贝伐珠单抗联合一线化疗晚期转移性结直肠癌的临床观察

目的：观察贝伐珠单抗联合一线化疗对晚期结直肠癌（metastatic colorectal cancer, mCRC）的疗效和毒副作用。方法30例经组织或细胞病理学证实的 mCRC 患者接受贝伐珠单抗与一线化疗药物联合治疗。贝伐珠单抗剂量为5 mg／kg 每2周重复,或7．5 mg／kg 每3周重复。一线化疗方案：18例联合 L-OHP 为主方案（FOLFOX 方案或者 CapeOx 方案）,12例联合 CPT-11为主方案（FOLFIRI方案）。评估疗效和不良反应并随访生存信息。结果30例中无 CR 患者,PR 15例（50．0％）,SD 10例（33．3％）,PD 5例（16．7％）;客观有效率50．0％,疾病控制率83．3％;中位无进展生存时间为10．809个月（95％CI：4．079～15．921）。贝伐珠单抗相关不良反应主要为高血压3例、鼻衄1例、蛋白尿1例。另有2例出现血液性毒性,考虑和化疗相关,接受 CPT-11方案者中4例出现迟发型腹泻。但上述副反应程度较轻,经对症处理后均可缓解,未影响治疗。结论贝伐珠单抗联合一线化疗对 mCRC 的疗效确切,不良反应发生率低、程度较轻,患者耐受性可,是mCRC一线治疗的理想选择。     

Neutropenia as a Predictive Factor in Metastatic Colorectal Cancer Treated With TAS-102

Background

TAS-102 significantly improves overall survival in patients with metastatic colorectal cancer. The most common treatment-related adverse event of TAS-102 is bone marrow suppression, which leads to neutropenia. The potential predictive value of neutropenia caused by cytotoxic drugs has been reported in various types of cancer.

结直肠癌化疗进展

在过去的20年中,无论是针对术后结直肠癌的辅助化疗或是转移性结直肠癌的化疗均取得了令人鼓舞的进展。在20世纪80年代末,仅有5-Fu一种化疗药物可选用,现在已经有了奥沙利铂、伊立替康、卡培他滨、贝伐单抗、西妥昔单抗等多种药物组成联合化疗方案供选择。通过目前的化疗方案治疗,75%的结直肠癌患者术后3年无复发,50%晚期结直肠癌患者生存期达2年。文章重点对化疗在辅助治疗与转移结直肠癌治疗中的作用进行了综述。     

Reinduction of an Anti-EGFR-based First-line Regimen in Patients with RAS Wild-type Metastatic Colorectal Cancer Enrolled in the Valentino Study

BackgroundIn patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC), growing evidence supports anti-epidermal growth factor receptor (EGFR) retreatment, whereas little is known on the outcomes of anti-EGFR-based reinduction therapy during the upfront strategy.MethodsWe included patients enrolled in the Valentino study who had disease progression and received at least one dose of post-progression therapy. The Kaplan–Meier method and Cox proportional hazards regression were used for the survival analysis. When comparing the outcomes of anti-EGFR-based reinduction versus any second line, a propensity score–based matching was used.ResultsLiver-limited/single site of disease (P < .001 and P = .002), left-sidedness (P = .029), surgery of metastases (P = .003), early tumor shrinkage, and deeper responses (P = .018 and P = .036) were associated with the use of anti-EGFR-based reinduction versus any other second line. All patients treated with reinduction had an anti-EGFR-free interval of at least 3 months. In the propensity score–matched population, progression-free survival (PFS) was similar in the 2 treatment groups, the overall survival (OS) was significantly longer for patients treated with reinduction (P = .029), and the response rate was higher in patients treated with reinduction (P = .033). An oxaliplatin-free interval ≥12 months, left-sidedness, and molecular hyperselection beyond RAS/BRAF were associated with significantly better outcomes after anti-EGFR-based reinduction.ConclusionsReinduction strategies with anti-EGFR-based regimens are commonly used in clinical practice. Our data highlight the importance of clinical–molecular selection for re-treatments and the need for prospective strategy trials in selected populations.     

