A Review of Clinical Studies and Practical Guide for the Administration of Triplet Chemotherapy Regimens with Bevacizumab in First-line Metastatic Colorectal Cancer

Data from a meta-analysis indicated that there was a benefit to using EGFR inhibitors with doublet chemotherapy as first-line therapy in patients with RAS wild-type mCRC [21, 49]. Furthermore, results from the FIRE-3 study, in which patients with KRAS exon2 wild-type mCRC were treated with FOLFIRI in combination with either bevacizumab or cetuximab, showed that while response rate and PFS were similar between treatment groups, median OS was longer in the cetuximab group than in the bevacizumab group (28.7 vs. 25.0 months; HR 0.77, 95 % CI: 0.62–0.96; p = 0·017) [45]. However, the first-line treatment of RAS wild-type mCRC with doublet chemotherapy in combination with a targeted agent is still a matter of debate, as data from relevant prospective trials are still pending. Thus far, in the phase III TRIBE study, a similar proportion of patients in both FOLFIRI + bevacizumab (39 %) and FOLFOXIRI + bevacizumab (37 %) arms had KRAS wild-type disease, and subgroup analyses showed that the treatment effect (i.e., reduced the risk of disease progression for patients receiving FOLFIXIRI + bevacizumab compared with those receiving FOLFIRI + bevacizumab) was independent of KRAS mutation status.

The BRAF V600E mutation is considered a strong prognostic marker in mCRC, and a putative predictive role of this BRAF mutation for resistance to anti-EGFR treatment has been hypothesized based on retrospective analyses. However, the hypothesis has not been universally accepted despite two recent meta-analyses showing that there is no clinically relevant benefit for the addition of an EGFR antibody to chemotherapy for patients with BRAF-mutated disease [50, 51]. The use of the BRAF V600E mutation as a prognostic marker has been demonstrated in survival analyses of mCRC first-line trials, in which patients with BRAF-mutated mCRC had a worse prognosis than those without BRAF mutations [52‐54]. Further, results in the TRIBE study indicated that BRAF-mutated disease (5.5 % of the study population) is an adverse prognostic factor for both PFS and OS (univariate analysis) [39].

Data suggest that triplet chemotherapy + bevacizumab may be a reasonable option in patients with BRAF-mutated disease. The TRIBE study, for example, showed that treatment effect was not significantly different between BRAF-wild-type and BRAF-mutant patient subgroups [41]. Moreover, in a phase II trial of 15 patients with BRAF-mutated mCRC who were treated with first-line FOLFOXIRI + bevacizumab, the 6-month progression-free rate (primary endpoint), median PFS, and OS were 73 %, 9.2 months, and 24.1 months, respectively [55]. These results, however, should be interpreted with caution due to small sample sizes.

CHARTA is a randomized phase II trial that seeks to evaluate the activity of an intensified first-line therapy for mCRC (FOLFOXIRI + bevacizumab) compared with standard treatment (FOLFOX + bevacizumab) in 250 patients with mCRC or recurrent CRC (Fig. 2a) [38]. Treatment will be administered until disease progression, intolerable toxicity, secondary resection, or for a maximum of 12 cycles (6 months). After 6 months of treatment and/or no disease progression, patients will continue with a maintenance regimen with bevacizumab and a fluoropyrimidine (choice of 5-FU or capecitabine at the investigator’s discretion) for up to 12 months in the absence of progression or intolerable toxicity. The maximum treatment duration, including maintenance therapy, is 18 months. The primary endpoint is PFS at 9 months. Notably, the CHARTA study includes a secondary endpoint of health-related quality of life (as assessed via the European Organisation for Research and Treatment of Cancer QLQ-C30, QLQ-CR29, and QLQ-CIPN20 scales), which may add valuable information regarding patient-reported outcomes of triplet chemotherapy + bevacizumab. Recruitment was completed in December 2014.

The primary endpoint of the TRIBE-2 study is Progression-free survival 2 (PFS2); the planned study length is approximately 4.5 years (Fig. 2b). The first patient was enrolled in February 2015, and the last patient visit is expected in May 2019. With an expected enrollment rate of 200 patients per year, an enrollment period of 3 years, and a minimum follow-up period of 18 months, the first data release is projected to occur in early 2020. The end of the study is defined as the time when all randomized patients will show evidence of second disease progression or will be discontinued from treatment, per protocol, for toxicity or medical decision.

METHEP-2 (ACCORD 21–PRODIGE 14) trial is a phase II randomized trial comparing doublet chemotherapy (FOLFIRI/FOLFOX) with FOLFIRINOX combined with a targeted therapy selected according to RAS mutational status (i.e., bevacizumab for tumors with mutated KRAS; cetuximab for wild-type KRAS) in patients with colorectal cancer and initially unresectable liver metastases (Fig. 2c). The primary endpoint is the comparison of secondary resection rates of liver metastases between the control arm (doublet chemotherapy + targeted therapy) vs. the experimental arm (triplet chemotherapy + targeted therapy). The total number of patients is 256, and accrual was closed in May 2015. Translational studies are planned.

