Multidisciplinary management of metastatic colorectal cancer

Surgical Oncology 7 (1998) 197 } 207

Multidisciplinary management of metastatic colorectal cancer Sam S. Yoon, Kenneth K. Tanabe* Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Cox 626, 100 Blossom Street, Boston, MA 02114, USA

Abstract When colorectal cancer metastasizes to distant organs, usually multiple sites are involved and treatment consists primarily of systemic chemotherapy and supportive care. Chemotherapeutic agents e!ective against metastatic colorectal cancer include 5-#uorouracil, often used in combination with leucovorin or methotrexate, and irinotecan (CPT-11). Median survival with optimal chemotherapy regimens ranges from 10 to 15 months. Less frequently, colorectal cancer metastasizes only to the liver or lung. In a minority of these cases, surgical resection can be performed and results in a median survival of 28}46 months for hepatic resections and 24}25 months for pulmonary resections. Five-year survival rates range from 24 to 38% and 21 to 44% for hepatic and pulmonary resections, respectively. For isolated liver metastases that are not surgically resectable, other regional therapies that can be considered are hepatic cryosurgery, radiofrequency ablation, and hepatic arterial infusion chemotherapy. Median survival following cryosurgery is between 26 and 30 months, while median survival following radiofrequency ablation has not been established in large series. Hepatic arterial infusion chemotherapy, especially with newer combination drug regimens, may increase survival in patients with isolated liver metastases compared to systemic chemotherapy, but this must be con"rmed in randomized, prospective trials. Colorectal cancer metastases to the brain can be treated with radiation therapy or surgical resection, but median survival with treatment is less than one year. ( 1999 Elsevier Science Ltd. All rights reserved. Keywords: Colorectal cancer; Metastasis; Chemotherapy; Hepatectomy; Cryosurgery; Radiofrequency ablation; Intra-arterial infusion; Pulmonary resection

1. Introduction With an estimated 131,600 new cases and 56,500 deaths in 1998, colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and the second leading cause of cancer death [1]. The overall "ve-year survival rate for CRC is about 50% [2]. At the time of initial diagnosis, 70% of patients with CRC will have limited disease that is resectable with curative intent and 30% will have advanced disease (i.e. unresectable local disease or distant metastases) [3]. Of patients with resectable CRC, about 35% will subsequently develop recurrent disease either in the form of local recurrence or distant metastases [3]. CRC can spread di!usely to several sites or can spread to one or two isolated organs. The majority of patients with initially advanced CRC or recurrent CRC have multiple sites of disease [3] and are commonly treated with systemic chemotherapy or supportive care. When CRC metastases are limited to one or at most two sites, * Corresponding author. Tel.: #1-617-726-8555; fax: #1-617-7243895.

regional therapies such as surgical resection can be considered. The liver is the most common site of distant metastasis from CRC, with liver metastases occurring in almost one-half of all patients with CRC. The next most common site of CRC metastasis is the lung. In one autopsy series of 1541 patients who died of CRC, 44% of autopsies revealed liver metastases and 21% revealed lung metastases [4]. Other sites of metastases included adrenal glands (7%), bone marrow (6%), spleen (3.4%), pleura (2.8%), and brain (2.5%). The treatment of primary CRC and local recurrences is discussed elsewhere in this edition. This article will discuss the management of disseminated CRC metastases with systemic chemotherapy, management of isolated metastases to the liver and lung with surgical resection and other regional therapies, and management of brain metastases with surgical resection and radiation therapy.

2. Surveillance The majority of CRC recurrences occur within the "rst 2.5 years of surgical resection, and the remainder of

0960-7404/99/$ - see front matter ( 1999 Elsevier Science Ltd. All rights reserved. PII: S 0 9 6 0 - 7 4 0 4 ( 9 9 ) 0 0 0 2 2 - 5

