Treatment of Malignant Liver Tumors

ANNALS OF SURGERY Vol. 225. No. 1. 39-50 1997 Lippincott-Raven Publishers .. Place of Cryosurgery in the Treatment of Malignant Liver Tumors Rehe Ada...
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ANNALS OF SURGERY Vol. 225. No. 1. 39-50 1997 Lippincott-Raven Publishers ..

Place of Cryosurgery in the Treatment of Malignant Liver Tumors Rehe Adam, M.D., Ph.D., Edip Akpinar, M.D., Marc Johann, M.D., Francis Kunstlinger, M.D., Pietro Majno, M.D., and Henri Bismuth, M.D., F.A.C.S. (Hon.) From Hepatobiliary Surgery and Liver Transplant Unit, Hopital Paul Brousse, Universit6 Paris Sud, Villejuif, France

Objective The authors evaluate the results of

cryosurgery

in malignant liver tumors.

Summary Background Data The outcome of primary or secondary liver tumors is poor when resection can not be achieved. Encouraging results of cryosurgery have been reported in unresectable liver tumors, but this treatment needs further evaluation of its efficacy in homogeneous groups of patients.

Methods From 63 patients with malignant liver tumors with various histology treated by cryosurgery in a 2.5-year period, the authors evaluated the results of 34 patients with nonresectable hepatocellular carcinoma (9 patients) or nonresectable metastases from colorectal cancer (25 patients). Cryosurgery was used either as a single treatment (4 hepatocellular carcinomas, 5 metastases) or in association with liver resection (5 hepatocellular carcinomas, 20 metastases). Systemic chemotherapy was used routinely before surgery and after surgery.

Results There was no intraoperative mortality. Mortality within 2 months was 3% and was unrelated to the procedure. Postoperative morbidity consisted of one sterile fluid collection and one biliary fistula (8%). At a mean follow-up of 16 months, (range, 2-27) local recurrence rate was 0% for hepatocellular carcinoma and 44% for metastases. Cumulative survival at 24 months was 63% and 52%, respectively, with 6 patients (67%) and 5 patients (20%) currently disease free. In the group of patients with metastases, survival was related to the size of the treated tumor (p = 0.06) and the absence of residual disease (p = 0.03). Conclusions Cryosurgery is safe and increases the number of patients with unresectable liver malignancies in whom surgery can aim at eradicating the tumor. Local recurrence is observed more frequently for metastases than for hepatocellular carcinoma. The benefit in survival is related to the complete treatment of the tumoral disease.

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Adam and Others

Liver resection is the best treatment of malignant liver tumors and the sole therapy giving a chance of cure. However, it may be achieved in only 10% to 20% of patients" 2 with 5-year survival of 25% to 39% for liver colorectal metastases3- and in 12% to 39% of patients with hepatocellular carcinoma (HCC).7 When curative liver resection can not be performed, palliative resection is of no significant benefit,8 and even when patients are treated by chemotherapy or chemoembolization, the outcome is poor. Median survival is around 12 months for unresectable liver metastases from colorectal cancer2 and from 1.6 to 4.0 months for unresectable HCC.9-" Cryosurgery recently has provided a new therapeutic approach for unresectable liver tumors. Pioneering groups reported encouraging results in patients treated by this technique.'2-'6 With the subsequent refinement of cryosurgery in the field of hepatic surgery and the widespread use of intraoperative ultrasonography of the liver, other reports have emerged on the potential benefit of cryosurgery in patients not amenable to curative resection.17-23 More recent studies even have suggested that cryosurgery may achieve results similar to those of resection.2425 The efficacy of cryosurgery in unresectable liver tumors is, however, difficult to assess because most reports include different varieties of tumors 15,1823 different patient selection criteria, and different treatment protocols (Table 1). 1420 Accordingly, the indications and results of cryosurgery for specific tumor types need further investigation. In this study, we analyzed the results of cryosurgery when used either alone or as an adjunct to resection in HCC and colorectal metastases not amenable to radical surgical excision, with the purpose of determining if this technique can be used as an alternative to surgery and/or as a complement to hepatic resection when hepatectomy by itself can not be curative.

