Abstract Loco-regional therapies such as radiofrequency ablation and transarterial chemoembolization have been used in the treatment of hepatocellular carcinoma not suitable for resection and have proven to increase survival. To improve outcomes, it is important to identify patient populations who can be appropriately treated with these modalities. Keywords Hepatocellular carcinoma (HCC) • Radiofrequency ablation (RFA) • Transarterial chemoembolization (TACE) Introduction Worldwide, hepatocellular carcinoma (HCC) is the sixth most common cancer and third leading cause of cancer-related deaths [ 1 ]. Historically, the rates of HCC have been lower in the United States compared to other countries. However, the incidence in the US tripled between 1975 and 2005 [ 2 ]. Given current screening protocols of patients with known cirrhosis , HCC is now increasingly recognized at an early stage [ 3 ]. Still, most patients are diagnosed in late stages so that less than one-third of the patients are candidates for surgical treatments such as resection or liver transplantation [ 4 – 6 ]. For patients who do not qualify for resection or liver transplantation, loco-regional therapies such as transcatheter arterial chemoembolization (TACE) and thermal ablation are accepted treatments that prolong survival by eradicating or controlling tumor while preserving liver function [ 7 ]. Both techniques have limitations in treating HCC, with incomplete necrosis of tumor and subsequent tumor recurrence using TACE, and inadequate control of medium to large size HCC for both TACE and ablative therapy. T. G. Van Ha (*) Section of Cardiovascular Interventional Radiology, Department of Radiology , University of Chicago , MC 2026 5841 South Maryland Ave , Chicago , IL 60615 , USA e-mail: [email protected] 140 The Barcelona-Clinic Liver Cancer classifi cation groups patients into fi ve stages and allocates treatment according to their status [ 8 – 10 ]. Briefl y, very early stage refers to HCC with tumor <2 cm in diameter, and early stage refers to with single tumor =/>2 cm or up to three satellite nodules, each 1. Overall, the RFA patients had better survival than the TACE patients with the 3 year survival of 71 % and 59 % respectively (P = 0.001). Of the initial patient population, 167 pairs of patients with PS of 0 and 68 pairs with PS of 1 or greater were entered into propensity score matching analysis. For the PS 0 group, RFA had signifi cantly better survival then the TACE group. However, in the analysis of the PS 1 or greater propensity matched patients, there was no signifi cant difference in survival. 12 Which Is Better Local Therapy for HCC, RFA or TACE? 142 Table 12.1 Studies comparing RFA to TACE directly Studies HCC size RFA cohort (Number of patients) TACE cohort (Number of patients) Overall survival (%) RFA/ TACE Median TTP (months) RFA/ TACE Tumor regression % RFA/ TACE Hsu et al. [ 16 ] Within Milan Criteria 315 215 3 years: 72/63 Not given Not given 5 years: 55/43 (p = 0.048) Propensity Score analysis 101 101 3 years: 60/55 Not given Not given 5 years: 41/36 (p = 0.476) Kim et al. [ 17 ] <=2 cm 165 122 3 years: 27/18 100/95.9 86.7/75.4 5 years: 74.5/63.1 (p = 0.079) Liu et al. [ 18 ] Within Milan Criteria 424 282 3 years: 71/59 (p = 0.001) PS 0 319 197 77/63 (p = 0.006) PS >=1 105 85 38/47 (p = 0.812) PS ECOG Propensity score, TTP Time to progression T.G. Van Ha 143 One additional study [ 19 ], though not a comparative analysis, evaluated patients who were eligible for RFA but instead underwent TACE. The study retrospectively analyzed 114 patients, who would have qualifi ed for RFA, with HCC, the largest less than 5 cm in diameter up to three nodules who have undergone TACE as initial treatment. Many of these patients were treated when RFA was not readily available. The 1-, 3-, 5-year survival rates were 80 %, 43 %, and 23 % respectively, which the authors concluded as being comparable to historical rates of survival for RFA treated patients. Recommendations RFA has been shown to be effective in the treatment of HCC with tumor size /= 100,000 plt/mcL. For patients with multifocal tumors, within the Milan criteria but not suitable for transplantation, resection could be performed, but no defi nitive recommendation can be made at this point due to lack of prospective comparison with loco-regional therapies. Liver transplantation is considered fi rst line treatment option for patients within Milan criteria but not candidates for surgical resection. Loco-regional treatments can be considered if the waiting list exceeds 6 months, even though long term outcomes are uncertain due to level of available evidence. 12 Which Is Better Local Therapy for HCC, RFA or TACE? 144 According to the guidelines, local ablation is considered fi rst line treatment option for patients with early stage HCC who are not candidates for surgical resection . Percutaneous ethanol injection has been shown to be inferior to RFA in lesions larger than 2 cm and is associated with high recurrence rate in lesions larger than 3 cm. Therefore, RFA is preferred over PEI as an ablative technique [ 24 ], but PEI can be employed where use of RFA is not possible. Other ablative therapies including microwave ablation and cryoablation are being used but strong evidence is currently lacking. Though there are studies comparing RFA and surgical resection of small solitary HCC, the results are mixed and ablation could not be recommended as alternative therapy to hepatic resection . TACE is recommended as fi rst line treatment for intermediate stage HCC, more specifi cally, those with multinodular HCC but without cancer related symptoms, vascular invasion, or extrahepatic spread. Although there is a lack of defi nitive evidence, chemotherapeutic agents recommended are doxorubicin and cisplatin and that TACE can be repeated 3–4 times per year. To minimize affecting non-tumoral hepatic tissue in an attempt to preserve liver function, it is also recommended that superselective chemoembolization, i.e. treatment limited to tumoral feeder vessels and sparing vessels to normal