Society of Surgical Oncology. Official publication of the Society of Surgical Oncology. In this issue:

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1 2006 Annual Cancer Symposium Symposia Highlights SSO Society of Surgical Oncology Official publication of the Society of Surgical Oncology In this issue: What s New in Ablative Therapies for Malignant Tumors? Multidisciplinary Management of Colorectal Cancer Metastases: Current and Emerging Trends Presorted Standard US Postage PAID St. Croix Press

2 SSO Society of Surgical Oncology Chair, Scientific Progam Heidi Nelson, MD Publisher Joseph J. Dennis Manager: Sales & Publications Gayle L. Miller Medical Writer Walter Jones Art Director Laurie Morgan-Ross 2006 Annual Cancer Symposium Symposia Highlights The 2006 Annual Cancer Symposium Symposia Highlights is published jointly by Medical Association Communications 2288 Second Street Pike Wrightstown, Pennsylvania and the Society of Surgical Oncology, Inc. 85 W. Algonquin Road, Suite 550 Arlington Heights, IL Medical Association Communications and the Society of Surgical Oncology, Inc. No content may be reproduced in any form without prior written permission of the publisher. The opinions expressed in this publication are those of the speakers and do not necessarily reflect the opinions or recommendations of their affiliated institutions, the publisher, the Society of Surgical Oncology, Inc., or any other persons. Some articles in this publication may discuss unapproved or off-label uses of products. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients conditions and of possible contraindications or dangers in use, review of any applicable manufacturers product information, and comparison with the recommendations of other authorities. 1 5 In this issue: What s New in Ablative Therapies for Malignant Tumors? Multidisciplinary Management of Colorectal Cancer Metastases: Current and Emerging Trends

3 SSO Symposia Highlights What s New in Ablative Therapies for Malignant Tumors? Energy-based ablation technologies are of keen interest to surgical oncologists for multiple reasons. In some instances, their ability to cause tumor debulking increases eligibility for potentially curative surgery. In other instances, ablation may be a useful treatment for unresectable tumors or for patients with recurrent malignancies who refuse additional surgery. Ablation may also provide effective palliation of pain in patients whose pain is refractory to standard therapies including radiation, or who cannot tolerate chronic exposure to opioids. Ablative techniques, especially radiofrequency ablation and cryoablation, have been evaluated in a number of clinical settings including primary and metastatic liver cancers, nonsmall-cell and metastatic lung cancers, osteoid malignancies, and renal cancers amenable to nephron-sparing procedures. Microwave ablation, although in its infancy, has shown some evidence of clinical efficacy. For all of these techniques, the accuracy of probe guidance via preoperative and intraoperative imaging is critical to clinical outcomes. Three-dimensional ultrasound, magnetic resonance imaging, robot-assisted probe guidance, and elastography all show promise for improving accuracy and, potentially, of significantly impacting survival. These issues were discussed in detail at the 2006 Annual Meeting of the Society of Surgical Oncology. This symposium was supported by an unrestricted educational grant from Valleylab. Radiofrequency Ablation of Hepatic Malignancies: An Update Although hepatic resection is the only curative option for hepatic malignancies, many patients are considered unresectable because of the size, number, and/or location of the tumor(s), bilobar disease, and/or inadequate hepatic reserve. Such patients may be candidates for tumor ablation. In patients undergoing cryosurgery for unresectable hepatic malignancies in the 1980s and early 1990s, the median 5-year survival approached that of resection, but the procedure was associated with high morbidity and mortality. The newer technique of radiofrequency ablation (RFA) is significantly safer. This utilizes an insulated probe guided directly into the tumor in a controlled manner to induce protein denaturation at 45 C, thermal coagulation (70 ), and ultimately tissue desiccation (100 C) whether conducted in an open abdomen, by laparoscope, or percutaneously. Anton J. Bilchik, MD, PhD of the John Wayne Cancer Institute (JWCI) opened the program by evaluating the effectiveness of RFA as local treatment for unresectable hepatic malignancies. In ten series reported between 1996 and 2005, the mean local recurrence rate was approximately 10%. However, these series consisted of a mixture of older and new technologies, the three technical approaches, and types of tumor. Additionally, follow-up was generally brief, recurrence was poorly defined, and imaging was inconsistent. A study of the JWCI experience from 1997 to 2005 reported an overall recurrence rate of 24% after a median follow-up of 33 months among 181 patients who underwent RFA for 521 tumors. The overall rate consisted of 17.8% for tumors 3 cm or less in diameter, and 28% for larger tumors (Amersi FF et al. Arch Surg. 2006;141: 527). The effectiveness of RFA is influenced by the evolution of technology. For example, in a smaller JWCI study (N=114) comparing outcomes in patients treated by older and new technologies and followed for a median of 26 months, newer imaging techniques were associated with significantly Anton J. Bilchik, MD, PhD fewer margin recurrences and longer disease-free survival (Ahmad MM et al. Amer Surgeon. 