Portal vein carcinoma embolism, as one of the biological features of hepatocellular carcinoma, has a very high incidence and is a very difficult problem in liver surgery. Currently available treatment options include surgical resection, interventional embolization chemotherapy, radiotherapy, various ablative therapies, biological and gene therapy. Among them, the application of radiation therapy is getting more and more attention, and its role is expanding from the past palliative treatment modality to curable treatment modality.
Radiation therapy for tumors is a method of treating malignant tumors by using α, β, γ rays generated by isotopes and x-rays, electron beams, proton beams and other particle beams generated by various types of x-ray therapy machines or gas pedals. According to the different treatment methods and routes, it is divided into: external radiation (long-distance irradiation) treatment and internal radiation (brachytherapy) treatment.
I. External radiation therapy
External radiation therapy is to irradiate the radiation source at a certain distance from the human body, and the radiation penetrates from the body surface into the body to a certain depth to achieve the purpose of treating tumors. The effect of radiation therapy is closely related to the radiation dose. The effective radiation dose for hepatocellular carcinoma should be more than 40 Gy, and if the effect of radical treatment is to be achieved, it should be around 60 Gy, but the tolerance of normal liver tissue is within 30-35 Gy. Traditional radiation therapy techniques, because of their inability to precisely locate the tumor target area, increase the radiation dose to achieve better tumor suppression effect while the damage to normal liver also increases, and even complications such as radioactive liver damage and liver failure occur. With the advancement of radiotherapy technology, three-dimensional conformal radiotherapy (3D-CRT), intensity modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT) and other technologies can precisely localize the tumor target area, increase the dose of radiation therapy in the target area and reduce the impact on the surrounding normal tissues. 3D-CRT is a technique that can increase the radiation dose to the target area and reduce the dose to the surrounding normal tissues.
By adjusting the incidence shape of the non-coplanar high-energy radiation beam, 3D-CRT forms a radiation volume with uniform dose distribution that matches the three-dimensional spatial shape of the target area, and outside this volume is a relatively low-dose area, which achieves precise treatment and reduces the irradiation range and dose to the surrounding normal tissues. According to its radiation source, the more commonly used clinically are γ-knife (with cobalt as the radiation source) and X-knife. IMRT, or Intensity Modulated Conformal Radiation Therapy, is a kind of 3D-CRT. It is a kind of 3D-CRT. Under the condition that the shape of the radiation field and the target area are consistent, the beam intensity is adjusted for the three-dimensional shape of the target area and the specific anatomical relationship between the target area and the surrounding tissues and organs, and the dose distribution within a single radiation field is not uniform, but the dose distribution within the whole target area is more uniform than that of 3D conformal radiotherapy.
3D-CRT and IMRT have achieved better efficacy and improved patient survival by reducing the irradiated volume of surrounding normal tissues and improving the dose distribution through highly conformal irradiation. However, the influence of some uncertainties (e.g. positional errors, respiratory motion) during radiotherapy can lead to off-target tumor and injure surrounding normal tissues or organs, and affect the distribution of irradiation dose. To solve these problems, radiation therapy machines or gas pedals are combined with imaging equipment to determine the treatment target area by acquiring image information during the treatment process and adjusting the position and dose distribution at any time, which is called IGRT. this technique better protects the normal tissues around the target area and further improves the uniformity of tumor irradiation dose and dose distribution. It also allows for rapid modification and adjustment of the treatment plan at any time during radiotherapy according to the changes in the tumor and surrounding normal tissues, and adaptive radiotherapy.
Cyberknife is a kind of image-guided radiotherapy. Through the combination of imaging and computer technology, the target area can be adjusted at any time by tracking the tumor’s movement with breathing position in real time during radiotherapy, which can well protect the surrounding normal tissues. Reports in the literature show that it has shown remarkable efficacy in the treatment of primary foci of hepatocellular carcinoma, enabling all 17 patients observed to achieve local control, but there are fewer reports on its efficacy on portal vein cancer thrombosis.
Spiral tomotherapy (helical tomotherapy) is a combination of spiral CT and linear gas pedal, in which a CT scan is first performed before each treatment, and according to the comparison of the scanned image with the localized CT image, the machine will automatically correct the pendulum error, and then the rays are focused around the tumor 3600 rotations layer by layer like a spiral CT scan. This technology has established its good therapeutic effect in clinical application.
Proton beam radiation therapy, developed after X-knife and γ-knife, kills the tumor target area with extreme precision by emitting extremely penetrating protons and producing unique Bragg peaks, which greatly reduces the damage to normal liver and tissue organs around the target area and largely improves the tumor radiobiological effect.
