American Journal of Clinical Oncology:
Surgical Therapies in Metastatic Colorectal Cancer With a Potential for Cure
Chua, Terence C. BScMed (Hons), MBBS*†; Liauw, Winston MBBS, FRACP‡; Koong, Heng-Nung MBBS, FRCS (Ed)§; Esquivel, Jesus MD, FACS†
From the *Department of Surgery, St George Hospital, Sydney, Australia; †Department of Surgery, St Agnes Hospital, Baltimore, MD; ‡Department of Medical Oncology, St George Hospital, Sydney, Australia; and §Department of Surgical Oncology, Thoracic Surgery, National Cancer Centre, Singapore, Singapore.
Supported by St George Medical Research Foundation (to T.C.C.) for work on metastatic gastrointestinal cancers.
Dr. Terence Chua is a surgical oncology research scholar.
Reprints: Terence C. Chua, BScMed (Hons), MBBS, Department of Surgery, St George Hospital, University of New South Wales, Sydney, Australia. E-mail: email@example.com.
Metastatic colorectal cancer has evolved from a paradigm that was previously centered upon the use of systemic chemotherapy to one of multimodality therapy. Hepatectomy, pulmonary metastasectomy, and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy are surgical procedures that are now routinely performed in specialized institutions treating patients with metastatic colorectal cancer. Emerging evidence suggests that in selected patients, these procedures are safe and may be beneficial in contributing to long-term survival.
Colorectal cancer (CRC) continues to be a significant health problem in the world and it is estimated each year, in the United States; 148,810 men and women will be diagnosed, of which a third comprising of some 49,960 will die of CRC.1 Five-year relative survival rate calculated between periods 1996 and 2004 was 64.4%. In 1975, the 5-year relative survival rate was 50%.1 This improvement in survival is a result of primary preventative measures where greater awareness and advocacy for CRC screening has effectively allowed early detection and prevention through various therapeutic endoscopic procedures such as polypectomy, which reduced the incidence of advanced disease.2 Secondarily, chemotherapy advances with the introduction of oxaliplatin to the duo agents of fluorouracil and leucovorin, have improved the effectiveness of adjuvant therapy and is now regarded as the best available systemic chemotherapy.3 Lastly, the treatment of metastases has also improved. Within the medical armamentarium, systemic chemotherapy alone has evolved to include other novel targeted therapies, such as bevacizumab, cetuximab, and panitumumab. A combination of these novel systemic agents have been shown in randomized clinical trials of patients with metastatic colorectal cancer (mCRC) to result in median survival of up to 20 months4–9 compared with a survival of 6 to 8 months that has been historically associated with this group of patients.10–12 In addition, it has been shown that there are distinct incremental benefits of these diverse regimens on progression-free survival.13
In parallel with developments in the medical management of CRC, substantive advances have occurred with respect to the surgical management of metastases. Historically, the medical management of CRC and the surgical management of metastases have occurred separately and have fortuitously resulted in the advent of highly active chemotherapy and novel surgical treatments. When combined, it has the potential to become an effective anticancer treatment. This new era that we have been led towards requires medical and surgical oncologists to cooperate to achieve the best results for patients. An example is the emergence of the concept of neoadjuvant chemotherapy and adjuvant chemotherapy in relation to metastasectomy for hepatic disease where a multimodality approach combines expertise from medical management with systemic agents, surgical management with resection of metastases and/or radiologic interventions that administer direct targeted radiotherapy or chemotherapy to sites of CRC metastases.
To this end, several investigators have begun developing predictive tools based on prognostic factors for outcome prediction.14–17 These tools may in the future be applied clinically to select patients for these surgical therapies, allowing individuals to clarify their likely outcomes of each particular treatment option and allows the selection of the most appropriate choice to derive the maximal benefit. Therefore, it is of foremost interest in this developing field of oncosurgical management of mCRC that these surgical options be examined through a review of landmark studies to determine the clinical efficacy of these various aggressive surgical procedures employed in the treatment of patients with critical sites of CRC metastases in the liver, lung, and peritoneum.
