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Prognostic factors for cryotherapy of colorectal liver metastases
EJSO (2004) 30, 34–40
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Prognostic factors for cryotherapy of colorectal liver metastases J.K. Seifert, Th. Junginger* Department of Surgery, Johannes Gutenberg-University, Mainz, Germany Accepted for publication 17 October 2003
KEYWORDS Colorectal cancer; Liver metastases; Cryotherapy; Cryosurgery; Prognostic factors
Summary Background. Cryotherapy is a local ablative treatment option for nonresectable liver tumours. We aimed to identify prognostic indicators, that may allow better selection or stratification for adjuvant therapies of patients. Methods. Fifty-five patients had cryotherapy for colorectal liver metastases. The patient-, tumour- and operative details were recorded prospectively. Mean follow up was 24 months. A uni- and multivariate analysis for possible prognostic factors was performed. Results. There was a trend towards better survival for patients with unilobar liver metastases, preoperative serum levels of carcinoembrional antigen (CEA) not exceeding 20 ng/ml and patients undergoing ‘R0’-treatment. Patients with multiple or large (.4 cm) liver metastases, patients undergoing cryotherapy combined with liver resection and patients receiving blood transfusion intraoperatively, especially when exceeding 4 units packed red cells, had a significantly impaired survival in univariate analysis. In multivariate analysis (Cox regression) the amount of intraoperative blood transfusion was the only independent prognostic indicator. Conclusion. Intraoperative blood transfusion has a negative impact on survival following hepatic cryotherapy for colorectal liver metastases and should be avoided by refinement of surgical technique whenever possible. Patients with multiple liver metastases or metastases of more than 4 cm in size have an impaired prognosis— therefore trials of adjuvant therapies following hepatic cryotherapy for colorectal liver metastases should include number and size of metastases for stratification of patient groups. Q 2003 Elsevier Ltd. All rights reserved.
Introduction Cryotherapy is a local ablative treatment option for non-resectable liver tumours.1 During the last *Corresponding author. Address: Klinik und Poliklinik fu ¨r Allgemein-und Abdominalchirurgie der Johannes GutenbergUniversita ¨t, Langenbeckstr. 1, D 55101 Mainz, Germany. Tel.: þ 49-6131-17-7291; fax: þ 49-6131-17-6630. E-mail address: [email protected]
decade numerous reports about the use of cryotherapy for colorectal liver metastases have been published.1 – 12 However, only little data regarding possible prognostic indicators following cryotherapy for colorectal liver metastases is available.7,13 We aimed to identify prognostic indicators, that may allow better patient selection or stratification of patients for neoadjuvant or adjuvant therapies, which are widely used in combination with hepatic cryotherapy.2,3,7,8,14,15
0748-7983/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2003.10.009
Cryotherapy of liver metastases—prognostic factors
Patients and methods Between January 1996 and September 2002, 55 patients had cryotherapy (25 of these in combination with liver resection) for colorectal liver metastases in our department. The patient-, tumour- and operative details were recorded prospectively. Preoperative staging included abdominal ultrasound and abdominal CT, chest X-ray, serum analysis of tumour markers, liver function tests and colonoscopy. Recently we have increasingly used MRI of the liver, particularly for better assessment of the tissue changes following cryotherapy. Cryotherapy was used if complete resection of all liver metastases was not feasible and if no extrahepatic disease was diagnosed preoperatively. We performed cryosurgery alone or in combination with liver resection if we could assume that all liver metastases may be destroyed completely. Metastases were judged non-resectable, if: (i) they were multiple in both liver lobes; (ii) they were in an anatomical position that did not allow liver resection without sacrificing an unreasonable amount of liver parenchyma or (iii) if resection would have involved too high a risk for the patient. In very few patients with resectable lesions, who denied to undergo liver resection, cryotherapy, preferably laparoscopically was performed. Postoperatively most patients were monitored on the intensive care unit, usually for 24 h. Prior to discharge, a CT-scan or MRI-scan of the liver was performed in patients who underwent cryotherapy. Cryotherapy was usually performed via a bilateral subcostal incision. Before treatment inspection and palpation of the abdominal cavity, the liver and the hilar region, including intraoperative ultrasound and frozen section of suspicious lesions was