate for biologic variability. There are different rates of mutations in key oncogenes and tumor suppressor genes between right- and left-sided CRCs [235,236]. However, in another preliminary analysis of data from the CALGB 80405 trial presented at the 2017 ASCO meeting, the prognostic influence of primary tumor location appeared independent from molecular features, including RAS and BRAF mutation status .
Other reasons for the discrepant results from these three trials are unclear. Differences in second-line chemotherapy treatment and the possibility that resistance to cetuximab may be accompanied by increased expression of VEGF and corresponding enhanced sensitivity to anti-VEGF agents have also been hypothesized to explain the superiority of first-line cetuximab in the FIRE-3 trial [238-240].
DUAL ANTIBODY THERAPY — The benefit of simultaneously targeting both vascular endothelial growth factor (VEGF) and the endothelial growth factor receptor (EGFR) has been addressed in three trials:
●The BOND-2 randomized phase II trial compared cetuximab/bevacizumab with (CBI) and without irinotecan (CB) in 76 patients with irinotecan- and oxaliplatin-refractory but bevacizumab-naive mCRC . Response rates (37 versus 20 percent), time to tumor progression (TTP, 7.3 versus 4.9 months) and overall survival (15.4 versus 11.4 months) all favored CBI. These outcomes with CBI were unprecedented in the salvage setting, and were much less impressive in a subsequent phase II study of this regimen (9 percent response rate, TTP 3.9 months, median survival 10.6 months) .
●The PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) trial tested the addition of panitumumab to standard first-line oxaliplatin (n = 823) or irinotecan-based therapy (n = 230) plus bevacizumab . Panitumumab treatment was stopped after a preplanned interim analysis detected a significantly inferior progression-free survival (PFS) in the panitumumab/oxaliplatin group; median overall survival was also lower (19.4 versus 24.5 months).
●The CAIRO2 trial studied first-line bevacizumab plus XELOX with or without cetuximab . PFS was significantly worse with dual antibody therapy. Even patients with wild-type KRAS tumors did not benefit from the addition of cetuximab. (See 'Agents targeting the EGFR' above.)
The reason for this lack of synergy is unknown. However, at least some data suggest that bevacizumab treatment reduces tumor targeting of anti-EGFR antibodies, effectively preventing delivery of the drug to the tumor cells .
Regardless of the mechanism, these results suggest that dual antibody therapy is not appropriate, at least in the first-line setting. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Dual antibody therapy'.)
COMBINATION VERSUS SEQUENTIAL SINGLE AGENTS — First-line therapy with combinations of fluoropyrimidines, oxaliplatin or irinotecan, and bevacizumab has markedly improved response rates, progression-free survival (PFS) and survival compared to fluoropyrimidines alone. However, survival is positively impacted by subsequent therapy, and upfront combination therapy also increases toxicity and cost.
The question of whether patients should receive initial combination therapy or fluoropyrimidine monotherapy has been addressed in two randomized trials, neither of which showed that survival was adversely impacted by initial single agent therapy [77,246]. However, the median survival for all groups in both trials (which ranged from 13.9 to 17.4 months) was lower than expected for modern chemotherapy.
One possible reason is the low number of patients who eventually received all three active drugs in both trials. The proportion of patients receiving all three active agents correlates strongly with median survival in all large published phase III trials over the last decade . Furthermore, neither trial used bevacizumab or cetuximab either as first-line or salvage therapy. These agents improve PFS, and bevacizumab also improves overall survival when used in the first-line regimen (see 'Agents targeting VEGF' above).
Thus, the available evidence continues to support initial combination chemotherapy for most patients, particularly for those whose metastases might be potentially resectable after an initial chemotherapy response. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Neoadjuvant chemotherapy'.)
These trial results and the implications for clinical practice are discussed in detail elsewhere. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Initial doublet combinations versus sequential single agents'.)
PATIENTS WITH REFRACTORY DISEASE
Regorafenib — Regorafenib (BAY 73-4506) is an orally active inhibitor of angiogenic (including the vascular endothelial growth factor [VEGF] receptors 1 to 3), stromal, and oncogenic receptor tyrosine kinases. It is structurally similar to sorafenib and targets a variety of kinases implicated in angiogenic and tumor growth-promoting pathways.