Cetuximab in the Treatment of Metastatic Colorectal Cancer: a Model-Based Cost-Effectiveness Analysis

Abstract

Cetuximab (Erbitux^®) has shown activity in patients with metastatic colorectal cancer (mCRC). To evaluate the cost-effectiveness of this drug combined with irinotecan in mCRC, a model-based cost-effectiveness analysis (CEA) was performed. Data on cetuximab obtained from Medline in December 2004 and from the 2004 ASCO-meeting were analyzed for life years gained (LYG) with regard to the use of this monoclonal antibody (MAb). Norwegian prices as of January 2005 were employed. The LYG ranged between 1.7 and 2.0 years. The median cost per patient treated was calculated to €34,256 to € 45,764 yielding a cost per LYG in the range between € 205,536 and € 323,040. Sensitivity analysis documented price of cetuximab and survival gain to be the major factors influencing the cost-effectiveness ratio. In conclusion, the analysis indicates cetuximab to be a promising, but very expensive antibody.     

Mean Platelet Volume as a Prognostic Marker in Metastatic Colorectal Cancer Patients Treated with Bevacizumab-Combined Chemotherapy

Background: Recent studies have revealed a prognostic impact of the MPV (mean platelet volume)/platelet count ratio in terms of survival in advanced non-small cell lung cancer. However, there has been no direct analysis of the survival impact of MPV in patients with mCRC. The aim of the study is to evaluate the pretreatment MPV of patients with metastatic and non-metastatic colorectal cancer (non-mCRC) and also the prognostic significance of pretreatment MPV to progression in mCRC patients treated with bevacizumab-combined chemotherapy. Materials and Methods: Fifty-three metastatic and ninety-five non-metastatic colorectal cancer patients were included into the study. Data on sex, age, lymph node status, MPV, platelet and platecrit (PCT) levels were obtained retrospectively from the patient medical records. Results: The MPV was significantly higher in the patients with mCRC compared to those with non-mCRC (7.895±1.060 versus 7.322±1.136, p=0.013). The benefit of bevacizumab on PFS was significantly greater among the patients with low MPV than those with high MPV. The hazard ratio (HR) of disease progression was 0.41 (95%CI, 0.174-0.986; p=0.04). In conclusion, despite the retrospective design and small sample size, MPV can be considered a prognostic factor for mCRC patients treated with bevacizumab-combined chemotherapy.     

XELOX Plus Bevacizumab vs. FOLFIRI Plus Bevacizumab Treatment for First-line Chemotherapy in Metastatic Colon Cancer: a Retrospective Study of the Anatolian Society of Medical Oncology

Background: XELOX plus bevacizumab (XELOX-Bev) and FOLFIRI plus Bevacizumab (FOLFIRI - Bev)treatments are an effective strategies patients with metastatic colorectal cancer (mCRC).The aim of this studywas to compare efficacy of first-line XELOX-Bev treatment vs FOLFIRI-Bev treatment for mCRC. Materialsand Methods: A total of 409 patients with mCRC who received chemotherapy were included and divided into 2groups. Group 1 (n=298) received XELOX-Bev and Group 2 (n=111) FOLFIRI-Bev. Comparisons were made interms of overall (OS) and progression-free (PFS) survival, response rate (RR), and grade 3-4 toxicity. Results:Median follow-up was 11 months in Group 1 and 15 months for Group 2. Complete remission was observed in29 (9.7%) and 2 (1.8%) patients, partial remission in 139 (46.6%) and 27 (24.5%) , stable disease in 88 (29.5%)and 49 (44.1%) and progressive disease in 42 (14.1%) and 33 (30.0%) patients in Group 1 and 2, respectively.Median OS was 25 months (range 2-57 months, 95%CI; 22.2-27.7) for Group 1 and 20 months (range 1-67 months,95%CI; 16.8-23.1) for Group 2 (p=0.036). Median PFS was 9.6 months (range 2-36 months, 95%CI; 8.8-10.4) forGroup 1 and 9 months (range 1-44 months, 95%CI; 7.4-10.5) for Group 2 (p=0.019). Objective RR was 56.4%in Group 1 and 26.1% in Group 2 (p<0.001). Conclusions: First-line XELOX-Bev is more effective with a betterresponse rate, prolongation of median PFS/OS, and a superior safety profile compared with FOLFIRI-Bev.     

