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Liver metastases from colorectal cancer
Annals of Oncology 8. 393-399, 1997. © 1997 Kluwer Academic Publishers Printed in the Netherlands
Clinical case Liver metastases from colorectal cancer S. Cascinu,V. Catalano, M. Scartozzi, A. M. Baldelli & R. Cellerino Clinica di Oncologia Medica, Scuola di Speciahzzaztone in Oncologia, Untversita degh Studt di Ancona, Ancona, Italy
Case report
In July 1994, a 58-year-old man presented to his general practitioner with a 2-month history of abdominal pain, constipation and rectal bleeding. He had no relevant medical history except for painful hemorrhoids treated with topical preparations. On examination, there was generalized abdominal distension and tenderness. Colonoscopy revealed a stenosing, bleeding carcinoma of the ascending colon. A CT scan demonstrated two lesions in the left lobe of liver, probably metastases. At laparotomy, the stenosing carcinoma of colon and the liver metastases were confirmed. Left hemicolectomy and reanastomosis, together with left hepatectomy, were performed. Histological examination of the resected specimens showed a moderately differentiated adenocarcinoma of the colon infiltrating the surrounding adipose tissue, with positive lymph nodes and liver metastases from intestinal adenocarcinoma (pT3N2Mi). His postoperative recovery was uncomplicated. The patient was well until May 1995, when an abdominal CT scan revealed two liver metastases (Figure 1); he was operated on again. Wedge resection of the two liver metastases was radical and a catheter was placed in the hepatic artery and connected to a pump placed in an abdominal wall pocket. Postoperative therapy was administered: fluorodeoxyuridine (FUDR) was delivered by continuous infusion through the pump for 14 days, alternating with normal saline solution for 14 days, at the dose of 0.2 mg/kg. In September 1995, at the end of the planned postoperative therapy, a NMR showed progressive disease in the liver. The patient complained of vague pains in the right hypocondrium, which had increased over the previous few months. In October 1995, he was seen for the first time in our department. Because of pain, he was started on systemic chemotherapy with a combination of methotrexate (MTX) 200 mg/m2m i.v. on day 1 and 5-fluorouracil 600 mg/m2 i.v. 24 hours later. Leucovorin was given orally at the dose of 10 mg/m2, every 6 hours x 6 beginning 24 hours after MTX. After 4 cycles of chemo-
therapy, an NMR showed stable disease; there was a reduction in pain and no severe toxicity induced by chemotherapy. A further 4 cycles of chemotherapy were
(b)
Figure 1 CT scan of the abdomen showing two lesions in the VI (a) and VII (b) segments.
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Key words: chemotherapy, colorectal cancer, liver metastases, surgical approach
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Discussion Colorectal cancer is the third most common malignancy in Western countries. Liver metastases are present at diagnosis in 15% to 25% of patients and will develop in a further 60% of patients with progressive disease, making the liver the most common site of metastatic disease [1]. The presence of hepatic metastases has a major influence on survival, even when metastatic disease is present at other sites. The average duration of survival for patients with untreated liver metastases is brief, on the order of 4 to 9 months [2] although some retrospective surveys have shown a very variable natural history with a median survival of up to 24 months in selected patients without treatment [3, 4].
Surgery In several non-randomized clinical trials, liver resection for hepatic metastases has repeatedly been demonstrated to produce long-term disease-free survival in 20% to 25% of patients (Table 1). Nevertheless, it is curative only in a patient subset, which needs to be defined accurately. Patients should have a good performance, but age alone should not be a criterion for exclusion. Preoperatively, all patients should be completely staged to determine the extent of intrahepatic and extrahepatic metastases and to determine renal function and hepatic reserve: the capacity to regenerate after surgery is correlated with the underlying physiological state of the normal liver parenchyma. It should be emphasized that the presence of extrahepatic disease is not an absolute contraindication to hepatic resection [8, 17, 18]. By the same token, the presence of locally recurrent disease does not exclude a patient from a liver resection if the local disease can be resected completely. If the metastasis is present at the time of primary diagnosis, a general rule could be to perform the resection of the primary tumor and a biopsy of the metastatic
Table I. Results of hepatic resection for colorectal metastases. Author
No. of patients
5-Year survival
Mortality
Adson, 1984 Nordlinger, 1987 Hughes, 1988 Scheele, 1990 Schlag, 1990 Ringe, 1990 Doci, 1991 vanOoijen, 1991 Steele, 1991 Rosen, 1992 Nordlinger, 1996 Marmorale. 1996
141 80 859 226 122 157 100 118 150 280 1568 73
23 25 33 31 30 23 30 21 25 25 28 27
2.8 5 _ 5 4 5 5 8 2.7 4 2.3 13
Ref.
5
6 7 8 9 10 11 12 13 14 15 16
lesion, leaving open the option of reoperation and formal liver resection should it later be deemed appropriate [19]. In concomitant cases, observation for 4 to 6 months before elective hepatic resection will not impair chances of cure [20]. The criteria for performing simultaneous liver resection are: single metastatic lesion that can be removed by limited resection, minimal blood loss or contamination, uncomplicated bowel resection, the possibility of an appropriate incision for resection, medical status permitting both procedures, and a surgeon who is comfortable with the procedure [21]. Several groups have found that patients with concomitant lesions did not fare as well, in terms of survival, as patients in whom the liver lesions were identified some time after the resection of the primary lesion [22-24]. Liver metastases that are identified some time after resection of the primary colorectal cancer may represent a subgroup of favorable, slow-growing lesions. In one large series of 800 liver resections the patients had a mean 5-year survival rate of 33% and a 5-year diseasefree survival rate of 21% [7]. In general, prolonged survival is more likely after resection of single metastases than after excision of multiple metastases [25, 26]. Data suggest that patients with one or two metastases have the same 5-year survival; moreover, it seems that resecting two or three hepatic lesions, whether unilobar or bilobar, yields the same survival as resecting solitary metastases [7]. The Hepatic Registry reported a 5-year survival of 18% for patients with four or more liver metastases compared with 37% with one or two lesions. However, an 18% survival rate can be an acceptable outcome [7]. The maximum number of lesions amenable to resection remains somewhat controversial; most authors agree that resection of up to four metastases is quite reasonable, and several large studies from Europe have included resection of four or more lesions with good results [11, 27]. Prognostic scoring systems have been proposed to evaluate the chances for cure of patients after resection of liver metastases from colorectal carcinoma. Factors related to increased risk of recurrence and death were
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given up to March 1996, when progression of disease was demonstrated by a new NMR and the treatment was stopped. The patient was in good clinical condition but had abdominal pain: chemoembolization was attempted in May 1996, as part of a pilot clinical trial. Embolization was performed after selective catheterization of the hepatic artery. Polyvinyl alcohol (ivalon) mixed with full-strength iodinated radiographic contrast and mytomicin-C (25 mg/m2) were given under direct fluoroscopic control. His pain resolved rapidly and the CEA level fell from 150 ng/ml to 50 ng/ml over the next month. An NMR showed stable disease with an increase in tumor necrosis. Now, four months later, the patient is well and asymptomatic. He is checked regularly by clinical examinations and NMR of the abdomen.
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Cryosurgery
Hepatic cryosurgery is a relatively new technique that may be a therapeutic option in the treatment of selected patients with unresectable metastatic colon carcinoma. With this technique tumors are destroyed by subzero temperature: cryosurgery appears to work simply by nonspecific tissue destruction [29]. Cryosurgery's advantage is that it is a focal treatment, sparing more normal liver tissue than resection, making it possible to treat multiple lesions in both lobes of the liver. In addition, with cryosurgery, major vessels withflowingblood are protected.
