Multicentre study of the learning curve and surgical performance of cytoreductive surgery with intraperitoneal chemotherapy for pseudomyxoma peritonei.

BACKGROUND: The learning curves for cytoreductive surgery with intraperitoneal chemotherapy for treatment of pseudomyxoma peritonei (PMP) were explored between international centres/surgeons to identify institutional or other factors that might affect performance. METHODS: Data from patients with PMP treated with the combined procedure across 33 international centres between 1993 and 2012 were analysed retrospectively. A risk-adjusted sequential probability ratio test was conducted after defining the target outcome as early oncological failure (disease progression within 2 years of treatment), an acceptable risk for the target outcome (odds ratio) of 2, and type I/II error rates of 5 per cent. The risk prediction model was elaborated and patients were evaluated sequentially for each centre/surgeon. The learning curve was considered to be overcome and proficiency achieved when the odds ratio for early oncological failure became smaller than 2. RESULTS: Rates of optimal cytoreduction, severe postoperative morbidity and early oncological failure were 84·4, 25·7 and 29·0 per cent respectively. The median annual centre volume was 17 (range 6-66) peritoneal malignancies. Only eight of the 33 centres and six of 47 surgeons achieved proficiency after a median of 100 (range 78-284) and 96 (86-284) procedures respectively. The most important institutional factor affecting surgical performance was centre volume. CONCLUSION: The learning curve is extremely long, so centralization and/or networking of centres is necessary to assure quality of services. One centre for every 10-15 million inhabitants would be ideal.

Importance of gender in diffuse malignant peritoneal mesothelioma.

BACKGROUND: Combined therapy involving cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy has been shown to improve survival outcomes for patients with diffuse malignant peritoneal mesothelioma (DMPM). The present study aims to investigate gender as a potential prognostic factor on overall survival. PATIENTS AND METHODS: Over a period of two decades, 294 patients who underwent CRS and perioperative intraperitoneal chemotherapy were selected from a large multi-institutional registry to assess the prognostic significance of gender on overall survival. RESULTS: Female patients were shown to have a significantly improved survival outcome than male patients (P < 0.001). Staging according to a recently proposed tumor-node-metastasis categorization system was significant in both genders. Older female patients had significantly worse survival than younger female patients (P = 0.019), a finding that was absent in male patients. Female patients with low-stage disease were found to have a very favorable long-term outcome after combined treatment. CONCLUSIONS: Gender has demonstrated a significant impact on overall survival for patients with DMPM after CRS and perioperative intraperitoneal chemotherapy. An improved understanding of the role of estrogen in the pathogenesis of DMPM may improve the prognostication of patients and determine the role of adjuvant hormonal treatment in the future.

Multi-institutional experience of diffuse intra-abdominal multicystic peritoneal mesothelioma.

BACKGROUND: This study was undertaken to measure survival of patients with multicystic peritoneal mesothelioma treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy through a multi-institutional collaboration. METHODS: A multi-institutional data registry, established by the Peritoneal Surface Oncology Group, was used to identify patients with peritoneal mesothelioma and the subgroup with multicystic tumours, treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Outcomes for this subgroup are reported. The primary endpoint was overall survival. A secondary endpoint was the incidence of treatment-related complications. RESULTS: Of 405 patients with peritoneal mesothelioma, 26 (6·4 per cent) had multicystic tumours. There were 20 women and six men with a mean(s.d.) age of 42(12) years. The median peritoneal carcinomatosis index (PCI) was 14 (range 6-39). There was no perioperative mortality. Six patients developed grade III or IV complications. After a median follow-up of 54 (range 5-129) months, all 26 patients were still alive. CONCLUSION: Multicystic peritoneal mesothelioma appears to be a distinct subtype of peritoneal mesothelioma, where long-term survival may be achieved through cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Accuracy and clinical relevance of computed tomography scan interpretation of peritoneal cancer index in colorectal cancer peritoneal carcinomatosis: a multi-institutional study.

