Hepatocellular carcinoma is a highly prevalent malignancy that is often incurable and causes great suffering to patients because it is mostly detected at an advanced stage. Often, clinicians refer to the nationally published guidelines for the treatment of liver cancer to develop treatment plans for patients.
And the guidelines issued in China are different from the guidelines issued in the United States. What exactly are the differences?
Surgical resection: more lenient indications for surgery in China
For those patients with liver cancer whose conditions allow it, the best treatment is surgical resection.
But because most patients with liver cancer have tumors that are too large or have spread throughout the liver as well as throughout the body, there is some other cause of liver damage that makes complete removal of the tumor unlikely.
So in the guidelines, staging is done for those patients without cirrhosis and extrahepatic metastases:
- Stage Ia: One tumor only and no larger than 5 cm in diameter.
- Stage Ib: One tumor only and no larger than 5 cm in diameter.
- Stage Ib: only one tumor and greater than 5 cm in diameter; or 2 to 3 tumors and no greater than 3 cm in diameter.
- Stage IIa: 2 tumors and no greater than 5 cm in diameter.
- Stage IIa: 2 to 3 tumors with a diameter greater than 3 cm.
- Stage IIa: 2 to 3 tumors with a diameter greater than 3 cm.
- Stage IIb: 4 or more tumors.
Patients with stages Ia, Ib, and IIa have good hepatic reserve and the Chinese guidelines set them as the first indication for surgical resection; for stage IIb patients, surgery can be considered after preoperative adjuvant therapy.
However, the National Comprehensive Cancer Network (NCCN) guidelines question whether surgery should be performed in patients with multiple tumors (no less than 3).
It is clear that the indications for surgery in China are more liberal than in the United States, and that patients are more aggressively pursued for radical surgery.
In addition, Chinese guidelines suggest that preoperative adjuvant therapy such as transcatheter arterial chemoembolization (TACE), external radiation, and hepatic artery ligation cannulation for unresectable patients may shrink the tumor in some patients to gain access to surgery. Adjuvant therapy can be given postoperatively to prolong patient survival in patients with high-risk recurrence and with venous cancer thrombosis, respectively.
The US guidelines are silent on the issue of preoperative and postoperative adjuvant therapy.
Liver transplantation: liver transplantation for liver cancer in China is more widely available
Liver transplantation is the removal of a diseased liver and its replacement with a healthy liver from another person, which is a complete cure for liver cancer. For patients who have cirrhosis or very large tumors, liver transplantation may become the primary treatment option. The effectiveness of liver transplantation is recognized in both China and the United States.
But how do you determine if a patient is a good candidate for liver transplantation treatment? This is where the criteria used by the US and China diverge.
Criteria for suitability for liver transplantation
The United States relies on the Milan criteria, the University of California, San Francisco (UCSF) criteria, and others.
In China, there is no uniform standard. In China, several institutions and scholars have proposed different criteria, including the Hangzhou criteria, the Shanghai Fudan criteria, the Huaxi criteria, and the Sanya consensus. They are all relatively consistent for the absence of large vessel invasion, lymph node metastasis, and extrahepatic metastasis, but the requirements for the size and number of tumors vary.
Compared with the criteria adopted in the United States, our criteria have all expanded the scope of liver transplantation for liver cancer to varying degrees, which may allow more liver cancer patients to benefit from liver transplantation, but have failed to significantly reduce overall postoperative survival and tumor-free survival rates. Collaborative multicenter studies are needed to clarify which criteria are more beneficial to patients.
Post-liver transplantation treatment options
What treatments should patients receive after liver transplantation? There are also differences between the United States and China.
Tumor recurrence may occur in some patients after liver transplantation for liver cancer due to differences in tumor stage and vascular invasion, and once recurrence occurs, it can significantly reduce post-transplant survival.
China used a reduced dosage of reduced early post-transplant calcium-regulated phosphatase inhibitors or an immunosuppressive regimen using target of rapamycin (mammalian target of rapamycin, mTOR) inhibitors to prevent tumor recurrence and improve survival.
However, this therapy is not recommended in US guidelines, so its efficacy needs to be further confirmed by clinical studies.
Local treatment: more diverse radiotherapy approaches in China
Most patients with hepatocellular carcinoma are combined with cirrhosis, or most of them are already in the mid- to late-stage when diagnosed, so fewer patients, about 20% to 30%, have access to surgical resection.
What about patients who do not have access to surgery? Local therapy offers an opportunity to treat these patients.
Local treatment includes local ablation, arterial embolization, and radiation therapy.
Local ablation therapy
This therapy is a type of treatment that uses medical imaging technology (e.g., guided by ultrasound) to localize the tumor and use physical or chemical methods locally to directly kill the tumor tissue.