Activity in refractory metastatic colorectal cancer (mCRC) was initially shown in the CORRECT trial, in which 760 patients who had progressed after multiple standard therapies were randomly assigned to best supportive care plus regorafenib (160 mg orally once daily for three of every four weeks) or placebo. Patients assigned to regorafenib had a modest though statistically significant improvement in median overall survival (6.4 versus 5 months, hazard ratio 0.77, 95% CI 0.64-0.94) . The difference in progression-free survival (PFS) was statistically significant with a hazard ratio of 0.49 (median 1.9 versus 1.7 months). The disease control rate was higher with regorafenib (41 versus 15 percent), but only five patients (1 percent) experienced a partial response (versus one patient, 0.4 percent, receiving placebo). The group receiving regorafenib had more grade 3 or 4 hand-foot skin reaction (17 versus 0.4 percent), fatigue (10 versus 5 percent), hypertension (7 versus 1 percent), diarrhea (7 versus 1 percent), and skin rash (6 versus 0 percent). Fatal hepatic failure occurred in 1.6 percent of patients treated with regorafenib versus 0.4 percent in the placebo group. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)
In October 2012, regorafenib received approval from the US Food and Drug Administration (FDA) for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, and, if KRAS wild type, an anti-EGFR therapy. It was approved by the European Medicines Agency in August 2013.
Benefit for regorafenib monotherapy was confirmed in the multicenter CONCUR trial, in which 204 Asian patients with mCRC who progressed after standard therapies were randomly assigned to regorafenib (160 mg daily for 21 of every 28 days) or placebo . Prior anti-VEGF or anti-epidermal growth factor receptor (EGFR) targeted therapy was allowed but not mandatory; approximately 40 percent of patients in each group had received no prior targeted therapy. Regorafenib was associated with a significantly longer median PFS (3.2 versus 1.7 months) and overall survival (8.8 versus 6.3 months). As was seen in the CORRECT trial, the disease control rate was significantly higher with regorafenib (51 versus 7 percent), although only 6 patients (4 percent) achieved a partial response (versus none in the placebo group). The adverse event profile of regorafenib was similar to that seen in the CORRECT trial.
The initial approved dose of regorafenib (160 mg daily for 21 days of every 28-day cycle) may be too high for many patients. In the phase II ReDOS trail, a weekly dose escalating strategy (starting with 80 mg daily, escalating weekly in the absence of treatment-related toxicity to a target of 160 mg daily) allowed more patients to continue therapy beyond the first response assessment at eight weeks compared with starting at 160 mg per day . In a preliminary report, presented at the 2018 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, median overall survival also trended better in the dose escalation cohort (9 versus 5.9 months), and toxicity was more favorable.
Trifluridine-tipiracil — Trifluridine-tipiracil (TAS-102) is an oral cytotoxic agent that consists the nucleoside analog trifluridine (trifluorothymidine, a cytotoxic antimetabolite that, after modification within tumor cells, is incorporated into DNA causing strand breaks) and tipiracil, a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well . Benefit in refractory mCRC is suggested by the following data:
●Efficacy was suggested in a randomized placebo-controlled phase II trial of 172 patients with refractory mCRC in whom trifluridine-tipiracil significantly prolonged median overall survival (9 versus 6.6 months); the most common grade 3 or 4 toxicity was hematologic .
Based upon these results, trifluridine-tipiracil was approved in Japan for treatment of refractory mCRC.
