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Systemic Treatment of Hepatocellular Carcinoma: Comparison
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Please note this is a comparison between Version 2 by Camila Xu and Version 3 by Camila Xu.

Hepatocellular carcinoma (HCC) is the most common liver primary tumor with a high rate of mortality.

  • hepatocellular carcinoma
  • quality of life
  • PROs

1. Introduction

Hepatocellular carcinoma (HCC) is the most common liver primary tumor with a high rate of mortality. Only about 20% of patients will access curative options, and even in these cases relapse rates are high. Most patients are diagnosed at an advanced stage and are not suitable for curative treatments. Therapeutic options are locoregional treatments such as resection, chemo-embolization, radio-embolization or radiotherapy, and systemic treatments, such as anti-angiogenics, or more recently, immunotherapy. Given the severity of this disease and the modest benefit of treatments, quality of life (QoL) of the patient becomes very relevant and should be a major concern to clinicians.

2. Quality of Life and Hepatocellular Carcinoma (HCC)

2.1. Main Tools for Measuring Quality of Life in Patients Followed for HCC

Health-related QoL has been defined as physical, mental and social well-being. Several scales have been validated to measure the specific QoL of liver cancer patients (Table 1).
Table 1. QoL scales and symptoms assessed.
EORTC QLQ-C30 EORTC QLQ-HCC18 FACT-Hep FSHI QOL-LC
Global health status/quality of life

Physical functioning

Role functioning

Cognitive functioning

Social functioning

Fatigue

Nausea/Vomiting

Pain

Dyspnea

Sleep disturbances

Appetite loss

Constipation

Diarrhoea

Financial difficulties		 Shoulder pain

Abdominal pain

Wegth

Eating

Fever

Jaundice

Thirst

Abdominal swelling

Figure of the abdomen

Vitality Pruritus

Taste

Temperature regulation

Muscle loss

Nutrition

Sleepiness

Sexuality		 Pain

Weight loss

Digestion

Diarrhea

Fever

Fatigue

Jaundice

Dry mouth

Stomach pain

Change in appearance

Daily activities

Pruritus

Taste

Chills

Control of bowels

Constipation

Appetite		 Pain

Pain

Weight loss

Fatigue

Jaundice Nausea		 Pain

Weight loss

Digestive problem

Diarrhea

Fever
FACT–Hep (Functional Assessment of Cancer Therapy-Hepatobiliary) [1] is a 45-item quality of life scale, containing 18 items specific to hepatobiliary disease. The minimally clinically important difference (MCID) of the FACT-Hep score is 8 to 9 points. EORTC QLQ-HCC18 (Quality of Life Questionnaire) [2] includes 18 specific items and completes the QLQ-C30, a health-related QoL score for general cancer. For the different scales of the EORTC QLQ-C30 tool, a 5 to 10-point change from baseline (either deterioration or improvement) is ‘a little’ change, a 10 to 20-point change is a ‘moderate’ change, and a ‘very large’ change corresponds to a change greater than 20. FHSI (FACT Hepatobiliary Symptom Index) [3] uses 8 items from FACT-Hep and is intended to evaluate symptoms (e.g., pain, fatigue, nausea, weight loss, and jaundice). QOL-LC (Quality of Life-liver cancer) [4] included symptoms and adverse events in a Chinese cohort with liver cancer.

