Stefano Guadagni

Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion in the treatment of recurrent epithelial ovarian cancer: a phase II clinical study.

Aims and Background The optimal salvage therapy for recurrent ovarian carcinoma has not been clearly established. Response to second-line chemotherapy is low, with a short median survival (8.8-15 months). We investigated the effect of an aggressive approach consisting of surgery followed by intraperitoneal drug delivery and local hyperthermia. Patients and Methods In a phase II clinical study, 27 patients with advanced/recurrent ovarian carcinoma were treated with cytoreductive surgery and intraperitoneal hyperthermic perfusion. Median patient age was 53 years (range, 30-67) and mean follow-up was 17.4 months (range, 0.3-36.0). Patients had been surgically staged and heavily pretreated with cisplatin-based, taxol-based or taxol/platinum-containing regimens. Nineteen (70%) patients were cytoreduced to minimal residual disease <2.5 mm. The intraperitoneal hyperthermic perfusion was performed with the closed abdomen technique, using a preheated polysaline perfusate containing cisplatin (25 mg/m2/L) + mitomycin C (3.3 mg/m2/L) through a heart-lung pump (mean flow of 700 mL/min) for 60 min in the hyperthermic phase (42.5 °C). Results Two-year overall survival was 55%. Median times to overall progression and local progression were 16 months and 21.8 months, respectively. Variables that affected the overall survival or time to progression were as follows: residual disease (P = 0.00025), patient age (P = 0.04), and lag time between diagnosis and cytoreductive surgery + intraperitoneal hyperthermic perfusion (P = 0.04). Treatment-related morbidity, mortality and acute toxicity (grade II-III) rates were 11%, 4% and 11%, respectively. Eight (89%) of 9 patients had ascites resolution. Conclusion Our results suggest that cytoreductive surgery + intraperitoneal hyperthermic perfusion is a well-tolerated, feasible and promising alternative in the management of selected patients with recurrent ovarian cancer, but further randomized controlled studies are needed in order to confirm our findings.

Evaluation of the Maruyama Computer Program Accuracy for Preoperative Estimation of Lymph Node Metastases from Gastric Cancer

Controversy still exists about the optimal lymph node (LN) dissection for potentially curable gastric cancer. For rational LN dissection it is important to know the incidence of metastasis at each LN station. For this purpose a computer program was developed using data from 4302 primary gastric cancers treated at the National Cancer Center Hospital in Tokyo between 1969 and 1989. To evaluate the accuracy of the computer program, the differences between the individual reports generated by the computer and the stored data were investigated in 282 Italian patients submitted to curative gastrectomy and D2 or more extended LN dissections for gastric cancer. Receiver operating characteristic (ROC) analysis was used to assess the sensitivity and specificity of the program for predicting LN metastases in each of the 16 regional LN stations. The computer program showed good predictive ability for LN metastases in most of the 16 LN stations, as the areas under the curve ranged from 0.741 (station 15) to 0.944 (station 8), with a mean of 0.856. A critical cutoff point of 18% of the programs expected percentage was the value maximizing the validity of the prediction. Using an “absolute” cutoff point of 0%, the overall rate of false-negative (FN) predictions in 176 N+ patients was 11.9%; of these, 11 (6.2%) were absolute FNs, in which the program totally failed to estimate LN metastases; the remaining 10 cases (5.7%) were relative FNs because the specific prediction was positive for a different depth of stomach invasion. The low number of D3/D4 lymphadenectomies in the historical database may affect the low estimate of metastases to N3/N4 nodes generated by the program. Based on these data, the program predicts with good accuracy the extent of LN metastases from gastric cancer, but it is not recommended for directing the surgeon to perform more extensive lymphadenectomy.

Causes of Death and Recurrence after Surgery for Early Gastric Cancer

Abstract. The postoperative course of 172 patients with early gastric cancer (EGC) was followed for a median 7 years to evaluate the causes of death, incidence and patterns of recurrence, and characteristic findings in the recurrent cases. The cumulative 10-year mortality rate (± SE) was 22 ± 3.7%. Seven patients (4.1%) died of operative mortality, 11 (6.4%) died of a recurrence of the gastric cancer, and 13 (7.6%) died of unrelated causes. Unrelated causes of death were metachronous primary cancer (n = 6), cardiovascular disease (n= 2), pneumonia (n= 3), sepsis (n= 1), and car accident (n= 1). Four patients died from gastric stump recurrence, three from liver metastases, two from lymph node metastases, and two from peritoneal dissemination. Using Cox multivariate analysis, histologic type had the most significant effect on recurrence. Although influenced by the tumor nature, the EGC prognosis is relatively good. Based on the results of this study, particularly in Western institutions, histologic examination of resection margins and lymphadenectomy should be improved. Moreover, patients must be carefully followed for late recurrence and metachronous cancer.

