Claudio Zanon

Cytoreductive Surgery and Intraperitoneal Chemohyperthermia for Recurrent Peritoneal Carcinomatosis from Ovarian Cancer

Aggressive surgical cytoreduction has been shown to have a positive impact on survival of patients with ovarian cancer. After first-line chemotherapy, 47% of patients relapse within 5 years, and median survival after second line chemotherapy is 10—15 months. Adding intraperitoneal chemohyperthermia (IPCH) to surgical cytoreduction could further control ceolomic spread of disease. The aim of this study was to determine morbidity and mortality, regional relapse-free survival and, preliminarily, overall survival after combining cytoreductive surgery with IPCH for the treatment of peritoneal carcinomatosis from ovarian epithelial cancer relapsed after prior chemotherapy. Thirty women affected with such a relapse were included. Patients underwent extensive cytoreductive surgery including tumor resections and peritonectomy, followed by intraoperative IPCH with cisplatin. Complete surgical cytoreduction down to nodules less than 2.5 mm (CC0—CC1) was obtained in 23 patients (77%). One patient died postoperatively from a pulmonary embolism. Major postoperative morbidity was 5/30 (16.7%). We registered one case of anastomotic leakage, a spontaneous ileum perforation, a postoperative cholecystitis, a hydrothorax, and one patient with bone marrow toxicity. Kaplan-Meier estimates of median locoregional relapse-free survival and median overall survival were 17.1 months and 28.1 months, respectively. Patients with CC0—CC1 had locoregional relapse-free and overall survival rates of 24.4 and 37.8 months, whereas the remainder had survival rates of 4.1 and 11.0 months. We concluded that cytoreductive surgery combined with IPCH is feasible with acceptable morbidity and mortality and seems to promise good results in selected patients affected with peritoneal carcinomatosis from ovarian cancer.

Palliative treatment of malignant refractory ascites by positioning of Denver peritoneovenous shunt.

Malignant ascites is relatively common in patients with certain types of end-stage cancer. Traditional treatments based on fluid and salt restriction and diuretic therapy often are not able to contain neoplastic ascites. These patients consequently undergo repeated abdominal paracentesis, with further plasma protein loss and risk of injury to abdominal viscera. The aim of this study was to evaluate our experience with Denver peritoneovenous shunt and the outcome of patients with malignant ascites and suggest some modifications to improve device patency. From February 1997 to December 1999, 44 Denver peritoneovenous shunts were placed in 42 patients, 17 women and 25 men, aged between 38 and 77 years (mean, 62.3), affected with malignant ascites due to advanced abdominal cancer. At the time of admission, 72% of patients had pain, 88% dysphagia, 66% nausea and/or vomiting, and 83% dyspnea. Eleven patients underwent local anesthesia with lidocaine and 33 general anesthesia with rapidly metabolized drugs. In 27 cases we used the peritoneal-internal jugular right vein surgical approach and in 3 cases the peritoneal-femoral vein surgical access, joining the saphena vein to the cross. In 10 cases, a radiological positioning of the Denver peritoneovenous shunt was effected by a trans-subclavian access. Relief of ascites symptoms was obtained in 87.5% of cases, with reduction of dyspnea, an increased appetite and improved ambulation. Denver peritoneovenous shunt is a good device to relieve malignant ascites, thereby reducing the risk of complications and the number of hospital admissions due to repeated paracentesis and consequently improving the quality of life. A careful patient selection, an accurate follow-up and some device modifications could improve the shunt performance, allowing a wider application of the Denver peritoneovenous shunt.

Percutaneous implantation of a catheter with subcutaneous reservoir for intraarterial regional chemotherapy: technique and preliminary results.