●Benefit was confirmed in two subsequent placebo-controlled phase III trials (the RECOURSE and TERRA trials) [252,253]. In the larger of the two, 800 patients who were refractory to or intolerant of fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, and anti-EGFR agents (if wild-type KRAS) were randomly assigned to trifluridine-tipiracil (35 mg/m2 orally twice daily on days 1 through 5, and 8 to 12 of each 28-day cycle) or placebo . Trifluridine-tipiracil was associated with a significant prolongation in median overall survival, the primary endpoint (7.1 versus 5.3 months, HR 0.68, 95% CI 0.58-0.81), and this benefit was irrespective of prior regorafenib use. Although patients treated with trifluridine-tipiracil had a significantly higher disease control rate (44 versus 16 percent), only eight patients had an objective response (versus one patient in the placebo arm). The most frequently observed toxicities were gastrointestinal and hematologic. Serious adverse events were observed in 30 percent of patients receiving trifluridine-tipiracil compared with 34 percent of the placebo group, and there was one treatment-related death with trifluridine-tipiracil. Importantly, gastrointestinal toxicities with trifluridine-tipiracil were almost all grade 1 and 2 with few grade ≥3 events recorded. That is relevant to the treatment of patients with longstanding treatment-refractory disease who are often battling gastrointestinal distress as a consequence of their disease and are not tolerant of high-grade gastrointestinal toxicity.
Largely based upon these results, trifluridine-tipiracil was approved in the United States for treatment of mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an antiangiogenic biologic product, and a monoclonal antibody targeting the epidermal growth factor receptor, if RAS wild-type .
Immunotherapeutic approaches — Immunotherapeutic approaches to cancer therapy are based upon the premise that the immune system plays a key role in surveillance and eradication of malignancy, and that tumors evolve ways to elude the immune system. Historically, mCRC was considered non-immunogenic, that is, incapable of inducing immune-mediated tumor destruction. However, the importance of the immune system in the biology of CRC is underscored by the finding that infiltration of the tumor by specific T cell immune infiltrates is highly correlated with better disease-free and overall survival at all tumor stages. (See "Pathology and prognostic determinants of colorectal cancer", section on 'Host immune response'.)
These data suggest that an immune response to specific tumor antigens might drive improved outcomes. However, most tumor-associated antigens in CRC, while expressed at higher levels within tumor, are also expressed in other tissues. As a result, the tolerance mechanisms that suppress the immune response to self-antigens to minimize autoimmune disease may also serve to suppress the immune response to these tumor antigens . Based upon data on the immunogenicity of mutated antigens in melanoma, it has been hypothesized that "neoantigens" generated from tumor-specific mutations of self-antigens within CRC may be recognized by the immune system as foreign and could therefore trigger an antitumor immune response. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Rationale' and "Principles of cancer immunotherapy".)
Immune checkpoint inhibitors and mismatch repair deficient tumors — Mutations in one of several DNA mismatch repair (MMR) genes are found in Lynch syndrome (hereditary nonpolyposis CRC [HNPCC]) and in 15 to 20 percent of sporadic colon cancers. The characteristic genetic signature of tumors with deficient MMR (dMMR) is a high number of DNA replication errors (RER+) and high levels of DNA microsatellite instability (MSI). (See "Pathology and prognostic determinants of colorectal cancer", section on 'Mismatch repair deficiency' and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Genetics'.)
Tumors that lack the mismatch repair mechanism harbor many more mutations (ie, they are hypermutated) than do tumors of the same type without such MMR defects [256,257], and as noted above, the neoantigens generated from mutations such as these have the potential to be recognized as "non-self" immunogenic antigens.
Several steps are required for the immune system to effectively attack tumor cells. These include tumor recognition, presentation of tumor antigen to T cells, T cell activation, and direct attack of tumor. Several immune checkpoints exist to dampen the immune response in order to protect against detrimental inflammation and autoimmunity. In the setting of malignancy, such immune checkpoints can lead to immune tolerance of the tumor and subsequent progression of malignancy. One well-characterized checkpoint being targeted in several tumor types, including mCRC, is the programmed death receptor 1 (PD-1). PD-1 is upregulated on activated T cells, and upon recognition of tumor via the T cell receptor, PD-1 engagement by programmed death ligand 1 (PD-L1) can lead to T cell inactivation (figure 1). (See "Principles of cancer immunotherapy".)