BACKGROUND: Evaluation of peritoneal metastases by computed tomography (CT) scans is challenging and has been reported to be inaccurate. METHODS: A multi-institutional prospective observational registry study of patients with peritoneal carcinomatosis from colorectal cancer was conducted and a subset analysis was performed to examine peritoneal cancer index (PCI) based on CT and intraoperative exploration. RESULTS: Fifty-two patients (mean age 52.6 ± 12.4 years) from 16 institutions were included in this study. Inaccuracies of CT-based assessment of lesion sizes were observed in the RUQ (P = 0.004), LLQ (P < 0.0005), RLQ (P = 0.003), distal jejunum (P = 0.004), and distal ileum (P < 0.0005). When CT-PCI was classified based on the extent of carcinomatosis, 17 cases (33%) were underestimations, of which, 11 cases (21%) were upstaged from low to moderate, 4 cases (8%) were upstaged from low to severe, and 2 cases (4%) were upstaged from moderate to severe. Relevant clinical discordance where an upstage occurred to severe carcinomatosis constituted a true inaccuracy and was observed in six cases (12%). CONCLUSIONS: The actual clinical impact of inaccuracies of CT-PCI was modest. CT-PCI will remain as a mandatory imaging tool and may be supplemented with other tools including positron emission tomography scan or diagnostic laparoscopy, in the patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

The current practice of cytoreductive surgery and HIPEC for colorectal peritoneal metastases: Results of a worldwide web-based survey of the Peritoneal Surface Oncology Group International (PSOGI).

BACKGROUND: At present, selected patients with resectable colorectal peritoneal metastases (CRC-PM) are increasingly treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study was to investigate the current worldwide practice. METHODS: HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning their personal expertise and current hospital and countrywide practice. RESULTS: It is estimated that currently more than 3800 patients with CRC-PM (synchronous and metachronous) are annually treated with CRS and HIPEC in 430 centers. Integration of CRS and HIPEC in national guidelines varies, resulting in large treatment disparities between countries. Amongst the experts, there was general agreement on issues related to indication, surgical technique and follow up but less on systemic chemotherapy or proactive strategies. CONCLUSION: This international survey demonstrates that CRS and HIPEC is now performed on a large scale for CRC-PM patients. Variation in treatment may result in heterogeneity in surgical and oncological outcomes, emphasising the necessity to reach consensus on several issues of this comprehensive procedure. Future initiatives directed at achieving an international consensus statement are needed.

Systematic review of cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis in primary and recurrent ovarian cancer.

The aim of this systematic review is to critically evaluate cytoreductive surgery combined with heated intraoperative intraperitoneal chemotherapy in the treatment of ovarian cancer. A systematic review of all manuscripts published in the English literature that met predetermined inclusion criteria was carried out. Data concerning cytoreductive surgery, method and agents for administration of heated intraoperative intraperitoneal chemotherapy, morbidity, mortality, hospital stay and survival were extracted, critically reviewed and tabulated. Fourteen studies were analyzed. A wide variety of drug doses, methods of intraperitoneal chemotherapy administration and volume of chemotherapy solution were used. Seven studies showed that patients with complete cytoreduction had the greatest benefit. The median overall survival for primary and recurrent disease ranged from 22 to 54 months and the median disease-free survival from 10 to 26 months. The rates of significant morbidity associated with this combined treatment were low, ranging from 5% to 36%. The median mortality was 3% (range 0%-10%). Cytoreductive surgery combined with heated intraoperative intraperitoneal chemotherapy is a treatment option for patients with ovarian cancer that is worthy of further investigation. Selection criteria for patients most likely to benefit need to be defined.

Management of an inguinal hernia in patients with pseudomyxoma peritonei.