In various small series, 15% to 29% of cryosurgery patients were still alive at two years, without evidence of disease. There were no operative deaths and morbidity rates (15%—20%) were acceptable [30, 31]. Complications of this procedure include hepatic cracking secondary to the thermal stresses that occur with rapid freezing [29, 30]. Cracking is usually associated with hemorrhage, which may require packing. Hemorrhage can also result from direct vascular injury from probe insertion. Asymptomatic right-sided pleural effusions, probably secondary to the irritative process beneath the diaphragm, occur in almost all patients. Elevation in serum AST, biliary fistula, hepatic abscess and thrombocytopenia have been reported [30-32]. As cryosurgery avoids removal of surrounding tissue, patients with bilobar disease and multiple lesions can undergo this procedure. Patients with diffuse infiltrative disease or in whom bilobar lesions have grown to a large size, requiring multiple penetrations with a single cryoprobe, must be excluded, because complete treatment is often not technically feasible and there might be a risk of hepatic failure. No data are available to determine whether the patient's disease is too extensive for cryosurgery; the decision is based on subjective assessment [30]. Hepatic cryosurgery is an investigational procedure with possible complications and should be reserved only for patients who cannot undergo surgical resections. Chemotherapy
Available data suggest that surgical management of metastatic hepatic colorectal cancer may affect the natural course of the disease. However, surgery alone is not enough and most patients will still die of metastatic disease after liver resection. Chemotherapy after liver resection Whether adjuvant chemotherapy can influence survival after liver resection for colorectal metastases is unclear at the present time. Regional chemotherapy might be suitable after initial hepatic resection of metastases since a significant proportion of failures reappear in the liver. However, clinical data on adjuvant intraportal chemotherapy after resection have provided no evidence that locoregional chemotherapy can prevent further recurrence in the liver [33]. Systemic chemotherapy for non-operable disease Surgical procedures are not always appropriate: most patients need a medical treatment. A variety of chemotherapy regimens have been evaluated in advanced colorectal cancer. There is some evidence that chemotherapy can improve survival and quality of life, although prolongation is measured in months [34].
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age, CEA level, stage of the primary tumor (extension into the bowel wall, involvement of nodes, metastases), disease-free interval, number of liver nodules and resection margins. Cady et al. have proposed a preliminary scoring index based on four risk factors: number of the metastatic nodules in the liver, disease-free interval after resection of the primary cancer, level of CEA, and the margins of resection [20]. Others have proposed a system including the number of preoperative hypotensive episodes, number of metastases, CEA level, and location of the primary cancer [28]. Recently, Nordlinger et al. have proposed a simple prognostic scoring system based on evaluation of the following factors in 1568 patients undergoing a resection for liver metastases: age, size of largest metastasis or CEA level, stage of the primary tumor, disease-free interval, number of liver nodules and resection margins. With one point for each factor, the population was divided into three groups with different 2-year survival rates: 79% (0-2), 60% (3-4), 43% (5-7) (15). When resection of liver metastases is considered, the scoring index can help to define the risk for patients and can be used to stratify patients according to their characteristics in prospective studies evaluating prognosis or natural history. Nevertheless, before these scoring systems can be routinely used in clinical practice they need to be validated in other studies assessing different groups of patients. The most common site of recurrence, after liver resection for metastatic disease, is the lung, followed by the liver. The liver will continue to be the site of recurrent disease in some of these patients and, consequently, they will remain candidates for additional attempts of curative liver resections. Liver metastasis recurs after resection in 60% to 70% of patients, in some instances soon after surgery. However, a small percentage of recurrent metastases appear to be solitary or localized in one lobe of the liver. The indication for further resection depends on the operative risk, as compared with first resections, and long-term results. About a quarter of patients who undergo complete resection will be cured again. The operative death rate is l%-2% in the literature, whereas morbidity rates of 20%-52% have been reported [8,15].
396
Intrahepatic arterial chemotherapy (HAI) Several observations support the rationale for regional chemotherapy: 1) liver metastases derive their blood supply from the hepatic artery, while normal hepatocytes do so from the portal vein; 2) some drugs have a high first-pass hepatic extraction, resulting in high local concentrations with low systemic toxicity; 3) the liver is often the first and only site of metastatic disease in colorectal cancer patients. Metabolism and extraction by the liver of agents such as fluoropyrimidines may eliminate more than 80% of the infused drug dose and result in lower systemic concentrations [40,41]. Hepatic arterial infusion (HAI) can be administered by several methods: an arterial port or a percutaneously placed catheter can be connected to an external pump, or a totally implantable pump can be inserted surgically. A study compared the three methods of administration: surgical placement of a hepatic artery catheter, percu-
Table 2 Randomized studies of hepatic arterial vs. systemic chemotherapy for hepatic metastases from colorectal carcinoma. Author
No. of patients
Regimen
Objective responses (%)
Median survival
Ref
Kemeny, 1987
49 51 32 32 67 76 39 35 81 41 41 51 49
HAI/FUDR IVC/FUDR HAI/FUDR IVC/FUDR HAI/FUDR IVC/FUDR HAI/FUDR IVC/5FU HAI/FUDR IVC/5FU No treatment HAI/FUDR Palliation
50 20 62 17 42 10 48 21 43 9 0 40 0
17 mos 12 mos 17mos" 13mos a 16.7 mos 16.1 mos 12.5 mos 10.5 mos 15 mos 11 mos 11 mos 13.5 mos 7.5 mos
46
Chang, 1987 Hohn, 1989 Martin, 1990 Rougier, 1992
Allen-Mersch, 1994
47 48 49 50
51
Abbreviations: 5-FU - 5-fluorouracil; FUDR - fluorodeossiuridine, HAI - hepatic arterial infusion; IVC - intravenous chemotherapy. a Data drawn from survival curves
taneous placement of a hepatic artery catheter, and surgical implantation of a reservoir connected to the hepatic artery catheter [42]. The three systems were able to deliver chemotherapy for 31, 25, and 115 days, respectively. Implanted pumps allow for better long-term patency of both the hepatic artery and the catheter than the arterial ports or percutaneous catheters; implanted pumps are also associated with a lower risk of infection [42]. Phase II trials using FUDR or 5-FU in patients with liver metastases from colon cancer have shown response rates ranging from 20% to 80%; most patients were previously treated and often resistant to systemic chemotherapy [43-45]. Several prospective randomized trials have compared intrahepatic and systemic chemotherapy (Table 2). Response rates are significantly better in the HAI group: 42% to 62% as compared with 10% to 49% in the systemic arms. However, despite adequate response in the liver, systemic failure has been reported in up to 50% of patients, most commonly in the lung. Safi et al. tried to reduce extrahepatic tumor progression using simultaneous i.v. therapy delivered through a dual infusaid pump; results showed a decreased incidence of extrahepatic disease but no impact on survival [52]. The most common toxic effects of HAI are hepatobiliary and ulcer disease, myelosuppression, nausea, vomiting and diarrhea. Hepatic toxicity due to chemical hepatitis can occur in 26% to 79% of patients receiving HAI, while biliary sclerosis occurs in less than 10% of those under careful monitoring. Treatment should be stopped if the hepatic enzymes show a three-fold increase, and should not be restarted until levels return to less than two times normal [46, 47, 53]. The incidence of biliary sclerosis associated with HAI of FUDR could be reduced by shortening the FUDR infusion duration, lowering FUDR dosage, alternating a shorter FUDR course with 5-FU, and mixing FUDR
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5-Fluorouracil (5-FU) remains the most effective single chemotherapy agent, with response rates of about 10%—20%. There have been numerous attempts to increase the efficacy of 5-FU by changing its dose, schedule and route of administration. Response rates improve when prolonged multiweek 5-FU infusions are used but there is no improvement in survival [35]. Most attempts to improve systemic treatment have consisted of empirically adding drugs to 5-FU. Regimens with the addition of methyl-CCNU, vincristine, mitomycin, streptozotocin all failed to yield significant survival gains [36]. Recent attempts to improve the therapeutic effectiveness of 5-FU have focused on the scientific principles of biochemical modulation to produce selective enhancement of cytotoxicity. Two recent meta-analyses suggest that the response rate is higher with the addition of leucovorin (LV) or methotrexate. The latter combination also showed a small survival advantage [37, 38]. Despite the modest advantage, the 5-day regimen of fluorouracil plus low-dose leucovorin is often considered the standard treatment for patients with advanced colorectal cancer because of low drug cost, tolerable toxicity, and symptom relief [36]. A study from northern Europe seemed to demonstrate that approximately one-third of patients with symptomatic advanced colorectal cancer have an improvement in quality of life during cytotoxic treatment. This improvement usually depends on an antitumor effect, although this may not be large enough to be classified as an objective response [39]. It should be borne in mind that while there can be no question of relief of symptoms in asymptomatic patients, survival and symptom-free time are marginally affected and chemotherapy is likely to be toxic. Options should be discussed with a completely informed patient. However, when disease progresses and the patient becomes symptomatic, the possible side effects of therapy may be more acceptable.
