Significant increase of synchronous disease in first-line metastatic colorectal cancer trials: Results of a systematic review

BackgroundAlthough synchronous and metachronous metastases are considered as separate entities of metastatic colorectal cancer (mCRC) with different outcomes, its proportion is reported infrequently. We compared inclusion rates and survival of synchronous versus metachronous mCRC in different types of studies investigating initial systemic therapy or surgical treatment of mCRC.MethodsWe searched PubMed and EMBASE (January 2004 – February 2016) for mCRC studies investigating first-line systemic therapy or surgical treatment of mCRC including information on synchronous versus metachronous metastases. Outcomes were the proportion of synchronous mCRC, and estimated median overall survival (OS) of the total study population. Spearman analysis (r_s) was used to study correlations between outcomes and median year of study enrolment.ResultsWe included 46 articles, reporting data from 23 phase 3 randomised controlled trials (RCTs), twenty cohort and three population-based studies (total: 25,941 patients). Seventeen different definitions for synchronous mCRC were identified. In systemic therapy RCTs, we observed an increased proportion of synchronous mCRC during recent years (r_s .77, p < .001). In these trials, estimated median OS slightly improved over time (r_s .48, p = .03). No significant inclusion or survival trends were observed in included cohort and population-based studies.ConclusionsIn recent years, the proportion of patients with synchronous compared with metachronous mCRC enrolled in first-line systemic therapy RCTs increased. Estimated median OS of the total study population in these RCTs slightly increased over time. Many different definitions of synchronous disease were used. Uniform definitions and consistent reporting of the proportion of synchronous versus metachronous metastases could improve cross-study comparisons and interpretation of reported data in all mCRC studies.     

Does severe toxicity affect global quality of life in patients with metastatic colorectal cancer during palliative systemic treatment? A systematic review

BackgroundNew palliative systemic treatment regimens in patients with metastatic colorectal cancer (mCRC) have significantly improved overall survival and prognosis. These treatment regimens are often accompanied by increased toxicity, which may impair patients’ quality of life (QOL). We systematically reviewed whether severe toxicity affects global QOL in patients with mCRC receiving palliative systemic treatment in recent published randomized controlled trials (RCTs).Materials and methodsPhase III RCTs evaluating palliative systemic treatments in patients with mCRC and published between 2004 and 2016 were considered. Studies were evaluated on the basis of global QOL scores, toxicity during treatment (assessed by scoring relevant adverse events) and primary outcomes (POs).ResultsA total of 30 studies were identified in which 19863 patients were included. In 25 out of these 30 trials (83%), no difference in global QOL between treatment arms was observed. In contrast, 22 out of 30 trials (73%) showed increased toxicity during treatment in the experimental arm as compared with the control arm. In 19 out of 22 trials with higher toxicity (86%) global QOL outcomes remained unaffected or improved. In ten out of eleven studies with a better PO, no improvement in global QOL was seen.ConclusionGlobal QOL of patients with mCRC included in phase III RCTs evaluating palliative systemic treatment did not differ across treatment arms despite consistently higher toxicity during treatment of the experimental compared with the standard treatment arms. Based on these findings we conclude that the use of global QOL for comparing treatment arms in RCTs for patients with mCRC does not provide information of clinical relevance. Further consideration of how to better assess the net effect of new agents on patients’ QOL is urgently needed.     

Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials

BackgroundThere is increasing evidence that metastatic colorectal cancer (mCRC) is a genetically heterogeneous disease and that tumours arising from different sides of the colon (left versus right) have different clinical outcomes. Furthermore, previous analyses comparing the activity of different classes of targeted agents in patients with KRAS wild-type (wt) or RAS wt mCRC suggest that primary tumour location (side), might be both prognostic and predictive for clinical outcome.MethodsThis retrospective analysis investigated the prognostic and predictive influence of the localization of the primary tumour in patients with unresectable RAS wt mCRC included in six randomized trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181), comparing chemotherapy plus EGFR antibody therapy (experimental arm) with chemotherapy or chemotherapy and bevacizumab (control arms). Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) for patients with left-sided versus right-sided tumours, and odds ratios (ORs) for objective response rate (ORR) were estimated by pooling individual study HRs/ORs. The predictive value was evaluated by pooling study interaction between treatment effect and tumour side.ResultsPrimary tumour location and RAS mutation status were available for 2159 of the 5760 patients (37.5%) randomized across the 6 trials, 515 right-sided and 1644 left-sided. A significantly worse prognosis was observed for patients with right-sided tumours compared with those with left-sided tumours in both the pooled control and experimental arms for OS [HRs = 2.03 (95% CI: 1.69–2.42) and 1.38 (1.17–1.63), respectively], PFS [HRs = 1.59 (1.34–1.88) and 1.25 (1.06–1.47)], and ORR [ORs = 0.38 (0.28–0.50) and 0.56 (0.43–0.73)]. In terms of a predictive effect, a significant benefit for chemotherapy plus EGFR antibody therapy was observed in patients with left-sided tumours [HRs = 0.75 (0.67–0.84) and 0.78 (0.70–0.87) for OS and PFS, respectively] compared with no significant benefit for those with right-sided tumours [HRs = 1.12 (0.87–1.45) and 1.12 (0.87–1.44) for OS and PFS, respectively; P value for interaction <0.001 and 0.002, respectively]. For ORR, there was a trend (P value for interaction = 0.07) towards a greater benefit for chemotherapy plus EGFR antibody therapy in the patients with left-sided tumours [OR = 2.12 (1.77–2.55)] compared with those with right-sided tumours [OR = 1.47 (0.94–2.29)]. Exclusion of the unique phase II trial or the unique second-line trial had no impact on the results. The predictive effect on PFS may depend of the type of EGFR antibody therapy and on the presence or absence of bevacizumab in the control arm.ConclusionThis pooled analysis showed a worse prognosis for OS, PFS and ORR for patients with right-sided tumours compared with those with left-sided tumours in patients with RAS wt mCRC and a predictive effect of tumour side, with a greater effect of chemotherapy plus EGFR antibody therapy compared with chemotherapy or chemotherapy and bevacizumab, the effect being greatest in patients with left-sided tumours. These predictive results should be interpreted with caution due to the retrospective nature of the analysis, which was carried out on subpopulations of patients included in these trials, and because none of these studies contemplated a full treatment sequence strategy.     

Outcomes Following Treatment with FOLFOX for Patients with Resectable or Potentially Resectable Metastatic Colorectal Cancer: A Population-based Cohort Study

AimsTo evaluate the safety and effectiveness of oxaliplatin-based combination chemotherapy for patients with metastatic colorectal cancer (mCRC) to extrahepatic sites.Materials and methodsWe conducted a population-based retrospective study examining the safety and effectiveness of perioperative oxaliplatin for resectable or potentially resectable colorectal metastases in Ontario, Canada. Outcomes were also compared with patients with liver-only metastases. Patients received oxaliplatin for mCRC between 1 January 2013 and 30 June 2020.ResultsIn total, 192 patients had extrahepatic metastases. Seventy per cent had R0 metastasectomy. The 3-year disease-free survival and overall survival were 62% and 79%, respectively; <4% of patients died within 60 days of metastasectomy and 74–90% of patients received treatment according to recommendations from a multidisciplinary setting. Compared with liver-only controls (n = 1306), patients had mCRC to the lung only (n = 115), lung and liver (n = 55) and liver with non-pulmonary site (n = 22). Extrahepatic metastases were more likely to be found for patients whose primary colorectal resection had positive margins (14% versus 7%, P = 0.005) and primary tumours located in the rectum [odds ratio 4.01 (2.31–6.97)]. After adjustment, there was no difference in overall survival between liver-only controls and patients with lung-only [hazard ratio 0.82 (0.59–1.15)] or liver and lung metastases [hazard ratio 1.26 (0.85–1.87)] (P = 0.24). In total, 79/115 (69%) of patients with lung-only metastases had a metastasectomy compared with 645/1306 (49%) and 15/55 (27%) of patients with liver-only and liver and lung metastases, respectively. Hospital visits were similar between patients with liver-only and extrahepatic metastases.ConclusionOxaliplatin-based chemotherapy for patients with resectable or potentially resectable mCRC with extrahepatic metastases was safe and resulted in similar outcomes in appropriately selected patients when compared with patients with liver-only metastases.     

