Current Status of Multidisciplinary Treatment Strategies for Hepatocellular Carcinoma in the Era of Advanced Systemic Therapies

Recent advances in systemic therapy for hepatocellular carcinoma (HCC) have led to debates about the feasibility of combination therapies, such as systemic therapy combined with surgery or transarterial chemoembolization, for patients with advanced HCC. However, a lack of consensus on the oncological resectability criteria has hindered discussions of “conversion therapy” and the optimal management in patients with HCC. To address this issue, the Japan Liver Cancer Association (JLCA) and the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) established a working group and discussed the concept of borderline resectable HCC. Herein, we present a consensus statement from this expert panel on the resectability criteria for HCC from the oncological standpoint under the assumption of technically and liver-functionally resectable situations. The criteria for oncological resectability in HCC are classified into three grades: resectable, representing an oncological status for which surgery alone may be expected to offer clearly better survival outcomes as compared with other treatments; borderline resectable 1, representing an oncological status for which surgical intervention as a part of multidisciplinary treatment may be expected to offer survival benefit; and borderline resectable 2, representing an oncological status for which the efficacy of surgery is uncertain and the indication for surgery should be determined carefully under the standard multidisciplinary treatment. These criteria aim to provide a common language for discussing and analyzing the treatment strategies for advanced HCC. It is also expected that these criteria will be optimized, modified, and updated based on further advancements in systemic therapies and future validation studies.

The aim of this study was to evaluate the newly established oncological criteria of resectability of hepatocellular carcinoma (HCC) for selecting suitable candidates for systemic and combination therapy. The data of 156 consecutive HCC patients with intrahepatic target nodules who had initially received systemic therapy (lenvatinib and atezolizumab plus bevacizumab) were reviewed. The patients were classified into three groups according to the novel oncological criteria for resectability (R, resectable; BR1, borderline resectable 1; and BR2, borderline resectable 2). The prognostic ability and clinical utility for selecting this population to receive combined use of multiple systemic sequential and locoregional therapy was then evaluated. Combined use of systemic sequential therapy with more than two agents and locoregional treatment was defined as multidisciplinary combination therapy (MCT), while systemic sequential therapy only and repeated locoregional treatment was defined as a single treatment procedure (STP). Patients classified as R and BR1 had significantly better overall survival (OS) compared with BR2 (R vs. BR2, p=0.012; BR1 vs. BR2, p=0.004). However, there was no significant difference between R and BR1 (p=1.000), in spite of significantly worse oncological status in the BR1 patients. Following a R0 resection and MCT, the BR1 patients had significantly better OS compared with those receiving STP or no additional treatment (median OS, not reached vs. 25.2months and 20.1 vs. 11.3months, respectively; p=0.034). In patients with advanced HCC with intrahepatic target nodules the BR1 category is one of the favorable candidates for selecting those to be treated with MCT strategies.

Evolving Strategies in the Management of Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis: A Narrative Review of Locoregional and Surgical Therapies.