COLORECTAL LIVER METASTASES
Colorectal liver metastases are observed in up to 25% of patients at the time of initial diagnosis.18,19 After primary colonic resection, 50% to 75% of patients will develop a recurrence in the liver within 3 years,20,21 hence making the liver the most common site of secondary disease in CRC. Spread of tumor in the liver occurs through hematogenous dissemination whereby tumor growth factors produces vascular endothelial growth factor that mediates subsequent generation of endothelial cells via the process of angiogenesis from pre-existing vessels.22 Through this process of tumor angiogenesis, malignant cells invade into microscopic vessels to become disseminated in the portal venous system of the gastrointestinal tract. They lodge within the liver sinusoids, which is the first draining organ, and forms a metastatic niche in this microenvironment that is suitable for tumor establishment.
In the 1970s to the 1990s, the treatment of liver metastases was largely based on cytotoxic treatment administered intravenously or directly into the liver parenchyma via the hepatic artery.23,24 The overall median survival following hepatic artery infusion was about 20 months.23,24 This treatment was superior to watchful waiting, where patients with untreated colorectal liver metastases had a median survival ranging between 6 and 12 months25 or a 5-year survival of 3%.26 However, during this time, long-term survival following hepatectomy for colorectal liver metastases had already been reported (first reported in the 1970s).27 Nonetheless, it was not embraced and remained controversial,28,29 despite insurmountable evidence that demonstrate the survival benefit of hepatectomy.30–33 It was not until the mid 1990s that this nihilistic attitude was overcome.
In the largest early report from one of the most established hepatobiliary units, the group at the Memorial Sloan Kettering Cancer Centre, which holds the largest published experience of hepatic surgery first reported a cohort of 456 consecutive liver resections who were treated between July 1985 and December 1991. In their experience, the authors report a perioperative mortality rate of 2.8%, a median survival of 46 months and a 5-year survival rate of 38%.34 Subsequently, an update of their experience in a larger cohort of 1001 patients reported similar 5-year survival result, with a 10-year survival rate of 22%. Factors that predicted a poor long-term outcome include positive margins, extrahepatic disease, node-positive primary, disease-free interval from primary to metastases of less than 12 months, more than 1 hepatic tumor, tumor size >5 cm, and carcinoembryonic antigen (CEA) >200 ng/mL.35 Following this, numerous liver surgery units worldwide have begun to offer hepatectomy to patients with colorectal liver metastases.
The increasing number of hepatobiliary surgeons offering this procedure together with further clinical investigations rapidly expanded the criteria of resectability. In patients in whom diseases were deemed unresectable, administration of neoadjuvant chemotherapy allowed the down-staging of liver metastases to allow a feasible liver resection that achieved a 5-year survival of 40%.36 This combined treatment has been shown to be equally effective without compromising the overall survival,36 hence the number of metastases in the liver is unlikely to be relevant if an eventual liver resection can be performed after neoadjuvant chemotherapy. Other strategies that have also been shown to be useful in improving resectability and eradication of metastases include portal vein embolization to induce hypertrophy of the uninvolved segments to increase the remnant liver volume37,38 and combining liver resection with ablative techniques, such as cryotherapy39,40 or radiofrequency ablation41,42 to treat involved surgical margins or residual lesions in patients with bilobar disease for which achieves comparable or reasonable survival outcomes. Technically challenging resections have also been performed safely following better surgical techniques and perioperative care with radical liver resections, such as an extended hepatectomy with vascular resection and/or reconstruction, allowing resection of larger tumors and multiple metastases successfully with 5-year survival ranging between 25% and 40%.43–45 It may also be technically possible to perform a 2-stage hepatectomy for extremely challenging situations where there are bilobar and multiple metastases when it is impossible to resect all lesions within a single procedure.46 Further, there are also reports that a 5-year survival of up to 51.3% is achievable after undergoing simultaneous and sequential lung and liver metastasectomy for the treatment liver metastases and extrahepatic disease.47–50 In our institution, we have an experience of 16 patients who were treated aggressively with cytoreductive surgery (CRS) including hepatectomy and perioperative intraperitoneal chemotherapy for peritoneal and liver metastases from CRC with a 2-year survival of 58%.51
A review summarizing the survival outcomes following liver resection of colorectal liver metastases from an extensive body of literature comprising of 529 clinical series of which 30 were included for a systematic analysis reported a mortality rate from liver resection to be low (median 2.8%) with the only serious postoperative complications being bile leak and perihepatic abscesses. The 5-year survival was estimated to be 30% following an R0 resection with a disease-free survival ranging between 11.6 and 17 months (median, 14.3 months).52
