• bevacizumab
• effectiveness
• metastatic colorectal cancer
• safety
• unresectable metastases

• Humans
• Female
• Male
• Aged
• Bevacizumab/pharmacology
• Bevacizumab/therapeutic use
• Activities of Daily Living
• Comorbidity
• Hypertension
• Venous Thromboembolism
• Colonic Neoplasms

The 5-fluorouracil-based chemotherapy combined with oxaliplatin or irinotecan is usually used in colorectal cancer (CRC). The addition of a targeted agent (TA) to this combination chemotherapy is currently the standard treatment for metastatic CRC. However, the efficacy and safety of combination chemotherapy for metastatic CRC in patients aged above 80 years has yet to be established.

To assess the clinical outcomes and feasibility of combination chemotherapy using a TA in extremely elderly patients with CRC.

Eligibility criteria were: (1) Age above 80 years; (2) Metastatic colorectal cancer; (3) Palliative chemotherapy naïve; (4) Eastern Cooperative Oncology Group performance status 0-1; and (5) Adequate organ function. Patients received at least one dose of combination chemotherapy with or without TA. Response was evaluated every 8 wk.

Of 30 patients, the median age of 15 patients treated with TA was 83.0 years and that of those without TA was 81.3 years. The median progression-free survival (PFS) and overall survival (OS) in patients treated with TA were 7.4 mo and 15.4 mo, respectively, compared with 4.4 mo and 15.6 mo, respectively, in patients treated without TA. There was no significant difference in PFS (P: 0.193) and OS (P: 0.748) between patients treated with and without TA. Common grade 3/4 hematologic toxicities were anemia (16.7%) and neutropenia (10.0%). After disease progression, the median OS of patients who were treated with and without salvage chemotherapy were 23.5 mo and 7.0 mo, respectively, suggesting significant difference in OS (P = 0.001).

Combination chemotherapy with TA for metastatic CRC may be considered feasible in patients aged above 80 years, when with careful caution. Salvage chemotherapy can help improve OS in some selected of these elderly patients.

• Combination chemotherapy
• Targeted agent
• Colorectal cancer
• Salvage chemotherapy
• Elderly patient

• Chemotherapy
• Metastatic colorectal cancer
• Population-based

• Adenocarcinoma/drug therapy
• Adenocarcinoma/mortality
• Adenocarcinoma/pathology
• Age Factors
• Aged
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Camptothecin/analogs & derivatives
• Camptothecin/therapeutic use
• Colonic Neoplasms/drug therapy
• Colonic Neoplasms/mortality
• Colonic Neoplasms/pathology
• Female
• Fluorouracil/therapeutic use
• France/epidemiology
• Humans
• Leucovorin/therapeutic use
• Male
• Middle Aged
• Organoplatinum Compounds/therapeutic use
• Palliative Care/statistics & numerical data
• Registries
• Retrospective Studies

Background Bevacizumab, a humanized monoclonal antibody, known to block the binding of all known vascular endothelial growth factor-A isomers to their receptors, is used in solid cancers, especially in advanced settings where its role is proven to be stronger than localized stages. Furthermore, various studies have suggested that adding bevacizumab to first-line standard therapy in advanced solid cancers, such as colorectal cancer, lung cancer, ovarian cancer, renal cancer, and breast cancer, significantly prolongs progression-free survival, overall survival, and response rates. However, this ability is limited and variable in cancer subtype. The toxicity profile of bevacizumab is outspread, ranging from mild gastrointestinal side effects, proteinuria to life-threatening hemorrhagic tendency, ischemic thromboembolism, and intestinal perforation. However, it has never been studied in Indian subset of patients till date.

Materials and Methods We performed an institutional retrospective study of 41 patients with a pathologically proven ovarian, colorectal, lung, mesothelioma, melanoma, round cell tumors, and GBMs who received bevacizumab (2.5 mg/kg/week [5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks]) with or without chemotherapy, between January 2016 and January 2019 at our center in North India.