liver, be used. Other Recommendations Similar to EASL recommendations, CEPO, an oncologist group of specialists who provide evidence based guidelines for clinicians in the province of Quebec, Canada, recommends that TACE be considered standard of practice for palliative treatment of HCC in eligible patients [ 25 ]. CEPO also states that DEB-TACE be considered an alternative and equivalent treatment to TACE. Bland embolization and radioembolization are not considered standard treatments for HCC currently by either group. Sorafenib, an oral agent, inhibitor of multi-tyrosine kinase, is the only systemic drug that has shown survival benefi t [ 26 ] and it is recommended for patients with well-preserved liver function (Child-Pugh A) and with advanced HCC, or tumors progressing on loco-regional therapies. No recommendation can be made with sorafenib in Child-Pugh B patients at this point. Outside these recommendations, there are a few RCT favoring the use of TACE/ RFA combination therapy over RFA alone. In a meta-analysis [ 27 ] consisting of 7 RCTs that included 571 patients who were treated with TACE and RFA or RFA alone, found that there was a signifi cant differences in the 1- and 3-year survival rates favoring the combination group. Recurrence free survival at 1 and 3-year also favors the combination group. In a more recent publication, a meta-analysis consisting of 12 studies and 1952 patients comparing clinical outcome of small HCC among the various treatment, divided the study group into two different cohorts [ 28 ]. One arm consisted of patients receiving surgical resection and the other arm patients undergoing nonsurgical loco-regional treatment or treatments including RFA , PEI, TACE, and T.G. Van Ha 145 TACE plus RFA combination. The results showed that there were no signifi cant survival advantage at 1 and 3 year, but the 5 year survival rate favored the surgical resection group. However, no signifi cant difference was noted in the 1 or 5 year progression free survival. In addition, there was a signifi cant decrease in the incidence of adverse events in the surgical resection group and the local recurrence rate was signifi cantly higher in the non-surgical group. The authors acknowledged that the number of trials of non-surgical ablation to be insuffi cient and that the number of cases undergoing PEI and TACE were also insuffi cient to compare the nonsurgical modalities to each other. This publication illustrates the lack of suffi cient evidence to suggest one non-surgical technique over another in the treatment of small HCC. As seen above, there are only a few head to head studies of RFA vs. TACE and no RCT. However, due to available evidence, there are recommendations that for tumors that are non- resectable , RFA should be performed if the tumors are in early stages or smaller than 3 cm, and for intermediate tumors, TACE should be used as palliative treatment. From the few studies directly comparing the two treatment techniques above, it appears that for the patients within Milan criteria, there is survival advantage for patients undergoing RFA over TACE. However in one study this advantage is no longer seen in the propensity score model and is seen in only in the ECOG PS 0 group and not the PS 1 or greater group. For the study involving tumors less than 2 cm, there was no difference in overall survival though there was a difference in tumor response rate. However, in this study the results were not straightforward as there was signifi cant crossover in terms of subsequent treatments [ 18 ]. What these studies suggest is that RFA is superior in survival advantage for patients with good performance status. Additionally, RFA appears to be more effective in terms of tumor response rate in early HCC and total tumor volume of less than 11 cm 3 . TACE, though recommended as palliative therapy, should be considered in patients with tumors who might not qualify for RFA otherwise, due to contraindications, such as central tumors close to large bile duct s, or tumors adjacent to other organs [ 16 – 18 ]. Another treatment gaining acceptance in the treatment of HCC is combination therapy, TACE followed by RFA . This therapy makes use of the synergistic effect of TACE, which blocks blood fl ow the tumor and can extend the ablated area when followed by RFA soon after, among other potential effects. A Personal View of the Data For small tumors, RFA appears to be effective in achieving complete response. However, for tumors approaching 5 cm, the response rate and survival rate advantage diminish. With tumors 5 cm or larger, RFA results are rather poor and therefore TACE should really be used for palliation. When tumors qualify for possible RFA but due to contraindication to thermal ablation, TACE is a reasonable alternative. Combination of TACE followed by RFA appears to increase the effectiveness of 12 Which Is Better Local Therapy for HCC, RFA or TACE? 146 RFA over RFA alone and this treatment might very well be recommended in the future for intermediate size HCC if RCT can substantiate the preliminary results. Recommendations Loco-regional therapy is for patients who are not eligible for surgical resection and who are on transplant list with wait time longer than 6 months. For patients with very early and no contraindication to RFA , • RFA should be fi rst line treatment. • If RFA not possible, consider TACE as a reasonable alternative. For patients with early HCC (within Milan) • RFA if possible. • Consider TACE/ RFA combination if largest lesion approaching 5 cm to increase tumor response rate. • TACE if RFA not possible. References 1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917. 2. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27(9):1485–91. 3. CDC. Hepatocellular carcinoma—United States, 2001–2006. MMWR 2010. 59(17): 517–20. Reported by O’Connor S and Ward JW. 4. Bruix J, Sherman M. Management of heptocellular carcinoma: an update. AASLD practice guideline. Hepatology. 2011;53(3):1020–2. 5. Former A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245–55. 