Andrew M. Averbach

Prospective randomized trial of early postoperative intraperitoneal chemotherapy as an adjuvant to resectable gastric cancer.

OBJECTIVE Surgeons have postulated on numerous occasions that cancer resection may participate in the dissemination of a malignancy. This randomized trial sought to determine whether a large volume of chemotherapy solution used perioperatively to flood the peritoneal cavity could eliminate microscopic residual disease and thereby improve survival of patients with gastric cancer. SUMMARY BACKGROUND DATA Surgical treatment failures in patients with gastric cancer are confined to the abdomen in most patients. Resection site and peritoneal surface spread, along with liver metastases, are the most common areas of recurrence. Survival and quality of life of patients with gastric cancer would be improved if disease progression at these anatomic sites was reduced. METHODS In a prospective randomized trial of 248 patients, intraperitoneal mitomycin C on day 1 and intraperitoneal 5-fluorouracil on days 2 through 5 were administered after gastric cancer resection. Patients who were thought to have stage II or stage III disease were randomized after resection to surgery alone versus surgery plus early postoperative intraperitoneal chemotherapy. After final pathologic examinations, there were 39 patients with stage I, 50 with stage II 95 with stage III, and 64 with resected stage IV cancer. RESULTS The 5-year survival of the surgery-only group was 29.3%, and the surgery-plus-intraperitoneal chemotherapy group was 38.7% (p = 0.219). In a subset analysis, the patients with stage I, stage II, and stage IV disease showed no statistically significant difference in survival. The 5-year survival rate of patients with stage III disease who underwent surgery only was 18.4% versus a survival rate of 49.1% for patients who underwent surgery plus intraperitoneal chemotherapy (p = 0.011). CONCLUSIONS In a subset analysis, patients with stage III gastric cancer have shown a statistically significant improvement in survival when treated with perioperative intraperitoneal chemotherapy. Further studies in patients with gastric cancer with surgically directed chemotherapy are suggested.

Heated Intraoperative Intraperitoneal Mitomycin C and Early Postoperative Intraperitoneal 5-Fluorouracil: Pharmacokinetic Studies

Purpose: The purpose of this study was to report the pharmacokinetics of heated intraoperative intraperitoneal mitomycin C (MMC) and to analyze the impact of heat, extent of peritoneal resections, and effect of intraoperative hyperthermic chemotherapy on the pharmacological properties of the peritoneal plasma barrier. Methods: Sixty patients with peritoneal carcinomatosis were included in a phase I/II study combining cytoreductive surgery with 2 h of heated intraperitoneal mitomycin C in an intraoperative lavage technique and one cycle of early postoperative 5-fluorouracil (5-FU) given on postoperative days 1–5. Three pharmacokinetic analyses were performed: (1) pharmacokinetics of heated intraoperative intraperitoneal MMC was determined for 18 patients by sampling peritoneal fluid, plasma, and urine during the 2-h procedure; (2) impact of peritoneal resections on MMC pharmacokinetics was assessed by comparing a group of patients who underwent ≤1 peritonectomy procedure (minimal surgery) to a group of patients who underwent ≥2 peritonectomy procedures (extensive surgery), and (3) effects of heated intraoperative intraperitoneal chemotherapy on the pharmacokinetics of early postoperative intraperitoneal 5-FU by comparing a group of patients treated with heated intraoperative intraperitoneal MMC to a control group who did not receive heated intraoperative intraperitoneal chemotherapy. Results: The mean dose of heated intraoperative intraperitoneal MMC per patient was 22.5 ± 7.1 mg (12.9 ± 3.8 mg/m2). Drug absorption from perfusate was 14.3 ± 2.7 mg. The mean aeras under the curve (AUC) for perfusate and plasma were, respectively, 340 ± 138 and 15 ± 4 µg/ml × min. The mean AUC peritoneal fluid/plasma ratio was 23.5 ± 5.8. Patients who underwent extensive peritoneal resections exhibited a significantly (p = 0.037; Wilcoxon rank test) increased peak plasma concentration of MMC, a significantly (p = 0.029) increased AUC of plasma concentrations and a significantly (p = 0.034) decreased peritoneal fluid/plasma AUC ratio. Pharmacokinetic studies of early postoperative intraperitoneal 5-FU showed no significant difference in plasma AUC, perfusate AUC and AUC ratio between patients who received and those who did not receive heated intraoperative intraperitoneal MMC. Conclusions: Heated intraoperative intraperitoneal chemotherapy achieves high peritoneal concentrations of MMC with limited systemic absorption. Systemic drug absorption during heated intraoperative intraperitoneal chemotherapy is increased when extensive peritoneal resections are performed, but such slight increases are unlikely to change the risk of systemic drug toxicities. Heated intraoperative intraperitoneal chemotherapy does not alter the pharmacokinetics of early postoperative intraperitoneal 5-FU.

