Safety and tolerability of PD-1/PD-L1 inhibitors in elderly and frail patients with advanced malignancies

Sakakida, Tomoki; Ishikawa, Takeshi; Uchino, Junichi; Tabuchi, Yusuke; Komori, Satoshi; Asai, Jun; Arai, Akihito; Tsunezuka, Hiroaki; Kosuga, Toshiyuki; Konishi, Hirotaka; Hongo, Fumiya; Inoue, Masayoshi; Hirano, Shigeru; Ukimura, Osamu; Taguchi, Tetsuya; Takayama, K.; Itoh, Yoshito

doi:10.3892/ol.2020.11875

Cited by 13 publications

(14 citation statements)

References 44 publications

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“…However, the incidence of irAEs varies according to different ICIs. In addition, the incidence of irAEs is also higher in patients who received combined immunotherapy than monotherapy (26,27). In this study, the irAE incidence for the 21 patients who were treated with ICI monotherapy was 42.8%, with mainly mild to moderate clinical manifestation of thyroid dysfunction.…”

Section: Discussionmentioning

confidence: 60%

Programmed cell death protein-1 inhibitors in the treatment of digestive system tumors in Chinese population: an observational study of effectiveness and safety

Yang¹,

Chang²,

Guo³

et al. 2021

Ann Palliat Med

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Background: Tumor of the digestive system is a common malignancy with high morbidity and mortality.Although programmed cell death-1 (PD-1) inhibitors have become an effective treatment strategies for many kinds of tumors, there is still some uncertainty in digestive tumors, including: (I) therapeutic effects of PD-1 inhibitors are relatively limited; (II) responses of digestive system tumors to immunotherapies are highly heterogeneous. In the present study, we investigated the outcomes of PD-1 inhibitors for digestive system tumors in Chinese patients to analyze factors that may affect the effects of immunotherapies in digestive system tumors.Methods: Data were obtained from the Hospital Information System (HIS) of the Department of Digestive Oncology (Henan Cancer Hospital) between January 2019 and December 2019. Inclusion criteria included patients receiving the same PD-1 inhibitor continuously for advanced or recurrent/metastatic digestive system tumors. Indicators including age, sex, clinical diagnosis, height, weight, gene status, PD-1 inhibitors, treatment regimen, medication cycle, efficacy evaluation results, and adverse reactions were analyzed retrospectively. The clinical outcomes were progression-free survival (PFS) and safety.Results: A total of 2,767 patients were discharged from HIS, of which 64 (37 male/27 female) were included in this study. Thirty-eight (59.4%) of the patients were aged <60 years. Tumors included esophageal, gastric, liver, colorectal, and pancreatic cancer. Up until 30 June 2020, 51 patients were followed up to median progression-free survival (PFS), which was 5 months; the longest PFS was 18.5 months. There was no statistical significance in grouping according to sex, age and body mass index. Nevertheless, the median PFS differed statistically between monotherapy (9.4 months) versus combined therapy (4.7 months), and Cox regression analysis suggested that patients might benefit more from monotherapy than combined therapy The incidence of adverse reactions was 47.7%, with thyroid dysfunction the most common adverse reaction.The incidence of grade 3-4 adverse reactions was 9.2% and mainly included pulmonary infection, immuneassociated hepatitis, and severe oral ulcers. Conclusions:In digestive tumors, especially for second-line treatment and beyond, PD-1 monotherapy might be more beneficial than combined therapy. However, this might be related to the patient's tolerance.Large-sample prospective studies are needed for confirmation.

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Section: Discussionmentioning

confidence: 60%

Programmed cell death protein-1 inhibitors in the treatment of digestive system tumors in Chinese population: an observational study of effectiveness and safety

Yang¹,

Chang²,

Guo³

et al. 2021

Ann Palliat Med

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“…The CCI was developed and used to precisely quantify the comorbidity burden [ 75 ]. Additionally, CCI could be used as an indirect denominator of frailty in retrospective cohorts [ 76 ]. A large body of data demonstrated decreased survival and increased toxicity in patients with higher CCI treated with chemotherapy [ 77 , 78 ].…”

Section: Discussionmentioning

confidence: 99%

The Association between Early Changes in Neutrophil-Lymphocyte Ratio and Survival in Patients Treated with Immunotherapy

