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JAMA Apr 2023For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor... (Comparative Study)
Comparative Study Randomized Controlled Trial
Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial.
IMPORTANCE
For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined.
OBJECTIVE
To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015-January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022).
INTERVENTIONS
Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days.
MAIN OUTCOMES AND MEASURES
The primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate.
RESULTS
In the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%).
CONCLUSIONS AND RELEVANCE
Among patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02394795.
Topics: Aged; Female; Humans; Male; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Leucovorin; Panitumumab; Oxaliplatin; ErbB Receptors; Vascular Endothelial Growth Factors
PubMed: 37071094
DOI: 10.1001/jama.2023.4428 -
Journal of Clinical Oncology : Official... Mar 2023Neoadjuvant chemotherapy (NAC) has potential advantages over standard postoperative chemotherapy for locally advanced colon cancer but requires formal evaluation. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Neoadjuvant chemotherapy (NAC) has potential advantages over standard postoperative chemotherapy for locally advanced colon cancer but requires formal evaluation.
METHODS
Patients with radiologically staged T3-4, N0-2, M0 colon cancer were randomly allocated (2:1) to 6 weeks oxaliplatin-fluoropyrimidine preoperatively plus 18 postoperatively (NAC group) or 24 weeks postoperatively (control group). Patients with -wildtype tumors could also be randomly assigned 1:1 to receive panitumumab or not during NAC. The primary end point was residual disease or recurrence within 2 years. Secondary outcomes included surgical morbidity, histopathologic stage, regression grade, completeness of resection, and cause-specific mortality. Log-rank analyses were by intention-to-treat.
RESULTS
Of 699 patients allocated to NAC, 674 (96%) started and 606 (87%) completed NAC. In total, 686 of 699 (98.1%) NAC patients and 351 of 354 (99.2%) control patients underwent surgery. Thirty patients (4.3%) allocated to NAC developed obstructive symptoms requiring expedited surgery, but there were fewer serious postoperative complications with NAC than with control. NAC produced marked T and N downstaging and histologic tumor regression (all < .001). Resection was more often histopathologically complete: 94% (648/686) versus 89% (311/351), < .001. Fewer NAC than control patients had residual or recurrent disease within 2 years (16.9% [118/699] 21.5% [76/354]; rate ratio, 0.72 [95% CI, 0.54 to 0.98]; = .037). Tumor regression correlated strongly with freedom from recurrence. Panitumumab did not enhance the benefit from NAC. Little benefit from NAC was seen in mismatch repair-deficient tumors.
CONCLUSION
Six weeks of preoperative oxaliplatin-fluoropyrimidine chemotherapy for operable colon cancer can be delivered safely, without increasing perioperative morbidity. This chemotherapy regimen, when given preoperatively, produces marked histopathologic down-staging, fewer incomplete resections, and better 2-year disease control. Histologic regression after NAC is a strong predictor of lower postoperative recurrence risk so has potential use as a guide for postoperative therapy. Six weeks of NAC should be considered as a treatment option for locally advanced colon cancer.
Topics: Humans; Fluorouracil; Oxaliplatin; Panitumumab; Chemotherapy, Adjuvant; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Staging; Colonic Neoplasms
PubMed: 36657089
DOI: 10.1200/JCO.22.00046 -
The New England Journal of Medicine Sep 2013Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy.
METHODS
In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%.
RESULTS
Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified.
CONCLUSIONS
Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME ClinicalTrials.gov number, NCT00364013.).
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; ErbB Receptors; Fluorouracil; GTP Phosphohydrolases; Genes, ras; Humans; Leucovorin; Membrane Proteins; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins
PubMed: 24024839
DOI: 10.1056/NEJMoa1305275 -
Journal of Clinical Oncology : Official... Sep 2022To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan... (Randomized Controlled Trial)
Randomized Controlled Trial
Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO.
PURPOSE
To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for and wild-type (wt) metastatic colorectal cancer (mCRC).
METHODS
TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable and wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect ≥ 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722).
RESULTS
From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, = .526). No differences in early tumor shrinkage rate (57%/58%, = .878) and deepness of response (median: 48%/47%, = .845) were reported, nor in R0 resection rate (25%/29%, = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, = .277).