Regorafenib combined with programmed cell death-1 inhibitor against refractory colorectal cancer and the platelet-to-lymphocyte ratio’s prediction on effectiveness

BACKGROUNDThe effectiveness of regorafenib plus programmed cell death-1 (PD-1) inhibitor in treating microsatellite stable (MSS) metastatic colorectal cancer (mCRC) remains controversial. AIMTo investigate the benefits of regorafenib combined with PD-1 inhibitor in treating MSS mCRC and explore indicators predicting response. METHODSThis retrospective study included a total of 30 patients with microsatellite stable metastatic colorectal cancer treated with regorafenib combined with programmed cell death-1 inhibitor at Henan Provincial People’s Hospital between December 2018 and December 2020. During a 4-wk treatment cycle, regorafenib was performed for 3 continuous weeks. PD-1 inhibitor was intravenously injected starting on the first day of the oral intake of regorafenib. We reviewed tumor response, progression-free survival (PFS), overall survival, and treatment-related adverse events (TRAEs) and evaluated association between platelet-to-lymphocyte ratio (PLR) and outcomes in this retrospective study. RESULTSStable disease and progressive disease were found in 18 (60.0%) and 12 (40.0%) patients, respectively. The disease control rate was 60.0%. The median follow-up time was 12.0 mo, and median PFS was 3.4 mo [95% confidence interval (CI): 2.2-4.6 mo]. Of the 12 patients with progressive disease, 10 (83.3%) had liver metastasis before starting the combined treatment. Among the 18 patients with SD, 10 (55.6%) did not have liver metastases. One patient without liver metastases at baseline was found with a substantially prolonged PFS of 11.2 mo. The liver metastasis, the choice of programmed cell death-1 inhibitor other than nivolumab or pembrolizumab and previous exposure to regorafenib was’t associated with treatment outcome. The median PFS in the low-PLR group was 4.2 mo (95%CI: 3.5-4.9 mo), compared with 2.8 mo (95%CI: 1.4-4.2 mo) in the high-PLR group (P = 0.005). The major TRAEs included hand-foot syndrome (33.3%), hypertension (23.3%), malaise (20.0%), and gastrointestinal reaction (16.7%). The incidence of grade 3 TRAEs was 13.3% (4/30), which comprised abnormal capillary proliferation (n = 1), transaminase elevation (n = 1), and hand-foot syndrome (n = 2). No grade 4 or higher toxicity was observed. CONCLUSIONRegorafenib combined with PD-1 inhibitor could lead to a longer PFS in some patients with MSS mCRC. The PLR might be a prediction of the patient response to this therapy.     

Relationship among circulating tumor cells,CEA and overall survival in patients with metastatic colorectal cancer

BackgroundWe previously reported results of a prospective trial evaluating the significance of circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC). This secondary analysis assessed the relationship of the CTC number with carcinoembryonic antigen (CEA) and overall survival.Patients and methodsPatients with mCRC had CTCs measured at baseline and specific time points after the initiation of new therapy. Patients with a baseline CEA value ≥10 ng/ml and CEA measurements within ±30 days of the CTC collection were included.ResultsWe included 217 patients with mCRC who had a CEA value of ≥10 ng/ml. Increased baseline CEA was associated with shorter survival (15.8 versus 20.7 months, P = 0.012). Among all patients with a baseline CEA value of ≥25 ng/ml, patients with low baseline CTCs (<3, n = 99) had longer survival than those with high CTCs (≥3, n = 58; 20.8 versus 11.7 months, P = 0.001). CTCs added prognostic information at the 3–5- and 6–12-week time points regardless of CEA. In a multivariate analysis, CTCs at baseline but not CEA independently predicted survival and both CTCs and CEA independently predicted survival at 6–12 weeks.ConclusionsThis study demonstrates that both CEA and CTCs contribute prognostic information for patients with mCRC.     

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study

BackgroundA targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy.Patients and methodsPatients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety.ResultsThree hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75–1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81–1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups.ConclusionBevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment.Clinical trial identifierUMIN000002557.     

Comparison of absolute benefits of anticancer therapies determined by snapshot and area methods

BackgroundReporting of relative risk reduction as the measure of treatment effect in randomized clinical trials (RCTs) may be difficult to understand. Here, we compare two methods for assessing absolute benefits of anticancer therapies.Materials and methodsWe searched PubMed for RCTs comparing therapies for breast and colorectal cancers published 1975–2009 (adjuvant setting) and 2000–2010 (metastatic setting). Eligible trials reported statistically significant differences. Kaplan–Meier curves were assessed for absolute differences in time-to-event end points at a single point (snapshot method) and as the area between curves (area method). Pooled absolute benefits determined by both methods were compared by the Pitman–Morgan test.ResultsEighty-three and 39 paired curves were assessed in the adjuvant and metastatic settings, respectively. In trials of adjuvant therapy, absolute benefits were larger and more variable when assessed at different time points by the snapshot compared with the area method (median and ranges for 60-month difference in overall survival: 7.6% [2.5%–28.4%] and 4.5% [1.8%–13.6%]; P = 0.002, respectively). For metastatic disease, both methods were within 0.5 month of each other in 62% of trials.ConclusionsThe area method provides an alternative measure of absolute treatment effect, which uses all of the available data and is less dependent on the shape of survival curves.     

