Hepatic Cryotherapy Research Articles

World Survey on the Complications of Hepatic and Prostate Cryotherapy

Cryotherapy is used as a treatment for nonresectable liver tumors and adenocarcinoma of the prostate. Morbidity and mortality following cryotherapy are generally considered to be infrequent, but a syndrome of multiorgan failure, severe coagulopathy, and disseminated intravascular coagulation following hepatic cryotherapy has been described and referred to as the cryoshock phenomenon. In this study we aimed to assess and describe the incidence and clinical features of the cryoshock phenomenon following cryosurgery from the surveyed experience of a large number of clinical centers and to relate the data to the overall mortality and morbidity of this treatment. A questionnaire was sent to all cryotherapy users (n = 299) of whom we were aware. We requested information on the number of patients treated, the occurrence, and the clinical features of cryoshock and mortality and morbidity following cryotherapy of the prostate or liver. Altogether 134 completed questionnaires were returned (44.8%). Seventy-two centers had experience with hepatic cryotherapy and 62 with prostate cryotherapy. Following hepatic cryotherapy, the phenomenon of cryoshock was observed in 21 of 2173 patients (1%) and was responsible for 6 of 33 perioperative deaths (18.2%). Cryoshock was rare following prostate cryotherapy (2 of 5432 patients, 0.04%) and did not contribute to the overall mortality of 0.06%. Hepatic and prostate cryotherapy are safe. Cryoshock is rare after prostate cryotherapy but occurs in 1% of patients following hepatic cryotherapy. Cryoshock is associated with a high risk of death, being responsible for 18.2% of deaths in this survey. Research regarding the mechanism and possible avoidance of cryoshock is required.

World survey on the complications of hepatic and prostate cryotherapy.

Cryotherapy is used as a treatment for nonresectable liver tumors and adenocarcinoma of the prostate. Morbidity and mortality following cryotherapy are generally considered to be infrequent, but a syndrome of multiorgan failure, severe coagulopathy, and disseminated intravascular coagulation following hepatic cryotherapy has been described and referred to as the cryoshock phenomenon. In this study we aimed to assess and describe the incidence and clinical features of the cryoshock phenomenon following cryosurgery from the surveyed experience of a large number of clinical centers and to relate the data to the overall mortality and morbidity of this treatment. A questionnaire was sent to all cryotherapy users (n = 299) of whom we were aware. We requested information on the number of patients treated, the occurrence, and the clinical features of cryoshock and mortality and morbidity following cryotherapy of the prostate or liver. Altogether 134 completed questionnaires were returned (44.8%). Seventy-two centers had experience with hepatic cryotherapy and 62 with prostate cryotherapy. Following hepatic cryotherapy, the phenomenon of cryoshock was observed in 21 of 2173 patients (1%) and was responsible for 6 of 33 perioperative deaths (18.2%). Cryoshock was rare following prostate cryotherapy (2 of 5432 patients, 0.04%) and did not contribute to the overall mortality of 0.06%. Hepatic and prostate cryotherapy are safe. Cryoshock is rare after prostate cryotherapy but occurs in 1% of patients following hepatic cryotherapy. Cryoshock is associated with a high risk of death, being responsible for 18.2% of deaths in this survey. Research regarding the mechanism and possible avoidance of cryoshock is required.

Indicators of recurrence following cryotherapy for hepatic metastases from colorectal cancer.

This retrospective review aimed to assess the incidence of local recurrence at the cryosite, hepatic and extrahepatic recurrence and the corresponding disease-free intervals. Prognostic indicators following hepatic cryotherapy were also identified. Eighty-five patients underwent complete cryotreatment of colorectal liver metastases between April 1990 and May 1997. Possible prognostic indicators were tested for their impact on the disease-free interval at the cryosite, liver disease-free survival and overall disease-free survival with univariate and multivariate analysis. At a median follow-up of 22 months 66 patients developed tumour recurrence: 18 in the liver only; 15 in the liver and lung; 22 in the liver and extrapulmonary areas; and 11 at extrahepatic sites only. Local recurrence at the cryosite occurred in 28 patients. Cryotreated metastases larger than 3 cm were associated with a shorter disease-free interval at the cryosite and liver disease-free survival; persistently raised serum carcinoembryonic antigen (CEA) levels after operation were associated with shorter liver disease-free and overall disease-free intervals in multivariate analysis. Improvements in probe placement and monitoring of the freezing process are required to allow successful treatment of large liver metastases. A failure in complete postoperative CEA response indicates that hepatic or extrahepatic disease was not detected before operation, which may be avoided with better staging procedures.