performed to exclude additional disease. For cryotherapy, we have used a CMS AccuProbe 450System with single-use cryoprobes with an isolated shaft and a diameter of 3 or 8 mm at the tip. Since 3 years we have preferably used the Erbokryo CS-6 cryosystem (Erbe, Elektromedizin GmbH, Tu ¨bingen, Germany) with 3.6 mm probes. Only the probetips are cooled, allowing the treatment of central lesions deep within the liver parenchyma without freezing the liver surface. The probe insertion and the freezing process are controlled by intraoperative ultrasound. All tumours are frozen with a surrounding margin of at least 1 cm of normal tissue and the freezing process is continued at least 15 min. After a passive thaw of the iceball a second freeze cycle is used to optimize tumour destruc-
35 tion.16 In some patients cryotherapy was performed laparoscopically. R0-treatment was assumed when a complete resection or cryo-treatment of all visible tumour with adequate margins was achieved. R1-treatment was assumed when all tumours were resected or cryoablated, but the surgeon was concerned about the adequacy of the freezing margin or a resection margin in patients with liver resection was histologically involved. R2-treatment was defined as macroscopically detectable untreated tumour (including preoperative imaging) left behind after surgery. Patients were followed up until September 2002 or death. Mean follow-up was 24 months (1 – 73). Patients had regular 3 monthly follow-up investigations for local recurrence or hepatic recurrence at other locations and extrahepatic recurrence. Survival was calculated using the Kaplan – Meier method.17 The log-rank test18 was used to test for differences between the two groups. A significant difference was assumed for p , 0:05: Cox regression (Cox’s proportional hazard model)19 with the forward-stepwise method (likelihood ratio) and enter and remove limits of p , 0:05 and p . 0:10; respectively was used for multivariate analysis with covariates showing a significant ðp , 0:05Þ or close to significant ðp # 0:1Þ influence on survival in univariate analysis. Statistical analysis was performed using SPSS for Windows, version 10.0.7.
Results The median age of the patients was 63 years (37 – 78), 24 were females. The patient- and tumour details, as well as the results of the univariate analysis for prognostic indicators of survival are summarized in Table 1. Patient age and gender, depth of infiltration, nodal status and differentiation of the primary tumour, preceding liver resection or systemic chemotherapy, as well as the time of development of liver metastases and the presence of extrahepatic disease at laparotomy did not have an impact on survival. There was a trend towards better survival for patients with unilobar liver metastases (Fig. 1), preoperative serum levels of carcinoembrional antigen (CEA) not exceeding 20 ng/ml (Fig. 2) and patients undergoing ‘R0’-treatment (Fig. 3), which did not reach statistical significance. The number and size (Table 1) of liver metastases had a significant impact on survival. Patients undergoing cryotherapy alone had a significantly
36
Table 1 Prognostic factors in 55 patients with hepatic cryotherapy for colorectal liver metastases
Age (years) Gender Depth of infiltration of the primary tumour
Nodal involvement at resection of the primary tumour
Histological differentiation of primary
Chemotherapy prior to cryotherapy
Liver resection prior to cryotherapy Extrahepatic disease at laparotomy Time of diagnosis of liver metastases Number of liver metastases
Diameter of liver metastases (cm) Distribution of liver metastases Operation type
CEA preoperatively (ng/ml) Intraoperative blood transfusion
a
Mean survival time.
Median survival (months)
3-Year survival (%)
p
33 22 24 31 46 8 1 21 33 1 31 14 10 35 18 2 16 39 45 10 17 38 28 19 8 43 12 30 25 30 25 47 8 37 18 36 13 6
38 28 29 29 32 16 – 29 29 – 29 32 – 28 (40a) – 32 28 29 17 28 29 (51a) 27 14 32 15 (46a) 27 (45a) 23 29 27 38 28 58 15 11
56 26 46 43 49 25 – 44 45 – 45 41 – 39 59 – 46 44 48 0 48 42 59 38 15 48 37 51 36 50 36 49 18 52 25 63 18 0
0.42 0.93 0.40 (T1-3 vs. T4) 0.70 (Involved vs. not involved) 0.57 (Well/moderate vs. poor) 0.19 (Chemo vs. not) 0.42 0.29 0.91 0.004
0.019 0.066 0.03 0.10 0.09 ,0.001
J.K. Seifert, T. Junginger
Radicality
#65 .65 Female Male Not exceeding pericolic fat Serosa/neighbourning organs Unknown No involved nodes Involved nodes Unknown Well/moderate Poor Unknown Yes No Unknown Yes No No Yes Synchronous Metachronous 1 2–4 .4 #4 .4 Unilobar Bilobar Cryotherapy only Cryotherapy and liver resection R0 R1/2 #20 .20 no Yes, 1–4 units Yes, .4 units
Patients (n)
Cryotherapy of liver metastases—prognostic factors
Figure 1 Survival (Kaplan– Meier) following cryotherapy (^resection) for colorectal liver metastases. Prognostic influence of distribution of liver metastases.