The percentage of stage IV colorectal tumors that are characterized as microsatellite instability-high (MSI-H)/dMMR ranges from 3.5 to 6.5 percent [258-260]. The hypothesis that dMMR mCRCs might be particularly susceptible to immune checkpoint blockade was addressed in the following reports:
●In a phase II study, pembrolizumab, an IgG4 monoclonal antagonist antibody to PD-1, was administered intravenously at a dose of 10 mg/kg every 14 days to 11 patients with dMMR mCRC, 21 patients with MMR-proficient (pMMR) mCRC, and 9 patients with noncolorectal dMMR metastatic cancers; all had been heavily pretreated . In the latest analysis of an expanded cohort of 54 patients with dMMR or pMMR mCRC, presented at the 2016 meeting of the ASCO, patients with dMMR mCRC had a 50 percent objective response rate (ORR) and a 89 percent disease control rate (DCR; objective response or stable disease) . In contrast, the ORR was 0 percent and DCR was 16 percent in the patients with pMMR mCRC. After a median treatment duration of 5.9 months, no patients in the dMMR group who responded had progressed. Overall survival and PFS were not reached in the dMMR group versus a median PFS of 2.3 months and an overall survival of 7.6 months in the pMMR group. Interestingly, patients with germline MMR mutations (Lynch syndrome) were less likely to respond than were those with other forms of MMR deficiency (ORR 27 versus 100 percent) .
Adverse events were consistent with other studies of pembrolizumab in other tumor types; the most common all-grade toxicities were rash/pruritus (24 percent), pancreatitis (15 percent), and thyroid dysfunction (10 percent) . (See "Toxicities associated with checkpoint inhibitor immunotherapy".)
Largely based upon these data, on May 23, 2017, the FDA granted accelerated approval to pembrolizumab for the treatment of patients with advanced MSI-H or dMMR mCRC that has progressed following conventional chemotherapy . The approval of pembrolizumab also extended to a variety of advanced solid tumors other than CRC (eg, endometrial, other gastrointestinal, breast, prostate, bladder, thyroid, and other sites) that were MSI-H or dMMR, that had progressed following prior treatment, and for which there were no satisfactory alternative treatment options.
●Benefit for immunotherapy in patients with dMMR tumors was also suggested in a second trial, CheckMate 142, in which patients with dMMR (n = 59) or pMMR (n = 23) mCRC received nivolumab (a fully human anti-PD-L1 monoclonal antibody) with or without ipilimumab, a monoclonal antibody directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) . In a preliminary report presented at the 2016 annual ASCO meeting, immunotherapy benefited those with dMMR tumors (13 confirmed partial responses; median PFS 5.3 months). In contrast, there were no objective responses among those with pMMR tumors, and the median PFS was 1.4 months.
In a later analysis of 74 patients with dMMR mCRC treated with nivolumab alone (3 mg/kg every two weeks), at a median follow-up of 12 months, 23 had an objective response (31 percent), and the median duration of response had not been reached. Eight had responses lasting 12 months or longer . Responses were observed regardless of tumor PD-L1 expression level, or BRAF or KRAS mutation status. The most common grade 3 or 4 drug-related adverse events were increased levels of lipase and amylase.
Largely based upon these data, in August 2017, the FDA extended the approval of nivolumab to MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan . The approved dose is 240 mg every two weeks.
Patients who experience disease progression on either of these drugs should not be offered the other.
A subsequent report of the CheckMate 142 cohort treated with combined nivolumab plus ipilimumab (four doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every three weeks, followed by nivolumab alone 3 mg/kg every two weeks) suggested an even greater degree of benefit for targeting two different immune checkpoints that restrain the adaptive immune response . (See "Principles of cancer immunotherapy", section on 'The "immune synapse"'.)
Of the 119 patients in this cohort, 76 percent had received two or more prior systemic therapies. At a median follow-up of 13.4 months, the ORR was 55 percent (51 percent partial, 3 percent complete), and the disease control rate for 12 weeks or longer was 80 percent. Responses were observed regardless of PD-L1 expression, or BRAF or RAS mutation status. Responses appeared to be durable; at 12 months, 71 percent remained progression free and 85 percent were still alive. Grade 3 or 4 treatment-related adverse events occurred in 32 percent of patients and were manageable. The most common were elevations in aspartate transaminase (AST; 8 percent) or alanine transaminase (ALT; 7 percent). Overall, the most common adverse events of any grade were diarrhea (22 percent, 2 percent severe), fatigue (18 percent, 2 percent severe), pruritus (17 percent, 2 percent severe), and pyrexia (15 percent, none severe).