2006; in press). At present, three-dimensional ultrasound imaging appears to optimize the placement of the RFA probe and PET imaging provides the most sensitive and accurate method for evaluating local recurrence. An important issue in determining the efficacy of RFA is whether the technique used or the biology of the patient s disease is the more influential in predicting local recurrence. A univariate analysis of data from the large JWCI study previously cited revealed that number of lesions, tumor size, and type of malignancy were all independent indicators of local recurrence. Interestingly, when the same data were submitted to multivariate analysis, tumor size (greater or less than 3 cm) and type of procedure were significant predictors of local recurrence. While the difference between recurrence rates for patients undergoing laparoscopic treatment or laparotomy was not significant, the rate for percutaneous RFA was significantly greater than that for open surgery (p=0.005). The difference is explained by improved accuracy in both identifying and targeting tumors by using a combination of preoperative imaging and intraoperative ultrasound. The latter technique identifies between 15% and 30% of metastases not seen by preoperative imaging. Although RFA is relatively safe, complication rates averaging approximately 10% (range 0-63%) with 1.2% mortality have been reported, with the highest complications rates associated with percutaneous treatment. The rate was 13% in the JWCI series. Postoperative hepatic abscess is the most common complication overall, and the most common in open surgical treatment. Other complications include biliary and thermal injury. Does RFA improve survival? The 1

4 What s New in Ablative Therapies for Malignant Tumors? benchmark for evaluating survival is a combination of two factors: historical data on survival following cryoablation (Litvak DA et al. Ann Surg Oncol. 2002; 9:148) and survival following medical treatment with oxaliplatin-based chemotherapy (Goldberg RM et al. J Clin Oncol. 2004;22:4). In each of these, the median survival was 20 months for patients with unresectable hepatic metastases from colorectal cancer. Studies published thus far on patients treated only with RFA indicate consistent one-year survival approaching a mean of 90% and 2-year survival ranging from 56% to 89%. Three-year survival data are less abundant, but the rates that have been reported to range from 34% to 60% despite a high frequency of hepatic relapse. A retrospective study comparing RFA, RFA plus resection, and chemotherapy alone concluded that survival following RFA only is significantly greater than with chemotherapy alone (Abdalla EK et al. Ann Surg. 2004;239: 818). The survival data for patients undergoing RFA for unresectable hepatocellular carcinoma are more mature than those for metastatic disease. Three large studies with a total enrollment of 1,060 patients have reported median 1-year, 3-year, and 5-year survival rates averaging 90%, 73%, and 52%, respectively. In addition, RFA has been demonstrated to be an effective bridge to transplantation for patients with hepatocellular carcinoma. In a series of 52 patients, all pretreated with percutaneous RFA, 42 patients received transplanted livers without recurrence of malignant disease at 14.9 months. The 3-year survival rate was reported at 76% (Lu D et al. Hepatology. 2005;41:1130). Survival rates associated with RFA do not compare favorably with hepatic resection in patients with metastatic colorectal disease or hepatocellular carcinoma. Abdalla and colleagues have reported significantly superior survival in patients who underwent partial hepatectomy compared with those treated with RFA (p< ), a result that was confirmed by a JWCI study (p<0.006) (Abdalla EK et al. op. cit.; 2004; Ahmad MM et al. SSO, 2006). The data are somewhat less compelling in the setting of hepatocellular carcinoma. In a study of 123 patients with comorbid cirrhosis, 1-year survival rates were comparable, but 2-year survival was significantly better in the group with hepatic resection (p=0.002) (Vivarelli M et al. Ann Surg. 2004;240:102). In contrast, in a study of comparable size that enrolled patients with comorbid hepatitis virus B or C, there were no significant differences in 1-year and 2-year survival between the two treatment groups (Hong SN et al. J Clin Gastroenterol. 2005; 39:247). A review of 560 studies comparing RFA with alternative treatments concluded that additional retrospective efforts are not likely to provide further guidance on treatment options (Seidenfeld J et al. J Amer Coll Surg. 2002;195: 378). Prospective, randomized trials are thus needed to resolve some of the unanswered questions. One such trial, which recruited 142 patients with hepatocellular carcinoma, compared RFA with percutaneous ethanol ablation. There was a significantly lower local recurrence rate and longer recurrence-free survival in the RFA cohort, but overall 2- year survival in the two groups was comparable (Lencioni R. Radiol. 2003; 228:235). In a study of 180 patients randomized in equal numbers to receive either hepatic resection or percutaneous RFA for solitary hepatocellular malignancies of less than 5cm in diameter, overall survival and disease-free survival were virtually identical in the two groups Microwave Ablation: The Next Modality Despite the many advantages of RFA, it is not without disadvantages. Most important among these are that (i) it is time-consuming, (ii) recurrence rates remain high, (iii) and its performance near blood vessels is poor because they act as tumor-protective heat sinks. An alternative approach involves the replacement of radiofrequency waves with electromagnetic energy (non-ionizing radiation) delivered by microwave antennae that require no grounding. David M. Mahvi, MD (University of Wisconsin) cited the potential advantages of MWA as a basis for its further development. The apparent advantages of MWA are several. First, the field of power distribution is not limited to the probe 4 years after treatment. Thirty-eight percent of patients in the RFA trial arm required two or three procedures to achieve complete tumor necrosis (Chen MS