better survival compared to patients treated with cryotherapy combined with liver resection (Fig. 4). Finally, the amount of intraoperative blood transfusion was prognostic with patients receiving no blood transfusion having the best and patients receiving more than 4 units packed red cells having the worst prognosis (Fig. 5). The multivariate analysis was performed in two ways. First, all seven covariates, that had a prognostic or close to prognostic impact on survival in univariate analysis were entered in a Cox regression using the same categories, as used for univariate analysis. Secondly, the same covariates were entered, not using categories but the actual values for the numerical
Figure 2 Survival (Kaplan– Meier) following cryotherapy (^resection) for colorectal liver metastases. Prognostic influence of preoperative CEA serum level.
37
Figure 3 Survival (Kaplan– Meier) following cryotherapy (^resection) for colorectal liver metastases. Prognostic influence of completeness of treatment.
covariates whenever possible (actual number of blood transfusion and metastases, diameter of metastases in centimetre and concentration of preoperative serum CEA in ng/ml). In both analyses the amount of intraoperative blood transfusion was the only independent prognostic indicator with an increased risk of death (risk ratio) by factor 1.32 per unit blood transfused intraoperatively ðp , 0:0001Þ:
Discussion Liver resection is the recommended treatment for patients with colorectal liver metastases in the
Figure 4 Survival (Kaplan– Meier) following cryotherapy (^resection) for colorectal liver metastases. Prognostic influence of the type of treatment (cryotherapy alone vs. cryotherapy in combination with liver resection).
38
Figure 5 Survival (Kaplan –Meier) following cryotherapy (^ resection) for colorectal liver metastases. Prognostic influence of intraoperative blood transfusion.
absence of extrahepatic disease whenever removal of all tumour with clear margins and perseverance of an adequate functional liver reserve is feasible.20,21 However, liver resection is possible in only 5 – 25% of patients presenting with colorectal liver metastases.22 For some of these patients, cryotherapy may offer a potentially curative treatment option. In this reported series of 55 patients we have observed a median survival time of 29 months and 3 and 5year survival rates of 44 and 26%, which is comparable to published results of liver resection.22,23 However, most patients have eventually developed tumour recurrence and died of their disease. Surprisingly, the only independent prognostic indicator was the amount of intraoperative blood transfusion: patients receiving no blood transfusion had a median survival time of 58 months and a 3year survival rate of 63%, patients receiving 1 – 4 units of packed red cells had a median survival time of only 15 months and a 3-year survival rate of 18% and none of the six patients receiving more than 4 units of packed red cells survived three years (Table 1). For each additional unit of intraoperative blood transfusion the risk of death was increased by 32%. This may partly reflect more complex procedures in patients with a greater tumour load: only 4 patients (14%) received intraoperative blood transfusion when cryotherapy alone was used, whereas 13 (54%) had blood transfusion when cryotherapy and resection were used. Only 4 of 27 patients (15%) with solitary metastases, as compared to 13 of 26 (50%) with multiple metastases received intraoperative blood transfusion. While 7 of eleven
J.K. Seifert, T. Junginger
patients (64%) with metastases of more than 4 cm in diameter needed intraoperative blood replacement, this was only necessary for 10 of 42 (24%) with smaller lesions. However, neither number nor size of metastases nor the additional use of liver resection had an independent prognostic effect in this study. An independent prognostic effect of blood transfusion itself following liver resection for colorectal metastases was described earlier by Rosen et al.,24 who suspected that the immunosuppressive effects of blood transfusion may be resulting in impaired survival. Similar findings were reported by other investigators: Stephenson et al. have found an independent prognostic effect of perioperative blood transfusion after resection of colorectal liver metastases with an increase of risk of death by 7% per unit blood transfused.25 Younes et al. have seen a negative effect on disease-free survival of intraoperative episodes of hypotension and intraoperative blood transfusion after resection of colorectal liver metastases in univariate analysis. However, intraoperative episodes of hypotension, but not blood transfusion was confirmed as independent prognostic indicator in multivariate analysis.26 Interestingly, in another series of hepatic cryotherapy for colorectal liver metastases blood transfusion had a negative prognostic effect in univariate, bur not in multivariate analysis.7 A randomized trial for patients undergoing liver resection or cryotherapy for colorectal liver metastases, comparing a very restrictive approach to intraoperative blood transfusion with the current approach of blood transfusion when a haemoglobin of less than 10 g/dl is observed intraoperatively, with the outcome measures of perioperative morbidity and long-term prognosis would certainly be interesting. Several other parameters had a prognostic effect in univariate, but not multivariate analysis in this paper. Not surprisingly, the amount of tumour in the liver was of prognostic importance: larger number and size of liver metastases had an adverse effect on prognosis and there was a strong trend towards inferior prognosis in patients with bilobar disease. This is in accordance with the findings of many investigators looking at prognostic factors after liver resection of colorectal liver metastases.27 In another investigation on prognostic indicators after hepatic cryotherapy size, but not number of liver metastases was identified as prognostic.7 This may partly be explained by the routine use of adjuvant regional hepatic arterial chemotherapy in this series,7 as opposed to our current investigation, where no adjuvant treatment was routinely administered.
