Background

The assessment of Venous Thromboembolism (VTE) risk in cancer outpatients still represents an evolving topic. Current international guidelines recommend an intermediate to high-risk group as identified by a Khorana score (KS) ≥ 2 as the cut-off for considering primary prophylaxis. In the previously reported prospective ONKOTEV study, we developed a 4 variables risk-assessment-model (RAM): KS > 2, metastatic disease, vascular/lymphatic compression and previous VTE. The goal of the current study is to validate the ONKOTEV score as a novel RAM in an independent cohort.

Methods

ONKOTEV-2 is a prospective, observational study conducted in Italy, Germany, and United Kingdom from May 2015 to September 2019. Clinical, laboratory and imaging data were collected at baseline, to calculate the ONKOTEV score before any cancer treatment. Each patient was followed up for 8 months, to detect VTE, by clinical examination and/or imaging performed in the routine practice.

Results

Overall, 473 patients were included in the study. The most common primary sites in all cohorts were breast, esophagus/stomach, colon, rectum, lung and pancreas. In accordance with the KS, the population study was stratified into the following risk categories: low (58%), high (18%) and very-high (24%). In accordance with the ONKOTEV score, 27 %, 55%, 15% and 2.4% of patients had 0, 1, 2 and 3 score, respectively. Overall, the cumulative incidence (CI) of VTE was 12.7%. The CI for the risk of developing VTE by KS and ONKOTEV score is shown in the table. Table: 1670MO

Cumulative incidence function (at 12 months) for the risk of VTE by Khorana and ONKOTEV score

Conclusions

ONKOTEV score ≥ 2 identified a category of high-risk group of cancer outpatients and significantly improved the VTE predictability of pre-existing RAMs. Therefore, ONKOTEV score has been validated as a new easy-to-use RAM for risk stratification and decision making about primary prophylaxis in cancer outpatients, with promising implications in clinical practice. The study was awarded within the EORTC Young Investigator program (2015-2018).

Legal entity responsible for the study

C.A. Cella.

Funding

EORTC.

Disclosure

All authors have declared no conflicts of interest.

Background

Transfusion therapy occasionally impedes the transition of patients with hematological malignancies to specialized palliative care. This study investigated differences in the opinions of hematologists (HOs) and palliative care physicians (PCs) regarding indications for end-of-life transfusion therapy.

Methods

This cross-sectional questionnaire survey, conducted from August to September, 2020, included 1000 HOs and 759 PCs. The questionnaire had questions on the cutoff of indications for and on opinions on transfusion therapy for treating anemia in patients with hematological malignancies after the end of anticancer treatment. We determined the hemoglobin (Hb) cutoff, as more than 70% HOs and PCs considered it an indication for transfusion therapy.

Results

In total, 596 responses (269 HOs and 327 PCs) were considered valid. For asymptomatic inpatient cases, more than 70% of HOs responded that the Hb cutoff value for recommending transfusion was 6.0 g/dL, whereas only 41.4% PCs responded that they would recommend transfusion therapy even if the Hb value was <6.0 g/dL. As Hb value <6.0 g/dL was not provided as an option in the responses, the cutoff considered by PCs could not be determined. For symptomatic inpatient cases, more than 70% of HOs and PCs considered Hb cutoffs of 8.0 and 7.0 g/dL, respectively. Most HOs (76.1%) and PCs (71.1%) agreed to reduce the frequency of transfusion therapy (p=0.119), and PCs more likely agreed to discontinue transfusion therapy than HOs (19.7% vs. 9.3%, p<0.001). More HOs, than PCs, agreed to continue transfusion therapy until patients and/or families required it (52.4% vs. 17.8%, p<0.001). More HOs, than PCs, considered patients with performance status 4 as being eligible for transfusion (39.5% vs. 18.6%, p<0.001).