et al. Ann Surg. 2006;243:321). The most ambitious Phase III trial in a setting of unresectable hepatic metastases of colorectal cancer compares percutaneous RFA with or without resection in combination with oxaliplatin-based chemotherapy alone. This CLOCC (Chemotherapy and Local Ablation vs. Chemotherapy) trial is powered to detect a 37% increase in overall survival between the two trial arms (N=390). Accrual problems and the unavailability of bevacizumab in the United Kingdom have limited the enrollment to date to approximately 100 patients. Dr. Bilchik concluded from the available data that RFA is an effective local treatment, particularly for hepatocellular carcinoma, when performed by laparoscopic and open procedures that include intraoperative ultrasound. Improved techniques are resulting in decreased local recurrence rates, but they remain higher than in study populations undergoing partial hepatectomy. The standard of care continues to be hepatic resection in eligible patients, even though hepatectomy has never been evaluated by a randomized, prospective Phase III study. area itself, but extends about 2.5 cm in all directions. Second, multiple probes can be used simultaneously. Third, the effectiveness of treatment appears not to be diminished by blood flow, an advantage over RFA in the vicinity of vessels. Fourth, very high temperatures can be achieved quickly without charring the liver. The principal disadvantage of MWA is that its high temperature and field of distribution may induce tissue necrosis beyond the tumor, and may even cause wide-area thermal injury. Efficacy data on MWA in hepatic disease are sparse, and there is no clinical evidence to date suggesting its superiority over hepatic resection or RFA. 2

5 SSO Symposia Highlights Data are limited largely to three small retrospective case studies. In one, dysplastic nodules in 30 patients with cirrhosis were ablated without recurrence (Liang P et al. Amer J Rentgenol. 2005; 184:1657). Another study reported a local recurrence rate of 12% in 93 patients undergoing MWA for unresectable lesions, with complication rates similar to those observed with RFA (Lu MD et al. J Gastroenterol. 2005;40: 1054). Finally, in study (N=447) involving patients with unresectable hepatocellular carcinoma, 35% of patients had local recurrence (Liang P et al. Radiol. 2005;235:299). Further engineering development of MWA systems and validation in Phase II trials are required before MWA can be considered a competitive clinical option. Ablative Approaches to Pulmonary, Renal, and Bone Tumors Robert C. G. Martin, II, MD from the University of Louisville Division of Surgical Oncology reviewed clinical evidence regarding the efficacy of ablative therapy in sites other than the liver. The use of RFA for treating pulmonary lesions was first reported in The theoretical basis for promoting RFA in pulmonary malignancies is that cytoreduction by ablation may create an opportunity for the improved effectiveness of chemotherapy and/or radiotherapy, which currently have a combined 5-year survival rate of only 15%. In primary lung cancers the indications for RFA are (i) early-stage lesions that are unresectable because of cardiopulmonary comorbidities, (ii) limited local recurrence in individuals who refuse additional surgery, and (iii) palliation for pain control. In cases of pulmonary metastasis, the principal indication for RFA is small-volume disease. In both primary and metastatic disease, RFA is limited to solitary spherical tumors of 3 cm or less in diameter that are not contiguous with the hilum, a large airway, or a pulmonary artery or vein. The Radiofrequency Ablation of Pulmonary TUmors Response Evaluation (RAPTURE) Trial is the richest source of data on the efficacy and safety of RFA in non-small-cell lung cancer (NSCLC) and pulmonary metastases. It was a prospective single-arm trial involving 107 patients who had not previously undergone pneumonectomy and who had three or fewer lung tumors with diameters of 3.5 cm or less. The overall complication rate in RAPTURE was 20% consisting of 12% and 26%, respectively, for patients with NSCLC and colorectal metastases. By far the most common complication was pneumothorax. The 2-year survival rate among patients with metastatic cancer was 62% compared with 48% among individuals with NSCLC. Median survival rates were 21 months (NSCLC) and 27 months (metastatic disease). These cancer-specific survival outcomes support the use of RFA for NSCLC or colorectal metastases in patients who are unable to tolerate resection (Lencioni R. Radiological Society of North America, 2005). A recent single-institution trial involved 19 patients (14 with metastatic cancer) with a total of 49 identified lesions. Forty-five percent of lesions required only one application, and an intra-procedural pneumothorax prevented the completion of only one of 27 sessions. Manageable postoperative pneumothorax and pleural effusion were the most common complications. Tumor sizes were reduced by approximately 33% to 55%. The investigators concluded that RFA is safe and feasible for the treatment of malignant thoracic tumors (Iguchi T et al. J Vasc Intervent Radiol.2006;17:184). However, Dr. Martin cautioned, the procedure remains palliative rather than curative. An increase of 60% in the incidence of renal carcinoma in the last 15 years has prompted investigation of nephronsparing techniques, a search that has been aided by the increased use of CT scan. Both open and laparoscopic partial nephrectomies have been found efficacious, and energy-based ablation techniques have subsequently been investigated as alternatives for use in individuals ineligible for more invasive methods. Treatment considerations for any type of nephron-sparing operation include number and size (4 cm or less) of lesions, Robert C. G. Martin, II, MD extent of tumor involvement, and proximity to major hilar