Cryotherapy of liver metastases—prognostic factors
Patients undergoing cryotherapy alone had a better prognosis than patients who underwent liver resection in combination with cryotherapy. This certainly is explained by patient selection. We have usually used a combined treatment strategy for patients with multiple bilobar liver metastases, aiming to resect the majority of tumours on one side of the liver and use cryotherapy only for the remaining contralobar lesions. Cryotherapy alone was mainly used for patients with one or two small liver metastases, which were located centrally in the liver, mostly close to the hepatic venous hilum, or in the centre of a remaining liver lobe after previous liver resection. Therefore, patients undergoing cryotherapy alone had a smaller tumour lode than patients with combined treatment: all eight patients with more than four liver metastases and 15 of 18 patients with 2 –4 liver metastases had combined treatment. The completeness of treatment did not reach statistical significance as a prognostic determinant. However, there were only eight patients with incomplete treatment and there was a strong trend towards improved survival for patients with complete treatment, which may well reach statistical significance with larger patient numbers, as was reported by another group.7
39
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Conclusions Cryotherapy is a valuable treatment option for patients with non-resectable liver metastases from colorectal cancer and is associated with 5-year survival in 26% of patients. Intraoperative blood transfusion has a negative impact on survival and should be avoided by refinement of surgical technique whenever possible. Patients with multiple liver metastases or metastases of more than 4 cm in size have an impaired prognosis—therefore trials of adjuvant therapies following hepatic cryotherapy for colorectal liver metastases should include number and size of metastases for stratification of patient groups.
15.
16.
17. 18.
19. 20.
21.
References 1. Onik G, Rubinsky B, Zemel R, Weaver L, Diamond D, Cobb C, Porterfield B. Ultrasound-guided hepatic cryosurgery in the treatment of metastatic colon carcinoma. Cancer 1991;67: 901—907. 2. Morris D, Ross WB, Iqbal J, Mccall JL, Kind J, Clingan P. Cryoablation of hepatic malignancy: an evaluation of tumour marker data and survival in 110 patients. GI Cancer 1996;1: 247—251. 3. Adam R, Akpinar E, Johann M, Kunstlinher F, Majno P,
22. 23.
24.
Bismuth H. Place of cryosurgery in the treatment of malignant liver tumors. Ann Surg 1997;225:39—50. Ravikumar T, Kane R, Cady B, Jenkins R, Clouse M, Steele G. A 5 year study of cryosurgery in the treatment of liver tumors. Arch Surg 1991;126:1520—1524. Ravikumar T, Kane R, Cady B, Jenkins R, Mcdermott W, Onik G, Clouse M, Steele G. Hepatic cryosurgery with intraoperative ultrasound monitoring for metastatic colon carcinoma. Arch Surg 1987;122:403—409. Seifert JK, Junginger Th, Morris DL. A collective review of the world literature on hepatic cryotherapy. J R Coll Surg Edinb 1998;43:141—154. Seifert JK, Morris DL. Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer. Ann Surg 1998;228:201—208. Shafir M, Shapiro R, Sung M, Warner R, Sicular A, Klipfel A. Cryoablation of unresectable malignant liver tumors. Am J Surg 1996;171:27—31. Seifert JK, Heintz A, Junginger T. Cryotherapy for primary and secondary liver tumours. Zentralbl Chir 2002;127: 275—281. Seifert JK, Morris DL. Indicators of recurrence following cryotherapy for hepatic metastases from colorectal cancer. Br J Surg 1999;86:234—240. Finlay IG, Seifert JK, Stewart GJ, Morris DL. Resection with cryotherapy of colorectal metastases has the same survival as resection alone. Eur J Surg Oncol 2000;26:199—202. Wallace JR, Christians KK, Pitt HA, Quebbeman EJ. Cryotherapy extends the indications for treatment of colorectal liver metastases. Surgery 1999;126:766—772. Weaver ML, Ashton JG, Zemel R. Treatment of colorectal liver metastases by cryotherapy. Semin Surg Oncol 1998;14: 163—170. Sheen AJ, Poston GJ, Sherlock DJ. Cryotherapeutic ablation of liver tumours. Br