Reduction of Liver Metastasis Stiffness Improves Response to Bevacizumab in Metastatic Colorectal Cancer

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Efficacy and Safety of Bevacizumab in Chinese Patients with Metastatic Colorectal Cancer

Objective: To evaluate the efficacy and safety of bevacizumab in the treatment of patients with metastatic colorectal cancer (mCRC). Methods: In a single-center, observational study of 91 Chinese patients with mCRC who received bevacizumab in combination with chemotherapy was conducted. Objective response rates (ORRs), progression-free survival (PFS), overall survival (OS) and adverse events were recorded, and the relationships between various clinical factors and PFS or OS were evaluated by Cox proportional hazards models. Results: Treatment with bevacizumab and chemotherapy was effective and tolerable. Univariate analysis showed that PFS and OS were significantly associated with the Eastern Cooperative Oncology Group performance status (ECOGPS) score, duration of bevacizumab exposure, and whether chemotherapy was continued after discontinuation of bevacizumab treatment. A multivariate analysis showed that the duration of bevacizumab exposure and whetherchemotherapy was continued after discontinuation of bevacizumab were independent prognostic factors for PFS and OS. Conclusion: In Chinese mCRC population, the shorter the duration of exposure to bevacizumab and chemotherapy, the worse the prognosis is.     

Economic Evaluation of Adding Bevacizumab to Chemotherapy for Metastatic Colorectal Cancer (mCRC) Patients in Indonesia

Objective: Since 2016, bevacizumab has been widely used to treat metastatic colorectal cancer (mCRC) in Indonesia. Nevertheless, the high cost of bevacizumab has raised the question of whether the therapy is considered cost-effective and should be included in the national health insurance system. This study aimed to assess the cost-effectiveness of bevacizumab plus chemotherapy versus chemotherapy alone for the treatment of mCRC patients. Methods: A Markov model was applied using the perspective of the Indonesian healthcare system to assess cost-effectiveness. The health outcomes were expressed in terms of quality-adjusted life years (QALY) using the validated EuroQoL-5D-5L instrument. Data for medical costs were collected from hospital billings in four hospitals located in three different cities in Indonesia. Meanwhile, data for utility were obtained from interviewing 90 patients who came to the hospital. We compared those mCRC patients who received chemotherapy alone either with FOLFOX or FOLFIRI, versus patients who received the addition of bevacizumab. Results: With the perspective of societal, the incremental cost-effectiveness ratio (ICER) of adding bevacizumab was USD 49,312 per QALY gained using secondary data and USD 28,446 per QALY using real world data. Conclusion: Using either a healthcare or societal perspective, the addition of bevacizumab for mCRC treatment was considered not cost-effective.     

贝伐珠单抗在结直肠癌治疗中的应用

近年来,随着对肿瘤生物学认识的深入,以贝伐珠单抗、西妥昔单抗为代表的分子靶向治疗药物正逐渐丰富着晚期结直肠癌的治疗选择.贝伐珠单抗是一种人源化、人鼠嵌合抗血管内皮生长因子的单克隆抗体,是第一个被美国FDA批准用于治疗晚期结直肠癌患者的抗血管生成药物,以贝伐珠单抗为基础进行的临床研究也证实了它能改善晚期结直肠癌患者的生存期.全文通过回顾近年来发布的结直肠癌治疗领域有关贝伐珠单抗的临床研究,对其在晚期结直肠癌一线、二线和维持治疗以及在结直肠癌术后辅助治疗领域中的应用做一系统综述.     