PATIENTS AND METHODS Between October 1993 and February 1996, 63 patients with malignant liver tumors were treated by cryosurgery in our center. There were 13 patients with HCC, 40 patients with metastases originating from colorectal adenocarcinoma, and 10 patients with liver metastases from cancer of noncolorectal origin. To focus on the results of the two more common pathologic varieties of hepatic malignancy (i.e., HCC and colorectal liver metastases), we excluded from the study the 10 patients with metastases from noncolorectal origin. During the study period, 251 patients with HCC were Address reprint requests to Professor R. Adam, Hepato-Biliary Surgery and Liver Transplant Research Center, H6pital Paul Brousse, 94804 Villejuif, France. Accepted for publication August 25, 1996.

Ann. Surg. * January 1997

admitted to our center, of whom 60 (24%) were resected-30 (12%) by partial liver resection, 4 of those with cryosurgery applied on the resection margins, and 30 (12%) by liver transplantation-and 191 (76%) were considered as nonresectable. Of these 191, 44 (23%) had symptomatic treatment only, 138 (72%) received arterial chemoembolization alone, and 9 (5%) were treated by cryosurgery. Also, 273 patients with colorectal metastases were admitted, of whom 102 (37%) underwent a liver resection (15 with cryosurgery of the resected margins) and 171 (63%) were considered nonresectable. One hundred forty-six (85%) of these patients with unresectable disease were treated by chemotherapy alone and 25 (15%) were treated by cryosurgery, either exclusively or in association with resection and chemotherapy. Of the 53 patients with either HCC or colorectal liver metastases treated by cryosurgery, there were 19 patients whose tumor had been resected but with a reduced margin of security (

|

64%

Tumor Sizes30 mm (16 pts)

.5 Tumor Size>30 mm (9 pts)

.3 .2 .1 0

0

6

12

18

24

30 Months

Figure 3. Cumulative survival of patients with unresectable colorectal liver metastases in relation to the size of the tumor treated by cryosurgery (log-rank test - p = 0.06).

16 months (range, 2-27). Eleven patients with metastases presented with a local recurrence after cryosurgery, of whom 6 were confirmed on pathologic analysis and 5 were diagnosed by combination of size increase of the cryotreated lesion and increased tumor markers. The overall recurrence rate of the disease at 16 months was 54% in the colorectal metastases group and 33% in the HCC group. Recurrence patterns are presented in Table 5.

Subsequent Hepatic Resection and Associated Extrahepatic Surgery In the group of patients with metastases, two patients were submitted to hepatic resection for local recurrence within 5 and 7 months, respectively, after cryosurgery and five patients had repeat hepatic resection, four for local recurrence at 4, 7, 10, and 12 months and one for recurrence outside the site of cryosurgery at 8 months. Four patients with metastases underwent resection of lung metastases, whereas no patient with HCC was submitted to extrahepatic surgery.

Patient Survival After a mean follow-up of 16 months, 13 patients (38%) have died, 3 (33%) in the HCC group and 10 (40%) in the colorectal metastases group. Overall survival of the colorectal metastases group was 77% at 12 months and 52% at 24 months (Fig. 2). Median survival was not achieved at a follow-up of 16 months (Fig. 2). In the HCC group, overall survival was 77% and 63%, respectively. Currently, five patients (20%) with colorectal metastases and six patients (67%) with HCC are disease free. In the colorectal metastases group, patients with tumors smaller than 30 mm had an increased survival as compared to those with tumors of 30 mm and greater (64% vs. 33% at 2 years, p = 0.06) (Fig. 3). Survival was significantly

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higher when cryosurgery was macroscopically curative as compared to patients having persistent tumor (e.g., hepatic or extrahepatic) after the procedure (64% vs. 21% at 2 years, p = 0.03) (Fig. 4). When the maximum size of the lesions was smaller than 30 mm and was combined with the absence of any residual tumor (e.g., hepatic or extrahepatic) after cryosurgery, survival was significantly better than with patients with a maximum size of lesions greater than 30 mm and presence of residual tumor (72% vs. 20%, p = 0.02).

