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Prognostic impact of C-reactive protein and alpha-fetoprotein in immunotherapy score in hepatocellular carcinoma patients treated with atezolizumab plus bevacizumab: a multicenter retrospective study

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Abstract

Aim

This study aimed to investigate the utility of C-reactive protein (CRP) and alpha-fetoprotein (AFP) in immunotherapy (CRAFITY) score in hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/Bev).

Methods

This retrospective cohort study included a total of 297 patients receiving Atez/Bev from September 2020 to November 2021 at 21 different institutions and hospital groups in Japan. Patients with AFP ≥ 100 ng/mL and those with CRP ≥ 1 mg/dL were assigned a CRAFITY score of 1 point.

Results

The patients were assigned CRAFITY scores of 0 points (n = 147 [49.5%]), 1 point (n = 111 [37.4%]), and 2 points (n = 39 [13.1%]). AFP ≥ 100 ng/mL and CRP ≥ 1.0 mg/dL were significantly associated with progression-free survival (PFS) and overall survival (OS). The median PFS in the CRAFITY score 0, 1, and 2 groups was 11.8 months (95% confidence interval [CI] 6.4-not applicable [NA]), 6.5 months (95% CI 4.6–8.0), and 3.2 months (95% CI 1.9–5.0), respectively (p < 0.001). The median OS in patients with CRAFITY score 0, 1 and 2 was not reached, 14.3 months (95% CI 10.5-NA), and 11.6 months (95% CI 4.9-NA), respectively. The percentage of patients with grade ≥ 3 liver injury, any grade of decreased appetite, any grade of proteinuria, any grade of fever, and any grade of fatigue was lowest in patients with a CRAFITY score of 0, followed by patients with CRAFITY scores of 1 and 2.

Conclusions

The CRAFITY score is simple and could be useful for predicting therapeutic outcomes and treatment-related adverse events.

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Acknowledgement

RELPEC study group member includes Takeshi Hatanaka, Satoru Kakizaki, Atsushi Hiraoka, Toshifumi Tada, Kazuya Kariyama, Koichi Takaguchi, Ei Itobayashi, Kunihiko Tsuji, Toru Ishikawa, Satoshi Yasuda, Hidenori Toyoda, Noritomo Shimada, Takaaki Tanaka, Hideko Ohama, Kazuhiro Nouso, Akemi Tsutsui, Takuya Nagano, Michitaka Imai, Atsushi Naganuma, Shinichiro Nakamura, Takashi Kumada.

Funding

There is no funding sources.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Kamishindenmachi 564-1, Maebashi, Gunma, 371-0821, Japan

    Takeshi Hatanaka

  2. Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan

    Satoru Kakizaki

  3. Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Gunma, Japan

    Satoru Kakizaki

  4. Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan

    Atsushi Hiraoka & Takaaki Tanaka

  5. Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan

    Toshifumi Tada & Shinichiro Nakamura

  6. Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan

    Masashi Hirooka, Yohei Koizumi & Yoichi Hiasa

  7. Department of Gastroenterology, Okayama City Hospital, Okayama, Japan

    Kazuya Kariyama & Kazuhiro Nouso

  8. Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan

    Joji Tani & Asahiro Morishita

  9. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan

    Masanori Atsukawa, Norio Itokawa, Tomomi Okubo & Taeang Arai

  10. Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan

    Koichi Takaguchi, Akemi Tsutsui & Takuya Nagano

  11. Department of Gastroenterology, Asahi General Hospital, Asahi, Japan

    Ei Itobayashi

  12. Premier Departmental Research of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan

    Shinya Fukunishi & Hideko Ohama

  13. Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan

    Kunihiko Tsuji

  14. Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan

    Toru Ishikawa & Michitaka Imai

  15. Department of Gastroenterology, Toyama University Hospital, Toyama, Japan

    Kazuto Tajiri

  16. Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama, Japan

    Hironori Ochi & Kouji Joko

  17. Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan

    Satoshi Yasuda & Hidenori Toyoda

  18. Department of Gastroenterology, Japanese Red Cross Takamatsu Hospital, Takamatsu, Japan

    Chikara Ogawa

  19. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hyogo College of Medicine, Nishinomiya, Japan