BACKGROUND: Pseudomyxoma peritonei is a disease that results from a perforated mucinous neoplasm of the appendix so that mucinous ascites and mucin-producing tumor cells are widely disseminated in a characteristic pattern throughout the abdomen and pelvis. The intraabdominal mucus can accumulate in the inguinal canal and by physical examination be indistinguishable from the usual inguinal hernia. METHODS: A database of patients with pseudomyxoma peritonei was used to identify patients who had an inguinal hernia prior to or at the time of cytoreductive surgery (CRS) and perioperative hyperthermic chemotherapy (HIPEC). At the time of CRS, care was taken in all patients to remove the peritoneal lining of the inguinal canal. Patients who had the inguinal hernia repaired prior to definitive treatment with CRS and HIPEC had all tissue and mesh associated with prior herniorrhaphy resected. RESULTS: In 178 pseudomyxoma peritonei patients, 17 had a new onset or previously repaired inguinal hernia that required extraction of mucus and mucinous tumor from the hernia site. No repair of the open inguinal canal was attempted at the time of CRS. No recurrent inguinal hernias were recorded and no patients required an inguinal incision at a later time to resect progressive disease within the inguinal canal. CONCLUSIONS: Inguinal hernias caused by mucinous ascites and tumor were definitively treated by cytoreductive surgery plus HIPEC. Extraction of tumor and peritoneum from the inguinal canal facilitates fibrous closure of the hernia defect so that hernia recurrence was not observed.

Symptoms, signs and radiologic findings in patients having reoperative surgery for malignant peritoneal mesothelioma.

BACKGROUND: A reasonable estimate is that 50% of patients treated with cytoreductive surgery (CRS) and perioperative chemotherapy for malignant peritoneal mesothelioma will recur. Recognition of this recurrence and knowledgeable selection for additional surgical intervention is important in improving survival of patients who progress. MATERIAL AND METHODS: Patients treated for malignant peritoneal mesothelioma with CRS and perioperative chemotherapy were placed in follow-up for assessment of symptoms and signs and radiologic abnormalities by CT. The data were prospectively maintained and retrospectively reviewed. RESULTS: From a database of 130 patients with malignant peritoneal mesothelioma, 38 patients who had 50 reoperations with disease recurrence that was histologically confirmed were studied. The median time to first recurrence was 14 months with a range of 3-102. Considering 50 reoperative events the most common symptoms or signs were abdominal pain (40%) and abdominal distention (34%). The most common radiologic finding was a tumor mass (56%). Patients with an abdominal or pelvic mass had a reduced prognosis (p = 0.006) and patients with an absence of radiologic abnormalities had an improved survival (p = 0.047). CONCLUSIONS: In patients having reoperative surgery, symptoms, signs and radiologic abnormalities associated with recurrent (progressive) malignant peritoneal mesothelioma are abdominal pain, abdominal distention, and a tumor mass. An abdominal or pelvic mass was associated with a reduced prognosis and an absence of radiologic abnormalities with an improved prognosis.

Long-term regional chemotherapy for patients with epithelial malignant peritoneal mesothelioma results in improved survival.

PURPOSE: Malignant peritoneal mesothelioma (MPM) is a rare disease with about 300 new cases per year in the USA. Its natural history is described as local progression within the peritoneal space in the absence of liver metastases or systemic disease. METHODS: Cytoreductive surgery (CRS) is a series of peritonectomy procedures and visceral resections with a goal of complete removal of all visible disease from the abdomen and pelvis. Over 20 years, three protocols investigating increasing efficacy of additional chemotherapy treatments added to CRS have been initiated. Initially, hyperthermic perioperative chemotherapy (HIPEC) with doxorubicin and cisplatin was used in the operating room. Then, early postoperative intraperitoneal chemotherapy (EPIC) with paclitaxel was added for the first 5 days after CRS. The third protocol employed HIPEC, then EPIC, and then long-term intraperitoneal (IP) paclitaxel or IP pemetrexed plus intravenous (IV) cisplatin as a adjuvant normothermic intraperitoneal chemotherapy (NIPEC). RESULT: The 5-year survival of 42 patients treated with CRS and HIPEC was 44%, for 58 patients treated with EPIC and HIPEC was 52% and 29 patients who received HIPEC, EPIC, and NIPEC was 75% (p = 0.0374). Prognostic variables of age, gender, treatment administered, peritoneal cancer index (PCI) and completeness of cytoreduction were significant by univariate analysis and treatments administered and completeness of cytoreduction significant by multivariate analysis. CONCLUSIONS: Long-term regional chemotherapy was associated with improved survival in patients with MPM. In this rare disease, additional phase 2 investigations are suggested.