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recurrences occur within the next 2.5 years [2]. The goal of surveillance of patients with a history of CRC is to discover recurrences as early as possible to optimize the results of further therapy. A reasonable surveillance schedule for patients who have undergone surgical resection of CRC with curative intent includes regular history and physical examination, digital rectal examination, and fecal occult blood testing. Carcinoembryonic antigen (CEA) levels may be monitored every three months for 3 years for patients who are candidates for aggressive evaluation and therapy should the levels rise. For patients with rectal cancer, a pelvic computed tomography (CT scan) may be obtained three or four months after operation to establish a baseline and then annually for three years. Colonoscopy should be performed after one year and repeated every three years as long as no abnormalities are found. A chest X-ray may be obtained every year for "ve years. Surveillance will diagnose recurrent disease earlier but there is no de"nitive evidence that intense surveillance will improve survival. One meta-analysis of seven nonrandomized studies reported that patients receiving intensive follow-up including CEA monitoring had a 9% better "ve-year survival than patients receiving minimal or no follow-up [5]. Subsequent randomized, prospective studies have failed to con"rm this bene"t. In one study, 597 patients were randomized to frequent or infrequent follow-up and prospectively followed, but neither group had CEA monitoring [6]. The frequent follow-up group had their recurrences diagnosed earlier and underwent more operations, but there was no di!erence in survival between the frequent and infrequent follow-up groups. An ongoing prospective, randomized trial in the United Kingdom is monitoring CEA levels monthly after resection of CRC [7]. If the CEA level rises above 10 ng/ml, patients are randomized to either physician and patient noti"cation or no noti"cation. Thus far, there has been no di!erence in survival between the 2 groups. Thus, the intensity of follow-up and CEA monitoring should be determined on an individual basis.

3. Systemic chemotherapy For the majority of patients with initially advanced CRC or recurrent CRC, disease will have advanced to the point where systemic chemotherapy and supportive care are the only therapeutic options. 5-#uorouracil (5-FU) is the most commonly used agent against CRC [8]. Clinical toxicity from 5-FU includes anorexia, nausea, stomatitis, diarrhea, myelosuppression, hair loss, and skin changes [9]. Although objective response rates for 5-FU widely vary, an objective response rate of about 20% is generally attainable [10]. The administration of 5-FU is associated

with a median survival of 6}8 months in all patients and 12}18 months in patients with an objective response [7]. Continuous infusion of 5-FU as opposed to bolus administration has been demonstrated to improve response rates and provide a small survival advantage in one meta-analysis [11]. Biochemical modulation strategies have been used to increase the e$cacy of 5-FU against CRC. The most successful strategy thus far has been the addition of leucovorin. A meta-analysis of nine randomized studies found 5-FU combined with leucovorin resulted in better response rates than 5-FU alone, but no survival advantage was observed [12]. Objective tumor response rates with this combination have been about 20}25%, and median survival has been about 10}12 months in all patients [8]. In addition, biochemical modulation with methotrexate at least 24 h prior to 5-FU administration has been shown in a meta-analysis of randomized trials to have a small survival advantage over 5-FU alone [13]. The addition of interferon or N-(phosphonacetyl)-L-aspartate (PALA) has not been shown to be more e!ective than 5-FU alone in randomized trials [14]. Combination chemotherapy with 5-FU and several other chemotherapeutic agents has been used against CRC with mixed results. Combinations of 5-FU, methyl-CCNU, mitomycin, vincristine, and streptozocin have not demonstrated a survival advantage in randomized trials [7]. While the combination of 5-FU with cisplatin was initially encouraging, several randomized trials have failed to demonstrate a better response rate or increased survival compared to 5-FU alone [7]. One promising agent for metastatic CRC is irinotecan (CPT-11), a topoisomerase I inhibitor. In a prospective, randomized trial of 279 patients with metastatic CRC who failed 5-FU therapy, irinotecan treatment led to a one-year survival of 36% compared to 14% after treatment with best supportive care [15]. The irinotecan-treated group also experienced improved quality of life. Another prospective, randomized trial compared irinotecan to infusional 5-FU in 267 patients with metastatic CRC who had failed conventional 5-FU therapy [16]. One-year survival was 45% for the irinotecan group compared to 32% for the infusional 5-FU group, and the irinotecan group had a longer period until quality of life deteriorated. Toxicity from irinotecan includes severe diarrhea and neutropenia [8]. Thus, for patients with advanced or widely metastatic CRC, initial systemic chemotherapy should include 5-FU possibly combined with a biochemical modulator such as leucovorin or methotrexate. If there is no response to 5-FU-based therapy, irinotecan is currently the best second-line agent. Patients who do not respond to irinotecan can be considered for participation in clinical trials of investigational agents.