Results Forty-one patients, including 12 (29) advanced ovarian cancer, 12 (29) colon cancer, 10 (24) rectal cancer, 1 (2) appendicular cancer, 1 (2) mesothelioma, 1 (2) melanoma, 1 (2) desmoplastic round cell tumor, and 3 (7) GBM, were treated with bevacizumab. The incidence of arterial thrombus and hemorrhage was 2 and 10%, respectively, whereas venous thrombus and fistula were not seen and not related to age. No fatal adverse event was recorded. The global incidence of severe (grade 3/4) arterial hypertension (HTN) was 49%. It was safely managed in all cases, and no grade 4 (life-threatening complication) occurred. The incidence of severe HTN was significantly higher in elderly patients than in younger ones (72 vs. 40%), proteinuria was found to be more frequent in the younger age group as compared with older age group (7 vs. 3%). Also to note, the incidence of congestive heart failure and subacute intestinal obstruction was found in 5% of patients, wherein all four patients belonged to the older subgroup. Furthermore, Grade 3 hypersensitivity reaction was found in one patient in the younger subgroup which warranted immediate termination of bevacizumab.

• bevacizumab
• monoclonal antibody
• vascular endothelial growth factor α

• Aged
• Aging
• Clinical Trials as Topic
• Colorectal Neoplasms/drug therapy
• Humans
• Rectal Neoplasms
• Risk Assessment

• P30 CA006927 NCI NIH HHS

• Adverse events
• Efficacy
• Gastrointestinal cancer
• Geriatric oncology
• Older patients
• Targeted agents

• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/therapy
• Combined Modality Therapy
• Hepatectomy
• Humans
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Practice Guidelines as Topic/standards
• Prognosis
• Quality of Life
• Survival Rate
• Watchful Waiting/standards

Colorectal cancer (CRC) is the third most common cancer worldwide. As with many other cancers, the risk for CRC increases with age. This is also true for comorbidities, which may hamper sufficient treatment of the cancer. Due to restrictive inclusion criteria, older patients and patients with comorbidities are underrepresented in clinical trials. Comprehensive knowledge about modern effectiveness of oncological treatments in older and/or comorbid patients is sparse. Due to the lack of clinical trials, this issue is investigated in real-life settings predominantly. In our retrospective study we show that patients benefit from oncological treatments irrespective of comorbidities, measured by the age-adjusted Charlson Comorbity (aaCCI) index, and age. Differences found in treatment outcomes are marginal and are likely due to less intense treatment of comorbid or elderly patients. Balancing risk and benefit for treatment decisions should take potential under-treatment of comorbid and older patients into account.

We aimed to investigate the effectiveness of oncological treatments in metastatic CRC related to comorbidities and age. This retrospective study included 1105 patients from three oncological centers. aaCCI and CCI was available from 577 patients. An aaCCI > 3 was of the highest predictive value compared to other aaCCI-levels, CCI or age (p < 0.001 for all). Treatment (best supportive care (BSC), systemic treatment only (STO) and resection of metastases (ROM)) significantly prolonged survival in patients with aaCCI > 3 (STO: HR 0.39, CI 0.29–0.51; ROM: HR 0.16, CI 0.10–0.24) and patients older than 70 years (STO: HR 0.56, CI 0.47–0.66; ROM: HR 0.23, 0.18–0.30). Median overall survival was shorter in patients with aaCCI or age > 70 years and interaction for treatment type not significant for aaCCI, but significant for age older or younger than 70 years (STO: p = 0.01; ROM p = 0.02). BSC is more often considered as optimal care for patients with an aaCCI > 3 (37.6% vs. 12.4%; p < 0.001) or age > 70 years (35.7% vs. 11.2%; p < 0.001). Older patients or patients with comorbidities benefit from cancer-specific therapy independently of their age and comorbidities.