Hepatocellular carcinoma (HCC) is a particularly serious kind of liver cancer. Liver cancer ranks third in terms of mortality rate worldwide, putting it among the leading causes of deaths from cancer. HCC is the primary kind of liver cancer and makes up the vast majority of cases, accounting for approximately 90% of occurrences. Numerous research have verified this information. the progress of fatty liver, alcohol induced cirrhosis, smoking habits, obesity caused by overweight, and metabolic diseases such as diabetes. The treatment strategies for HCC can be divided into two categories: One is curative treatment, including liver transplantation, surgical resection, and ablation therapy or selective arterial radiation embolization, aimed at completely eliminating the lesion; Another type is non curative treatment options, including transarterial chemoembolization and systemic therapy, which focus on controlling disease progression and prolonging patient survival. The majority of HCC patients are found to be in an advanced stage and need systemic therapy. Sorafenib and lenvatinib are frequently used as first-line medications in traditional HCC treatment to slow the disease's progression. For second-line treatment, regorafenib, cabozantinib, or remdesizumab are used to inhibit tumors through different mechanisms and prolong survival. In recent years, with the in-depth exploration of the pathogenesis and progression mechanism of HCC, as well as the rapid progress within the domain of tumor immunotherapy, the treatment prospects for advanced HCC patients have shown a positive transformation. This transformation is reflected in the fact that more and more patients are gradually gaining significant and considerable therapeutic advantages from advanced immunotherapy regimens, bringing unprecedented improvements to their treatment outcomes. In order to enable activated T cells to attack tumor cells, immune checkpoint inhibitors interfere with the inhibitory. To evaluate the effects of nivolumab in combination with cabozantinib on patient tumor markers and immune function, as well as the therapeutic efficacy of this combination in treating advanced HCC, a study was conducted. In all, 100 patients with advanced HCC who were brought to our hospital between July 2022 and July 2023 and who did not match the requirements for surgical resection had their clinical data thoroughly analyzed retrospectively in this study. Among them, half of the patients (50 cases) only received oral cabozantinib as a single treatment regimen (set as the control group), while the other half of the patients (50 cases) received intravenous infusion of nivolumab in addition to oral cabozantinib (set as the observation group). The objective of the probe is to examine the variations in disease control rate (DCR) and objective response rate (ORR) between two groups; At the same time, changes in the levels of T lymphocyte subsets (CD3+, CD4+, CD8+) and tumor markers, including AFP, GP-73, and AFP-L3, were evaluated; In addition, changes in liver and kidney function indicators and adverse reactions during treatment were also monitored. For patients with advanced HCC, this research also calculated and analyzed the progression free survival of two patient groups throughout the course of a 12-month follow-up to assess the effectiveness and safety of this therapeutic approach. Upon comparing baseline information for both groups of subjects before treatment, it was found that no statistically significant alterations had occurred (P > 0.05). After the therapeutic intervention, the observation group and control group's ORR and DCR differed statistically significantly (P < 0.05). The observation group's scores significantly improved. Subsequent examination revealed that the observation group's T lymphocyte subset levels had significantly changed, mostly exhibiting an increase in CD3+, CD4+, and CD4+/CD8+ levels while CD8+ levels had comparatively dropped. There was a significant difference (P < 0.05) between these changes and those in the control group. The observation group also showed positive improvements in tumor markers; AFP, GP-73, and AFP-L3 levels were considerably lower in the group under observation than in the control group, with statistically significant differences (P < 0.05). When liver function was assessed, total bilirubin and alanine aminotransferase were found to be considerably lower in the observation group than in the control group (P < 0.05). The incidence of adverse responses was not statistically significant (P > 0.05), indicating that the incidence of adverse responses did not differ significantly between the two groups. When treating advanced HCC, nivolumab and cabozantinib together have the ability to increase T lymphocyte numbers, reduce tumor marker levels, effectively prolong survival time, and have better efficacy than simple control treatment, with good safety.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second most frequent cause of cancer-related mortality worldwide. HCC predominantly arises in cirrhotic livers as a consequence of underlying chronic diseases including viral hepatitis, alcoholic liver disease and non-alcoholic steatohepatitis. Treatment options for advanced HCC are limited. Sorafenib (Nexavar®) has been the only approved drug for the management of advanced HCC for the past ten years. Recently, additional multikinase inhibitors entered the clinic, however, without significantly improving overall survival as compared to sorafenib. Major advancements are expected to be achieved with the introduction of immune checkpoint inhibitors such as nivolumab (Opdivo®), but biomarkers to identify patients who may benefit from the treatment are currently missing. Moreover, several additional drugs have failed to meet clinical end points in large phase III trials, indicating a need for new drug discovery for HCC. A major obstacle for the development of new therapies is the lack of suitable preclinical animal models or cell culture systems that allow a faithful translation of basic research findings into the clinical setting. This thesis describes the generation of organoids derived from needle biopsies of HCCs. The use of tumor biopsies instead of surgically resected HCC specimens is important because it allows to generate organoids from all tumor stages, whereas surgical resection of HCCs is limited to a minority of patients with small, early stage tumors. These tumors are typically not treated with systemic therapies, and material derived from them might have limited value for developing new treatments for advanced HCCs. Because of the very limited amount of tissue that can be obtained with a needle biopsy, generation of HCC organoids was technically challenging. A key to our success was the immediate sample processing. The biobank of tumor organoids described in this study encompasses different etiologies and, most importantly, all clinical tumor stages. Our study design also allowed to compare the organoids with the originating tumor biopsies. We found that HCC organoids preserve the morphological characteristics and tumor marker expression of their originating tumors. Moreover, a comprehensive analysis of the genetic landscape in both, primary tumors and corresponding organoids, revealed a high concordance of the molecular alterations and the genetic heterogeneity, confirming that the organoids are a genuine representation of the originating tumors. In addition, tumor organoids can be successfully transplanted and propagated in immunodeficient mice to generate xenografts. Finally, in a proof of concept study, we show that tumor organoids can be used to test sensitivities to clinically-relevant drugs and provide a promising novel tool for developing tailored therapies.

