Staging in HCC.pptx

Staging in hepatocellular carcinomas from a radiation oncology perspective

1. Staging in Hepatocellular cancer : is it time to look beyond TNM? Lt col Sankalp singh Associate professor (rad onco ) Army hospital( r&r ), delhi

2. OVERVIEW Purpose of staging in cancer TNM staging in HCC Other major staging systems Brief comparisons of staging systems Implications of staging on Radiotherapy

3. Hepatocellular carcinoma ( HCC) M ost common primary liver cancer Third leading cause of cancer-related death worldwide High incidence in Asia , leading to a heavy disease burden Surgery is only curative option but upto 85% fail to undergo surgery as an initial treatment Most HCC is preceded by liver cirrhosis, complicating and influencing the potential treatment modality and subsequent survival outcomes

4. Hepatocellular carcinoma ( HCC) A variety of treatment modalities are available including Surgery Liver transplantation Tumour resection Ablative therapies SBRT/HFRT radiofrequency , microwave , laser cryoablation injection of chemical agents ( ethanol) Transarterial therapies – TACE, TARE Systemic therapy

5. Purpose of Staging in Cancer Prognostication of disease Comparison of similar patient subsets during clinical trials Selection for treatment modality ;

6. Fifteen-year Survival of Melanoma Patients Based on Tumor-Node-Metastasis Stage Group. Effect of Microsatellite Instability on Survival of Colon Cancer Patients. Microsatellite instability in sporadic colon cancer is associated with improved prognosis. Reprinted from Samowitz WS, Curtin K, Ma KN, et al1 with permission from Cancer Epidemiol Biomarkers Prev.

7. Challenges in HCC staging Etiology –driven malignancy with etiology - specific risk factors Severe hepatic fibrosis & cirrhosis is a key determinant of prognosis Underlying liver function plays a large role in selection of therapeutic approach & overall prognosis Significant regional variation in Risk factors Treatment offered to patients with similar disease burden

8. History of TNM staging Staging of cancer started over a hundred years ago. French surgeon Pierre Denoix : first to develop the tumor-node-metastasis (TNM) classification in 1952 1958: first international TNM recommendations published by the UICC for the clinical stage classification of breast and larynx cancers The latest (8 th ) edition of TNM staging was published by the UICC & AJCC in 2017 Challenges for anatomic staging: how to adapt current taxonomy with the numerous non-anatomic prognostic factors currently in use or under study

9. TNM Staging in HCC: AJCC 8 th edition The 8 th edition of TNM staging in HCC has been revised with particular focus on international expertise from Asia, where the incidence of hepatobilliary cancer is high

10. TNM Staging in HCC: AJCC 8 th edition Survival after resection for HCC according to stage grouping. Data from Vauthey et al . Survival after liver transplantation for HCC according to stage grouping. Data from Vauthey et al. Vauthey JN, et al. Simplified staging for hepatocellular carcinoma. J Clin Oncol . 2002 Mar 15;20(6):1527-36. doi : 10.1200/JCO.2002.20.6.1527. PMID: 11896101. Vauthey JN, Ribero D, Abdalla EK, et al. Outcomes of liver transplantation in 490 patients with hepatocellular carcinoma: validation of a uniform staging after surgical treatment. Journal of the American College of Surgeons. May 2007;204(5):1016–1027; discussion 1027–1018

11. TNM Staging in HCC: AJCC 8 th edition Comparison of the new classification for solitary tumor and the 7th Edition classification for multiple HCC. Data from Shindoh et al. Shindoh J, Andreou A, Aloia TA, et al. Microvascular invasion does not predict long-term survival in hepatocellular carcinoma up to 2 cm: reappraisal of the staging system for solitary tumors . Annals of surgical oncology. 2013;20(4):1223–1229.