抗VEGF与抗EGFR靶向药物联合化疗一线治疗转移结直肠癌Meta分析

目的 NCCN指南推荐抗VEGF或抗EGFR作为伴RAS野生型的转移结直肠癌(metastatic colorectal canc-er,mCRC)一线治疗的标准方案,但抗VEGF与抗EGFR在转移结直肠癌预后的差异性罕见系统评价参考.本研究拟通过系统评价分析抗VEGF与抗EGFR靶向药物联合化疗对转移结直肠癌疗效的影响.方法 计算机检索Cochrane、Pubmed、Web of science、Embase、ASCO、ESMO、Clinical Trials和中国生物医学文献数据库等,同时追溯参考文献.收集抗VEGF联合化疗对比抗EGFR联合化疗治疗mCRC头对头的随机对照试验(Randomized controlled trial,RCT),根据Cochrane系统评价手册5.3质量评价标准,采用Stata 12.0和Revman 5.3进行Meta分析.结果 共纳入3篇临床随机对照试验,共2014例研究对象.Meta分析结果显示,一线给予抗EGFR或抗VEGF联合化疗的mCRC患者,无论KRAS野生型(HR=1.03,95%CI为0.93~1.13)或RAS野生型(HR=0.92,95%CI为0.71~1.18)的无进展生存期(pogression free survival,PFS)均差异无统计学意义,P<0.05.一线给予抗EGFR联合化疗方案的总生存期(overall survival,OS)KRAS野生型(HR=0.82,95%CI为0.72~0.93)和RAS野生型患者(HR=0.79,95%CI为0.67~0.93)均优于抗VEGF联合化疗,P<0.05.mCRC伴KRAS野生型患者,接受抗EGFR联合化疗客观缓解率(objective re-sponse rate,ORR)显著提高,RR=0.84,95%CI为0.76~0.94;这种优势对于所有的RAS野生型患者更加明显,RR=0.80,95%CI为0.68~0.93.无论使用抗EGFR或抗VEGF联合化疗,左半结直肠癌患者相比右半结肠癌患者有生存获益PFS(HR=0.64,95%CI为0.45~0.91)及OS(HR=0.53,95%CI为0.36~0.76).结论 mCRC伴KRAS或RAS野生型患者的一线治疗,抗EGFR单克隆抗体可能是替代抗VEGF治疗作为晚期mCRC的初始治疗的最佳治疗方案.而对于肿瘤的位置而言,无论接受何种靶向药物治疗,左半结肠肿瘤相比右半结肠肿瘤的患者都具有更好的生存优势.     

FOLFOXIRI-Bevacizumab or FOLFOX-Panitumumab in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer: A Propensity Score-Based Analysis

BackgroundDoublets plus anti‐epidermal growth factor receptors (EGFRs) are the preferred upfront option for patients with left‐sided RAS/BRAF wild‐type metastatic colorectal cancer (mCRC). Initial therapy with FOLFOXIRI‐bevacizumab is superior to doublets plus bevacizumab independently from primary tumor sidedness and RAS/BRAF status. No randomized comparison between FOLFOXIRI‐bevacizumab versus doublets plus anti‐EGFRs is available in left‐sided RAS/BRAF wild‐type mCRC.Materials and MethodsWe selected patients with left‐sided RAS and BRAF wild‐type mCRC treated with first‐line FOLFOX‐panitumumab or FOLFOXIRI‐bevacizumab in five randomized trials: Valentino, TRIBE, TRIBE2, STEAM, and CHARTA. A propensity score‐based analysis was performed to compare FOLFOXIRI‐bevacizumab with FOLFOX‐panitumumab.ResultsA total of 185 patients received FOLFOX‐panitumumab and 132 received FOLFOXIRI‐bevacizumab. Median progression‐free survival (PFS) and median overall survival (OS) were 13.3 and 33.1 months in the FOLFOXIRI‐bevacizumab group compared with 11.4 and 30.3 months in the FOLFOX‐panitumumab group (propensity score‐adjusted hazard ratio (HR) for PFS, 0.82; 95% confidence interval (CI), 0.64–1.04; p = .11; propensity score‐adjusted HR for OS, 0.80; 95% CI, 0.59–1.08; p = .14). No significant differences in overall response rate and disease control rate were observed. A statistically nonsignificant difference in favor of FOLFOXIRI‐bevacizumab was observed for OS after secondary resection of metastases. Chemotherapy‐related adverse events were more frequent in the FOLFOXIRI‐bevacizumab group, with specific regard to grade 3 and 4 neutropenia (48% vs. 26%, adjusted p = .001).ConclusionAlthough randomized comparison is lacking, both FOLFOXIRI‐bevacizumab and FOLFOX‐panitumumab are valuable treatment options in left‐sided RAS/BRAF wild‐type mCRC.Implications for PracticeA propensity score‐based analysis of five trials was performed to compare FOLFOX‐panitumumab versus FOLFOXIRI‐bevacizumab in left‐sided RAS/BRAF wild‐type metastatic colorectal cancer (mCRC). No significant differences were observed, but FOLFOXIRI‐bevacizumab achieved numerically superior survival outcomes versus FOLFOX‐panitumumab. Chemotherapy‐related adverse events were more frequent in the FOLFOXIRI‐bevacizumab group. These observations suggest that although doublet chemotherapy plus anti‐EGFRs remains the preferred treatment in patients with left‐sided RAS/BRAF wild‐type mCRC, FOLFOXIRI‐bevacizumab is a valuable option able to provide similar, if not better, outcomes at the price of a moderate increase in toxicity and may be adopted based on patients’ preference and potential impact on quality of life.     