DISCUSSION This study explores the possible benefit of cryosurgery in the treatment of unresectable hepatic malignancy, which indeed represents the majority of primary and secondary liver tumors. Our standard approach when resection was impossible was to use systemic chemotherapy for liver colorectal metastases28 and chemoembolization for HCC.29 The results of such palliative treatments were poor except when a subsequent liver resection was performed in some patients having responded dramatically to chemotherapy.30 For HCC, the rate of survival of our patients treated by arterial chemoembolization alone was 24% at 2 years in the absence of cirrhosis. It was 49% for patients with cirrhosis class A, 29% for class B, and 9% for class C.29 Similarly, median survival of patients with unresectable colorectal metastases treated by our standard systemic chemotherapy protocol was 15 months.28 It is, therefore, in this group of patients with unresectable disease where the role of cryosurgery should be explored. Our patient selection in the study period showed that cryosurgery could not be applied to a high proportion of patients with unresectable tumors, even when the presence of extrahepatic disease was not considered as a contraindication to the use of this technique. Patients treated by cryosurgery within the study period represented 5% and 15%, respectively, of patients treated for unresectable HCC and metastases of colorectal cancer. However, this has to be compared to arterial chemoembolization and systemic chemotherapy used as single therapies for 72% of unresectable HCC and for 85% of unresectable colorectal metastases, respectively, during the same period. This proportion is merely a rough indicator that possibly underestimates the place of the technique because a new procedure needs a period of evaluation before being used more extensively. In addition, cryosurgery also was used in resectable patients when tumors were resected with narrow margins of security. The aim in this indication was to devitalize an additional rim of juxtatumoral tissue, therefore helping resection to be curative. No local recurrence was observed in these patients. In accordance with previous reports,12-22 the results of

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Adam and Others

Ann. Surg. * January 1997

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Cryosurgery in the Treatment of Malignant Liver Tumors

Vol. 225 * No. 1

47

Table 5. TUMOR RECURRENCE PATTERNS FOLLOWING LIVER CRYOSURGERY

Metastases of colorectal cancer Cryosurgery alone Cryosurgery + resection Overall Hepatocellular carcinoma Cryosurgery alone Cryosurgery + resection Overall

No. of Patients

Local Recurrence*

5 20 25

4 (80) 7 (35) 11 (44) 0 0 0

4 5 9

Hepatic Recurrence*

Extrahepatic Recurrence*

3 (60) 12 (60) 15 (60)

4 (80) 6 (30) 10 (40)

1 (25) 2 (40) 3 (33)

1 (25) 1 (20) 2 (22)

Values are no. (%).

our study clearly show that cryosurgery was s,afe because no significant complication related to the trejatment was observed in the series. In terms of local tunnor control, encouraging results were observed for HCC because no patent local recurrence was observed in an' y of the 10 nodules treated by cryosurgery. By contrast, a high local recurrence rate (44%) was observed for color ectal metastases. A difference of sensitivity of tumoral tis;sue to cryosurgery between HCC and colorectal metas tases could explain the disparity in recurrence rates. No da ta are available in the literature concerning the rate of local recurrence of HCC after cryosurgery, and only twto series reported recurrence rates of 9%18 and 22%'3 after cryosurgery of colorectal metastases. We have no1U 1ctar explanation for the high recurrence rate of cryotreated colorectal metastases in our series. It is pos;sible that a selection bias favoring a negative outcome e)dists for our patients as compared to other series: resectalble extrahepatic disease was not considered as a contrain(dlication and in some patients, not excluded from the stucly, cryosurgery could not treat all the liver lesions as irntended miltially. These factors, however, would be expec ted toaffect 21

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Cumulative Percent Surviving .9 .8 .7 .6 .5 .4 .3 .2 .1 0

All Tumor Mass Treated (17 pts)

Non Trated Tumor Mass (8 pts) 0

6

12

18

24

30 Months

Figure 4. Cumulative survival of patients with unresectcable colorectal liver metastases in relation to the presence of residual di,sease (hepatic or extrahepatic) after cryosurgery (log-rank test - p = 0.03).

hepatic or extrahepatic recurrence rather than local recurrence. A different technique of cryosurgery as compared to others also may be argued, but our protocol of two freezing-thawing cycles per lesion with an iceball of 1 cm around the lesion was similar to that used by other groups. Finally, our policy of obtaining histologic material from any suspicious modification of the cryotreated site may have been more sensitive in the diagnosis of recurrence. Disease-free survival rates of only 28% and 11% for 24 and 30 months follow-up, respectively, have been reported by Ravikumar et al.'8 and Weaver et al.2' similar to ours, indicating that recurrence after cryosurgery may be more frequent than commonly admitted. Our study suggests that cryosurgery of a tumor does not achieve total destruction of the tumoral tissue in all cases. The histologic type of the tumor, the size of the treated lesion, as well as the method used for cryosurgery probably influence the radicality of the treatment. We are, therefore, reluctant to claim that cryosurgery has similar results to resection. Cryosurgery alone was used in only a few patients