    Takashi Nishimura & Hiroko Iijima

  20. Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan

    Noritomo Shimada

  21. Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Kazuhito Kawata

  22. Department of Surgery, Kansai Medical University, Hirakata, Japan

    Hisashi Kosaka & Masaki Kaibori

  23. Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan

    Atsushi Naganuma

  24. Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan

    Takashi Kumada

Authors
  1. Takeshi Hatanaka
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  2. Satoru Kakizaki
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  3. Atsushi Hiraoka
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  4. Toshifumi Tada
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  5. Masashi Hirooka
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  6. Kazuya Kariyama
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  7. Joji Tani
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  8. Masanori Atsukawa
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  9. Koichi Takaguchi
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  10. Ei Itobayashi
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  11. Shinya Fukunishi
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  12. Kunihiko Tsuji
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  13. Toru Ishikawa
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  14. Kazuto Tajiri
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  15. Hironori Ochi
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  16. Satoshi Yasuda
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  17. Hidenori Toyoda
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  18. Chikara Ogawa
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  19. Takashi Nishimura
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  20. Noritomo Shimada
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  21. Kazuhito Kawata
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  22. Hisashi Kosaka
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  23. Takaaki Tanaka
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  24. Hideko Ohama
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  25. Kazuhiro Nouso
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  26. Asahiro Morishita
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  27. Akemi Tsutsui
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  28. Takuya Nagano
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  29. Norio Itokawa
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  30. Tomomi Okubo
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  31. Taeang Arai
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  32. Michitaka Imai
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  33. Atsushi Naganuma
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  34. Yohei Koizumi
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  35. Shinichiro Nakamura
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  36. Kouji Joko
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  37. Masaki Kaibori
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  38. Hiroko Iijima
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  39. Yoichi Hiasa
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  40. Takashi Kumada
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Consortia

On behalf of the Real-life Practice Experts for HCC (RELPEC) Study Group, and HCC 48 Group (hepatocellular carcinoma experts from 48 clinics in Japan)

Contributions

TH, SK, AH, TTad, AN, and TK conceived the study, and participated in its design and coordination. TH, SK, AH, TTad, MH, KKar, JT, MA, KTak, EI, SF, KTs, TI, KTaj, HOc, SY, HT, CO, TNi, NS, KKaw, TTan, HOh, KN, AM, AT, TNa, NI, TO, TA, MI, AN, YK, SN, KJ, HI, and YH performed data curation. TH performed statistical analyses and interpretation. TH, SK, AH, TTad, AN, TK, HK, and MK drafted the text. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Takeshi Hatanaka.

Ethics declarations

Conflict of interest

Takeshi Hatanaka received lecture fees from Eisai. Atsushi Hiraoka received lecture fees from Bayer, Eisai, Eli Lilly, Otsuka, and Chugai. Takashi Kumada received lecture fees from Eisai.Satoru Kakizaki, Toshifumi Tada, Masashi Hirooka, Kazuya Kariyama, Joji Tani, Masanori Atsukawa, Koichi Takaguchi, Ei Itobayashi, Shinya Fukunishi, Kunihiko Tsuji, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Chikara Ogawa, Takashi Nishimura, Noritomo Shimada, Kazuhito Kawata, Hisashi Kosaka, Takaaki Tanaka, Hideko Ohama, Kazuhiro Nouso, Asahiro Morishita, Akemi Tsutsui, Takuya Nagano, Norio Itokawa, Tomomi Okubo, Taeang Arai, Michitaka Imai, Atsushi Naganuma, Yohei Koizumi, Shinichiro Nakamura, Kouji Joko, Masaki Kaibori, Hiroko Iijima,and Yoichi Hiasa, have no potential conflicts of interest to declare.

Ethical approval

The study protocol was granted approval by the Institutional Ethics Committee of Ehime Prefectural Central Hospital (IRB No. 30–66) (UMIN000043219). All procedures were performed in accordance with the Declaration of Helsinki.

Informed consent

Written informed consent was obtained from all patients.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The RELPEC study group member are mentioned in the Acknowledgement section.

Supplementary Information

Below is the link to the electronic supplementary material.

12072_2022_10358_MOESM1_ESM.tif

(a) The correlation between CRP and the ALBI score (r=0.44, p<0.001). (b) Receiver operating curve analysis. The cutoff value of the ALBI score for CRP ≥1 mg/dL was -2.348; the area under the receiver operating curve was 0.736 (95% CI 0.670-0.803; specificity, 0.648; sensitivity, 0.746). The present cutoff value was close to that of mALBI grade 2a and 2b (i.e., -2.27) (TIF 750 KB)

