Subgroup Analysis of Hazard Ratios for Death in the Two Study Groups How to Read

i Introduction

Colorectal cancer (CRC) is one of the most usually diagnosed malignancies. In 2012, there were an estimated 1.36 million new cases of CRC and 694,000 CRC-related deaths worldwide.^[i] Although the five-year survival rate of CRC patients has increased from 51% to 65%, and more patients are being diagnosed at earlier stages, almost half of all CRC patients volition eventually develop metastasis, leading to inoperable metastatic colorectal cancer (mCRC).^[2] Moreover, approximately a quarter of all CRC patients present with mCRC at diagnosis.^[iii] Chemotherapy is the preferred treatment for mCRC patients for whom consummate resection cannot be accomplished. Over the past few decades, pregnant advances accept been fabricated in mCRC handling, resulting in improved outcomes and prolonged survival. Several drugs accept been developed to treat mCRC, such as oxaliplatin,^[4] the fluoropyrimidines 5-fluorouracil (5-FU)^[five] and capecitabine,^[6] irinotecan,^[vii] the epidermal growth gene receptor antibodies cetuximab^[8] and erlotinib,^[9] and the vascular endothelial growth gene (VEGF) antibiotic bevacizumab.^[10] Starting time-line therapy with bevacizumab combined with multi-drug chemotherapeutic regimens (e.g., FOLFOX, XELOX/CAPOX, and FOLFIRI) has increased response rates to 50% to 60%, median progression-costless survival (PFS) to nine to 11 months, and median overall survival (OS) to 30 months in patients with unresectable mCRC.^[11]

However, at that place is no consensus on the optimal follow-up treatment strategy—maintenance therapy, continuous chemotherapy, or ascertainment lonely—for mCRC patients who benefit from first-line therapy. Continuous chemotherapy leads to an increase in drug-related side effects, and long-term exposure to chemotherapeutic drugs reduces cancer cell sensitivity to drugs, resulting in drug resistance. Moreover, treatment pause significantly reduces the efficacy of chemotherapy and may fifty-fifty touch on a patient's PFS and Bone. The concept of maintenance treatment envisages a period of high-intensity chemotherapy, after which those agents that are mainly responsible for cumulative toxicity are stopped. The results from two large, prospective, observational studies propose that continued VEGF inhibition with bevacizumab beyond the initial affliction progression could play an important role in improving the overall success of therapy in mCRC patients.^[12,xiii] A comparative assessment of bevacizumab-based maintenance strategies, continuous chemotherapy, and observation solitary may help identify the optimal chemotherapeutic regimen for the sequential treatment of mCRC patients who benefit from start-line therapy. Nosotros therefore conducted a meta-analysis of randomized controlled trials evaluating the safety and efficacy of the above three strategies in terms of PFS and Os in order to identify the optimal follow-up treatment strategy for mCRC patients.

ii Materials and methods

two.1 Data sources and search strategy

Potentially relevant studies were independently identified by 2 authors who conducted a structured literature search of the PubMed, Embase, and Cochrane Library databases and the meeting abstracts of American Order of Clinical Oncology and European Guild for Medical Oncology published through March 2018. The searches were systematically performed using Medical Subject Headings, and the full-text search terms for the literature search included "colorectal cancer," "bevacizumab," and "maintenance." The online abstracts of the retrieved studies were screened for eligibility. The references of all eligible studies were manually reviewed to notice boosted relevant studies.

2.2 Study option

The inclusion criteria for the studies were as follows: phase Iii randomized controlled trials involving patients with histopathologically confirmed CRC; studies comparing bevacizumab-based maintenance therapy with observation alone or those comparing bevacizumab-based maintenance therapy with continuous chemotherapy; studies that reported one or more of the master or secondary outcomes; and studies from which we could directly obtain or calculate run a risk ratios (HRs) and 95% confidence intervals (95% CIs).

