Severe Chemotherapy-related Toxicity Research Articles

Prediction of moderate and severe toxicities of chemotherapy in older patients with cancer: a propensity weighted analysis of ELCAPA cohort.

Currently available predictive models for chemotherapy-related toxicity are not sufficiently discriminative in older patients with cancer and do not consider moderate toxicities. The purpose of this study was to identify factors associated with moderate and severe chemotherapy toxicities in older patients with cancer. Patients aged 70+ recruited in the prospective ELCAPA cohort were analyzed. A total of 837 patients with data on toxicities had received chemotherapy without other systemic treatment and were included between 2015 and 2022. To adjust for any imbalances in the distribution of covariates between patients receiving single-agent chemotherapy vs combination chemotherapy, we applied overlap weighting (a propensity-score-based technique). We used multinomial logistic regression. Median (interquartile range) age was 81 (77-84). Forty-one percent experienced moderate toxicity, and 33% experienced severe toxicity. Hematologic toxicities accounted for 53% of severe toxicities and 66% of moderate toxicities. Age <80 years, cancer type, metastatic status, Eastern Cooperative Oncology Group performance status (ECOG-PS) >1, no cognitive impairment were associated with combination chemotherapy decision. In a univariate analysis with overlap weighting, no factors were associated with moderate toxicity. Hemoglobin < 0g/dL and a CIRS-G score >12 were associated with severe toxicity. In a multivariate analysis, only hemoglobin < 10g/dL was independently associated with severe toxicity, adjusted OR 2.96 (95% CI, 1.20-7.29). By addressing indication bias for combination chemotherapy decision, only anemia and not cancer type, combination chemotherapy was predicting for severe chemotherapy-related toxicity in older patients with cancer. We did not find any predictors of moderate chemotherapy-related toxicity.

Predictive model of chemotherapy-related toxicity in elderly Chinese cancer patients.

Purpose: Older cancer patients are more likely to develop and die from chemotherapy-related toxicity. However, evidence on drug safety and optimal effective doses is relatively limited in this group. The aim of this study was to develop a tool to identify elderly patients vulnerable to chemotherapy toxicity. Patients and methods: Elderly cancer patients ≥60years old who visited the oncology department of Peking Union Medical College Hospital between 2008 and 2012 were included. Each round of chemotherapy was regarded as a separate case. Clinical factors included age, gender, physical status, chemotherapy regimen and laboratory tests results were recorded. Severe (grade ≥3) chemotherapy-related toxicity of each case was captured according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Univariate analysis was performed by chi-square statistics to determine which factors were significantly associated with severe chemotherapy toxicity. Logistic regression was used to build the predictive model. The prediction model was validated by calculating the area under the curve of receiver operating characteristic (ROC). Results: A total of 253 patients and 1,770 cases were included. The average age of the patients was 68.9years. The incidence of grade 3-5 adverse events was 24.17%. Cancer type (non-GI cancers), BMI<20kg/m2, KPS<90%, severe comorbidity, polychemotherapy, standard dose chemotherapy, low white blood cells count, anemia, low platelet cells count, low creatine level and hypoalbuminemia were associated with severe chemotherapy-related toxicity. We used these factors to construct a chemotherapy toxicity prediction model and the area under the ROC curve was 0.723 (95% CI, 0.687-0.759). Risk of toxicity increased with higher risk score (11.98% low, 31.51% medium, 70.83% high risk; p < 0.001). Conclusion: We constructed a predictive model of chemotherapy toxicity in elderly cancer patients based on a Chinese population. The model can be used to guide clinicians to identify vulnerable population and adjust treatment regimens accordingly.

Differences in Treatment Modalities and Prognosis of Elderly Patients with Ovarian Cancer: A Two-Center Propensity Score-Matched Study.