397
Chemoembolization Variable tumor vascularization is a critical problem for HAI. Tumors may be either hypervascular or hypovascular and this is an important prognostic factor in regional chemotherapy of liver tumors. The lack of response to regional chemotherapy could be related to poor perfusion of either the entire tumor or portions of it. Only low concentrations of drug may reach hypovascular areas, where dormant cells could be responsible for subsequent disease progression. Chemoembolization is performed after selective catheterization of the hepatic artery using a femoral approach. Embolizing agents, such as gelfoam, ivalon, or microspheres, used to obtain a peripheral embolization are mixed with full-strength iodinated radiographic contrast and cytotoxic drugs. Chemoembolization offers several advantages over hepatic artery infusion, since embolizing agents go preferentially to high-flow areas, redirecting residual arteriolar flow toward previously ischemic areas, as demonstrated with the aid of dynamic CAT scan analysis [56]. Furthermore, the increased transit time through the hepatic circulation has been used to improve the extraction of concurrently infused drugs. A reduction in systemic exposure, secondary to increased uptake by the liver, has been demonstrated for 5-FU, MMC, carmustine and doxorubicin [57]. Results from clinical trials do not allow definitive conclusions to be drawn because of the small sample size and because of the heterogeneity of patient populations and treatments. Available data include several
small studies with a total of approximately 160 patients (most of them previously treated): response rates range from 15% to 30%, the median survival reaches 11 months and palliation of symptoms is obtained in a large number of patients [58, 59]. The possible utility of this approach has to be confirmed in randomized clinical trials. Nevertheless, the presence of nausea/vomiting, fever and pain in almost all patients, the risk of liver abscesses and cholecystitis in about 10% of patients, and finally, the less frequent but life-threatening toxicity represented by hepatic failure (1% of the cases) suggest the use of caution in adopting its generalized use. At present it should be considered an experimental procedure for carefully selected patients with < 50% hepatic replacement by tumor and normal liver function. Percutaneous ethanol Percutaneous ethanol injection (PEI) is a relatively simple and inexpensive method of therapy. This technique may be considered in the management of patients with liver metastases from colorectal cancer who are not candidates for surgery. In general ultrasound percutaneous ethanol injection is more appropriate for hepatocellular carcinoma, because the majority of patients with this cancer have cirrhosis and cannot tolerate conventional surgical or medical treatments. PEI seems to be indicated in the treatment of metastases from colorectal cancer smaller than 3 cm in diameter; when metastases are greater than 3 cm, responses are only partial [60,61]. PEI has proved safe, but its impact on survival or symptom relief has yet to be demonstrated. Conclusions This case illustrates several aspects of an intensive approach to the management of liver metastases from colorectal cancer. By most standards, the treatment given to our patient would be classified as particularly aggressive. He underwent two operations for resection of liver metastases and three different attempts of regional and systemic chemotherapy. Surgical intervention plays a very important role in the management of liver metastases. Even in the presence of liver recurrence after a resection for metastases, a new operation can produce a cure in about 20%-25% of selected patients who can undergo a complete resection. Regional chemotherapy seems to show interestingly high response rates with a possible advantage in survival. The choice of a systemic chemotherapy after failure of HAI depended upon the patient's good clinical condition in the presence of symptoms. Furthermore, the mechanism of action by which the MTX/5-FU combination exerts its activity is different from that of 5-FU or FUDR alone.
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with dexamethasone [49, 55]. Gastritis is found in 8% to 21% of patients and gastric ulcers may occur in 8% to 17%ofpatients[46,47,49]. Recently, a meta-analysis of six randomized clinical trials comparing HAI to intravenous chemotherapy (IV) was carried out to objectively and quantitatively appraise the benefits of HAI in terms of tumor response rate and overall survival [55]. The response rate was 41% for patients allocated to HAI with FUDR compared to 14% for patients allocated to IV with FUDR or 5-FU, and this difference was highly significant. Survival analysis showed a statistically significant advantage for HAI with FUDR over that of IV when all trials with different chemotherapeutic combinations were taken into account (P = 0.0009), but not when the survival analysis was restricted to trials comparing HAI with FUDR (16 months) and IV with FUDR or 5-FU only (12.2 months), (P - 0.14 ). These results seem to confirm that HAI can achieve higher response rates than systemic therapy in patients with liver metastases from colorectal cancer, but the impact on survival is not clear and the therapeutic benefit should be analyzed in further well designed randomized trials, taking into account also the possible side effects and the economic costs of HAI.
398 The use of chemoembolization is more debatable. Our patient was treated with this procedure as part of a pilot clinical trial designed to explore the clinical benefit (objective response and symptom control) in previously treated patients. After the failure of regional and systemic chemotherapy he showed a promising response to chemoembolization in terms of symptom relief. We would not recommend this approach outside a clinical research setting. Our patient is well two years after first surgery for primary and liver metastases. This seems to suggest that an aggressive approach is justifiable in carefully selected patients.
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20. 21.
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References
25.
1. Kemeny N. The systemic chemotherapy of hepatic metastases from colorectal cancer Semin Oncol 1983; 10. 148-58. 2. Bengtsson G, Carlsson G, Hafstrom L et al. Natural history of patients with untreated liver metastases from colorectal cancer. Am J Surg 1981; 141: 586-9. 3. Goslin R, Steele G Jr, Zamcheck N et al. Factors influencing survival in patients with hepatic metastases from adenocarcinoma of the colon and rectum. Dis Colon Rectum 1982; 25. 749-54. 4. Wagner JS, Adson MA, Van Heerden JA et al. The natural history of hepatic metastases from colorectal cancer. Ann Surg 1984; 199. 502-7 5. Adson MA, van Heerden JA, Adson MH et al. Resection of hepatic metastases from colorectal cancer. Arch Surg 1984, 119: 647-51. 6. Nordlinger B, Pare R, Delva E, et al. Hepatic resection for colorectal liver metastases. Ann Surg 1987; 205: 256-63 7. Hughes K, Simon R, Songhorabodi S et al. Resection of the liver for colorectal carcinoma metastases: A multi-institutional study of indications for resection. Registry of hepatic metastases. Surgery 1988; 103: 278-84. 8. Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carcinoma: Impact of surgical resection on the natural history. Br J Surg 1990; 77: 1241-6. 9. Schlag P, Hohenberger P, HoltingTet al. Hepatic arterial infusion (HAI) chemotherapy for liver metastases of colorectal cancer using 5-FU. Eur J Surg Oncol 1990, 16. 99-104. 10. Ringe B, Beehstein WO, Raab R, et al. Leberresektion bei 157 patienten mit colorectalen metastasen. Chirurg 1990; 61: 272-9. 11. Doci R, Gennari L, Bignami P et al. One hundred patients with hepatic metastases from colorectal cancer treated by resection: Analysis of prognostic determinants. BrJ Surg 1991; 78: 797-801. 12 van Ooijen B, Wiggers T, Meijer S et al. Hepatic resection for colorectal metastases in The Netherlands - a multiinstitutional 10-year study. Cancer 1991; 70. 28-34. 13. Steele G Jr, Bleday R, Mayer RJ et al. Prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group Protocol 6584. J Clin Oncol 1991; 9: 1105-12. 14. Rosen CB, Nagorney DM, Taswell HF et al. Perioperative blood transfusion and determinants of survival after resection for metastatic colorectal carcinoma. Ann Surg 1992; 216: 493-505. 15. Nordlinger B, Guiguet M, Vaillant JC et al. Surgical resection of colorectal carcinoma metastatic to the liver. Cancer 1996, 77: 1254-62. 16. Marmorale C, Miconi G, De Luca S, et al. Surgical treatment of hepatic metastatic colorectal cancer. Ann Ital Chir 1996; 4: 1-6. 17. Hughes K, Scheele J, Sugarbaker PH. Surgery for colorectal cancer metastatic to the liver: Optimizing the results of treatment. Liver Surg 1989: 69. 339-59. 18. Bozzetti F, Doci R, Bignami Pet al. Patterns of failure following
26 27.