vessels. Laparoscopic cryoablation aided by intraoperative ultrasound or magnetic resonance imaging (MRI) is generally easier to control in the kidney than RFA. Seven series of renal cryoablation, mostly by laparoscopy, have been reported totaling 326 patients. With a median followup of 30.8 months, the persistence/ recurrence rate is 4.6%. The morbidity rate of 10.8% is slightly higher than for laparoscopic partial nephrectomy. In seven studies of renal RFA, the persistence/recurrence (7.9%) and morbidity (13.9%) rates are higher than in the cryoablation studies after a median follow-up of only 10 months. Although both of these techniques appear to be promising alternatives to partial nephrectomy, long-term follow-up is needed to assess them accurately. In the United States, between 50% and 70% of all people diagnosed with cancer eventually experience skeletal metastases. As new surgical techniques and chemotherapy regimens extend their lives, these patients pose a growing treatment challenge. Current methods of treatment (radiotherapy, surgery, hormone therapy, bisphosphonates, chemotherapy, and opioids) are characterized by limited success and unacceptable side effects with accompanying deterioration in quality of life. The initial small trial (N=16) of RFA in bone metastasis reported significant decreases in the visual analogue pain scale following treatment for all lesions except large pelvic and sacro-iliac tumors 3

6 What s New in Ablative Therapies for Malignant Tumors? (Dupuy DE et al. Radiol. 1998;209 (suppl):389). Four years later a study of 12 patients treated with RFA reported significant pain reduction in single metastases ranging from 1 cm to 11 cm refractory to chemoradiation (Callstrom MR et al. Radiology. 2002;24:87). In a multicenter international trial involving 43 patients with documented bone metastases with pain refractory to standard treatments including radiation, RFA was focused on the area of greatest pain and the interface of bone and tumor. During 24 weeks of follow-up in which patients took analgesics, the Brief Pain Inventory indicated a 95% clinically significant decrease in pain (Goetz MP et al. J Clin Oncol. 2004;22:300). These data indicate that RFA is safe and effective in the palliation of painful bone metastases that have failed standard treatments. Where Do We Go From Here? Improving Targeting and Monitoring of Ablative Therapy If ablative techniques are to have a significant impact on survival, they must either achieve complete tumor necrosis or induce sufficient cytoreduction to improve symptoms or prolong survival. Although statistics indicate considerable progress some areas, ablation often fails. According to Michael A. Choti, MD (Johns Hopkins Medical Institutions), the dominant reasons for failure are (i) tumor protection in heat sinks, (ii) unpredictability of ablation size and shape, (iii) location, (iv) difficulty in probe guidance, (v) imprecise intraoperative monitoring of the ablation zone, and (vi) difficulty documenting adequate margins. In order to overcome these barriers, five avenues of improvement must be pursued, two of them clinical and three of them engineering challenges. Identifying the appropriate indications Selecting patients for ablative techniques is based on clinical observations and oncologic judgment as to appropriate organs, tumor types, tumor sizes, location, patient characteristics, and the extent of systemic disease. All of these need continued refining along with the definitions of resectability and ablatability. Individualizing the best approach Operative, laparoscopic, and percutaneous techniques have individual advantages and disadvantages, and the one that suits one patient or organ, tumor type, or location may not suit another. Currently, most RFA in the United States is done percutaneously despite evidence that, in some disease types, this is associated with higher recurrence rates than open or laparoscopic approaches. Better guidelines are needed for choosing among techniques for individual patients and sites of disease. Improving the devices and technology There is evidence that improved technology correlates with improved clinical outcomes in certain tumor types. Both the biological and engineering parameters for these variations require better understanding. Whether the method of destruction uses radiofrequency, microwave, cryotherapy, or some other method, device performance is being improved regularly. Questions still remain, however. What is the best energy-based technology? How do we compare device efficiency using relevant clinical parameters? Assisted probe guidance Clinical evidence indicates a correlation between the accuracy of probe guidance and clinical results in ablation studies. It is probable that one reason for the improved efficacy of RFA with small tumors is that probe guidance requires less precision. When tumors are larger, more precision is required, including at times multiple overlapping ablation zones. Studies are currently in progress developing improved methods of probe targeting using real-time ultrasound and intraoperative MRI, in some cases using computer-assisted robot technologies (Boctor EM et al. Computer Aided Surg. 2004; 9:175). A study using three-dimensional ultrasound determined that with lesser guidance technologies, probe placement may be unacceptable in as much as 45% of cases (Rose SC et al. J Vasc Intervent Radiol. 2002; Michael A. Choti, MD 13: 1060). Further development in this direction, including in the area of planning and visualization software, is essential to the future role of ablative technologies. Improved real-time ablation monitoring and quality control Imprecise monitoring of ablation and difficulty in documenting adequate margins are major causes for failure in ablation. Current methods of monitoring include impedance changes, temperature measures, the appearance of microbubbles on ultrasound, and rarely magnetic resonance thermography. One monitoring method under investigation is strain imaging, or elastography, which relies on the principle that thermally ablated tissue becomes harder than normal liver tissue and that the image differences between compressed and uncompressed tissue can define the margin of ablation. Until recently, improving the size and speed of ablation were considered most important. In the future, however, the important parameters will be the capability to target, shape, monitor, and confirm ablative therapy. It is likely that with such advances, minimally invasive tumor destruction will increase the number of patients eligible for local therapy and, in some cases, may even replace tumor resection as the treatment of choice. 4