6. McGlynn KA, London WT. The global epidemiology of hepatocellular carcinoma: present and future. Clin Liver Dis. 2011;15:223–43, vii–x. 7. Llovet JM, Lencioni R, Di Bisceglie AM, et al. EASL-EORTC Clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43. 8. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classifi – cation. Semin Liver Dis. 1999;19:329–38. 9. Llovet JM, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transplant. 2004;10(Supp):S115–20. 10. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2. 11. Lencioni R. Loco-regional treatment of hepatocellular carcinoma. Hepatology. 2010;52:762–73. 12. Liang P, Wang Y, Yu X, Dong B. Malignant liver tumors: treatment with percutaneous microwave ablation—complications among cohort of 1136 patients. Radiology. 2009;251:933–40. T.G. Van Ha 147 13. Georgiades CS, Hong K, Geschwind J. Radiofrequency ablation and chemoembolization for hepatocellular carcinoma. Cancer J. 2008;14:17–122. 14. Llovet JM, Real MI, Montana X, et al. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet. 2002;359:1734–9. 15. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial Lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35:1164–71. 16. Hsu C, Huang Y, Chiou Y, et al. Comparison of radiofrequency ablation and transarterial chemoembolization for hepatocellular carcinoma within the Milan criteria: a propensity score analysis. Liver Transpl. 2011;17:556–66. 17. Kim JW, Kim JH, Sung K, et al. Transarterial chemoembolization vs. radiofrequency ablation for the treatment of single hepatocellular carcinoma 2 cm or smaller. Am J Gastroenterol. 2014;109:1234–40. 18. Liu P, Lee Y, Hsu C, et al. Survival advantage of radiofrequency ablation over transarterial chemoembolization for patients with hepatocellular carcinoma and good performance status within the Milan criteria. Am Surg Oncol. 2014;21(12):3835–43. 19. Liem M, Poon R, Lo C, Tso W, Fan S. Outcome of transarterial chemoembolization in patients with inoperable hepatocellular carcinoma eligible for radiofrequency ablation. World J Gastroenterol. 2005;11:4465–71. 20. Lu DS, Raman SS, Limanond P, et al. Infl uence of large peritumoral vessels on outcome of radiofrequency ablation of liver tumors. J Vasc Interv Radiol. 2003;14:1267–74. 21. Kapoor BS, Hunter DW. Injection of subphrenic saline during radiofrequency ablation to minimize diaphragmatic injury. Cardiovasc Interv Radiol. 2003;26:302–4. 22. Raman SS, Aziz D, Chang X, et al. Minimizing diaphragmatic injury during radiofrequency ablation: effi cacy of intraabdominal carbon dioxide insuffl ation. Am J Roentgenol. 2004;183:197–200. 23. Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology. 2004;127 Suppl 1:S179–88. 24. Bouza C, Lopez-Cuadrado T, Alcazar R, Saz-Parkinson Z, Amate JM. Meta-analysis of percutaneous radiofrequency ablation versus ethanol injection in hepatocellular carcinoma. BMC Gastroenterol. 2009;9:31. 25. Boily G, Villeneuve J, Lacoursiere L, et al. Transarterial embolization therapies for the treatment of hepatocellular carcinoma: CEPO review and clinical recommendations. Int HepatolPancreat- Biliary Assoc. 2014;17:52–65. 26. Llovet JM, Ricci S, Mazzaferro V, et al. SHARP investigators study group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90. 27. Liu Z, Goa F, Yang G, et al. Combination of radiofrequency ablation with transarterial chemoembolization for hepatocellular carcinoma: an up-to-date meta-analysis. Tumor Biol. 2014;35:7407–13. 28. Dong W, Zhang T, Wang Z, Liu H. Clinical outcome of small hepatocellular carcino © Springer International Publishing Switzerland 2016 149 J.M. Millis, J.B. Matthews (eds.), Diffi cult Decisions in Hepatobiliary and Pancreatic Surgery, Diffi cult Decisions in Surgery: An Evidence-Based Approach, DOI 10.1007/978-3-319-27365-5_13 Chapter 13 When Should Patients with Liver Metastases from Colorectal Cancer Receive Chemotherapy? Malini D. Sur and Eugene A. Choi Abstract Advances in hepatic resection techniques and cytotoxic therapy over the last 30 years have led to vast improvements in outcomes after hepatic resection in patients with colorectal liver metastases (CLM). Nonetheless, the optimal sequence of therapy for CLM remains a signifi cant clinical challenge. This chapter will summarize the evidence-based literature that pertains to the timing of chemotherapy in relation to surgery for CLM in the absence of extra-hepatic metastases. Keywords Colorectal liver metastases • Chemotherapy • Hepatectomy Introduction Hepatic metastases are the most common indication for liver resection in the United States [ 1 ]. For many aggressive primary cancers, there is no strong evidence to support surgery for secondary tumors in the liver. However, long-term survival after resection of colorectal liver metastases (CLM) in well-selected patients was observed as early as 1976 [ 2 ]. Signifi cant advances in both hepatic resection techniques and chemotherapeutic agents over the last 30 years have led to vast improvements in outcomes after hepatic resection in patients with CLM, with a median survival currently estimated at 3.6 years [ 3 ]. Nevertheless, the management of CLM remains challenging in part due to the debate about the optimal sequence of treatments. This chapter will review the evidence-based literature about the timing of chemotherapy in relation to surgery for CLM in the absence of extra-hepatic metastases. M. D. Sur Department of Surgery , University of Chicago Medicine , Chicago , IL , USA E. A. Choi (*) Department of Surgery , Baylor College of Medicine , One Baylor Place MS: BCM390 , Houston , TX 77030 , USA e-mail: [email protected] 150 Overall Risks and Benefi ts of Treatment Sequence Options Historically, patients with clearly resectable CLM were quickly taken to the operating room to avoid tumor progression spread and conversion to unresectable disease. Adjuvant therapy was proposed as a way to reduce the rate of early recurrences [ 4 ], but there were concerns that administering systemic chemotherapy prior to surgery might increase the rate of post-operative complications. These concerns were heightened as the