12. TNM Staging in HCC : AJCC 8 th edition The Ishak fibrosis scoring system Beyond the factors used to assign T, N, or M categories, no additional prognostic factors are required for stage grouping. Tumor grade is based on the degree of nuclear pleomorphism , as described by Edmonson & Steiner. CHILD-PUGH SCORE Class A = 5–6 points; Class B = 7–9 points; Class C = 10–15 points. Class A: Good operative risk Class B: Moderate operative risk Class C: Poor operative risk

13. Prognostic factors for liver cancer (HCC ) Prognostic factors Tumour related Host related Environment related Essential Major vascular invasion * Microvascular invasion * Size >5 cm Multiple ( vs single) Tumour differentiation Fibrosis of underlying liver * Tumour growth rate Patient performance status at diagnosis Liver function Degree of portal hypertension Treatment factors: Post resection residual disease (R0, R1, R2) Post ablation residual disease Post embolization residual disease Additional AFP level DCP/PIVKA II level Hepatitis activity New and promising 5 gene score (genetic profile) Cancer stem cell markers Circulating micro RNA, DNA, circulating cancer Cells IGF 1 combined with CLIP Regulatory T cells C reactive protein (CRP), Interleukin 10 (IL 10), Vascular endothelial growth factor (VEGF), Neutrophil to lymphocyte ratio, MnSOD (magnesium superoxide dismutase) Source: UICC Manual of Clinical Oncology, Ninth Edition. Edited by Brian O’Sullivan, James D. Brierley, Anil K. D’Cruz , Martin F. Fey, Raphael Pollock, Jan B. Vermorken and Shao Hui Huang. © 2015 UICC. Published 2015 by John Wiley & Sons, Ltd.

14. TNM Staging in HCC : LIMITATIONS Prognostic information only based on the anatomic extent/pathologic characteristics of disease Absence of clinical factors & treatment recommendations No formal assessment of patient’s general health or performance status Underlying liver function or remnant functional liver is not included in the prognostic stage grouping The degree of liver fibrosis/cirrhosis is not included in the stage grouping Tumour differentiation grade not included in prognostic group.

15. Treatment Decisions with TNM

16. Other staging systems in HCC The Okuda staging system Cancer of the Liver Italian Program (CLIP) BCLC ( Barcelona Clinic Liver Cancer) Staging classification Groupe d’Etude et de Traitement du Carcinome Hépatocellulaire (GRETCH) Chinese University Prognostic Index (CUPI) Japan Integrated Staging Score (JIS)

17. Other staging systems in HCC Model to Estimate Survival in Ambulatory HCC patients score (MESIAH score) China Integrated Score Memorial Sloan-Kettering Cancer Center nomogram Advanced Liver Cancer Prognostic System Bilirubin , Albumin , Lens culinaris agglutinin reactive alpha-fetoprotein (AFP-L3), AFP and DCP Score (BALAD score ) Tokyo score Estrogen receptor classification Taipei Integrated Score System AFP staging 5-gene score Hong Kong Liver Cancer classification

18. The Okuda staging system Developed by a Japanese group in 1984 First to use a combination of tumour size & liver function to prognosticate patients of HCC Showed a variation in OS of 11.5 months and 0.9 months between stages I and III respectively Major drawbacks: Tumour size criteria is too rough Does not include variables such as multicentricity , vascular invasion or extrahepatic metastasis Applicability limited to patients with advanced disease

19. Cancer of Liver Italian Programme (CLIP) Includes liver function (Child-Pugh class), tumour biology (size and invasion) and portal vein thrombosis Includes Alpha fetoprotein as a surrogate marker of tumour biology Classifies patients as per score (0 to 6) with median survival ranging from several years (0/6) to few weeks (6/6) Relative inability to discriminate prognostic differences in early stage HCC Generally favoured for non-surgical patients with advanced HCC Offers no treatment recommendations

20. Barcelona Clinic Liver Cancer (BCLC) staging F irst introduced in 1999 comprises five stages that select the best candidates for the best therapies available. It includes variables related to tumor stage , liver functional status , physical status , and cancer related symptoms and links the five stages described with a treatment strategy. It remains one of the most comprehensive and widely used and validated prognostic tools: endorsed by the EORTC, EASL and AASLD