7 SSO Symposia Highlights Multidisciplinary Management of Colorectal Cancer Metastases: Current and Emerging Trends The criteria for hepatic resection in patients with metastatic colorectal cancer have been a subject of debate among surgical oncologists for more than 20 years. Although they have never been established definitively, in the era of ineffective chemotherapy for this disease the common recurring contraindications were extrahepatic involvement, four or more intrahepatic lesions, narrow surgical margins (<1 cm), a disease-free interval of less than 12 months, technical inability to achieve total resection, and elevated levels of carcinoembryonic antigen. With the introduction of oxaliplatinand irinotecan-based regimens with or without biologic agents, median survival and 5-year survival have improved significantly, and their cytoreductive activity has increased the proportion of resectable patients. With the aid of these agents and newer surgical techniques, many of the conventional contraindications, including extrahepatic involvement, need not always disqualify patients from hepatectomy. Only disease progression while undergoing chemotherapy and technical barriers to complete resection continue to contraindicate surgery. These and related matters were discussed in detail at The Annual Meeting of the Society of Surgical Oncology in March, This symposium was supported by an educational grant from sanofi-aventis US. Expanding the Criteria for Hepatic Resection: Are Old Criteria Obsolete? The criteria for hepatic resection have been evolving, albeit confusingly, since 1984, when a seminal study of 141 patients with metastatic colorectal cancer concluded that the presence of extrahepatic disease precludes 5-year survival (Adson MA et al. Arch Surg. 1984;119: 647). The first expanded criteria were published two years later from a smaller study (N=72) of similar patients. A multivariate data analysis suggested that hepatic resection should be undertaken only when there are fewer than four hepatic lesions, when no extrahepatic metastases are detected, and when a resection margin of at least 1 cm can be obtained, because there were few longterm survivors among patients who failed at least one criterion (Ekberg H et al. Br J Surg. 1986;73:727). The first large (N=859) multi-institutional study concluded that close surgical margins, the nodal stage of the primary colorectal cancer, the diseasefree interval, the level of circulating carcinoembryonic antigen (CEA), and the size of the largest hepatic metastasis all impact negatively on survival. However, when considered individually, none of these factors alone precluded long-term survival, suggesting that combinations of these prognostic factors might be more important in selecting patients for hepatic resection. Extrahepatic involvement or the presence of four or more metastases were still considered contraindications Michael D Angelica, MD (Registry of Hepatic Metastases. Surgery. 1988;103:278). Similarly, Cady and colleagues concluded from a study of 129 patients that a CEA level greater than 200 ng/ml or the presence of four or more metastatic nodules should rule out resection, as should the probability of achieving less than a 1 cm surgical margin (Cady B. Arch Surg. 1992;127: 561). Fong and Blumgart suggested a broader guideline in 1995: extrahepatic disease and inability to resect all hepatic disease are the only absolute contraindications to resection (Fong Y, Blumgart LH. Curr Prob Surg. 1995;32: 333). As the result of a thorough multivariate analysis of data from 1,001 patients, however, they refined their criteria. Extrahepatic metastatic disease plus positive margins plus a high clinical risk score should determine the appropriateness of hepatic resection. The clinical risk score was defined as the sum of five prognostic factors, all of which are determinable before surgery: nodal status of the primary colorectal malignancy, a disease-free interval of less than 12 months, the presence of more than one hepatic lesion, at least one liver tumor larger than 5 cm in diameter, and a CEA level greater than 200 ng/ml Table 1. Clinical Risk Score Predicts Survival After Resection, n = Survival Score 1-yr 3-yr 5-yr Median (mos) 0 93% 72% 60% % 66% 44% % 60% 40% % 42% 20% % 38% 25% % 27% 14% 22 Score 0, 1, or 2 resection Score 3, 4, or 5 "experimental adjuvant trials" 5