Irinotecan hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: A phase II clinical study

Aims and background The advantage of delivering chemotherapy by hepatic arterial infusion is the acquisition of a high concentration of the drug in the target. Irinotecan (CPT-11) is active for the treatment of advanced colorectal cancer. In phase I studies, doses of 20 mg/m2/d for 5 days given every 4 weeks as continuous infusion or 200 mg/m2 as a short 30-min infusion given every 3 weeks is recommended for phase II studies. Methods and study design Twelve patients with a median liver substitution of 30% (20-50%) were enrolled, 6 progressed after a FOLFOX-induced partial response and 6 progressed after 5-fluorouracil and folinic acid. All patients had a surgically (n = 6) or angiographically placed port (n = 6). They received hepatic arterial infusion chemotherapy with CPT-11 (200 mg/m2) on an outpatient basis, every 3 weeks as a short 30-min infusion for six cycles. Results Four partial responses were observed (33%) lasting 24, 15, 12 and 8+ weeks, 3 stable disease (25%) lasting more than 12 weeks, and 5 progressions (41%). Six patients (50%) presented a >30% reduction in CEA. Toxicity was G2 diarrhea in 5 patients (41%) and G2 myelosuppression in 6 (50%); one patient had abdominal right upper quadrant pain requiring analgesics. Conclusions CPT-11 is active as hepatic arterial infusion chemotherapy in liver metastases from colorectal cancer and can rescue systemically pretreated patients. Our schedule seems safe, feasible and well accepted on an outpatient basis.

Pharmacokinetics of Mitomycin C in Pelvic Stopflow Infusion and Hypoxic Pelvic Perfusion with and without Hemofiltration: A Pilot Study of Patients with Recurrent Unresectable Rectal Cancer

This pilot study was conducted to evaluate the advantage in drug delivery for regional chemotherapy in patients with unresectable recurrent rectal carcinoma by different methods. For this research, the pharmacokinetic advantages of mitomycin C delivery by four different methods were compared: intraaortic infusion with aortic stopflow; intraaortic infusion with inferior vena cava stopflow; intraaortic infusion with aortic and inferior caval vein stopflow (hypoxic pelvic perfusion); and hypoxic pelvic perfusion with hemofiltration. The results of this study indicate that pelvic stopflow infusion followed by hypoxic pelvic perfusion significantly increases mitomycin C concentrations in the blood coming from the tumor site. Also, use of hemofiltration reduces mitomycin C levels in peripheral blood after high‐dose regional chemotherapy. Further investigations involving more patients should be carried out in the future to validate these results.

Peritoneal carcinomatosis: Feature of dissemination. A review

Peritoneal carcinomatosis is a common event that develops in the natural history of many neoplastic diseases, representing a major problem encountered in cancer management. Peritoneal seedings are often associated with neoplastic ascites resulting in a source of significant discomfort to the patient. Considered in the past as a terminal condition, peritoneal carcinomatosis was approached during the last two decades as a curable disease. The introduction of cytoreductive surgery or peritonectomy in the treatment of peritoneal neoplastic diseases drastically changed the natural history of peritoneal carcinomatosis. Another technique that showed an important impact on disease control is intraperitoneal hyperthermic perfusion, one of the most fascinating treatments of peritoneal carcinomatosis that results in an impressive increase in overall survival and quality of life in treated patients with low morbidity. This review illustrates the modality of dissemination of peritoneal carcinomatosis in relation to the primary tumor site and grade of malignancy. Peritoneal carcinomatosis is a term used to define an advanced stage of many abdominal neoplastic diseases that differ in biologic aggressiveness and prognosis. The different presentation of peritoneal carcinomatosis in relation to a different primary tumor and different grade of malignancy strongly influences the potentially therapeutic radical approaches using new and advanced modalities like cytoreductive surgery and intraperitoneal hyperthermic perfusion.

