Watch-and-wait strategy for complete responders after conversion therapy for initially unresectable hepatocellular carcinoma

1. Introduction Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. HCC is the sixth most frequently diagnosed cancer and the third leading cause of cancer-related mortality worldwide.[1] Partial hepatectomy is recommended for patients with early stage HCC.[2] A large proportion of patients with HCC in China are diagnosed in the intermediate to advanced HCC stages, rendering them ineligible for hepatectomy due to aspects such as liver dysfunction, insufficient residual liver volume, or surgical technique.[3] The overall 5-year survival rate for these patients is below 15%.[4] Conversion therapy is a promising strategy for downstaging unresectable or borderline resectable HCC, enabling curative resection and potentially improving long-term survival outcomes for patients with initially unresectable HCC (uHCC).[5] The systemic treatment of HCC has advanced, particularly with the development and subsequent clinical application of immune checkpoint inhibitor (ICI)-based therapies.[6] Local treatment modalities, such as hepatic artery infusion chemotherapy (HAIC), either alone or in combination with transarterial chemoembolization (TACE), have been shown to increase the objective response rate (ORR) in patients with advanced HCC.[7–9] The combination of ICI-based therapies with locoregional treatments, such as TACE or HAIC, increases the ORR and improves survival outcomes, with complete response (CR) rates ranging from 8% to 14.1%, as assessed by the modified Response Evaluation Criteria in Solid Tumors (mRECIST).[7,10,11] These outcomes have remarkably challenged the traditional treatment paradigms and achieved a breakthrough in HCC management.[2] Although advances have been achieved in treating HCC, the necessity of surgical resection following CR must be assessed. The watch-and-wait strategy was developed by Habr-Gama et al. for managing locally advanced rectal cancer.[12] The treatment outcomes of the watch-and-wait strategy are comparable to those of radical surgery in patients who have achieved clinical CR (cCR) following neoadjuvant radiotherapy.[13] The watch-and-wait strategy avoids the complications associated with abdominoperineal resection and mitigates the negative impact of permanent colostomy on patient quality of life.[14] The successful implementation of the watch-and-wait strategy in those with advanced rectal cancer has encouraged its consideration as a management approach for patients with HCC who have achieved CR after conversion therapies. Hepatobiliary surgeons and oncologists are evaluating whether radical hepatectomy confers additional survival benefits to patients with uHCC who have achieved CR after conversion therapy given the promising outcomes associated with systemic HCC treatments. 2. Watch-and-wait strategy The watch-and-wait strategy was developed in 1998, when Habr-Gama et al. reported the feasibility of nonoperatively managing rectal cancer in patients who had achieved cCR after neoadjuvant therapy,[12] In 2004, Habr-Gama et al. published the long-term outcomes of patients with rectal cancer who received nonoperative management after achieving cCR following neoadjuvant chemoradiotherapy (nCRT). The findings showed that radical surgery conferred no additional long-term survival benefits compared with nonoperative management.[15] The study introduced a concept in rectal cancer management, highlighting the potential for preserving organs using the watch-and-wait strategy.[15] The watch-and-wait strategy has since received widespread attention and sparked debate among colorectal surgeons worldwide, particularly regarding safety, oncologic efficacy, and long-term outcomes compared with those of surgical resection.[16–18] The watch-and-wait strategy in rectal cancer management has been refined, and evidence of its results has accumulated from updated protocols and outcomes reported by multiple cancer centers worldwide.[14] The long-term survival outcomes are similar between the watch-and-wait strategy and radical resection in patients with rectal cancer who achieved cCR following nCRT, providing robust evidence supporting the integration of the watch-and-wait strategy into clinical practice for rectal cancer.[13,14,19–22] The evidence regarding the application of the watch-and-wait strategy in HCC remains limited. Therefore, the feasibility of a watch-and-wait strategy for managing HCC must be investigated. 3. Prerequisites for implementing watch-and-wait strategy in patients with uHCC The clinical feasibility of the watch-and-wait strategy for managing rectal cancer is dependent on the high CR rates achieved after nCRT.[23] nCRT achieves a pathological complete response (pCR) in approximately 20% of patients with rectal cancer, and a pCR strongly predicts improved long-term survival outcomes.[24,25] Neoadjuvant treatments for rectal cancer have considerably varied across studies, including chemotherapy regimens, radiotherapy doses, and treatment schedules, where cCR rates have ranged from 10% to 78%.[26,27] Therefore, high CR rates must be achieved following conversion therapy for determining the potential application of the watch-and-wait strategy. The concept of CR must be fully understood in patients with HCC.[28] A radiological complete response (rCR) is defined as the complete disappearance of arterial enhancement in all target lesions according to the mRECIST criteria.