(four HCC and five colorectal metastases) in our study, illustrating our policy to treat concomitant liver lesions by resection whenever possible. The causes of unresectability were different between HCC and colorectal metastases. Although the presence of underlying cirrhosis combined with the ill location of the tumors was the main contraindication to resect HCC, multinodular or large le-

sions were the principal contraindications for resecting colorectal metastases. The results also were different. Although three of four patients with HCC treated exclusively by cryotherapy show at present no residual liver disease, recurrence developed in four of five patients with colorectal metastases and three have died. The benefit of cryosurgery in the latter patients is not shown, possibly because the widespread diffusion of the disease favored the recurrence of the tumor despite preoperative and postoperative chemotherapy. However, our present results do

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Adam and Others

not advocate the use of cryosurgery alone in patients with widespread multinodular disease. From the results of our study, the main indication for cryosurgery is as a complement to hepatic resection in patients in whom hepatectomy has dealt with the main tumor mass, but some residual tumor can not be resected. In our experience, this group of patients has a more favorable prognosis than have patients with multinodular bilateral disease, less amenable to tumor-ablating procedures. Accordingly, the current survival rate of patients treated with a multimodality associating cryosurgery, resection, and either systemic chemotherapy or arterial chemoembolization (52% for colorectal metastases and 67% for HCC at 24 months) compares favorably with the reported survival of patients treated only by chemotherapy or chemoembolization. Cryosurgery, when associated concomitantly with resection, often was limited to one to three residual tumors of small size. This condition probably explains the better results as compared with cryosurgery alone. Furthermore, the survival rate of patients with colorectal metastases smaller than 30 mm tended to be higher than that of patients with larger tumors (64% vs. 33% at 2 years). This suggests that the efficacy of cryosurgery for eradication of tumors is dependent on the size of the lesion. This point also has been stressed by Zhou et al.14'22 for HCC and Onik et al. '3 for colorectal metastases. Another important result of our study was the demonstration that the benefit of cryosurgery was observed when no residual tumor (i.e., hepatic or extrahepatic) was left after the treatment (64.5% vs. 21.0% survival at 2 years, respectively). Indeed, a poor outcome was observed even when subsequent macroscopically curative hepatectomy or extrahepatic surgery could be performed on residual untreated disease. Accordingly, our present tendency is not to offer cryosurgery to patients with widespread liver disease or with extrahepatic metastases. In conclusion, cryosurgery may increase the number of patients with initially unresectable liver tumors in whom surgery can be curative. The benefit is related to the complete treatment of tumor, a goal that rarely can be obtained in patients with widespread multinodular disease. The results of our study, despite the short follow-up, suggest that a benefit exists, mainly when cryosurgery is associated with liver resection. Rather than an alternative to resection, cryosurgery is to be regarded as a complement to hepatectomy and as an additional means to achieve tumor eradication when total excision can not be accom-

plished.

References 1. Steele U, Ravikumar TS, Benotti PN. New surgical treatments for recurrent colorectal cancer. Cancer 1990; 65:723-730.