Purpose: We present the technique and the preliminary results of percutaneous implantation of intraarterial catheters connected to a subcutaneous infusion reservoir for prolonged regional chemotherapy of hepatic and extrahepatic tumors.Methods: Two hundred patients with primary or secondary hepatic neoplasms, pelvic, pancreatic, renal, lingual, and breast cancer underwent the procedure. The access was the left axillary artery (188 patients) and the femoral artery (12 patients). The catheter tip was placed in the hepatic (170 patients), hypogastric (18), splenic (4), internal thoracic (2), gastroduodenal (3), renal (2) or the external carotid artery (1). The catheter was connected to a subcutaneous reservoir and filled with heparin: chemotherapeutic infusion was subsequently started.Results: One hundred percent immediate technical success was obtained. Forty-three of 200 (21.5%) patients had a complication: 29 patients had a catheter dislodgment, nine had arterial thrombosis, three had a pseudoaneurysm of the left axillary artery and two had a port pocket hematoma. Most complications (37/43, 86%) were treated percutaneously without interruption of chemotherapy. In only six cases (3% of the total population) was chemotherapy discontinued due to the complication itself. The mean duration of catheter patency was 7.2 months.Conclusion: Percutaneous placement of an intraarterial catheter is feasible and causes less discomfort to the patient than the surgical approach. The technique has an acceptable complication rate (21.5%), similar to that for surgical implantation (17.8%), with the advantage that in most cases the complications can be resolved percutaneously. This technique represents an alternative to surgical implantation in the treatment of liver metastases from colorectal cancer and opens new therapeutic possibilities for the local prolonged treatment of other kinds of tumor, though its clinical efficacy must be assessed in selected trials.

Combined regional and systemic chemotherapy by a mini-invasive approach for the treatment of colorectal liver metastases.

&NA; From February 1996 to December 1998, 95 patients affected with colorectal liver metastases underwent the positioning of an intraarterial hepatic catheter by a transcutaneous subclavian access, under local anesthesia. All patients were evaluated for catheter implantation complications. Moreover, 61 patients of 95 treated at our center were retrospectively evaluated for results of chemotherapy performed with two different schedules of hepatic artery infusion (HAI) combined with systemic chemotherapy (SC). Eleven patients (group A) were treated with combined SC (5‐fluorouracil continuous infusion) and HAI (floxuridine). A subsequent 50 patients underwent HAI (floxuridine, 4 cycles) followed, if a response or stable disease were observed, by combined SC and HAI (group B). Three cases of aneurysm of subclavian artery occurred, which were treated by the positioning of a radiologic arterial stent and the reimplantation of the catheter by a femoral access. Thrombosis of the hepatic artery was registered in four cases. We observed 10.5% occurrence of dislocation of the catheter, which was always moved again in the hepatic artery. In group A, with 45% clinical objective response rate and 10% stable disease rate, median survival time and median time to extrahepatic progression were 9 and 6 months, respectively. In group B, we observed 44% clinical objective responses and 26% stable disease after HAI. Patients without disease progression and therefore submitted to sequential SC and HAI had a median survival time of 21 months and a median time to extrahepatic progression of 16 months. The development of the miniinvasive technique of implantation of an arterial port can avoid laparotomy for HAI. Percutaneous implantation of an arterial port has a low rate of technical complications. HAI followed by combined systemic and regional chemotherapy has good results in terms of survival and time to extrahepatic progression.

Role of different techniques for the placement of Denver peritoneovenous shunt (PVS) in malignant ascites.

The aim of the study is to evaluate 3 different techniques of Denver peritoneovenous shunt (PVS) placement. Fifty-three patients with malignant ascites underwent placement of 55 Denver PVS by a surgical (33 cases) or percutaneous (18) or laparoscopically assisted (4) procedure. There were 2 cases of postoperative mortality due to cardiac failure, and 7 cases of shunt obstruction (2 of them required replacement). Twenty patients underwent subsequent palliative treatment with chemotherapy or surgery. Complication and control of ascites rates are similar for the 3 techniques. Placement of Denver PVS for the treatment of malignant ascites appears to be a safe and useful procedure. Surgical dissection of the jugular vein is not mandatory. The percutaneous technique is the easiest, fastest, and least invasive procedure. Laparoscopic-assisted positioning is recommended if a peritoneal biopsy and/or abdominal exploration is required for a definitive diagnosis.

Intra-arterial continuous infusion for treatment of pancreatic and biliary tract cancer