28
29 30.
31. 32.
33.
34
35.
36. 37.
38.
39.
40 41
42.
Downloaded from https://academic.oup.com/annonc/article-abstract/8/4/393/217957 by guest on 11 January 2019
24.
surgical resection of colorectal cancer liver metastases Ann Surg 1986; 305: 264-70 Bush E, Kemeny MM. Colorectal cancer. Hepatic-directed therapy The role of surgery, regional chemotherapy, and novel modalities Semin Oncol 1995, 22: 494-508. Cady B, Stone MD. The role of surgical resection of liver metastases in colorectal carcinoma. Semin Oncol 1991; 18: 399-406 Hughes KS, Rossi RL. Colorectal cancer metastatic to the liver: Resection. In Cameron JL (ed). Current Surgical Therapy, 4th ed. St. Louis, MO: Mosby 1992; 285 Logan SE, Meier SJ, Ramming KP et al Hepatic resection of metastatic colorectal carcinoma: A ten-year experience. Arch Surg 1982; 117:25-8. Morrow CE, Grage TB, Sutherland DER et al. Hepatic resection for secondary neoplasms. Surgery 1982; 92: 610-4 Tomas de la Vega JE, Donahue EJ, Doolas A et al. A ten-year experience with hepatic resection. Surg Gynecol Obstet 1984; 159: 223-8. Nagorney DM. Hepatic resection for metastases from colorectal cancer. Prob General Surg 1987; 4- 83-92. Iwatsuki S, Esquivel CO, Gordon RD et al. Liver resection for metastatic colorectal cancer. Surgery 1986; 100: 804-10. Elias D, Lasser P, Rougier P et al. Another failure in the attempt of definition of the indications to the resection of the liver metastases of colorectal origin J Chir 1992; 129: 59-65 Younes RN, Rogatko A, Brennan MF The influence of intraoperative hypotension and perioperative blood transfusion on disease-free survival in patients with complete resection of colorectal liver metastases. Ann Surg 1991; 214- 107-113. Ravikumar TS, Steele GD Jr. Hepatic cryosurgery. Liver Surg 1989; 69: 433-40. Onik G, Rubinsky B, Zemel R et al. Ultrasound-guided hepatic cryosurgery in the treatment in metastatic colon carcinoma. Cancer 1991; 67: 901-7. Shafir M, Shapiro R, Sung M et al. Cryoablation of unresectable malignant liver tumors. Am J Surg 1996; 171: 27-31. Stewart GJ, Preketes A, Horton M et al. Hepatic cryotherapy Double-freeze cycles achieve greater hepatocellular injury in man. Cryobiology 1995; 32: 215-9. Vahrmeijer AL, van Dierendonckm JH, van de Velde CJH. Treatment of colorectal cancer metastases confined to the liver Eur J Cancer 1995; 31A. 1238-42. Scheithauer W, Rosen H, Kornek GV et al. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 1993, 306: 752-5. Lokich JJ, Ahlgren JD, Gullo JJ et al. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: A MidAtlantic Oncology Program study J Clin Oncol 1989; 7: 425-32. Moertel CG. Chemotherapy for colorectal cancer. N Engl J Med 1994:330: 1136-42. The Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovonn in patients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol 1992; 10: 896-903. Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. J Clin Oncol 1994; 12: 960-9. Glimehus B, Hoffman K, Graf W et al Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer. Cancer 1994; 73: 556-62. Collins JM. Pharmacological rationale for regional drug delivery. J Clin Oncol 1984, 2: 498-504. Chen GHG, Gross JF. Intraarterial infusion of anticancer drugs: theoretic aspects of drug delivery and review of responses. Cancer Treat Rep 1980; 64: 31—40. Yasuda S, NotoT, Ikeda M et al. Hepatic arterial infusion chemotherapy using implantable reservoir in colorectal liver metastasis. GanTo Kagaku Ryoho 1990; 17. 1815-9.
399
54.
55.
56.
57.
58.
59.
60. 61
randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 1990; 8: 1885-93. Kemeny N, Seiter K, Niedzwiecky D et al A randomized trial of intrahepatic infusion of fiuorodeoxyuridine with dexamethasone versus fluorodeoxyundine alone in the treatment of metastatic colorectal cancer. Cancer 1992; 69: 327-34. The Meta-Analysis Group in Cancer. Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. J Natl Cancer Inst 1996; 88: 252-8. Civallen D, Scopinaro G, Simoni G et al. Starch microspheres induced arterial flow redistribution after occlusion of replaced hepatic arteries in patients with liver metastases. Cancer 1986; 58' 2151-5 Lindell B, Aronsen KF, Nosslin B, et al Studies in pharmacokinetics and tolerance of substances temporarily retained in the liver by microsphere embolization. Ann Surg 1978; 187. 95-9. Cascinu S, Wadler S. Chemo-embolization in the treatment of liver metastases from colorectal cancer. CancerTreat Rev 1996; in press. Civallen D, Pector JC, Hakansson L et al. Treatment of patients with unresectable liver metastases from colorectal cancer by chemo-occlusion with degradable starch microspheres. Br J Surg 1994; 81: 1338-41. Giovanmni M, Seitz JF. Ultrasound-guided percutaneous alcohol injection of small liver metastases. Cancer 1994; 73. 294-7 Livraghi T, Vettori C, Lazzaroni S. Liver metastases: results of percutaneous ethanol injection in 14 patients. Radiology 1991; 179. 709-12.
