In a narrow sense, conversion therapy refers to tumors that cannot be removed by primary surgery achieve the effect of tumor reduction and downstage through preoperative treatment, so as to achieve the purpose of radical resection at the surgical technical level. However, the hepatectomy is often limited by requirements such as liver function and FLV, so the author thinks, conversion therapy of HCC is not limited to the decline of preoperative clinical stage, but it should be through multidisciplinary comprehensive diagnosis and treatment, using personalized plans to make the disease develop in a direction that is more conducive to the prognosis.The conversion therapy of HCC is not a new concept of treatment, Sitzmann et al. treated unresectable advanced HCC by external radiotherapy combined with I131-antiferritin chemotherapy in 1993, the tumor reduction rate of 14 patients was more than 50% and hepatectomy was performed successfully. There are various specific conversion treatment strategies for HCC, but the response rate of both local treatment and systemic treatment is low, and it cannot achieve the ORR as high as 70% like colorectal cancer liver metastasis, which limits the development of conversion treatment for HCC [11,12]. HCC is the fourth cause of cancer-related death in the world, and the five-year survival rate of patients with advanced HCC treated by systematic treatment is less than 20%. Therefore, while perfecting the monitoring system for high-risk patients with liver cancer, transforming advanced HCC that cannot be removed by primary surgery into operable, is of great significance for improving the prognosis and the OS of HCC patients [13,14].
Due to the anatomical characteristics of the liver and the biological characteristics of HCC, HCC easily invades the intrahepatic vascular system, especially the formation of PVTT. It has been reported that the proportion of advanced patients with PVTT in the first diagnosis of HCC is 10-40%. Compared with the advanced patients without PVTT, the OS decreased from 10-24 months to 2- 4 months [15,16]. VP classification of Japan  and Cheng’s classification of China  are commonly used clinically to classify PVTT. The main difference between the two classifications are that Vp4 includes PVTT Ⅲ which invades the main portal vein and PVTT Ⅳ which invades the superior mesenteric vein, while PVTT Ⅰincludes VP1 and VP2 that tumor thrombus is confined to the secondary portal vein and below. According to EASL guidelines and NCCN guidelines, stage Barcelona clinic liver cancer(BCLC)C HCC with portal vein invasion is an absolute contraindication for surgical resection, and systematic treatment is recommended[19,20]. However, the CNLC guidelines believe that for tumors confined to the hemi-liver and PVTT confined to the left or right branches, that is, PVTTⅠand PVTTⅡ(Vp0, 1, 2, 3), surgical resection of tumor and removal of thrombus through portal vein should be considered if the technology permits. And hepatic arterial chemoembolization(TACE), portal vein chemotherapy or other systematic treatment can be given after operation. Studies have shown that surgical resection can still provide better survival benefits than TACE and other non-operative treatments for patients with advanced HCC and PVTT, especially for patients with single mass and PVTT Ⅰ and Ⅱ [22,23].Therefore, neoadjuvant therapy is given before surgery to successfully reduce the tumor and improve the stage, or improve the classification of PVTT in patients with advanced HCC, and then radical resection of the tumor is given. That is significant for advanced patients who do not meet the surgical resection standards specified in the guidelines.The preoperative imaging of our case showed PVTT Ⅲ. After 4 cycles of MTDs and ICIs combined therapy, not only the mass was significantly reduced (58.9% smaller in size), but also the PVTT was successfully reduced to type Ⅱ, and the AFP also dropped to normal. The histopathology results showed CR, indicating a good prognosis of the patient.
The conversion therapy of HCC has always been limited by the low response rate of adjuvant therapy. In recent years, MTDs and ICIs have been proven to be effective in the treatment of advanced HCC, However, the objective response rate of monotherapy is still only 2%-24.1% [2,3,24,25,26]. In 2020, several clinical studies have proved that the combination of the two drugs shows a 1: 1 > 2 effect in advanced HCC, which brings a new approach for the conversion therapy of HCC. The phase III clinical study IMbrave-150 showed that although the ORR of Bevacizumab combined with Atezolizumab in the treatment of advanced HCC was only 27.3%, the CRR was as high as 5.5%, while none of the patients in Sorafenib group achieved CR . The KEYNOTE-524 clinical study enrolled 104 patients with advanced HCC. The ORR of Len combined with Pembrolizumab was as high as 46%, of which the CRR was 11% and the partial response rate (PRR) was 35% .The PRR of Apatinib combined with Camrelizumab in the treatment of stage BCLC C HCC also reached 50% . In the study of combined therapy with double ICIs, the ORR of 22.7%-31% was also achieved, which is twice or higher than that of single drug [30,31]. The ORR of the IMbrave-150 study was 27.3%, of which the disease-free progression rate in 6 months was 54.5%. The KEYNOTE-524 clinical study showed that 73% of the 46% objective response patients achieved long-term remission for 6 months or more, indicating that the combination of MTDs and ICIs can improve the TIM in the anti-tumor process and play a long-term role in the anti-tumor effect.