hepatotoxic effects of standard chemotherapeutic agents used against colorectal cancer , 5-fl uorouracil, oxaliplatin, and irinotecan, were increasingly recognized [ 5 ]. Another disadvantage of upfront chemotherapy is signifi cant tumor response that would make planning liver surgery diffi cult. The desire to maximize the functional liver remnant must be balanced with the risk of leaving behind radiographically undetectable but microscopic residual disease that may be present within the tissue occupied by the original lesion [ 6 – 8 ]. By 2001, it became apparent that a proportion of patients with CLM initially deemed unresectable would respond to chemotherapy to become surgical candidates [ 9 ]. The principle that neoadjuvant chemotherapy could reduce the extent of necessary hepatic resection to remove all metastatic disease was applicable to patients with resectable but bulky CLM. Prioritizing the administration of chemotherapy in the setting of metastatic disease refl ects the desire to treat all disease (primary and metastatic) as quickly as possible. In addition, any occult or micrometastatic disease can be treated with chemotherapy. Although upfront chemotherapy delays surgery and might risk progression of disease, this approach may help select patients with favorable tumor biology for surgery. Those responding to treatment can undergo hepatectomy , while those with unfavorable tumor biology avoid high-risk surgery that is unlikely to be have signifi cant long-term benefi ts. Patients who undergo resection after chemotherapy might also benefi t from an increased likelihood of having margin negative resections [ 10 ]. Following surgery, an adjuvant chemotherapy regimen could be tailored to individual patients based on the pathologic response to the pre-operatively administered agent. Finally, neoadjuvant therapy avoids the risk of delays in systemic treatment after surgery due to postoperative complications that are frequent after major liver resection s. The effect of hepatotoxicity of neoadjuvant agents on post-operative complication rates has also been raised, as the extent of liver resection and need for blood transfusion may be more infl uential factors [ 11 ]. Table 13.1 summarizes the proposed advantages and disadvantages of adjuvant versus neoadjuvant chemotherapy for CLM. Search Strategy A literature search of English language publications from 2004 to 2014 was conducted to identify published data addressing the timing of chemotherapy administration in relation to liver surgery for patients with potentially resectable liver M.D. Sur and E.A. Choi 151 metastases from primary colorectal cancer . The PICO outline was used, as demonstrated in Table 13.2 . Databases searched were PubMed and Web of Science. Terms used in the search were “timing,” “ surgery ,” “chemotherapy,” AND “liver metastatic colorectal cancer ” OR “colorectal liver metastases.” References cited within the resulting articles were carefully reviewed and included if they met inclusion and exclusion criteria. Articles were included only if they compared adjuvant chemotherapy to surgery alone, perioperative chemotherapy to surgery alone, or adjuvant chemotherapy to perioperative chemotherapy. Articles were excluded if they primarily addressed chemotherapy for unresectable metastatic colorectal cancer , timing of colorectal Table 13.1 Proposed advantages and disadvantages of adjuvant versus neoadjuvant chemotherapy for colorectal liver metastases Adjuvant chemotherapy Neoadjuvant chemotherapy Proposed advantages Minimize risk of progression of resectable disease into disease that is unresectable or resectable with greater morbidity Prioritize treatment of systemic disease, treating potentially occult micrometastases Avoid risk of increased surgical morbidity due to hepatotoxic effects of cytotoxic agents Select patients with favorable tumor biology to undergo hepatectomy Optimize chances of resecting all disease by avoiding inadequate resection in areas of disappearing metastases Allow time for portal vein embolization if needed Increase rates of margin-negative resection Adjust adjuvant therapy regimen based on response to neoadjuvant agent Proposed disadvantages Post-operative complications may substantially delay administration of systemic therapy Risk progression of resectable disease into disease that is unresectable or resectable with greater morbidity Patients with unfavorable tumor biology may undergo major liver resection only to relapse very soon after Hepatotoxicity of cytotoxic agents may increase morbidity of major liver resections Table 13.2 PICO table for timing of chemotherapy for resectable colorectal liver metastases P (Patients) I (Intervention) C (Comparator) O (Outcomes) Patients with resectable colorectal liver metastases (a) Adjuvant chemotherapy (a) Surgery alone Progression-free survival, recurrence rate, recurrencefree survival, disease-free survival, overall survival, post-operative morbidity and mortality (b) Perioperative chemotherapy (b) Surgery alone (c) Neoadjuvant chemotherapy alone or perioperative chemotherapy (c) Surgery alone or adjuvant chemotherapy 13 When Should Patients with Liver Metastases from Colorectal Cancer Receive… 152 surgery in relation to liver surgery alone, early versus delayed liver surgery alone, management of extrahepatic metastases, management of recurrent liver metastases, use of radiation, use of liver-directed ablative therapies, use of hepatic arterial infusion (HAI), or use of targeted therapy. Retrospective studies featuring fewer than 100 patients were excluded, as were case reports, chapters, comments, and nonsystematic review papers. Review papers focusing on the timing of chemotherapy and surgery were included. Three randomized control trials (RCT), one pooled analysis, and three retrospective cohort studies were included in our fi nal analysis. The identifi ed literature was classifi ed using the GRADE system. Results No RCT has directly compared outcomes of CLM patients treated with adjuvant chemotherapy to those treated with perioperative chemotherapy. Our current