Simple SummaryThe standard of care for patients with ovarian cancer is well established. While the prognosis of younger patients has improved significantly, the survival of older patients remains low. Reasons accounting for the poor survival among older patients are controversial. This study aimed to describe the difference in treatment received by older patients in China and to evaluate the prognostic significance of both chronological age and different treatment modalities using a propensity score-matched cohort. Cytoreduction with no residual tumor and the completion of adjuvant chemotherapy were the most important prognostic factors. Chronological age, however, had no influence on recurrence. This relatively large case–controlled study provides evidence that the difference between the standard of care and the treatment of older patients was the main reason that handicaps the efficacy of therapy.Background: The prognosis of older patients with ovarian cancer is poor. We evaluated the effect of chronological age and different treatment characteristics on the prognosis of older patients with ovarian cancer; Methods: The study retrospectively analyzed patients aged over 60 years who underwent cytoreduction followed by platinum-based adjuvant chemotherapy between January 2011 and December 2019 in two national centers in China. Propensity score matching (PSM, 1:1) was performed to stratify the comorbidity- and treatment-related factors. The Kaplan–Meier method was employed to estimate progression-free survival (PFS) in the original cohort and the cohort after PSM; Results: A total of 324 patients were evaluated. The Age ≥ 70 group often received more neoadjuvant chemotherapy (62.3% vs. 31.2%, p < 0.001), more discontinuation of adjuvant chemotherapy (31.2% vs. 10.8%, p < 0.001), and had more severe chemotherapy-related toxicity (45.6% vs. 34.2%, p = 0.040) than the Age < 70 group. After matching, the PFS of the Age < 70 group was not significantly different from the Age ≥ 70 group (median PFS = 12.4 and 11.9 months, respectively, p = 0.850). Furthermore, the advanced FIGO stage, non-R0 cytoreduction, and discontinuation of adjuvant chemotherapy were all found to be poor prognostic factors. Serum albumin level <40 g/L (HR = 2.441, p = 0.018) and age ≥ 70 years (HR = 2.639, p = 0.008) led to more severe chemotherapy-related toxicity. Additionally, poor renal function (HR = 5.128, p = 0.002) was in association with discontinuation of adjuvant chemotherapy; Conclusions: The chronological age of older patients cannot be seen as a poor prognostic factor. Older patients may benefit most from R0 cytoreduction followed by the completion of chemotherapy. Postoperative poor renal function and serum albumin level <40 g/L may help predict the discontinuation of adjuvant chemotherapy.

P50.10 Intravenous (IV) versus IV/oral route of etoposide administration: impact on real-world SCLC survival outcomes

Platinum-etoposide doublet (PE) is the recommended first-line (1L) chemotherapy for small cell lung cancer (SCLC). Evidence shows that oncology patients prefer oral treatment to IV. This study compared outcomes between 1L intravenous (IV), and IV followed by oral (IV/oral) route of etoposide administration in real-world SCLC patients in Alberta, Canada. SCLC patients who were diagnosed between 2010 and 2016 and completed 1L etoposide at an academic tertiary cancer centre, (Tom Baker Cancer Centre) were included. Data were retrieved from the Glans-Look database excluding those with mixed histology. Outcomes explored included, a] overall survival, (OS), the time in months from diagnosis date to death/last contact, b] tumor objective response rate (ORR), the complete and partial responses as defined by the RECIST v1.1 criteria, using diagnostic imaging reports within 4-8 weeks post 1L or as reported in oncologist progress notes, and c] 1L-related toxicity rate, derived from progress notes, graded using the CTCAE criteria (version 5). Also measured was the progression free survival (PFS): time difference in months from diagnosis date to first progression post 1L or death, whichever occurs first. Comparison between IV/oral and IV groups was performed using Fisher’s Exact (point estimates), Log-Rank tests (Kaplan-Meier survival estimates) and Cox proportional hazard model (survival outcome predictors). A priori statistical significance was p < 0.05. Analyses were performed using SPSS statistical software (version 25). There were 222 patients, 1L was mostly PE [93%] employing etoposide in combination with cisplatin [61%] or carboplatin [32%]. 168 [76%] were IV/oral group. Median age was 66 years, 132 [60%] female, and 138 [62%] had extensive stage SCLC (ES). Performance status (ECOG) was 0-2 in 112 (51%), ≥3 in 9 (4%) and unknown in 101 (46%) patients. IV and IV/oral patients have similar characteristics, but compared to IV/oral, the IV group had less limited stage disease (LS), [p=0.28]. 100 patients experienced grade 3 or 4 toxicities, mainly neutropenia [83%]. The rates were similar for IV/oral versus IV group, p= 0.36. Stratified by stage however, toxicity from IV was greater in LS than ES patients [60 vs 39%]. Overall, ORR for IV/oral versus IV group was 71% vs 66%, [p=0.85]. Within stage, ORR was 79 vs. 89% in LS [p< 0.01] and 58 vs 71% in ES [p=0.23], IV/oral relative to IV group. There was no statistically significant difference in PFS or OS with IV/oral relative to IV groups [PFS: 14 vs 12 months for LS; both 6 months for ES; OS: 32 vs 25 mo. for LS; 12 vs 14 mo. for ES]. Predictors of favorable survival include presence of grade 3 or 4 toxicity in LS [HR= 0.45, p=0.03] and second-line chemotherapy receipt in ES [HR= 0.46, p<0.01]. Consistent with previous reports, we found high oral treatment rate in real-world SCLC patients and no statistically significant differences in SCLC survival outcomes comparing IV/oral versus IV group. Future studies may explore why severe chemotherapy-related toxicity (grade 3 or 4) in LS patients predicts favorable survival.