Conclusions

There are differences in the opinions of HOs and PCs regarding the indication for undergoing transfusion therapy for patients with end-stage hematological malignancies. In the future, it is expected that the referral rate of palliative care for patients with end-stage hematological malignancies will increase through mutual understanding and consensus on transfusion therapy.

Legal entity responsible for the study

The authors.

Funding

SASAKAWA Health Foundation.

Disclosure

All authors have declared no conflicts of interest.

Background

ICIs are a common therapeutic option for many solid tumors. While prior studies have shown that ATB exposure may negatively impact ICI outcomes through gut microbiome changes, many were small studies with heterogeneity in ATB classes and exposure windows. Here, we performed a population level retrospective cohort study to evaluate the impact of ATB exposure prior to ICI on OS.

Methods

We used administrative data to identify a cohort of cancer patients ≥ 65 years of age receiving ICIs from June 2012 to October 2018 in Ontario, Canada and deterministically linked with databases to obtain socio-demographic and clinical co-variates and ATB prescription claims. Multivariable cox-proportional hazard models evaluated the impact of ATB exposure both within 1 year and 60 days prior to starting ICI on OS, adjusted for age, gender, body mass index, comorbidities, autoimmune history, hospitalization in the past year and treatment facility level at start of ICI therapy.

Results

Among 2737 patients, median age 73; 43% received Nivolumab, 41% Pembrolizumab and 13% Ipilimumab; 53% were lung cancer, 34% melanoma. Median ATB treatment duration for patients receiving ATB within 1 year (59%) and 60 days (19%) prior to ICI were 14 days (SD=32) and 9 days (SD=13) respectively. Median OS estimate was 306 days. Any ATB exposure within 1 year prior to ICI was associated with worse OS (aHR=1.12 95% CI [1.12-1.23] p=0.03). A nonsignificant dose effect was seen based on weeks of ATB exposure 1 year prior to ICI (aHR=1.01 per week [1.00-1.02] p=0.10). ATB class analysis identified fluroquinolone exposure within 1 year (aHR=1.26 [1.13-1.40] p<0.001) and 60 days before ICI (aHR=1.20 [0.99-1.45] p=0.06) were associated with worse OS; with a dose effect based on total weeks of exposure over 1 year (aHR=1.07 per week [1.03-1.11] p<0.001) and 60 days (aHR=1.12 per week [1.03-1.23] p=0.01). Subgroup analysis showed similar results for patients receiving anti-PD1 ICIs and those with lung cancer and melanoma.

Conclusions

Exposure to ATBs and specifically fluroquinolones prior to ICI therapy is associated with worse OS. Interventions aimed at altering the gut microbiome may be required to help improve outcomes for patients on ICIs with prior ATB exposure.

Legal entity responsible for the study

The authors.

Funding

Canadian Association of Medical Oncologist Fellowship Award, ASCO/Conquer Cancer Foundation Young Investigator Award.

Disclosure

All authors have declared no conflicts of interest.

Background

Despite a range of treatment options, about 25% of patients with painful bone metastases suffer from uncontrolled pain. This Phase 3, randomized, double-blind, placebo-controlled trial (24-week treatment/24-week follow-up) examined the efficacy and safety of tanezumab, a monoclonal antibody against nerve growth factor, in subjects with moderate to severe cancer pain due to bone metastasis or multiple myeloma receiving background opioid therapy.

Methods

Subjects from 15 countries (Europe, South America, Asia-Pacific regions) were randomized and received double-blind subcutaneous placebo or tanezumab 20 mg at baseline, week 8, and week 16 while continuing optimized opioid therapy. The primary endpoint was change in daily average pain intensity (0 = no pain to 10 = worst possible pain) at the index bone metastasis cancer pain site from baseline to week 8, evaluated via analysis of covariance. Adverse events (AEs) and pre-specified joint safety events (rapidly progressive osteoarthritis [RPOA] type 1 or 2, primary osteonecrosis, subchondral insufficiency fracture, or pathologic fracture; adjudicated by an external expert committee) were also assessed.