understanding has therefore been largely shaped by trials comparing each modality to surgery alone as well as by cohort studies comparing the two modalities. While providing low-quality evidence, numerous single institution observational studies of patients undergoing a common sequence of treatments offer some additional insights. Table 13.3 summarizes the results of major studies comparing treatment options for CLM. Two major RCTs examined the benefi ts of adjuvant chemotherapy after marginnegative resection of up to four synchronous or metachronous CLM compared to resection alone. Both used an adjuvant regimen involving only bolus 5-fl uorouracil (5-FU) and leucovorin, which was standard at the time of enrollment. Unfortunately, this regimen is now known to be suboptimal compared to regimens combining 5-FU with oxaliplatin or irinotecan and therefore both studies have limited applicability today. Additionally, both trials were closed early and underpowered. The ENG (EORTC/NCIC-CTG/GVIVO) trial randomized 107 patients to fl uorouracil and leucovorin or observation after surgery for CLM but also included patients undergoing surgery for lung metastases [ 12 ]. Data initially presented in 2002 showed that patients who received adjuvant therapy tended to have longer recurrence-free survival (RFS) and overall survival (OS). However, the results lacked statistical signifi – cance and were not fully published. The FFCD ACHBTH AURC 9002 trial randomized 171 patients who had undergone R0 resections of CLM to surgery alone or adjuvant therapy with fl uorouracil and leucovorin as well [ 13 ]. No difference in 5-year OS was observed between the two groups, but the 5-year disease-free survival (DFS) rate was signifi cantly greater among patients receiving adjuvant chemotherapy. Mitry et al. performed a pooled analysis of data from both trials and showed no difference in median OS but did demonstrate a trend towards longer median progression-free survival (PFS) in the chemotherapy group (62.2 months) compared to the surgery only group (47.3 months) [ 14 ]. Based on these data, resection of CLM without plans of administering additional cytotoxic therapy was abandoned. M.D. Sur and E.A. Choi 153 Table 13.3 Studies comparing options for timing of chemotherapy for CLM Study author and year Study type Number of patients Outcome measures Arm 1 results Arm 2 results Statistics Quality of evidence Surgery alone vs. adjuvant chemotherapy Surgery alone Adjuvant chemotherapy Langer 2002 (EORTC/NCICCTG/GIVO trial) Randomized controlled trial 107 Median RFS 20 months 39 months p = 0.35 Low Median OS 43 months 53 months p=0.39 Portier 2006 (FFCD ACHBTH AURC 9002) Randomized controlled trial 171 5-year DFS 26.7 % 33.5 % OR = 0.66 [0.46–0.96], p = 0.028 Moderate 5-year OS 41.1 % 51.1 % OR = 0.73 [0.48–1.10], p = 0.13 Mitry 2008 Pooled analysis of 2 randomized trials 278 Median PFS 18.8 months 27.9 months HR = 1.32 [1.00–1.76], p = 0.058 Moderate Median OS 47.3 months 62.2 months HR = 1.32 [0.95–1.82], p = 0.095 Surgery alone vs. perioperative chemotherapy Surgery alone Perioperative chemotherapy Nordlinger 2008, 2013 (EORTC Intergroup Trial 40983) Randomized controlled trial 364 3-year PFS 29.9 % 39.0 % HR 0.78 [0.61–0.99], p = 0.035 Moderate 5-year OS 47.8 % 51.2 % p = 0.34 Median OS 54.3 months 61.3 months p = 0.34 Reversible complications 16 % 25 % p = 0.04 Surgery alone or adjuvant chemotherapy vs. neoadjuvant chemotherapy alone or perioperative chemotherapy Surgery alone or adjuvant chemotherapy Neoadjuvant chemotherapy alone or perioperative chemotherapy (continued) 13 When Should Patients with Liver Metastases from Colorectal Cancer Receive… 154 Table 13.3 (continued) Study author and year Study type Number of patients Outcome measures Arm 1 results Arm 2 results Statistics Quality of evidence Pawlik 2007 Retrospective cohort 212 Complications 30.5 % 35.3 % p = 0.79 Low 60-day mortality Scoggins 2009 Retrospective cohort 186 Median DFS 56 months 40 months p = 0.25 Low Median OS 65 months 56 months p = 0.30 Morbidity 47 % 49 % p = 0.81 90-day mortality 0.07 % 0 % p = 0.29 Pinto Marques 2012 Retrospective cohort with matched pair analysis and propensity score analysis 676 Morbidity after minor hepatectomy 16.5 % 17.9 % p = 0.72 Moderate Morbidity after major hepatectomy 14.2 % 23.1 % p = 0.06 5-year OS 55 % 43 % p = 0.009 410 (matchedpair analysis) Recurrence 41 % 51 % p = 0.03 5-year DFS 20 % 15 % p = 0.01 5-year OS 54 % 42 % p = 0.09 244 (propensity score analysis) Median OS 69.6 months 56.8 months p = 0.12 Scartozzi 2011 Retrospective cohort 104 Median OS 48 months 31 months p = 0.0358 Low Median PFS 25 months 16 months p = 0.031 Recurrence 52.5 % 75 % p = 0.0347 M.D. Sur and E.A. Choi 155 Study author and year Study type Number of patients Outcome measures Arm 1 results Arm 2 results Statistics Quality of evidence Spelt 2012 Retrospective cohort 233 Complications 63.2 % 62.9 % NS Low 90-day mortality 1.5 % 0 % NS Araujo 2013 Retrospective cohort 411 3-year OS 78 % 74 % p = 0.48 Low 5-year OS 60 % 56 % 3-year RFS 44 % 32 % p = 0.036; adjusting for CRS, p = 0.42 (low CRS), p = 0.74 (high CRS) 5-year RFS 38 % 31 % Complications 39 % 38.3 % p = 0.92 Zhu 2014 Retrospective cohort 466 5-year OS 48 % 52 % NS Low 30-day morbidity 25.8 % 33.9 % NS 30-day mortality 1.2 % 1.7 % NS RFS recurrence-free survival , DFS disease-free survival, PFS progression-free survival, OS overall survival , OR odds ratio, HR hazard ratio, NS non-signifi cant, CRS clinical risk score 13 When Should Patients with Liver Metastases from Colorectal Cancer Receive… 156 In 2008, the same year that Mitry et al. published results of the pooled analysis, Nordlinger et al. published initial data from the EORTC Intergroup 40983 trial [ 15 ]. Long-term results were presented in 2013 [ 16 ]. In this landmark study, 364 patients with up to four synchronous or metachronous CLM were randomly assigned to “perioperative” chemotherapy consisting of 6 cycles of neoadjuvant 5-FU, leucovorin, and oxaliplatin (FOLFOX4) combined with six cycles of adjuvant chemotherapy or to