Semin Surg Oncol

Anesthetic considerations for hepatic cryotherapy.

Year 1998
Littlewood K.
Department of Anesthesiology, Virginia Commonwealth University, Richmond 23298-0459, USA. KLITTLEWOOD@gems.vcu.edu
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.

Biochemical, hematologic, and immunologic alterations following hepatic cryotherapy.

Year 1998
Hamad GG. Neifeld JP.
Department of Surgery, Virginia Commonwealth University 23298, USA.
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.

Intraoperative monitoring and postoperative imaging of hepatic cryosurgery.

Year 1998
Brewer WH. Austin RS. Capps GW. Neifeld JP.
Department of Radiology, Virginia Commonwealth University, Richmond 23298-0615, USA.
Because intraoperative sonography displays segmental anatomy, allows discovery of more lesions than previously suspected from preoperative imaging, surgical inspection, or palpation, and permits more certain diagnosis of problematic masses, it facilitates surgical decision-making when liver resection or cryoablation is anticipated. Intraoperative sonography provides a guidance modality to accurately place cryosurgery probes in liver masses. More precise treatment of metastatic and primary tumors of the liver is possible with cryoablation because intraoperative sonography provides a means of monitoring the growth of the enlarging freeze zone to insure adequate surgical margins. Postoperative detection of acute complications after cryosurgery is best done with computed tomography. Normally cryosurgery defects shrink with time and lose the peripheral contrast opacification seen after surgery. Gas collections, seen as a result of tissue necrosis, must be discriminated from infection. Tumor recurrence can be detected well with computed tomography or magnetic resonance imaging following hepatic cryosurgery.

Complications of hepatic cryosurgery.

Year 1998
Sarantou T. Bilchik A. Ramming KP.
John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, California 90404, USA.
Cryosurgery may be considered for patients whose hepatic lesions are not amenable to surgical resection, i.e., patients with multiple hepatic lesions and/or lesions abutting major vascular structures. Because the size of the iceball created during the procedure can be carefully controlled, cryosurgery has the advantage of being a focal technique that spares much more noncancerous liver tissue than surgical resection. The major complications of hepatic cryosurgery are the same as those of hepatic resection: hemorrhage, pleural effusion, bile leak fistula, perihepatic abscess, and hepatic failure. In addition, there is a risk of coagulopathy when large tumors are frozen using multiple freeze-thaw cycles. In general, operative morbidity is related to the volume of frozen tissue, the number of freeze-thaw cycles, and number of cryoprobes. Further experience and accrual of long-term data should better define the indications for hepatic cryosurgery and minimize the incidence of complications.

Treatment of colorectal liver metastases by cryotherapy.

Year 1998
Weaver ML. Ashton JG. Zemel R.
Allegheny General Hospital, Pittsburgh, Pennsylvania, USA. mweaverl@aherf.edu
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 primary liver cancer.

Year 1998
Zhou XD. Tang ZY.
Liver Cancer Institute, Zhong Shan Hospital, Shanghai Medical University, People's Republic of China.
Between November 1973 and December 1996, the in situ freezing of tumor, i.e., cryotherapy, was performed with liquid nitrogen (-196 degrees C) on 235 patients with primary liver cancer (PLC). There were no operative mortalities or severe complications. The 5-year survival was 39.8% for the 235 PLC patients, and 55.4% for the 80 patients with small PLC (< or = 5 cm). When analyzed with respect to treatment modalities without considering the size of the tumor, the 5-year survival was 26.9% for 78 PLC patients treated by cryotherapy alone; 39.6% for 58 PLC patients treated by cryotherapy plus hepatic artery ligation and perfusion; 46.0% for 27 PLC patients treated by cryotherapy for residual tumor plus resection of the main tumor; and 60.4% for 72 PLC patients treated by cryotherapy followed by resection of the frozen tumor. These results indicate that cryotherapy is a safe and effective treatment for PLC.

Cryotherapy for neuroendocrine liver metastases.

Year 1998
Seifert JK. Cozzi PJ. Morris DL.
University Department of Surgery, University of New South Wales, St. George Hospital, Sydney, Australia.
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.

In vitro concentration response studies and in vitro phase II tests as the experimental basis for regional chemotherapeutic protocols.