The natural history, gross pathology, and histopathology of appendiceal epithelial neoplasms.

AIM: To report the pathology of appendiceal epithelial neoplasms a review of the Washington Cancer Institute experience and a PubMed literature search was performed. FINDINGS: Epithelial appendiceal neoplasms present a significant oncologic challenge. The clinical and pathologic features are unusually varied as compared to other gastrointestinal cancers and require expert clinical judgment for proper management. CONCLUSIONS: Appendiceal epithelial neoplasms should be regarded as a distinct clinical entity with special clinical treatments used for optimal management.

The approval process for hyperthermic intraoperative intraperitoneal chemotherapy.

AIMS: To clarify the requirements for Food and Drug Administration approval in the United States for hyperthermic intraoperative intraperitoneal chemotherapy administration. Also, to review the status of the approval process in Europe. METHODS: The obstacles to be overcome for approval by the Food and Drug Administration for a new drug approval and for a new device approval were reviewed. Drugs approved in the past were examined for their potential for current application in this technology. RESULTS: The likelihood that the approval of a heater circulator along with the approval for specific chemotherapy agents for heated intraoperative intraperitoneal chemotherapy was judged to be remote. Rather, the continued use of "homemade heater circulators" and the off-label use of appropriate chemotherapy agents augmented by heat will continue to be the standard of care. The European community currently has several heater circulators approved for hyperthermic intraoperative intraperitoneal chemotherapy administration. These devices have been specifically approved for oncologic indications. CONCLUSIONS: Continued research and development of heated intraoperative intraperitoneal chemotherapy is necessary. As the requirement for prevention and treatment of the peritoneal surface component of gastrointestinal and gynecologic oncology expands, new investigations into the approval process in the United States will be necessary. Publication of results from institutions pioneering these new treatment strategies will, of necessity, continue.

Significance of lymph node metastasis in patients with diffuse malignant peritoneal mesothelioma.

BACKGROUND: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and invariably fatal neoplasm. Some studies have shown that cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy (PIC) achieved an improved survival, as compared to historical controls. However, the significance of lymph node involvement in this disease has never been well defined. METHODS: One hundred patients with DMPM underwent CRS and PIC at the Washington Hospital Center. The inclusion criteria for surgery consisted of histological diagnosis of DMPM, age <80 years and good performance status. All data were collected prospectively. Lymph node status, seven clinical variables and eight treatment-related prognostic factors were analyzed for survival. RESULTS: Seven patients were lymph node positive and they all died of their disease within 2 years after the surgery. The remaining 93 patients had 5- and 7-year survival of 50% and 43%, respectively. Univariate analysis showed that gender (p<0.001), peritoneal cancer index (p=0.009), lymph node status (p<0.001), extra-abdominal invasion (p=0.026), histological type (p<0.001), intraoperative blood loss (p=0.035), completeness of cytoreduction (p<0.001), intraperitoneal chemotherapy regimen (p=0.041), and redo cytoreductive surgery (p=0.022) were significant for survival. Multivariate analysis demonstrated that female gender, lymph node metastasis not detected, epithelial type, and adequate cytoreduction were independently associated with an improved survival. CONCLUSIONS: CRS and PIC showed an improved survival for DMPM, as compared to historical controls. Lymph node status along with three other prognostic variables was significant in the multivariate analysis.

Laparoscopic intraperitoneal hyperthermic chemotherapy for palliation of debilitating malignant ascites.

