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肝細胞癌和肝硬化患者主要治療引起的毒性的臨床特征和處理

發(fā)表日期：2022-03-14

Clinical Characterisation and Management of the Main Treatment-Induced Toxicities in Patients with Hepatocellular Carcinoma and Cirrhosis

肝細胞癌和肝硬化患者主要治療引起的毒性的臨床特征和處理

The incidence of hepatocellular carcinoma continues to increase worldwide. In almost all cases, hepatocellular carcinoma develops in subjects with hepatic cirrhosis and patients can therefore present symptoms that are attributable to both conditions. There are several ablation techniques currently available for the treatment of unresectable HCC associated with early-stage cirrhosis. Moreover, novel therapies with biological agents and immunotherapy have come to be standard options in the approach to systemic treatment of hepatocellular carcinoma. However, in addition to being costly, these drugs are not devoid of adverse effects and their management cannot forgo the consideration of the underlying hepatic impairment. Therefore, these patients require a mandatory multidisciplinary management.

肝細胞癌的發(fā)病率在全球范圍內(nèi)持續(xù)增加。在幾乎所有情況下，肝細胞癌都會在患有肝硬化的受試者中發(fā)展，因此患者可能會出現(xiàn)可歸因于這兩種情況的癥狀。目前有幾種消融技術(shù)可用于治療與早期肝硬化相關(guān)的不可切除的 HCC。此外，生物制劑和免疫療法的新療法已成為肝細胞癌全身治療方法的標(biāo)準(zhǔn)選擇。然而，除了價格昂貴之外，這些藥物并非沒有副作用，而且它們的管理也不能放棄對潛在肝功能損害的考慮。因此，這些患者需要強制性的多學(xué)科管理。

細胞工廠

The incidence of HCC continues to increase worldwide, especially in Western countries, where its presence is closely related to that of hepatic cirrhosis [1]. In almost 80% of cases, the tumour develops in a liver that has undergone the evolutionary effects of anatomic remodelling and a transformation that have led to the development of cirrhosis. In addition, the aetiology that caused and influenced this evolution is very often associated with underlying hepatitis B or C infection, as well as alcohol abuse and metabolic conditions secondary to non-alcoholic steatohepatitis (NASH) [2]. This creates a diverse stratification not only of the aetiological factors underlying the transformation process and their consequent management, but also of the treatment of the tumour and the factors influencing prognosis. The prognosis for this kind of tumour has changed greatly over the last two decades with the advent of novel treatment options associated with the screening programmes provided to patients with cirrhosis that make it possible to identify HCC at an early stage, and therefore to implement potentially increasingly curative treatments. The treatment options for HCC can be broken down into surgical therapies (i.e., resection, cryoablation and liver transplantation) and nonsurgical therapies that can target the liver and are therefore termed “l(fā)ocoregional” (such as, for example, percutaneous ethanol injection, radiofrequency/microwave thermal ablation, transarterial chemoembolisation, external beam radiotherapy) or systemic treatments (chemotherapy, targeted therapy, immunotherapy with checkpoint inhibitors). In some cases, it is somewhat difficult to assess the benefits in terms of survival of a systemic therapy regimen in patients with advanced HCC, as survival is often determined not so much by the aggressiveness of the tumour or by the impact of a systemic treatment, but primarily by the degree of hepatic dysfunction generated by the liver disease. Systemic chemotherapy is not usually well tolerated by these patients with advanced HCC and its use has a limited scope, also in view of the rather disappointing results. Moreover, for patients with Child-Pugh class C cirrhosis and those with an impaired performance status (PS) or severe comorbidities, supportive care alone still appears to be the most indicated option. Prior to 2008, there was no truly efficacious systemic therapy for patients with advanced HCC or those who were refractory to locoregional therapies. There has been a consequent renewed interest in and enthusiasm for systemic therapy for HCC with the publication of data showing that the targeted agents sorafenib [3,4] and regorafenib [5] were able to improve survival compared to the best supportive therapy. Subsequently, the benefit in terms of survival was demonstrated also for second-line therapy with nivolumab [6,7,8], an immune checkpoint inhibitor, and lenvatinib [9] which was seen to be non-inferior to sorafenib as first-line therapy. Systemic therapy is now considered to be appropriate for patients with unresectable advanced HCC who are not eligible for or who have progression following locoregional treatment and whose liver function is likely to be able to tolerate the therapy (e.g., Child-Pugh class A or B7 cirrhosis). According to the most recent National Comprehensive Cancer Network (NCCN) guidelines [10], there are currently three systemic therapy options that can be used for first-line treatment (in chronological order of approval): sorafenib [3,4], lenvatinib [9,11] and the more recent atezolizumab plus bevacizumab combination [12]. In those patients who are not eligible for treatment with a tyrosine kinase inhibitor (TKI), immunotherapy with nivolumab can be considered [13]. At progression, in those patients who maintain Child-Pugh class A or, for certain agents, also class B7 liver function, and depending on the administered first-line treatment, there are a number of systemic therapy options: regorafenib (5), cabozantinib [14], ramucirumab [15], lenvatinib or immunotherapy with nivolumab [6,7,8], nivolumab plus ipilimumab [16], pembrolizumab [17], or sorafenib.