J Surg 2002;89:1396—1401. Rivoire M, De Cian F, Meeus P, Negrier S, Sebban H, Kaemmerlen P. Combination of neoadjuvant chemotherapy with cryotherapy and surgical resection for the treatment of unresectable liver metastases from colorectal carcinoma. Cancer 2002;95:2283—2292. Ravikumar T, Steele G, Kane R, King V. Experimental and clinical observations on hepatic cryosurgery for colorectal metastases. Cancer Res 1991;51:6323—6327. Kaplan L, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457—481. Mantel N. Evaluation of survival data and and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163—170. Cox DR. Regression models and life table. J Stat Soc 1972;34: 187—220. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer. Analysis of 1001 consecutive cases. Ann Surg 1999;230:309—321. Nordlinger B, Guiguet M, Vaillant J-C et al. Association Francaise de Chirurgie. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Cancer 1996;77:1254—1262. Scheele J, Stang R, Altendorf-Hoffmann A, Paul M. Resection of colorectal liver metastases. World J Surg 1995;19:59—71. Seifert JK, Junginger T. Resektion von Lebermetastasen kolorektaler—Tumoren. Eine uni- und multivariate Analyse von Prognosefaktoren. Langenbecks Arch Chir 1996;381: 187—200. Rosen CB, Nagorney DM, Taswell HF, Helgeson SL, Ilstrup DM, Van Heerden JA, Adson MA. Perioperative blood transfusion
40
and determinants of survival after liver resection for metastatic colorectal carcinoma. Ann Surg 1992;216: 493—505. 25. Stephenson KR, Steinberg SM, Hughes KS, Vetto JT, Sugarbaker PH, Chang AE. Perioperative bloofd transfusions are associated with decreased time to recurrence and decreased survival after resection of colorectal liver metastases. Ann Surg 1988;208:679—687. 26. Younes RN, Rogatko A, Brennan MF. The influence of
J.K. Seifert, T. Junginger
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. 27. Seifert JK, Junginger Th. Prognosefaktoren nach Resektion von Lebermetastasen kolorektaler Tumoren. In: Holzgreve A, Junginger Th (eds) Jahrbuch der Chirurgie. Mu ¨nster: Biermann, 1999. p. 35—51.
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Prognostic factors for cryotherapy of colorectal liver metastases J.K. Seifert, Th. Junginger* Department of Surgery, Johannes Gutenberg-University, Mainz, Germany Accepted for publication 17 October 2003
KEYWORDS Colorectal cancer; Liver metastases; Cryotherapy; Cryosurgery; Prognostic factors
Summary Background. Cryotherapy is a local ablative treatment option for nonresectable liver tumours. We aimed to identify prognostic indicators, that may allow better selection or stratification for adjuvant therapies of patients. Methods. Fifty-five patients had cryotherapy for colorectal liver metastases. The patient-, tumour- and operative details were recorded prospectively. Mean follow up was 24 months. A uni- and multivariate analysis for possible prognostic factors was performed. Results. There was a trend towards better survival for patients with unilobar liver metastases, preoperative serum levels of carcinoembrional antigen (CEA) not exceeding 20 ng/ml and patients undergoing ‘R0’-treatment. Patients with multiple or large (.4 cm) liver metastases, patients undergoing cryotherapy combined with liver resection and patients receiving blood transfusion intraoperatively, especially when exceeding 4 units packed red cells, had a significantly impaired survival in univariate analysis. In multivariate analysis (Cox regression) the amount of intraoperative blood transfusion was the only independent prognostic indicator. Conclusion. Intraoperative blood transfusion has a negative impact on survival following hepatic cryotherapy for colorectal liver metastases and should be avoided by refinement of surgical technique whenever possible. Patients with multiple liver metastases or metastases of more than 4 cm in size have an impaired prognosis— therefore trials of adjuvant therapies following hepatic cryotherapy for colorectal liver metastases should include number and size of metastases for stratification of patient groups. Q 2003 Elsevier Ltd. All rights reserved.