It has been suggested that alternating treatment every two cycles with FOLFOX + bevacizumab and FOLFIRI + bevacizumab (i.e., sequential FOLFOXIRI + bevacizumab) may improve the tolerability of the regimen without affecting efficacy [56], and may help guide the choice of second-line treatment. The phase II STEAM trial is investigating concurrent or sequential FOLFOXIRI + bevacizumab vs. FOLFOX + bevacizumab in patients with previously untreated mCRC (Fig. 2d). The coprimary efficacy endpoints are overall response rate and PFS.

At the time of a preplanned interim safety analysis, 94 patients were randomized (intention-to-treat population), and 93 patients received at least one dose of study treatment (safety population) [57]. The overall adverse event profile of FOLFOXIRI + bevacizumab was similar to that observed in previous trials of triplet chemotherapy + bevacizumab, including the TRIBE study [58], although the incidence of treatment-emergent adverse events in the sequential FOLFOXIRI + bevacizumab group were similar to those in the FOLFOX + bevacizumab arm. This suggests that alternating treatment with FOLFOX + bevacizumab and FOLFIRI + bevacizumab may improve the tolerability of the regimen, although more mature data are needed to confirm these results [57].

Data from these ongoing studies and others may shed light on how different combinations of chemotherapeutic agents administered in combination with bevacizumab, and how the use of these combinations across multiple lines of therapy impacts efficacy and safety in patients with mCRC.

It is estimated that more than half of all patients receiving chemotherapy for CRC experience diarrhea of any grade [59, 68, 69]. Severe (grade 3 and 4) diarrhea, observed in approximately one-fifth of the patients in the TRIBE study, imparts a significant health-related burden on the quality of life of patients.

Uncomplicated diarrhea may be managed through supportive care, including dietary modifications, and commonly used drugs [70, 71]. Several pharmacologic agents have been investigated for the prevention of treatment-induced diarrhea, but, to date, none have proven efficacy [71]. Loperamide (or codeine as an alternative), which works by binding to receptors in the gastrointestinal tract to slow transit time [61], is appropriate for the initial treatment of diarrhea [71]. For persistent diarrhea, despite loperamide treatment (or as initial treatment for grade 3 or 4 diarrhea), octreotide or tincture of opium may be effective [63, 71]. Racecadotril, which does not slow transit time, may be recommended in acute cases of diarrhea for which infection is suspected [72].

Probiotics, including lactobacillus and bifidobacterium, are thought to restore the balance of intestinal microbiota disrupted by chemotherapy [73, 74] and have been shown to reduce the incidence of grade ≥ 2 diarrhea [75, 76]. The Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology has therefore recently recommended probiotic use for the prevention of diarrhea [77]. However, caution should be exercised in immunocompromised patients with cancer, but rare or no cases of sepsis have been observed in this patient population [75, 76].

Nausea and vomiting (emesis) occur in approximately 29 % and 11 % of overall patients, respectively, receiving chemotherapy [78]. In the OLIVIA and TRIBE trials, patients were treated prophylactically (starting day 1 of chemotherapy) with 5-hydroxytryptamine-3 antagonists (i.e., palonosetron), dexamethasone, or with other antiemetics. Of note, the incidence of grade 3/4 nausea and vomiting was not significantly increased with the use of triplet + bevacizumab compared with doublet + bevacizumab in the two available randomized studies [37, 39]. In general, palonosetron and dexamethasone are recommended for patients receiving moderately emetogenic chemotherapy [79, 80].

Guidelines for management of oral mucositis include maintaining oral hygiene by brushing with a soft toothbrush that is frequently replaced, flossing, and rinsing with saline and applying topical anesthetics or transdermal fentanyl; painful mucositis may be treated with doxepin [81, 82]. While mucositis prophylaxis may include cryotherapy [81], it should be avoided in patients receiving oxaliplatin, as it may exacerbate acute neurologic symptoms [62] and cause laryngospasm for up to 48 h.

Patients with gastrointestinal mucositis may be treated with ranitidine or omeprazole to prevent epigastric pain following 5-FU treatment [81]. Adequate hydration and the potential for transient lactose intolerance and presence of bacterial pathogens should also be considered for at-risk patients [81].