S.S. Yoon, K.K. Tanabe / Surgical Oncology 7 (1998) 197 } 207

4. Surgical resection of isolated liver metastases Almost one-half of patients with CRC will develop liver metastases at some point in their course. About 15}25% of patients will have liver metastases at the time of primary CRC diagnosis and another 20% will develop metachronous liver metastases [17]. Unfortunately, only a small minority of patients with liver metastases are candidates for surgical resection, which o!ers a reasonable chance for long-term survival. Of all patients with CRC liver metastases, about 25% will have no other sites of metastases [18], and only 10}20% of these patients will have metastases that are surgically resectable [19]. Thus, of the more than 131,000 patients who developed CRC in 1998, an estimated 2000 patients will at some point have surgically resectable liver metastases. Careful preoperative assessment should be performed when considering surgical resection of CRC liver metastases to (1) exclude extrahepatic disease as reliably as possible; (2) determine the location of all metastases in relation to the liver's anatomic segments and vital structures; and (3) determine the ability of the patient to tolerate hepatic resection. Thus, the preoperative assessment should include a history and physical examination, hematology and chemistry panels, coagulation pro"les, liver function tests, CEA level, electrocardiogram, chest X-ray, and abdominal and pelvic CT scans. We routinely obtain chest CT scans to rule out pulmonary metastases. In a recent study of patients with apparently isolated CRC liver metastases and normal chest X-rays, chest CT scans had a positive yield of 4% and a positive predictive value of 36% for lung metastases [20]. Colonoscopy should be performed if not done within the past 12 months. Cardiology or pulmonology consultations should be obtained when necessary to better assess comorbid conditions. Further preoperative radiological evaluation is based upon surgeon preference. The sensitivity of helical CT scans with intravenous contrast for CRC liver metastases is about 80% [21,22]. The sensitivity of CT arterioportography (CTAP), in which intravenous contrast is injected into the superior mesenteric or splenic artery and CT images are obtained during the portal venous phase, is over 90% [23]. The speci"city of CTAP is reduced due to frequent perfusion abnormalities and pseudolesions [24]. Magnetic resonance imaging with liver-speci"c contrast agents is increasingly being used in the evaluation of liver metastases. MRI performed with contrast agents such as manganese-pyridoxyl diphosphate (Mn-DPDP) or superparamagnetic iron oxide particles (SPIO) can be as sensitive as CTAP for liver metastases and even more speci"c [25]. At the Massachusetts General Hospital, MRI with Mn-DPDP is currently the study of choice for the preoperative evaluation of CRC liver metastases. Radioimmunodetection (RAID), otherwise known as immunoscintigraphy (IS), is another modality used to

199

detect primary CRC and metastases. This test utilizes radiolabeled antibodies directed against tumor-associated antigens such as CEA or TAG-72. Following intravenous injection, the radiolabeled antibody binds to tumor foci, which can then be visualized on either planar scintigraphy or single-photon emission computed tomography (SPECT). RAID is less sensitive than CT scan in identifying liver metastases but more sensitive in identifying extrahepatic disease [26]. Thus, RAID has been advocated for use in patients considered for curative resection of CRC liver metastases to exclude extrahepatic disease [27}29]. However, Stocchi and Nelson have noted that almost 20% of patients with RAID would be incorrectly considered to have extrahepatic disease and denied potentially curative surgery because the speci"city of RAID for extrahepatic disease is only about 60% [26]. For this reason, we do not routinely perform RAID on patients with CRC liver metastases as part of the preoperative workup. Despite extensive preoperative evaluation, a small but signi"cant percentage of patients who undergo laparotomy for resection of CRC liver metastases have unresectable disease. Diagnostic tests are being investigated to more accurately identify those with unresectable disease. Laparoscopy combined with laparoscopic ultrasound may be the most sensitive technique for identi"cation of intra-abdominal disease. In one study, laparoscopy and laparoscopic ultrasound detected unresectable disease in 25% of patients with liver tumors judged to be resectable by conventional imaging studies [30]. Further studies are needed to determine if routine use of laparoscopy and laparoscopic ultrasound are bene"cial in all candidates for resection of their CRC liver metastases. Another modality that may help in identifying additional foci of CRC is radioimmunoguided surgery (RIGS). RIGS is performed by intravenously injecting a radiolabeled monoclonal antibody which is speci"c for a tumor-associated antigen. After a couple of weeks, during which time the background radioactivity declines, the patient undergoes an exploratory laparotomy, and a hand-held gamma detection probe is used to identify areas of increased radioactivity which can be biopsied or resected. In a series of patients operated on for CRC liver metastases, extrahepatic disease was identi"ed in 65% of patients operated on with RIGS while extrahepatic disease was identi"ed in only 28% of patients without RIGS [31]. The true sensitivity and speci"city of RIGS for identi"cation of extrahepatic disease and the impact of RIGS on survival in patients explored for apparently resectable CRC liver metastases is unknown. The utility of resecting all RIGS-positive tissue in these patients is also unknown. In the future, techniques such as laparoscopic ultrasound and RIGS may allow surgeons to more con"dently select patients who stand to bene"t from hepatic resection and help identify more metastases that can be resected.