Chemotherapy Toxicity in Elderly Population ≥65 Years: A Tertiary Care Hospital Experience from India

Abstract Context: Trials in the elderly have established that older individuals may benefit from chemotherapy to the same extent as younger individuals. Although the elderly patient is a prototype for cancer, very few clinical trials focus on the therapeutic decisions most directly facing older adults. Aims: This study was undertaken to study the chemotherapy-induced severe toxicity among elderly. Settings and Design: This study was a prospective, observational cohort study. The study commenced in October 2014 after obtaining clearance from the hospital ethics and protocol committee. Subjects and Methods: A total of 100 patients were included in the study. All patients were of age ≥65 years, had malignancy, and were planned to start with chemotherapy. Development of Grade 3/4/5 nonhematologic (NH) or Grade 4/5 hematologic (H) toxicities was taken as the development of severe toxicity. Statistical Analysis Used: The quantitative variables were expressed as a mean ± standard deviation and compared using unpaired t-test. P &lt; 0.05 was considered statistically significant. Results: Overall, 64 (64%) patients were able to complete their prescribed treatment. Forty-four patients (44%) of our study cohort experienced Grade 4 H or Grade 3/4 NH toxicity. The most common H Grade 4 toxicities were neutropenia (6%) and thrombocytopenia (5%). The most common NH toxicities were fatigue (18%), infection (10%), and cardiac abnormalities (4%). Conclusions: Less than 50% of elderly patients experience severe chemotherapy-related toxicity. First 30 days are most important for toxicity assessment as 45% of patients experienced toxicity in this time frame.

Prospective comparison of the value of CRASH and CARG toxicity scores in predicting chemotherapy toxicity in geriatric oncology.

Predicting the risk of severe adverse reactions to chemotherapy is of great clinical significance for proper selection of effective and safe treatment for elderly cancer patients. The present study aimed to verify and compare the value of two evaluation models of chemotherapy risk prediction for elderly cancer patients through prospective analysis. The two evaluation models assessed were the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) and Cancer Aging Research Group (CARG) toxicity scores. Elderly patients aged ≥70 with cancer were recruited at two participating hospitals in China and completed an assessment prior to starting chemotherapy. CRASH and CARG toxicity scores of each participant were calculated. Chemotherapy-related toxicity was recorded through each cycle of chemotherapy. A total of 106 participants were recruited between September 2015 and August 2018. The CRASH and CARG toxicity scores were positively correlated (r=0.689; P<0.01). Of the participants, 54 (50.9%) participants underwent a grade 3–5 chemotherapy-related toxicity and 21 (19.8%) experienced grade 3–5 nonhematological toxicity in the process of treatment. CRASH and CARG toxicity scores predicted severe chemotherapy-related toxicity and had a high discriminatory value based on receiver operating characteristic curve analysis (area under the curve of 0.772 and 0.760, respectively; P<0.001). The results of the present study indicate that the CRASH and CARG toxicity scores are helpful tools for the prediction of severe chemotherapy-related toxicity, and are recommended for routine oncology practice.