The description of prognostic factors by Fong et al35 has assisted in the selection of patients for liver resection. Today, in the practice of liver resection for colorectal liver metastases, expert consensus from the American Hepato-Pancreato-Biliary Association recommend; liver resection be performed to the extent of preserving 2 contiguous hepatic segments, adequate vascular in- and outflow, biliary drainage, and adequate future liver remnant (>20% in a healthy liver), the presence of extrahepatic disease is not an absolute contraindication provided patients are carefully selected and a complete metastasectomy of both intra- and extrahepatic metastases is feasible, and lastly, although a margin of 1 cm is a target when performing a liver resection, not being able to achieve 1 cm margins should nonetheless not constitute an exclusion criterion for resection.53 To maximize the survival outcomes following liver resection, consensus recommendations from an expert group of 21 surgeons and medical oncologist at the Sixth International Colorectal Liver Metastases Workshop54 made recommendations for the perioperative (neoadjuvant and adjuvant) use of systemic chemotherapy even in patients with both resectable and unresectable liver metastases based on the data from the EORTC-EPOC (European Organization for Research and Treatment of Cancer-Eloxatin for Peri-Operative Use) trial where an increase in 9.2% for progression-free survival at 3 years was derived through the use of perioperative chemotherapy with surgery.55 Although the use of neoadjuvant chemotherapy in patients with resectable liver metastases may present with a slightly increased risk of postoperative morbidity and mortality from chemotherapy induced liver injury,56,57 it has been shown in a study by Adam et al,58 which complete pathologic responders had superior survival outcomes with 5-year overall survival of 76% and a 5-year disease-free survival of 76%. Therefore, the use of chemotherapy prior to liver resection may serve to test the chemoresponsiveness of metastases to guide subsequent treatment after resection, eliminate micrometastatic disease, and improve the rate of complete resection through down-sizing of the metastasis. Therefore, integration of these multimodality therapies will likely lay the grounds for curative liver resections to be performed in patients with colorectal liver metastases for which is now regarded as the standard of care.59,60
COLORECTAL LUNG METASTASES
Lung metastases are often an indication of widespread hematogenous dissemination of cancer resulting in systemic and uncontrolled disease with a connotation of a poor clinical outcome. Despite this, pulmonary resection for metastatic disease has been carried out way back in the early 1900s, with reports of cases with a good outcome. Arguably, one of the earliest series of pulmonary resection for colorectal lung metastases was from the Memorial Sloan-Kettering Cancer Centre in the 1970s, where 35 patients were operated over an 18-year period, with a reported cumulative 5-year survival rate of 22% and a survival advantage that was observed in patients with Dukes' A or B tumors.61 Clearly, lung metastases, though a manifestation of systemic disease, may still be remediated with an aggressive surgical approach. The same authors reproached this controversial issue again by retrospectively reviewing their cumulated experience of 170 thoracotomies in 144 patients and again recapitulated encouraging survival results with a 5- and 10-year survival of 40% and 30%, respectively. These survival results are encouraging and have certainly extended the survival of these patients given that patients treated with chemotherapy alone are unlikely to survive beyond 24 months.62
To deliver this therapy to appropriate patients, it is the oncological factors that require careful consideration. In a study of prognostic factors of 165 patients undergoing curative pulmonary surgery for colorectal lung metastases at the Kansai Clinical Oncology Group, the 5-year survival rates were poorer in patients with hilar or mediastinal lymph node metastasis and in those with a prethoracotomy CEA level >10 ng/mL.63 The negative prognostic impact of lymph node metastasis was further studied through a cohort of 175 patients from a German institution, who reported an overall median survival of 47 months, with patients having intrapulmonary, hilar, and mediastinal nodal disease having a median survival of 86, 25, and 35 months, respectively,64 therefore suggesting the negative effect of extrapulmonary lymph node on survival and hence proposing a basis for the need to sample these nodes during the surgical procedure. In 2 other Japanese studies, multivariate analysis of prognostic factors identified tumor size, number of metastases, synchronous lung metastasis, positive hilar and/or mediastinal lymph node, and a raised prethoracotomy serum CEA level as independent factors associated with a poorer survival.65,66 The feasibility of repeat pulmonary metastasectomy to resect recurrences have also been addressed in the 20-year experience of Rena et al67 who performed second and third resections for recurrent metastases in 7 and in 4 patients, respectively, in their series of 98 procedures in 80 patients where a 5-year survival rate of 50% in patients undergoing second operations compared with 41.1% in patients undergoing a single resection, emphasizing the feasibility of reoperating to achieve long-term survival. Some studies have also began to addressed the issue of pulmonary metastasectomy in patients with a previous history of resected liver metastases, and have concluded that an aggressive surgical therapy to resect recurrent CRC metastases in selected patients with serial metastasectomy is safe and provides good long-term outcome.47–50