200

S.S. Yoon, K.K. Tanabe / Surgical Oncology 7 (1998) 197 } 207

Patients may be considered candidates for surgical resection of their liver metastases if they have no extrahepatic disease, all their liver metastases can be resected with a tumor-free margin (preferably of at least 1 cm), and adequate liver parenchyma can be spared. In the absence of underlying liver disease, about 75% of the liver can be removed without subsequent hepatic failure [32]. The operative procedure is carried out usually through a right subcostal incision frequently extended across the midline to the left. The abdominal cavity is thoroughly explored for extrahepatic disease and suspicious areas are biopsied. The liver is then fully mobilized by dissection of its supporting ligaments. Following visual inspection and palpation of the liver, intraoperative ultrasound is used to identify all liver lesions and delineate vascular anatomy. Liver resections are performed based on the liver's segmental anatomy as described by Couinaud [33]. One or more segmental resections are often performed as opposed to a major contiguous resection to spare more normal liver or to allow resection of distantly spaced metastases. A variety of techniques are used to divide liver tissue including "nger fracture, clamp fracture, electrocautery, morselization and aspiration with a small suction tip, and ultrasonic dissection and aspiration. Ideally, 1 cm surgical margins are obtained around all metastases. Surgical resection of CRC liver metastases o!ers the best chance of long-term survival. Median survival of patients with isolated CRC liver metastases after systemic chemotherapy is 10}16 months and 5-year survival is rare [34]. Retrospective analysis of patients with potentially resectable CRC liver metastases that went unresected have found mean survival to be about 20 months and "ve-year survival to be near 0% [35}38]. In contrast, surgical series have consistently reported median survival following resection of CRC liver metastases to be between 28 and 46 months and "ve-year survival between 22 and 45% (see Table 1) [39}45]. Major causes of operative mortality included bleeding, liver failure, and sepsis. Additional major causes of morbidity included biliary leak or "stula, intra-abdominal abscess, wound infection, pneumonia, and pleural e!usions. Operative morbidity rates ranged from 22 to 39%.

There are no absolute contraindications to surgical resection except when those criteria listed previously as prerequisites for operation are not met. However, numerous retrospective analyses have identi"ed factors that have been associated with decreased survival following surgical resection of CRC liver metastases. Table 2 lists the negative prognostic factors that have been reported to be statistically signi"cant in at least two studies from the past decade [40}46]. The majority of these factors suggest more aggressive tumor biology or larger tumor burden. The only factor under the surgeon's control is the size of the tumor margin, and Cady et al. have emphasized the importance of having at least 1 cm tumor-free margins [47]. Some groups have considered 4 or more liver metastases to be an absolute contraindication to resection. In the largest surgical series this decade from Memorial Sloan-Kettering Cancer Center, patients with 4 or more metastases had a 5-year survival of 24% [45]. While 4 or more metastases is certainly a negative prognostic factor, we do not de"nitively exclude such patients from surgical resection. About 65}80% of patients who undergo resection of their CRC liver metastases will develop a recurrence, and a signi"cant proportion of these patients will again have isolated metastases to the liver that are amenable to repeat liver resection. The criteria for repeat hepatic resection are the same as those for initial hepatic resection. There have been numerous small series and three series each with over 60 patients who underwent repeat hepatic resection for CRC liver metastases [48}50]. The "ve-year survival rates in the three largest series were 16, 32 and 41%. The majority of patients in the last study received adjuvant chemotherapy [50]. The mortality and morbidity rates were comparable to those after initial hepatic resection. Negative prognostic factors included incomplete resection, short interval between hepatectomies, three or more metastases, elevated CEA level, and extrahepatic disease. Some centers have performed hepatic resections on patients with unresectable liver metastases following regression from systemic chemotherapy or hepatic arterial infusion chemotherapy [51}53]. One study of 53 patients who underwent systemic chemotherapy followed by

