Yuan Tian1,2,3, Aiqin Gao1, Qing Wen4, Shuyun Wang1, Shuisheng Zhang5, Xiaowei Yang6, Guohai Su7, Yuping Sun1,8. 1. Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, China. 2. Department of Radiotherapy Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China. 3. Department of Radiotherapy Oncology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated With Shandong First Medical University, Jinan, China. 4. Jinan Clinical Research Center of Shandong First Medical University, Jinan, China. 5. Department of General Surgery, Peking University Third Hospital, Beijing, China. 6. Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China. 7. Department of Cardiovascular Diseases, Jinan Central Hospital Affiliated to Shandong University, Jinan, China. 8. Department of Oncology, Jinan Central Hospital affiliated to Shandong First Medical University, Jinan, China.
Abstract
Background: Systematic assessment of PD-1/PD-L1 inhibitor-related neurological toxicities is important for guiding anti-PD-1 and anti-PD-L1 immunotherapy. Therefore, we conducted this meta-analysis to reveal the relationship between PD-1/PD-L1 inhibitors and neurological toxicities among cancer patients. Methods: Clinical trials investigating PD-1/PD-L1 inhibitors in cancer patients were identified by a systematic search of PubMed. The random-effect model was used to synthesize individual studies. Neurological toxicities, including all-grades and grades 3-5, were taken into account for the final comprehensive meta-analysis. The Newcastle Ottawa Scale (NOS) was used to assess the quality of included trials. Results: Thirty-one clinical trials containing data of neurological toxicities were included. Compared with chemotherapy, the risk of all-grade neurological toxicities caused by PD-1/PD-L1 inhibitors was much lower in terms of peripheral neuropathy [OR = 0.07, 95%CI:(0.04, 0.13)], peripheral sensory neuropathy [OR = 0.07, 95%CI(0.04, 0.12)], dysgeusia [OR = 0.26, 95%CI:(0.19, 0.35)], paraesthesia [OR = 0.23, 95%CI:(0.14, 0.36)], and polyneuropathy [OR = 0.12, 95%CI:(0.01, 0.94)]. However, for grades 3-5, the statistically significant results were only seen in peripheral neuropathy [OR = 0.15, 95%CI:(0.07, 0.34)] and peripheral sensory neuropathy [OR = 0.13, 95%CI:(0.04, 0.40)]. No statistically significant difference regarding the risk of headache, dizziness, and Guillain-Barré syndrome was found between PD-1/PD-L1 inhibitors and chemotherapy. For PD-1/PD-L1 inhibitors plus chemotherapy, the risk trends of the above-mentioned neurological toxicities, especially grades 3-5 peripheral neuropathy [OR = 1.76, 95%CI:(1.10, 2.82)] was increased compared to chemotherapy alone. Conclusion: Our comprehensive analysis showed that PD-1/PD-L1 inhibitors alone exhibited lower neurological toxicities than chemotherapy. However, the risk of headache, dizziness, and Guillain-Barré syndrome was similar between PD-1/PD-L1 and chemotherapy. For PD-1/PD-L1 inhibitors plus chemotherapy, the incidence trend of neurological toxicities would be increased, especially for peripheral neuropathy of grades 3-5.
Background: Systematic assessment of PD-1/PD-L1 inhibitor-related neurological toxicities is important for guiding anti-PD-1 and anti-PD-L1 immunotherapy. Therefore, we conducted this meta-analysis to reveal the relationship between PD-1/PD-L1 inhibitors and neurological toxicities among cancerpatients. Methods: Clinical trials investigating PD-1/PD-L1 inhibitors in cancerpatients were identified by a systematic search of PubMed. The random-effect model was used to synthesize individual studies. Neurological toxicities, including all-grades and grades 3-5, were taken into account for the final comprehensive meta-analysis. The Newcastle Ottawa Scale (NOS) was used to assess the quality of included trials. Results: Thirty-one clinical trials containing data of neurological toxicities were included. Compared with chemotherapy, the risk of all-grade neurological toxicities caused by PD-1/PD-L1 inhibitors was much lower in terms of peripheral neuropathy [OR = 0.07, 95%CI:(0.04, 0.13)], peripheral sensory neuropathy [OR = 0.07, 95%CI(0.04, 0.12)], dysgeusia [OR = 0.26, 95%CI:(0.19, 0.35)], paraesthesia [OR = 0.23, 95%CI:(0.14, 0.36)], and polyneuropathy [OR = 0.12, 95%CI:(0.01, 0.94)]. However, for grades 3-5, the statistically significant results were only seen in peripheral neuropathy [OR = 0.15, 95%CI:(0.07, 0.34)] and peripheral sensory neuropathy [OR = 0.13, 95%CI:(0.04, 0.40)]. No statistically significant difference regarding the risk of headache, dizziness, and Guillain-Barré syndrome was found between PD-1/PD-L1 inhibitors and chemotherapy. For PD-1/PD-L1 inhibitors plus chemotherapy, the risk trends of the above-mentioned neurological toxicities, especially grades 3-5 peripheral neuropathy [OR = 1.76, 95%CI:(1.10, 2.82)] was increased compared to chemotherapy alone. Conclusion: Our comprehensive analysis showed that PD-1/PD-L1 inhibitors alone exhibited lower neurological toxicities than chemotherapy. However, the risk of headache, dizziness, and Guillain-Barré syndrome was similar between PD-1/PD-L1 and chemotherapy. For PD-1/PD-L1 inhibitors plus chemotherapy, the incidence trend of neurological toxicities would be increased, especially for peripheral neuropathy of grades 3-5.
