Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P40 ppsx

23 The Future: Combination Systemic Therapy for Hepatocellular Carcinoma 375 Fig. 23.1 Computed tomography images of the abdomen using four-phase imaging technique. Patient is a 59-year-old woman with right lobar moderately differentiated HCC, treated with right hepatectomy, and found to have a recurrence per her liver remnant a year later with serum AFP above 16,000 ng/mL. Top figure shows baseline CT with a restaging image after 16 weeks of treatment withbevacizumab and erlotinib; it shows decreased tumor size, increased central necrosis indicating anti-tumor effect. Bottom figure shows serum AFP level sharply declining to normal level after 16 weeks of treatment of this combination in patients with HCC. Ten patients achieved a partial response for a confirmed overall response rate (intent-to-treat) of 25% (sorafenib = 2.7%). The median progression-free survival (PFS) was 39 weeks (95% CI, 26–45 weeks; 9.0 months) (sorafenib 5.5 months), and the median overall survival was 68 weeks (95% CI, 48–78 weeks; 15.6 months) (sorafenib 10.7 months) (Fig. 23.1). 376 A.O. Kaseb and M.B. Thomas Table 23.3 Selected clinical trials of systemic therapy combinations in patients with advanced HCC Study Regimen Phase Sample size Response rate% Median survival (mos) Pastorelli et al. [41] Pegylated adriamycin + gemcitabine II 35 23 8.8 mos Thomas et al. [42] Bevacizumab + erlotinib II 40 20.6 15.6 (PFS 9 mos) Sun et al. [43] Capecitabine + oxaliplatin + bevacizumab II 30 11 PFS 5.4 mos Zhu et al. [44] GEMOX + bevacizumab II 33 20 9.6 mos Louafi et al. [45] GEMOX + cetuximab 243 23 9.2 O’Neil et al. [46] Capecitabine + oxaliplatin + cetuximab 2 25 11 TTP 4.3 Abou-Alfa et al. [47] Doxorubicin + sorafenib vs doxorubicin 2 47/49 4 vs 2 13.8 vs 6.5 Hsu et al. [48] Capecitabine + bevacizumab 234 (CLIP≤3) 98.2 Shen et al. [49] Sorafenib + UFT (Tegafur/Uracil) 2 24 12 PFS 3.7 Several targeted agents have been recently tested in patients with advanced HCC in combination with other systemic therapies (see Table 23.3)[41–49]. Current Challenges to Combination Systemic Therapy in HCC Management Perhaps the most significant recent advance in oncology therapeutics has been the approval of various “molecularly targeted” anti-cancer drugs, including antiangio- genic agents, either alone or in combination. However, clinical development of such drugs suffers from several handicaps, including a lack of effective ways to choose patients who are likely to respond, and monitoring the biologic activity as measured by tumor response. Traditional systemic chemotherapies target mitotic events in proliferating cells. By exploiting the growth fraction differential between tumor cells and those of nor- mal cells, tumor reduction might be eventually achieved. Furthermore, resistance to systemic chemotherapies may emerge as a result of tumor cellular changes, such as gene mutations, increased gene expression regulating drug efflux pumps, or down- regulation of mutations in drug targets [50]. Notably, resistance mechanisms are 23 The Future: Combination Systemic Therapy for Hepatocellular Carcinoma 377 often specific to the drug or drug class. Therefore, when using a multiagent regi- men, the emergence of resistance to one agent might not apply to others. One of the major challenges in this clinical setting is to develop a mechanism to discern sensitivity to the individual components of a treatment regimen once progression occurs, which may aid in reserving drugs for which there remains sensitivity for fur- ther use. Unlike the mutational mechanisms that underlie resistance with systemic chemotherapies, resistance to targeted agents probably emerges via the activation of alternate pathways involved with hepatocarcinogenesis. Several mechanisms of resistance to antiangiogenesis therapy in HCC have been proposed, including sig- naling via alternative pathways, an increase in pericytes of the tumor neovessels that could reduce VEGF dependency, and activation and recruitment of bone-marrow- derived proangiogenic cells [51]. Thus, resistance to targeted agents may be related to activation of existing processes, rather than genetic mutations. Another area of challenge is assessing response to targeted therapy combinations. For many years, the s tandard way to assess a patient’s response to treatment has been to measure tumor size on longitudinal computed tomography ( CT) or magnetic resonance imaging (MRI) scans, using bidimensional (World Health Organization [WHO]) or unidimensional (response evaluation criteria for solid tumor [RECIST]) criteria. However, because targeted agents inhibit molecular components of cellu- lar proliferation and angiogenesis and thus abrogate tumor growth, they are more likely to delay disease progression and stabilize tumor size. This might explain the observed survival benefit despite the low incidence of objective responses as defined by RECIST criteria. Indeed, there is a potential for a transient increase in tumor volume or bidimensional area, the traditional endpoint for the determination of efficacy in clinical trials and in clinical practice. In clinical trials, even transient progression in tumor size is an indication to remove a patient from a study and consider the investigational agent of no benefit. Thus, the long-term effects may never be seen. Therefore, development of surrogate endpoints, either circulating or image-based, to evaluate any possible efficacy became a major challenge for clinical investigators developing targeted