Meta-analysis comparing the efficacy of anti-EGFR monoclonal antibody therapy between KRAS G13D and other KRAS mutant metastatic colorectal cancer tumours

BackgroundMetastatic colorectal cancer (mCRC) tumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies (mAbs). However, observational evidence has led to speculation that mCRC patients with KRAS G13D mutant (MT) tumours may derive a benefit from treatment with anti-EGFR mAbs.MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between tumours harbouring a KRAS G13D mutation (KRAS G13D) and KRAS mutations other than G13D (other KRAS MT).ResultsEight RCTs (n = 5967) met the inclusion criteria for assessment of both overall survival (OS) and progression-free survival (PFS). For other KRAS MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 (95% confidence interval [CI]; 0.96, 1.17), compared to 1.08 (95% CI; 0.73, 1.60) for KRAS G13D [test for interaction p = 0.99]. In contrast, the hazard ratio for KRAS wild-type (WT) tumours was 0.85 (95% CI; 0.76, 0.95). Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 1.07 (95% CI; 0.92, 1.26) for other KRAS MT, 0.96 (95% CI; 0.73, 1.27) for KRAS G13D, and 0.68 (95% CI; 0.54, 0.85) for KRAS WT. Again, the test for interaction (p = 0.46) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT.ConclusionThis meta-analysis demonstrates no significant difference between KRAS G13D and other KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC.     

Extended Adjuvant Therapy With Aromatase Inhibitors for Early Breast Cancer: A Meta-analysis of Randomized Controlled Trials

BackgroundAromatase inhibitors (AIs) are widely used for early breast cancer, whereas the efficacy and safety of extended AI adjuvant therapy compared with shorter AI therapy, observation, or placebo remains controversial. We conducted a quantitative meta-analysis to summarize available randomized controlled trials (RCTs) regarding the efficacy and safety of extended AI therapy for early breast cancer.Materials and MethodsWe systematically searched PubMed, EmBase, and the Cochrane library to select studies published through March 2018. Studies designed as RCTs and that investigated overall survival (OS) or disease-free survival (DFS) for extended AI and shorter AI therapy, observation, or placebo were included. Hazard ratio (HR) and relative risk (RR) with 95% confidence intervals (CIs) were employed to pool analysis according to data type.ResultsWe identified 7 RCTs that involved 16,926 patients with early breast cancer. The summary HRs indicated that extended treatment with AIs was not associated with OS (HR, 0.95; 95% CI, 0.82-1.10; P = .488), whereas it could significantly improve DFS as compared with shorter AI therapy, observation, or placebo (HR, 0.75; 95% CI, 0.66-0.86; P < .001). Treatment with extended AIs significantly reduced contralateral breast cancer recurrence (RR, 0.46; 95% CI, 0.34-0.64; P < .001), whereas it has no significant effect on distant metastatic recurrence (RR, 0.80; 95% CI, 0.64-1.00; P = .055), and locoregional recurrence (RR, 0.76; 95% CI, 0.53-1.08; P = .127). There were no significant differences between treatment with extended AIs and control for grade 3 or more adverse events.ConclusionExtended AI therapy could significantly improve DFS, especially for contralateral breast cancer recurrence. There were no significant differences between treatment with AIs and control for OS, distant metastatic and locoregional recurrence, and serious adverse events.     