Hyperthermic intraperitoneal doxorubicin: pharmacokinetics, metabolism, and tissue distribution in a rat model

Background: The cytotoxic effect of several anticancer agents, including doxorubicin, can be enhanced by hyperthermia. The purpose of this study was to evaluate the effect of hyperthermia on the pharmacokinetics, metabolism, and tissue distribution of intraperitoneal (i.p.) doxorubicin in a rodent model. Methods: Doxorubicin was given i.p. to 20 Sprague-Dawley rats at a dose of 2 mg/kg over 60 min. Rats were randomized into two groups according to the temperature of the peritoneal perfusate: group NT received normothermic (37 °C) i.p. doxorubicin; group HT received hyperthermic (43 °C) i.p. doxorubicin. During the course of i.p. chemotherapy, peritoneal fluid and blood were sampled every 10 min. At the end of the procedure, rats were sacrificed and tissue samples (liver, spleen, small bowel, omentum, bladder, diaphragm, abdominal wall, heart) were collected. Concentrations of doxorubicin and its aglycone metabolites were determined in peritoneal fluid, plasma, and tissues by HPLC. Results: No significant differences in areas under the curve (AUC) of peritoneal fluid doxorubicin and plasma doxorubicin were found between group NT and group HT. AUC ratios (AUC peritoneal fluid/AUC blood) were 87.9 for group NT and 82.9 for group HT. Group HT exhibited increased doxorubicin concentrations for all intraabdominal tissues. These differences were significant for spleen (P = 0.03), small bowel (P = 0.03), and omentum (P = 0.03). Doxorubicin aglycone was detected in plasma of both groups within the first 10 min of the procedure. There was a significant (P < 0.001) increase in plasma aglycone AUC for group HT when compared with group NT. Group HT exhibited increased aglycone concentration for all tissues. This difference was significant for liver (P < 0.001) and bladder (P < 0.001). Conclusion: Hyperthermia did not affect significantly the pharmacokinetics of i.p. doxorubicin. Tissue concentrations of doxorubicin in small bowel, omentum, and spleen were significantly increased when the drug was administered by hyperthermic i.p. perfusion. Hyperthermia increased significantly the doxorubicin aglycone concentrations in plasma, liver, and bladder.

Anastomotic leak after double-stapled low colorectal resection

PURPOSE: Anastomotic leaks after double-stapled low anterior resection were associated with a number of factors related to patient condition, level of anastomosis, and variety of surgery-related and antitumor therapy-related factors. This retrospective analysis of a group of patients with consistent length of rectal stump was undertaken to determine the risk factors of anastomotic leak after low colorectal resection related to surgery and to intraperitoneal chemotherapy. METHODS: A group of 165 patients treated with surgery only, surgery with early postoperative intraperitoneal chemotherapy, and surgery with hyperthermic intraoperative and early postoperative intraperitoneal chemotherapy. All patients underwent surgery that used the double-stapled technique with transection of the rectum through its middle third. In univariate and multivariate analysis, the relationship between anastomotic leak rate and extent of colon resection, length of residual colon, presence of left colon, and type of applied treatment was studied. RESULTS: With a full length of residual colon, leak rate was 1 percent but increased progressively with the extent of proximal colon resection. Removal of the left colon was associated with the 2.7 odds ratio for anastomotic disruption. Leak rate after surgery only was 6 percent; surgery with normothermic intraperitoneal chemotherapy was 5 percent; and surgery with heated intraperitoneal chemotherapy was 20 percent. CONCLUSIONS: In this group of patients with consistent length of residual rectum, the incidence of anastomotic disruption was related to extent of proximal colon resection. Anastomotic integrity was not compromised by normothermic intraperitoneal chemotherapy. Hyperthermic intraperitoneal chemotherapy was associated with high leak rate only when extensive resection of the colon was performed. Variables other than extent of rectal excision are important in causing a leak of colorectal anastomosis.

Abdominal wall metastasis and peritoneal carcinomatosis after laparoscopic assisted colectomy for colon cancer

We report a case of a port-site recurrence with diffuse peritoneal carcinomatosis after laparoscopic-assisted right hemicolectomy. The interval between resection of the colonic adenocarcinoma and diagnosis of the recurrence was short (1 month), suggesting that intraperitoneal dissemination and tumour implantation on surgical wounds may represent the principal mechanism of recurrence after laparoscopic surgery. Review of the literature shows an alarming increase in the occurrence of this devastating complication. Although beneficial to the patient in the immediate post-operative period, the adequacy of laparoscopic-assisted colectomy in tumour is increasingly under question.