CONCLUSION
The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with and wt mCRC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Genes, ras; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Prospective Studies; Proto-Oncogene Proteins B-raf; Rectal Neoplasms; ras Proteins
PubMed: 35666229
DOI: 10.1200/JCO.22.00839 -
Journal of Clinical Oncology : Official... Jan 2022The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with... (Comparative Study)
Comparative Study Randomized Controlled Trial
Panitumumab Plus Fluorouracil and Folinic Acid Versus Fluorouracil and Folinic Acid Alone as Maintenance Therapy in Wild-Type Metastatic Colorectal Cancer: The Randomized PANAMA Trial (AIO KRK 0212).
PURPOSE
The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with wild-type metastatic colorectal cancer.
METHODS
Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov (NCT01991873).
RESULTS
Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months 5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85; = .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months 25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18; = .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36; = .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%).
CONCLUSION
In wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Genes, ras; Germany; Humans; Leucovorin; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Progression-Free Survival; Time Factors
PubMed: 34533973
DOI: 10.1200/JCO.21.01332 -
Radiology and Oncology Sep 2019Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have... (Review)
Review
Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have been identified and are used in clinical practice. The RAS gene family, which includes KRAS and NRAS act as predictors for anti-epithelial growth factor receptor treatment (anti-EGFR), and it has been suggested that NRAS mutations also play a role in prognosis: patients harboring NRAS alterations have a significantly shorter survival compared to those with wild type tumours. BRAF V600E mutations are rare and occur mostly in tumors located in the ascending colon in elderly female patients. BRAF is instrumental in establishing prognosis: survival is shorter by 10-16 months in BRAF-mutant patients, and BRAF may be a negative prognostic factor for patients who undergo hepatic or pulmonary metastasectomy. Moreover, this mutation is used as a negative predictive factor for anti-EGFR therapies. Two new biomarkers have recently been added to the metastatic colorectal cancer panel: HER2 and microsatellite instability. While HER2 is still being investigated in different prospective studies in order to validate its prognostic role, microsatellite instability already guides clinical decisions in substituted with advanced colorectal cancer. Conclusions There are current evidences that support using above mentioned genetic biomarkers to better identify the right medicine that is supposed to be used in the right patient. This approach contributes to a more individualized patient-oriented treatment in daily clinical practice.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Female; Genes, erbB-2; Genes, ras; Genetic Markers; Humans; Ipilimumab; Male; Microsatellite Instability; Mutation; Panitumumab; Prognosis; Proto-Oncogene Proteins B-raf; Sex Factors; Trastuzumab
PubMed: 31553708
DOI: 10.2478/raon-2019-0033 -
Cancer Discovery Apr 2018Although BRAF inhibitor monotherapy yields response rates >50% in -mutant melanoma, only approximately 5% of patients with colorectal cancer respond. Preclinical...
Although BRAF inhibitor monotherapy yields response rates >50% in -mutant melanoma, only approximately 5% of patients with colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of and mutations on disease progression. Thus, targeting adaptive feedback pathways in colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism. This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with colorectal cancer. Our findings highlight the MAPK pathway as a critical target in colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. .
Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Imidazoles; MAP Kinase Signaling System; Male; Mitogen-Activated Protein Kinase Kinases; Oximes; Panitumumab; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones
PubMed: 29431699
DOI: 10.1158/2159-8290.CD-17-1226 -
Journal of Clinical Oncology : Official... Apr 2008Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC).... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials.
PATIENTS AND METHODS
KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status.
RESULTS
KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population.
CONCLUSION
Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; Biomarkers, Tumor; Colorectal Neoplasms; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Panitumumab; Polymerase Chain Reaction; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins
PubMed: 18316791
DOI: 10.1200/JCO.2007.14.7116 -
Nature Medicine Aug 2022Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the...
Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926 ; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Circulating Tumor DNA; Colonic Neoplasms; Colorectal Neoplasms; Humans; Mutation; Panitumumab; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Rectal Neoplasms
PubMed: 35915157
DOI: 10.1038/s41591-022-01886-0