2.2. Description of Quality of Life of HCC Patients

A review of 36 articles analyzed the impact of disease and treatment on quality of life using EORTC QLQ-C30, EORTC QLQ-HCC18, FACT-Hep and FACT-G [4]. Compared to patients with chronic liver disease, patients with HCC had worse physical well-being and compared to the general population, worse QoL on physical, (p < 0.001), psychological (p < 0.001) and functional (p < 0.001) items, but better QoL on family and social level (p < 0.001). QoL was better after hepatic surgery, but not after hepatic intra-arterial therapy and radiotherapy.
The study by Steel et al. included in Fan’s meta-analysis included 272 patients (83 HCC, 51 chronic liver disease, 134 general population). The objective was to compare the FACT-Hep score in patients followed for HCC vs. chronic liver disease vs. the general population. Patients followed for chronic liver disease or HCC had, respectively, better social and family quality of life compared to the general population. Patients followed for HCC had a lower overall quality of life than those followed for chronic liver disease (p = 0.032) [5].
Another trial included in Fan’s meta-analysis (Kondo et al.) compared QoL in 97 patients with HCC and 97 patients with chronic liver disease. The latter was similar between the 2 groups but lower than in the general population. The liver function, and in particular the albumin level, were strongly predictive of QoL in multivariate analysis [6].
QoL improves with better liver function (as characterized by Child-Pugh score, albumin and bilirubinemia), localized stage of disease and absence of recurrence, and decreases with pain, fatigue, nausea and performance status.
Liver function is correlated with quality of life. Albumin, bilirubin, alkalin phosphatase (ALP), albumin to platelet ratio, albumin to ALP ratio, Child-Pugh classification, albumin-bilirubin (ALBI) grade, model for end-stage liver disease (MELD) and ascites have been shown as independent prognostic factors for QoL [7].
Demographically, QoL decreases with depressive symptoms, female gender, and feelings of uncertainty, and increases with age and satisfaction with medical services.
Several trials have shown a positive impact of psychosocial interventions on reducing negative feelings and strengthening QoL.

2.3. Prognostic Impact of QoL in HCC Patients

EORTC QLQ-HCC18 has been found to be prognostic for overall survival, independent of HCC stage and liver function [8]. Other trials have also demonstrated the prognostic value of QoL for unresectable HCC, regardless of the etiology of cirrhosis: HBV with the EORTC QLQ-C30 score [9] or alcoholism with the Spitzer QoL Index, a cancer-specific QoL measurement [10]. Diouf et al. also confirmed in patients of the CHOC cohort the prognostic value of quality of life measured by the EORTC QLQ C30 questionnaire [11][12].
In conclusion, HCC and altered liver function (either pre-existing or due to HCC) have a significant impact on patients’ quality of life and QoL may be an important prognostic marker.

3. Tolerance and Compliance of Treatments for HCC and Other Indications

3.1. Tolerance of Systemic Treatments (TKI and Immunotherapy) and the Impact on QoL

  • Toxicity of TKIs in HCC
The rate of discontinuation due to toxicity was similar for sorafenib (11%), regorafenib (10%), lenvatinib (9%) and cabozantinib (16%) [13][14][15][16][17]. The incidence of toxicities greater than or equal to grade III was 45% to 75%, with mainly: fatigue, diarrhea, hand-foot skin reaction, nausea, vomiting, anorexia, hypertension, and weight loss. The patterns of toxicities were very similar between sorafenib, regorafenib and cabozantinib, but lenvatinib showed a slightly different pattern, with less hand-foot skin reaction, but more hypertension.
  • Toxicity of immunotherapy for all indications
Anti-PD-1, anti-PD-L1, and anti-CTLA-4 have adverse events (AEs) that are different from TKIs, which may be infusion-related or immunologically based. These AEs can occur up to several months after discontinuation of treatment.
The most frequently reported AEs are skin toxicity (45% with ipilimumab, and 35% with nivolumab and pembrolizumab), asthenia (with anti-PD1: 16–37% and anti-PDL1: 12–24%) and endocrinopathies (e.g., dysthyroidism, with incidence of 5–10%, hypophysitis, diabetes). Multiple toxicities have also been observed including hepatic, gastrointestinal, pulmonary, neurological, cardiac, rheumatological, renal, ocular and hematological [18]. Grade 3 to 4 AEs from anti-CTLA-4 are more frequent than for anti PD-1 or PDL-1 [18]. For metastatic melanoma patients, 10 to 27% treated with ipilimumab [19] versus 12 to 20% with nivolumab [20][21] develop grade 3–4 AEs. In advanced unresectable stage III or IV melanoma, patients treated with ipilimumab had a lower QoL than those treated with pembrolizumab [22].
There does not appear to be a different safety profile for patients treated with immunotherapy for HCC than for those with immunotherapy for other indications [23].
In conclusion, the adverse effects of systemic therapies in HCC put patients at risk for QoL impairment.