• colorectal cancer
• comorbidities
• elderly
• metastases
• real-life
• treatment

• Cancer treatment
• age difference
• colon cancer
• decision-making

• chemotherapy
• elderly
• geriatric assessment
• metastatic colorectal cancer
• targeted therapies

• Chemotherapy
• Colorectal cancer
• Metastasis
• Older patient
• Targeted therapy

In spite of demonstrating prognostic and possibly predictive benefit in retrospective cohorts and meta-analyses of cancer populations, including colorectal cancer (CRC), prospective evaluation of the relationship between neutrophil to lymphocyte ratio (NLR) and treatment outcomes in previously untreated mCRC patients receiving bevacizumab-based therapy has not yet been performed.

An open-label, single arm, multi-centre study. Patients received first-line bevacizumab plus XELOX or mFOLFOX6 (Phase-A) and continued bevacizumab plus FOLFIRI beyond first progression (Phase-B). Analyses included the association of NLR with phase A progression free survival (PFS) and overall survival (OS). A sub-study investigated the safety in patients with the primary in situ tumor. An exploratory sub-study examined relationships of circulating proteomic markers with PFS.

Phase-A enrolled 128 patients; median age was 64 years (range: 26–84), 70 (55%) were female, 71 (56%) were PS-0 and 51 (40%) had primary in situ tumor. Fifty-three (41%) patients entered Phase-B. The median baseline (b) NLR was 3.2 (range: 1.5–20.4) with 32 (25%) patients having bNLR > 5. The PFS hazard ratio (HR) by bNLR > 5 versus ≤ 5 was 1.4 (95% CI: 0.9–2.2; p = 0.101). The median PFS was 9.2 months (95% CI: 7.9–10.8) for Phase-A and 6.7 months (95% CI: 3.0–8.2) for Phase-B. The HR for OS based on bNLR > 5 versus ≤ 5 was 1.6 (95% CI: 1.0–2.7; p = 0.052). The median OS was 25 months (95% CI: 19.2–29.7) for the full analysis set and 14.9 months for Phase-B. Baseline levels of nine proteomic markers showed a relationship with PFS. Treatment related toxicities were consistent with what has previously been published. There were 4 (3%) instances of GI perforation, of which, 3 (6%) occurred in the primary in situ tumor group.

Results from this study are aligned with the previously reported trend towards worse PFS and OS in patients with higher bNLR.

ClinicalTrials.gov: NCT01588990; posted May 1, 2012.

Population-based evaluations of the incidence of metastatic colorectal cancer at diagnosis among different age groups are lacking. Therefore, we investigated the effects of age at diagnosis on metastatic colorectal cancer and patients’ prognoses. The Surveillance, Epidemiology, and End Results database was used to identify patients diagnosed with metastatic colorectal cancer. Multivariate Cox regression analyses were performed to identify factors associated with poor survival. The Kaplan–Meier analysis was used to estimate survival differences between the subgroups. We identified 30,333 adult patients diagnosed with metastatic colorectal cancer between 2010 and 2014. The younger and middle-aged groups had better survival than the older group when brain metastasis was not involved. The liver was the most common site of metastasis followed by the liver and lung combined. Age at diagnosis was an independent factor in patients’ survival. Survival differences between two and three-sites of metastases were found in the middle-aged and older groups but not in the younger group. No survival differences between three and four sites of metastases were found in any of the age groups. Therefore, the incidence and prognosis of metastatic sites for metastatic colorectal cancer varied by age group.

• age
• incidence of metastasis
• metastatic colorectal cancer
• prognosis
• sites of metastases

Bevacizumab, a VEGF‐A inhibitor, in combination with chemotherapy, has proven to increase progression‐free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angiogenic factor angiopoetin‐2 (Ang‐2) is associated with poor prognosis in many cancers, including mCRC. Preclinical models demonstrate improved activity when inhibiting both VEGF‐A and Ang‐2, suggesting that the dual VEGF‐A and Ang‐2 blocker vanucizumab (RO5520985 or RG‐7221) may improve clinical outcomes. This phase II trial evaluated the efficacy of vanucizumab plus modified (m)FOLFOX‐6 (folinic acid (leucovorin), fluorouracil (5‐FU) and oxaliplatin) versus bevacizumab/mFOLFOX‐6 for first‐line mCRC.