21. Barcelona Clinic Liver Cancer (BCLC) staging Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022;76:681-693.

22. Barcelona Clinic Liver Cancer (BCLC) staging Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022;76:681-693.

23. BCLC staging limitations Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022;76:681-693. Stage B (intermediate stage) includes a heterogeneous population of HCC patients with varying degree of tumor extension, liver functional reserve and disease etiology resulting in prognostic heterogeneity and preventing the determination of optimal treatment. The variable ECOG PS is somewhat subjective compromising the reliability in predicting patient outcomes. The one-to- one correspondence treatment recommendations for each stage of the BCLC system may be not suitable for use in actual clinical practice ( i.e., resection or liver transplantation after TACE, the combination of TACE with RFA and/or the combination of TACE with sorafenib , TACE for patients with BCLC 0 or A status and resection for patients with BCLC B or C status ).

24. Model for End Stage Liver Disease (MELD) Originally developed to estimate peri -procedural mortality following TIPS Now validated for use in patients with cirrhosis for a wide range of procedures including liver transplant and hepatectomy Uses s erum bilirubin + Serum creatinine + INR to predict 90-day survival Useful in prognosticating and prioritizing patients to receive liver transplant – used by UNOS ( U nited Network for Organ Sharing)

25. Model for End Stage Liver Disease (MELD)

26. ALBI Score Uses serum albumin and bilirubin levels to assess liver function in patients of HCC ALBI score = (log 10  bilirubin [µ mol /L] × 0.66) + (albumin [g/L] × −0.0852). ALBI grades 1, 2, and 3 are as follows: ALBI score ≤ −2.60 (ALBI grade 1), > −2.60 to ≤ −1.39 (ALBI grade 2), > −1.39 (ALBI grade 3) Unlike CP and MELD can be used in patients with or without cirrhosis Has greater prognostic discriminatory capacity within a cohort of patients with unfavourable prognosis Has been validated to use on a wide spectrum of patients – early disease undergoing surgery to advanced diseases on Sorafenib

27. ALBI Score

28. Hong Kong Liver Cancer Staging System

29. Comparison between Staging systems BCLC investigators from China, Italy, US , Spain, South Korea and Egypt have demonstrated that the BCLC provides the best prognostic value in HCC patients with early to advanced stage tumors treated with various modalities a large scale trial from Taiwan ( n = 3892) showed that the treatment schedules determined according to the BCLC classification are reasonable and beneficial for survival in patients with HCC CLIP Score investigators from Japan, Canada, Italy , France , Taiwan, US and Germany have demonstrated that the CLIP score provides better prognostic value than other systems in HCC patients with advanced stage tumors receiving non-surgical treatment AJCC/TNM 7th edition Due to lack of factors related to the liver functional reserve, the prognostic relevance of the TNM staging system is limited to HCC patients with early-stage tumors and a preserved liver functional reserve . The prognostic ability of 7 th edition TNM staging was poorer than BCLC, esp. in advanced stages .

30. Comparison between Staging systems CUPI Studies from Taiwan and China have demonstrated that the CUPI is the best prognostic model in advanced HCC patients with portal vein invasion or extrahepatic metastasis. This score has not been validated in either a Western population or in patients with etiologies other than HBV infection. JIS A study from Japan showed that the JIS score provides the best prognostic value in HCC patients treated with surgical resection. Other studies from Japan have also demonstrated the JIS score to be the best prognostic model in HCC patients who receive various treatment modalities[83,84]. The JIS score has not been validated in countries outside of Japan.