surgery alone. Patients who underwent resection following chemotherapy did have a signifi cantly higher rate of reversible postoperative complications (25 %). At 3 years, the rate of PFS among eligible patients was 39.0 % in those who received perioperative chemotherapy compared to 29.9 % in those who underwent surgery alone (p = 0.035). However, no signifi cant difference in OS was detected between the two groups, with mortality rates of 59 % of the perioperative chemotherapy group and 63 % of the surgery only group at a median follow-up of 8.5 years. A survival benefi t may not have been identifi ed because the study was underpowered to detect the predefi ned 5 % difference in 5-year OS or because only 63 % of the perioperative chemotherapy group went on to actually receive post-operative chemotherapy [ 17 ]. Although the study authors advocate for perioperative therapy based on the demonstrated improvement in PFS alone, others argue that the lack of a clear survival benefi t challenges the routine use of neoadjuvant chemotherapy [ 17 ]. Moreover, the trial compared perioperative chemotherapy to surgery alone as opposed to surgery with adjuvant chemotherapy, and newer therapeutic agents were not studied. The NSABP C-11 trial is a phase III RCT currently underway to investigate the difference in RFS between patients with resectable CLM receiving perioperative chemotherapy and those receiving adjuvant therapy alone. Patients who are oxaliplatin- naïve will receive FOLFOX and those who have been previously treated with oxaliplatin will receive 5-FU, leucovorin, and irinotecan (FOLFIRI). Randomization will be stratifi ed according to the number of liver metastases, the planned chemotherapy regimen, and whether the disease is synchronous or metachronous. The results of this study will hopefully add critical insight into the optimal timing of cytotoxic agents in relation to surgery for CLM. The precise role of targeted therapy for CLM will need to be addressed in further investigations. In the absence of additional data from RCTs, multidisciplinary decision-making about the treatment of CLM must rely on several relevant retrospective cohort studies published over the last 10 years. By design, these studies are inherently limited in their ability to control for all the clinicopathological variables that infl uence the choice of treatment modalities for individual patients, leading to a considerable risk of selection bias. For example, patients with signs of more aggressive disease may be more likely to be offered neoadjuvant therapy . Many of the retrospective reports are also based on relatively small numbers of patients and thus lack statistical power to detect signifi cant differences in long-term outcomes . Finally, most of these studies demonstrate signifi cant heterogeneity in the treatment protocols between the comparative arms. While the RCTs described above had a surgery alone arm, retrospective studies have generally compared patients who received neoadjuvant chemotherapy to those who did not. The latter group sometimes included patients who M.D. Sur and E.A. Choi 157 received adjuvant chemotherapy as well as those who did not. Multiple chemotherapeutic regimens, some consisting of targeted therapies, as well as local liver-directed therapies were sometimes included. Despite these weaknesses, it is valuable to review the major retrospective cohort studies comparing different therapeutic sequence options for CLM. In 2009, Reddy et al. published a multi-institutional analysis of outcomes of 499 patients with CLM stratifi ed into four groups based on the timing of chemotherapy that was ultimately delivered: pre- hepatectomy alone, post-hepatectomy alone, perioperative (i.e. preand post-hepatectomy), and none [ 18 ]. Not surprisingly, those treated with prehepatectomy chemotherapy were often associated with a larger number of liver tumor s, a node-positive primary tumor, a major hepatectomy, and ablation procedures in addition to resection . After controlling for factors refl ecting decisions to treat with upfront chemotherapy, multivariate analysis revealed that posthepatectomy chemotherapy was signifi cantly associated with RFS and OS but prehepatectomy chemotherapy was associated with no survival benefi t. Because outcomes in those treated with perioperative chemotherapy were similar to those in the post-hepatectomy chemotherapy alone group, the investigators argued that chemotherapy administered after liver resection had the strongest oncologic benefi t. The study was limited, however, by substantial variation in resectability criteria, resection techniques, choice of pre-operative imaging, and chemotherapeutic regimens across the participating institutions. In addition, given the retrospective nature, patients were grouped according to the chemotherapy schedule they ultimately received as opposed to the planned chemotherapy schedule. Patients treated with pre-hepatectomy chemotherapy who developed disease progression that precluded resection were not included. Four years later, Pinto Marques et al. performed the largest of the retrospective studies known to date and also attempted to control for confounding through matched pair and propensity score analyses [ 19 ]. Among their 676 study patients, those who received neoadjuvant chemotherapy were more likely to have a lymph node positive primary tumor, synchronous disease, and a greater number of liver metastases. When all patients were considered, post-operative complications were signifi cantly increased from 14.2 to 23.1 % with the addition of chemotherapy prior to major but not minor hepatectomy for CLM. Without controlling for baseline characteristics, 5-year OS was signifi cantly worse in the patients treated with neoadjuvant therapy compared to patients who did receive chemotherapy prior to surgery (43 % vs. 55 %). A 1:1 matched-pair analysis was then undertaken using 205 pairs of patients with similar pathological characteristics. This still revealed a signifi cantly higher rate of recurrence (51 % compared to 41 %, p = 0.03) and lower rate of 5-year DFS (15 % compared to 20 %, p = 0.01), but the difference in 5-year OS was not signifi cant. Acknowledging the limitations of matched-pair analyses, the authors performed a third analysis based on propensity score matching using 244 patients that again revealed no signifi cant difference in median OS. Thus, controlling for baseline characteristics demonstrated neither an advantage nor disadvantage in terms of long-term outcomes with the administration of pre-operative chemotherapy. 