HCC 的發(fā)病率在世界范圍內(nèi)持續(xù)增加，特別是在西方國家，其存在與肝硬化密切相關(guān) [ 1 ]。在幾乎 80% 的病例中，腫瘤發(fā)生在肝臟中，該肝臟經(jīng)歷了解剖重塑的進化效應(yīng)和導(dǎo)致肝硬化發(fā)展的轉(zhuǎn)變。此外，導(dǎo)致和影響這種演變的病因通常與潛在的乙型或丙型肝炎感染，以及繼發(fā)于非酒精性脂肪性肝炎 (NASH) 的酒精濫用和代謝狀況有關(guān) [ 2]。這不僅對轉(zhuǎn)化過程及其后續(xù)管理的病因因素進行了多樣化的分層，而且對腫瘤的治療和影響預(yù)后的因素也進行了分層。在過去的二十年中，隨著與提供給肝硬化患者的篩查計劃相關(guān)的新型治療方案的出現(xiàn)，這種腫瘤的預(yù)后發(fā)生了很大變化，這使得早期識別 HCC 成為可能，因此可能越來越多地實施治療性治療。HCC 的治療選擇可以分為手術(shù)治療（即切除、冷凍消融和肝移植）和可以靶向肝臟并因此被稱為“局部區(qū)域”的非手術(shù)治療（例如，經(jīng)皮乙醇注射、射頻/微波熱消融、經(jīng)動脈化療栓塞、外照射放療）或全身治療（化療、靶向治療、檢查點抑制劑免疫治療）。在某些情況下，很難評估晚期 HCC 患者全身治療方案對生存的益處，因為生存通常不是由腫瘤的侵襲性或全身治療的影響決定的，但主要由肝病產(chǎn)生的肝功能障礙程度決定。這些晚期 HCC 患者通常不能很好地耐受全身化療，并且其使用范圍有限，同樣考慮到相當(dāng)令人失望的結(jié)果。此外，對于 Child-Pugh C 級肝硬化患者和體能狀態(tài)（PS）受損或有嚴(yán)重合并癥的患者，單獨的支持性護理似乎仍然是最合適的選擇。在 2008 年之前，對于晚期 HCC 或?qū)植恐委煙o效的患者，沒有真正有效的全身治療。隨著數(shù)據(jù)的公布顯示靶向藥物索拉非尼[3 , 4 ] 和瑞戈非尼 [ 5 ] 與最佳支持療法相比能夠提高生存率。隨后，免疫檢查點抑制劑nivolumab [ 6 , 7 , 8 ] 和 lenvatinib [ 9 ]的二線治療也證明了生存方面的益處] 這被認為不劣于索拉非尼作為一線治療。全身治療現(xiàn)在被認為適用于不適合或在局部治療后出現(xiàn)進展且肝功能可能能夠耐受治療的不可切除的晚期 HCC 患者（例如 Child-Pugh A 級或 B7 級肝硬化））。根據(jù)最新的美國國家綜合癌癥網(wǎng)絡(luò) (NCCN) 指南 [ 10 ]，目前有三種全身治療方案可用于一線治療（按批準(zhǔn)時間順序）：索拉非尼 [ 3 , 4 ]、樂伐替尼 [ 9 , 11 ] 和最近的 atezolizumab 加貝伐單抗組合 [ 12]。對于那些不適合接受酪氨酸激酶抑制劑 (TKI) 治療的患者，可以考慮使用納武單抗進行免疫治療 [ 13 ]。在進展時，對于維持 Child-Pugh A 級或某些藥物的 B7 級肝功能的患者，根據(jù)給予的一線治療，有許多全身治療選擇：瑞戈非尼 (5)、卡博替尼[ 14 ]、雷莫蘆單抗 [ 15 ]、樂伐替尼或免疫療法與納武單抗 [ 6、7、8 ]、納武單抗加伊匹單抗 [ 16 ]、派姆單抗 [ 17 ] 或索拉非尼。