31. Comparison between Staging systems Although there are over a dozen staging systems proposed for patients with HCC, no consensus has been made on the best classification available Survival after diagnosis with HCC is due primarily to three related factors : cancer biology , delivery of an optimal cancer-directed therapy , and the patient’s underlying health and liver function No single staging system can incorporate all the nuances of treatment, given the complex and heterogeneous nature of HCC and various factors that play a role in decision making

32. Compared the ability of staging systems (AJCC/UICC, Japanese TNM, Pittsburgh, UNOS, CLIP, JIS, and BCLC) to predict survival after liver transplantation for HCC   490 patients who underwent liver transplantation for HCC at 4 centers (1985 to 2005) In only three systems- AJCC/UICC , Japanese TNM, and Pittsburgh--were OS & RFS longer for patients with low stage versus more advanced stage The AJCC/UICC staging system provided the best stratification of prognosis for patients undergoing liver transplantation for HCC

33. Liver Cancer Study Group of Japan (LCSGJ) prospectively collected clinicopathologic data of 63,736 patients with primary liver cancer from 1995 to 2001. Among them, 13,772 patients received curative hepatic resection The accuracy of the Japanese TNM staging system for predicting patient survival was compared with that of the AJCC/UICC staging system Both the LCSGJ-T and the AJCC-T had good discriminating ability, the former was significantly superior ( P 0.0007). 5 year OS% T1 T2 T3 T4 Jap TNM 70% 58% 41% 24% AJCC/UICC 61% 46% 30%

34. Chen, L. J., Chang, Y. J., & Chang, Y. J. (2021). Survival Predictability Between the American Joint Committee on Cancer 8th Edition Staging System and the Barcelona Clinic Liver Cancer Classification in Patients with Hepatocellular Carcinoma. Oncologist, 26(3), e445–e453. https://doi.org/10.1002/onco.13535 C ompared the prognostic significance between the AJCC 8th edition (TNM ) staging and the BCLC staging in 37,062 Taiwanese patients with HCC. 25.6 % patients underwent initial surgery Multivariate Cox proportional hazards model revealed that both systems significantly predicted stage-wise OS, DFS, cancer specific survival and local recurrence-free rate The 8th TNM system presented better goodness-of-fit for all kinds of survival. For patients in the non-surgery group, adoption of the 8th TNM system fit more precisely than the BCLC classification For patients in the surgery group, adoption of the BCLC classification fit more precisely than the 8th TNM system.

35. Chen, L. J., Chang, Y. J., & Chang, Y. J. (2021). Survival Predictability Between the American Joint Committee on Cancer 8th Edition Staging System and the Barcelona Clinic Liver Cancer Classification in Patients with Hepatocellular Carcinoma. Oncologist, 26(3), e445–e453. https://doi.org/10.1002/onco.13535 OS by TNM CS-S by TNM OS by BCLC CS-S by BCLC

36. Chen, L. J., Chang, Y. J., & Chang, Y. J. (2021). Survival Predictability Between the American Joint Committee on Cancer 8th Edition Staging System and the Barcelona Clinic Liver Cancer Classification in Patients with Hepatocellular Carcinoma. Oncologist, 26(3), e445–e453. https://doi.org/10.1002/onco.13535 Univariate Cox regression of OS, CS-S, DFS and local recurrence-free rate regarding the TNM ( 8th edition) and the BCLC classification in patients with HCC

37. Comparison between Staging systems

38. Comparison between Staging systems As non-anatomic prognostic factors become widely used, TNM will remain a solid foundation on which to build prognostic classifications. Methods are needed to express overall prognosis without losing the vital anatomic content of TNM. These methods should be able to integrate multiple prognostic factors, including TNM, yet permit TNM to remain intact and distinct.

39. HCC Staging in Indian context In a study from AIIMS, New Delhi 324 patients with HCC, patients were staged according to Child-Pugh class, Okuda, CLIP and BCLC staging. Only, Okuda staging was observed as the independent predictor of survival . In a prospective study from PGIMER, 101 HCC patients were diagnosed and stratified according to 7 different staging systems; CLIP, Tokyo score and BCLC staging system showed a significant difference in the probability of survival. All other staging systems failed to show a significant difference in survival. Most patients in India report at an advanced stage, hence the staging systems like BCLC which are applicable in advanced stage and help in prognostication and treatment decision may be more useful.

40. Staging for Radiotherapy? Situations in which SBRT maybe favoured over RFA or TACE. - Downstaging

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