Repeat hepatic cryotherapy for recurrent metastases from colorectal cancer

CRYOTHERAPY HAS BEEN SHOWN TO BE a safe and effective treatment option for nonresectable liver metastases from colorectal cancer.1,2 Many patients, however, will have recurrent disease, and this is confined to the liver in some patients. Repeated liver resection is safe and associated with disease-free and overall survival results similar to those after first liver resection.3 There is no previous report that studies the results of repeat hepatic cryotherapy.

Repeat hepatic cryotherapy for recurrent metastases from colorectal cancer

Cryotherapy has been shown to be a safe and effective treatment option for nonresectable liver metastases from colorectal cancer.1,2 Many patients, however, will have recurrent disease, and this is confined to the liver in some patients. Repeated liver resection is safe and associated with disease-free and overall survival results similar to those after first liver resection.3 There is no previous report that studies the results of repeat hepatic cryotherapy.

Pretreatment echogenicity of colorectal liver metastases predicts survival after hepatic cryotherapy.

There is currently no knowledge of the prognostic value of echogenicity of colorectal liver metastases in patients receiving no treatment, hepatic cryotherapy, or any other treatment modality. We sought to determine whether differences in echogenicity of colorectal liver metastases predict prognosis after hepatic cryotherapy. Between April 1990 and May 1997 the echogenicity of liver metastases was assessed intraoperatively in 48 patients undergoing cryotherapy for in situ destruction of colorectal liver metastases, with use of an Aloka machine with a 5-MHz scanner. Survival time was calculated by the Kaplan-Meier method, and the prognostic value of echogenicity and several other possible prognostic factors was tested with the log-rank test. Thirty-three patients were found to have hyperechoic metastases. These patients had a favorable outcome, with a median survival time of 50 months, as compared with a median survival time of 24 months in the 15 patients with hypoechoic metastases (P = 0.0074). Regarding the remaining prognostic factors that were tested, only age less than 51 years, absence of involved nodes at primary resection, small diameter of liver metastases, and low preoperative serum carcinoembryonic antigen levels were associated with a favorable outcome. We believe that this is an original description of the prognostic importance of echogenicity of colorectal liver metastases. Differences in echogenicity may be related to tumor biology. This will be addressed in further studies.

Cryotherapy of the resection edge after liver resection for colorectal cancer metastases.

An involved or inadequate (< 1 cm) resection margin is associated with a high rate of local tumour recurrence and reduced survival rates after liver resection for colorectal metastases. This paper assesses whether or not hepatic cryotherapy of the resection edge is suitable to improve local disease control. From April 1990 to May 1997, we performed cryotherapy of the resection edge in 44 patients after liver resection for colo rectal liver metastases with an involved or inadequate resection margin. The reasons for performing edge cryotherapy instead of extension of resection were: proximity of hepatic veins or portal sheath (n = 12); avoidance of extended left or right hemihepatectomy (n = 15); inadequate liver tissue reserve after resection (n = 16); and patient unfit to undergo further major resection (n = 1). Histological examination showed the resection margin to be involved in 24 patients and close (< 1 cm) in 20 patients. Two patients died after surgery. Morbidity consisted of intra-abdominal collections (n = 6), postoperative bleeding (n = 1), wound infection (n = 1) and transient liver failure (n = 1). At a median follow-up of 19 months, 16 patients are alive and disease-free, 26 patients developed recurrence and 15 of them died. Nineteen patients developed recurrence which involved the liver but only five of these were at the resection edge. Median overall and liver disease-free survival was 33 and 23 months, respectively. Cryotherapy of the resection edge after resection of colorectal liver metastases with involved or inadequate resection margins considerably improves local disease control and may allow a greater proportion of patients with liver metastases to undergo potentially curative treatment.