Efficacy and Safety of Bevacizumab in Metastatic Colorectal Cancer: Pooled Analysis From Seven Randomized Controlled Trials

Purpose.

This analysis pooled individual patient data from randomized controlled trials (RCTs) to more thoroughly examine clinical outcomes when adding bevacizumab to chemotherapy for patients with metastatic colorectal cancer (mCRC).

Patients and Methods.

Patient data were pooled from the first-line AVF2107, NO16966, ARTIST, AVF0780, AVF2192, and AGITG MAX RCTs and the second-line E3200 RCT. All analyses were based on the intent-to-treat population. To assess differences in time-to-event variables by treatment (chemotherapy with or without placebo vs. chemotherapy plus bevacizumab), stratified random-effects (overall) and fixed-effects (subgroup comparisons) models were used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs).

Results.

The analysis population comprised 3,763 patients (1,773 chemotherapy with or without placebo; 1,990 chemotherapy plus bevacizumab). The addition of bevacizumab to chemotherapy was associated with statistically significant increases in overall survival (OS; HR, 0.80; 95% CI, 0.71–0.90) and progression-free survival (PFS; HR, 0.57; 95% CI, 0.46–0.71). The effects on OS and PFS across subgroups defined by chemotherapy backbone (oxaliplatin-based, irinotecan-based), extent of disease (liver metastases only, extensive disease), age (<65, ≥65 years), Eastern Cooperative Oncology Group performance status (0, ≥1), and KRAS status (wild-type, mutant) were consistent with the overall analysis. Incidence rates of grade ≥3 hypertension, proteinuria, bleeding, wound-healing complications, gastrointestinal perforations, and thromboembolic events were increased with bevacizumab treatment.

Conclusion.

The use of bevacizumab with chemotherapy resulted in statistically significant increases in OS and PFS for patients with mCRC. The PFS benefit extended across the clinically relevant subgroups examined. The observed safety profile of bevacizumab was consistent with that reported in individual trials.     

Long-Term Survivors of Metastatic Colorectal Cancer Treated with Systemic Chemotherapy Alone: A North Central Cancer Treatment Group Review of 3811 Patients,N0144

BackgroundAlthough systemic chemotherapy in patients with unresectable metastatic colorectal cancer (mCRC) is palliative in nature, some patients experience long-term remission beyond 5 years consequent to treatment with chemotherapy alone.Patients and MethodsWe reviewed clinical data from 32 prospective North Central Cancer Treatment Group chemotherapy trials in mCRC that enrolled patients from 1972 to 1995. Metastatic CRC was verified histologically. Excluded from analyses were patients who withdrew consent to the study, enrolled in > 1 study, were ineligible, or had major protocol violations. We defined patients with survival beyond 5 years from the initiation of systemic treatment of mCRC as long-term survivors (LTS).ResultsA total of 36 of 3407 (1.1%) patients were LTS. A total of 13 patients (0.4%) are without evidence of disease or disease progression > 5 years from cessation of last chemotherapy, with a median follow-up of 10.6 years (minimum, 7.6 years). Long-term survivors were more likely to have received 5-fluorouracil (5-FU)–based treatment (33 of 2503 [1.3%]) as opposed to other, less effective therapy (3 of 904 [0.3%]), suggesting that the chemotherapy played an important role among LTS (P = .01). Clinical characteristics of LTS were similar to the overall population in terms of age, sex, performance status, and tumor grade.ConclusionThis study establishes a baseline for long-term outcomes of mCRC in the era when effective treatment was limited to 5-FU. With the development of improved systemic therapy for mCRC, cure without salvage surgery might be possible for a small, but important number of patients. Clinical trials should follow patients for > 5 years to document the long-term outcomes.     