Introduction Cryotherapy is a local ablative treatment option for non-resectable liver tumours.1 During the last *Corresponding author. Address: Klinik und Poliklinik fu ¨r Allgemein-und Abdominalchirurgie der Johannes GutenbergUniversita ¨t, Langenbeckstr. 1, D 55101 Mainz, Germany. Tel.: þ 49-6131-17-7291; fax: þ 49-6131-17-6630. E-mail address: [email protected]
decade numerous reports about the use of cryotherapy for colorectal liver metastases have been published.1 – 12 However, only little data regarding possible prognostic indicators following cryotherapy for colorectal liver metastases is available.7,13 We aimed to identify prognostic indicators, that may allow better patient selection or stratification of patients for neoadjuvant or adjuvant therapies, which are widely used in combination with hepatic cryotherapy.2,3,7,8,14,15
0748-7983/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2003.10.009
Cryotherapy of liver metastases—prognostic factors
Patients and methods Between January 1996 and September 2002, 55 patients had cryotherapy (25 of these in combination with liver resection) for colorectal liver metastases in our department. The patient-, tumour- and operative details were recorded prospectively. Preoperative staging included abdominal ultrasound and abdominal CT, chest X-ray, serum analysis of tumour markers, liver function tests and colonoscopy. Recently we have increasingly used MRI of the liver, particularly for better assessment of the tissue changes following cryotherapy. Cryotherapy was used if complete resection of all liver metastases was not feasible and if no extrahepatic disease was diagnosed preoperatively. We performed cryosurgery alone or in combination with liver resection if we could assume that all liver metastases may be destroyed completely. Metastases were judged non-resectable, if: (i) they were multiple in both liver lobes; (ii) they were in an anatomical position that did not allow liver resection without sacrificing an unreasonable amount of liver parenchyma or (iii) if resection would have involved too high a risk for the patient. In very few patients with resectable lesions, who denied to undergo liver resection, cryotherapy, preferably laparoscopically was performed. Postoperatively most patients were monitored on the intensive care unit, usually for 24 h. Prior to discharge, a CT-scan or MRI-scan of the liver was performed in patients who underwent cryotherapy. Cryotherapy was usually performed via a bilateral subcostal incision. Before treatment inspection and palpation of the abdominal cavity, the liver and the hilar region, including intraoperative ultrasound and frozen section of suspicious lesions was performed to exclude additional disease. For cryotherapy, we have used a CMS AccuProbe 450System with single-use cryoprobes with an isolated shaft and a diameter of 3 or 8 mm at the tip. Since 3 years we have preferably used the Erbokryo CS-6 cryosystem (Erbe, Elektromedizin GmbH, Tu ¨bingen, Germany) with 3.6 mm probes. Only the probetips are cooled, allowing the treatment of central lesions deep within the liver parenchyma without freezing the liver surface. The probe insertion and the freezing process are controlled by intraoperative ultrasound. All tumours are frozen with a surrounding margin of at least 1 cm of normal tissue and the freezing process is continued at least 15 min. After a passive thaw of the iceball a second freeze cycle is used to optimize tumour destruc-
35 tion.16 In some patients cryotherapy was performed laparoscopically. R0-treatment was assumed when a complete resection or cryo-treatment of all visible tumour with adequate margins was achieved. R1-treatment was assumed when all tumours were resected or cryoablated, but the surgeon was concerned about the adequacy of the freezing margin or a resection margin in patients with liver resection was histologically involved. R2-treatment was defined as macroscopically detectable untreated tumour (including preoperative imaging) left behind after surgery. Patients were followed up until September 2002 or death. Mean follow-up was 24 months (1 – 73). Patients had regular 3 monthly follow-up investigations for local recurrence or hepatic recurrence at other locations and extrahepatic recurrence. Survival was calculated using the Kaplan – Meier method.17 The log-rank test18 was used to test for differences between the two groups. A significant difference was assumed for p , 0:05: Cox regression (Cox’s proportional hazard model)19 with the forward-stepwise method (likelihood ratio) and enter and remove limits of p , 0:05 and p . 0:10; respectively was used for multivariate analysis with covariates showing a significant ðp , 0:05Þ or close to significant ðp # 0:1Þ influence on survival in univariate analysis. Statistical analysis was performed using SPSS for Windows, version 10.0.7.