Current guidelines recommend that primary granulocyte colony-stimulating factor (G-CSF) prophylaxis be used when the overall risk (i.e., due to regimen and patient factors) for febrile neutropenia is ≥ 20 % [83]. However, the use of G-CSF to treat febrile neutropenia should be carefully considered, as studies have shown that G-CSF has been overutilized in patients with low risk of febrile neutropenia, but underutilized in those with high risk [84, 85]. Individual patient factors are to be considered in cases with a 10–20 % risk, while G-CSF is not indicated for patients with a risk < 10 % [83]. The rate of febrile neutropenia with FOLFOXIRI and bevacizumab is reported to be 8.8–13 %; therefore, a general primary GCSF prophylaxis is not necessary [37, 39]. However, G-CSF has also been shown to be effective as a secondary prophylaxis in patients who experienced febrile neutropenia in a previous treatment cycle [86]. If the goal is to induce rapid regression of liver metastases to achieve secondary resection, G-CSF may be considered for primary prophylaxis to avoid delays or dose reductions in chemotherapy administration [17].

Because patients receiving bevacizumab have an increased incidence of severe hypertension, blood pressure monitoring every 2–3 weeks is recommended [24], and antihypertensive treatment should be provided [24] on the basis of recommended guidelines [87]. Patients with grade 2 hypertension may be treated with antihypertensive monotherapy (e.g., an angiotensin-converting enzyme inhibitor), and may resume bevacizumab treatment once blood pressure is controlled to < 150/100 mm Hg. Patients experiencing grade 3 hypertension may require more than one antihypertensive agent or more intensive therapy (i.e., a diuretic or calcium channel blocker). Bevacizumab treatment should be suspended in patients with grade 3 hypertension that is not controlled by medical management, and it should be discontinued in patients with hypertensive crisis or hypertensive encephalopathy.

There are no recommended dose reductions for bevacizumab [24], and no reductions were permitted in the phase II and phase III clinical trials, which assessed bevacizumab in combination with triplet chemotherapy. However, management of adverse events, dose interruptions, or discontinuations of therapy were recommended in the study protocols in certain, well-defined situations (see Table 3). The prescribing information recommends that bevacizumab be temporarily suspended in patients with uncontrolled, severe hypertension and severe proteinuria [24]. In addition to these recommendations, the protocols also specified guidelines for the management of hypertension (i.e., angiotensin-converting enzyme inhibitor for grade 2 and a three-drug medication for grade 3) and monitoring of proteinuria (see Table 3). Furthermore, because bevacizumab impairs wound healing, suspension of bevacizumab dosing is recommended prior to elective surgery (4 weeks according to the guidelines of the US Food and Drug Administration and 6–8 weeks according to the guidelines of the European Medicines Agency) until the patient is fully healed [24, 25]. In the event of severe infusion reactions, gastrointestinal perforation, surgery and wound-healing complications, severe arterial thromboembolic events, life-threatening venous thromboembolism, hypertensive crisis/encephalopathy, posterior reversible encephalopathy syndrome, or nephritic syndrome, bevacizumab should be permanently discontinued [24]. The protocols, moreover, recommended a delay in bevacizumab dosing in the event of grade 4 febrile neutropenia, a delay or discontinuation for grade ≥ 2 pulmonary hemorrhage and grade 2 nonthromboembolic fistulae, and a discontinuation for any-grade central nervous system (CNS) hemorrhage, grade ≥ 3 nonpulmonary and non-CNS hemorrhage, and any-grade thromboembolic fistulae (see Table 3).

According to the TRIBE study protocol, dose adjustments were recommended for all three components or a subset of the triplet regimen for specific adverse events (see Table 3). Generally, dose delays may be implemented until an adverse event resolves to a lower grade or baseline. For example, a dose should be delayed in patients with grade ≥ 3 neutropenia occurring for < 5 days, grade ≥ 2 thrombocytopenia, or grade ≥ 2 diarrhea and/or stomatitis. Dose reductions to 75 % are recommended at the recurrence of a prior adverse event that led to a dose reduction (e.g., third occurrence of neutropenia), or at the first occurrence of a higher-grade adverse event (e.g., grade 4 neutropenia lasting ≥ 5 days, febrile neutropenia, grade ≥ 3 thrombocytopenia, or grade ≥ 3 related significant organ toxicities). Triplet chemotherapy should be discontinued for grade 4 thrombocytopenia. For other adverse events, dose modifications of individual components of the triplet regimen are recommended. For example, 5-FU/LV dose may be reduced for grade ≥ 3 hand–foot syndrome or mucositis, or after a second occurrence for these events of grade ≥ 2. Furthermore, for persistent, unresolved grade ≥ 2 neurosensory events, oxaliplatin is recommended to be temporarily discontinued [62]. For the second occurrence of diarrhea that requires a dose delay or the first occurrence of a grade ≥ 3 event, both irinotecan and 5-FU/LV may be reduced to 75 % of the starting dose.