agents and for clinicians treating patients under treatment with targeted agents either alone or in combination with other systemic therapies. Changes in tumor microvasculature, as measured by changes in blood flow and volume and transit time, have been recommended as standards for describ- ing the kinetics of a given dynamic or functional imaging modality in antiangiogenic studies. However, these observations will need to be validated prospectively. Clinical Trial Design for Combination Systemic Therapy in HCC As noted previously, the availability in the clinic of several novel biologic agents and the urgent need for effective therapies for advanced hepatocellular carcinoma has led to the evaluation of many of these agents in HCC, principally in Phase II trials. The SHARP trial is the first to demonstrate a statistically significant survival benefit for any chemotherapy agent in patients with HCC. This trial was, however, conducted 378 A.O. Kaseb and M.B. Thomas in patients with excellent performance status and well-preserved ( Childs A) liver function. The efficacy and safety of sorafenib in patients with poorer performance status and more advanced hepatic dysfunction is yet to be established. Assessment of patient safety and tolerance is essential to combination therapy trials in HCC given the prevalence of hepatic dysfunction in this population. This can be accomplished by conducting separate Phase I (dose-escalation) trials or combination Phase I–II trials. A key objective going forward is to continue assessing new biologic agents in combination with sorafenib, across the broad spectrum of HCC patients seen in the community. The traditional approach in oncology research has been to evaluate new agents in single-arm Phase II studies using classic radiological response criteria such as WHO or RECIST [52–55] as a measure of anti-tumor activity. A “favorable” rate of radiographic response would be considered a biologic signal that supports tran- sitioning promising agents forward into randomized, controlled Phase III clinical trials. This approach, however, is being questioned since traditional radiographic tumor shrinkage is uncommon with biologic agents, although they clearly lead to meaningful patient benefit in a wide variety of malignancies [56]. This is clearly the case in HCC where radiological assessment is notoriously difficult due to poor delineation of tumors in the liver and tumor necrosis may occur without any change in overall tumor dimensions [57]. These observations have led some investigators to develop Phase II studies with a major focus on correlative studies that may help delineate a mechanism of action for a particular drug (e.g., a kinase inhibitor along one of the different cell cycle pathways) such as downregulation of a downstream kinase which may predict response or by using novel radiological techniques that use changes in blood flow as criteria by which to assess biologic activity of antian- giogenic therapies [58–61]. Another option i s to use the randomized Phase II trial design that by providing a contemporary control group may permit a more con- fident assessment of the likelihood that a particular agent is worthy to progress to Phase III [62–64]. Clinical trials are costly, time consuming, and use precious patient resources, and there is inevitable tension between designing trials based on empirically combining agents based on “rational” targets vs the longer process of first developing preclinical data that support combinations, which may or may not be confirmed in human trials. Key considerations in the planning and design of clinical trials of combination agents in HCC include as follows: • There is no lack of new agents to study in HCC. • Nearly all major carcinogenic mechanisms are “candidates” for targeted therapy in HCC. • It is critical to avoid “shotgun” approach of doing Phase II studies of every new available agent, in the absence of preclinical supporting evidence. • Conduct rational, evidenced-based drug selection. and preclinical “target valida- tion” if possible. • Combination regimens must be both efficacious and safe in HCC patients, especially in those with hepatic dysfunction. 23 The Future: Combination Systemic Therapy for Hepatocellular Carcinoma 379 • Patient selection in Phase II clinical trials can be challenging due to lack of consistent definition of what constitutes “advanced disease.” • Assessing clinically meaningful anti-cancer activity. Currently the RECIST cri- teria used to evaluate changes in unidimensional tumor size are inadequate to capture changes in tumor vascularity commonly seen with biologic agents in HCC. Future clinical trials should include validated functional imaging techniques to truly capture the anti-tumor activity targeted agents. Conclusions Conducting controlled clinical trials of systemic chemotherapy regimens in HCC patients is challenging. Obstacles include the multiple comorbidities of patients with cirrhosis, the intrinsic chemo-resistance of HCC, the advanced nature of HCC at presentation in a majority of patients, patients selection, lack of biomarkers, both circulating and image-based, to response or resistance to therapy, pharmacothera- peutic challenges of treating a cancer that arises in an already-damaged liver, and the distribution of the majority of patients primarily in developing nations where multi-disciplinary treatment of HCC may not be available. 