AIM: To report the use of laparoscopic Intraperitoneal Hyperthermic Chemotherapy (LIPHC) in the treatment of malignant ascites. METHODS: From September 2001 to December 2003, 14 patients between the age of 56 and 78years were treated. Ascites was from gastric cancer (5 cases), colorectal cancer (3 cases), ovarian cancer (3 cases), breast cancer (2 cases) and peritoneal mesothelioma (1 case). The LIPHC was carried out at 42 degrees C for 90 min with 1.5% dextrose solution as a carrier. Chemotherapy was cisplatin and doxorubicin or mitomycin depending on the type of primary tumor. The drains were left in situ after surgery and removed when perfuse drainage ceased. RESULTS: Ascites was controlled in all the treated cases. A CT scan performed in follow-up showed a small, clinically undetectable, fluid accumulation in the pelvis of one patient. CONCLUSIONS: This method resulted in benefit for those peritoneal carcinomatosis patients with debilitating malignant ascites who were excluded from cytoreductive surgery. Proficiency in laparoscopic staging procedures and experience in the management of carcinomatosis and intraperitoneal hyperthermic chemotherapy (IPHC) are required for the success of the procedure.

Comprehensive management of diffuse malignant peritoneal mesothelioma.

AIMS: In the past, diffuse malignant peritoneal mesothelioma (DMPM) has been regarded as a terminal condition. The length of the survival was dependent upon the aggressive versus indolent biology of the neoplasm, nevertheless cure was not considered as a reasonable expectation and the overall median survival was approximately one year. METHODS: A comprehensive literature review and a collection of pertinent data published on DMPM from the Washington Cancer Institute were used to construct this report. RESULTS: Recent publications from Bethesda MD, New York, Milan Italy, Lyon France and Washington DC have shown a remarkable prolongation in the median survival of this group of patients with approximately half the patients alive at 5 years. These prolonged survivors were treated with an intensive local-regional treatment strategy that included cytoreductive surgery (CRS) with peritonectomy and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) and some patients with early postoperative intraperitoneal chemotherapy (EPIC). As larger numbers of patients have been treated, clinical features by which to select patients most likely to benefit from this approach have been identified. Also, as the experience in the management of patients receiving these treatments has increased, the morbidity and mortality associated with their management is being reduced. CONCLUSIONS: A new standard of care involves surgical removal of large disease deposits combined with perioperative intraperitoneal chemotherapy. Knowledgeable management uses selection criteria and incurs low morbidity and mortality.

Neoadjuvant treatment of gastric cancer with peritoneal dissemination.

AIMS: To report our experience of neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) for patients having a complete resection of the primary gastric cancer and peritoneal carcinomatosis (PC). PATIENTS AND METHODS: Patients with advanced peritoneal dissemination of primary gastric cancer had the placement of a peritoneal port system. For intraperitoneal chemotherapy, 40 mg of docetaxel and 150 mg of carboplatin were introduced in 1000 ml of saline on a weekly basis. Simultaneously, 100 mg/m2 of methotrexate and 600 mg/m2 of 5-fluorouracil were infused via a peripheral vein. A minimum of two cycles and up to six cycles of NIPS were used prior to cancer resection. At surgery a complete removal of the primary gastric cancer and the peritoneal implants by peritonectomy was attempted. RESULTS: Sixty-one patients were enrolled in the study. Thirty-nine had positive intraperitoneal cytology which reverted to negative cytology after treatment in 22. Thirty-eight showed a partial response. Thirty patients came to resection and 14 patients could be made disease-free. Median survival time of all patients was 14.4 months. Patients who received a complete resection had a median survival time of 20.4 months. Grade III/IV toxicities were not found after two courses of NIPS, but did develop in seven patients after more than three courses of NIPS. CONCLUSION: NIPS can downstage large volume peritoneal dissemination of gastric cancer. When combined with gastrectomy including peritonectomy a complete surgical resection was possible in one-quarter of the patients and resulted in a prolonged survival. This combined intraperitoneal and systemic chemotherapy for PC from gastric cancer is worthy of consideration for phase III clinical investigations.

Pseudomyxoma peritonei arising from colonic polyps.