A simplified approach to hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) using a self retaining retractor

There are both pharmacologic and practical reasons for recommending intraoperative intraperitoneal chemotherapy. From a pharmacologic point of view, direct installation of selected drugs into the peritoneal cavity results in a large increase in the amount of chemotherapy that reaches abdominal and pelvic surfaces. This pharmacologic advantage is the result of the peritoneal-plasma barrier. Molecules of large hydrophyllic drugs leave the peritoneal cavity more slowly than they are metabolized systemically. Three-fore, a great concentration difference exists at all times between drug concentration within the peritoneal cavity and drug concentration in the plasma [1,2].

Peritoneal mesothelioma: Treatment approach based on natural history

A more modern treatment strategy for diffuse malignant peritoneal mesothelioma may be suggested (figure 3). Clinical suspicion of diffuse malignant mesothelioma (peritoneal carcinomatosis) calls for laparoscopy with evaluation of parietal and visceral peritoneum and multiple biopsies sufficient for definitive histologic diagnosis. Cytologic examination of ascitic fluid is not likely to be of benefit. CT of chest, abdomen, and pelvis is needed for evaluation of visceral involvement and the presence of distant metastases. Contrast enhancement of the gastrointestinal and urinary tract is necessary with the CT. Additional radiologic techniques for detection of distant metastases should be used if there are clinical or laboratory signs of extraperitoneal spread. After histologic diagnosis and extent of tumor spread have been documented, and if no symptoms of intestinal obstruction are present, the patient may be subjected to two to three courses of induction intraperitoneal chemotherapy. This will provide the clinician with important information on tumor response to chemotherapy, minimize tumor accumulation on bowel surfaces, and provide time for surgical conditioning. The time devoted to induction chemotherapy will allow occult distant metastases to be detected. In patients with a response or stable disease, cytoreductive surgery is attempted approximately 2 months after completion of induction chemotherapy. Surgery must be aimed at achieving complete or near-complete cytoreduction through the use of peritonectomy procedures [46,47]. Additional intraperitoneal chemotherapy should be administered intraoperatively and in the early postoperative period (figure 3). This treatment strategy may be the most feasible one according to existing knowledge of the natural history of diffuse malignant peritoneal mesothelioma. Only further phase II clinical trials can reveal the extent to which it is beneficial. Because of the rare occurrence of this disease, the quickest answer would come as a result of cooperative study by several groups experienced in these treatment modalities.

Cancer recurrence following laparoscopic colectomy

PURPOSE: Use of laparoscopic techniques for resection of colon and rectal cancer has raised considerable controversy. There is increasing concern that wound recurrence and peritoneal dissemination may represent a potentially fatal complication of this technique. METHODS: The surgical literature was reviewed, and clinical course of two patients is presented. RESULTS: Our two patients had tumor recurrence in the laparoscopy port sites within one year after laparoscopic-assisted colectomy for Dukes B adenocarcinoma of the colon. At laparotomy, diffuse peritoneal carcinomatosis without lymph node or liver metastases were found in both patients. They were treated by surgical resection of recurrent disease combined with heated intraoperative intraperitoneal mitomycin C chemotherapy and five days of early postoperative intraperitoneal 5-fluorouracil. These patients are clinically free of disease at 1.5 years after treatment of peritoneal implants. CONCLUSIONS: Cancer recurrence in abdominal wall incisions after laparoscopic colectomy has been reported in an increasing number of patients. It is possible that this technique should be abandoned. Cytoreductive surgery combined with intraperitoneal chemotherapy may represent the most adequate treatment of recurrent cancer that occurs following laparoscopic colectomy.

Methodologic considerations in treatment using intraperitoneal chemotherapy.

Over the past decade several research groups have investigated the possible benefits of intraperitoneal chemotherapy in the management of intraabdominal cancers in both an adjuvant setting after resection for cure [1–10] and in an attempt to improve margins of excision following cytoreductive surgery [11–16]. Several important lessons may be learned from these clinical studies, which are relevant to a modern utilization of intraperitoneal chemotherapy. These observations should be used for further improvement of the methodology of chemotherapy delivery into the peritoneal cavity. These methodologic refinements may result in increased survival, alteration of a tumor’s natural history, and improved quality of life of patients.

Krukenberg syndrome as a natural manifestation of tumor cell entrapment

In summary, confusion exists among clinicians regarding the possibilities of treatment for ovarian metastases in general, and of the Krukenberg tumors in particular. The ovaries themselves are easily removable irrespective of their sizes, but disappointing long-term results of oophorectomy alone leave most surgeons with only the choice of conservative therapy unless there is a debilitating tumor mass. In most patients nothing is done until surgical palliation becomes mandatory. There is a group of patients with isolated peritoneal dissemination of gastrointestinal cancers who are eligible for new treatment strategies. This group includes patients who have small-volume peritoneal spread or who can be completely cytoreduced, and those who have no evidence of liver or extraabdominal metastases. An aggressive approach with cytoreductive surgery and intraperitoneal chemotherapy with or without additional systemic chemotherapy should be considered for the treatment of selected patients.