Second-Line Chemotherapy with Mitoxantrone as a Single Agent in Metastatic Breast Cancer

Summary

Ninety-three evaluable patients with metastatic breast cancer previously treated with chemotherapy, received mitoxantrone as a single agent (14 mg/m², by rapid intravenous infusion, once every 3 weeks). Patients received a median of 7 courses (range 2 to 18), with a mean cumulative total dose of 133 mg (range 36 to 342). A complete response (CR) was achieved in 2 patients (2%). Partial response (PR) was observed in 23 patients (25%). The overall response rate (CR + PR) was thus 27%, with a median duration of 9 months (range 3 to 18). Responses were observed in all metastatic sites, except for brain and peritoneum. Stabilization (S) occurred in 26 patients (28%). The remaining 42 patients (45%) showed clear progression of their metastatic disease while on therapy. The actuarial 24-month survival for the whole group was 13%, increasing to 29% in responders (CR + PR), as compared with only 10% for non- responders (S + P; P<0.0001). Mitoxantrone was generally well tolerated; nausea, vomiting and hair loss were mild. Nine out of 625 treatment cycles resulted in leukopenic fever with uneventful recovery. All patients had serial MUGA scans; 3 patients (cumulative total doses of 200, 250 and 342 mg, respectively) developed a significant drop in the left ventriculur ejection fraction. Clinical evidence of congestive heart failure was observed in one patient who had received prior doxorubicin-based adjuvant chemotherapy. Mitoxantrone seems to be as effective as other drugs given singly or in combination as second-line chemotherapy in patients with metastatic breast cancer. Its low morbidity makes its use attractive in this setting.     

Somatic Mutations of K-Ras and BRAF in Thai Colorectal Cancer and their Prognostic Value

Background: The study aimed to determine the incidence of K-ras and BRAF mutations in colorectal cancers(CRCs) in Thai patients and evaluate association with clinicopathological parameters including treatmentoutcomes in terms of event free survival (EFS). Materials and Methods: Two-hundred colorectal cancer specimenswere collected for studies of K-Ras codon 12, 13 and 61, and BRAF codon 600 by polymerase chain reaction anddirect nucleotide sequencing. Results: The overall incidence of K-Ras mutations in our patients was 23%. K-rasmutation frequencies in CRC stages (AJCC) I, II, III and IV were 6.7%, 16.1%, 23.3% and 26.6%, respectively(p-value>0.05). The three most common mutation forms were G12D, G12V and G13D. K-Ras mutation status wasassociated with poorer EFS in stage I-III CRCs (p-value 0.03). Conclusions: The study found a lower mutationfrequency of K-Ras and BRAF compared to reports involving other ethnic groups. However, K-Ras mutationsdid have a negative prognostic value in early-stage CRCs.     

Tolerance and Efficacy of Regorafenib according to UGT Pharmacogenetical Status in the Treatment of Metastatic Refractory Colorectal Cancer

Introduction: Regorafenib is a multi tyrosin-kinase inhibitor prescribed in metastatic refractory colorectal cancer treatment. Its toxicity is significant but inconstant. The metabolism of regorafenib includes oxydation via cytochrome P3A4, then glucuroconjugation. A pharmacogenetical approach of mutational status of Uridine-Diphospho-Glucuronosyltransfersase (UDP-glucuronosyl-transferase, UGT) could be a strategy to optimise the use of regorafenib. Patients and Method: This is a restrospective, unicentric study. All adult patients treated with regorafenib for a metastatic colorectal cancer in our center between 2013 and 2017 were analysed. UGT1A1 polypmorphism was previously researched in the laboratory after written informed consent. Results: Thirty-five patients received regorafenib during the study period. A TA repetition in UGT1A1 gene was present for 16 patients including two Gilbert syndrome. There were no more adverse events on patients with a heterozygous TA repetition or with a Gilbert syndrome compared with patients without UGT polymorphism, whatever the dosage at initiation of regorafenib. Adverse events grade 2 or superior, and grade 3 or superior tended to be more noticeable when the starting dose was 120 or 160 mg per day compared to 80 mg per day, but not statistically significant. No difference was observed on progression-free survival neither depending on UGT status nor depending on initating dose of regorafenib. Conclusion: This is a preliminary study evaluating safety of regorafenib according to UGT1A1 polymorphism. Larger and prospective studies are needed to evaluate dose-escalation strategy in patients with variable activity of glucuroconidation, especially Gilbert syndrome, or with abnormalities in other UGT enzymes such as UGT1A9.     