Results

Tanezumab 20 mg (N =72) met the primary endpoint by demonstrating significantly (p = 0.038 with α = 0.048) greater improvement in daily average pain intensity at the index bone metastasis cancer pain site at week 8 compared with placebo (N = 73). LS mean (95% CI) change in pain was -1.25 (-1.94, -0.55) for placebo and -2.03 (-2.73, -1.33) for tanezumab 20 mg. Differences past week 8 were not statistically significant. During the treatment period, the AE profile of tanezumab 20 mg was generally consistent with AEs expected in subjects with cancer pain due to bone metastasis and the known safety profile of tanezumab. The proportion of subjects adjudicated with a pre-specified joint safety event during the study was 0% for placebo and 2.8% for tanezumab 20 mg (pathological fracture near the site of bone metastasis, n = 2). No events of RPOA were reported.

Conclusions

Tanezumab 20 mg improved metastatic cancer-related bone pain compared with placebo and the AE profile was generally consistent with previous studies of tanezumab.

Clinical trial identification

NCT02609828.

Editorial acknowledgement

Medical writing assistance was provided by Matt Soulsby, PhD, CMPP of Engage Scientific Solutions and was funded by Pfizer Inc and Eli Lilly & Company.

Legal entity responsible for the study

Pfizer Inc.

Funding

Pfizer Inc and Eli Lilly & Company.

Disclosure

M. Fallon: Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Other, Investigator for the study: Pfizer and Eli Lilly & Company. M. Sopata: Financial Interests, Personal, Other, Investigator for this study: Pfizer and Eli Lilly & Cmpany; Financial Interests, Personal, Other, National coordinator for this study: Pfizer and Eli Lilly & Company. E. Dragon: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. M.T. Brown: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. L. Viktrup: Financial Interests, Personal, Full or part-time Employment: Eli Lilly & Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly & Company. C.R. West: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. K. Hamlett: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. W. Bao: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. A. Agyemang: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer.

Background

Olanzapine (OLZ) 5 mg combined with dexamethasone (DEX), neurokinin-1 receptor antagonist (NK₁-RA), and palonosetron (PALO) has been established as the standard for patients (pts) receiving cisplatin (CDDP)-containing highly emetogenic chemotherapy (HEC). This study aimed to clarify the non-inferiority of DEX sparing when combined with NK₁-RA, PALO, and OLZ in CDDP-containing HEC.

Methods

Pts with a solid malignant tumor who were treated with CDDP (≥50 mg/m²) for the first time were randomly assigned to Arm D4 (DEX on days 1-4) or Arm D1 (DEX on day 1). The primary endpoint was complete response (CR), which was defined as no emetic episodes and no rescue antiemetic medication, during the delayed phase (24-120 h after the start of CDDP). Secondary endpoints included CR rates in the acute (0-24 h) and overall (0-120 h) phases, complete control (CC) and total control (TC) rates, adverse events with the patient-reported outcome (PRO) CTCAE, and QOL with EORTC QLQ-C30 on day 8. We assumed delayed CR rates would be 75 % in both arms. The planned sample size of 280 provided a power of 80% to detect the non-inferiority of Arm D1 to D4 with the margin of difference by 15% in delayed CR rate (one-sided α = 0.025).

Results

Between October 2018 and March 2021, 281 pts were enrolled, out of which 274 pts were evaluable. Baseline characteristics were well-balanced. CR, CC, and TC are shown in the table. In PRO-CTCAE evaluation, pts with nausea (P < 0.01), appetite loss (P < 0.01), and diarrhea (P = 0.015) were more observed in Arm D1; however, there was no significant difference in the severity of nausea. Scores in global health status in QOL were not significantly different between the two arms (P = 0.38). Table: LBA63

Conclusions

DEX administration on days 2 to 4 can be spared when combined with NK₁-RA, PALO, and OLZ 5 mg in CDDP-containing HEC.

Clinical trial identification

UMIN000032269.