Results The median age of the patients was 63 years (37 – 78), 24 were females. The patient- and tumour details, as well as the results of the univariate analysis for prognostic indicators of survival are summarized in Table 1. Patient age and gender, depth of infiltration, nodal status and differentiation of the primary tumour, preceding liver resection or systemic chemotherapy, as well as the time of development of liver metastases and the presence of extrahepatic disease at laparotomy did not have an impact on survival. There was a trend towards better survival for patients with unilobar liver metastases (Fig. 1), preoperative serum levels of carcinoembrional antigen (CEA) not exceeding 20 ng/ml (Fig. 2) and patients undergoing ‘R0’-treatment (Fig. 3), which did not reach statistical significance. The number and size (Table 1) of liver metastases had a significant impact on survival. Patients undergoing cryotherapy alone had a significantly
36
Table 1 Prognostic factors in 55 patients with hepatic cryotherapy for colorectal liver metastases
Age (years) Gender Depth of infiltration of the primary tumour
Nodal involvement at resection of the primary tumour
Histological differentiation of primary
Chemotherapy prior to cryotherapy
Liver resection prior to cryotherapy Extrahepatic disease at laparotomy Time of diagnosis of liver metastases Number of liver metastases
Diameter of liver metastases (cm) Distribution of liver metastases Operation type
CEA preoperatively (ng/ml) Intraoperative blood transfusion
a
Mean survival time.
Median survival (months)
3-Year survival (%)
p
33 22 24 31 46 8 1 21 33 1 31 14 10 35 18 2 16 39 45 10 17 38 28 19 8 43 12 30 25 30 25 47 8 37 18 36 13 6
38 28 29 29 32 16 – 29 29 – 29 32 – 28 (40a) – 32 28 29 17 28 29 (51a) 27 14 32 15 (46a) 27 (45a) 23 29 27 38 28 58 15 11
56 26 46 43 49 25 – 44 45 – 45 41 – 39 59 – 46 44 48 0 48 42 59 38 15 48 37 51 36 50 36 49 18 52 25 63 18 0
0.42 0.93 0.40 (T1-3 vs. T4) 0.70 (Involved vs. not involved) 0.57 (Well/moderate vs. poor) 0.19 (Chemo vs. not) 0.42 0.29 0.91 0.004
0.019 0.066 0.03 0.10 0.09 ,0.001
J.K. Seifert, T. Junginger
Radicality
#65 .65 Female Male Not exceeding pericolic fat Serosa/neighbourning organs Unknown No involved nodes Involved nodes Unknown Well/moderate Poor Unknown Yes No Unknown Yes No No Yes Synchronous Metachronous 1 2–4 .4 #4 .4 Unilobar Bilobar Cryotherapy only Cryotherapy and liver resection R0 R1/2 #20 .20 no Yes, 1–4 units Yes, .4 units
Patients (n)
Cryotherapy of liver metastases—prognostic factors
Figure 1 Survival (Kaplan– Meier) following cryotherapy (^resection) for colorectal liver metastases. Prognostic influence of distribution of liver metastases.
better survival compared to patients treated with cryotherapy combined with liver resection (Fig. 4). Finally, the amount of intraoperative blood transfusion was prognostic with patients receiving no blood transfusion having the best and patients receiving more than 4 units packed red cells having the worst prognosis (Fig. 5). The multivariate analysis was performed in two ways. First, all seven covariates, that had a prognostic or close to prognostic impact on survival in univariate analysis were entered in a Cox regression using the same categories, as used for univariate analysis. Secondly, the same covariates were entered, not using categories but the actual values for the numerical
Figure 2 Survival (Kaplan– Meier) following cryotherapy (^resection) for colorectal liver metastases. Prognostic influence of preoperative CEA serum level.
37
Figure 3 Survival (Kaplan– Meier) following cryotherapy (^resection) for colorectal liver metastases. Prognostic influence of completeness of treatment.
covariates whenever possible (actual number of blood transfusion and metastases, diameter of metastases in centimetre and concentration of preoperative serum CEA in ng/ml). In both analyses the amount of intraoperative blood transfusion was the only independent prognostic indicator with an increased risk of death (risk ratio) by factor 1.32 per unit blood transfused intraoperatively ðp , 0:0001Þ:
Discussion Liver resection is the recommended treatment for patients with colorectal liver metastases in the
Figure 4 Survival (Kaplan– Meier) following cryotherapy (^resection) for colorectal liver metastases. Prognostic influence of the type of treatment (cryotherapy alone vs. cryotherapy in combination with liver resection).
38
Figure 5 Survival (Kaplan –Meier) following cryotherapy (^ resection) for colorectal liver metastases. Prognostic influence of intraoperative blood transfusion.