Table 1 Results of resection of CRC liver metastases Study (year)

Number of patients

Operative mortality (%)

Operative morbidity (%)

Median survival (months)

5-year survival (%)

Schlag [39] (1990) Doci [40] (1991) Rosen [41] (1992) Gajowski [42] (1994) Scheele [43] (1995) Wanebo [44] (1996) Fong [45] (1997)

122 100 280 204 434 74 456

4 5 4 0 4.4 7 2.8

34 39 * * 22 38 24

28 * 33.6 33 * 35 46

* 30 25 32 33 24 38

S.S. Yoon, K.K. Tanabe / Surgical Oncology 7 (1998) 197 } 207 Table 2 Negative prognostic factors after surgical resection of CRC liver metastases [40}46] Primary colorectal tumor characteristics

Metastases characteristics

Surgical resection characteristics

Advanced stage High grade

Lymph node involvement Extrahepatic metastases Large size Increased number Satellitosis Bilobar distribution Short disease-free interval Synchronous metastases Elevated CEA level

Less than 1 cm tumor-free margin Extensive resection

201

seminated intravascular coagulation and multisystem organ failure) [54]. The risk for many of these complications appears to be proportional to the volume of normal liver parenchyma that is treated. The results with hepatic cyrosurgery have been encouraging in patients with unresectable CRC liver metastases who normally have a median survival with systemic or hepatic artery infusion chemotherapy between 12 and 17 months [34]. Median survival in the two largest series of patients with CRC liver metastases treated with cryotherapy was 26}30 months and "ve-year survival for one study was 13.4% [55,56]. Thus, for patients with unresectable but isolated CRC liver metastases, hepatic cryosurgery is a reasonable option.

6. Radiofrequency ablation

surgical resection of initially unresectable CRC liver metastases reported a "ve-year survival of 40% [53]. Such aggressive treatment should be left for experienced centers as part of a clinical trial.

5. Hepatic cryosurgery In situ liver tumor ablation allows treatment of a wider range of metastatic liver disease and avoids some of the dangers of surgical resection. Hepatic cryosurgery destroys liver tumors in situ by freezing them. Presently, it is used to treat patients with isolated CRC liver metastases who have: (1) lesions that are not surgically resectable; (2) residual lesions not encompassed by a performed surgical resection; (3) an involved or close surgical margin; or (4) comorbidity that precludes a major liver resection [54]. Hepatic cryosurgery is performed during an operative procedure by placing a cryoprobe into the center of a liver tumor either under direct vision or with ultrasound guidance. Liquid nitrogen is circulated through the cryoprobe and an `iceballa is created which is observed with ultrasound. The liquid nitrogen is circulated until the iceball extends at least 1 cm beyond the tumor margin. Two freeze}thaw cycles appear to enhance tumor destruction. Some surgeons use hepatic in#ow occlusion to increase the size of the iceball or the speed with which it forms. However, this maneuver theoretically places vessel walls and bile ducts at greater risk for injury. Postoperative mortality from this procedure ranges from 0.9 to 3.7% in the largest series [55,56]. Complications are not uncommon and include cracking of the frozen liver with subsequent bleeding, rightsided pleural e!usion, intra-abdominal abscess, bile collection or "stula, thrombocytopenia, myoglobinuria, acute renal failure, and cryoshock phenomenon (dis-