The single largest study of 5206 cases of pulmonary metastasectomy of various cancers studied through a multicentric clinical trial under the International Registry of Lung Metastases, where 645 cases of bowel origin were evaluated, prognostic factors identified from this registry study were a complete resection, long disease-free interval and single metastasis were favorable measurements for long-term survival.68 Specific to colorectal lung metastases, a collective review of all available published literature on pulmonary metastasectomy was reviewed of which 20 series were included in a systematic review by Pfannschmidt et al.69 The authors reported the outcomes of resection of colorectal lung metastases from a total of 1684 patients from 17 different studies with a subset of studies reporting also the outcomes of resection of both the liver and lung metastases. The postoperative mortality ranged from 0% to 2.5%. The overall 5-year survival reported ranged from 41% to 56% (median 48%). The outcomes of patients who underwent both pulmonary and hepatic metastasectomy had a median 5-year survival of 31% (range, 30%–38%). From the reviewed studies, 14 prognostic factors were evaluated. These variables include patient demographics, tumor characteristics, characteristics of the lung metastases, surgical variables, timing of metastasectomy, and prethoracotomy carcinoembyronic antigen level. Multivariate analyses determined that stage of the primary CRC, distribution of lung metastases (unilateral or bilateral), disease-free interval between resection of primary tumor to time of pulmonary metastasectomy, surgical approach, surgical procedure, repeat pulmonary metastasectomy, number and tumor size, and the use of neoadjuvant or adjuvant systemic therapy had no impact on survival. The only factors affecting survival were prethoracotomy CEA level, radicality of resection, and lymph node involvement. The effect of combined liver and lung resection was not associated with a poorer outcome.
Like other metastasectomy, pulmonary metastasectomy has been a subject of criticism as a practice centered upon weak evidences from uncontrolled retrospective series, a harmful procedure due to resultant permanent loss of lung function and an unjustifiable cost.70 However, it may be performed safely with an operative morbidity under 15% and mortality rate under 3% in experienced centers.71–73 It appears that when appropriate patients are selected, the clinical efficacy of pulmonary metastasectomy and the curative potential that it ensues should be regarded as an effective treatment option.
COLORECTAL PERITONEAL METASTASES
Peritoneal metastases from CRC is traditionally regarded a terminal condition with survival from historical patients being in the order of about 6 months. The terminal nature of this disease has been demonstrated in a large cohort registry study and a clinical trial.10,74 The French multicentric EVOCAPE 1 trial, which prospectively followed 370 patients with peritoneal carcinomatosis from various primary cancers from diagnosis till death showed a mean and overall median survival of 6.0 and 3.1 months, respectively.74 This clinical entity occurs when the growth of the tumor invades through the serosal lining of the bowel lumen allowing malignant cells to exfoliate and shed to become freely circulating within the peritoneal fluid. Iatrogenic manipulation during the surgical procedure or transection of lymphatics or blood vessels may likewise lead to seeding of tumor cells within the peritoneal cavity.75 These tumor cells implant in the nourished microenvironment of the peritoneum that is enriched with blood vessels and lymphatics. Favored sites of the peritoneum include the upper abdominal regions; commonly on the subphrenic regions and in the lesser sac, on the bowel surfaces and mesentery, and in the pelvis. This is due to the direction of peritoneal fluid circulation as well as the effects of gravitational forces. Implantation of cells leads to subsequent formation of tumor plaques and masses that may involve a vast extent of peritoneal surfaces. Peritoneal metastases are observed in up to 7% of patients at diagnosis and in up to 44% of patients at time of recurrence of CRC.75
The dire survival outcome of this condition is often a reflection of the failure of conventional systemic chemotherapy and palliative surgery on disease control. Although various novel agents have been introduced and may prove to be effective, the evaluation of the efficacy of these modern chemotherapy regimen including FOLFOX (oxaliplatin plus FU/LV regimen) and FOLFIRI (infusional fluorouracil, leucovorin, and irinotecan) in combination with biologic agents such as Cetuximab and Bevacizumab in patients with mCRC specific to the peritoneum is lacking.4,76 None of these large clinical trials evaluating modern agent systemic chemotherapy have reported the results of response and survival specific to patients with peritoneal metastases. Owing to the poor prognosis and extensive tumor burden that characterizes this fatal malignant progression, it is generally considered an untreatable condition. Aggressive treatments are abandoned and management is directed largely at symptom palliation.