8 Multidisciplinary Management of Colorectal Cancer Metastases: Current and Emerging Trends (Fong Y et al. Ann Surg. 1999;230:309). Table 1 depicts the correlation between clinical risk score and both overall survival and median survival up to 5 years. Michael D Angelica, MD of the Memorial Sloan-Kettering Cancer Center (MSKCC) concluded from the foregoing data that the most common recurring contraindications are extrahepatic metastases, the presence of four or more legions, achievable margins of less than 1 cm, and inability to resect all hepatic tumors. He observed, however, that these are old criteria because they are based on data from the age of ineffective chemotherapy for colorectal cancer. The addition of oxaliplatin- and irinotecan-based regimens, biologic agents, and two-class combinations to options for treating metastatic colorectal cancer has resulted in significantly improved overall and median survival rates, both with and without surgery. Importantly, the improvements appear to apply even to patients with extrahepatic disease. In a large French study, patients were heavily treated before and after surgery and underwent additional surgical procedures for recurrences during a rigorous median follow-up of 99 months. Importantly, a multivariate analysis indicated that extrahepatic metastases were not an independent risk factor for poor survival; rather, the critical issue was the overall bulk of disease measured as number of tumors and not whether they were intrahepatic or extrahepatic (Elias D et al. Ann Surg Oncol. 2005;12:900). Similarly, data from an unpublished study conducted at MSKCC involving 1,120 patients, 136 of whom had simultaneous resection of extrahepatic metastases, observed significantly lower median survival (34 months vs. 47 months) and 5-year survival (26% vs. 39%) among individuals with extrahepatic involvement (p=0.01). The differences between patients with and without extrahepatic disease were not sufficient to preclude surgery for patients with limited extrahepatic disease. In this study, patients were also stratified by clinical risk score as applicable to liver disease. Although there were significant differences in 5-year and overall survival rates between patients with risk scores of 2 or below and those with higher scores, survival comparable to what originally encouraged hepatic resection for limited disease was found. Synchronous presentation with the primary malignancy, neoadjuvant chemotherapy, surgical margins, and the presence of local vs. distant extrahepatic disease were not associated with outcome. Three recent retrospective reviews have been conducted testing the old hypothesis that the presence of four or more metastases precludes long-term survival after hepatic resection. Median follow-up ranged from 27 to 32 months, and overall survival rates were reported in the range of 28% to 51%. The poorest outcome (5-year overall survival of 28%) was observed in a study that was heavily weighted with data from the era of older chemotherapy (Adam R et al. Ann Surg. 2004;240:1052). The most favorable outcome (5-year overall survival of 51%) occurred in a study that included data from , indicating a balance between older and newer preoperative chemotherapies (Pawlik TM et al. J Gastrointest Surg. 2006;10: 240). The yet-to-be-published Sloan- Kettering study reports a 5-year overall survival rate of 33% in 98 patients all treated preoperatively in the era of newer chemotherapy options. These data appear to indicate that the presence of four or more metastases need no longer be considered a contraindication of hepatic resection. All three of the preceding studies reported that disease progression during chemotherapy was an independent predictor of poor survival. In addition, in all three studies the recurrence rates were approximately 80% with a median time to recurrence of 10 to 12 months, suggesting that multiple courses of postoperative chemotherapy and multiple surgical procedures and/or ablations are probable. Thus, patients contemplating hepatic resection should be counseled that they may expect to be treated as if for a chronic disease. The importance of surgical margins as a predictor of outcomes remains unsettled. In a review of 1,019 patients treated at Memorial Sloan-Kettering from 1991 through 2003, margins correlated significantly in a univariate analysis with median survival when patients were divided into three groups: (i) those with margins of less than 1 mm the reference group (median survival 30 months), (ii) those with margins of 1 to 10 mm (median survival 42 months), and (iii) those with margins greater than 1 cm (median survival 55 months). When sub- jected to multivariate analysis, however, close margins ceased to be an indicator of survival, while wider margins greater than 1 cm retained significance as a predictor of outcome. A multicenter study based at the M. D. Anderson Cancer Center involving 557 patients observed markedly different results. Although patients with marginal involvement did poorly, with a precipitous decline in survival after 40 months, there were no significant differences between margin widths for negative margins (Pawlik TM et al. Ann Surg. 2005;241:715). Some historically accepted contraindications namely extrahepatic disease, the presence of four or more tumors, and close surgical margins are no longer strictly applicable. Despite these apparently contradictory findings, Dr. D Angelica concluded that margins do contribute to clinical outcomes, although the complex interrelation between tumor biology and surgical technique would be impossible to elucidate. Nevertheless, because of favorable survival rates among patients with close margins as contrasted with involved margins these patients should be considered candidates for hepatic resection. Dr. D Angelica concluded that the criteria for hepatic resection for patients with colorectal cancer metastases have never been well defined because of the limited ability to predict outcomes with standard clinicopathologic data. Improved chemotherapeutic options and innovative surgical techniques have expanded the criteria. Thus, some historically accepted contraindications namely extrahepatic disease, the presence of four or more tumors, and close surgical margins are no longer strictly applicable. Multiple tumors limited to the liver or necessarily close margins need not preclude resection if technically resectable. Highly selected patients with limited overall disease and extrahepatic involvement limited to one organ site should be considered for resection if they have not progressed on chemotherapy. 6