Authors: S Cuzzubbo; F Javeri; M Tissier; A Roumi; C Barlog; J Doridam; C Lebbe; C Belin; R Ursu; A F Carpentier Journal: Eur J Cancer Date: 2017-01-05 Impact factor: 9.162
Authors: James Larkin; Vanna Chiarion-Sileni; Rene Gonzalez; Jean-Jacques Grob; Piotr Rutkowski; Christopher D Lao; C Lance Cowey; Dirk Schadendorf; John Wagstaff; Reinhard Dummer; Pier F Ferrucci; Michael Smylie; David Hogg; Andrew Hill; Ivan Márquez-Rodas; John Haanen; Massimo Guidoboni; Michele Maio; Patrick Schöffski; Matteo S Carlino; Céleste Lebbé; Grant McArthur; Paolo A Ascierto; Gregory A Daniels; Georgina V Long; Lars Bastholt; Jasmine I Rizzo; Agnes Balogh; Andriy Moshyk; F Stephen Hodi; Jedd D Wolchok Journal: N Engl J Med Date: 2019-09-28 Impact factor: 91.245
Authors: H Vallet; A Gaillet; N Weiss; C Vanhaecke; S Saheb; V Touitou; N Franck; N Kramkimel; A Borden; M Touat; D Ricard; M Verny; T Maisonobe; D Psimaras Journal: Ann Oncol Date: 2016-03-02 Impact factor: 32.976
Authors: Julie Brahmer; Karen L Reckamp; Paul Baas; Lucio Crinò; Wilfried E E Eberhardt; Elena Poddubskaya; Scott Antonia; Adam Pluzanski; Everett E Vokes; Esther Holgado; David Waterhouse; Neal Ready; Justin Gainor; Osvaldo Arén Frontera; Libor Havel; Martin Steins; Marina C Garassino; Joachim G Aerts; Manuel Domine; Luis Paz-Ares; Martin Reck; Christine Baudelet; Christopher T Harbison; Brian Lestini; David R Spigel Journal: N Engl J Med Date: 2015-05-31 Impact factor: 91.245
Authors: Luis Paz-Ares; Mikhail Dvorkin; Yuanbin Chen; Niels Reinmuth; Katsuyuki Hotta; Dmytro Trukhin; Galina Statsenko; Maximilian J Hochmair; Mustafa Özgüroğlu; Jun Ho Ji; Oleksandr Voitko; Artem Poltoratskiy; Santiago Ponce; Francesco Verderame; Libor Havel; Igor Bondarenko; Andrzej Kazarnowicz; György Losonczy; Nikolay V Conev; Jon Armstrong; Natalie Byrne; Norah Shire; Haiyi Jiang; Jonathan W Goldman Journal: Lancet Date: 2019-10-04 Impact factor: 79.321
Authors: Martin Reck; Delvys Rodríguez-Abreu; Andrew G Robinson; Rina Hui; Tibor Csőszi; Andrea Fülöp; Maya Gottfried; Nir Peled; Ali Tafreshi; Sinead Cuffe; Mary O'Brien; Suman Rao; Katsuyuki Hotta; Melanie A Leiby; Gregory M Lubiniecki; Yue Shentu; Reshma Rangwala; Julie R Brahmer Journal: N Engl J Med Date: 2016-10-08 Impact factor: 91.245
Authors: Leora Horn; Aaron S Mansfield; Aleksandra Szczęsna; Libor Havel; Maciej Krzakowski; Maximilian J Hochmair; Florian Huemer; György Losonczy; Melissa L Johnson; Makoto Nishio; Martin Reck; Tony Mok; Sivuonthanh Lam; David S Shames; Juan Liu; Beiying Ding; Ariel Lopez-Chavez; Fairooz Kabbinavar; Wei Lin; Alan Sandler; Stephen V Liu Journal: N Engl J Med Date: 2018-09-25 Impact factor: 91.245
Authors: Hossein Borghaei; Luis Paz-Ares; Leora Horn; David R Spigel; Martin Steins; Neal E Ready; Laura Q Chow; Everett E Vokes; Enriqueta Felip; Esther Holgado; Fabrice Barlesi; Martin Kohlhäufl; Oscar Arrieta; Marco Angelo Burgio; Jérôme Fayette; Hervé Lena; Elena Poddubskaya; David E Gerber; Scott N Gettinger; Charles M Rudin; Naiyer Rizvi; Lucio Crinò; George R Blumenschein; Scott J Antonia; Cécile Dorange; Christopher T Harbison; Friedrich Graf Finckenstein; Julie R Brahmer Journal: N Engl J Med Date: 2015-09-27 Impact factor: 91.245