Effectiveness of Combining Bevacizumab With First-Line Chemotherapy Regimens for Metastatic Colorectal Cancer in Real-World Practice

BackgroundAnti–vascular endothelial growth factor (VEGF) agents have shown clinical benefits against metastatic colorectal cancer (mCRC) when combined with cytotoxic chemotherapeutic drugs. Because randomized controlled trials have restrictive enrollment criteria, and because the participants typically do not resemble actual patients, we here investigated the efficacy of bevacizumab as part of a combination therapy for mCRC in a Korean real-world practice setting.Patients and MethodsWe retrospectively evaluated 3748 patients with an initial diagnosis of mCRC or recurrent colorectal cancer with distant metastasis who received first-line chemotherapy in a tertiary cancer center. The primary study endpoint was overall survival. We used multivariate analysis using the Cox regression hazard model and propensity score matching (PSM) methods to adjust for any confounding clinicopathologic factors. Subgroup analysis was also performed for patients who did not receive local treatments for metastatic lesions before receipt of first-line chemotherapy.ResultsIn an initial crude analysis, patients who received first-line FOLFOX or FOLFIRI showed better survival outcomes if these regimens were combined with bevacizumab (median overall survival, 3.5 vs. 2.3 years; hazard ratio [HR] = 0.66; 95% confidence interval [CI], 0.59-0.73; P < .001). However, Cox regression hazard model adjusted analysis using PSM methods revealed no significant survival differences between these groups (3.0 vs. 2.6 years; HR = 0.92; 95% CI, 0.79-1.07; P = .2612). We performed further survival analysis of 2814 patients with unresectable disease without metastasectomy who received metastatic radiofrequency ablation before chemotherapy. Cox regression and PSM analysis indicated that bevacizumab group showed better survival (HR = 0.82; 95% CI, 0.71-0.94; P = .005; and HR = 0.84; 95% CI, 0.71-0.99; P = .018).ConclusionThe addition of bevacizumab to a first-line chemotherapeutic regimen provides survival benefits in a real-world setting for mCRC patients who cannot undergo curative-intent local treatment for metastatic lesions.     

Genotype-based selection of treatment of patients with advanced colorectal cancer (SETICC): a pharmacogenetic-based randomized phase II trial

BackgroundThere has been little progress toward personalized therapy for patients with metastatic colorectal cancer (mCRC). TYMS-3′untranslated region (UTR) 6 bp ins/del and ERCC1-118C/T polymorphisms were previously reported to facilitate selecting patients for fluoropyrimidine-based treatment in combination with oxaliplatin as first-line therapy. We assessed the utility of these markers in selecting therapy for patients with mCRC.Patients and methodsThis randomized, open-label phase II trial compared bevacizumab plus XELOX (control) versus treatment tailored according to TYMS-3′UTR 6 bp ins/del and ERCC1-118C/T polymorphisms. Patients randomized to the experimental treatment received bevacizumab plus FUOX, FUIRI, XELIRI, or XELOX depending on their combination of favorable polymorphisms for FUOX treatment (TYMS-3′UTR ins/del or del/del; ERCC1-118T/T). Progression-free survival (PFS) was the primary end point.ResultsOverall, 195 patients were randomized (control n = 65; experimental n = 130). The primary objective was not met: median PFS was 9.4 months in the control group and 10.1 months in the experimental group (P = 0.745). Median overall survival was similar in both groups (16.5 versus 19.1 months, respectively; P = 0.797). Patients in the experimental group had a significantly higher overall response rate (ORR; 65% versus 47% in the control group; P = 0.042) and R0 resection rate (86% versus 44%, respectively; P = 0.018). Neuropathy, hand–foot syndrome, thrombocytopenia, and dysesthesia were significantly less common in the experimental group.ConclusionsThis study did not show survival benefits after treatment personalization based on polymorphisms in mCRC. However, the improved ORR and R0 resection rate and fewer disabling toxicities suggest that tailoring therapy by TYMS-3′UTR and ERCC1-118 polymorphisms warrants further investigation in patients with mCRC.ClinicalTrials.govNCT01071655.     

Estimating 12-week death probability in patients with refractory metastatic colorectal cancer: the Colon Life nomogram

BackgroundRegorafenib and TAS-102 have recently demonstrated statistically significant survival gains in patients with refractory metastatic colorectal cancer (mCRC). Life expectancy ≥12 weeks was an inclusion criterion in registrative trials, and the identification of proper clinical selection tools for the daily use of these drugs in heavily pre-treated patients is needed to improve the cost-benefit ratio. We aimed at building a nomogram able to predict death probability within 12 weeks from the date of assessment of refractory mCRC.Patients and methodsFour hundred eleven refractory mCRC patients with ECOG performance status (PS) ≤2 receiving regorafenib, TAS-102 or other treatments were used as developing set. Putative prognostic variables were selected using a random forest model and included in a binary logistic model from which the nomogram was developed. The nomogram was externally validated and its performance was evaluated by examining calibration (how close predictions were to the actual outcome) and discriminative ability (Harrell C index) both on developing (internal validation) and validating (external validation) sets.ResultsFour variables were selected and included in the nomogram: PS (P < 0.0001), primary tumor resection (P = 0.027), LDH value (P = 0.0001) and peritoneal involvement (P = 0.081). In the developing set, the nomogram discriminative ability was high (C = 0.778), and was confirmed in the validating set (C = 0.778), where the overall outcome was better as a consequence of the enrichment in patients receiving regorafenib or TAS-102 (46% versus 34%;P < 0.0001).ConclusionsOur nomogram may be a useful tool to predict the probability of death within 12 weeks in patients with refractory mCRC. Based on four easy-to-collect variables, the ‘Colon Life’ nomogram and free app for smartphones may improve mCRC patients’ selection for later-line therapies and assist researchers for the enrollment in clinical trials in this setting.     