Cost Implications of Reactive Versus Prospective Testing for Dihydropyrimidine Dehydrogenase Deficiency in Patients With Colorectal Cancer: A Single-Institution Experience.

Background:Severe toxicity is experienced by a substantial minority of patients receiving fluoropyrimidine-based chemotherapy, with approximately 20% of these severe toxicities attributable to polymorphisms in the DPYD gene. The DPYD codes for the enzyme dihydropyrimidine dehydrogenase (DPD) important in the metabolism of fluoropyrimidine-based chemotherapy. We questioned whether prospective DPYD mutation analysis in all patients commencing such therapy would prove more cost-effective than reactive testing of patients experiencing severe toxicity.Methods:All patients experiencing severe toxicity from fluoropyrimidine-based chemotherapy for colorectal cancer in an Irish private hospital over a 3-year period were tested for 4 DPYD polymorphisms previously associated with toxicity. The costs associated with an index admission for toxicity in DPD-deficient patients were examined. A cost analysis was undertaken comparing the anticipated cost of implementing screening for DPYD mutations versus current usual care. One-way sensitivity analysis was conducted on known input variables. An alternative scenario analysis from the perspective of the Irish health-care payer (responsible for public hospitals) was also performed.Results:Of 134 patients commencing first-line fluoropyrimidine chemotherapy over 3 years, 30 (23%) patients developed grade 3/4 toxicity. Of these, 17% revealed heterozygote DPYD mutations. The cost of hospitalization for the DPYD-mutated patients was €232 061, while prospectively testing all 134 patients would have cost €23 718. Prospective testing would result in cost savings across all scenarios.Conclusions:The cost of hospital admission for severe chemotherapy-related toxicity is significantly higher than the cost of prospective DPYD testing of each patient commencing fluoropyrimidine chemotherapy.

Risk Factors for Chemotherapy-Related Toxicity and Adverse Events in Elderly Thai Cancer Patients: A Prospective Study

Objectives: To assess factors predisposing to severe chemotherapy-related toxicity and adverse events (AEs) and dose modification in aging cancer patients. Methods: Cancer patients aged ≥70 years scheduled to receive the first cycle of a new chemotherapy regimen were enrolled. On the day of starting chemotherapy, demographic data, performance status (PS), and geriatric parameters were recorded. AEs and chemotherapy modification were recorded. Quality of life (QOL) was assessed at baseline and 3 months after starting chemotherapy or at the end of chemotherapy. Results: We included 151 patients (mean age, 76.4 years) with gastrointestinal (47%), lung (24%), breast (9%), or genitourinary (6%) cancer. All-grade and severe AEs occurred in 83 and 42% of patients, respectively; 51.6% of patients required chemotherapy modification due to toxicities. A higher incidence of severe AEs (71% vs. 39%, p = 0.01) and poorer QOL was found in patients with PS 2 than in those with PS 0-1. Patients with PS 2 or who received palliative-intent chemotherapy or had multiple comorbidities were more likely to discontinue chemotherapy because of toxicity. Conclusions: PS remains a key predictor of chemotherapy-related toxicity in elderly patients. PS 2 was correlated with higher incidence of severe AEs, premature treatment discontinuation, and worsening QOL after treatment.

Association of muscle mass with pathologic response and toxicity in localized bladder cancer patients treated by neoadjuvant chemotherapy (NAC) and radical cystectomy (RC).

e16022 Background: Sarcopenia, the condition of low muscle mass, is a prognostic factor across many cancer types including bladder cancer. Moreover, sarcopenia was shown to predict severe toxicity induced by many anticancer agents. Conversely, NAC may increase the prevalence of sarcopenia before surgery. This retrospective study aimed to investigate the association of sarcopenia with pathologic response and toxicity in localized bladder cancer patients treated by NAC and RC. Methods: Among the 52 patients who underwent RC after NAC between Jan 2010 and Dec 2016, the preoperative sarcopenia status could be determined for 39 patients. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured on CT scan images, and sarcopenia was defined as skeletal muscle index of &lt; 43 cm2/m2 for men with body mass index (BMI) &lt; 25 kg/m2, SMI &lt; 53 cm2/m2 for men with BMI &gt; 25 kg/m2, and SMI &lt; 41 cm2/m2 for women. The criteria for efficacy was pathologic response defined by pathological down-staging to ≤ pT1N0. Patients were compared using χ2 or Fischer’s exact test when appropriate. Results: 48% of patients were sarcopenic before RC. A significant higher rate of pathological response was found in non-sarcopenic patients compared to sarcopenic patients (13/20 vs 5/19, P = 0.01). More severe chemotherapy related toxicity was found in sarcopenic patients compared to non-sarcopenic patients for neutropenia (P = 0.06), thrombopenia (P = 0.15), and neuropathy (P = 0.23). Among the 21 patients for whom sarcopenia status before chemotherapy was available, 3 patients became sarcopenic and 4 patients initially sarcopenic gained muscle mass on post-chemotherapy CT scan. Conclusions: Sarcopenia is frequent in localized bladder cancer patients. Muscle mass correlates with pathological response to NAC.

Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone is beneficial but toxic in very elderly patients with diffuse large B-cell lymphoma: a population-based cohort study on treatment, toxicity and outcome

To assess treatment strategies, toxicity and outcome in very elderly patients (aged ≥ 75 years) diagnosed with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, an observational population-based cohort study was performed. From 103 patients with a median age of 81 years, data of clinical characteristics, treatment, toxicity and outcome were evaluated. Advanced stage DLBCL was documented in 74 patients. In 80 patients chemotherapy was initiated; 70 patients received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). In this group, 39 patients completed all cycles and 30 patients achieved a complete remission. Severe chemotherapy-related toxicity occurred in 69%. Two-year overall survival was 70% for elderly patients who completed chemotherapy, 28% for those treated with incomplete or suboptimal chemotherapy and 21% for those receiving palliative radiotherapy or supportive care. In conclusion, the ability to complete R-CHOP was associated with better overall survival compared to other treatment strategies at the expense of severe treatment-related toxicity.

Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer in the Elderly: A Population-Based Study in Ontario, Canada

Non-small-cell lung cancer (NSCLC) is predominantly a disease of the elderly. Retrospective analyses of the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial and the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis suggest that the elderly benefit from adjuvant chemotherapy. However, the elderly were under-represented in these studies, raising concerns regarding the reproducibility of the study results in clinical practice. By using the Ontario Cancer Registry, we identified 6,304 patients with NSCLC who were treated with surgical resection from 2001 to 2006. Registry data were linked to electronic treatment records. Uptake of chemotherapy was compared across age groups: younger than 70, 70 to 74, 75 to 79, and ≥ 80 years. As a proxy of survival benefit from chemotherapy, we compared survival of patients diagnosed from 2004 to 2006 with survival of those diagnosed from 2001 to 2003. Hospitalization rates within 6 to 24 weeks of surgery served as a proxy of severe chemotherapy-related toxicity. In all, 2,763 (43.8%) of 6,304 surgical patients were elderly (age ≥ 70 years). Uptake of adjuvant chemotherapy in the elderly increased from 3.3% (2001 to 2003) to 16.2% (2004 to 2006). Among evaluable elderly patients, 70% received cisplatin and 28% received carboplatin-based regimens. Requirements for dose adjustments or drug substitutions were similar across age groups. Hospitalization rates within 6 to 24 weeks of surgery were similar across age groups (28.0% for patients age < 70 years; 27.8% for patients age ≥ 70 years; P = .54). Four-year survival of elderly patients increased significantly (47.1% for patients diagnosed from 2001 to 2003; 49.9% for patients diagnosed from 2004 to 2006; P = .01). Survival improved in all subgroups except patients age ≥ 80 years. Uptake of adjuvant chemotherapy for NSCLC increased in patients age 70 years or older following reporting of pivotal adjuvant chemotherapy trials, but it remained below that for patients younger than age 70 years. Adoption of adjuvant chemotherapy appears to be associated with significant survival benefit in the elderly (age ≥ 70 years), with tolerability apparently similar to that of patients who are younger than age 70 years.