Received 9 December 1996; accepted 21 January 1997. Correspondence to Stefano Cascinu, MD Clinica di Oncologia Medica Universita degli Studi di Ancona Ospedale di Torrette 60020 Ancona, Italy
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43. Ensminger WD, Rosowsky A, Gross JF. A clinical pharmacological evaluation of hepatic arterial infusion of 5-luoro-2'-deoxyuridine and 5-fluorouracil. Cancer Res 1978, 38: 3784-92. 44. Niederhuber JE, Ensminger WD, Gyves JW et al. Regional chemotherapy of colorectal cancer to the liver. Cancer 1984; 53: 1336-43. 45. Shepard KW, Levin B, Karl RC et al. Therapy for metastatic colorectal cancer with hepatic artery infusion chemotherapy using a subcutaneous implanted pump. J Clin Oncol 1985; 3. 161-9. 46. Kemeny N, Daly J, Reichman B et al.lntrahepatic or systemic infusion of fiuorodeoxyuridine in patients with liver metastases from colorectal carcinoma A randomized trial. Ann Intern Med 1987, 63.742-7. 47. Chang AE. Schneider PD, Sugarbaker PH et al. A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyundine chemotherapy in the treatment of colorectal liver metastases Ann Surg 1987; 206: 685-93. 48. Hohn DC, Stagg RJ, Friedman MA et al. A randomized trial of continuous intravenous versus hepatic intra-arterial floxuridine in patients with colorectal cancer metastatic to the liver: The NCOGT. J Clin Oncol 1989; 7: 1646-54. 49. Martin JK, O'Connel MJ.Wieand HS et al. Intraarterial floxuridine vs. systemic fluorouracil for hepatic metastases from colorectal cancer Arch Surg 1990; 125: 1022-7. 50. Rougier P, Laplanche A, Huguier M et al. Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol 1992; 10: 1112-8. 51. Allen-Mersh TG, Earlam S, Fordy C et al. Quality of life and survival with continuous hepatic artery floxuridine infusion for colorectal liver metastases. Lancet 1994; 344- 1255-60 52. Safi F. Continuous simultaneous intraarterial and intravenous therapy of liver metastases of colorectal carcinoma. Results of a prospective randomized trial Proc Am Soc Clin Oncol 1992, 11' 490 (Abstr). 53. Wagman LD, Kemeny MM, Leong L et al. A prospective,
Clinical case Liver metastases from colorectal cancer S. Cascinu,V. Catalano, M. Scartozzi, A. M. Baldelli & R. Cellerino Clinica di Oncologia Medica, Scuola di Speciahzzaztone in Oncologia, Untversita degh Studt di Ancona, Ancona, Italy
Case report
In July 1994, a 58-year-old man presented to his general practitioner with a 2-month history of abdominal pain, constipation and rectal bleeding. He had no relevant medical history except for painful hemorrhoids treated with topical preparations. On examination, there was generalized abdominal distension and tenderness. Colonoscopy revealed a stenosing, bleeding carcinoma of the ascending colon. A CT scan demonstrated two lesions in the left lobe of liver, probably metastases. At laparotomy, the stenosing carcinoma of colon and the liver metastases were confirmed. Left hemicolectomy and reanastomosis, together with left hepatectomy, were performed. Histological examination of the resected specimens showed a moderately differentiated adenocarcinoma of the colon infiltrating the surrounding adipose tissue, with positive lymph nodes and liver metastases from intestinal adenocarcinoma (pT3N2Mi). His postoperative recovery was uncomplicated. The patient was well until May 1995, when an abdominal CT scan revealed two liver metastases (Figure 1); he was operated on again. Wedge resection of the two liver metastases was radical and a catheter was placed in the hepatic artery and connected to a pump placed in an abdominal wall pocket. Postoperative therapy was administered: fluorodeoxyuridine (FUDR) was delivered by continuous infusion through the pump for 14 days, alternating with normal saline solution for 14 days, at the dose of 0.2 mg/kg. In September 1995, at the end of the planned postoperative therapy, a NMR showed progressive disease in the liver. The patient complained of vague pains in the right hypocondrium, which had increased over the previous few months. In October 1995, he was seen for the first time in our department. Because of pain, he was started on systemic chemotherapy with a combination of methotrexate (MTX) 200 mg/m2m i.v. on day 1 and 5-fluorouracil 600 mg/m2 i.v. 24 hours later. Leucovorin was given orally at the dose of 10 mg/m2, every 6 hours x 6 beginning 24 hours after MTX. After 4 cycles of chemo-
therapy, an NMR showed stable disease; there was a reduction in pain and no severe toxicity induced by chemotherapy. A further 4 cycles of chemotherapy were
(b)
Figure 1 CT scan of the abdomen showing two lesions in the VI (a) and VII (b) segments.
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Key words: chemotherapy, colorectal cancer, liver metastases, surgical approach
394
Discussion Colorectal cancer is the third most common malignancy in Western countries. Liver metastases are present at diagnosis in 15% to 25% of patients and will develop in a further 60% of patients with progressive disease, making the liver the most common site of metastatic disease [1]. The presence of hepatic metastases has a major influence on survival, even when metastatic disease is present at other sites. The average duration of survival for patients with untreated liver metastases is brief, on the order of 4 to 9 months [2] although some retrospective surveys have shown a very variable natural history with a median survival of up to 24 months in selected patients without treatment [3, 4].
Surgery In several non-randomized clinical trials, liver resection for hepatic metastases has repeatedly been demonstrated to produce long-term disease-free survival in 20% to 25% of patients (Table 1). Nevertheless, it is curative only in a patient subset, which needs to be defined accurately. Patients should have a good performance, but age alone should not be a criterion for exclusion. Preoperatively, all patients should be completely staged to determine the extent of intrahepatic and extrahepatic metastases and to determine renal function and hepatic reserve: the capacity to regenerate after surgery is correlated with the underlying physiological state of the normal liver parenchyma. It should be emphasized that the presence of extrahepatic disease is not an absolute contraindication to hepatic resection [8, 17, 18]. By the same token, the presence of locally recurrent disease does not exclude a patient from a liver resection if the local disease can be resected completely. If the metastasis is present at the time of primary diagnosis, a general rule could be to perform the resection of the primary tumor and a biopsy of the metastatic
Table I. Results of hepatic resection for colorectal metastases. Author
No. of patients
5-Year survival
Mortality
Adson, 1984 Nordlinger, 1987 Hughes, 1988 Scheele, 1990 Schlag, 1990 Ringe, 1990 Doci, 1991 vanOoijen, 1991 Steele, 1991 Rosen, 1992 Nordlinger, 1996 Marmorale. 1996
141 80 859 226 122 157 100 118 150 280 1568 73
23 25 33 31 30 23 30 21 25 25 28 27
2.8 5 _ 5 4 5 5 8 2.7 4 2.3 13
Ref.
5
6 7 8 9 10 11 12 13 14 15 16
lesion, leaving open the option of reoperation and formal liver resection should it later be deemed appropriate [19]. In concomitant cases, observation for 4 to 6 months before elective hepatic resection will not impair chances of cure [20]. The criteria for performing simultaneous liver resection are: single metastatic lesion that can be removed by limited resection, minimal blood loss or contamination, uncomplicated bowel resection, the possibility of an appropriate incision for resection, medical status permitting both procedures, and a surgeon who is comfortable with the procedure [21]. Several groups have found that patients with concomitant lesions did not fare as well, in terms of survival, as patients in whom the liver lesions were identified some time after the resection of the primary lesion [22-24]. Liver metastases that are identified some time after resection of the primary colorectal cancer may represent a subgroup of favorable, slow-growing lesions. In one large series of 800 liver resections the patients had a mean 5-year survival rate of 33% and a 5-year diseasefree survival rate of 21% [7]. In general, prolonged survival is more likely after resection of single metastases than after excision of multiple metastases [25, 26]. Data suggest that patients with one or two metastases have the same 5-year survival; moreover, it seems that resecting two or three hepatic lesions, whether unilobar or bilobar, yields the same survival as resecting solitary metastases [7]. The Hepatic Registry reported a 5-year survival of 18% for patients with four or more liver metastases compared with 37% with one or two lesions. However, an 18% survival rate can be an acceptable outcome [7]. The maximum number of lesions amenable to resection remains somewhat controversial; most authors agree that resection of up to four metastases is quite reasonable, and several large studies from Europe have included resection of four or more lesions with good results [11, 27]. Prognostic scoring systems have been proposed to evaluate the chances for cure of patients after resection of liver metastases from colorectal carcinoma. Factors related to increased risk of recurrence and death were
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given up to March 1996, when progression of disease was demonstrated by a new NMR and the treatment was stopped. The patient was in good clinical condition but had abdominal pain: chemoembolization was attempted in May 1996, as part of a pilot clinical trial. Embolization was performed after selective catheterization of the hepatic artery. Polyvinyl alcohol (ivalon) mixed with full-strength iodinated radiographic contrast and mytomicin-C (25 mg/m2) were given under direct fluoroscopic control. His pain resolved rapidly and the CEA level fell from 150 ng/ml to 50 ng/ml over the next month. An NMR showed stable disease with an increase in tumor necrosis. Now, four months later, the patient is well and asymptomatic. He is checked regularly by clinical examinations and NMR of the abdomen.
395
Cryosurgery
Hepatic cryosurgery is a relatively new technique that may be a therapeutic option in the treatment of selected patients with unresectable metastatic colon carcinoma. With this technique tumors are destroyed by subzero temperature: cryosurgery appears to work simply by nonspecific tissue destruction [29]. Cryosurgery's advantage is that it is a focal treatment, sparing more normal liver tissue than resection, making it possible to treat multiple lesions in both lobes of the liver. In addition, with cryosurgery, major vessels withflowingblood are protected.