The exclusion criteria were every bit follows: studies that had only a single treatment arm; studies in which information on the primary or secondary outcomes were non available; studies for which we were unable to obtain the total text or those that provided insufficient data; and case reports, meeting abstracts, literature reviews, and brute experiments.

ii.3 Data extraction

Data extraction was performed independently past 2 authors, and the extracted data were entered into a standard information canvas. Data on the following variables were extracted: beginning author'due south name, yr of publication (acronym of the trial), journal, affiliated establishment, country, written report phase, format (full text or abstract), interventional and control treatments, HRs with 95% CIs for PFS and OS, median PFS and Bone, randomization method, assay tool, number of patients randomized, demographic and clinical data (e.g., historic period, sex activity, ethnicity, histology), and toxicity (grade three/4). Any disagreements were resolved by consensus, if necessary, by a third author. When boosted data was required, the corresponding authors were contacted via email. All selected trials published every bit full-text manufactures were analyzed and classified using the Jadad score when possible. Studies with a Jadad score ≥3 were graded as high quality.

ii.4 Statistical assay

All meta-analyses were performed using the software Review Managing director, version v.3 (The Cochrane Collaboration). Nosotros performed meta-analyses of PFS, Os, and form 3/4 toxicities afterward maintenance treatment versus observation solitary and maintenance treatment versus continuous handling. PFS was defined as the time from maintenance randomization to disease progression or death (not including the induction therapy time). To standardize the information, PFS values from several studies were adjusted to friction match the above definition. OS was defined equally the fourth dimension from maintenance randomization to death (not including the induction therapy time).

Heterogeneity betwixt the studies was analyzed using the chi-squared test, with a test boundary value of α = 0.1. The fixed-furnishings model was first used to combine the HRs of each group. Significant heterogeneity was deemed present among the studies if the heterogeneity tests yielded a P-value of ≤.ten or an I ² value of >fifty%. In this example, we practical the random-effects.

Statement: Our meta-analysis does not accost the bailiwick's life, wellness, dignity, privacy, and other related bug. All analyses were based on previous published studies, thus no ethical approval or patient consent was required.

3 Results

3.one Search results

A total of 208 manufactures were retrieved using the initial search query. Subsequently a full-text review, 9 trials (in 8 papers), with a combined study population of 3121 mCRC patients, were included in the meta-analysis (Fig. 1). Four of these trials (AIO 0207,^[fourteen] CAIRO3,^[15] SAKK 41/06,^[16] and PRODIGE nine^[17]) compared bevacizumab-based maintenance therapy until progression with ascertainment alone, while v trials (MACRO TTD,^[18] "Finish and Go," ^[19] Nordic Human activity,^[20] AIO 0207, and DREAM OPTIMOX3^[21]) compared bevacizumab-based maintenance therapy with continuous treatment. The AIO 0207 study had iii treatment arms, and thus counted as 2 trials. The baseline characteristics of all 9 trials have been summarized in Table 1. Seven of the 8 studies had a Jadad score ≥iii and were graded as loftier quality (Tabular array ii).

Figure 1:

Flow nautical chart of trial selection.

Table 1:

Characteristics of identified randomized controlled trials.

Table 2:

Quality of literature included in the meta-assay (Jadad score).

3.ii Bevacizumab-based maintenance therapy versus ascertainment lonely

A total of 4 manufactures (5 trials) provided PFS. Meaning heterogeneity was detected amid these trials (P < .00001, I ^two = 86%). Therefore, a random-furnishings model was used for the analysis (Fig. 2). The results showed that whatsoever bevacizumab-based maintenance therapy (with or without fluoropyrimidine) after a bevacizumab-based induction regimen improved PFS (Hr = 0.62, 95% CI: 0.47–0.82). The 5 trials were separated into those studying bevacizumab monotherapy and those studying a combination of bevacizumab plus a fluoropyrimidine. The data showed that single-agent maintenance therapy with bevacizumab significantly increased PFS compared with observation alone (HR: 0.77, 95% CI: 0.67–0.88; Fig. 3). The more-intensive maintenance therapy with bevacizumab plus a fluoropyrimidine farther increased PFS compared with observation alone (HR: 0.43; 95% CI: 0.35–0.52; Fig. 4). No significant difference was observed between the bevacizumab-based maintenance therapy strategies and ascertainment lonely with respect to Os (HR: 0.93, 95% CI: 0.83–one.05). In addition, no significant heterogeneity was observed in the OS analyses (P = 0.57, I ² = 0%; Fig. 5).

Effigy ii:

Progression-gratuitous survival in trials comparing bevacizumab-based maintenance treatment versus observation alone.

Figure 3:

Progression-free survival in trials comparing maintenance treatment with bevacizumab monotherapy versus observation alone.

Effigy 4:

Progression-gratuitous survival in trials comparing maintenance treatment with bevacizumab plus a fluoropyrimidine versus observation alone.