400 Background: The incidence of advanced unresectable hepatocellular carcinoma (HCC) is increasing in several developed countries and the prognosis of advanced HCC remains poor. Real-world evidence of treatment patterns and patient outcomes can highlight the unmet clinical need within this population. Methods: We conducted a retrospective population-based cohort study of advanced unresectable HCC patients diagnosed in Alberta, Canada between 2008-2018 using electronic medical records and administrative claims data. A chart review was conducted among patients treated with systemic therapy to capture additional treatment information that is not available in the administrative data. The objectives of this study were to describe the treatment patterns, overall survival, and healthcare resource utilization of advanced HCC patients. Results: A total of 1,297 advanced HCC patients were included in this study, of which 555 (42.8%) were recurrent cases and the remainder were advanced unresectable cases at diagnosis. Median age at diagnosis was 64 (range: 21-94) and 82.1% were men. Only 274 patients (21.1%) received first-line systemic therapy and of those 32 patients (11.7%) initiated second-line therapy. Nearly all of the patients treated with systemic therapy received sorafenib (&gt; 96.4%) in first-line and over half of these patients (55.8%) had a dose reduction during the course of treatment. Patients who received systemic therapy had considerably higher median overall survival (12.23 months; 95% CI: 10.72-14.10) compared to patients not treated with systemic therapy (2.66 months; 95% CI: 2.33-3.12; log-rank p-value &lt; 0.001). Among patients who received first-line systemic therapy, the 2-year and 5-year survival rates were 17.9% (95% CI: 13.7-23.4) and 3.9% (95% CI: 1.8-8.6), respectively. Among patients treated with systemic therapy, overall survival was highest for recurrent cases, patients with Child-Pugh A, patients with hepatitis C virus or multiple known HCC risk factors, and for recurrent patients who received transarterial chemoembolization and ablation (separate procedures) in early stage (log-rank: p &lt; 0.05). No significant differences in survival were observed for dose reduction in first-line therapy, age group, sex, the presence of cirrhosis, or the presence of metastatic disease (log-rank: p &gt; 0.05). Among patients that received first-line systemic therapy, the average time spent in hospital was 9, 9, and 8 days per patient within years 1, 2, and 3, respectively. Conclusions: In a Canadian real-world setting, patients who received systemic therapy had considerably greater survival than those who did not, but the initiation rate was low and dose reductions were common. The low uptake of systemic therapy and the modest survival gains highlight the importance of earlier diagnosis and the need for novel and more effective first-line therapies.