3.2. Quality of Life and QALYs under TKI and Immunotherapy

The assessment of quality of life in studies is, in most cases, a secondary endpoint.
  • QoL of patients undergoing TKI for diverse cancers
Epidermal growth factor inhibitors (EGFRI) are frequently prescribed for patients with solid tumors. However, most patients treated with EGFRI would present dermatologic toxicities such as pruritus, xerosis, papulopustular eruption, paronychia, mucositis or hair changes. These AEs would usually appear during the first month of treatment. Although the presence and the severity of cutaneous symptoms has a positive correlation with response to treatment [24][25], they also have a negative impact on QoL. In a sub-analysis of 85 patients treated by EGFRI, xerosis and pruritus had the most negative impact on QoL. In this study, QoL was evaluated during the first six weeks of treatment of EGFRI, using five different questionnaires: the DERETT-P (Dermatological Reactions Targeted Therapy–Patients), the Functional Assessment of Cancer Therapy-EGFRI (FACT-EGFRI-18), the Functional Assessment of Cancer Therapy-General (FACT-G), the 36-Item Short Form Health Survey (SF-36), and the Skindex-16 [26]. Despite these dermatologic toxicities impacting QoL, QoL seems to be better for patients treated with EGFRI than for patients treated by chemotherapy; in a cohort of 345 patients with lung adenocarcinoma EGFR mutated, patients treated with afatinib had a better QoL compared to patients treated with chemotherapy [27].
Treatment with a combination of two targeted therapies is not necessarily associated with an increase of toxicities and negative impact on QoL. For example, in the COMBI-v [28] randomized study, patients treated with dabrafenib and trametinib had a better QoL compared to patients treated with vemurafenib.
  • QoL of patients undergoing immunotherapy for diverse cancers
  • Toxicity of immunotherapy in HCC
Immunotherapy has a better safety profile than chemotherapy or targeted therapies, and frequently improves QoL as compared with other treatment.
Among patients with metastatic melanoma, advanced squamous-cell non-small-cell lung cancer (NSCLC) or with recurrent or metastatic squamous cell carcinoma of the head and neck, QoL was significantly better with anti-PD-1 than with chemotherapy [29][30][31].
In the phase 3 CheckMate-214 trial [32], patients with an advanced or metastatic renal clear-cell carcinoma treated with nivolumab plus ipilimumab had a significantly better QoL than patients treating with sunitinib.
The same results were observed with everolimus, another TKI, compared to nivolumab in the phase 3 CheckMate 025 trial, in a cohort of patients with advanced renal cell carcinoma in 2nd or 3rd line treatment [33].
  • QoL during systemic therapy for patients followed for HCC
Sorafenib was the first TKI approved in advanced HCC. The median time to symptomatic progression (which was defined as either a decrease of four or more points from the baseline score on the FHSI8 questionnaire or an ECOG status of four or death) was not significantly longer in the sorafenib group, compared to placebo group [14].
Other TKIs have been approved for advanced HCC. In first-line treatment, lenvatinib was not inferior to sorafenib, with a median survival time of 13.6 months compared to 12.3 months with sorafenib (hazard ratio 0.92, 95% CI 0.79–1.06) [16]. Patients treated with lenvatinib or sorafenib experienced a deterioration of QoL based on EORTC QLQ-C30 and EORTC QLQ-HCC18 questionnaires [16]. There was no difference in the summary score between the two groups, but for three items from QLQ-C30 (role functioning, pain and diarrhea) and two items from QLQ-HCC18 (nutrition and body image) deterioration was earlier in the sorafenib group than in the lenvatinib group. Kobayashi et al [34] had evaluated the cost-effectiveness of lenvatinib compared with sorafenib for Japanese HCC patients included in the REFLECT trial; due to its better PFS, lenvatinib had improved QALYs.
In second-line treatment, three antiangiogenics have been approved: regorafenib, ramucirumab and cabozantinib. Regorafenib and ramucirumab [35] did not improve QoL compared to placebo. Regorafenib was associated with significantly lower QoL than placebo (using FACT-Hep), but the difference did not reach the clinically-significant threshold [15]. Cabozantinib increased QALYs significantly but modestly compared to placebo (+0.092, 95% CI 0.016 to 0.169; p = 0.018), in a post hoc analysis [36] of CELESTIAL trial [17].
In conclusion, most TKIs have not shown any benefit in terms of improvement of QoL. Some may have been associated with a negative effect. Lenvatinib appears to have a slightly better patient experience profile than sorafenib. Anti-PD-1 and atezolizumab-bevacizumab appear to be associated with better QoL than sorafenib.

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