Radiofrequency (RF) ablation uses RF energy rather than freezing to destroy tumors. The indications for its use are similar to those for hepatic cryosurgery. RF ablation is performed percutaneously, laparoscopically, or intraoperatively by insertion of a RF electrode into the center of a liver tumor under ultrasound or CT guidance [57]. RF energy is run through the low-resistance electrode and absorbed by the highresistance liver tumor, leading to tissue heating and destruction. Recent advances such as internal cooling of the tip of the RF electrode and multi-probe arrays have allowed the RF energy to be dispersed over larger areas and enabled treatment of larger tumors [58,59]. Mortality from RF ablation has not been reported, and morbidity is uncommon. In "ve published studies, two reported no complications and the three other studies reported a total of three minor complications (two cases of self-remitting bleeding and one case of transient ascites) [59}63]. At the Massachusetts General Hospital, over 100 tumors have been treated with only two minor complications. The e!ectiveness of RF ablation compared to cryosurgery in destroying liver metastases is unclear. The published studies using RF ablation to treat CRC liver metastases have been small, lacked long-term follow-up, and used equipment and techniques that have since been improved. Solbiati et al. treated 29 patients with 44 liver metastases, mostly from CRC, and found at 18 months an overall survival of 89% and a disease-free survival of 33% [59]. Of lesions treated with RF ablation, 34% progressed during follow-up. Another study of 14 patients with 24 liver metastases found that 52% of tumors had complete necrosis six months after treatment [60]. RF ablation of CRC liver metastases is currently under investigation. Technological advances are needed to increase the ability of RF energy to destroy tumors of

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S.S. Yoon, K.K. Tanabe / Surgical Oncology 7 (1998) 197 } 207

larger diameter and to ensure all tumor tissue is destroyed. Presently, numerous overlapping ablation zones are required to treat tumors greater than 3.5 cm in diameter. This strategy requires a precision that may not be attainable. Given the low incidence of complications and the ability to perform this technique percutaneously or laparoscopically, RF ablation holds signi"cant promise as a future therapy for CRC liver metastases.

7. Hepatic arterial infusion chemotherapy For patients with isolated CRC liver metastases that are not surgically resectable, regional chemotherapy through the hepatic artery has been extensively investigated. Hepatic arterial infusion (HAI) chemotherapy has theoretical advantages over systemic chemotherapy in that (1) liver metastases larger than a few millimeters are supplied primarily by the hepatic artery while normal liver is supplied primarily by the portal vein [64]; and (2) "rst-pass clearance of certain chemotherapeutic agents by the liver limits systemic toxicity [65]. HAI of the most commonly used agent, #oxuridine (FUDR), allows a level of liver exposure 100}400 times greater than with intravenous administration [66]. HAI chemotherapy requires laparotomy for placement of an HAI pump and cannula. Patients initially undergo a preoperative angiogram to de"ne the arterial anatomy because over one-third of patients have variant arterial anatomy [67]. During laparotomy, a careful search is performed for extrahepatic metastases. If metastases outside the liver are identi"ed, HAI pump and cannula placement is generally contraindicated since therapy does not generally help patients with extrahepatic disease. The gallbladder is removed to prevent subsequent chemotherapy-induced cholecystitis. Meticulous dissection is performed to identify the artery to be cannulated (usually the gastroduodenal artery) and to prevent misperfusion of the stomach, duodenum, or pancreas [68]. The HAI pump is placed in a subcutaneous pocket in the anterior abdominal wall, and the cannula is connected to the pump, tunneled into the abdomen, and inserted into the appropriate artery. The procedure is completed by