Editorial acknowledgement

We thank the support for the writing of the abstract from Dr. Takashi Kawaguchi.

Legal entity responsible for the study

The authors.

Funding

Japan Agency for Medical Research and Development.

Disclosure

H. Arioka: Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical Co., LTD; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharmaceutical; Financial Interests, Personal, Advisory Board: Taiho Pharmaceutical; Financial Interests, Personal, Advisory Board: Otsuka Pharmaceutical; Financial Interests, Personal, Advisory Board: Delta-Fly Pharma. N. Izawa: Financial Interests, Personal, Speaker’s Bureau: Lilly; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Scib; Financial Interests, Personal, Speaker’s Bureau: Taiho; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Takeda pharm; Financial Interests, Personal, Speaker’s Bureau: Guardant health. T. Yamaguchi: Financial Interests, Personal and Institutional, Other, Member of Endowment Department: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Writing Engagements: Ono Pharmaceutical Co., Ltd. T.E. Nakajima: Financial Interests, Personal, Invited Speaker: Takeda pharm; Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal, Invited Speaker: Bristol Myers Scib; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Ono Pharm; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim Japan; Financial Interests, Personal, Invited Speaker: Dainipponsumitomo; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Research Grant: Chugai; Financial Interests, Personal, Research Grant: Nihon kayaku. All other authors have declared no conflicts of interest.

Background

Chemotherapy induced nausea and vomitting (CINV) is associated with significant deterioration in quality of life. The standard antiemetic therapy for highly emetogenic chemotherapy are combination therapies, and dexamethasone is a necessary component. However, dexamethasone has diverse side effects and it may not be an appropriate antiemetic for use in immunotherapy. Guidelines recommend using olanzapine (10mg) in preventing CINV, but excessive sedation was reported. A trail reported that lower dose olanzapine (5mg) was effective in control of CINV and had less serious sedation events. We initiated this trial to validate whether olanzapine (5mg) could be a non-inferiority alternative of dexamethasone in the triplet antiemetic combination therapy.

Methods

The predicted sample size in this trial (NCT04437017) is 548 (power=80%, α=0.05, non-inferiority margin=10%). Eligible patients are randomized in a 1: 1 ratio into two groups to receive olanzapine or dexamethasone plus a 5-HT3 receptor antagonist (5-HT3 RA) and a NK-1 receptor antagonist (NK-1 RA). The primary endpoint is 0–120 h complete response (CR) rate, and the secondary endpoints are 25–120 h CR rate and 0–120 h no nausea rate. The endpoints and side effects will be recorded after the initiation of chemotherapy for 5 days.

Results

Patients in the olanzapine group achieved a 0–120 h CR rate (83.6% v.s. 84.9%, difference [one-sided 95% CI]: 1.2% [-∞, 6.4%], P _{noninferiority} = 0.003), 25–120 h CR rate (85.5% v.s. 85.6%, difference [one-sided 95% CI]: 0.1% [-∞, 5.1%], P _{noninferiority} = 0.024) and 0–120 h no nausea rate (38.7% v.s. 39.9%, difference [one-sided 95% CI]: 1.2% [-∞, 8.1%], P _{noninferiority} = 0.001) non-inferior to that in patients in the olanzapine group. Moreover, side effects such as constipation (P = 0.045), hiccups (P < 0.001) as well as insomnia (P < 0.001) were more frequent in patients receiving dexamethasone than in those receiving olanzapine.

Conclusions

Olanzapine (5mg) could be a non-inferiority alternative of dexamethasone in the triplet combination anti-emetic therapy and has less side effects than dexamethasone.

Legal entity responsible for the study

The Fifth Affiliated Hospital of Sun Yat-sen University.

Funding

Beijing Xisike Clinical Oncology Research Foundation and the Investigator-Initiated Clinical Trial foundation of the Fifth Affiliated hospital of Sun Yat-sen University.

Disclosure

All authors have declared no conflicts of interest.