9 SSO Symposia Highlights Multimodal Therapy in Downstaging Hepatic Metastases and Improving Resectability The efficacy of new oncologic medications in reducing the overall disease burden in responding patients with colorectal cancer metastases is such that those agents have increased the number of resectable patients by as much as onethird. This was demonstrated in a study of 1,459 patients with metastatic disease in which 355 patients (23%) were resectable at presentation and an additional 138 patients (10%) were resectable as a result of preoperative chemotherapy. Moreover, although the survival benefit for patients who were resectable only after chemotherapy were less favorable than for those who were resectable on presentation, their survival rates were considerable at 3 years (52% vs. 66%), 5 years (33% vs.48%), and 10 years (23% vs. 30%) (Adam R et al. Ann Surg. 2004;240:644). From the surgical perspective, chemotherapy that effectively downsizes the bulk of disease increases not only the resectability rate, but the curative resection rate as well (Parikh AA. J Gastrointest Surg. 2003;7:1082), while allowing more conservative surgery and making it possible to tailor postoperative chemotherapy to avoid ineffective treatment of synchronous metastases (Allen PJ. J Gastrointest Surg. 2003;7:109). J. Nicholas Vauthey, MD (M. D. Anderson Cancer Center) cautioned, however, that there are limits to hepatic resectability. It was demonstrated recently that the complication rate is significantly lower in patients with future liver remnants of greater than 20% compared with those with smaller future remnants (12% vs. 50%; p<0.05) (Abdalla EK et al. Arch Surg. 2002;137:675). Furthermore, variations in intrahepatic distribution of liver volume may be problematic. Radiologic measurement techniques and a simple calculation determine the probable future remnant as a fraction of original total liver volume. If the result is less than 20%, percutaneous portal vein embolization may stimulate regeneration and optimize the size of the future remnant by 8% to 14% based on 15 populations studied. Nuclear medicine studies and monitoring studies of biliary excretion indicate that the increase in volume associated with portal vein embolization is accompanied by improved hepatic function as well. In Dr. Vauthey s series of 127 consecutive extended hepatectomies, 24% of patients required portal vein embolization with an overall morbidity rate of 31%, of which 19% were transient hepatic complications, and perioperative mortality rate of 0.8% (Vauthey JN et al. Ann Surg. 2004;239:722) compared with 6.2% in a reference study of patients undergoing extended hepatectomy without portal vein embolization (Melendez J et al. J Amer Coll Surg. 2001;192:47). From the surgical perspective, chemotherapy that effectively downsizes the bulk of disease increases not only the resectability rate, but the curative resection rate as well. For patients with single hepatic metastases of colorectal cancer, the recurrence rate is significantly less in resected patients than in those treated with radiofrequency ablation (5% vs. 37%; p<0.001), based on an M.D. Anderson Cancer Center study. In a subset of patients whose metastases were 3 cm or less in diameter, the local recurrence rate associated with resection was 3% compared with 31% for radiofrequency ablation (p=0.001). Patients who underwent resection also had a longer recurrencefree interval (p=0.02), and their 71% 5- year overall survival was significantly greater (p<0.001) than for patients treated with radiofrequency ablation (Aloia T. Arch Surg. 2006;141:460). Unpublished data on 243 patients appear to indicate that survival is maximized by a multimodality sequence of oxaliplatinor irinotecan-based chemotherapy followed by resection and the resumption of chemotherapy. Chemotherapy-related injury has been reported widely from previous studies of patients undergoing hepatectomy. For example, steatosis has been associated with significant morbidity and a trend toward higher mortality in patients, especially obese patients, who have undergone hepatectomy following chemotherapy (Kooby DA et al. J Gastrointest Surg. 2003;7:1034). Complications are increased in patients with steatohepatitis, a progressive fatty liver disease associated with fibrosis and cirrhosis, hepatocellular carcinoma, and impaired regeneration. The association of 5-fluorouracilbased chemotherapy regimens with an increased risk for steatosis is well documented. More recently an association has been reported between irinotecan and steatohepatitis. The risk of steatohepatitis was increased in patients with high body mass indices (BMI) (Fernandez FG et al. J Am Coll Surg. 2005;200:845). In an M. D. Anderson study, 20% of patients treated with irinotecan experienced steatohepatitis (p= vs. patients not treated). Importantly, chemotherapy-related steatohepatitis is associated with statistically significant increases in both 90-day mortality (15% vs. 2%; p=0.001) and death from liver failure (6% vs.1%; p=0.01) in patients undergoing hepatectomy (Vauthey JN et al. J Clin Oncol. 2006;24:2065). Consequently, irinotecan should be avoided in patients with high BMI or preexisting steatosis who are potential candidates for major hepatic resection. Oxaliplatin has been reported to cause sinusoidal dilation in as many as 78% of patients treated. The incidence was 20% (p= vs. patients with no chemotherapy) in a series studied at M. D. Anderson. Oxaliplatin is also associated with fibrosis and venous occlusion with prolonged exposure plus surgery, but there is no known association between oxaliplatin and steatosis (Rubbia-Brandt L et al. Ann Oncol. 2004;15:460). The combination of oxaliplatin, folinic acid, and 5-FU has been associated with splenomegaly. Morbidity is directly related to the number of cycles of chemotherapy (Karoui M et al. Ann Surg. 2006;243:1). 7