Figure 5:

Overall survival in trials comparing bevacizumab-based maintenance handling versus ascertainment alone.

A subgroup assay of toxic furnishings suggested that compared with the ascertainment-lone strategy, the bevacizumab-based maintenance therapy strategies increased the incidence of hypertension (odds ratio: 0.56, 95% CI: 0.43–0.74), mitt-and-foot syndrome (OR: 0.19, 95% CI: 0.eleven–0.31), and sensory neuropathy (OR: 0.51, 95% CI: 0.34–0.77; Fig. half-dozen).

Figure half-dozen:

Adverse events related to bevacizumab-based maintenance treatment versus observation solitary.

three.3 Bevacizumab-based maintenance therapy versus continuous chemotherapy

Five trials comparing bevacizumab-based continuous chemotherapy (bevacizumab plus five-FU, erlotinib, or capecitabine) with bevacizumab-based maintenance therapy provided data on PFS. Significant heterogeneity was institute among these trials (P = .0003, I ² = 80%; Fig. 7). The data showed that compared with continuous chemotherapy, bevacizumab-based maintenance therapy (with or without fluoropyrimidine) did non significantly prolong PFS (Hr: 0.91, 95% CI: 0.70–ane.xviii). Similarly, there was no significant inter-group difference between bevacizumab-based maintenance therapy and bevacizumab-based continuous therapy with respect to Bone (Hr: 0.88, 95% CI: 0.74–1.04). No significant heterogeneity was observed in the Bone analyses (P = .22, I ² = 31%; Fig. eight).

Figure 7:

Progression-complimentary survival in trials comparing bevacizumab-based continuous chemotherapy versus maintenance therapy.

Figure 8:

Overall survival in trials comparing bevacizumab-based continuous chemotherapy versus maintenance therapy.

Using a random-furnishings model, we plant that compared with the continuous strategy, the maintenance strategy was associated with a lower incidence of grade 3/4 agin events (OR: 0.57, 95% CI: 0.43–0.76; Fig. 9). The well-nigh common grade 3/iv adverse events were hypertension (OR: 1.12, 95% CI: 0.76–1.67), fatigue (OR: 0.51, 95% CI: 0.39–0.66), neutropenia/fever (OR: 0.58, 95% CI: 0.37–0.91), paw-and-foot syndrome (OR: 0.45, 95% CI: 0.29–0.67), diarrhea (OR: 0.35, 95% CI: 0.12–0.97), nausea/airsickness (OR: 0.59, 95% CI: 0.37–0.95), and sensory neuropathy (OR: 0.68, 95% CI: 0.25–1.85).

Figure nine:

Agin events related to bevacizumab-based maintenance therapy versus continuous chemotherapy.

iii.4 Publication bias

We generated funnel plots of PFS indicators in both comparisons (Figs. 10 and xi). The inverted funnel plots were symmetric, indicating that there was no publication bias amid the included studies.

Figure 10:

Publication bias in trials comparing bevacizumab-based maintenance therapy versus observation alone.

Figure 11:

Publication bias in trials comparison bevacizumab-based maintenance therapy versus continuous chemotherapy maintenance therapy versus observation alone.

iv Discussion

Bevacizumab, a humanized monoclonal antibody against VEGF, selectively blocks VEGF binding to the VEGFR-ane and VEGFR-2 receptors, thereby inhibiting the tumor angiogenesis.^[22] The addition of bevacizumab to five-FU-based combination chemotherapy results in improvements in the overall response rate, PFS, and OS among mCRC patients.^[x] This meta-analysis has clearly showed that compared with ascertainment alone, bevacizumab-based maintenance therapy has a significant benefit in terms of PFS and has a trend toward prolonging OS in mCRC patients who benefit from kickoff-line therapy. Compared with ascertainment alone, bevacizumab-based maintenance therapy significantly improved PFS (HR: 0.62, 95% CI: 0.47–0.82) and showed a trend toward prolonged OS (Hour: 0.93, 95% CI: 0.83–1.05). Although the toxicity of bevacizumab-based maintenance therapy was increased, the patients were well tolerated. However, there were no difference of PFS (HR: 0.91, 95% CI: 0.70–ane.xviii) and Bone (Hr: 0.88, 95% CI: 0.74–1.04) between the bevacizumab solitary and combination chemotherapy groups. Furthermore, the toxicity including diarrhea and sensory neuropathy was increased in bevacizumab combination chemotherapy group. Together, these information suggested the bevacizumab alone maintenance therapy perhaps the optimal strategy for mCRCs patients.

