Do you know what disease is known as the “king of cancers”?
Primary liver cancer is cancer that originates in the cells of the liver. Another type of liver cancer is secondary cancer, which occurs when cancer from another part of the body metastasizes to the liver.
Primary cancers are insidious, not easily detected, and prone to recurrence or other complications, which means that the disease is not progressing well, hence the name King of Cancers.
China is a major liver disease country, and it is also a major liver cancer country due to poor medical care and inadequate prevention and control mechanisms, as well as environmental pollution and food quality. According to statistics, there are about 800,000 new cases each year worldwide, and surprisingly, about half of them occur in China.
The radical cure of liver cancer is usually surgical resection. Recent advances in drug therapy such as targeted therapy and immunotherapy have brought a new light to the comprehensive treatment of liver cancer and converted the predominantly surgical treatment of liver cancer into a multidisciplinary and integrated treatment model.
In fact, different tumor stages will use different treatments. Early-stage liver cancer is still dominated by radical means such as resection and radiofrequency ablation, while mid- to late-stage liver cancer is treated locally in combination with systemic therapy to prolong patient survival. So, what are the new advances in the field of liver cancer treatment in different tumor stages in the just past 2019?
Early-stage liver cancer: which is better: resection, ablation, or radiation therapy?
We all know that “early detection, early diagnosis, and early treatment” are most important in the fight against cancer, and liver cancer is no exception. The goal of early liver cancer is to completely control the tumor and achieve the goal of eradication, so that patients can seek long-term survival.
Surgical resection and local ablation are still the most common radical treatments for early-stage liver cancer, and thanks to advances in laparoscopic liver resection, more and more patients with early-stage liver cancer can be cured through minimally invasive laparoscopic resection. The laparoscopic hepatectomy can successfully remove the tumor and has the advantage of being minimally invasive, so it can be the treatment of choice for early-stage liver cancer.
“Two flowers have blossomed,” and after more than 20 years of clinical application and technical development, local ablation therapy, represented by radiofrequency ablation, has finally been affirmed in the past year. Radiofrequency ablation is the insertion of a radiofrequency electrode needle into the liver lesion, which generates high temperature in the local tissue of the lesion through radiofrequency energy, ultimately coagulating and inactivating the diseased tissue.
At the 2019 meeting of the American Society of Clinical Oncology (ASCO,American Society of Clinical Oncology), Japan reported on a national multicenter clinical study – comparing radiofrequency ablation with surgical resection for small hepatocellular carcinoma (also called subclinical hepatocellular carcinoma or early-stage hepatocellular carcinoma, which is defined as a number of tumors ≤3; maximum diameter ≤3 cm).
In this study, 600 patients with small hepatocellular carcinoma were randomized 1:1 to surgical resection or radiofrequency ablation at multiple centers throughout Japan. 308 patients have completed treatment, and preliminary analysis of the results showed that the 3-year recurrence-free survival rates were 49.8% and 47.7% for surgical resection and radiofrequency ablation, respectively, with no significant differences. There was also no significant difference in the incidence of surgical complications and surgery-related mortality; and the operative time and hospital stay were shorter in the radiofrequency treatment group.
Recent data published by Korean scholars showed that the 5-year and 10-year survival rates after ablation were 83.7% and 74.2%, respectively, in 467 patients with small hepatocellular carcinoma treated for the first time.
The results of a randomized controlled trial study reported in JAMA Oncology by our Eastern Hepatobiliary Surgery Hospital showed that for recurrent hepatocellular carcinoma meeting the Milan criteria (ie, single tumor diameter ≤5 cm; multiple tumors less than 3 and maximum diameter ≤3 cm), there was no statistical difference in overall survival at 1, 3, and 5 years between patients undergoing repeat hepatectomy and radiofrequency ablation, with the surgical group having 85%, 52.4%, and 36.2% in the surgery group (n=107) and 74.2%, 41.7%, and 30.2% in the radiofrequency ablation group (n=110).
These high-quality findings reaffirm the efficacy and status of local ablation for small hepatocellular carcinoma, as well as its minimally invasive nature and safety relative to surgical resection.
In addition, stereotactic body radiotherapy (SBRT) has received more attention in recent years for the treatment of early-stage hepatocellular carcinoma. It has been reported that its therapeutic efficacy is close to that of radiofrequency ablation therapy, but rigorously designed randomized controlled trial studies are still needed to demonstrate this. However, in current clinical practice, radiotherapy may provide an effective alternative treatment option for patients with small hepatocellular carcinoma who are not suitable for surgical resection and radiofrequency ablation.
Moderately advanced hepatocellular carcinoma
Chemotherapy + targeted drugs work wonders
Current evidence supports a model of local therapy combined with systemic therapy for intermediate to advanced liver cancer, with the goal of prolonging overall survival.
Therapy with hepatic artery embolization (TACE) is one of the most common local treatments for inoperable intermediate to advanced hepatocellular carcinoma.
A randomized controlled trial study by Japanese scholar Kudo found that TACE combined with the antitumor drug sorafenib prolonged progression-free survival (PFS, the time from randomization to the first occurrence of disease) in patients with hepatocellular carcinoma that had not yet developed vascular invasion and distant metastases compared with treatment with TACE alone. progression or death from any cause: 25.2 months:13.5 months, P=0.006). However, the study did not compare overall survival (Overall Survival, OS) between the two groups, and the effect of combination therapy on OS has yet to be confirmed.