Fluorodeoxyuridine causes bilomas after hepatic cryotherapy.

Hepatic cryotherapy is a method of in situ cytodestruction used for unresectable liver tumours that can be combined with regional cytotoxic administration. We have used intra-arterial chemotherapy with 5-fluorouracil (5-FU) after hepatic cryotherapy but changed to 5-fluorodeoxyuridine (FUDR) because of the arterial toxicity of 5-FU. A new complication was seen. A retrospective case note study was performed of 130 patients who had undergone hepatic cryotherapy followed by regional chemotherapy at our centre. Seven patients received FUDR; 123 received 5-FU. Biloma at the cryotherapy sites was seen in three patients in the FUDR group; two other patients in this group had other types of hepatic collection. Our previous experience with intra-arterial 5-FU in 123 patients after hepatic cryotherapy showed no evidence of this syndrome. Intra-arterial FUDR should not be used after hepatic cryotherapy, at least during the immediate postoperative period.

Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer.

To establish the prognostic importance of different patient and tumor characteristics in cryotherapy for liver metastases from colorectal cancer. Hepatic cryotherapy has been used as a treatment of nonresectable liver metastases from colorectal cancer in almost 1000 patients worldwide, and its safety and efficacy are well established. However, tumor eventually recurs in most patients and they die of their disease. The knowledge of prognostic factors would allow the selection of patients who are more likely to benefit from this treatment and patients who may need additional treatment. Between April 1990 and May 1997, 195 patients were treated with hepatic cryotherapy. Out of this group, the authors identified 116 patients with colorectal cancer who received cryotherapy for ablation of liver metastases. Survival was estimated with the Kaplan-Meier method, using the log-rank test for univariate analysis for significance of possible prognostic factors. For multivariate analysis, a Cox regression was used. One patient (0.9%) died of postoperative myocardial infarction. The total perioperative morbidity rate was 27.6%. Median survival and the 5-year survival rate were 26 months and 13.4%. The following factors were identified as independently associated with a favorable outcome: low presurgical serum level of carcinoembryonic antigen (CEA), small (< or =3 cm) diameter of cryoablated metastases, absence of untreated extrahepatic disease at laparotomy, absence of nodal involvement at primary resection, complete cryotreatment, synchronous development of liver metastases, and good or moderate differentiation of the primary tumor. Although univariate analysis suggested a favorable prognosis in patients who did not receive blood transfusion during surgery and patients younger than 51 years, this was not confirmed in multivariate analysis. In addition, normalization of the serum CEA level after treatment was an important prognostic marker in the subgroup of patients with elevated serum CEA levels before surgery. Hepatic cryotherapy is a safe and effective treatment option for patients with nonresectable liver metastases from colorectal cancer, with promising results regarding survival. The prognostic factors established in this series may allow better patient selection to improve the outcome in suitable patients.

Renal Impairment in Hepatic Cryotherapy

Cryoshock is a syndrome of coagulopathy, renal, and pulmonary injury following cryotherapy, and its etiology is unknown. The aim of this study was to assess the impact of hepatic cryotherapy on renal function, and whether this effect is related to volume of cryotherapy, and to identify any predictors of renal impairment in patients who undergo cryotherapy. A retrospective analysis of all patients with primary or secondary hepatic malignancy treated with cryotherapy from April 1990 to October 1996 was conducted. Ten of 204 patients with renal impairment (elevation in creatinine of greater than 0.02 mmol/L for more than 2 days postprocedure) were identified. One patient had postoperative pancreatitis with late renal impairment (20 days) and was excluded. The severity of renal impairment was usually modest (mean rise in creatinine of 0.31 mmol/L; SD, 0.19). Two patients required temporary hemodialysis. Only one patient, who had significant cardiac disease, had associated pulmonary injury and shock. Demographic data in both groups were comparable, except for a trend toward more noncolorectal cancer patients in the renal impairment group (4/9 vs 33/194). Patients in the renal impairment group had a greater number of lesions than those of the nonrenal impairment group (3.4 vs 2.1,P< 0.01), as well as larger lesion diameter (2.9 vs 1.9,P< 0.01), increased freezing time (74.7 vs 44.3,P< 0.01), and a higher aspartate transaminase (AST) (2254 vs 1157,P< 0.01). This study suggests that renal impairment is more likely to be seen in patients undergoing more extensive cryotherapy. The number and diameter of lesions together with AST data link renal injury with magnitude of liver injury—all renal impairment patients had an AST > 1000, compared with only 28% of patients who did not.