Intra-arterial hepatic chemoembolization in liver metastases from neuroendocrine tumors: A phase II study

Abstract Neuroendocrine tumors, particularly those of gastrointestinal tract origin, have a predisposition for metastasizing to the liver, causing parenchymal substitution and paraneoplastic syndrome. Lipiodol embolization combined with anticancer drugs is a recent tool in regional therapy. It has been proven that chemoembolization reduces tumor bulk and hormone levels, and that it palliates the symptoms of many patients with liver-dominant neuroendocrine metastases. Beginning in December 1988, ten patients with unresectable and chemotherapy-refractory liver metastatic neuroendocrine tumors were treated with chemoembolization based on a mixture of lipiodol, mitomycin, cisplatin, epirubicin, followed by gelfoam powder and contrast media. Toxicity encountered included: upper right quadrant pain requiring narcotics, elevation of lactate dehydrogenase, alkaline phosphatase, and transaminases. One patient had liver abscess and persistent fever for 2 weeks. We obtained two complete remissions lasting 12 and 34 months and 5 partial remissions. The median survival was 22 months. Four patients had urinary elevation of 5-hydroxyindolacetic acid (5-HIAA). They showed more than a 75% decrease in urinary secretion after treatment. In a patient with transplanted liver we noticed a partial response lasting 7 months. We conclude that chemoembolization will improve the clinical condition of a significant percentage of patients with liver metastases, that future therapy of carcinoid tumors will be based on specific tumor biology and that treatment will be customized for each individual patient combining the use of cytoreductive procedures including radiofrequency ablation, laser treatment and chemoembolization.

N-nitroso compounds in the gastric juice of normal controls, patients with partial gastrectomies, and gastric cancer patients

It has been suggested that the variation of biochemical and microbiological parameters in the gastric juice may play a role in the development of gastric cancer. In the present study we concurrently assessed the presence of N‐Nitroso compounds (NOC) and their precursors, bacteria and carcinoembryonic antigen (CEA) in the gastric juice of normal controls, patients with gastric resection, and advanced gastric cancer.

Prospective randomized evaluation of preoperative endoscopic vital staining using CH-40 for lymph node dissection in gastric cancer

AbstractBackground: CH-40 is a suspension of activated carbon particles that was developed in Japan to carry anticancer drugs to regional nodes and peritoneal seedings of gastric cancer. Methods: Forty-five consecutive patients who had surgical resection and D2 lymph node dissection for gastric cancer over a 2-year period were randomly assigned to preoperative endoscopic submucosal injection of CH-40 (group A) or no staining (group B). A total of 21 patients in group A and 24 in group B were available for analysis. Results: The number of resected nodes per patient was significantly higher (t=6.06; 40df; P<.0001) in group A (mean±S.E.=35.3±1.24) than in group B (mean±S.E.=25.5±1.02). The rate of metastatic nodes resected was significantly higher (χ2=6.903 ; 1df; P=.009) in stained (22.5%) than in non-stained (14.7%) nodes of group A and also (χ2=6.906 ; 1df; P=.009) in stained nodes of group A than in group B (15.8%). Conclusions: Preoperative endoscopic vital staining with CH-40 proved to be rapid, safe, and effective in all cases in this series. Its use allowed surgeons to resect a higher number of lymph nodes, and to identify and examine more metastatic nodes. It also permitted identification of nodal micrometastases on routine histopathologic examination.

Irinotecan hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: results of a phase I clinical study.

Background Hepatic arterial infusion chemotherapy is a promising approach in liver metastases from colorectal cancer, but chemical hepatitis, biliary sclerosis, arterial thrombosis and right upper quadrant pain are limiting factors. Irinotecan (CPT-11) is an active drug in colorectal cancer. We planned a short hepatic arterial infusion of CPT-11 to describe the toxicity, to determine the dose-limiting toxicity, and to define the doses of CPT-11 to be recommended for phase II studies. Patients and Methods Fourteen patients with a median liver substitution of 30% (10-60%) were enrolled. All patients received hepatic arterial infusion chemotherapy with CPT-11 on an outpatient basis every 3 weeks as a short, 30-min infusion. Results At 240 mg/m2, 2 of 4 patients experienced grade 4 diarrhea and neutropenia, and 3 of them also reported grade 4 abdominal pain of the right upper quadrant. The maximum tolerated dose was reached at 240 mg/m2. The recommended doses of CPT-11 for phase II studies is 200 mg/m2, given every 3 weeks. Conclusions CPT-11 presents a low hepatic toxic profile and could be considered a new active drug, suitable for hepatic arterial infusion in liver metastases from colorectal cancer.