Introduction: Based on trials performed over a 25-year period, the Early Breast Cancer Trialists Collaborative Group (EBCTCG) identified a small but significant benefit of adjuvant bisphosphonates (BP) in reducing bone recurrence with a subsequent modest improvement in breast cancer-specific survival in post-menopausal women. Multiple studies show that contemporary event rates in early-stage breast cancer are much lower than those observed over a decade ago. This observation likely reflects the impact of modern adjuvant systemic therapy such as anthracycline and taxane chemotherapy and aromatase inhibitors. Therefore, re-evaluating the benefit of adjuvant bisphosphonate in the modern era is warranted. Methods: We reviewed reports of randomized trials of adjuvant BP that accrued patients exclusively beyond 2000 and extracted 5-year disease free survival (DFS) and overall survival (OS) in BP and control group arm along with hazard ratios (HR) when reported. The mean 5-year DFS and OS weighted by study sample size was calculated for each group. HR for DFS and OS were pooled in a meta-analysis using generic inverse variance and random effects modelling. Trial level absolute differences in DFS and OS between BP and control arms were calculated. Meta-regression comprising linear regression weighted by sample size (mixed effects) was then performed to explore association between disease and treatment related factors and absolute differences in benefit from BP. Quantitative significance was explored using methods described by Burnand et al. Analyses were performed using SPSS version 28 (IBM Corp, Armonk NY) and Review manager v5.4. Results: Twelve trials comprising 24109 patients were included in the analysis. Weighted mean DFS and OS in patients receiving BP were 85.8% and 91.7% respectively. For control group patients, these estimates respectively were 83.4% and 91.0%. For DFS, pooled HR across trials was 0.89 (0.81-0.97) with a 2.9% weighted mean difference favoring BP over control. Among patients receiving anthracycline and taxane based chemotherapy (n=3007), relative benefits were smaller; (HR DFS 0.94, 0.85-1.05). There was no significant OS benefit with BP (HR 0.92, 0.82-1.03) and this finding was observed irrespective of type of chemotherapy. The impact of BP on OS was smaller in both relative and absolute terms in studies with recruitment occurring more recently. Meta-regression results are shown in Table. There was lesser benefit in higher risk patients (node+, larger tumor size, ER-, grade 3 or those receiving chemotherapy). Overall, 1.13% patients experienced osteonecrosis related to BP therapy. Conclusions: Compared to EBCTCG data, relative and absolute benefit from BP is similar or modestly lower among more recent trials. Benefit from adjuvant BP appears smaller in patients treated with more contemporary adjuvant systemic therapy especially anthracycline and taxane containing chemotherapy. It is uncertain if the impact of BP on OS (rather than breast-cancer specific survival) is of a clinically meaningful magnitude. Despite de-escalated dosing compared to metastatic disease, osteonecrosis was observed in &amp;gt;1% of patients. It is possible that the benefits of BP are driven by patients with clinically low-risk disease rather than those with at high-risk. The balance between benefits and risks of adjuvant BP should be considered in individual patients. Table 1: Metaregression Results Citation Format: Abhenil Mittal, Faris Tamimi, Consolacion Molto Valiente, Massimo Di Iorio, Eitan Amir. Benefit of adjuvant bisphosphonates in early breast cancer treated with contemporary systemic therapy: A meta-analysis of randomized control trials [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-01.

334 Background: Currently, combined immunotherapy of atezolizumab (anti-PD-L1 antibody) plus bevacizumab (a humanized anti-VEGF monoclonal antibody) is the standard first-line treatment in patients with advanced hepatocellular carcinoma (HCC). At the threshold of this new era, there is limited information about tumor microenvironment (TME) in advanced HCC. Several studies on TME in HCC have analyzed samples obtained via hepatic resection. In general, hepatic resection is indicated for patients with limited size and number of intrahepatic nodules, i.e., early stage HCC. In contrast, most patients who have an indication for systemic therapy have developed macroscopic vascular invasion (MVI) or/and extrahepatic metastasis, namely in advanced stage HCC. Progression from an early stage HCC to an advanced stage HCC involves a lengthy clinical course, therefore, the TME at the time of initial diagnosis may differ from that at the time of systemic therapy indication. The present study was aimed to analyze the TME by using needle biopsy samples obtained prior to initiation of systemic therapy in patients with advanced HCC. Methods: Between March 2019 and May 2020, 80 patients underwent liver tumor biopsy at the time of indication for systemic chemotherapy. HCC was confirmed via pathological examination in 70 patients and their samples were analyzed. Microsatellite instability (MSI) was evaluated using polymerase chain reaction. Programed death-ligand 1 (PD-L1) expression and the levels of tumor-infiltrating lymphocytes (TIL) were evaluated using immunohistochemical staining. PD-L1 expression was defined as per the tumor proportion score (TPS; the number of PD-L1-positive cells/total number of tumor cells) and was classified as low (TPS &lt; 1%) or high (TPS &gt;1%). Levels of TIL were defined as the mean number of CD8-positive lymphocytes in the tumor per 1 mm2 and classified as low or high using the median value. Results: Out of the 70 tumors, one was MSI-high and 69 were MSI-negative. The PD-L1 expression was &lt; 1% in 50 samples, 1%–10% in 12, 11%–20% in 7, and 21%–30% in 1. The median level of TIL was 266/mm2. PD-L1highTILhighwas present in 20.0%, PD-L1lowTILlowin 38.5%, PD-L1highTILlowin 8.6%, and PD-L1lowTILhighin 32.9%. In the MSI-high tumor, PD-L1 expression was &lt; 1% and the level of TIL was 142/mm2. High PD-L1 expression and high levels of TIL were associated with hepatitis C virus infection, high alpha-fetoprotein levels, and presence of MVI respectively. We are currently performing RNA-sequencing in order to obtain more details about TME in patients with advanced HCC. Conclusions: MSI-high advanced HCC was detected in 1.4% patients and was not necessarily associated with a “hot” immune microenvironment. PD-L1 expression and levels of TIL were associated with some clinical parameters. In the present study, we also reported the changes in the TME over time.