高效搖瓶

In almost all cases, HCC develops in subjects with hepatic cirrhosis, often as the result of hepatitis B or C virus infection, alcohol abuse or metabolic forms secondary to non-alcoholic steatohepatitis. Patients with HCC and hepatic symptoms can therefore present symptoms that are attributable to both conditions. This creates a diverse stratification not only of the aetiological factors underlying the transformation process and their consequent management, but also of the treatment of the tumour and the factors influencing prognosis. The prognosis for HCC has changed greatly over the last two decades with the advent of novel treatment options associated with the screening programmes provided to patients with cirrhosis that make it possible to identify HCC at an early stage, and therefore to implement potentially increasingly curative treatments. The treatment options for HCC can be broken down into surgical therapies (i.e., resection, cryoablation and liver transplantation) and nonsurgical therapies that can target the liver and are therefore termed “l(fā)ocoregional”. After the failure of locoregional therapies, systemic treatment with Sorafenib has been the standard of care for advanced HCC for a long time. AEs commonly reported with TKIs include hypertension, diarrhoea, and HFSR and most AEs occur within the first month of treatment and resolve when treatment is put on hold. Patient education and frequent monitoring for symptoms are the key to appropriately managing TKI toxicities. The development of IO therapies for patients with HCC has advanced rapidly, and clinicians should be aware of the potential toxicities. The most common irAEs are similar to those with other tumour types, but the rate of hepatitis may be slightly higher. Most relevant, toxicities should be recognized early on and addressed appropriately. Recently, ICIs have shown potential in combination treatment for advanced HCC, although they have been quite unsuccessful as single agents. Some approaches attempted for use of ICIs in combination are anti-PD-L1 plus anti-VEGF (e.g., atezolizumab plus bevacizumab), anti-PD-1 plus TKI (e.g., pembrolizumab plus lenvatinib), anti-PD-L1 plus anti-CTLA-4 (e.g., nivolumab plus ipilimumab). In IMbrave 150 trial, the combination of atezolizumab plus bevacizumab has shown an OS advantage over TKI sorafenib, joining today this therapy as a frontline option for advanced HCC. For those who are not candidates for the atezolizumab—bevacizumab combination, either sorafenib or lenvatinib are appropriate alternative. Multiple ongoing trials with ICIs, VEGF inhibitors, and TKIs in the systemic treatment of advanced HCC promise expanding options for frontline and second-line therapies in HCC. These patients require a multidisciplinary management, especially calling for close interaction between the hepatologist and the oncologist. However, there are currently no biomarkers able to predict the toxicity of a given systemic treatment. A careful selection of patients based on their comorbidities and the functional status of their chronic liver disease therefore remains crucial. In order not to deprive patients of a systemic therapeutic option a priori, it is common clinical practice to adopt the empirical convention of initiating treatment with prudential doses of TKI before gradually increasing them in accordance with their tolerance.