In addition, a phase III clinical study published in JAMA Oncology in 2019 by the Center for Cancer Control and Prevention at Sun Yat-sen University explored the use of hepatic artery infusion chemotherapy (HAIC) in intermediate to advanced hepatocellular carcinoma. The results showed that HAIC treatment with sorafenib combined with FOLFOX regimen significantly prolonged patient survival compared with sorafenib monotherapy (13.37 months:7.13 months, P <0.001). In addition, 16 patients in the combination group underwent concomitant radical surgical resection, including 3 patients with complete tumor necrosis. The combination regimen demonstrated promising results in terms of tumor control and translational resection.
A study by Professor Cheng Shuqun’s team at the Eastern Hepatobiliary Surgery Hospital showed that patients with hepatocellular carcinoma invading the main portal trunk or left or right branches who received preoperative neoadjuvant radiotherapy achieved a partial response (PR) in 20% of patients, with a 1-year survival rate of 75.2% and a 2-year survival rate of 27.4%. In contrast, patients who underwent direct surgical resection had 1- and 2-year survival rates of 43.1% and 9.4%, respectively (P=0.001).
In recent years, targeted agents have gained breakthroughs in the treatment of liver cancer, and sorafenib is no longer a one-trick pony. On the one hand, positive results were achieved with regorafenib as a second-line treatment after sorafenib progression, and on the other hand, a phase III clinical trial designed to compare lenvatinib with sorafenib in the treatment of unresectable hepatocellular carcinoma (uHCC), the REFLECT study, established lenvatinib’s as the 2nd first-line agent after sorafenib in the fight against hepatocellular carcinoma. Since then, patients have had more options.
Donafinib is another China-developed antitumor drug, an oral multitargeted protein kinase inhibitor class of small-molecule antitumor drugs that has also been effective in extending overall survival in first-line treatment of advanced hepatocellular carcinoma (from the ZGDH3 study, the largest enrolled large clinical trial in Chinese patients with hepatocellular carcinoma, with data pending formal publication). Donafinib is expected to be the 3rd first-line targeted drug for liver cancer after sorafenib and lenvatinib.
Immunotherapy enters the era of immune combination therapy
In immunotherapy, following the 2018 liver cancer immunotherapy clinical trials CheckMate040 and KEYNOTE224, which established nabumab (Nivolumab) and pembrolizumab (Pembrolizumab) as second-line treatments for liver cancer, nabumab and pembrolizumab were further investigated in phase III studies compared with sorafenib Although no positive results were obtained, the objective response rate (based on objective measurements such as change in tumor size, change in blood tests, etc.) and complete remission rates were better for immunotherapy than for sorafenib, and the median survival rate for nabumab was as high as 16.4 months.
The field of immunotherapy (ICIs) in combination with other tools has also seen impressive results.
Preliminary results from the phase Ib (mid-stage cancer) study (KEYNOTE 524) of lenvatinib in combination with pabrolizumab in patients with unresectable hepatocellular carcinoma showed a median overall survival of 20.4 months, a median progression-free survival of 9.7 months, and an objective response rate of 44.8% under the mRECIST criteria, with the combination showing good efficacy and The combination showed good efficacy and tolerability.
The IMbrave150 study, presented at the European Society of Medical Oncology Asia Annual Meeting (ESMO ASIA) in Singapore in late November 2019, included 501 patients with unresectable hepatocellular carcinoma randomized to treatment with atezolizumab in combination with bevacizumab, or sorafenib monotherapy. treatment. The results showed that the median overall survival was 13.2 months for patients in the sorafenib group and not yet reached in the combination group (P = 0.0006); while the progression-free survival was 4.3 months for patients in the sorafenib group and 6.8 months for patients in the combination group (P<0.0001) , all of which reached significant differences. In terms of objective remission rate (ORR, the proportion of patients whose tumor volume shrank to a prespecified value and who were able to maintain the minimum time requirement), it was 13% in the sorafenib group and 33% in the combination group (P<0.0001, mRECIST criteria); the benefit was equally significant.
The above encouraging results promise to be a new standard of care for liver cancer and herald an era of immunotherapy into immune combination therapy, making intermediate to advanced liver cancer no longer an incurable disease.
Conclusion
What we can see from the advances in liver cancer treatment in 2019:
- Treatment for early-stage liver cancer is trending toward minimally invasive, enabling early-stage patients to achieve the same radical results at a less invasive cost.
- For mid- to late-stage hepatocellular carcinoma, combination therapy has been the trend, and the adoption of local therapy combined with systemic therapy has been the inevitable choice.
- Targeted drugs as the first-line drugs for advanced liver cancer treatment will be the basis of liver cancer drug therapy. The emergence of immune checkpoint inhibitors has greatly enriched the options of liver cancer drug therapy and set off a revolution in the field of tumor treatment, making the systemic treatment of liver cancer enter the era of drug combination therapy from monotherapy.
However, despite significant advances in liver cancer drugs and treatment modalities in recent years, the overall outcome of liver cancer treatment is still unsatisfactory, and there is still a long way to go to improve liver cancer treatment outcomes. In comprehensive tumor treatment, surgeons, who are the mainstay of liver cancer treatment, should improve their surgical skills while keeping pace with the times, familiarize themselves with various means of liver cancer, emphasize comprehensive tumor treatment, and reasonably use multiple treatments such as drugs, in an effort to improve efficacy and prolong survival rates for the true benefit of liver cancer patients. At the same time, people with hepatitis virus infection, patients with cirrhosis, as well as alcoholics, smokers and obese people need to pay more attention in their daily lives. They can reduce the risk of liver cancer by actively treating underlying diseases, quitting smoking and drinking, maintaining a healthy weight, and not eating foods containing aflatoxin.