Treatment for Hepatocellular Carcinoma in South Asia

Chapter 4: Chemotherapy and radiotherapy

TPS623 Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of bevacizumab (Bev) and atezolizumab (Atezo) is the preferred frontline therapy for advanced HCC, but a minority of patients (pts) respond, and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment, mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP3 is a genetically modified herpes simplex virus 1 (HSV-1) that expresses the fusogenic GALV-GP R- protein, an anti–CTLA-4 antibody-like molecule, CD40 ligand, and 4-1BB ligand. The direct oncolytic effect coupled with immune stimulation by RP3 in the tumor microenvironment is intended to provide systemic anti-tumor activity and reverse therapeutic resistance to anti-PD-1/PD-L1 agents. Pre-clinical data has demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev supporting the clinical combination of RP3 with Bev. RP3 combined with anti-PD1 therapy has demonstrated clinical activity and safety in pts with various malignant solid tumors. This study will evaluate the safety and efficacy of RP3 combined with Atezo and Bev as 1st (1L) and 2nd (2L) line systemic therapies for inoperable and advanced HCC. Methods: The 1L and 2L cohorts will each enroll up to 30 pts with advanced, unresectable HCC. Pts in the 1L cohort may not have received prior systemic treatment; pts in the 2L cohort must have progressed on or following one prior line of systemic therapy, which must have included a PD-(L)1 directed agent. Key inclusion criteria include advanced unresectable HCC with at least 1 measurable tumor of ≥1 cm in longest diameter, Childs-Pugh Class A, and ECOG Score of 0 or 1. Important exclusion criteria include untreated esophageal and/or gastric varices with bleeding or at high risk for bleeding, and macroscopic invasion of tumor into major blood vessels and/or main bile ducts. Pts with a history of medically refractory hepatic encephalopathy and/or hepato-renal syndrome are also excluded. Pts in 1L cohort will receive 1200 mg Atezo and 15mg/kg Bev Q3W together with RP3 intratumorally (IT) Q3W for a total of up to 8 doses. In 2L pts will receive RP3 Q2W for 4 doses with Bev Q3W starting on C1D1, then RP3 and Bev Q3W for up to 4 more doses with Atezo Q3W being added on C4D1. The primary endpoint includes overall response rate (ORR) by RECIST v1.1. Secondary endpoints are safety, ORR using HCC mRECIST, duration of response, complete response rate, and progression-free survival.

