Ausr. N.Z. J . Surg. 1991,61,55-58
55
EFFECT OF HEPATIC CRYOTHERAPY ON SERUM CEA CONCENTRATION IN PATIENTS WITH MULTIPLE INOPERABLE HEPATIC METASTASES FROM COLORECTAL CANCER R. M.CHARNLEY, M.THOMAS AND D.L.MORRIS Department of Surgery, University Hospital, Nottingham, UK Eleven patients with multiple hepatic metastases from colorectal cancer, all judged inoperable, were treated by cryotherapy using a probe through which liquid nitrogen was circulated using a single freeze thaw sequence. Localization of metastases, positioning of the probe and monitoring of ice ball size was by intra-operative ultrasound. Serum carcinoembryonic antigen (CEA) was measured in these patients: there was a postoperative fall in all but two. In all but one, there has been a subsequent rise. Speed and degree of rise of CEA varied between patients. Serial CEA may be an effective means of monitoring the effect of hepatic cryotherapy.
Key words:CEA,colorectal cancer, cryotherapy, hepatic metastases.
Introduction Hepatic metastases are one of the common modes of dissemination of colorectal cancer. There has been some progress in the treatment of colorectal hepatic metastases: resection is now a much safer procedure and can achieve 5-year survival rates of approximately 25%. Chemotherapy delivered via local arterial infusion can achieve high response rates.* The proportion of patients who are suitable for resection, however, is small and chemotherapy probably only benefits patients with low percentage hepatic replacement. Our principal interest in hepatic cryotherapy was to find a technique which could increase the proportion of patients treatable by a local technique. Contact ultrasound is a relatively new procedure which allows the detection of small hepatic metastases3 and is also important in facilitating the accurate placement of a cryoprobe and monitoring iceball size. The concept of hepatic cryotherapy is relatively r e ~ e n t . It~ may . ~ allow us to treat lesions which are not surgically resectable for anatomic reasons and afford a procedure which is much less difficult and dangerous than resection, which may be an advantage to high risk patients.4s5 The authors recently described a cryoprobe, utilizing circulated liquid nitrogen as coolant, which can be placed under contact ultrasound control into hepatic lesions without damaging much overlying liver tissue.'
'
Correspondence: D. L. Moms. Prof. Surgery. The St George Hospital. Kogarah. NSW 2217. Australia. Accepted for publication I August 1990.
The effectiveness of hepatic cryotherapy clearly must be measured ultimately by hard clinical parameters such as survival. Radiographic assessment of effectiveness is difficult because the changes following cryo-destruction cannot easily be differentiated from tumour. We chose, therefore, to study the serum carcinoembryonic antigen (CEA) concentration in patients with colorectal cancer undergoing cryotherapy of hepatic metastases. Serum CEA concentrations are used in the diagnosis of recurrence/metastases of colorectal cancer.'^^ If CEA is, therefore, a sensitive marker for metastatic colorectal cancer. and successful response to resection or chemotherapy produces a fall in this, then serial CEA measurement may be a useful method of evaluating this new technique.'
Method Eleven patients with multiple hepatic metastases from colorectal cancer, who were all judged unresectable due to number, anatomical consideration or extra-hepatic disease (one elderly woman had 2 hepatic metastases diagnosed at laparotomy for an obstructing metachronous tumour). All patients underwent thorough laparotomy through a roof top incision. Patients with unresectable extra hepatic disease were not treated. Cryotherapy was administered using a CRYOTEC liquid nitrogen system via the insulated circulating coolant probe previously described or by a circular coil probe for surface lesions.6 ha-operative ultrasound (Bruel & Kjaer, Denmark) was used in localizing lesions, controlling probe placement and monitoring iceball size. We attempted to achieve an iceball radius of I cm more than metastasis. A single freezdthaw sequence was used; clamping the hepatic artery and
CHARNLEY ET AL.
56
portal vein was only used in one patient with very large metastases. Core body temperature was monitored; a warming mattress, warmed intravenous fluids and a rebreathing anaesthetic circuit were used to minimize heat loss. Other anti-cancer therapy was not used in these patients during this study. The patients had regular follow-up in a dedicated clinic and serial serum CEA values were measured.
blood sample was not taken, in error), a postoperative fall in CEA concentration was seen at I month. In addition, in all but one patient there was a subsequent postoperative rise in CEA, indicating tumour recurrence. The speed and degree of rise of CEA varied between patients. The time in months until return to the preoperative CEA concentration is given in Table I ; this varied between 2-6 months, but in 1 patient, who had a pre-treatment CEA of only 2, this fell postoperatively to undetectable levels and has not yet risen to the pre-treatment value.' (CT scan in this patient shows no evidence of recurrence.)