All patients received mFOLFOX‐6 and were randomized 1:1 to also receive vanucizumab 2,000 mg or bevacizumab 5 mg/kg every other week. Oxaliplatin was given for eight cycles; other agents were continued until disease progression or unacceptable toxicity for a maximum of 24 months. The primary endpoint was investigator‐assessed PFS.

One hundred eighty‐nine patients were randomized (vanucizumab, n = 94; bevacizumab, n = 95). The number of PFS events was comparable (vanucizumab, n = 39; bevacizumab, n = 43). The hazard ratio was 1.00 (95% confidence interval, 0.64–1.58; p = .98) in a stratified analysis based on number of metastatic sites and region. Objective response rate was 52.1% and 57.9% in the vanucizumab and bevacizumab arm, respectively. Baseline plasma Ang‐2 levels were prognostic in both arms but not predictive for treatment effects on PFS of vanucizumab. The incidence of adverse events of grade ≥3 was similar between treatment arms (83.9% vs. 82.1%); gastrointestinal perforations (10.8% vs. 8.4%) exceeded previously reported rates in this setting. Hypertension and peripheral edema were more frequent in the vanucizumab arm.

Vanucizumab/mFOLFOX‐6 did not improve PFS and was associated with increased rates of antiangiogenic toxicity compared with bevacizumab/mFOLFOX‐6. Our results suggest that Ang‐2 is not a relevant therapeutic target in first‐line mCRC.

This randomized phase II study demonstrates that additional angiopoietin‐2 (Ang‐2) inhibition does not result in superior benefit over anti–VEGF‐A blockade alone when each added to standard chemotherapy. Moreover, the performed pharmacokinetic and pharmacodynamic analysis revealed that vanucizumab was bioavailable and affected its intended target, thereby strongly suggesting that Ang‐2 is not a relevant therapeutic target in the clinical setting of treatment‐naïve metastatic colorectal cancer. As a result, the further clinical development of the dual VEGF‐A and Ang‐2 inhibitor vanucizumab was discontinued.

This phase II trial evaluated the efficacy of vanucizumab plus mFOLFOX‐6 versus bevacizumab/mFOLFOX‐6 in the first‐line setting of metastatic colorectal cancer.

• Angiopoetin-2
• Bevacizumab
• First-line metastatic colorectal cancer
• VEGF-A
• Vanucizumab

• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Bevacizumab/adverse effects
• Camptothecin/therapeutic use
• Colorectal Neoplasms/drug therapy
• Disease-Free Survival
• Fluorouracil/adverse effects
• Humans
• Leucovorin/adverse effects
• Neoplasm Metastasis
• Organoplatinum Compounds/adverse effects

• Colorectal cancer
• Metastatic
• Systematic review
• Treatment

• Age Factors
• Aged
• Aged, 80 and over
• Aging/physiology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/epidemiology
• Colorectal Neoplasms/pathology
• Female
• Humans
• Male
• Molecular Targeted Therapy/methods
• Neoadjuvant Therapy
• Neoplasm Metastasis
• Observational Studies as Topic/statistics & numerical data
• Standard of Care
• Survival Analysis
• Treatment Outcome

• Merck KGaA

• Bevacizumab
• Capecitabine
• Colorectal cancer
• Cost-effectiveness
• Elderly patients

• Aged
• Colorectal neoplasm
• Frail elderly
• Molecular targeted therapy
• Neoplasm metastasis

• bevacizumab
• efficacy
• metastatic breast cancer
• metastatic colorectal cancer
• ovarian cancer
• overall survival
• progression-free survival
• safety

• Colon cancer
• Insurance status
• National Cancer Database
• Socioeconomic status
• Survival outcomes