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2. Strangl R, Altendorf-Hoffmann A, Chamley RM, et al. Factors influencing the natural history of colorectal liver metastases. Lancet 1994; 343:1405-1410. 3. Adson MA. Resection of liver metastases-when is it Worthwhile? World J Surg 1987; 11:511-520. 4. Hughes KS, Simon R, Songhorabodi S, et al. Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of indications for resection. Surgery 1988; 103:278-288. 5. Nordlinger B, Jaeck D, Guiguet M, et al. Traitement des metastases hepatiques des cancers colorectaux. Monographies de l'Association Fran,aise de Chirurgie (AFC). New York: Springer-Verlag; 1992:129-146. 6. Scheele J, Stang R, Altendorf-Hofmann A, et al. Resection of colorectal metastases. World J Surg 1995; 19:59-71. 7. Farmer DG, Rososve MH, Shaked A. Current treatment modalities for hepatocellular carcinoma. Ann Surg 1994; 219:236-247. 8. Scheele J, Strangl R, Altendorf-Hofmann A. Hepatic colorectal metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg 1990; 77:1241-1246. 9. Okuda K, Ohtsuki T, Obata H, et al. Prognosis of primary hepatocellular carcinoma. Hepatology 1984; 4:35-65. 10. Nagasue N, Yukaya K, Hamada T. The natural history of hepatocellular carcinoma: A study of 100 untreated cases. Cancer 1984; 54:1461-1465. 11. Falkson G, Cnaan A, Schutt AJ, et al. Prognosis factors for survival in hepatocellular carcinoma. Cancer Res 1988; 48:7314-7318. 12. Ravikumar TJ, Kane R, Cady B, et al. Hepatic cryosurgery with intraoperative ultrasound monitoring for metastatic colon carcinoma. Arch Surg 1987; 122:403-409. 13. Onik G, Rubinsky B, Zemel R, et al. Ultrasound-guided hepatic cryosurgery in the treatment of colorectal metastatic colon carcinoma. Preliminary results. Cancer 1991; 67:901-907. 14. Zhou XD, Tang ZY, Yu YQ, et al. Clinical evaluation of cryosurgery in the treatment of primary liver cancer. Report of 60 cases. Cancer 1988; 61:1889-1892. 15. Charnley RM, Doran J, Morris DL. Cryotherapy for liver colorectal metastases: A new approach. Br J Surg 1989; 76:1040-1041. 16. Ravikumar TS, Steele GD. Hepatic cryosurgery. Surg Clin North Am 1989; 60:433-440. 17. Ravikumar TS, Steele G, Kane R, et al. Experimental and clinical observations on hepatic cryosurgery for colorectal metastases. Cancer Res 1991; 51:6323-6327. 18. Ravikumar TS, Kane R, Carly B, et al. A 5 year study of cryosurgery in the treatment of liver tumors. Arch Surg 1991; 126:1520-1524. 19. Onik GM, Atkinson D, Zemel R, et al. Cryosurgery of liver cancer. Semin Surg Oncol 1993; 9:309-317. 20. Preketes AP, Caplehom JRM, King J, et al. Effect of hepatic artery chemotherapy on survival of patients with hepatic metastases from colorectal carcinoma treated with cryotherapy. World J Surg 1995; 19:768-771. 21. Weaver ML, Atkinson D, Zemel R. Hepatic cryosurgery in treating colorectal metastases. Cancer 1995; 76:210-214. 22. Zhou XD, Tang ZY, Yu YQ, et al. The role of cryosurgery in the treatment of hepatic cancer: a report of 113 cases. Cancer Res Clin Oncol 1993; 120:100-102. 23. Shafir M, Shapiro R, Sung M, et al. Cryoablation of unresectable malignant liver tumors. Am J Surg 1996; 171:27-31. 24. Cady B, Stone MD, McDermott WV, et al. Technical and biological factors in disease free survival after hepatic resection for colorectal metastases. Arch Surg 1992; 127:561-569. 25. Steele G. Cryoablation in hepatic surgery. Semin Liver Dis 1994; 14:120-125. 26. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer 1981; 47:207-214.

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27. Bismuth H, Adam R, Mathur S, et al. Options for elective treatment of portal hypertension in cirrhotic patients in transplantation era. Am J Surg 1990; 160:105-110. 28. Ldvi F, Misset JL, Brienza Z, et al. A chronopharmacologic phase II clinical trial with 5-Fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. Cancer 1992; 69:893-900. 29. Bismuth H, Morino M, Sherlock D, et al. Primary treatment of hepatocellular carcinoma by arterial chemoembolisation. Am J Surg 1992; 163:387-394. 30. Adam R, Ldvi F, Navarro F, et al. Combined treatment of irresectable liver metastases of colorectal cancer by chemotherapy and subsequent hepatic resection. Br J Surg 1992; 79(Suppl):S79.