In order to improve the radiotherapy effect, the combination therapy of 3D-CRT plus intervention is mostly used in clinical practice. Since portal vein cancer thrombus also receives blood supply from portal vein wall, interventional treatment can cause ischemic necrosis of the cancer thrombus, and at the same time promote G0 stage cells to proliferate and reoxygenate the hypoxic cells, thus improving radiosensitivity, so the combination of the two can achieve synergistic anti-cancer effect. According to recent reports on this combination therapy, the effective rate is between 39.6 and 80.0, and the one-year survival rate is between 40.0 and 58.8.
External radiation therapy has become an important and effective treatment modality for patients with HCC with PVTT, but there is no unified standard for the dose of external radiation therapy for hepatocellular carcinoma tissue and cancer thrombus tissue. However, how to estimate the maximum tolerated dose according to the patient’s functional status, the degree of cirrhosis and the volume of the irradiated liver, etc., and how to give the highest dose within the tolerated dose range and adopt the best treatment plan are yet to be further studied. In addition, how to choose the best combination plan and sequential order of radiotherapy as one of the combined treatment modalities should be further explored clinically.
II. Internal radiation therapy
Internal radiation therapy is to inject radionuclide into hepatic artery or implant into tumor through interventional method, percutaneous hepatic puncture technique or intraoperative, which can block tumor blood supply through embolization of blood vessels and kill tumor cells through targeted internal radiation, so it can achieve better curative effect. Currently, 133I, 125I, 90Y and 32P are the main nuclides used in clinical treatment of portal vein cancer embolism in hepatocellular carcinoma.
133I is a radionuclide commonly used in clinical practice. 133I-iodinated oil injected via hepatic artery can not only embolize tumor microvessels, but also release β-rays, which can have a killing effect on tumor cells, and has good efficacy in prolonging the survival period and improving the quality of survival of patients with portal vein cancer embolism of hepatocellular carcinoma.
The radiation released by 125I radionuclide particles can effectively cover the tumor and its surrounding invasion area, and emit short-distance and continuous radiation through the miniature radiation source to play a continuous radiotherapy effect on the tumor.
90Y and 32P are pure beta-radiation emitting radionuclides, which can produce large radiation energy locally without involving adjacent organs. However, the half-life of 90Y is only 67 h, and the intrahepatic action time is short, which limits its application to a certain extent. 32P is a high-purity β-radiation source with a half-life of 14.3 d. Its microspheres are physicochemically and chemically stable, and the maximum range of β-radiation released can reach 1 cm, and its energy is twice that of β-radiation produced by 133I, which is a better internal radioactive agent at present. Selective transhepatic arterial infusion of 90Y microspheres for the treatment of patients with HCC with PVTT can significantly improve the quality of survival and prolong the survival period of patients.
Currently, the safe and effective irradiation dose for internal radiation therapy for HCC with PVTT is not uniform. It is generally believed that an internally absorbed dose of 50-60 Gy is required to achieve a radical killing effect. In addition, for patients with obvious hepatic arteriovenous shunts, injection via hepatic artery should be contraindicated because it is not sufficient to kill cancer cells, but may injure normal tissues and organs such as liver and lung. Within a certain range, high dose irradiation of liver tumors and cancer emboli can increase the rate of necrosis and shrinkage, but various complications accompanying it also increase. Therefore, how to implement individualized internal irradiation plan in terms of dose selection and drug injection route according to the patient’s cancer embolus staging and liver function status should be further studied and discussed.
3 Prospect
Currently, radiation therapy for hepatocellular carcinoma combined with portal vein thrombosis has become a more effective treatment method and is widely used. Intensity-modulated radiotherapy and image-guided radiotherapy (including spiral tomography radiotherapy) developed on the basis of 3D conformal radiotherapy have further improved the uniformity of tumor irradiation dose and dose distribution, better protected the normal tissues around the tumor, and improved the survival rate of patients. In addition, the combination therapy with radiotherapy as one of the combined treatment methods has also obtained certain efficacy. However, the selection of radiation dose, the formulation of the combination plan, and the implementation of the most effective individualized treatment plan according to the development of cancer thrombus and the patient’s liver function status need to be further discussed and practiced to make it more and more perfect.
In addition, Cheng Shuqun et al. classified cancer embolism into four types according to the degree of development of cancer embolism. This provides a valuable reference for the clinical treatment and prognosis of cancer embolism. For HCC with type I and type II PVTT, surgical treatment can achieve better efficacy, but for patients with HCC with type III and type IV PVTT, there are still many controversies in treatment. We believe that for these patients, preoperative radiotherapy should be given first to reduce the size of the cancer thrombus and tumor before considering surgical resection or other treatments, which may improve the surgical resection rate and prolong the survival of patients, but the validation of clinical prospective controlled trials is still needed. Four-dimensional radiotherapy, which is born from the addition of time-control factors to three-dimensional radiotherapy, is also expected to produce better treatment results. In addition, the IGRT technique combined with the evolving molecular imaging can select the irradiation dose and arrange the dose distribution according to the different growth states of tumors and cancer thrombi, which is expected to achieve satisfactory treatment results.