• CAPEOX
• Colon cancer
• Elderly
• XELOX
• mCRC

• Adverse events
• Frailty
• Interventions
• Neoplasms
• Older patients

• VEGF
• bevacizumab
• clinical trials
• neoangiogenesis
• prostate cancer

• elderly
• intensive treatment
• metastatic colorectal cancer
• triplet chemotherapy plus bevacizumab
• unfit

• bevacizumab
• elderly
• first-line chemotherapy
• metastatic colorectal cancer

• anti-angiogenic
• pulmonary arterial hypertension
• renal cell carcinoma

• Colon cancer
• chemotherapy
• decision-making
• older adult

• Age
• Colorectal cancer
• Elderly
• Metachronous
• Palliative chemotherapy

• Aged
• Antineoplastic Agents, Immunological/therapeutic use
• Bevacizumab/therapeutic use
• Carcinoma/complications
• Carcinoma/drug therapy
• Female
• Humans
• Hypertension/chemically induced
• Middle Aged
• Ovarian Neoplasms/complications
• Ovarian Neoplasms/drug therapy
• Retrospective Studies

• Capecitabine
• FOLFIRI
• FOLFOX
• Outcomes
• mCC

Metastatic colorectal cancer (mCRC) is mainly a disease of elderly, however, geriatric population is underrepresented in clinical trials. Patient registries represent a tool to assess and follow treatment outcomes in this patient population. The aim of the study was with the help of the patients’ register to determine the safety and efficacy of bevacizumab plus chemotherapy in elderly patients who had previously untreated metastatic colorectal cancer.

The registry of patients with mCRC was designed to prospectively evaluate the safety and efficacy of bevacizumab-containing chemotherapy as well as selection of patients in routine clinical practice. Patient baseline clinical characteristics, pre-specified bevacizumab-related adverse events, and efficacy data were collected, evaluated and compared according to the age categories.

Between January 2008 and December 2010, 210 patients with mCRC (median age 63, male 61.4%) started bevacizumab-containing therapy in the 1^st line setting. Majority of the 210 patients received irinotecan-based chemotherapy (68%) as 1^st line treatment and 105 patients (50%) received bevacizumab maintenance therapy. Elderly (≥ 70 years) patients presented 22.9% of all patients and they had worse performance status (PS 1/2, 62.4%) than patients in < 70 years group (PS 1/2, 35.8%). Difference in disease control rate was mainly due to inability to assess response in elderly group (64.6% in elderly and 77.8% in < 70 years group, p = 0.066). The median progression free survival was 10.2 (95% CI, 6.7–16.2) and 11.3 (95% CI, 10.2–12.6) months in elderly and < 70 years group, respectively (p = 0.58). The median overall survival was 18.5 (95% CI, 12.4–28.9) and 27.4 (95% CI, 22.7–31.9) months for elderly and < 70 years group, respectively (p = 0.03). Three-year survival rate was 26% and 37.6% in elderly vs. < 70 years group (p = 0.03). Overall rates of bevacizumab-related adverse events were similar in both groups: proteinuria 21/22 %, hypertension 25/19 %, haemorrhage 2/4 % and thromboembolic events 10/6 %, for elderly and < 70 years group, respectively.

In routine clinical practice, the combination of bevacizumab and chemotherapy is effective and well-tolerated regimen in elderly patients with metastatic colorectal cancer.

• bevacizumab
• chemotherapy
• elderly
• metastatic colorectal cancer

Over the last decade, multiple chemotherapies/targeted biologics have been approved for metastatic colorectal cancer (mCRC). However, evidence is limited with regards to the array of treatments received by mCRC patients.

This study examines treatment sequences (first- to third-line chemotherapy/targeted biologics) and the factors associated with first-line targeted biologics and common treatment sequences for elderly mCRC patients treated in a community setting.

A retrospective cohort study was conducted in mCRC patients diagnosed from January 2004 through December 2009 using the Surveillance, Epidemiology and End Results Medicare-linked database. The treatment sequences administered to elderly mCRC patients were empirically identified.