Güven

Şahin

Erul

et al. 2022

JCM

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Dynamic changes in the blood-based biomarkers could be used as a prognostic biomarker in patients treated with immune checkpoint inhibitors (ICIs), although the data are limited. We evaluated the association between the neutrophil–lymphocyte ratio (NLR) and early NLR changes with survival in ICI-treated patients. We retrospectively evaluated the data of 231 patients with advanced-stage cancer. We recorded baseline clinical characteristics, baseline NLR and fourth-week NLR changes, and survival data. A compound prognostic score, the NLR2-CEL score, was developed with the following parameters: baseline NLR (<5 vs. ≥5), ECOG status (0 vs. ≥1), Charlson Comorbidity Index (CCI, <9 vs. ≥9), and fourth-week NLR change (10% or over NLR increase). In the multivariable analyses, higher NLR (HR: 1.743, p = 0.002), 10% or over NLR increase in the fourth week of treatment (HR: 1.807, p = 0.001), higher ECOG performance score (HR: 1.552, p = 0.006), higher LDH levels (HR: 1.454, p = 0.017), and higher CCI (HR: 1.400, p = 0.041) were associated with decreased OS. Compared to patients with the lowest scores, patients in the highest score group had significantly lower OS (HR: 7.967, 95% CI: 3.531–17.979, p < 0.001) and PFS. The composite score had moderate success for survival prediction, with an AUC of 0.702 (95% CI: 0.626–0.779, p < 0.001). We observed significantly lower survival in patients with higher baseline NLR values and increased NLR values under treatment.

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“…Among 92 patients 70 years of age or older who received CPI for metastatic melanoma, the prevalence of grade 3–5 was 17% and 27% for the fit and frail patients, respectively [ 59 ]. Other studies have corroborated the safety of CPI among older cancer patients who experienced various grades of frailty ranging from low to severe [ 39 , 60 ]. Even though the data are only preliminary and involve a small number of patients, they suggest that frailty is not an absolute contraindication for immunotherapy in older cancer patients.…”

Section: Potential Disadvantages Of Cpi Compared To Cisplatin-based C...mentioning

confidence: 94%

“…The safety of CPI is also confirmed through real-world data. In a group of 197 patients with various malignancies ranging from head and neck cancer to renal cell carcinoma treated with different types of CPI, the grade 3–5 toxicity was 48.3% and 37.4% ( p = 0.1) for patients 75 years old or above ( n = 58) and less than 75 ( n = 139), respectively [ 39 ]. The response rate to CPI was also similar to the one reported in the literature for older cancer patients [ 40 ].…”

Section: Efficacy and Tolerance Of Older Cancer Patients To Cpimentioning

confidence: 99%

Immunotherapy and Modern Radiotherapy Technique for Older Patients with Locally Advanced Head and Neck Cancer: A Proposed Paradigm by the International Geriatric Radiotherapy Group

Nguyen

Kim

Thariat

et al. 2022

Cancers

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The standard of care for locally advanced head and neck cancer is concurrent chemoradiation or postoperative irradiation with or without chemotherapy. Surgery may not be an option for older patients (70 years old or above) due to multiple co-morbidities and frailty. Additionally, the standard chemotherapy of cisplatin may not be ideal for those patients due to oto- and nephrotoxicity. Though carboplatin is a reasonable alternative for cisplatin in patients with a pre-existing hearing deficit or renal dysfunction, its efficacy may be inferior to cisplatin for head and neck cancer. In addition, concurrent chemoradiation is frequently associated with grade 3–4 mucositis and hematologic toxicity leading to poor tolerance among older cancer patients. Thus, a new algorithm needs to be developed to provide optimal local control while minimizing toxicity for this vulnerable group of patients. Recently, immunotherapy with check point inhibitors (CPI) has attracted much attention due to the high prevalence of program death-ligand 1 (PD-L1) in head and neck cancer. In patients with recurrent or metastatic head and neck cancer refractory to cisplatin-based chemotherapy, CPI has proven to be superior to conventional chemotherapy for salvage. Those with a high PD-L1 expression defined as 50% or above or a high tumor proportion score (TPS) may have an excellent response to CPI. This selected group of patients may be candidates for CPI combined with modern radiotherapy techniques, such as intensity-modulated image-guided radiotherapy (IM-IGRT), volumetric arc therapy (VMAT) or proton therapy if available, which allow for the sparing of critical structures, such as the salivary glands, oral cavity, cochlea, larynx and pharyngeal muscles, to improve the patients’ quality of life. In addition, normal organs that are frequently sensitive to immunotherapy, such as the thyroid and lungs, are spared with modern radiotherapy techniques. In fit or carefully selected frail patients, a hypofractionated schedule may be considered to reduce the need for daily transportation. We propose a protocol combining CPI and modern radiotherapy techniques for older patients with locally advanced head and neck cancer who are not eligible for cisplatin-based chemotherapy and have a high TPS. Prospective studies should be performed to verify this hypothesis.

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Safety and tolerability of PD-1/PD-L1 inhibitors in elderly and frail patients with advanced malignancies

Cited by 13 publications

References 44 publications

Programmed cell death protein-1 inhibitors in the treatment of digestive system tumors in Chinese population: an observational study of effectiveness and safety

Programmed cell death protein-1 inhibitors in the treatment of digestive system tumors in Chinese population: an observational study of effectiveness and safety

The Association between Early Changes in Neutrophil-Lymphocyte Ratio and Survival in Patients Treated with Immunotherapy

Immunotherapy and Modern Radiotherapy Technique for Older Patients with Locally Advanced Head and Neck Cancer: A Proposed Paradigm by the International Geriatric Radiotherapy Group

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