PETG血清培養(yǎng)基瓶

在幾乎所有情況下，HCC 都會在患有肝硬化的受試者中發(fā)展，這通常是由于乙型或丙型肝炎病毒感染、酗酒或繼發(fā)于非酒精性脂肪性肝炎的代謝形式所致。因此，患有 HCC 和肝臟癥狀的患者可能會出現(xiàn)可歸因于這兩種情況的癥狀。這不僅對轉(zhuǎn)化過程及其后續(xù)管理的病因因素進行了多樣化的分層，而且對腫瘤的治療和影響預(yù)后的因素也進行了分層。在過去的二十年中，隨著與提供給肝硬化患者的篩查計劃相關(guān)的新型治療方案的出現(xiàn)，HCC 的預(yù)后發(fā)生了巨大變化，這使得早期識別 HCC 成為可能，從而實施可能越來越治愈的治療。HCC 的治療選擇可分為手術(shù)治療（即切除、冷凍消融和肝移植）和可以靶向肝臟并因此被稱為“局部區(qū)域”的非手術(shù)治療。在局部區(qū)域治療失敗后，索拉非尼的全身治療長期以來一直是晚期 HCC 的標(biāo)準(zhǔn)治療。TKI 通常報告的 AE 包括高血壓、腹瀉和 HFSR，大多數(shù) AE 發(fā)生在治療的第一個月內(nèi)，并在治療暫停時消退。患者教育和經(jīng)常監(jiān)測癥狀是適當(dāng)管理 TKI 毒性的關(guān)鍵。針對 HCC 患者的 IO 療法發(fā)展迅速，臨床醫(yī)生應(yīng)注意潛在的毒性。最常見的 irAE 與其他腫瘤類型相似，但肝炎的發(fā)病率可能略高。最相關(guān)的毒性應(yīng)及早發(fā)現(xiàn)并適當(dāng)處理。最近，ICIs 在晚期 HCC 的聯(lián)合治療中顯示出潛力，盡管它們作為單一藥物相當(dāng)不成功。嘗試聯(lián)合使用 ICI 的一些方法是抗 PD-L1 加抗 VEGF（例如，atezolizumab 加貝伐單抗）、抗 PD-1 加 TKI（例如，派姆單抗加樂伐替尼）、抗 PD-L1 加抗CTLA-4（例如，納武利尤單抗加易普利姆瑪）。在 IMbrave 150 試驗中，atezolizumab 加貝伐單抗的組合顯示出優(yōu)于 TKI 索拉非尼的 OS 優(yōu)勢，今天加入該療法作為晚期 HCC 的一線選擇。對于那些不適合 atezolizumab-bevacizumab 組合的人，索拉非尼或樂伐替尼是合適的替代方案。多項正在進行的 ICI、VEGF 抑制劑和 TKI 在晚期 HCC 系統(tǒng)治療中的試驗有望擴大 HCC 一線和二線治療的選擇。這些患者需要多學(xué)科管理，特別是需要肝病學(xué)家和腫瘤學(xué)家之間的密切互動。然而，目前沒有生物標(biāo)志物能夠預(yù)測給定全身治療的毒性。因此，根據(jù)合并癥和慢性肝病的功能狀態(tài)仔細選擇患者仍然至關(guān)重要。為了不剝奪患者先驗的全身治療選擇，通常的臨床實踐是采用經(jīng)驗慣例，即在開始治療時謹(jǐn)慎劑量的 TKI，然后根據(jù)患者的耐受性逐漸增加劑量。晚期 HCC 全身治療中的 VEGF 抑制劑和 TKI 有望擴大 HCC 一線和二線治療的選擇。這些患者需要多學(xué)科管理，特別是需要肝病學(xué)家和腫瘤學(xué)家之間的密切互動。然而，目前沒有生物標(biāo)志物能夠預(yù)測給定全身治療的毒性。因此，根據(jù)合并癥和慢性肝病的功能狀態(tài)仔細選擇患者仍然至關(guān)重要。為了不剝奪患者先驗的全身治療選擇，通常的臨床實踐是采用經(jīng)驗慣例，即在開始治療時謹(jǐn)慎劑量的 TKI，然后根據(jù)患者的耐受性逐漸增加劑量。