Of 4418 mCRC patients who received treatment, 1370 (31 %) received first, second, and third line; 1164 (26 %) received first and second line; and 1884 (43 %) received only first line. The most common first line of treatment for mCRC patients was 5-fluorouracil/leucovorin + oxaliplatin (FOLFOX) + bevacizumab (23 %) and FOLFOX (23 %). 5-fluorouracil/leucovorin + irinotecan (FOLFIRI)-based regimens were commonly (22 %) administered in second line. The most common treatment sequence was first-line oxaliplatin or irinotecan followed by second-line oxaliplatin or irinotecan + bevacizumab followed by a third-line targeted biologic. Of patients who received first-line therapy, 47 % also received a targeted biologic, and the factors associated were age, comorbidity score, cancer site, geographic location, and year of diagnosis.

Elderly mCRC patients receive a multitude of treatments in various sequences. Further exploration of the comparative effectiveness of treatment sequences may yield important information for improving mCRC survival.

The online version of this article (doi:10.1007/s40801-015-0059-9) contains supplementary material, which is available to authorized users.

• Colorectal cancer
• Palliative systemic therapy
• Peritoneal metastases
• Synchronous
• Targeted therapy

• Colorectal cancer
• bevacizumab
• chemotherapy
• elderly patients
• irinotecan
• metastasis
• oxaliplatin

• Advanced
• Brachytherapy
• Metastases
• SIRT
• Yttrium-90

• Bevacizumab
• Capecitabine
• Elderly
• Metastatic colorectal cancer
• Older patients

This study was designed to evaluate the efficacy and safety of XELOX plus bevacizumab in a Japanese metastatic colorectal cancer population that included elderly patients.

This was a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated metastatic colorectal cancer, presence of measurable lesions, age ≥20 years; Eastern Cooperative Oncology Group performance status of 0–2, and adequate organ function. Patients received bevacizumab (7.5 mg/kg on day 1) and XELOX (130 mg/m² oxaliplatin on day 1 plus 1,000 mg/m² capecitabine b.i.d. on days 1–14) every 3 weeks. The primary endpoint was confirmed objective response rate.

The study included 47 patients (male/female 30/17; median age 69 years; age range 38–81 years with 10 patients ≥75 years; PS 0/1/2, 40/5/2) enrolled between May 2010 and March 2011. Responses were assessed in 46 eligible patients. The objective response rate was 52.2 % (95 % confidence interval [CI] 37.0–67.1). The median progression-free survival and overall survival were 10.0 months (95 % CI 7.8–12.3) and 34.6 months (95 % CI 19.9–not estimable), respectively. Frequently encountered grade 3 and 4 adverse events in this study were aspartate aminotransferase elevation (23.4 %), alanine aminotransferase elevation (21.3 %), anorexia (12.8 %), neutropenia (10.6 %), fatigue (8.5 %) and anemia (6.4 %). Grade 3 or 4 peripheral neuropathy was not observed.

First-line treatment with XELOX plus bevacizumab showed a promising response rate and an acceptable tolerability profile in the clinical practice of Japanese metastatic colorectal cancer patients that included elderly patients.

UMIN-CTR, ID number: UMIN000003915, URL:https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000004706&language=E

• Bevacizumab
• First-line chemotherapy
• Metastatic colorectal cancer
• Multicenter single-arm open-label prospective clinical trial
• XELOX

• Bevacizumab
• Chemotherapy
• Colorectal
• Elderly
• Outcomes
• Surgery

• Age Factors
• Aged
• Aged, 80 and over
• Australia/epidemiology
• Colorectal Neoplasms/epidemiology
• Colorectal Neoplasms/secondary
• Colorectal Neoplasms/therapy
• Combined Modality Therapy
• Delivery of Health Care/methods
• Disease-Free Survival
• Female
• Geriatric Assessment/methods
• Humans
• Male
• Morbidity/trends
• Neoplasm Metastasis
• Prognosis
• Prospective Studies
• Registries
• Survival Rate

• Anti-angiogenic agents
• Colorectal metastasectomy
• Conversion therapy
• Metastatic colorectal cancer
• Targeted agents