SummaryBackground. Systemic chemotherapy does not satisfactorily improve the poor prognosis of pancreas and biliary tract cancer unresectable or metastatic to the liver. Intra-arterial infusion of antineoplastic agents can give higher concentrations to the tumor and slighter concentrations to the whole body, with a potential of efficacy and lower toxicity, due to the hepatic clearance. Methods. Based on a safe and ambulatorial technique of transcutaneous arterial port implantation, this study was designed to evaluate feasibility and toxicity of 5-fluorouracil (5-FU) intra-arterial continuous infusion combined with systemic gemcitabine with dose escalation. Seventeen patients affected by pancreatic (14) or biliary tract (3) cancer received up to six cycles of treatment. Treatment consisted of intravenous gemcitabine on d 1 and 8 and intra-arterial 5-FU continuous infusion on d 1–14 every 21 d. Dose-escalation levels were 900 and 1000 mg/m2 for gemcitabine and 8, 10, 12, 15, and 17 mg/kg/d for 5-FU. Consecutive cohorts of three patients were planned at each dose level. Results. Gastrointestinal toxicity (vomiting and diarrhea [3rd–4th degree] and gastritis), constituted the dose-limiting toxicity, with a maximum-tolerated dose of 1000 mg/m2 for gemcitabine and 15 mg/kg/d for 5-FU. Hematological toxicity was present in a minority of patients. No patient had acute or later complications such as arterial thrombosis related to the implanted arterial port, sclerosis cholangitis, or chemical cholecistitis.Conclusion. 5-Fluorouracil intra-arterial continuous infusion, combined with systemic gemcitabine, seems to be a feasible and safe regimen that could give interesting results in pancreatic cancer.

Gemcitabine and oxaliplatin in patients with pancreatic adenocarcinoma: clinical and pharmacokinetic data.

Objectives: This phase 2 study evaluated clinical efficacy, toxicity, and pharmacokinetics of combination gemcitabine (GEM) and oxaliplatin (OXA) in patients with advanced pancreatic adenocarcinoma. Methods: Of 30 eligible patients, 20 had metastatic disease and 10 had nonmetastatic unresectable locally advanced disease. Gemcitabine 1000 mg/m2 as a 10 mg/m2/min intravenous infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour intravenous infusion on day 2 were administered every 2 weeks. Pharmacokinetics were evaluated in 11 patients by administering the 2 drugs in opposing sequences GEM-OXA (GEM day 1, OXA day 2) and OXA-GEM (OXA day 1, GEM day 2). Results: Of 30 patients evaluated, 9 had a partial response, 11 had disease stabilization, and 10 had disease progression. Median progression-free survival and overall survival were 5.5 and 9.5 months, respectively. The 1-year survival was 37% for all patients. This study revealed no significant pharmacokinetic interaction between the 2 drugs in the GEM-OXA or in the OXA-GEM sequence. Conclusions: The combination of GEM and OXA was well tolerated and showed a promising activity in patients with advanced pancreatic adenocarcinoma; no sequence-dependent pharmacokinetic interaction occurred when comparing the GEM-OXA versus the OXA-GEM sequence, with a 24-hour interval.

Sorbitol removal by the metastatic liver: a predictor of systemic toxicity of intra-arterial chemotherapy in patients with liver metastases

BACKGROUND/AIM Hepatic arteriovenous shunting in the metastatic liver reduces the advantages of intraarterial infusion of chemotherapeutic agents because of the passage of drugs into the systemic circulation. The aim of this study was to quantitatively assess spontaneous functional hepatic arteriovenous shunting in patients with liver metastases and to determine its implication in the increase in systemic toxic effects of intra-arterial infusion chemotherapy with floxuridine. METHODS Twenty-five patients who underwent implantation of arterial ports for regional chemotherapy of liver metastases were studied. Functional hepatic arterio-venous shunting was evaluated through the bioavailability of intra-arterially administered D-sorbitol, a safe, natural compound whose kinetic features make its hepatic clearance flow dependent. In addition, D-sorbitol hepatic clearance (a parameter reflecting functional liver blood flow) and common liver function tests were evaluated for each studied patient. Patients were then grouped with respect to the percentage of medically-assessed liver occupation by metastases and with respect to systemic toxicity of the chemotherapeutic treatment. Both univariate and multivariate analyses by Students t-test and stepwise logistic regression, respectively, were performed in both groups for each of the evaluated parameters (age, liver function tests, D-sorbitol hepatic clearance and arterial bioavailability). RESULTS Arterial bioavailability of D-sorbitol ranged between 0.05 and 0.72 and was significantly greater in patients with more than 50% liver occupation (0.39+/-0.19) compared with those with minor liver involvement (0.17+/-0.13; p = 0.003); it was also significantly greater in patients experiencing high-grade systemic toxicity (0.40+/-0.19) compared with those with low-grade toxicity (0.16+/-0.11; p<0.001). Multivariate analysis showed that arterial bioavailability of D-sorbitol was the only parameter among those evaluated which was able to predict systemic toxicity of this kind of chemotherapy. CONCLUSIONS Our results show that, in the metastatic liver, arterial bioavailability of D-sorbitol, an index of functional arteriovenous shunting, varies widely, is significantly greater in patients with massive liver occupation and it is a good predictor of systemic toxicity of intra-arterial regional chemotherapy with floxuridine.