Hepatocellular carcinoma (HCC) is a malignant tumor which is becoming more prevalent worldwide. Patients at high risk of developing HCC, namely hepatitis B- and C-related liver cirrhosis patients, should be entered into surveillance programs, which should be performed using both ultrasonography and 3 tumor markers (AFP, PIVKA-II, AFP-L3). The surveillance interval needs to be shortened for patients at higher risk of HCC. Therefore, super-high-risk patients should be screened at 3- to 4-month intervals based on their risk of developing HCC. Sonazoid-enhanced US is extremely useful to characterize hepatic tumors when compared with multidetector-row computed tomography (MDCT). Moreover, Sonazoid-enhanced US with defect reperfusion imaging is a breakthrough approach in the treatment of HCC. This technique will markedly change the therapeutic strategy for liver cancer. Furthermore, diagnostic capability using the new imaging technique Gd-EOB-DTPA MRI is promising. A reduced uptake (low intensity) in the hepatobiliary phase of Gd-EOB-DTPA MRI strongly suggests HCC (including early-stage HCC) or a high-grade dysplastic nodule with high malignant potential. Empirically, intrahepatic arterial infusion chemotherapy using implanted reservoir port is known to be effective for advanced HCC with vascular invasion; however, no randomized study exists to prove its efficacy. Further controlled study is necessary to establish this treatment option as a standard of care in a treatment algorithm for HCC. In contrast, sorafenib was established as the first choice of treatment as a standard of care in advanced HCC patients with preserved liver function and vascular invasion/extrahepatic spread. Furthermore, global clinical trials are now ongoing using sorafenib as an adjuvant setting after resection, ablation or TACE. Efficacy of combined use of sorafenib with TACE or intra-arterial infusion chemotherapy is not clear. In order to clarify this issue a randomized clinical trial for intermediate and advanced HCC comparing sorafenib alone versus sorafenib combined with maintenance TACE/intra-arterial infusion chemotherapy and/or intra-arterial infusion chemotherapy is scheduled to be initiated in Japan in 2009. If positive results are obtained by these trials, its impact on treatment strategy for HCC will be drastically changed.

The treatment strategy of hepatocellular carcinoma applied following scientific guidelines is only supported by 77 randomized controlled trials published so far, a figure that clearly pinpoints hepatocellular carcinoma as an 'orphan' cancer in terms of clinical research when compared with other high-prevalent cancers worldwide. A systematic review analysing 61 randomized controlled trials (1978-2002) showed a modest survival benefit from chemoembolization in patients with intermediate tumours, and the lack of an effective first-line treatment option for patients with advanced disease. These conclusions have been endorsed by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. The present updated evidence-based approach includes 16 randomized controlled trials published from 2002 to 2005 assessing percutaneous ablation (seven), other loco-regional therapies (three) and systemic therapies (six). Eight showed high-quality methodological profiles. Four randomized controlled trials demonstrated a better local hepatocellular carcinoma control in tumours larger than 2 cm treated by radiofrequency ablation compared with ethanol injection. No survival advantages were obtained from systemic treatments in patients with advanced hepatocellular carcinoma, an area that is an unmet need. Therefore, there is an urgent request to conduct well-designed phase III investigations in hepatocellular carcinoma patients.

BACKGROUND: The incidence of advanced unresectable hepatocellular carcinoma (HCC) is increasing in developed countries and the prognosis of advanced HCC remains poor. Real-world evidence of treatment patterns and outcomes can highlight the unmet clinical need. METHODS: We conducted a retrospective population-based cohort study of patients with advanced unresectable HCC diagnosed in Alberta, Canada (2008-2018) using electronic medical records and administrative claims data. A chart review was conducted on patients treated with systemic therapy to capture additional information related to treatment. RESULTS: A total of 1,297 advanced HCC patients were included of whom 555 (42.8%) were recurrent cases and the remainder were unresectable at diagnosis. Median age at diagnosis was 64 (range 21-94) years and 82.1% were men. Only 274 patients (21.1%) received first-line systemic therapy and, of those, 32 patients (11.7%) initiated second-line therapy. Nearly all of the patients received sorafenib (>96.4%) in first-line, and these patients had considerably higher median survival (12.23 months; 95% CI 10.72-14.10) compared with patients not treated with systemic therapy (2.66 months; 95% CI 2.33-3.12; log-rank p <0.001). Among patients treated with systemic therapy, overall survival was higher for recurrent cases, patients with Child-Pugh A functional status, and patients with HCV or multiple known HCC risk factors (p <0.05). CONCLUSIONS: In a Canadian real-world setting, patients who received systemic therapy had greater survival than those who did not, but outcomes were universally poor. These results underscore the need for effective front-line therapeutic options.

Barcelona Clinic Liver Cancer 2022 update: Linking prognosis prediction and evidence-based treatment recommendation with multidisciplinary clinical decision-making.