[29] However, no consensus has been reached on standardized criteria indicating cCR after conversion therapy for HCC. We drew upon the cCR definitions established for other malignancies and integrated the mRECIST criteria to propose that cCR in HCC can be defined using the following criteria[30]: (a) achieving rCR for all tumors, (b) the absence of distant metastases, (c) initial elevated alpha-fetoprotein levels (>20 ng/mL, one time higher than the upper limit of normal) that subsequently normalize (<20 ng/mL), and (d) meeting the previous criteria over 2 consecutive follow-up assessments (with an interval of at least 1 month).[30] Our cCR criteria differ from the definitions of CR in RECIST 1.1 and mRECIST by incorporating the normalization of initially elevated serum tumor markers and the assessment timing. pCR is defined as the absence of residual viable tumor cells, as confirmed through hematoxylin and eosin staining of the resected specimens.[31,32] Novel antiangiogenic-targeted therapies and programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors have markedly increased treatment efficacy in advanced HCC since 2017.[6,33,34] Atezolizumab combined with bevacizumab yielded an ORR of 27.3% in the IMbrave150 study on HCC.[34] The Keynote-524 trial reported an ORR of 36% for combined lenvatinib and pembrolizumab treatment of HCC.[35] Treating HCC with a combination of tremelimumab and durvalumab resulted in an ORR of 20.1% in the HIMALAYA study.[36] Other targeted therapies have been combined with immunotherapy, such as bevacizumab analogs combined with sintilimab or apatinib combined with camrelizumab, achieving ORRs of over 20% in treating uHCC.[37,38] Locoregional modalities have been combined with antiangiogenic targeted agents and ICIs to increase local tumor control and improve survival outcomes in patients with HCC.[9,39,40] The efficacy of transarterial therapies, such as TACE and/or HAIC, in combination with antiangiogenic targeted agents and ICIs is higher than that of prior therapies among patients with uHCC, with ORRs of 42%–67.6% and CR rates of 8%–14.1%.[7,10,11,41] Furthermore, radiotherapy may enhance tumor immunogenicity in HCC and potentiate immunotherapy responses.[42] Combining radiotherapy with targeted agents and ICIs achieved ORRs of 52.4%–58.7% in patients with uHCC.[43,44] These findings warrant a critical evaluation of the need for surgical resection in patients with uHCC who have attained rCR or cCR following conversion therapy. 4. Preliminary watch-and-wait strategy data in patients uHCC The successful application of the watch-and-wait strategy for patients with advanced rectal cancer supports its application in HCC. We have clinically observed that patients with HCC who achieved CR after conversion therapy and were subsequently managed with nonoperative treatment also survived in the long term. However, evidence regarding the application of the watch-and-wait strategy in HCC remains limited. Thus, we retrospectively evaluated the feasibility and clinical outcomes of surgical resection in patients with initial uHCC who achieved CR following conversion therapy.[30] We included patients who fulfilled the following criteria in this study: (a) HCC diagnosed according to clinical practice guidelines; (b) absence of extrahepatic metastases; (c) initially ineligibility for R0 resection due to insufficient residual liver volume or inadequate resection margins; (d) liver lesions evaluated as achieving rCR after conversion therapy, as per the mRECIST criteria, assessed through enhanced computed tomography scan or magnetic resonance imaging (MRI); (e) receiving liver resection or with regular follow-up after rCR; (f) Child-Pugh class A or B; and (g) Eastern Cooperative Oncology Group (ECOG) performance scores of 0 to 1. Patients who underwent surgical resection were routinely followed up once every 3–4 months for the first 2 years and then once every 6 months thereafter until tumor recurrence or death. Patients in the watch-and-wait group were routinely followed up once every 2–3 months for the first 2 years and then once every 3–6 months thereafter. We found that the watch-and-wait strategy yielded overall survival (OS) rates comparable to those of surgical resection in patients with uHCC who achieved rCR after conversion therapy, albeit with inferior in patients with uHCC who achieved rCR after conversion therapy progression-free survival. The OS and PFS rates of patients who achieved cCR in the Watch-and-Wait group were comparable to those in the surgical resection group. These findings suggest that the watch-and-wait strategy can be offered as an alternative treatment option for patients with uHCC who achieve CR after conversion therapy. A study on whether salvage hepatectomy is beneficial to the survival of patients with uHCC who achieved cCR after conversion therapy[45] reported comparable 1-, 2-, and 3-year OS and disease-free survival rates between the surgical and nonsurgical groups. These findings show that salvage hepatectomy may not be essential in patients with uHCC who achieve cCR, which is consistent with our results.[30] Moreover, long-term survival can be attained in patients with uHCC who achieve CR after ICI-based combination therapies, indicating that the watch-and-wait strategy is a feasible management approach for these patients.