In China, these include radiofrequency ablation, microwave ablation, cryotherapy, high-powered focused ultrasound ablation, and anhydrous ethanol injection therapy, but high-powered focused ultrasound ablation is not recommended in the United States, and the remaining methods do not differ significantly.
Radiotherapy
Radiotherapy (radiotherapy) is divided into two methods: external radiotherapy and internal radiotherapy.
- External radiotherapy uses radiation (photons or particles) produced by radiotherapy equipment to irradiate tumors from outside the body for treatment.
- Internal radiotherapy is an effective method to treat liver cancer locally by implanting radionuclides into the tumor through the body’s ducts or through needle channels.
There are some differences in the modalities of internal radiation therapy between China and the United States. In China, there are various types of internal radiation therapy, including Y-microsphere therapy, I monoclonal antibody, radioiodinated oil, and I particle implantation, but only Y-microsphere therapy is recommended in the US guidelines for liver cancer treatment.
Arterial embolization therapy
TACE therapy, or interventional therapy, is used in China, and it is currently recognized as one of the most common methods of nonsurgical treatment for liver cancer. However, in addition to TACE, transcatheter arterial embolization (TAE) and drug-loaded microsphere embolization (transarterial chemoembolization with drug- eluting beads, DEB-TACE) therapies.
Systemic therapy: fewer targeted and immunologic agents recommended in China
Systemic therapies for hepatocellular carcinoma include systemic chemotherapy, targeted therapies, and immunotherapy.
Systemic chemotherapy
Chemotherapy is a common treatment for advanced malignancies, in which chemotherapeutic drugs enter the body and “sweep” the body’s fast-growing cells (both tumor cells and actively growing normal cells), killing tumor cells to treat the cancer.
The main chemotherapy drugs used in China are the FOLFOX4 regimen containing oxaliplatin and arsenic trioxide (arsenic).
However, because the chemotherapy drugs do not distinguish between the “enemy and the patient” during treatment, they remove all cells that are actively growing, killing tumor cells while “accidentally” injuring a large number of normal cells in the body, leading to significant side effects. The US guidelines say that this therapy provides limited benefit to patients.
Targeted therapy
Targeted therapy
Is there a drug that recognizes tumor cells from normal cells and kills only tumor cells?
During the development of malignant tumors, there is a class of proteins (usually expressed by mutated gene fragments) that cause normal tissues and cells to become cancerous, or promote tumor growth and metastasis. If they are inactive, they will block the process of tumor cell growth or metastasis and contain the development of malignant tumors.
So scientists have continued to develop drugs that target these proteins (or gene fragments). The drugs, once in the body, are like missiles looking for a target, directly attacking these proteins (or gene fragments) so that they are no longer the “drivers” of malignant tumor development. “The first time I saw this, I was able to get to the body.
This is called “targeted therapy” and these drugs are called “molecularly targeted drugs”.
Targeted therapies for liver cancer currently available in the United States include sorafenib and regorafenib. The NCCN recommends sorafenib as a first-line agent for systemic therapy, and regorafenib is a second-line agent after failure of sorafenib and is also recommended in the NCCN guidelines.
In China, only sorafenib has been recommended in the guidelines, and regorafenib for hepatocellular carcinoma was approved in December 2017 but has not yet been recommended in the guidelines.
Immunotherapy
Immunotherapy, also known as biologic therapy or biologic response modification therapy, is a treatment that uses the body’s own defense mechanisms to fight cancer.
White blood cells are the body’s first line of defense against disease. Immunotherapy can stimulate white blood cells in a variety of ways that increase the immune response to cancer with little or no effect on healthy tissue.
Immunotherapy commonly used in China includes immunomodulators (interferon α, thymidine α1, etc.), immune checkpoint inhibitors (cytotoxicTlymphocyte-associated antigen-4, CTLA-4; programmed cell death protein-1, programmed death 1, PD-1; programmed cell death protein ligand, PD-L1), tumor vaccines (dendritic cell vaccines, etc.), and cellular immunotherapy (cytokine-induced killer cells).
In China, the immune checkpoint inhibitor nabumab is still in clinical phase 3 trials. In the US, the NCCN guidelines recommend nabumab, which opens a new era of immunotherapy for liver cancer.
Multidisciplinary collaborative care
There are also some differences in the philosophy of multidisciplinary treatment (MDT) between the United States and China.
The United States emphasizes multidisciplinary collaboration, and MDT is a common and well-practiced approach to cancer care in the United States. The Chinese academic community is also trying to experiment with this model, but China is still in the beginning stages of MDT due to the traditional system of subspecialty care, the yet to be accumulated evidence-based medicine, and the economic level.