In various small series, 15% to 29% of cryosurgery patients were still alive at two years, without evidence of disease. There were no operative deaths and morbidity rates (15%—20%) were acceptable [30, 31]. Complications of this procedure include hepatic cracking secondary to the thermal stresses that occur with rapid freezing [29, 30]. Cracking is usually associated with hemorrhage, which may require packing. Hemorrhage can also result from direct vascular injury from probe insertion. Asymptomatic right-sided pleural effusions, probably secondary to the irritative process beneath the diaphragm, occur in almost all patients. Elevation in serum AST, biliary fistula, hepatic abscess and thrombocytopenia have been reported [30-32]. As cryosurgery avoids removal of surrounding tissue, patients with bilobar disease and multiple lesions can undergo this procedure. Patients with diffuse infiltrative disease or in whom bilobar lesions have grown to a large size, requiring multiple penetrations with a single cryoprobe, must be excluded, because complete treatment is often not technically feasible and there might be a risk of hepatic failure. No data are available to determine whether the patient's disease is too extensive for cryosurgery; the decision is based on subjective assessment [30]. Hepatic cryosurgery is an investigational procedure with possible complications and should be reserved only for patients who cannot undergo surgical resections. Chemotherapy
Available data suggest that surgical management of metastatic hepatic colorectal cancer may affect the natural course of the disease. However, surgery alone is not enough and most patients will still die of metastatic disease after liver resection. Chemotherapy after liver resection Whether adjuvant chemotherapy can influence survival after liver resection for colorectal metastases is unclear at the present time. Regional chemotherapy might be suitable after initial hepatic resection of metastases since a significant proportion of failures reappear in the liver. However, clinical data on adjuvant intraportal chemotherapy after resection have provided no evidence that locoregional chemotherapy can prevent further recurrence in the liver [33]. Systemic chemotherapy for non-operable disease Surgical procedures are not always appropriate: most patients need a medical treatment. A variety of chemotherapy regimens have been evaluated in advanced colorectal cancer. There is some evidence that chemotherapy can improve survival and quality of life, although prolongation is measured in months [34].
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age, CEA level, stage of the primary tumor (extension into the bowel wall, involvement of nodes, metastases), disease-free interval, number of liver nodules and resection margins. Cady et al. have proposed a preliminary scoring index based on four risk factors: number of the metastatic nodules in the liver, disease-free interval after resection of the primary cancer, level of CEA, and the margins of resection [20]. Others have proposed a system including the number of preoperative hypotensive episodes, number of metastases, CEA level, and location of the primary cancer [28]. Recently, Nordlinger et al. have proposed a simple prognostic scoring system based on evaluation of the following factors in 1568 patients undergoing a resection for liver metastases: age, size of largest metastasis or CEA level, stage of the primary tumor, disease-free interval, number of liver nodules and resection margins. With one point for each factor, the population was divided into three groups with different 2-year survival rates: 79% (0-2), 60% (3-4), 43% (5-7) (15). When resection of liver metastases is considered, the scoring index can help to define the risk for patients and can be used to stratify patients according to their characteristics in prospective studies evaluating prognosis or natural history. Nevertheless, before these scoring systems can be routinely used in clinical practice they need to be validated in other studies assessing different groups of patients. The most common site of recurrence, after liver resection for metastatic disease, is the lung, followed by the liver. The liver will continue to be the site of recurrent disease in some of these patients and, consequently, they will remain candidates for additional attempts of curative liver resections. Liver metastasis recurs after resection in 60% to 70% of patients, in some instances soon after surgery. However, a small percentage of recurrent metastases appear to be solitary or localized in one lobe of the liver. The indication for further resection depends on the operative risk, as compared with first resections, and long-term results. About a quarter of patients who undergo complete resection will be cured again. The operative death rate is l%-2% in the literature, whereas morbidity rates of 20%-52% have been reported [8,15].
396
Intrahepatic arterial chemotherapy (HAI) Several observations support the rationale for regional chemotherapy: 1) liver metastases derive their blood supply from the hepatic artery, while normal hepatocytes do so from the portal vein; 2) some drugs have a high first-pass hepatic extraction, resulting in high local concentrations with low systemic toxicity; 3) the liver is often the first and only site of metastatic disease in colorectal cancer patients. Metabolism and extraction by the liver of agents such as fluoropyrimidines may eliminate more than 80% of the infused drug dose and result in lower systemic concentrations [40,41]. Hepatic arterial infusion (HAI) can be administered by several methods: an arterial port or a percutaneously placed catheter can be connected to an external pump, or a totally implantable pump can be inserted surgically. A study compared the three methods of administration: surgical placement of a hepatic artery catheter, percu-
Table 2 Randomized studies of hepatic arterial vs. systemic chemotherapy for hepatic metastases from colorectal carcinoma. Author
No. of patients
Regimen
Objective responses (%)
Median survival
Ref
Kemeny, 1987
49 51 32 32 67 76 39 35 81 41 41 51 49
HAI/FUDR IVC/FUDR HAI/FUDR IVC/FUDR HAI/FUDR IVC/FUDR HAI/FUDR IVC/5FU HAI/FUDR IVC/5FU No treatment HAI/FUDR Palliation
50 20 62 17 42 10 48 21 43 9 0 40 0
17 mos 12 mos 17mos" 13mos a 16.7 mos 16.1 mos 12.5 mos 10.5 mos 15 mos 11 mos 11 mos 13.5 mos 7.5 mos
46
Chang, 1987 Hohn, 1989 Martin, 1990 Rougier, 1992
Allen-Mersch, 1994
47 48 49 50
51
Abbreviations: 5-FU - 5-fluorouracil; FUDR - fluorodeossiuridine, HAI - hepatic arterial infusion; IVC - intravenous chemotherapy. a Data drawn from survival curves
taneous placement of a hepatic artery catheter, and surgical implantation of a reservoir connected to the hepatic artery catheter [42]. The three systems were able to deliver chemotherapy for 31, 25, and 115 days, respectively. Implanted pumps allow for better long-term patency of both the hepatic artery and the catheter than the arterial ports or percutaneous catheters; implanted pumps are also associated with a lower risk of infection [42]. Phase II trials using FUDR or 5-FU in patients with liver metastases from colon cancer have shown response rates ranging from 20% to 80%; most patients were previously treated and often resistant to systemic chemotherapy [43-45]. Several prospective randomized trials have compared intrahepatic and systemic chemotherapy (Table 2). Response rates are significantly better in the HAI group: 42% to 62% as compared with 10% to 49% in the systemic arms. However, despite adequate response in the liver, systemic failure has been reported in up to 50% of patients, most commonly in the lung. Safi et al. tried to reduce extrahepatic tumor progression using simultaneous i.v. therapy delivered through a dual infusaid pump; results showed a decreased incidence of extrahepatic disease but no impact on survival [52]. The most common toxic effects of HAI are hepatobiliary and ulcer disease, myelosuppression, nausea, vomiting and diarrhea. Hepatic toxicity due to chemical hepatitis can occur in 26% to 79% of patients receiving HAI, while biliary sclerosis occurs in less than 10% of those under careful monitoring. Treatment should be stopped if the hepatic enzymes show a three-fold increase, and should not be restarted until levels return to less than two times normal [46, 47, 53]. The incidence of biliary sclerosis associated with HAI of FUDR could be reduced by shortening the FUDR infusion duration, lowering FUDR dosage, alternating a shorter FUDR course with 5-FU, and mixing FUDR
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5-Fluorouracil (5-FU) remains the most effective single chemotherapy agent, with response rates of about 10%—20%. There have been numerous attempts to increase the efficacy of 5-FU by changing its dose, schedule and route of administration. Response rates improve when prolonged multiweek 5-FU infusions are used but there is no improvement in survival [35]. Most attempts to improve systemic treatment have consisted of empirically adding drugs to 5-FU. Regimens with the addition of methyl-CCNU, vincristine, mitomycin, streptozotocin all failed to yield significant survival gains [36]. Recent attempts to improve the therapeutic effectiveness of 5-FU have focused on the scientific principles of biochemical modulation to produce selective enhancement of cytotoxicity. Two recent meta-analyses suggest that the response rate is higher with the addition of leucovorin (LV) or methotrexate. The latter combination also showed a small survival advantage [37, 38]. Despite the modest advantage, the 5-day regimen of fluorouracil plus low-dose leucovorin is often considered the standard treatment for patients with advanced colorectal cancer because of low drug cost, tolerable toxicity, and symptom relief [36]. A study from northern Europe seemed to demonstrate that approximately one-third of patients with symptomatic advanced colorectal cancer have an improvement in quality of life during cytotoxic treatment. This improvement usually depends on an antitumor effect, although this may not be large enough to be classified as an objective response [39]. It should be borne in mind that while there can be no question of relief of symptoms in asymptomatic patients, survival and symptom-free time are marginally affected and chemotherapy is likely to be toxic. Options should be discussed with a completely informed patient. However, when disease progresses and the patient becomes symptomatic, the possible side effects of therapy may be more acceptable.