Indirect comparisons suggest that combined immunotherapy using ipilimumab and nivolumab provides improved efficacy over anti-PD-1 monotherapy and has a favorable benefit:risk ratio. Although the final determination of the relative risks and benefits of combined immunotherapy over monotherapy will require large randomized trials (as have been completed in melanoma), the combination of ipilimumab and nivolumab is a reasonable alternative to immune checkpoint inhibitor monotherapy.
Further exploration of the data from these trials is needed to understand why there was a complete lack of response in microsatellite-stable tumors, which represents the vast majority of patients with mCRC . In fact, at least some preliminary data support the view that immune checkpoint inhibitor therapy may benefit at least some patients with microsatellite-stable mCRC. As an example, MEK is a component of the mitogen-activated protein (MAP) kinase pathway, which is activated in many cancers, including melanoma (figure 2). In preclinical models, targeted inhibition of MEK enhances anti PD-L1 activity. Benefit for combined therapy with the MEK inhibitor cobimetinib plus atezolizumab, an engineered antibody that inhibits binding of PD-L1 to its receptors, was suggested in a phase I study that included 23 patients with mCRC (22 KRAS mutant) . In a preliminary report presented at the 2016 annual ASCO meeting, there were four objective responses, three of which were in pMMR tumors.
Immune checkpoint inhibitors are associated with a unique spectrum of toxicities, many of which are immune mediated. These are discussed in detail elsewhere. (See "Toxicities associated with checkpoint inhibitor immunotherapy" and "Ocular side effects of systemically administered chemotherapy", section on 'Immune checkpoint inhibitors'.)
HER2-targeted therapy — The human epidermal growth factor receptor 2 (HER2) oncogene encodes for a transmembrane glycoprotein receptor that functions as an intracellular tyrosine kinase. As with other epidermal growth factor receptor (EGFR) receptors, HER2 is critical in the activation of subcellular signal transduction pathways controlling epithelial cell growth and differentiation, and possibly angiogenesis. Amplification of the HER2 gene or overexpression of its protein product is observed in approximately 20 percent of human breast cancers (as well as approximately 10 to 20 percent of gastric adenocarcinomas), and targeted therapies that block HER2 (eg, trastuzumab, lapatinib, pertuzumab) have become important therapeutic options for patients with HER2-overexpressing tumors. (See "HER2 and predicting response to therapy in breast cancer" and "Systemic treatment for HER2-positive metastatic breast cancer" and "Systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'HER2-overexpressing adenocarcinomas'.)
A minority of colorectal cancers overexpress HER2 oncogene, which can be detected by immunohistochemical staining for HER2 protein, in situ hybridization for gene amplification, or reverse transcription polymerase chain reaction (RT-PCR) for overexpression of HER2 RNA. (See "HER2 and predicting response to therapy in breast cancer", section on 'Testing for HER2 expression'.)
The potential for benefit from HER2-targeted therapy in mCRC is illustrated by the following early results:
●The efficacy of dual targeted therapy with trastuzumab (a monoclonal antibody that binds the extracellular domain of HER2) plus lapatinib (a tyrosine kinase inhibitor against EGFR1 and HER2 that results in inhibition of signaling pathways downstream of HER2) in patients with KRAS exon 2 wild-type, HER2-overexpressing mCRC was evaluated in the proof-of-concept multicenter open-label phase II trial (HERACLES) . Only 48 of the 914 patients with KRAS wild-type tumors (5 percent) were HER2-positive, and 27 were eligible to participate. All received intravenous trastuzumab (4 mg/kg loading dose initially followed by 2 mg/kg weekly) plus oral lapatinib (1000 mg daily) until progression. At a median follow-up of 94 weeks, there were eight objective responders (30 percent), one complete, and 12 others (44 percent) had stable disease. Treatment was reasonably well-tolerated, with grade 3 toxicity in only six patients (22 percent; consisting of fatigue, skin rash, or hyperbilirubinemia) and no grade 4 or 5 events.