Anesthetic considerations for hepatic cryotherapy.

The evolution of hepatic cryotherapy as an accepted treatment for patients with non-resectable hepatic malignancy has required concurrent evaluation and development of perioperative anesthetic management of these cases. Review of published and institutional experience demonstrates that hepatic cryotherapy presents the anesthesiologist with an array of challenges, all of which are not intuitively apparent. Specifically, such issues as management of coexisting physiologic perturbations of the oncology patient, heat conservation during the procedure, and readiness for a more extensive procedure would be readily anticipated by most clinicians. Description and reasonable management of problems ranging from mild or moderate postoperative thrombocytopenia to the so-called cryoshock syndrome with the possibility of severe postoperative coagulopathy, renal dysfunction, and pulmonary complications, however, could emerge only with the education of experience. The goal of this article is to address the key issues faced by anesthesiologists consulted in the perioperative care of patients undergoing hepatic cryotherapy.

Experimental basis for hepatic cryotherapy

Hepatic cryotherapy has emerged as a viable therapeutic option in the treatment of liver tumors, both primary and secondary. We will provide the experimental basis for its application in the liver with particular reference to safety and efficacy issues. Also discussed are experiments with the use of hepatic cryotherapy in animals that have demonstrated the effectiveness of the technique, and improvements in technology that have enabled better delivery. The future of this modality looks bright with increasing advances in technology to enable better application. Its use in combination with other treatment modalities could offer improved success in treating liver tumors. Semin. Surg. Oncol. 14:110–115, 1998. © 1998 Wiley-Liss, Inc.

Experimental basis for hepatic cryotherapy.

Hepatic cryotherapy has emerged as a viable therapeutic option in the treatment of liver tumors, both primary and secondary. We will provide the experimental basis for its application in the liver with particular reference to safety and efficacy issues. Also discussed are experiments with the use of hepatic cryotherapy in animals that have demonstrated the effectiveness of the technique, and improvements in technology that have enabled better delivery. The future of this modality looks bright with increasing advances in technology to enable better application. Its use in combination with other treatment modalities could offer improved success in treating liver tumors.

Treatment of colorectal liver metastases by cryotherapy.

One hundred fifty-eight procedures were performed on 136 patients with unresectable hepatic metastases using hepatic cryotherapy to ablate the tumors. The median age was 62 years. Patients included 90 males and 46 females. Fifty-eight patients had synchronous metastases, 55 had bilobar lesions, and 90 had precryo chemotherapy. Median preoperative carcinoembryonic antigen (CEA) level was 14.4 ng/dl. The numbers of lesions treated, frozen, and resected were two and one. Median survival of all patients was 30 months. Survival for 39 patients was 37 months. Patients with a CEA level > 100 ng/dl had a statistically worse survival rate than those with a level < 100 ng/dl (P < .001). Twenty patients underwent recryotherapy with median survival of 34 months. Recurrent disease developed in 78% of patients--82% of the patients developed liver recurrence. Complication rates were comparable to liver resection. Operative mortality was 3.7%. Hepatic cryotherapy is effective and safe in treating colorectal hepatic metastases under ultrasound guidance.

Cryotherapy for neuroendocrine liver metastases.

While the prognosis for patients with untreated liver metastases from neuroendocrine primaries is rather good, they often suffer disabling symptoms due to syndromes of hormonal excess. Thirteen patients with metastatic neuroendocrine tumours were treated by hepatic cryotherapy; seven patients were symptomatic and five of these had elevated levels of hormonal tumour markers. Twelve patients are alive and mostly asymptomatic with a median follow up of 13.5 months; one patient died after 45 months of bronchopneumonia without evidence of tumour recurrence. All patients with elevated preoperative tumour markers have had a significant fall in markers postoperatively. Two patients were returned to the operating theatre for coagulopathy-associated bleeding: one patient each developed acute renal failure and pulmonary embolism, but there was no mortality. This study shows that hepatic cryotherapy offers a useful treatment option for this group of patients, alleviates symptoms and may have an impact on survival.