Pemetrexed is Mildly Active with Good Tolerability for Treatment of Patients with Colorectal Cancer

Purpose: This systematic analysis was conducted to evaluate the efficacy and safety of pemetrexed basedsalvage chemotherapy for treatment of patients with metastatic colorectal cancer. Methods: Clinical studiesevaluating the efficacy and safety of pemetrexed based regimens on response and safety for patients with colorectalcancer were identified using a predefined search strategy. Pooled response rates (RRs) were calculated. Results:For pemetrexed based regimens, 4 clinical studies including 201 patients with advanced colorectal cancer wereconsidered eligible for inclusion. The analysis suggested that, in all patients, pooled RR was 20.4% (41/201).Major adverse effects were neutropenia, anorexia, fatigue, and anemia. No treatment related death occurredwith pemetrexed based treatment. Conclusion: This systematic analysis suggests that pemetrexed based regimensare associated with mild activity with good tolerability in treating patients with metastatic colorectal cancer.     

Prognostic Model Built on Blood-based Biomarkers in Patients with Metastatic Colorectal Cancer

Background: We had previously showed that the neutrophil lymphocyte ratio (NLR), γ-glutamyl transpeptidase (GGT) and carcinoembryonic antigen (CEA) are prognostic factors for metastatic colorectal cancer (mCRC) patients. In this study we developed a prognostic model based on these three indices. Materials and Methods: A total of 243 patients who were initially diagnosed as mCRC between 2005 and 2010 in the Sun Yat-sen University Cancer Center were studied. The endpoint was overall survival (OS). Results: NLR>3, elevated GGT and elevated CEA were confirmed as independent risk factors which could predict poor prognosis. Patients could be divided into three groups according to the number of risk factors they had. Those with two or three were defined as thehigh risk group, individuals with one risk factor as the modest risk group and patients without risk factor as the low risk group. The OS values for these three groups were 16.2 months (2.80~68.8), 24.2 months (4.07~79.0), and 37.2 months (12.6~87.8), respectively (p<0.001). Conclusions: We developed a simple but useful model based on NLR, GGT and CEA to provide prognostic information to clinical practice in highly selected mCRC patients. Further prospective and multi-center studies are warranted to test our model.     

Mucinous Histology Is Associated with Resistance to Anti-EGFR Therapy in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer

BackgroundLimited studies have suggested that mucinous histology is associated an attenuated response to anti-epidermal growth factor receptor (EGFR) therapy.MethodsWe conducted a single-institution, retrospective study to review the anti-EGFR response and the molecular profile of patients with left-sided microsatellite stable RAS/BRAF wild-type mucinous metastatic colorectal cancer.ResultsIn comparison to nonmucinous population (n = 98), mucinous histology (n = 20) was associated with a younger age (48 vs 54, P = .02), wild-type APC (80% vs 15.3%, P < .0001), and wild-type TP53 (40% vs 8.2%, P = .001). Guanine nucleotide binding protein, alpha stimulating (GNAS) mutations were exclusively found in mucinous tumors (20% vs 0, P < .0001). Genomic alterations associated with resistance to anti-EGFR therapy, such as ERBB2 amplification, PIK3CA mutation, MAP2K1 mutation, and KRAS amplification, were identified in patients with left-sided RAS/BRAF wild-type mucinous metastatic colorectal cancer. Mucinous histology was not associated with a worse outcome than non-mucinous histology (34.3 vs 42.2 months, P = .85). However, patients with left-sided RAS/BARF wild-type mucinous colorectal cancer treated with first-line anti-EGFR therapy had significantly worse progression-free survival (4 vs 6.5 months, hazard ratio [HR] = 5.3, 95% confidence interval [CI] 1.3-21.7, P = .01) than patients treated with the first-line vascular endothelial growth factor A antibody, bevacizumab. Anti-EGFR therapy was associated with limited responses and a short PFS across all lines of therapy in 12 patients with left-sided RAS/BRAF wild-type mucinous colorectal cancer.ConclusionsMucinous histology is associated with diminished benefits from anti-EGFR therapy in patients with left-sided RAS/BRAF wild-type colorectal cancer. These patients should be considered for bevacizumab-based therapy in the first- and second-line settings.     