10 Multidisciplinary Management of Colorectal Cancer Metastases: Current and Emerging Trends A New Era in Colorectal Cancer Treatment: Agents that Work! Fluoropyrimidine-based regimes have rapidly been replaced as the agents of choice for treating colorectal cancer by oxaliplatin-based and irinotecanbased regimens as well as by biologic agents that target vascular endothelial growth factor (VEGF) or endothelial growth factor receptor (EGFR) for antineoangiogenesis. Of particular interest to hepatobiliary surgeons is a two-arm study in which first-line oxaliplatin-based treatment followed by one based on irinotecan more than doubled the number of patients whose hepatic metastases were downsized to resectability compared with patients treated in the reverse order (Tournigand C et al. J Clin Oncol. 2004;22:229). Lee S. Rosen, MD, a medical oncologist affiliated with the John Wayne Cancer Institute, turned quickly from the newer chemotherapeutic agents to the biologics. He noted that although they are thought to inhibit neoangiogenesis and, therefore, to deprive tumors of blood supply needed for cell division, there is a competing hypothesis: the increased efficacy of chemotherapeutic agents when used in combination with angiogenesis inhibitors may indicate that the latter improve circulation in the tumor microenvironment, thus increasing the access of cytotoxic substances to tumor cells. This may explain why bevacizumab, a humanized monoclonal antibody against VEGF, produces little single-agent benefit in colorectal cancer, but works well in combination with cytotoxic medications. Thus, in a large placebo-controlled study, the addition of bevacizumab to a regimen of irinotecan, 5-FU, and leucovorin resulted in significant increases in months of progression-free survival (p< ), median survival (p= ), clinical response (p=0.0036), and duration of response (p=0.0014) (Hurwitz H et al. N Engl J Med. 2004;350:2335). Similarly, in a study utilizing oxaliplatin in three combinations, the addition of bevacizumab improved response rates to all chemotherapeutic regimens (Hochster H et al. ASCO Abstr 3515). Although bevacizumab is relatively nontoxic, it was associated with a 1.5% rate of gastrointestinal perforation in a large placebo-controlled trial in patients with metastatic colorectal cancer (Hurwitz H et al op cit). Cetuximab, an anti-egfr agent, has been shown in EGFR-positive individuals who are refractory to irinotecan to improve Lee S. Rosen, MD partial response (p=0.0074) and time to progression (p<0.0001) (Cunningham D et al. ASCO Abstr 1012; Van Laethem JL et al. ASCO Abstr 1058). In EFGR-positive patients with metastatic colorectal cancer, the addition to cetuximab to an oxaliplatin-based regimen results in an overall response rate of approximately 80%. Adding both bevacizumab and cetuximab to irinotecan therapy confers no significantly different improvement. An important adverse affect of neoangiogenesis inhibitors is posterior and reversible leukoencephalopathy syndrome (PRES). The posterior circulation of the brain is less well supported by connective tissue than is the anterior portion. During treatment, changes in blood flow may occur with hypertension, leakage of fluid, and vasogenic edema. Stroke is a rare complication. Tailoring Chemotherapy in Metastatic Colorectal Cancer Using Molecular Profiling Robert Diasio, MD (University of Alabama at Birmingham) observed that molecular profiling has the potential for advancing the management of metastatic colorectal cancer by improving assessment of prognosis and by predicting individual responses to specific chemotherapy agents. Prognostic factors that are currently at the center of investigation are the loss of heterozygosity of chromosome 18Q, microsatellite instability (MSI), tumor growth factor- 1-R11 mutation (TGF 1-R11), thymidylate synthase, the methylation phenotype marker, and genes such as p53 and Ki- 67 that are important in tumor development. Predictive profiling is aimed at identifying probable responders and nonresponders to specific chemotherapeutic agents and individuals who are likely to experience toxicities. Dr. Diasio offered several examples of established genetic factors. Thymidylate synthase, which is critical for the action of 5-FU and its oral prodrug capecitabine, is predictive as well as prognostic. EGFR status is thought to be theoretically important in predicting the response to several of the new EGFR inhibitors. The status of multiple genes involved in the formation of covalent bonds with platinum in DNA may predict response to oxaliplatin. The 1A1 isotype of the uridine glucoronosyltransferase gene (UGT 1A1 ) is potentially valuable for predicting irinotecan toxicity and has recently been approved by the Food and Drug Administration (FDA) as a means of reducing toxicity from irinotecan. Reduced UGT 1A1 activity increases risk for severe toxicity including neutropenia. Several genes have been demonstrated to affect 5-FU metabolism. For example, dihydropyrimidine dehydrogenous (DPD) deficiency significantly reduces an individual s ability to metabolize 5-FU, thereby increasing the risk for toxicity similar to that of 5-FU overdose. Thymidine phosphorylase expression has been suggested to be potentially important in predicting response to the oral 5-FU prodrug capecitabine. The foregoing examples comprise a snapshot of the current status of pharmacogenetics and the use of genetic profiling to aid in the selection of oncologic agents in the treatment of colorectal cancer. Further studies are needed to clarify the value of these tests in the general oncology practice setting. 8

11 The Society of Surgical Oncology would like to thank the following companies for their support of this publication: sanofi-aventis US Valleylab

12 Mark you calendars now for the Society of Surgical Oncology s 60th Annual Cancer Symposium March 15 18, 2007 Marriott Wardman Park Hotel Washington, DC W A S H I N G T O N D C