absence of extrahepatic disease whenever removal of all tumour with clear margins and perseverance of an adequate functional liver reserve is feasible.20,21 However, liver resection is possible in only 5 – 25% of patients presenting with colorectal liver metastases.22 For some of these patients, cryotherapy may offer a potentially curative treatment option. In this reported series of 55 patients we have observed a median survival time of 29 months and 3 and 5year survival rates of 44 and 26%, which is comparable to published results of liver resection.22,23 However, most patients have eventually developed tumour recurrence and died of their disease. Surprisingly, the only independent prognostic indicator was the amount of intraoperative blood transfusion: patients receiving no blood transfusion had a median survival time of 58 months and a 3year survival rate of 63%, patients receiving 1 – 4 units of packed red cells had a median survival time of only 15 months and a 3-year survival rate of 18% and none of the six patients receiving more than 4 units of packed red cells survived three years (Table 1). For each additional unit of intraoperative blood transfusion the risk of death was increased by 32%. This may partly reflect more complex procedures in patients with a greater tumour load: only 4 patients (14%) received intraoperative blood transfusion when cryotherapy alone was used, whereas 13 (54%) had blood transfusion when cryotherapy and resection were used. Only 4 of 27 patients (15%) with solitary metastases, as compared to 13 of 26 (50%) with multiple metastases received intraoperative blood transfusion. While 7 of eleven
J.K. Seifert, T. Junginger
patients (64%) with metastases of more than 4 cm in diameter needed intraoperative blood replacement, this was only necessary for 10 of 42 (24%) with smaller lesions. However, neither number nor size of metastases nor the additional use of liver resection had an independent prognostic effect in this study. An independent prognostic effect of blood transfusion itself following liver resection for colorectal metastases was described earlier by Rosen et al.,24 who suspected that the immunosuppressive effects of blood transfusion may be resulting in impaired survival. Similar findings were reported by other investigators: Stephenson et al. have found an independent prognostic effect of perioperative blood transfusion after resection of colorectal liver metastases with an increase of risk of death by 7% per unit blood transfused.25 Younes et al. have seen a negative effect on disease-free survival of intraoperative episodes of hypotension and intraoperative blood transfusion after resection of colorectal liver metastases in univariate analysis. However, intraoperative episodes of hypotension, but not blood transfusion was confirmed as independent prognostic indicator in multivariate analysis.26 Interestingly, in another series of hepatic cryotherapy for colorectal liver metastases blood transfusion had a negative prognostic effect in univariate, bur not in multivariate analysis.7 A randomized trial for patients undergoing liver resection or cryotherapy for colorectal liver metastases, comparing a very restrictive approach to intraoperative blood transfusion with the current approach of blood transfusion when a haemoglobin of less than 10 g/dl is observed intraoperatively, with the outcome measures of perioperative morbidity and long-term prognosis would certainly be interesting. Several other parameters had a prognostic effect in univariate, but not multivariate analysis in this paper. Not surprisingly, the amount of tumour in the liver was of prognostic importance: larger number and size of liver metastases had an adverse effect on prognosis and there was a strong trend towards inferior prognosis in patients with bilobar disease. This is in accordance with the findings of many investigators looking at prognostic factors after liver resection of colorectal liver metastases.27 In another investigation on prognostic indicators after hepatic cryotherapy size, but not number of liver metastases was identified as prognostic.7 This may partly be explained by the routine use of adjuvant regional hepatic arterial chemotherapy in this series,7 as opposed to our current investigation, where no adjuvant treatment was routinely administered.
Cryotherapy of liver metastases—prognostic factors
Patients undergoing cryotherapy alone had a better prognosis than patients who underwent liver resection in combination with cryotherapy. This certainly is explained by patient selection. We have usually used a combined treatment strategy for patients with multiple bilobar liver metastases, aiming to resect the majority of tumours on one side of the liver and use cryotherapy only for the remaining contralobar lesions. Cryotherapy alone was mainly used for patients with one or two small liver metastases, which were located centrally in the liver, mostly close to the hepatic venous hilum, or in the centre of a remaining liver lobe after previous liver resection. Therefore, patients undergoing cryotherapy alone had a smaller tumour lode than patients with combined treatment: all eight patients with more than four liver metastases and 15 of 18 patients with 2 –4 liver metastases had combined treatment. The completeness of treatment did not reach statistical significance as a prognostic determinant. However, there were only eight patients with incomplete treatment and there was a strong trend towards improved survival for patients with complete treatment, which may well reach statistical significance with larger patient numbers, as was reported by another group.7
39
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Conclusions Cryotherapy is a valuable treatment option for patients with non-resectable liver metastases from colorectal cancer and is associated with 5-year survival in 26% of patients. Intraoperative blood transfusion has a negative impact on survival and should be avoided by refinement of surgical technique whenever possible. Patients with multiple liver metastases or metastases of more than 4 cm in size have an impaired prognosis—therefore trials of adjuvant therapies following hepatic cryotherapy for colorectal liver metastases should include number and size of metastases for stratification of patient groups.
15.
16.
17. 18.
19. 20.
21.
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