Results The number and diameter of metastases treated are shown in Table I . A mean of 5.2 (s.d. = 3.3) metastases of mean diameter 4.5 cm (+ 2.8) were frozen. Only on three occasions were more than 6 metastases treated. The effect of cryotherapy on circulating CEA concentrations is shown in Fig. 1, where the latter are plotted as % change from the immediate preoperative value. This method of presentation was chosen for clarity. Actual values are given in Table 2. In 3 patients referred from other hospitals, the only pre-operative CEA value was the one taken immediately pre-operatively. CEA concentrations rose in all patients where two or more CEA values had been done before surgery and, in all but 2 patients (in one of whom a I month postoperative
Discussion The management of patients with hepatic metastases includes the diagnosis, accurate assessment and therapy of such lesions. Important recent advances have been made in all these areas. It is now well established that prolonged survival is experienced by a sizeable proportion (20-30%) of patients following successful resection of favourable lesions. l o . ' l This can also be achieved with less than 5 % mortality, even in elderly patients. The proportion of patients with hepatic metastases suitable for resection is, however, depressingly small. This fact is probably better appreciated by general
Table 1. Hepatic cryotherapy. number and diameter of metastases, relationship to CEA fall and length of reduction Patient Metastases (no.) Max. diameter (cm) CEA YO fall Months to base Survival(months)
I
2
3
4
5
6
7
8
9
10
II
9 4 19 2 D4
12 2.5
3 12 25 2 A17
3 3 45
5 2 0
5 4 67
2 5 75
6 5
2 5
ND
8 6 38
All
6 All
2 2 40 5 A6
NY A6
A4
A3
A2
0 D16
5 A13
ND: not done; NY: not yet returned to pre-treatment level; A: alive; D: dead.
Table 2. Effect of hepatic cryotherapy on serum CEA values Months prelpost operation -4 -3 -2
Serum CEA concentration (pglL) Patient I 68
2
3
4
11.6
5
6
7
8
9
33
10
II
10
II
16 89
-I 51
2
615 450 I550
3
2900
370
0
I 4 5 6
330
250 560 810
2.7 2.2 < 1.5
38 42
< 1.5
54
3.4 6.4
72
14 20 4.6 5 7.4 16 39
2
55
EFFECT OF HEPATIC CRYOTHERAPY ON SERUM CEA CONCENTRATION IN PATIENTS WITH MULTIPLE INOPERABLE HEPATIC METASTASES FROM COLORECTAL CANCER R. M.CHARNLEY, M.THOMAS AND D.L.MORRIS Department of Surgery, University Hospital, Nottingham, UK Eleven patients with multiple hepatic metastases from colorectal cancer, all judged inoperable, were treated by cryotherapy using a probe through which liquid nitrogen was circulated using a single freeze thaw sequence. Localization of metastases, positioning of the probe and monitoring of ice ball size was by intra-operative ultrasound. Serum carcinoembryonic antigen (CEA) was measured in these patients: there was a postoperative fall in all but two. In all but one, there has been a subsequent rise. Speed and degree of rise of CEA varied between patients. Serial CEA may be an effective means of monitoring the effect of hepatic cryotherapy.
Key words:CEA,colorectal cancer, cryotherapy, hepatic metastases.
Introduction Hepatic metastases are one of the common modes of dissemination of colorectal cancer. There has been some progress in the treatment of colorectal hepatic metastases: resection is now a much safer procedure and can achieve 5-year survival rates of approximately 25%. Chemotherapy delivered via local arterial infusion can achieve high response rates.* The proportion of patients who are suitable for resection, however, is small and chemotherapy probably only benefits patients with low percentage hepatic replacement. Our principal interest in hepatic cryotherapy was to find a technique which could increase the proportion of patients treatable by a local technique. Contact ultrasound is a relatively new procedure which allows the detection of small hepatic metastases3 and is also important in facilitating the accurate placement of a cryoprobe and monitoring iceball size. The concept of hepatic cryotherapy is relatively r e ~ e n t . It~ may . ~ allow us to treat lesions which are not surgically resectable for anatomic reasons and afford a procedure which is much less difficult and dangerous than resection, which may be an advantage to high risk patients.4s5 The authors recently described a cryoprobe, utilizing circulated liquid nitrogen as coolant, which can be placed under contact ultrasound control into hepatic lesions without damaging much overlying liver tissue.'
'
Correspondence: D. L. Moms. Prof. Surgery. The St George Hospital. Kogarah. NSW 2217. Australia. Accepted for publication I August 1990.