13 When Should Patients with Liver Metastases from Colorectal Cancer Receive… 158 In 2013, Araujo et al. published another notable retrospective study based on their experience with 411 patients undergoing resection of CLM [ 20 ]. Once again, patients who received perioperative chemotherapy had generally less favorable disease as evidenced by higher clinical risk scores (CRS). CRS was established in 1999 as a strong marker for recurrence risk after resection of CLM and is determined by summing the presence of each of the following factors: a node-positive primary tumor, a disease-free interval from primary tumor to appearance of liver metastases under 12 months, more than one metastasis, pre-operative carcinoembryonic antigen (CEA) level above 200 ng/ml, and largest tumor size above 5 cm [ 21 ]. Scores of 2 or less are classifi ed as low CRS while scores of 3 or greater are classifi ed high CRS. Furthermore, a large number of patients in the adjuvant group received HAI, which is not routinely used at many institutions. Nonetheless, the authors detected no signifi cant differences in the rates of post-operative complications, 3-year OS, or 5-year OS between patients who were treated with perioperative chemotherapy and those who received adjuvant therapy . Although a signifi cantly higher rate of 3- and 5-year RFS among patients treated with adjuvant chemotherapy alone was found on univariate analysis, this was not observed once adjustments were made for clinicopathological and clinical risk scores (CRS). Additional retrospective studies comparing outcomes between patients treated with and without neoadjuvant chemotherapy include investigations by Pawlik et al. Scoggins et al. Scartozzi et al. Spelt et al. and Zhu et al. [ 22 – 26 ]. Of these, all but one failed to detect major differences in post-operative morbidity and/or oncologic outcomes. Based on their analysis of 104 patients with CLM, Scartozzi et al. found a signifi cantly longer median OS in those who did not receive neoadjuvant FOLFOX (48 months vs. 31 months, p = 0.0358) [ 24 ]. However, patients treated with neoadjuvant chemotherapy more often had tumors larger than 5 cm and although CRS appeared similar in both groups, scores were only available in 69 % of patients. In addition, it was not clear if the neoadjuvant patients were also treated with adjuvant chemotherapy (i.e. a perioperative approach). Finally, data regarding surgical margins were not presented and could explain the poor survival among patients treated in the neoadjuvant setting, especially since the rate of recurrence was substantially higher in this group (75 % vs. 52.5 %, p = 0.0347). Additional Considerations There are three additional considerations that are important in determining the optimal timing of chemotherapy in relation to hepatectomy for CLM. First, CLM may present in a synchronous or metachronous fashion. In synchronous cases, surgery may need to be prioritized if the primary colorectal cancer is symptomatic. In the face of life-threatening bleeding or perforation, the risks of delaying surgery for the administration of neoadjuvant chemotherapy are increased and should be avoided. Obstructing cancers can be treated surgically, but endoscopic stent ing may theoretically allow symptom relief while reducing the time-delay to delivery of neoadjuvant M.D. Sur and E.A. Choi 159 chemotherapy. Although a combined colon and liver resection can be considered in stable symptomatic patients with easily resectable liver lesions, acutely ill patients should undergo the simplest operation that will treat the acute symptoms. In asymptomatic patients with synchronous disease, a decision must be made not only about the timing of chemotherapy but also about the timing of colorectal resection in relation to hepatectomy. There is evidence that the colorectal resection can be safely performed at the same time as the hepatectomy in well-selected patients [ 27 , 28 ]. For CLM presenting in a metachronous manner, the presence of a long disease-free interval and an easily resectable solitary metastasis may support a decision to pursue upfront hepatectomy followed by adjuvant chemotherapy. Second, although often grouped together in the discussion of CLM, colon cancer and rectal cancer have different treatment algorithms. The management of CLM in the setting of a rectal primary must account for local staging after assessment with endorectal ultrasound or pelvic magnetic resonance imaging . A patient with CLM in the setting of a locally advanced rectal cancer is an ideal candidate for upfront systemic chemotherapy , as the primary lesion will require neoadjuvant chemoradiation . A single- or two-stage resection may then be performed. In contrast, there is no clear role for neoadjuvant chemoradiation for primary colon cancers. Third, the extent and anticipated morbidity of the planned hepatectomy must be considered. Criteria for resectability have changed signifi cantly over time. Early in the surgical experience with CLM, bilobar disease was regarded as a contraindication to resection [ 4 ], but the current surgical paradigm classifi es as resectable any patient with CLM that can be technically removed with negative margins and an adequate functional liver remnant [ 29 ]. Assessment of pre-operative liver function should include a history focusing on alcohol intake and risk factors for hepatitis along with liver enzymes, bilirubin, prothrombin time, and platelet levels. Percutaneous biopsy may be performed for confi rmation of suspected chronic liver disease. Patients with pre-existing cirrhosis are poor