injecting #uorescein into the pump sideport and observing abdominal organs under a Wood's lamp to con"rm full hepatic perfusion and no extrahepatic perfusion. A radiolabeled, macroaggregated albumin scan is obtained about 3 days postoperatively to again verify full hepatic perfusion and exclude misperfusion. Following recovery from the operation, HAI chemotherapy can be initiated. A typical regimen at the Massachusetts General Hospital involves a 14-day continuous infusion of 0.15 mg/kg/day of FUDR, 4 mg/m2/day of leucovorin, and 20 mg/14 days of dexamethasone, followed by a 14day continuous infusion of heparinized saline. The cycle is then repeated. Liver function tests are followed closely to guide dose adjustments, and follow-up abdominal CT scans are obtained to monitor response. Complications include chemical hepatitis, biliary sclerosis, misperfusion leading to gastritis, duodenitis, or pancreatitis, catheter or arterial thrombosis, and pump pocket collections [68]. Five prospective, randomized trials have compared HAI of FUDR with intravenous administration of FUDR or 5-FU (see Table 3) [69}73]. Two European trials compared HAI chemotherapy to best supportive care, which in a majority of cases did not include systemic chemotherapy [74,75]. Response rates for HAI of FUDR in these studies has ranged from 42 to 62% compared to 10 to 21% for systemic chemotherapy. Median survival for patients treated with HAI of FUDR ranged from 12.6 to 17 months compared to 10.5 to 15.8 months for patients who received systemic chemotherapy. The only studies demonstrating a di!erence in overall survival were those in which many patients in the control group received supportive care only [74,75]. New studies have investigated HAI of a combination of agents (FUDR with leucovorin and dexamethasone) and HAI infusion of FUDR combined with intravenous administration of FUDR, 5-FU, or CPT-11 [76]. Additional studies have examined HAI chemotherapy in the adjuvant setting following surgical resection of CRC liver metastases [76]. Many of these studies have demonstrated improved response rates and overall survival compared to historical controls, but randomized prospective trials are needed to con"rm their bene"ts.

Table 3 Prospective randomized clinical trials of HAI chemotherpy versus systemic chemotherapy! Study (year)

Study size

HAI treatment (sample size)

Systemic treatment (sample size)

Median survival HAI vs. systemic (months)

p value

Kemeny [69] (1987) Chang [70] (1987) Hohn [71] (1989) Martin [72] (1990) Wagman [73] (1990)

99 64 143 69 41

FUDR FUDR FUDR FUDR FUDR

FUDR [51] FUDR [32] FUDR [76] 5-FU [36] 5-FU [10]

17 vs. 12 17 vs. 12 15.5 vs. 15.8 12.6 vs. 10.5 13.8 vs. 11.6

NS NS NS NS NS

[48] [32] [67] [33] [31]

!Cancer Vol. 78, No. 8, 1996, 1639}45. Copyright ( (1996) American Cancer Society. Adapted by permission of Wiley-Liss, Inc., a Subsidary of John Wiley Sons, Inc.

S.S. Yoon, K.K. Tanabe / Surgical Oncology 7 (1998) 197 } 207

8. Surgical resection of lung metastases The second most common site of metastases from CRC is the lung [4]. For the small percentage of patients with CRC metastases to the lung and no other organs, surgical resection may be considered. The preoperative assessment of these patients is similar to that for patients with isolated liver metastases. Pulmonary function tests may be helpful in some patients. Chest MRI is as sensitive as chest CT scan in identi"cation of lung metastases [77], but is more expensive and usually adds little information to chest CT scan. Upon completion of preoperative testing, criteria for resection are the following: (1) there is no extrapulmonary disease; (2) all pulmonary metastases can be removed with clear surgical margins; and (3) the patient has adequate pulmonary reserve and overall health to allow a pulmonary resection [78]. Isolated pulmonary metastases may be resected using video-assisted thoracoscopic surgery (VATS). Alternatively, a posterior lateral thoracotomy may be performed for unilateral metastases and staged bilateral thoracotomies or a median sternotomy for bilateral metastases. Open thoracotomies allow manual palpation of the lung to identify possible additional lesions [78]. Patients with a history of CRC and two or more new pulmonary nodules can be considered to have metastatic disease. In patients with a solitary pulmonary nodule, one cannot exclude the possibility of a new primary lung

203

cancer. In these patients, a more aggressive pulmonary resection and mediastinal lymph node dissection is generally indicated in case the "nal diagnosis turns out to be primary lung cancer. The reported survival of patients undergoing resection of isolated lung metastases for CRC in surgical series of 35 or more patients over the past decade has been 24}44% at "ve years and 19}26% at ten years (see Table 4) [79}85]. Median survival was reported in only 2 of these studies and was 24}25 months [79,85]. Operative mortality and morbidity in these series ranged from 0}4.8% to 2}15%, respectively. Negative prognostic factors included greater than 1}2 metastases, CEA level greater than 5 ng/ml prior to resection, and incomplete resection. In patients with CRC metastases to both the lung and liver and no other sites of metastases, some groups have resected metastases at both sites [79,85}91]. These studies included a total of only 77 patients, and median survival ranged from 16 to 27 months. This is relatively low given the highly select nature of this study group. Five-year survival reported in one retrospective study was 9% for resected patients and 0% for unresected patients [91]. Given the small number of patients and modest results in these studies, the bene"t of surgical resection in patients with CRC metastases to both the liver and lung is unclear. These resections should be performed on an individualized basis.