Biochemical, hematologic, and immunologic alterations following hepatic cryotherapy.

Hepatic cryosurgery causes hepatocellular damage primarily by inducing the formation of ice crystals. Cell necrosis is enhanced using two or more freeze-thaw cycles. The resultant damage to hepatocytes induces alterations in a number of biochemical and hematologic parameters, including hepatic function tests, serum bilirubin, serum and urine myoglobin, platelet count, and coagulation measures. Further, in experimental models, cryogenic surgery appears to stimulate the immune system of the host leading to an anti-tumor immune response. These perturbations in biochemical and hematologic parameters are usually transient, and long-term adverse sequelae are uncommon and preventable.

Hepatic cryotherapy and subsequent hepatic arterial chemotherapy for colorectal metastases to the liver.

This paper presents an experience of thirty consecutive patients with hepatic colorectal metastases who were treated with hepatic cryotherapy and subsequent hepatic arterial infusion (HAI) chemotherapy using 5FU. Patients with colorectal metastases confined to the liver but not suitable for resection, and with liver involvement of less than 50% were offered the treatment. Prospective documentation of all patients was undertaken with data being recorded on a computerised database. Patients had a median of 6 (2–15) lesions with sizes ranging from 1–12 cm. There was no 30 day mortality. Postoperative complications developed in 8 patients but were followed by full recovery in all instances. Side effects from chemotherapy occured in 23% of cycles. Twenty seven patients have died. Median survival from the time of cryotherapy was 18.2 months (7–34), or 23months (9–44) from diagnosis of liver lesions. Hepatic cryotherapy with subsequent arterial chemotherapy is safe and well tolerated. The results suggest survival of patients with colorectal hepatic metastases can be improved by the use of this modality of treatment.

Anaesthetic experience with laparoscopic cryotherapy

Laparoscopic cryotherapy is a new technique for treating hepatic tumors that obviates the need for a laparotomy and may reduce the amount of surgical trauma and heat loss associated with the open technique. Liquid nitrogen is applied to the tumor via a cryoneedle probe introduced through a laparoscopic port. The aim of this study was to assess the effect on body temperature and the hematological and biochemical changes associated with this technique. Five patients who underwent this procedure were studied prospectively under a standardized general anaesthetic. Core and peripheral temperature were measured during the procedure, and blood samples were taken for hematological and biochemical analysis. Freezing time ranged 19-57 min and measured blood loss 0-1000 ml. In one case, bleeding resulted from hepatic surface cracking. Three patients required a blood transfusion. The mean fall in both nasopharyngeal and right atrial temperature was 0.4 degree C. Postoperatively, all patients showed a large rise in alanine aminotransferase (ALT) and a fall in platelet count. A systemic inflammatory response syndrome was seen in some cases, but all patients survived to hospital discharge. Laparoscopic hepatic cryotherapy can be performed without significant temperature changes, but it entails significant morbidity.

Computed tomography changes following cryotherapy for hepatic cancer

Encouraging survival and tumour marker results have been described in patients where the focally destructive technique, hepatic cryotherapy, is used to treat primary and secondary hepatic malignancy. Radiology allows assessment of the cryotherapy procedure and follow-up treatment. This paper aims to review and describe the appearance of hepatic cryotherapy by CT.

Primary resection and synchronous regional hepatic chemotherapy or cryotherapy for colorectal cancer with liver metastases.

Twenty-two patients with colorectal cancer and synchronous unresectable hepatic metastases were treated by resection the primary tumour with concurrent insertion of an Infusaid infusaport system for regional chemoperfusion (hepatic arterial 20, portal venous 2). Four patients in addition had cryotherapy the liver metastases. Morbidity from the synchronous procedures was minimal. Median survival was 10 months. Four patients with poorly-differentiated tumours had a poor response, with a median survival of 3.75 months.