397
Chemoembolization Variable tumor vascularization is a critical problem for HAI. Tumors may be either hypervascular or hypovascular and this is an important prognostic factor in regional chemotherapy of liver tumors. The lack of response to regional chemotherapy could be related to poor perfusion of either the entire tumor or portions of it. Only low concentrations of drug may reach hypovascular areas, where dormant cells could be responsible for subsequent disease progression. Chemoembolization is performed after selective catheterization of the hepatic artery using a femoral approach. Embolizing agents, such as gelfoam, ivalon, or microspheres, used to obtain a peripheral embolization are mixed with full-strength iodinated radiographic contrast and cytotoxic drugs. Chemoembolization offers several advantages over hepatic artery infusion, since embolizing agents go preferentially to high-flow areas, redirecting residual arteriolar flow toward previously ischemic areas, as demonstrated with the aid of dynamic CAT scan analysis [56]. Furthermore, the increased transit time through the hepatic circulation has been used to improve the extraction of concurrently infused drugs. A reduction in systemic exposure, secondary to increased uptake by the liver, has been demonstrated for 5-FU, MMC, carmustine and doxorubicin [57]. Results from clinical trials do not allow definitive conclusions to be drawn because of the small sample size and because of the heterogeneity of patient populations and treatments. Available data include several
small studies with a total of approximately 160 patients (most of them previously treated): response rates range from 15% to 30%, the median survival reaches 11 months and palliation of symptoms is obtained in a large number of patients [58, 59]. The possible utility of this approach has to be confirmed in randomized clinical trials. Nevertheless, the presence of nausea/vomiting, fever and pain in almost all patients, the risk of liver abscesses and cholecystitis in about 10% of patients, and finally, the less frequent but life-threatening toxicity represented by hepatic failure (1% of the cases) suggest the use of caution in adopting its generalized use. At present it should be considered an experimental procedure for carefully selected patients with < 50% hepatic replacement by tumor and normal liver function. Percutaneous ethanol Percutaneous ethanol injection (PEI) is a relatively simple and inexpensive method of therapy. This technique may be considered in the management of patients with liver metastases from colorectal cancer who are not candidates for surgery. In general ultrasound percutaneous ethanol injection is more appropriate for hepatocellular carcinoma, because the majority of patients with this cancer have cirrhosis and cannot tolerate conventional surgical or medical treatments. PEI seems to be indicated in the treatment of metastases from colorectal cancer smaller than 3 cm in diameter; when metastases are greater than 3 cm, responses are only partial [60,61]. PEI has proved safe, but its impact on survival or symptom relief has yet to be demonstrated. Conclusions This case illustrates several aspects of an intensive approach to the management of liver metastases from colorectal cancer. By most standards, the treatment given to our patient would be classified as particularly aggressive. He underwent two operations for resection of liver metastases and three different attempts of regional and systemic chemotherapy. Surgical intervention plays a very important role in the management of liver metastases. Even in the presence of liver recurrence after a resection for metastases, a new operation can produce a cure in about 20%-25% of selected patients who can undergo a complete resection. Regional chemotherapy seems to show interestingly high response rates with a possible advantage in survival. The choice of a systemic chemotherapy after failure of HAI depended upon the patient's good clinical condition in the presence of symptoms. Furthermore, the mechanism of action by which the MTX/5-FU combination exerts its activity is different from that of 5-FU or FUDR alone.
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with dexamethasone [49, 55]. Gastritis is found in 8% to 21% of patients and gastric ulcers may occur in 8% to 17%ofpatients[46,47,49]. Recently, a meta-analysis of six randomized clinical trials comparing HAI to intravenous chemotherapy (IV) was carried out to objectively and quantitatively appraise the benefits of HAI in terms of tumor response rate and overall survival [55]. The response rate was 41% for patients allocated to HAI with FUDR compared to 14% for patients allocated to IV with FUDR or 5-FU, and this difference was highly significant. Survival analysis showed a statistically significant advantage for HAI with FUDR over that of IV when all trials with different chemotherapeutic combinations were taken into account (P = 0.0009), but not when the survival analysis was restricted to trials comparing HAI with FUDR (16 months) and IV with FUDR or 5-FU only (12.2 months), (P - 0.14 ). These results seem to confirm that HAI can achieve higher response rates than systemic therapy in patients with liver metastases from colorectal cancer, but the impact on survival is not clear and the therapeutic benefit should be analyzed in further well designed randomized trials, taking into account also the possible side effects and the economic costs of HAI.
398 The use of chemoembolization is more debatable. Our patient was treated with this procedure as part of a pilot clinical trial designed to explore the clinical benefit (objective response and symptom control) in previously treated patients. After the failure of regional and systemic chemotherapy he showed a promising response to chemoembolization in terms of symptom relief. We would not recommend this approach outside a clinical research setting. Our patient is well two years after first surgery for primary and liver metastases. This seems to suggest that an aggressive approach is justifiable in carefully selected patients.
19.
20. 21.
22.
23
References
25.
1. Kemeny N. The systemic chemotherapy of hepatic metastases from colorectal cancer Semin Oncol 1983; 10. 148-58. 2. Bengtsson G, Carlsson G, Hafstrom L et al. Natural history of patients with untreated liver metastases from colorectal cancer. Am J Surg 1981; 141: 586-9. 3. Goslin R, Steele G Jr, Zamcheck N et al. Factors influencing survival in patients with hepatic metastases from adenocarcinoma of the colon and rectum. Dis Colon Rectum 1982; 25. 749-54. 4. Wagner JS, Adson MA, Van Heerden JA et al. The natural history of hepatic metastases from colorectal cancer. Ann Surg 1984; 199. 502-7 5. Adson MA, van Heerden JA, Adson MH et al. Resection of hepatic metastases from colorectal cancer. Arch Surg 1984, 119: 647-51. 6. Nordlinger B, Pare R, Delva E, et al. Hepatic resection for colorectal liver metastases. Ann Surg 1987; 205: 256-63 7. Hughes K, Simon R, Songhorabodi S et al. Resection of the liver for colorectal carcinoma metastases: A multi-institutional study of indications for resection. Registry of hepatic metastases. Surgery 1988; 103: 278-84. 8. Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carcinoma: Impact of surgical resection on the natural history. Br J Surg 1990; 77: 1241-6. 9. Schlag P, Hohenberger P, HoltingTet al. Hepatic arterial infusion (HAI) chemotherapy for liver metastases of colorectal cancer using 5-FU. Eur J Surg Oncol 1990, 16. 99-104. 10. Ringe B, Beehstein WO, Raab R, et al. Leberresektion bei 157 patienten mit colorectalen metastasen. Chirurg 1990; 61: 272-9. 11. Doci R, Gennari L, Bignami P et al. One hundred patients with hepatic metastases from colorectal cancer treated by resection: Analysis of prognostic determinants. BrJ Surg 1991; 78: 797-801. 12 van Ooijen B, Wiggers T, Meijer S et al. Hepatic resection for colorectal metastases in The Netherlands - a multiinstitutional 10-year study. Cancer 1991; 70. 28-34. 13. Steele G Jr, Bleday R, Mayer RJ et al. Prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group Protocol 6584. J Clin Oncol 1991; 9: 1105-12. 14. Rosen CB, Nagorney DM, Taswell HF et al. Perioperative blood transfusion and determinants of survival after resection for metastatic colorectal carcinoma. Ann Surg 1992; 216: 493-505. 15. Nordlinger B, Guiguet M, Vaillant JC et al. Surgical resection of colorectal carcinoma metastatic to the liver. Cancer 1996, 77: 1254-62. 16. Marmorale C, Miconi G, De Luca S, et al. Surgical treatment of hepatic metastatic colorectal cancer. Ann Ital Chir 1996; 4: 1-6. 17. Hughes K, Scheele J, Sugarbaker PH. Surgery for colorectal cancer metastatic to the liver: Optimizing the results of treatment. Liver Surg 1989: 69. 339-59. 18. Bozzetti F, Doci R, Bignami Pet al. Patterns of failure following
26 27.