Technetium-99m labelled macroaggregated albumin arterial catheter perfusion scintigraphy: prediction of gastrointestinal toxicity in hepatic arterial chemotherapy

Abstract.Gastrointestinal toxicity from hepatic arterial infusion (HAI) of floxuridine in patients with liver metastases is probably due to extrahepatic perfusion or to partial escape of the drug from first-pass liver extraction. The aim of this study wasto verify the role of technetium-99m-labelled macroaggregated albumin (99mTc-MAA) arterial catheter perfusion scintigraphy at the beginning of each chemotherapy cycle in decreasing or preventing gastrointestinal toxicity. We studied 167 consecutive patients. On the basis of the scintigraphic follow-up and the presence or absence of an intrahepatic arteriovenous shunt (IHAVS), we classified our patients into the following groups: (1) FU+ hepatic distribution pattern (DP), comprising 29 patients with regular scintigraphic follow-up who showed the expected distribution pattern at each control or a distribution pattern with transient alterations (extrahepatic escape) promptly reversed by the replacement of the catheter. Among these 29 patients there was one case of gastrointestinal toxicity. (2) FU– hepatic DP, comprising 128 patients who were evaluated with 99mTc-MAA only at the beginning of the first chemotherapy cycle, showed the expected distribution pattern and underwent HAI with no further scintigraphic evaluation. Among these 128 patients there were 28 cases of gastrointestinal toxicity. (3) FU+ pulmonary DP, comprising three patients with abnormally elevated pulmonary uptake (higher than 5%) and with regular scintigraphic follow-up. There were two cases of gastrointestinal toxicity among these three patients. (4) FU– pulmonary DP, comprising seven patients with abnormally elevated pulmonary uptake and without regular scintigraphic follow-up. There were four cases of gastrointestinal toxicity among these seven patients. The incidence of toxicity was significantly higher in group FU– hepatic DP than in group FU+ hepatic DP (21.9% vs 3.4%, P<0.05). In both the FU+ pulmonary DP and FU– pulmonary DP groups, the incidence of gastrointestinal toxicity was higher than 50%, with no significant difference between them. We conclude that, when performing 99mTc-MAA perfusion scintigraphy, the presence of an abnormally elevated pulmonary uptake (IHAVS higher than 5%) is the most relevant positive prognostic index for the development of gastrointestinal toxicity. Furthermore, in the absence of abnormal pulmonary uptake (IHAVS lower than 5%), strict scintigraphic follow-up is useful since it is able to promptly diagnose the presence of extrahepatic abdominal perfusion and thus to prevent the occurrence of gastrointestinal toxicity.

Ramirez's abdominoplasty technique combined with intraperitoneal chemohyperthermia after surgical cytoreductive procedures for the treatment of advanced intraperitoneal cancer in patients with ventral hernia.

Patients affected by peritoneal carcinomatosis are frequently submitted to repeated laparotomies to reduce intra-abdominal bulky lesions and to enhance the systemic chemotherapeutic action. Aim of our study is to evaluate feasibility and results of cytoreductive surgery and intraperitoneal chemohypertermic (IPCH) perfusion combined with Ramirezs abdominoplastic technique in selected patients with voluminous ventral hernias.At the same time, we support the hypothesis that Ramirez’ technique would allow a normal intra-abdominal pressure leading to an optimal capability of penetration of chemotherapeutic agents in IPCH.From January 1998 to December 2003, 30 patients were submitted to a surgical debulking and IPCH through a laparotomic approach involving a ventral hernia. After extensive cytoreductive surgery, we closed the large abdominal wall damage with Ramirezs abdominoplasty technique, followed by IPCH. The technique described by Ramirez uses bilateral muscle flap complexes transposed medially to reconstruct the central abdominal wall without using meshes to supply or reinforce the abdominal reconstruction.A total of 23 patients (76.7%) were completely cytoreducted and subjected to IPCH. Postoperative mortality was 1/30 (3.3%). Major morbidity was 5/30 (16.7%). After a mean follow-up of 3 years, no sign of recurrent ventral hernia was noted in the survivors.This study suggests that surgical debulking combined with IPCH is feasible in patients with a previously large abdominal wall defect using the functional Ramirezs abdominoplasty technique. The reconstructive technique allows a regular IPCH procedure without recurrence of the ventral hernia confirmed by clinical examination and abdominal computed tomography.