The conversional therapies of HCC are various, including TACE, HAIC, stereotactic body radiation therapy (SBRT), concurrent radiochemotherapy (CCRT), transarterial radioembolization (TARE), MTDs, ICIs and the combined application of various treatments. There are some retrospective analyses and case reports, but is still a lack of prospective studies to prove the efficacy of specific conversional treatments for HCC [32,33,34,35]. With the development of MTDs and ICIs, successful cases of the two drugs in the conversional therapy of HCC are often reported. Many patients not only have OR or CR pathologically after treatment, but also achieve a tumor-free survival of up to 48 months in the later follow-up (Table 2). There are few research reports on MTDs combined ICIs for conversional therapy at present. Chen et al. reported a case of massive HCC that was intolerant by Sorafenib. At the first diagnosis, the maximum section of the tumor was 15.0cm×10.8cm, and the necrotic area was 39.47cm2. After 4 cycles of treatment with Len combined with Nivolumab, the maximum section of the tumor was reduced to 13.0cm×8.5cm, and the necrotic area was enlarged to 48.84cm2. Finally, the enlarged right hepatic resection was performed successfully, and the patients were discharged safely and followed up regularly. Won et al. reported a case of a BCLC C patient with double lesions on the right liver and tumor thrombus in the right anterior portal vein. AFP increased from 17,528ng/mL to 30,070ng/mL in just 12 days at admission. After 4 cycles Cobimetinib combined with Nivolumab treatment, the primary focus was reduced by 37.3%, and the AFP was reduced by more than 99% from the treatment baseline (down to 12.9ng/mL). After the right hepatectomy, the histopathology revealed that a lesion was 100% necrotic, and The necrotic area of another was more than 80%. There was active immune cell infiltration in the marginal tissue of the tumor. The patient was followed up every 3 months after operation, and there was no recurrence for 2 years. Zhang et al. conducted a prospective study on the conversion therapy of advanced HCC with intrahepatic vascular tumor thrombus. In the treatment of 33 patients with Len combined with PD-1 inhibitors, the ORR was 45.5% ,the disease control rate(DCR) was 81.8%, the conversion success rate based on imaging evaluation was 42.4%, and the actual operation rate was 30.3%, during the median follow-up time of 11.5 months, the recurrence-free rate was 60.0% at 6 months after surgery. As of November 2020, the median survival time and recurrence-free survival time had not yet reached the end point . At the ASCO conference in 2020, Sun et al. reported that 60 patients who were unresectable in first diagnosis were treated with Len combined with PD-1 inhibitors, and 11 patients became resectable, and 9 of them had completed the operation. As of the last follow-up, 7 patients remained tumor-free . In this patient, we used Len combined with Tor. After twice combined treatments, the patient’s AFP dropped from baseline>1210ng/ml to 25.23ng/ml. The length, width and depth of the PVTT were significantly reduced, which provided the possibility of radical resection at the surgical technical level.
The indications for surgery after MTDs combined ICIs therapy, the withdrawal time before operation, and whether to continue the combined therapy after surgery are still inconclusive. Our case did not benefit further in the two imaging evaluations of 2021.04.21 and 2021.05.06, and the classification of PVTT was reduced from Ⅲ to Ⅱ. From the level of surgical technology, radical resection can be achieved. According to the recommendations of 《Chinese expert consensus on Transforming Therapy of Advanced HCC based on Immunization combined with targeting regimen (2021 Edition)》，we performed " right hepatectomy plus cholecystectomy plus portal vein tumor thrombus removal and intestinal adhesion lysis" under general anesthesia on December 2021. The tumor-free results of postoperative pathology also suggested that the patient reached the standard of R0 resection. As an anti-angiogenic drug, Len may cause intraoperative and postoperative complications such as increased bleeding and delayed healing. The half-life of Len is about 28h-35h, and the duration of interruption before invasive operation is at least 1 week . We told the patient to discontinue the use of Len when the patient came to the hospital for review on May 5, 2021. As of the start of the operation, the patient stopped using Len for 7 days, stopped using Tor for 21 days. The intraoperative bleeding was 500ml.The patient recovered well and was discharged smoothly 9 days after operation. No operation-related adverse events occurred. The patient was asked to review after one month. After evaluating the curative effect, we planned to continue treatment according to the same regimen for 6 to 12 months.