DISCUSSION DR. R. MARGREITER (Innsbruck, Austria): I am one of those who does not know anything about cryosurgery, but I still do have a few questions. It is certainly a nice approach and an excellent work like everything coming out from our President's department, but I would be interested to know if there was a correlation between the increase in liver enzymes and the response, maybe even the survival, because if you have a sharp increase in transaminases, that would mean that you treated also the surrounding tissues because you would not get an increase in enzyme inside the tumor only. This would be my first question. Second question would be: Has there been performed any concomitant systemic treatment for those patients suffering from colorectal metastases? And I saw that you removed all those extra hepatic lesions that were seen, I think, in all together five or seven patients. Could you say a little bit about the tumors? You have, I think if I recall correctly, two patients who had only one nodule and all together five patients who had only two nodules. Usually such singular metastases can be resected by classical typical resection. Another thing: You showed a significant difference between those patients treated only with cryosurgery and those who have had it combined with a resection. What was that resection? Was it just enucleation or was it with a tumor-free margin of 1 cm or something like that? Could you specify what you mean by resection combined with cryosurgery? What kind of resection was it? I appreciate very much that you changed your conclusion: In your summary, you said "resection to achieve a curative treatment." I think you cannot say curative if you achieve only 30% to 50% survival at 2 years. That would be my comment rather than my question. DR. A. JOHNSON (Sheffield, UK): Could you tell me something about the position of the tumors in regard to the unresectability? We have limited experience with this technique. If they are close to vena cava, for example, which is one of the reasons they may not be resected, then it is very difficult to achieve adequate freezing and the cardiac complications increased if you are cooling down the vena cava. DR. BROELSCH (Hamburg, Germany): I have very much appreciated this interesting approach. I do have a question regarding the concept of this approach in the context of a multisegmentectomy, which is coming particularly from Professor Bismuth's institution. When do you do multisegmentectomy? Why do you

Cryosurgery in the Treatment of Malignant Liver Tumors

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really prefer cryosurgery, which seems to be an effective but really only a palliative procedure? I am quite uncertain where this concept fits into your approach for unresectable malignancies. The last question I have is regarding the side effects of this cryotherapy. There are some case reports, a few from Pittsburgh, dealing with subsequent shock after extended cryotherapy and this was related to the release of cytokines and some toxic substances deriving from necrotizing liver tissue. If you look back into all data of heat shock proteins, I would expect some reaction of the body to this tremendous trauma. DR. ALMEIDA (Lisboa, Portugal): What negative temperature do you use? How many degrees negative do you advise to give? And the second question is: Do you use the Pringle's maneuver in cryosurgery? One is the degree of the temperature that you arrive because it is important in many studies and the second question, if you do use the Pringle's maneuver to obtain a lower temperature of the liver because it is easier to obtain a low temperature with this? DR. HARDER (Basel, Switzerland): Henri Bismuth last year presented a series of unresectable liver tumors treated with polychemotherapy very aggressively during up to a year or even more. What is the difference in indication when you choose this approach, when you choose this multiple chemotherapy, and the second question is how does this cryotherapy compare with alcoholic installation? DR. MORRIS (Oxford, UK): Do you think that now you have enough information to plan a prospective randomized trial of this therapy?

DR. R. ADAM (Closing Discussion): I would like to thank all the discussants for their kind comments and questions. Dr. Margreiter asked about the possible relation between the raise in liver enzymes and the response to therapy. We did not study precisely this factor, but my feeling is that there is no correlation: If it is true that an increase in transaminase may mean that there is a fair amount of necrosing healthy liver tissue as a safety margin around the lesion, it may also mean that we performed more extensive cryotherapy on a larger lesion, which may have a less favorable prognosis. With regard to the second question concerning associated forms of treatment, our usual approach in hepatocellular carcinoma is to perform arterial chemoembolization, and all the patients treated by surgery or by cryosurgery had preoperative chemoembolization (1 to 5 courses). In patients with unresectable colorectal metastases, systemic chemotherapy combining 5-FU, folinic acid, and oxaliplatin had been given. We use Paul Brousse protocols with chronomodulated chemotherapy based on the principle that for every drug used, there is a known time period in the 24 hours in which the toxicity is less, and we administer the drugs at that time to increase the dose and to try to optimize the efficacy. Dr. Margreiter also asked about the criteria defining unresectable disease, and about the kind of procedures performed when liver resection was associated with cryosurgery. There was a major difference in the reasons for unresectability between patients with HCC and those with colorectal metastases. All pa-

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