Chemotherapy intensity and toxicity among black and white women with advanced and recurrent endometrial cancer

The purpose of this study was to confirm whether black and white women with endometrial cancer are equally tolerant of chemotherapy and identify factors that impact survival. A retrospective review of 169 black women and 982 white women with the International Federation of Gynecologists and Obstetricians stage III, stage IV, or recurrent endometrial carcinoma was performed. All patients received doxorubicin combined with cisplatin. Chemotherapy parameters that were reviewed included relative dose, relative time, and relative dose intensity. Treatment cycles > or =7 were defined as treatment completion. Although black patients were more likely to experience grades 3-4 anemia (20% vs 14%) and genitourinary (5% vs 1%) toxicity, and less likely to experience severe gastrointestinal toxicity (10% vs 17%), the overall incidence of grades 3-4 treatment-related chemotoxicity was the same between the 2 groups (82% vs 82%). There were no differences in the number of cycles received, relative dose (0.57 vs 0.58), relative time (0.77 vs 0.78), or relative dose intensity (0.76 vs 0.76) for black and white patients. Black patients with advanced stage or recurrent endometrial cancer, treated on 4 Gynecologic Oncology Group (GOG) protocols, had similar dose intensity and severe chemotherapy-related toxicity compared with white patients, suggesting that previously described racial disparities in survival among patients in GOG trials may have an novel etiology.

Risk factors for severe cancer chemotherapy toxicity in the outpatient setting: Results of a nested case control study using a novel patient cohort

6545 Background: Risk factors for severe cancer chemotherapy-related toxicity (resulting in hospitalization and/or death) in the adult outpatient setting are largely unknown. Between 2003–2006, we identified all chemotherapy patients from a single hospital-affiliated outpatient cancer center who required admission to the hospital, and using a structured process that included monthly peer review meetings, we determined which admissions were due to chemotherapy toxicity. Among 2,082 patients who received chemotherapy, 185 required at least one admission. In this study we describe the development of a prediction model for severe chemotherapy-related toxicity. Methods: We undertook a nested case control study by randomly selecting 98 patients admitted to the hospital within 30 days of their last chemotherapy administration and 173 controls. We selected 33 clinical and demographic variables that we hypothesized might predict severe toxicity, and used standard descriptive, univariate and regression methods to characterize the data and develop a prediction model. Results: We were able to identify the following variables that predicted for severe chemotherapy toxicity: increasing age; increasing Charlson Comorbidity index (CCI); treatment with a prior chemotherapy regimen; prior admission for chemotherapy toxicity; decreasing hemoglobin and absolute neutrophil count (ANC) and increasing creatinine, and albumin. Independent variables that did not predict for increased risk for severe toxicity included the following: performance status; chemotherapy intent (curative, adjuvant or palliative); full dose versus reduced dose for cycle I; cisplatin-based chemotherapy; median income (by postal codes). Using logistic regression we created a parsimonious model (ROC AUC of 0.69) that included four clinical independent variables: CCI; prior chemotherapy regimen; ANC; and albumin. Conclusions: This analysis may permit the development of a predictive model which will include CCI, prior chemotherapy regimen, ANC, and albumin to help identify patients prior to the initiation of chemotherapy who are risk for severe toxicity. No significant financial relationships to disclose.

Actual Body Weight for Determining Doses of Chemotherapy in Obese Cancer Patients: Evaluation of Treatment Tolerability

In our Department, doses of chemotherapy in obese cancer patients are routinely calculated according to actual body weight. As some physicians question this policy, we prospectively evaluated the safety of this approach. Of 606 consecutive patients, 178 (29%) were obese, defined as body mass index > or =27.3 kg/m2 for females and > or =27.8 kg/m2 for males; full-dose chemotherapy was initiated in 147 (24%). Severe chemotherapy- related toxicity (SCRT) (neutropenic fever, severe thrombocytopenia associated with significant bleeding and/or requiring platelet transfusion, or grade 3-4 nonhematologic toxicity other than alopecia, nausea, and vomiting) during the first three cycles was evaluated. SCRT was noted in 16/147 (11%) during the first cycle, 10/146 (7%) during the second cycle, and 6/142 (4%) during the third cycle. Drug doses were reduced due to toxicity in 15/146 (10%) during the second cycle and 11/142 (8%) during the third cycle. There were no treatment- related deaths. It was concluded that calculation of standard chemotherapy dose according to actual body weight in obese patients is relatively safe.