Year 1998
Link KH. Leder G. Pillasch J. Butzer U. Staib L. Kornmann M. Bruckner U. Beger HG.
Department of General and Visceral Surgery, University of Ulm, Germany.
The theoretical pharmacologic benefit of regional vs. systemic chemotherapy is defined and the concentration response behavior of cytostatic drugs and their optimal exposure times are described with human cancer cell lines (HT29, NMG64/84) and fresh human tumor cell suspensions in the human tumor colony assay (HTCA). The theoretical pharmacological advantages are 5.8 to 6 for adriamycin (ADM), 8 for cisplatinum (CDDP), 6.3 for epidoxorubicin (EPI), 22 to 58 for 5-fluorouracil (5FU), 4.6 for mitomycin C (MMC), and 6.3 for mitoxantrone (NOV). The drugs differed in their cytotoxic potency in vitro and thus also potential efficacy for regional chemotherapy; however, all but 5-fluorodeoxyuridine (5FUDR) exerted cytotoxicity dependent on exposure time and concentration. On average, elevation of the test concentrations by 1 lg doubled responses in fresh human tumor cell suspensions. From these results and clinical considerations, optimal times were defined for the regional chemotherapy strategies of hepatic artery infusion, intraperitoneal instillation, and chemoembolisation as performed at our institution.

Intra-arterial infusion: overview and novel approaches.

Year 1998
Aigner KR.
Asklepios Paulinen Klinik, Abteilung fur Chirurgische Onkologie, Wiesbaden, Germany.
Intra-arterial infusion includes a variety of treatment modalities, adjusted selectively to chemosensitivity and vascularization. For most drugs, response behaviour of different tumors is concentration dependent and requires improved modes of application of cytotoxics. In the treatment of liver metastases from colorectal cancer and hepatocellular carcinoma, blood flow reduction by micro-embolization with starch microspheres has brought significant advantage in response. Balloon stopflow infusion combined with micro-embolization induced 83% complete remissions in a study including 100 patients with locally recurrent breast cancer. Stepwise increased local exposure demonstrated concentration-dependent response. Stopflow infusion of the celiac axis combined with microspheres for advanced Stage III and IV pancreatic cancer induced a 96% remission rate (n = 24 patients) at a median survival of 10 months. This was confirmed in a series of consecutive studies including 242 patients. Quality of life was significantly improved in all responding patients. Overall pain response was 80%. A prospective randomized trial in this patient group, comparing systemic vs. regional chemotherapy in the form of intra-arterial infusion with tumor adjusted concentrations, was stopped in an early phase because median survival time was significantly prolonged (P = 0.001) in the arterial group.

Intraperitoneal chemotherapy and cytoreductive surgery for the prevention and treatment of peritoneal carcinomatosis and sarcomatosis.

Year 1998
Sugarbaker PH.
The Washington Cancer Institute, DC 20010, USA.
Intraperitoneal chemotherapy and cytoreductive surgery have been combined to reach treatment objectives in patients with peritoneal carcinomatosis or sarcomatosis that neither modality by itself can achieve. These treatments must be combined with the proper selection of patients in order to observe "high value" results from therapy. There are three principles of management to support treatments for peritoneal carcinomatosis and sarcomatosis. First, the clinician must select patients who have isolated disease distributed on the surfaces of abdominal and pelvic structures. Patients treated for peritoneal implants who have persistent disease at other sites will profit little or not at all. Second, this disease must be reduced to its lowest possible mass by peritonectomy procedures and resections of viscera. Third, maximal intraperitoneal and systemic chemotherapy are utilized to eradicate the disease on peritoneal surfaces as well as control the primary or recurrent tumor. These principles of management and a presentation of the results achieved to date are reviewed.

Delivery of anticancer drugs via isolated hepatic perfusion: a promising strategy in the treatment of irresectable liver metastases?

Year 1998
Vahrmeijer AL. Van Der Eb MM. Van Dierendonck JH. Kuppen PJ. Van De Velde CJ.
Department of Surgery, Leiden University Medical Center, The Netherlands.
The prognosis of patients with irresectable liver metastases derived from colorectal cancer is invariably poor; unfortunately, these tumours show only minor responses to conventional anticancer agents. The best responses have been obtained by fluoropyrimidines delivered as continuous infusion into the hepatic artery (HAI): their rapid uptake and detoxification by liver cells results in relatively low systemic drugs levels. This approach increases mean survival duration from 17 to 26 months and, in few patients, causes "down-staging" that may result in resectability. To improve opportunities for chemotherapy, the technique of 1-hour recirculating perfusion of the vascularly isolated liver (isolated hepatic perfusion, IHP) was developed. If leakage to the systemic circulation is negligible-and the compounds used do not readily cause hepatotoxicity-IHP allows usage of drug doses that would be fatal if delivered systemically. Because alkylating agents generally have steep dose-response curves, mitomycin C (MMC) and melphalan (L-PAM) entered phase I/II studies on IHP. Using these drugs, IHP was performed in principle as a single procedure in 60 otherwise untreated patients at our institution. However, despite preliminary data that indicate impressive clinical responses are obtained, improvement over HAI will probably be minor. Because IHP is a complicated way of drug delivery, one could argue that its use is justified only when it has the potential to kill all tumour cells in the liver. We critically discuss the possibilities of IHP and/or the use of gene therapy in an IHP setting.