Dynamic molecular analysis and clinical correlates of tumor evolution within a phase II trial of panitumumab-based therapy in metastatic colorectal cancer

BackgroundMutations in rat sarcoma (RAS) genes may be a mechanism of secondary resistance in epidermal growth factor receptor inhibitor-treated patients. Tumor-tissue biopsy testing has been the standard for evaluating mutational status; however, plasma testing of cell-free DNA has been shown to be a more sensitive method for detecting clonal evolution.Materials and methodsArchival pre- and post-treatment tumor biopsy samples from a phase II study of panitumumab in combination with irinotecan in patients with metastatic colorectal cancer (mCRC) that also collected plasma samples before, during, and after treatment were analyzed for emergence of mutations during/post-treatment by next-generation sequencing and BEAMing.ResultsThe rate of emergence of tumor tissue RAS mutations was 9.5% by next-generation sequencing (n= 21) and 6.3% by BEAMing (n = 16). Plasma testing of cell-free DNA by BEAMing revealed a mutant RAS emergence rate of 36.7% (n = 39). Exploratory outcomes analysis of plasma samples indicated that patients who had emergent RAS mutations at progression had similar median progression-free survival to those patients who remained wild-type at progression. Serial analysis of plasma samples showed that the first detected emergence of RAS mutations preceded progression by a median of 3.6 months (range, -0.3 to 7.5 months) and that there did not appear to be a mutant RAS allele frequency threshold that could predict near-term outcomes.ConclusionsThis first prospective analysis in mCRC showed that serial plasma biopsies are more inclusive than tissue biopsies for evaluating global tumor heterogeneity; however, the clinical utility of plasma testing in mCRC remains to be further explored.ClinicalTrials.gov IdentifierNCT00891930     

Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group

BackgroundHand–foot syndrome (HFS) is a common side-effect of capecitabine. S-1 is an oral fluoropyrimidine with comparable efficacy to capecitabine in gastrointestinal cancers but associated with a lower incidence of HFS in Asian patients. This study compares the incidence of HFS between S-1 and capecitabine as first-line treatment in Western metastatic colorectal cancer (mCRC) patients.Patients and methodsPatients with previously untreated mCRC and planned treatment with fluoropyrimidine monochemotherapy were randomized 1 : 1 to receive either capecitabine (1250 mg/m² orally for patients <70 years; 1000 mg/m² for patients ≥70 years, twice daily on days 1–14) or S-1 (30 mg/m² orally twice daily on days 1–14) in 3-weekly cycles, with bevacizumab optional in both groups. The primary endpoint was the incidence of any grade HFS, as assessed by both physicians and patients (diaries). Secondary endpoints included grade 3 HFS, other toxicities, relative dose intensity, progression-free survival, response rate and overall survival.ResultsA total of 161 patients were randomized in 27 centres. The incidence of any grade HFS as assessed by physicians was 73% in the capecitabine group (n = 80) and 45% in the S-1 group (n = 80) [odds ratio (95% confidence interval) 0.31 (0.16–0.60),P = 0.0005]. The incidence of grade 3 HFS was 21% and 4% (P = 0.003), respectively. Patient-assessed any grade HFS was 84% and 58%, respectively (P = 0.004). Grade 3 anorexia was more common in the S-1 group (3% versus 13%,P = 0.03). Median relative dose intensity was 88% in the capecitabine group and 95% in the S-1 group (P = 0.026). There were no statistically significant differences in median progression-free survival, response rate and overall survival rates.ConclusionTreatment with S-1 in Western mCRC patients is associated with a significantly lower incidence of HFS compared with capecitabine, with comparable efficacy.ClinicalTrials.gov registration numberNCT01918852.