Although the OS have not significantly departure between maintenance therapy with bevacizumab alone versus observation alone, there were significant benefits in terms of PFS. However, dissimilar follow-upwards intervals and assessment methods have an impact on PFS information. In the AIO 0207 trial, the median PFS after commencement-line therapy was slightly but significantly improved by bevacizumab maintenance compared with ascertainment (4.vi vs three.v months). Non-inferiority for bevacizumab lone was demonstrated for the primary endpoint in AIO 0207, and during the maintenance phases, CT or MRI scans were washed every vi weeks. In the SAKK 41/06 trial, the median PFS was 4.1 months for the bevacizumab maintenance therapy arm versus ii.nine months for the ascertainment lone arm. The follow-upwardly time and equipment were inconsistent in each trial. Not-inferiority could non be demonstrated for continuing bevacizumab monotherapy, CT scans were also done every 6 weeks until disease progression in SAKK 41/06 trials. CT scans were done every eight weeks to assess the disease condition in the PRODIGE 9 trial. There may exist a small difference between trials from the time to beginning maintenance treatment to the outset progression betwixt patients treated with bevacizumab and those in the observation group.

Cost-effectiveness was mentioned in the CAIRO3 trial^[23] and the SAKK41/06 trial. In the CAIRO3 experiment, bevacizumab-based maintenance therapy (CAP-B) price on average €36,845 more than the observation-alone strategy. In the SAKK41 trial, the boilerplate cost (in United states dollars) per patient was $37,596 (range, $4794–$229,038) for the bevacizumab maintenance arm and $8180 (range, $330–$83,465) for the observation grouping. Compared with observation, maintenance therapy leads to an improvement in the quality of life, but it also leads to an increment in costs. Although there is no consensus on the cost-effectiveness thresholds for cancer handling, the toll-effectiveness of maintenance handling cannot be ignored.

The beginning-line treatment should also be considered as a potential source of bias. Trials of oxaliplatin-based first-line therapy (100% of patients in the CAIRO3 and AIO KRK 0207 trials and 62% of patients in the SAKK 41/06 trial with 31% also receiving irinotecan) that compared maintenance therapy with observation lonely showed that maintenance handling had no meaning effect to extend Bone. In the PRODIGE ix trial (100% of patients receiving irinotecan), the irinotecan-based combination with bevacizumab maintenance therapy resulted in prolong the OS. The use of oxaliplatin has cumulative toxicity, particularly neurotoxicity. Using irinotecan-based chemotherapy may be more feasible than oxaliplatin-based chemotherapy, which may require more clinical trial on maintenance therapy to further ostend.

CRCs can be characterized by their primary tumor location within the colon. The right and left sides of the colon differ in the clinical features, and chromosomal and molecular characteristics. For the above reasons, in a big number of clinical studies on mCRC patients, the location of the primary colon tumor besides has an result on the therapeutic response.^[24] Based on mature survival data from AIO 0207 trial, patients with left-sided tumors showed a median Os of 24.8 months compared with the correct-sided cohort with 18.four months. In a multivariable model, location of the primary tumor proved to be an prognostic cistron.^[25] In the AIO 0207 and PRODIGE 9 trials, World Wellness Organization condition ≥two, and more than one metastatic site were associated with a shorter Os. Tumor BRAF mutations were a poor prognostic factor in both trials. In addition, in the CAIRO3 and PRODIGE 9 trials, patients with synchronized metastases who were given bevacizumab-based maintenance therapy had a ameliorate OS than the observation-solitary group. The PRODIGE 9 trial recommended that patients with poor prognostic molecular markers were unsuitable for maintenance therapy strategies. However, the OPTIMOX series of studies^[26] suggested that high-risk patients with poor prognosis tin receive maintenance therapy, while observation after offset-line therapy may be a more rational strategy in low-risk patients with a good prognosis.