A surgical approach combining CRS and hyperthermic intraperitoneal chemotherapy (HIPEC) is gaining increasing acceptance in the oncological community as a treatment option for patients with peritoneal metastases from CRC. This treatment was first described by Spratt et al in 198077 before being further developed by Paul Sugarbaker of the Washington Cancer Institute in the 1990s.78 This procedure involves stripping of the diseased peritoneum with multiple visceral resections performed with an aim of achieving a maximal cytoreduction of all visible peritoneal lesions within the abdomen. Following surgery, a heated chemotherapy perfusate is administered intraoperatively into the abdomen to chemically sterilize all raw peritoneal surfaces. Heated intraperitoneal chemotherapy allows a high local concentration of a cytotoxic drug to be achieved for microscopic cytoreduction to target any microscopic residual tumor volume with minimal systemic adverse effects. In addition, hyperthermia has been demonstrated to have a synergistic effect with the chemotherapy and can thus enhances the cytotoxicity of the drug.79
The survival benefits of this treatment was first reported by Verwaal et al80 in a randomized trial comparing systemic chemotherapy versus CRS with HIPEC, which showed an almost 2-fold (13 vs. 22 months; P = 0.032) survival benefit in the arm receiving HIPEC. Subsequently, a multi-institutional registry study corroborated by the Peritoneal Surface Oncology Group of 506 patients with CRC peritoneal metastases from 28 institutions treated with CRS and HIPEC showed a median survival of 32 months in patients who had a complete cytoreduction.81 A systematic review elegantly summarizes the results of all available studies; comprising of 2 randomized trials, one comparative study, the multi-institutional registry study, and 10 case series demonstrated a median survival ranging from 13 to 29 months.82 More recently, a retrospective comparative study of a highly selected group of patients with CRC peritoneal metastases who underwent either CRS, HIPEC, and systemic chemotherapy or palliative chemotherapy alone using current regimens of oxaliplatin and irinotecan showed a median survival of 63 months and 24 months, respectively; thus, further emphasizing the value of this treatment.83
Despite the positive survival results demonstrated in the literature from numerous level III evidences through observational clinical series and level II evidences from nonrandomized comparative studies, and the single randomized trial, the basis of modern day evidence-based clinical practice implies that with only one randomized trial of this treatment to date,80 there is insufficient evidence for the general acceptance of this treatment. Critics have also questioned the safety of this treatment.84 The complication rate of this treatment was recently compiled through a systematic review by Chua et al85 who reviewed the morbidity and mortality results from 24 treatment centers, of which 10 centers were regarded as high volume specialized centers based on the number of procedures performed. The findings of the review were that the major morbidity rate ranging from 12% to 52% and a mortality rate ranging from 0.9% to 5.8%. However, morbidity and mortality rates appeared to be lower in high volume centers. The safety of this treatment in specialized treatment center and the sound clinical judgment based on various peritoneal disease related indicators86 used to select appropriate patients for treatment will ensures that suitable candidates are offered and treated to derive the benefits of this treatment. Conversely, unsuitable candidates should be offered alternate therapies that may potentially be more beneficial.
From our experience, we are now receiving increasingly earlier referrals for consideration of CRS and HIPEC compared with before where patients were referred typically for a salvage treatment having failed first- and second-line systemic therapy. The earlier treatment of peritoneal metastases may prove to be a more effective strategy to combat this metastatic disease. Given the lack of universal acceptance of CRS and HIPEC even after the Dutch trial by Verwaal et al,80 the American College of Surgeons Oncology Group and the United States Military Cancer Institute multi-institutional Phase III clinical trial of CRS and HIPEC in patients with limited peritoneal dissemination from CRC without distant metastases, which have now began patient accrual will validate this treatment and define the role of CRS and HIPEC for patients with CRC peritoneal metastases.