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(a) PFS in patients with BCLC early and intermediate stage according to the CRAFITY score. The median PFS in the patients with CRAFITY scores of 0, 1, and 2 points was 11.8 months (95% CI 7.0-NA), 7.8 months (95% CI 6.5-12.5), and 3.2 months (95% CI 0.8-9.7), respectively. The PFS was significantly longer in the patients with a CRAFITY score of 0, followed by those with a CRAFITY score of 1, and those with a CRAFITY score of 2 points (p<0.001). (b) The PFS in patients with BCLC advanced and terminal stage according to CRAFITY score. The median PFS in the patients with CRAFITY scores of 0, 1, and 2 points was 6.8 months (95% CI 5.1-NA), 5.3 months (95% CI 3.5-7.6), and 3.0 months (95% CI 1.8-4.6), respectively, which amounted to a statistically significant difference (p=0.011). (c) The PFS in patients receiving Atez/Bev as front-line treatment according to CRAFITY score. The median PFS in the patients with CRAFITY score of 0, 1, and 2 points was 11.8 months (95% CI 6.2-NA), 6.5 months (95% CI 3.5-9.0), and 3.2 months (95% CI 1.6-NA), respectively (p=0.003). (d) The PFS in patients receiving Atez/Bev as later-line treatment according to CRAFITY score. The median PFS in the patients with CRAFITY score of 0, 1, and 2 points was 7.4 months (95% CI 6.1-NA), 6.7 months (95% CI 4.4-8.0), and 3.3 months (95% CI 1.5-5.8), respectively (p=0.001). Atez/Bev, atezolizumab and bevacizumab; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; CRAFITY score, C-reactive protein and alpha-fetoprotein in immunotherapy; NA, not applicable; PFS, progression-free survival (TIF 1173 KB)

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(a) The overall survival in patients with BCLC early and intermediate stage according to the CRAFITY score. The median OS in patients with CRAFITY score 0 was not reached and it was 14.3 months (95% CI 10.0-NA) in patients with CRAFITY score 1 and 11.9 months (95% CI 1.57-NA) in patients with CRAFITY score 2, which amounted to a statistically significant difference (p=0.030). The 6-month and 12-month OS rates were 96.3% (95% CI 85.8-99.1) and 89.9% (95% CI 74.3-96.2), respectively, in patients with CRAFITY score 0, 92.3% (95% CI 78.1-97.5) and 58.6% (95% CI 35.7-75.8) in patients with CRAFITY score 1, and 78.7% (95% CI 38.1-94.3) and 39.4% (95% CI 5.9-73.6) in patients with CRAFITY score 2. (b) Overall survival in patients with BCLC advanced and terminal stage according to the CRAFITY score. The median OS was not reached in patients with CRAFITY scores of 0 and 1, while it was 7.6 months (95% CI 4.4-NA) in patients with CRAFITY score of 2; this difference was statistically significant (p<0.001). The 6-month and 12-month OS rates were 92.9% (95% CI 82.1-97.3) and 74.3% (95% CI 51.4-87.6), respectively, in patients with CRAFITY score of 0, 93.3% (95% CI 83.2-97.4) and 67.6% (95% CI 46.8-81.7) in patients with CRAFITY score of 1, and 57.7% (95% CI 35.1-74.9) and 46.6% (95% CI 24.7-65.9) in patients with CRAFITY score of 2. (c) Overall survival in patients receiving Atez/Bev as front line treatment according to the CRAFITY score. The median OS was not reached in patients with CRAFITY scores of 0, 1, and 2. The 6-month and 12-month OS rates were 91.3% (95% CI 81.4-96.1) and 84.9% (95% CI 72.4-92.1), respectively, in patients with CRAFITY score of 0, 93.1% (95% CI 79.6-97.8) and 58.1% (95% CI 29.9-78.4) in patients with CRAFITY score of 1, and 64.8% (95% CI 37.3-82.6) and 56.7% (95% CI 29.0-77.0) in patients with CRAFITY score of 2 (p=0.009). (d) Overall survival in patients receiving Atez/Bev as later line treatment according to the CRAFITY score. The median OS was not reached in patients with CRAFITY scores of 0, while it was 14.3 months (95% CI 10.5-NA) in patients with CRAFITY score of 1 and 11.6 months (95% CI 4.3-NA) in patients with CRAFITY score of 2. The 6-month and 12-month OS rates were 100% (95% CI NA-NA) and 78.2% (95% CI 47.1-92.3), respectively, in patients with CRAFITY score of 0, 92.8% (95% CI 82.0-97.3) and 65.8% (95% CI 47.6-79.0) in patients with CRAFITY score of 1, and 62.3% (95% CI 33.8-81.3) and 26.7% (95% CI 4.8-56.3) in patients with CRAFITY score of 2 (p<0.001).Atez/Bev, atezolizumab and bevacizumab; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; CRAFITY score, C-reactive protein and alpha-fetoprotein in immunotherapy; NA, not applicable; OS, overall survival (TIF 1093 KB)

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Hatanaka, T., Kakizaki, S., Hiraoka, A. et al. Prognostic impact of C-reactive protein and alpha-fetoprotein in immunotherapy score in hepatocellular carcinoma patients treated with atezolizumab plus bevacizumab: a multicenter retrospective study. Hepatol Int 16, 1150–1160 (2022). https://doi.org/10.1007/s12072-022-10358-z

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