While drawing clear recommendations for optimal maintenance treatment options, we were able to identify key differences in PFS in clinical trials comparing single bevacizumab maintenance therapy with combination chemotherapy. The results of the MACRO trial suggest that single-amanuensis maintenance therapy with bevacizumab may be an appropriate option for mCRC patients. The "Stop and Go" trial proposes that maintenance therapy with bevacizumab plus capecitabine afterwards first-line chemotherapy with half-dozen cycles of bevacizumab + XELOX tin can be considered an appropriate choice. In the Nordic ACT trial and OPTIMOX3 trial, afterwards beginning-line chemotherapy, maintenance therapy with a combination of erlotinib and bevacizumab demonstrated better PFS than did maintenance therapy with bevacizumab lone. The old is a new non-chemotherapy-based maintenance regimen, whose relatively small-scale efficacy seems to exist outweighed by its significant toxicity, especially rash, diarrhea, and fatigue. Ongoing clinical and translational studies focus on identifying subgroups of patients that may do good from erlotinib in the maintenance setting. The AIO 0207 trial investigated whether ascertainment strategy or bevacizumab alone are non-junior to a fluoropyrimidine plus bevacizumab, following first-line treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab. The results showed that maintenance with a fluoropyrimidine plus bevacizumab provided longer PFS than did de-escalation to bevacizumab monotherapy or to no handling at all. Furthermore, we plant that the incidence of agin events tended to be higher later the bevacizumab combination commencement-line treatment regiments than after bevacizumab maintenance treatment or observation lone. Although the 8 trials showed that compared with observation lone, bevacizumab-based maintenance significantly prolonged PFS and improved quality of Life, only without improve OS. Further stratification based on the risk factors, such equally primary site of colon cancer, BRAF V600 and RAS mutation status, physical status and number of metastatic sites and and so on, the clinical trials of maintenance therapy based on further stratification may be prolong the patient'due south OS while increasing PFS.

The current meta-analysis has several limitations. Starting time of all, this is a meta-analysis at report level. We could not obtain individual patient data from the publication, thus we could non incorporate patients variables into the assay. Second, there were heterogeneities in the trial blueprint (superiority in CAIRO3 and noninferiority in AIO, KRK 0207, and SAKK 41/06). Furthermore, the variability in the baseline patient characteristics (e.g., the trial design, differences in induction treatments and fluoropyrimidine maintenance schedules, induction treatment duration, and drug intensity) could not be controlled for. This necessitated adjusting the data according to the written report design, which should be considered equally a potential source of bias.

v Decision

Compared with observation lone, bevacizumab-based maintenance therapy significantly prolonged the PFS of mCRC patients. Bevacizumab-based maintenance therapy seems take comparable effectiveness (in terms of PFS and OS) to unmarried drug maintenance chemotherapy with lower cumulative form iii/4 toxicity. Thus, maintenance therapy with bevacizumab may exist a valid option for mCRC patients. Although maintenance therapy has demonstrated meaning benefits in clinical studies, the treatment should notwithstanding exist individualized. Irinotecan-based starting time-line chemotherapy may be more probable to prolong OS than oxaliplatin-based induction chemotherapy, more than clinical studies are needed to confirm. Clinical studies are conducted on the basis of further stratification, which may prolong the Os of patients with mCRC.

Author contributions

Funding conquering: Hongbo Ma.

Investigation: Hongbo Ma, Nan Tang, Yanyan Li.

Methodology: Miaomiao Tao, Xianquan Zhang.

Project assistants: Hongbo Ma, Qi Zhou.

Resources: Hongbo Ma, Yanyan Li.

Software: Hongbo Ma, Xiaoli Wu, Miaomiao Tao.

Writing – original draft: Hongbo Ma.

Writing – review & editing: Hongbo Ma, Xianquan Zhang, Qi Zhou.

Qi Zhou orcid: 0000-0002-6391-0453

Hongbo Ma orcid: 0000-0003-0712-9926.

References

[ane]. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and bloodshed worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359–86.

• Cited Here

[two]. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9–29.

• Cited Here

[3]. Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin 2014;64:104–17.

• Cited Here

[4]. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line handling in avant-garde colorectal cancer. J Clin Oncol 2000;18:2938–47.

• Cited Here

[five]. Colucci G, Gebbia V, Paoletti Thou, et al. Stage 3 randomized trial of FOLFIRI versus FOLFOX4 in the treatment of avant-garde colorectal cancer: a multicenter report of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 2005;23:4866–75.

• Cited Here

[6]. Van Cutsem East, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a big stage 3 report. J Clin Oncol 2001;19:4097–106.