●The MyPathway study (NCT02091141) evaluated the combination of trastuzumab plus pertuzumab (a recombinant humanized monoclonal antibody that targets the extracellular HER2 dimerization domain and interferes with downstream HER2 signaling pathways) for patients with HER2-overexpressing/amplified tumors other than breast cancer. Of the 37 HER2-overexpressing mCRCs, there were 14 objective antitumor responses (38 percent) .
While these data provide proof of principle as to the potential for benefit from HER2-targeted therapy, it is premature to conclude that HER2-targeted therapy represents a standard treatment for HER2-overexpressing mCRC. Confirmation in larger trials is necessary. Clinicians are encouraged to enroll eligible patients with HER2-overexpressing tumors in prospective trials testing the efficacy of HER2-targeted therapies.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Colorectal cancer".)
●The majority of patients with metastatic colorectal cancer (mCRC) cannot be cured, although a subset with liver and/or lung-isolated disease are potentially curable with surgery. For other patients, treatment is palliative and generally consists of systemic chemotherapy.
●For decades, fluorouracil (FU) was the sole active agent. This has changed markedly since the year 2000, with the approval of irinotecan, oxaliplatin, three humanized monoclonal antibodies that target vascular endothelial growth factor (bevacizumab) and the epidermal growth factor receptor (EGFR; cetuximab and panitumumab), and most recently, intravenous aflibercept, a fully-humanized recombinant fusion protein consisting of vascular endothelial growth factor (VEGF) binding portions from the human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1, regorafenib, an orally active inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1 to 3) and other membrane and intracellular kinases, and trifluridine-tipiracil, another orally active agent that combines the nucleoside analog trifluridine (which inhibits thymidylate synthetase and, after modification within tumor cells, is incorporated into DNA causing strand breaks) and tipiracil, a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well. Most recently, the immune checkpoint inhibitors pembrolizumab and nivolumab have been approved for advanced microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) CRC that has progressed following conventional chemotherapy.
●Systemic chemotherapy produces meaningful improvements in median survival and progression-free survival (PFS). These benefits are most pronounced with regimens containing irinotecan or oxaliplatin in combination with FU. The median overall survival for patients with unresectable mCRC who receive best supportive care (BSC) alone is approximately five to six months. Although no trial has compared these regimens to BSC alone, median survival now routinely exceeds two years, and five-year survival with chemotherapy alone approximates 20 percent. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Chemotherapy versus supportive care'.)
●The available evidence supports initial combination chemotherapy for most patients, particularly for those whose metastases might be potentially resectable after an initial chemotherapy response. However, the best way to combine and sequence active agents is not established, nor is the optimal duration of treatment. In general, patients benefit more from access to all active agents than from a particular treatment sequence of specific regimens used as individual "lines" of therapy. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Overview of the therapeutic approach'.)
●Increasingly, biomarker expression is driving therapeutic decision-making:
•Benefit from monoclonal antibodies targeting the EGFR is restricted to patients whose tumors do not contain mutated RAS genes or a BRAF V600E mutation. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Agents targeting the EGFR'.)
Accumulating evidence suggests that for patients with RAS/BRAF wild-type tumors, benefit from initial therapy with an anti-EGFR agent versus bevacizumab is also influenced by the sidedness of the primary tumor. (See 'Bevacizumab versus an EGFR agent with first-line chemotherapy backbone' above.)
•Immune checkpoint inhibitors are active for patients with dMMR, MSI-H tumors. (See 'Immune checkpoint inhibitors and mismatch repair deficient tumors' above.)
•Exciting early results have been seen with agents targeting human epidermal growth factor receptor 2 (HER2) for those whose tumors overexpress this protein. However, it is premature to conclude that this approach represents a standard treatment for refractory mCRC. Clinicians are encouraged to enroll eligible patients with HER2-overexpressing tumors in prospective trials testing the efficacy of HER2-targeted therapies. (See 'HER2-targeted therapy' above.)