INTEGRATION OF MULTI-MODALITY THERAPIES FOR CURE
MCRC continues to be a management challenge. The availability of multimodality therapies and the integration of these therapies through various disciplines in clinical oncology appear promising. However, the current staging criteria for advanced CRC do not reflect the outcome of current treatment strategies or prognoses for patients with Stage IV CRC.87 A new staging system is therefore of urgent requirement for which will aid the appropriate selection of patients for an aggressive approach to ensure a low treatment failure rate. With a better understanding of the tumor biology, there has been an unraveling of the heterogeneity of this disease. The field of clinical and translational oncology has tremendously contributed to the identification of important prognostic clinical factors, histopathological characteristics, genetic and protein expressions that together may be used as biomarkers to better predict response to treatment and survival. For example, recent investigations into the optimization of epidermal growth factor receptor-directed monoclonal antibody therapy have shown that patients harboring mutations in the KRAS gene do not benefit from cetuximab or panitumumab treatment.88 Therefore, KRAS mutation testing will ensure that patients receive epidermal growth factor receptor based monoclonal antibody therapy appropriately. To personalized therapy, the prognostic implications of these biomarkers have now been used to formulate decision support tools through various mathematical and statistical modeling or artificial intelligence using learned computer systems to arrive at nomograms that are designed to assist and guide both clinicians and patients toward the choice of treatment approaches that will result in the greatest benefit.14–17
With respect to current and future research, the conduct of clinical trials combining various curative procedures with systemic regimens is appropriate and should be the approach for trials in metastatic disease to establish best practice evidence. However, it must be recognized that the unique and dynamic nature of how metastases present may limit the conduct of such trials. To address this, there may be a potential role for complementing clinical evidence-based practice from large multi-institutional registry data. Future studies of systemic therapy need to include potential curative surgery/metastasectomy as secondary end point. The challenges ahead include the need to understand the role of surgical metastasectomy in patients who have had second- and third-line chemotherapy. In addition, research into the sequence of surgery where the primary is intact is required, on whether systemic therapies should be administered before or after surgery in situations where a complete resection is achievable, and the relative benefit of surgery and systemic therapy as an individual modality to survival needs to be explored. The survival outcomes of patients undergoing resection of multiple sites of disease though appear encouraging is still limited by the quantity of evidence available and the basis of this requires further investigation.
Enormous progress in the treatment of mCRC through a multimodality approach of combining surgical treatments and systemic therapies in modern times has been made. Although there is now worldwide interest in such approaches, there needs to be broader dissemination of guidelines for metastasectomy. Expertises are required to offer such treatments and therefore it is only available in specialized institutions. Patients ought to be discussed in the context of a multidisciplinary team. The attitudes of patients and oncology healthcare professionals towards such a therapeutic approach are varied and range from reluctant acceptance to ambivalence to open hostility. The evolution of CRS and HIPEC, the increasing interest in pulmonary metastasectomy and the established role of hepatectomy in combination with modern systemic regimens will offer a cure in selected patients. Most of the evidences of these treatments stem from large cohort observational studies. Although randomized evidence is lacking, the extensive body of nonrandomized studies has demonstrated its clinical efficacy, making a randomized trial comparing treatment versus no treatment type trial unethical and impossible. Careful work is required to rigorously and judiciously select patients to ensure that these surgical options are not used in an uncontrolled manner and acquire negative connotations. It is reasonable to conclude that this multimodality approach is now an established option for patients, but it remains to be seen whether it has the legs it takes to demonstrate clinical utility in a Phase III setting to gain professional acceptance. Multicentric trials of a combined approach of these surgical procedures together with modern systemic therapies in mCRC are underway and the final results are keenly awaited.
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This article has been cited 1 time(s).
OncoimmunologyHepatic metastases of colorectal cancer are rather homogeneous but differ from primary lesions in terms of immune cell infiltrationOncoimmunology
colorectal cancer; cancer metastasis; liver metastases; lung metastases; peritoneal metastases; surgery
© 2011 Lippincott Williams & Wilkins, Inc.
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