[46,47] The watch-and-wait strategy appears to yield survival outcomes comparable to those of surgical resection in patients with initial uHCC who attain rCR or cCR following conversion therapy. The watch-and-wait strategy may be an alternative treatment option for these patients, particularly for those who have undergone surgical resection. 5. Challenges facing watch-and-wait strategy in uHCC Although the watch-and-wait strategy has been used to achieve desirable outcomes in patients with uHCC, the clinical implementation of the strategy is hindered by several challenges. The first challenge is increasing the CR rate following conversion therapy in patients with uHCC. nCRT can lead to a cCR in >20% of patients with advanced rectal cancer.[48] ICI-based nRCT has achieved a pCR rate exceeding 60% in patients with microsatellite instability-high tumors.[49] Despite advances in HCC management, combining locoregional modalities with antiangiogenic-targeted agents and ICIs yielded an rCR (assessed using the mRECIST) of less than 20%,[10,43] with even lower rates observed for cCR. Thus, the efficacy of conversion therapy must be increased for treating uHCC. The second challenge involves accurately assessing cCR following conversion therapy in patients with uHCC. cCR in rectal cancer is defined as the absence of detectable tumors on MRI, digital rectal examination, and endoscopic examination after nCRT. The term near-cCR refers to patients exhibiting a favorable treatment response with a high probability of reaching a cCR but do not show the typical features on endoscopy and/or MRI. Incorporating near-cCR may increase the number of patients eligible for the watch-and-wait strategy. However, consensus on the criteria for defining cCR or near-cCR in HCC has not been reached. Although several cCR assessment criteria following conversion therapy in uHCC have been proposed[28,30,45] controversy remains, particularly in patients who are negative for alpha-fetoprotein. Therefore, future expert consensus guidelines are needed to unify the definitions of cCR and near-cCR following conversion to uHCC. CR is theoretically defined as the absence of viable tumor cells. However, cCR does not equate to pCR or imply complete tumor eradication in clinical settings. A total of 28% of patients with rectal cancer who were managed with the watch-and-wait strategy after achieving cCR following nCRT experienced recurrence during a median follow-up of 2.6 years.[21] We found that the recurrence rate within 3 years was high, at 69.2%, for patients managed with the watch-and-wait strategy and achieved cCR after conversion therapy.[30] Furthermore, 4%–8% of the patients with rectal cancer who achieve pCR after nCRT experience recurrence and metastasis within 5 years.[20] In our study, nearly 30% of the patients with HCC who achieved pCR after conversion therapy developed intrahepatic recurrence and extrahepatic metastasis within 5 years.[30] Therefore, residual disease must be identified and patients at a high risk of recurrence must be distinguished from those who achieve CR for successfully implementing the watch-and-wait strategy in HCC. Residual disease after cCR may result in tumor recurrence, leading to failure of the watch-and-wait strategy. Minimal residual disease or molecular residual disease (MRD) testing involves the use of highly sensitive molecular techniques for detecting subclinical malignant cells after definitive treatment.[50] The biomarkers commonly used for detecting MRD include cell-free DNA, circulating tumor DNA, circulating methylated DNA, circulating tumor cells, circulating RNA, tumor-derived exosomes, and tumor-associated proteins.[50–55] Additionally, tumor-naive and tumor-informed next-generation sequencing (NGS) approaches and whole-genome sequencing have been employed to detect MRD.[52,53] MRD positivity is associated with an elevated risk of relapse and often guides treatment intensification, whereas MRD negativity supports therapeutic de-escalation, offering considerable clinical benefit.[50,56–58] The MRD status serves as a valuable biomarker in patients with rectal cancer who achieve cCR following nCRT, which guides subsequent treatment strategies.[53] Organ-preserving strategies may be inappropriate for patients who are MRD positive after treatment, for whom a more intensive surveillance protocol during watch-and-wait management should be considered. However, limited data are available regarding the role of MRD in guiding HCC management. We hypothesized, based on our experience with MRD in other malignancies, that the presence of MRD warrants cautious evaluation before implementing a watch-and-wait strategy in patients with HCC who achieve cCR after conversion therapy. Conversely, a watch-and-wait strategy may be considered for people who are MRD negative. Furthermore, MRD must be continuously monitored for the early detection of relapse and guiding timely therapeutic interventions. However, further high-quality real-world studies and prospective randomized controlled trials are needed to determine the role of MRD in the application of watch-and-wait strategies for uHCC. 6. Conclusions The watch-and-wait strategy, despite certain challenges, shows promise for managing patients with initial uHCC who achieve CR after conversion therapy. Moreover, MRD may serve as a valuable biomarker for guiding the use of watch-and-wait strategies in managing HCC.