candidates for resection of CLM. In general, upfront hepatectomy should be reserved for cases in which CLM can be completely resected with a minor liver resection and a low predicted risk of post-operative complications. When metastatic disease is technically resectable but requires a more extensive resection, portal vein embolization (PVE) of the lobe containing the bulk of the metastatic disease can be employed to encourage hypertrophy of the lobe that will remain after resection. Patients who require PVE are ideal candidates for neoadjuvant chemotherapy as hepatic regeneration occurs even as systematic cytotoxic agents are administered and complications do not appear to be increased [ 30 ]. However, in all patients receiving systemic therapy before surgery , the risk of post-operative liver failure after a major liver resection in the setting of potential chemotherapy-induced hepatotoxicity must be mitigated. 13 When Should Patients with Liver Metastases from Colorectal Cancer Receive… 160 Recommendations Based on the Data Given the limitations of the major relevant RCTs and retrospective studies, there is equipoise regarding the optimal timing of chemotherapy in relation to surgery for CLM. Nonetheless, a few general management recommendations can be made. First, in the absence of extrahepatic disease, patients with resectable colorectal liver metastases, if physiologically fi t, should be treated with both resection and chemotherapy (evidence quality moderate; strong recommendation). Second, in patients who present with synchronous colorectal liver metastases and a symptomatic primary tumor requiring surgery, surgery should not be delayed for the administration of neoadjuvant chemotherapy (evidence quality low; weak recommendation). Third, in patients who present with synchronous colorectal liver metastases and an asymptomatic primary tumor, administration of neoadjuvant chemotherapy should be strongly considered by a multidisciplinary team prior to a one-stage or two-stage resection (evidence quality low; weak recommendation). Proceeding directly to hepatectomy with a plan for adjuvant therapy only may be reasonable when there is a solitary, small liver metastasis that can be safely resected at the time of the colectomy and there is low clinical suspicion of occult disease. Fourth, in patients who present with metachronous colorectal liver metastases, administration of neoadjuvant chemotherapy should be strongly considered by a multidisciplinary team prior to hepatectomy (evidence quality low; weak recommendation). Proceeding directly to hepatectomy with a plan for adjuvant therapy only may be reasonable when there is a solitary, small liver metastasis that can be safely resected with a low risk of complications, when the disease-free interval is greater than 12 months, and there is low suspicion for additional occult disease. Finally, in patients who present with synchronous colorectal liver metastases and a locally advanced primary rectal cancer , administration of neoadjuvant chemotherapy targeting the liver should be strongly considered in conjunction with neoadjuvant chemoradiation for the pelvis (evidence quality low; weak recommendation). A Personal View of the Data Advances in liver resection techniques and anti- cancer drugs over the past 20 years have greatly improved the ability to treat patients with CLM. Although there is insuffi cient evidence to make strong generalizable recommendations for the timing of chemotherapy in relation to hepatectomy in these patients, it is clear that a multidisciplinary approach should be pursued including medical oncologists, radiation oncologists when appropriate, and surgeons experienced in surgical oncology, colorectal surgery , and hepatobiliary surgery . Patients with CLM who have a high suspicion of aggressive or occult disease are likely the best candidates for neoadjuvant chemotherapy. Such suspicion should arise in the presence of a large tumor burden, a short disease-free interval, and a high CEA level. Patients with small, M.D. Sur and E.A. Choi 161 solitary CLM without suspicion of occult disease may be considered for an upfront surgical approach. Results of the NSABP C-11 trial are eagerly awaited, and further investigations into the timing of targeted therapy with respect to surgery are warranted as well. In the absence of extrahepatic disease, patients with resectable colorectal liver metastases, if physiologically fi t, should be treated with both resection and chemotherapy . (evidence quality moderate; strong recommendation) In patients who present with synchronous colorectal liver metastases and a symptomatic primary tumor requiring surgery , surgery should not be delayed for the administration of neoadjuvant chemotherapy . (evidence quality low; weak recommendation) In patients who present with synchronous colorectal liver metastases and an asymptomatic primary tumor, administration of neoadjuvant chemotherapy should be strongly considered by a multidisciplinary team prior to a onestage or two-stage resection . Upfront surgery may be considered when there is a solitary, small liver metastasis that can be safely resected at the time of the colectomy and there is low suspicion for occult disease. (evidence quality low; weak recommendation) In patients who present with metachronous colorectal liver metastases, administration of neoadjuvant chemotherapy should be strongly considered by a multidisciplinary team prior to hepatectomy . Upfront surgery may be considered when there is a solitary, small liver metastasis that can be safely resected with a low risk of complications, when the disease-free interval is greater than 12 months, and there is low suspicion for occult disease. (evidence quality low; weak recommendation) In patients who present with synchronous colorectal liver metastases and a locally advanced primary rectal cancer , administration of neoadjuvant chemotherapy targeting the liver should be strongly considered in conjunction with neoadjuvant chemoradiation for the pelvis. 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