• Cited Hither

[7]. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone equally beginning-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041–7.

• Cited Here

[8]. Bokemeyer C, Van Cutsem Eastward, Rougier P, et al. Addition of cetuximab to chemotherapy equally beginning-line handling for KRAS wild-blazon metastatic colorectal cancer: pooled assay of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 2012;48:1466–75.

• Cited Here

[9]. Munoz A, Pericay C, Garcia-Giron C, et al. Phase II study of bevacizumab, capecitabine, and oxaliplatin followed past bevacizumab plus erlotinib equally get-go-line therapy in metastatic colorectal cancer. Oncol Res 2013;21:181–91.

• Cited Hither

[ten]. Hurwitz H, Fehrenbacher L, Novotny West, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. Northward Engl J Med 2004;350:2335–42.

• Cited Here

[11]. Fakih MG. Metastatic colorectal cancer: current land and futurity directions. J Clin Oncol 2015;33:1809–24.

• Cited Here

[12]. Van Cutsem E, Rivera F, Berry S, et al. Prophylactic and efficacy of commencement-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 2009;20:1842–vii.

• Cited Hither

[13]. Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol 2008;26:5326–34.

• Cited Here

[14]. Hegewisch-Becker South, Graeven U, Lerchenmuller CA, et al. Maintenance strategies after offset-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol 2015;xvi:1355–69.

• Cited Here

[15]. Simkens LH, van Tinteren H, May A, et al. Maintenance handling with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 2015;385:1843–52.

• Cited Hither

[16]. Koeberle D, Betticher DC, von Moos R, et al. Bevacizumab continuation versus no continuation after outset-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III not-inferiority trial (SAKK 41/06). Ann Oncol 2015;26:709–14.

• Cited Here

[17]. Aparicio T, Ghiringhelli F, Boige Five, et al. Bevacizumab maintenance versus no maintenance during chemotherapy-gratis intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE ix). J Clin Oncol 2018;36:674–81.

• Cited Here

[eighteen]. Diaz-Rubio E, Gomez-Spain A, Massuti B, et al. First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab every bit maintenance therapy in patients with metastatic colorectal cancer: the stage III MACRO TTD study. Oncologist 2012;17:15–25.

• Cited Here

[nineteen]. Yalcin S, Uslu R, Dane F, et al. Bevacizumab + capecitabine as maintenance therapy subsequently initial bevacizumab + XELOX treatment in previously untreated patients with metastatic colorectal cancer: phase III 'Stop and Get' study results--a Turkish Oncology Grouping Trial. Oncology 2013;85:328–35.

• Cited Here

[20]. Johnsson A, Hagman H, Frodin JE, et al. A randomized phase III trial on maintenance handling with bevacizumab lone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic Human activity Trial. Ann Oncol 2013;24:2335–41.

• Cited Hither

[21]. Tournigand C, Chibaudel B, Samson B, et al. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open up-characterization, phase three trial. Lancet Oncol 2015;16:1493–505.

• Cited Hither

[22]. Presta LG, Chen H, O'Connor SJ, et al. Humanization of an anti-vascular endothelial growth cistron monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997;57:4593–9.

• Cited Here

[23]. Franken Md, van Rooijen EM, May AM, et al. Price-effectiveness of capecitabine and bevacizumab maintenance treatment after get-go-line induction treatment in metastatic colorectal cancer. Eur J Cancer 2017;75:204–12.

• Cited Here

[24]. Stintzing South, Tejpar Due south, Gibbs P, et al. Agreement the role of primary tumour localisation in colorectal cancer treatment and outcomes. Eur J Cancer 2017;84:69–80.

• Cited Here

[25]. Hegewisch-Becker S, Nopel-Dunnebacke Southward, Hinke A, et al. Bear upon of primary neoplasm location and RAS/BRAF mutational status in metastatic colorectal cancer treated with outset-line regimens containing oxaliplatin and bevacizumab: prognostic factors from the AIO KRK0207 kickoff-line and maintenance therapy trial. Eur J Cancer 2018;101:105–13.

• Cited Here

[26]. Chibaudel B, Maindrault-Goebel F, Lledo Chiliad, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol 2009;27:5727–33.

• Cited Here

Keywords:

bevacizumab; maintenance therapy; meta-analysis; metastatic colorectal cancer

Copyright © 2019 the Author(s). Published past Wolters Kluwer Health, Inc.

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