Table 4 Results of resection of CRC lung metastases Study (year)

Number of patients

Operative mortality (%)

Operative morbidity (%)

5-year survival (%)

10-year survival (%)

Negative prognostic factors

Goya [79] (1989)

62

*

4.8

42

22

Tumor'3 cm

Mori [80] (1991)

35

*

*

38

*

Tumor'3 cm '1 metastasis

McAfee [81]! (1992)

139

1.4

12.2

30.5

19.1

'1 metastasis CEA'5 ng/ml

McCormack [82] (1992)

144

0

2.1

44

26

None

Regnard [83] (1995)

101

*

*

21"

*

Synchronous disease

van Halteren [84]! (1995)

38

*

*

43

*

Disease-free interval(24 months

Girard [85] (1996)

86

1.2

*

24

20

Incomplete resection CEA'5 ng/ml

!Series included only curative resections. "Survival rate only for those with curative resections.

204

S.S. Yoon, K.K. Tanabe / Surgical Oncology 7 (1998) 197 } 207

9. Brain metastases As noted previously, the brain is an infrequent site of metastasis from CRC and the vast majority of brain metastases are in conjunction with metastases to other sites. When CRC has spread to the brain and other organs, treatment is directed toward slowing the progression of systemic disease and palliation of symptoms. Treatments directed speci"cally at CRC brain metastases include steroids, whole brain radiation therapy, and surgical resection. Farnell et al. retrospectively reviewed 150 patients with CRC brain metastases and observed a median survival of 2 months with supportive care (usually with steroids), 3.7 months with radiation therapy, 10.4 months with surgery, and 9.7 months with surgery and radiation therapy [92]. Another retrospective study of 100 similar patients measured a median survival of 1 month with steroids, 3 months with radiation therapy, and 9 months with surgery [93]. A surgical series of 73 patients with CRC brain metastases found median survival after craniotomy to be 8.3 months [94]. The mortality rate in this last study was 4.1% within 30 days of craniotomy. Signi"cant negative prognostic factors following surgical resection of CRC brain metastases included systemic disease, memory loss, early onset of brain metastases, and infratentorial location [92}94].

10. Conclusion Colorectal cancers represent a heterogeneous group of tumors with varying tumor biology. When a colorectal tumor has progressed to the point where it can metastasize to distant organs, most often the tumor biology is fairly aggressive leading to disseminated disease. These aggressive tumors are best treated with systemic chemotherapy to incrementally prolong survival. However, cure for patients with such tumors is rare, and newer therapies are needed. Patients with brain metastases from CRC cancer usually have disseminated disease but, given their very short life-expectancy without treatment, may bene"t from whole brain radiation therapy or surgical resection. A minority of colorectal tumors have a tumor biology that is not overly aggressive, and these tumors metastasize preferentially to only the liver and/or lung. Most of these tumors are still too aggressive to allow cure with complete surgical resection, but a signi"cant minority of them can be cured with surgical resection. Numerous prognostic factors have been elucidated to help in deciding which liver or lung metastases are most likely to be cured with surgical resection, and most of these factors are indicators of favorable or unfavorable tumor biology. In most instances, however, isolated and resectable CRC liver or lung metastases should be surgically removed in medically "t individuals to obtain the best chance of long-term survival.

Often, surgical resection of isolated CRC liver metastases is not possible and other regional treatments can be employed. Hepatic cryosurgery has been tested in several large series and appears to be an e!ective supplemental ablative technique when surgical resection is not possible or is incomplete. RF ablation holds promise as a less invasive and morbid option to cryosurgery, but technological advances and more studies are needed. With fewer technical complications and newer combination drug regimens, HAI chemotherapy can be an e!ective option against di!use but isolated CRC liver metastases.

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