晚期 HCC 全身治療中的 VEGF 抑制劑和 TKI 有望擴大 HCC 一線和二線治療的選擇。這些患者需要多學(xué)科管理，特別是需要肝病學(xué)家和腫瘤學(xué)家之間的密切互動。然而，目前沒有生物標(biāo)志物能夠預(yù)測給定全身治療的毒性。因此，根據(jù)合并癥和慢性肝病的功能狀態(tài)仔細選擇患者仍然至關(guān)重要。為了不剝奪患者先驗的全身治療選擇，通常的臨床實踐是采用經(jīng)驗慣例，即在開始治療時謹(jǐn)慎劑量的 TKI，然后根據(jù)患者的耐受性逐漸增加劑量。晚期 HCC 系統(tǒng)治療中的 TKI 和 TKI 有望擴大 HCC 一線和二線治療的選擇。這些患者需要多學(xué)科管理，特別是需要肝病學(xué)家和腫瘤學(xué)家之間的密切互動。然而，目前沒有生物標(biāo)志物能夠預(yù)測給定全身治療的毒性。因此，根據(jù)合并癥和慢性肝病的功能狀態(tài)仔細選擇患者仍然至關(guān)重要。為了不剝奪患者先驗的全身治療選擇，通常的臨床實踐是采用經(jīng)驗慣例，即在開始治療時謹(jǐn)慎劑量的 TKI，然后根據(jù)患者的耐受性逐漸增加劑量。晚期 HCC 系統(tǒng)治療中的 TKI 和 TKI 有望擴大 HCC 一線和二線治療的選擇。這些患者需要多學(xué)科管理，特別是需要肝病學(xué)家和腫瘤學(xué)家之間的密切互動。然而，目前沒有生物標(biāo)志物能夠預(yù)測給定全身治療的毒性。因此，根據(jù)合并癥和慢性肝病的功能狀態(tài)仔細選擇患者仍然至關(guān)重要。為了不剝奪患者先驗的全身治療選擇，通常的臨床實踐是采用經(jīng)驗慣例，即在開始治療時謹(jǐn)慎劑量的 TKI，然后根據(jù)患者的耐受性逐漸增加劑量。這些患者需要多學(xué)科管理，特別是需要肝病學(xué)家和腫瘤學(xué)家之間的密切互動。然而，目前沒有生物標(biāo)志物能夠預(yù)測給定全身治療的毒性。因此，根據(jù)合并癥和慢性肝病的功能狀態(tài)仔細選擇患者仍然至關(guān)重要。為了不剝奪患者先驗的全身治療選擇，通常的臨床實踐是采用經(jīng)驗慣例，即在開始治療時謹(jǐn)慎劑量的 TKI，然后根據(jù)患者的耐受性逐漸增加劑量。這些患者需要多學(xué)科管理，特別是需要肝病學(xué)家和腫瘤學(xué)家之間的密切互動。然而，目前沒有生物標(biāo)志物能夠預(yù)測給定全身治療的毒性。因此，根據(jù)合并癥和慢性肝病的功能狀態(tài)仔細選擇患者仍然至關(guān)重要。為了不剝奪患者先驗的全身治療選擇，通常的臨床實踐是采用經(jīng)驗慣例，即在開始治療時謹(jǐn)慎劑量的 TKI，然后根據(jù)患者的耐受性逐漸增加劑量。目前沒有生物標(biāo)志物能夠預(yù)測給定全身治療的毒性。因此，根據(jù)合并癥和慢性肝病的功能狀態(tài)仔細選擇患者仍然至關(guān)重要。為了不剝奪患者先驗的全身治療選擇，通常的臨床實踐是采用經(jīng)驗慣例，即在開始治療時謹(jǐn)慎劑量的 TKI，然后根據(jù)患者的耐受性逐漸增加劑量。目前沒有生物標(biāo)志物能夠預(yù)測給定全身治療的毒性。因此，根據(jù)合并癥和慢性肝病的功能狀態(tài)仔細選擇患者仍然至關(guān)重要。為了不剝奪患者先驗的全身治療選擇，通常的臨床實踐是采用經(jīng)驗慣例，即在開始治療時謹(jǐn)慎劑量的 TKI，然后根據(jù)患者的耐受性逐漸增加劑量。