A Comparison of Folinic Acid,Fluorouracil and Irinotecan (FOLFIRI) plus Bevacizumab and FOLFIRI plus Aflibercept as Second-line Treatment for Metastatic Colorectal Cancer

AimTo compare the efficacy and safety of folinic acid, fluorouracil and irinotecan (FOLFIRI) plus bevacizumab or aflibercept in metastatic colorectal cancer (mCRC) patients pretreated with oxaliplatin-based chemotherapy.Materials and methodsWe analysed the treatment outcomes of patients receiving FOLFIRI in combination with bevacizumab or aflibercept as second-line treatment for mCRC between October 2017 and March 2020. This analysis included 67 patients receiving FOLFIRI plus aflibercept and 83 receiving FOLFIRI plus bevacizumab.ResultsThe overall response rate (ORR) was 13.6% (95% confidence interval 4.85–22.34) in the FOLFIRI–aflibercept group and 14.7% (95% confidence interval 6.68–22.71) in the FOLFIRI–bevacizumab group. This difference in ORR was not statistically significant. The median progression-free survival was 8.6 months in the FOLFIRI–bevacizumab group and 8.5 months in the FOLFIRI–aflibercept group (P = 0.752). Patients in the FOLFIRI–bevacizumab group showed a median overall survival of 12.4 months, whereas patients in the FOLFIRI–aflibercept group had a median overall survival of 13.7 months (P = 0.276). There were no significant differences in survival between the two treatment groups. The adverse events were also largely similar between the two groups. However, hypertension of grade 3 or more was more frequent in the FOLFIRI–aflibercept group.ConclusionFOLFIRI plus bevacizumab and FOLFIRI plus aflibercept had similar anti-tumour activities and toxicity profiles when used as second-line therapy in mCRC patients. Based on these data, both aflibercept and bevacizumab are suitable anti-angiogenic agents when used in combination with FOLFIRI for mCRC.     

Clinicopathological Characteristics and Prognostic Factors in Ovarian Metastases from Right- and Left-Sided Colorectal Cancer

Background: Secondary tumors of the ovary (STOs) account for 10–25% of all ovarian malignancies, including metastases from primary gynecological tumors. Colorectal cancer (CRC) has been recognized as one of the most common causes of STOs in Western countries. Despite it being well-known that CRC originating from the right versus left side of the colon/rectum differ substantially, there is a paucity of information regarding the effect of the primary tumor sidedness on the clinicopathological characteristics of STOs. Methods: This retrospective, observational chart review study included patients with histologically confirmed STOs of CRC origin diagnosed between January 2000 and December 2019. The clinicopathological characteristics of STOs originating from left-sided and right-sided CRC were compared. Univariable and multivariable analyses employing elastic net Cox proportional hazard models were used to evaluate potential prognostic factors. Further, the role of imaging methods in STOs diagnostics was evaluated. Results: Fifty-one patients with STOs of colorectal origin were identified. The primary tumor originated in the right and left colon/rectum in 39% and 61% of the cases, respectively. STOs originating from right-sided primary tumors were more frequently bilateral, associated with peritoneal carcinomatosis, had the ovarian surface affected by the tumor, and contained a mucinous component. The independent prognostic factors for overall survival in the whole cohort included: the presence of macroscopic residual disease after cytoreductive surgery, menopausal status, the application of systemic therapy, and the application of targeted therapy. In 54% of cases, the imaging methods failed to determine the laterality of the STOs correctly as compared to pathological reports and/or intraoperative findings. Conclusion: STOs originating from left-sided and right-sided CRC show distinct clinicopathological characteristics. Moreover, different metastatic pathways might be employed according to the primary tumor sidedness. Considering the discrepancies between radiological assessment and histopathological findings regarding the laterality of STOs, bilateral adnexectomy should be advised whenever feasible.