The effectiveness of hepatic cryotherapy clearly must be measured ultimately by hard clinical parameters such as survival. Radiographic assessment of effectiveness is difficult because the changes following cryo-destruction cannot easily be differentiated from tumour. We chose, therefore, to study the serum carcinoembryonic antigen (CEA) concentration in patients with colorectal cancer undergoing cryotherapy of hepatic metastases. Serum CEA concentrations are used in the diagnosis of recurrence/metastases of colorectal cancer.'^^ If CEA is, therefore, a sensitive marker for metastatic colorectal cancer. and successful response to resection or chemotherapy produces a fall in this, then serial CEA measurement may be a useful method of evaluating this new technique.'
Method Eleven patients with multiple hepatic metastases from colorectal cancer, who were all judged unresectable due to number, anatomical consideration or extra-hepatic disease (one elderly woman had 2 hepatic metastases diagnosed at laparotomy for an obstructing metachronous tumour). All patients underwent thorough laparotomy through a roof top incision. Patients with unresectable extra hepatic disease were not treated. Cryotherapy was administered using a CRYOTEC liquid nitrogen system via the insulated circulating coolant probe previously described or by a circular coil probe for surface lesions.6 ha-operative ultrasound (Bruel & Kjaer, Denmark) was used in localizing lesions, controlling probe placement and monitoring iceball size. We attempted to achieve an iceball radius of I cm more than metastasis. A single freezdthaw sequence was used; clamping the hepatic artery and
CHARNLEY ET AL.
56
portal vein was only used in one patient with very large metastases. Core body temperature was monitored; a warming mattress, warmed intravenous fluids and a rebreathing anaesthetic circuit were used to minimize heat loss. Other anti-cancer therapy was not used in these patients during this study. The patients had regular follow-up in a dedicated clinic and serial serum CEA values were measured.
blood sample was not taken, in error), a postoperative fall in CEA concentration was seen at I month. In addition, in all but one patient there was a subsequent postoperative rise in CEA, indicating tumour recurrence. The speed and degree of rise of CEA varied between patients. The time in months until return to the preoperative CEA concentration is given in Table I ; this varied between 2-6 months, but in 1 patient, who had a pre-treatment CEA of only 2, this fell postoperatively to undetectable levels and has not yet risen to the pre-treatment value.' (CT scan in this patient shows no evidence of recurrence.)
Results The number and diameter of metastases treated are shown in Table I . A mean of 5.2 (s.d. = 3.3) metastases of mean diameter 4.5 cm (+ 2.8) were frozen. Only on three occasions were more than 6 metastases treated. The effect of cryotherapy on circulating CEA concentrations is shown in Fig. 1, where the latter are plotted as % change from the immediate preoperative value. This method of presentation was chosen for clarity. Actual values are given in Table 2. In 3 patients referred from other hospitals, the only pre-operative CEA value was the one taken immediately pre-operatively. CEA concentrations rose in all patients where two or more CEA values had been done before surgery and, in all but 2 patients (in one of whom a I month postoperative
Discussion The management of patients with hepatic metastases includes the diagnosis, accurate assessment and therapy of such lesions. Important recent advances have been made in all these areas. It is now well established that prolonged survival is experienced by a sizeable proportion (20-30%) of patients following successful resection of favourable lesions. l o . ' l This can also be achieved with less than 5 % mortality, even in elderly patients. The proportion of patients with hepatic metastases suitable for resection is, however, depressingly small. This fact is probably better appreciated by general
Table 1. Hepatic cryotherapy. number and diameter of metastases, relationship to CEA fall and length of reduction Patient Metastases (no.) Max. diameter (cm) CEA YO fall Months to base Survival(months)
I
2
3
4
5
6
7
8
9
10
II
9 4 19 2 D4
12 2.5
3 12 25 2 A17
3 3 45
5 2 0
5 4 67
2 5 75
6 5
2 5
ND
8 6 38
All
6 All
2 2 40 5 A6
NY A6
A4
A3
A2
0 D16
5 A13
ND: not done; NY: not yet returned to pre-treatment level; A: alive; D: dead.
Table 2. Effect of hepatic cryotherapy on serum CEA values Months prelpost operation -4 -3 -2
Serum CEA concentration (pglL) Patient I 68
2
3
4
11.6
5
6
7
8
9
33
10
II
10
II
16 89
-I 51
2
615 450 I550
3
2900
370
0
I 4 5 6
330
250 560 810
2.7 2.2 < 1.5
38 42
< 1.5
54
3.4 6.4
72
14 20 4.6 5 7.4 16 39
2