28
29 30.
31. 32.
33.
34
35.
36. 37.
38.
39.
40 41
42.
Downloaded from https://academic.oup.com/annonc/article-abstract/8/4/393/217957 by guest on 11 January 2019
24.
surgical resection of colorectal cancer liver metastases Ann Surg 1986; 305: 264-70 Bush E, Kemeny MM. Colorectal cancer. Hepatic-directed therapy The role of surgery, regional chemotherapy, and novel modalities Semin Oncol 1995, 22: 494-508. Cady B, Stone MD. The role of surgical resection of liver metastases in colorectal carcinoma. Semin Oncol 1991; 18: 399-406 Hughes KS, Rossi RL. Colorectal cancer metastatic to the liver: Resection. In Cameron JL (ed). Current Surgical Therapy, 4th ed. St. Louis, MO: Mosby 1992; 285 Logan SE, Meier SJ, Ramming KP et al Hepatic resection of metastatic colorectal carcinoma: A ten-year experience. Arch Surg 1982; 117:25-8. Morrow CE, Grage TB, Sutherland DER et al. Hepatic resection for secondary neoplasms. Surgery 1982; 92: 610-4 Tomas de la Vega JE, Donahue EJ, Doolas A et al. A ten-year experience with hepatic resection. Surg Gynecol Obstet 1984; 159: 223-8. Nagorney DM. Hepatic resection for metastases from colorectal cancer. Prob General Surg 1987; 4- 83-92. Iwatsuki S, Esquivel CO, Gordon RD et al. Liver resection for metastatic colorectal cancer. Surgery 1986; 100: 804-10. Elias D, Lasser P, Rougier P et al. Another failure in the attempt of definition of the indications to the resection of the liver metastases of colorectal origin J Chir 1992; 129: 59-65 Younes RN, Rogatko A, Brennan MF The influence of intraoperative hypotension and perioperative blood transfusion on disease-free survival in patients with complete resection of colorectal liver metastases. Ann Surg 1991; 214- 107-113. Ravikumar TS, Steele GD Jr. Hepatic cryosurgery. Liver Surg 1989; 69: 433-40. Onik G, Rubinsky B, Zemel R et al. Ultrasound-guided hepatic cryosurgery in the treatment in metastatic colon carcinoma. Cancer 1991; 67: 901-7. Shafir M, Shapiro R, Sung M et al. Cryoablation of unresectable malignant liver tumors. Am J Surg 1996; 171: 27-31. Stewart GJ, Preketes A, Horton M et al. Hepatic cryotherapy Double-freeze cycles achieve greater hepatocellular injury in man. Cryobiology 1995; 32: 215-9. Vahrmeijer AL, van Dierendonckm JH, van de Velde CJH. Treatment of colorectal cancer metastases confined to the liver Eur J Cancer 1995; 31A. 1238-42. Scheithauer W, Rosen H, Kornek GV et al. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 1993, 306: 752-5. Lokich JJ, Ahlgren JD, Gullo JJ et al. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: A MidAtlantic Oncology Program study J Clin Oncol 1989; 7: 425-32. Moertel CG. Chemotherapy for colorectal cancer. N Engl J Med 1994:330: 1136-42. The Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovonn in patients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol 1992; 10: 896-903. Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. J Clin Oncol 1994; 12: 960-9. Glimehus B, Hoffman K, Graf W et al Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer. Cancer 1994; 73: 556-62. Collins JM. Pharmacological rationale for regional drug delivery. J Clin Oncol 1984, 2: 498-504. Chen GHG, Gross JF. Intraarterial infusion of anticancer drugs: theoretic aspects of drug delivery and review of responses. Cancer Treat Rep 1980; 64: 31—40. Yasuda S, NotoT, Ikeda M et al. Hepatic arterial infusion chemotherapy using implantable reservoir in colorectal liver metastasis. GanTo Kagaku Ryoho 1990; 17. 1815-9.
399
54.
55.
56.
57.
58.
59.
60. 61
randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 1990; 8: 1885-93. Kemeny N, Seiter K, Niedzwiecky D et al A randomized trial of intrahepatic infusion of fiuorodeoxyuridine with dexamethasone versus fluorodeoxyundine alone in the treatment of metastatic colorectal cancer. Cancer 1992; 69: 327-34. The Meta-Analysis Group in Cancer. Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. J Natl Cancer Inst 1996; 88: 252-8. Civallen D, Scopinaro G, Simoni G et al. Starch microspheres induced arterial flow redistribution after occlusion of replaced hepatic arteries in patients with liver metastases. Cancer 1986; 58' 2151-5 Lindell B, Aronsen KF, Nosslin B, et al Studies in pharmacokinetics and tolerance of substances temporarily retained in the liver by microsphere embolization. Ann Surg 1978; 187. 95-9. Cascinu S, Wadler S. Chemo-embolization in the treatment of liver metastases from colorectal cancer. CancerTreat Rev 1996; in press. Civallen D, Pector JC, Hakansson L et al. Treatment of patients with unresectable liver metastases from colorectal cancer by chemo-occlusion with degradable starch microspheres. Br J Surg 1994; 81: 1338-41. Giovanmni M, Seitz JF. Ultrasound-guided percutaneous alcohol injection of small liver metastases. Cancer 1994; 73. 294-7 Livraghi T, Vettori C, Lazzaroni S. Liver metastases: results of percutaneous ethanol injection in 14 patients. Radiology 1991; 179. 709-12.
Received 9 December 1996; accepted 21 January 1997. Correspondence to Stefano Cascinu, MD Clinica di Oncologia Medica Universita degli Studi di Ancona Ospedale di Torrette 60020 Ancona, Italy
Downloaded from https://academic.oup.com/annonc/article-abstract/8/4/393/217957 by guest on 11 January 2019
43. Ensminger WD, Rosowsky A, Gross JF. A clinical pharmacological evaluation of hepatic arterial infusion of 5-luoro-2'-deoxyuridine and 5-fluorouracil. Cancer Res 1978, 38: 3784-92. 44. Niederhuber JE, Ensminger WD, Gyves JW et al. Regional chemotherapy of colorectal cancer to the liver. Cancer 1984; 53: 1336-43. 45. Shepard KW, Levin B, Karl RC et al. Therapy for metastatic colorectal cancer with hepatic artery infusion chemotherapy using a subcutaneous implanted pump. J Clin Oncol 1985; 3. 161-9. 46. Kemeny N, Daly J, Reichman B et al.lntrahepatic or systemic infusion of fiuorodeoxyuridine in patients with liver metastases from colorectal carcinoma A randomized trial. Ann Intern Med 1987, 63.742-7. 47. Chang AE. Schneider PD, Sugarbaker PH et al. A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyundine chemotherapy in the treatment of colorectal liver metastases Ann Surg 1987; 206: 685-93. 48. Hohn DC, Stagg RJ, Friedman MA et al. A randomized trial of continuous intravenous versus hepatic intra-arterial floxuridine in patients with colorectal cancer metastatic to the liver: The NCOGT. J Clin Oncol 1989; 7: 1646-54. 49. Martin JK, O'Connel MJ.Wieand HS et al. Intraarterial floxuridine vs. systemic fluorouracil for hepatic metastases from colorectal cancer Arch Surg 1990; 125: 1022-7. 50. Rougier P, Laplanche A, Huguier M et al. Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol 1992; 10: 1112-8. 51. Allen-Mersh TG, Earlam S, Fordy C et al. Quality of life and survival with continuous hepatic artery floxuridine infusion for colorectal liver metastases. Lancet 1994; 344- 1255-60 52. Safi F. Continuous simultaneous intraarterial and intravenous therapy of liver metastases of colorectal carcinoma. Results of a prospective randomized trial Proc Am Soc Clin Oncol 1992, 11' 490 (Abstr). 53. Wagman LD, Kemeny MM, Leong L et al. A prospective,