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McMasters and Jean-Nicolas Vauthey Keywords HCC · Hepatic resection · Salvage therapy HCC · HCC Recurrence · Molecular markers Introduction Although liver transplantation has become a viable option for treatment of many patients with hepatocellular carcinoma (HCC), the limited availability of donor organs and the strict criteria for organ transplantation limit the use of transplantation for this disease. Hepatic resection remains the gold standard nontransplant treatment modality and is still the first-line treatment in many centers. For patients with unre- sectable disease, radiofrequency ablation and other ablative techniques are often now used with curative intent for patients with limited hepatic disease amenable to such strategies. Although advances in surgical technique and perioperative care have reduced operative mortality for patients with HCC dramatically, and several series have reported a 40–50% 5-year survival rate after resection for HCC, recurrence is the rule rather than the exception, and many patients succumb to this disease even after surviving 5 years. Recurrence after liver resection has been reported in the range of 75–100% in several series. Indeed, the first site of recurrence is most com- monly the liver in 78–96% of cases, either as a result of intrahepatic metastasis or as a multicentric disease arising in the liver remnant [1]. Recurrence after ablation also remains exceedingly high. Poon et al. [2] performed a systematic review of the English literature from 1980 until 1999 to evaluate risk factors associated with recurrence after resection for HCC. The authors found that pathologic factors that were significant in predict- ing tumor recurrence included vascular invasion, presence of satellite nodules, large tumor size (especially >5 cm), and advanced TNM stage; active hepatitis also was a K.M. McMasters (B) Department of Surgery, University of Louisville, Louisville, KY, USA 383 K.M. McMasters, J N. Vauthey (eds.), Hepatocellular Carcinoma, DOI 10.1007/978-1-60327-522-4_24, C  Springer Science+Business Media, LLC 2011 384 K.M. McMasters and J N. Vauthey significant factor predisposing patients to recurrence. Other pathologic factors such as tumor encapsulation, histologic differentiation, and DNA ploidy have not been shown to predict recurrence consistently. Molecular markers such as proliferating cell nuclear antigen (PCNA), telomerase activity, and various angiogenesis markers may also predict recurrence. Whether cirrhosis is a predictor of recurrence is also controversial. In terms of surgical factors affecting r ecurrence of HCC, certainly resection margins, intraoperative blood loss, and perioperative transfusion have been associated with a higher risk of postoperative recurrence. The number of tumors is also a predictor of recurrence-free survival. Unfortunately, to date, there are no proven effective adjuvant therapies to reduce the risk of recurrence after r esection or ablation. Given the high-risk of recurrence after resection or ablation for HCC and the potential for salvage therapy, careful postoperative surveillance is warranted. Follow-Up After Resection or Ablation for HCC Although many centers use slightly different surveillance strategies after resec- tion or ablation for HCC, all utilize a combination of tumor markers and imaging studies. The liver is the most common site of metastatic or recurrent disease; com- mon sites of extrahepatic disease, in order of prevalence, include lung, abdominal lymph nodes, bone, and adrenal gland. The United States National Comprehensive Cancer Network (NCCN) recommends high-quality cross-sectional imaging every 3–6 months for 2 years, then annually [3]. This can include multi-slice triple phase CT scanning or magnetic resonance imaging (MRI). In many centers around the world, however, ultrasound is used as the principal imaging modality for follow-up, although its sensitivity is somewhat less for detection of recurrence. Alpha-fetoprotein (AFP) levels, if initially elevated, should be checked every 3 months for 2 years, then every 6 months thereafter. The role of other tumor mark- ers, such as des-gamma carboxyprothrombin (DCP), AFP-L3, glypican-3, IGF-1, and HGF, remains unclear in this setting. Because pulmonary metastasis is the most common site of extrahepatic metastatic disease for HCC, chest x-ray or CT scan of the chest should also be evaluated at regular intervals. A bone scan for patients with symptoms of bone metastases is also warranted, but is not generally ordered routinely for surveillance. Salvage Therapy for Patients with Hepatic Recurrence of HCC Treatment modalities for patients with hepatic recurrence of HCC include liver transplantation, repeat resection, ablation, intra-arterial therapy, and systemic ther- apy. Transarterial chemoembolization (TACE) and intra-arterial drug-eluting bead therapy are discussed in Chapters 19 and 20, respectively; little is known about the use of these modalities for patients with recurrent HCC in the liver. Similarly, the . Karapanagiotou LM, Pandha H et al (2008) Targeted therapy for advanced renal cell cancer: cytokines and beyond. Curr Pharm Des 14:2229–2251 28. Rini BI, Flaherty K (2008) Clinical effect and future considerations. fluo- rouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342 23 The Future: Combination Systemic Therapy for Hepatocellular Carcinoma 381 34. Fernando NH, Hurwitz HI (2004) Targeted. ablation, intra-arterial therapy, and systemic ther- apy. Transarterial chemoembolization (TACE) and intra-arterial drug-eluting bead therapy are discussed in Chapters 19 and 20, respectively; little