AIMS: Pseudomyxoma peritonei may have as its primary site a mucinous gastrointestinal adenoma or carcinoma that gains access to the peritoneal cavity. This manuscript describes this disease arising from a benign or malignant colonic polyp. METHODS: From a database of over 1000 pseudomyxoma peritonei patients and colorectal carcinomatosis patients, three cases were identified in which the primary tumor site was a colonic polyp. The clinical history and course of these patients were studied. RESULTS: In a review of the clinical management of these patients, all three had an event whereby neoplastic cells from the surface of the colonic polyp could have gained access to the free peritoneal cavity. The patients developed the characteristic pseudomyxoma peritonei syndrome. All three patients were treated with cytoreductive surgery plus perioperative hyperthermic intraperitoneal chemotherapy. CONCLUSIONS: Colonic polyps can serve as a source of dysplastic cells whereby pseudomyxoma peritonei can result. Caution to prevent seeding to the free peritoneal cavity during surgery for colonic polyps should be observed. If pseudomyxoma peritonei develops, cytoreductive surgery and perioperative intraperitoneal chemotherapy should be considered for treatment.

Adjuvant intraperitoneal chemotherapy for advanced primary gastric cancer.

BACKGROUND: For gastric cancer dissemination to the peritoneal cavity is a large part of the natural history. Also, cancer dissemination caused from the trauma of cancer resection can release viable cancer cells into the free peritoneal cavity; these cells implant and then progress as peritoneal carcinomatosis. METHODS: From the medical literature a compilation of the results of adjuvant treatment of gastric cancer were reviewed and critically analyzed. A surgical rationale for integrating intraperitoneal chemotherapy into the management of advanced primary gastric cancer was sought. RESULTS: A theoretical basis for the application of cytotoxic effects of cancer chemotherapy within the peritoneal cavity as a part of the primary management of gastric cancer was explored. Numerous manuscripts suggested that there was an increased morbidity and mortality with perioperative intraperitoneal chemotherapy but the added number of complications was manageable. These data suggest that intraperitoneal chemotherapy is of benefit in an adjuvant setting in gastric cancer patients who have a complete resection but who are at high likelihood of local-regional recurrence. SUMMARY: Adjuvant intraperitoneal chemotherapy for advanced primary gastric cancer has a strong rationale. Numerous reports have established benefit. Wider application of this treatment modality is necessary through education, through additional clinical trials, and through continued publications from peritoneal surface malignancy treatment centers around the world.

Augmentation of interleukin-2 immunotherapeutic effects by lymphokine-activated killer cells and allogeneic stimulation in murine tumor cells.

Interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells were used in intraperitoneal and pulmonary tumor models in C57BL/6 mice. To maintain the immunotherapeutic effects of IL-2 plus LAK treatment but reduce its toxicity, ways were sought to augment IL-2 effects. The investigation showed that the adoptive transfer of LAK cells was a prerequisite for successful therapy of intraperitoneal cancer. When LAK cells were given on consecutive days within one course of immunotherapy, antitumor efficacy was augmented with additional doses of LAK cells. However, with the reduction of 1 complete cycle of IL-2 + LAK cells, no further reduction in intraperitoneal tumor was observed as compared to the reduction after 2 or 4 cycles. LAK cells generated from splenocytes of mice that had received an allogeneic tumor challenge 1 week earlier exerted a highly increased cytotoxicity as compared to normal LAK cells. Furthermore, the potentiation effect of an allogeneic response of the host at the tumor site was demonstrated by decreased numbers of lung implants and improved survival in mice given mixtures of syngeneic and allogeneic tumor cell suspensions. An alloimmune response within the microenvironment of tumor tissue markedly enhanced the antitumor effect of IL-2 against the syngeneic tumor. It was concluded that there is a fundamental need to improve the recruitment of adoptively transferred LAK cells or LAK precursors into tumor tissue. This may be the next step required in the further development of IL-2 and LAK immunotherapy.

Transient carcinoembryonic antigen (CEA) elevations following resection of colorectal cancer: a limitation in the use of serial CEA levels as an indicator for second-look surgery.

In a previous study, other investigators recommended second-look surgery for colorectal cancer primarily on the basis of plasma carcinoembryonic antigen (CEA) rises and prepared a nomogram for ready recognition of these "significant" increases. We found 25 patients whose CEA levels met the recommended criteria for significance; however, in 9 of these patients the rises were transient. Eight had no clinical evidence of recurrent cancer and they might have had negative second-look surgery had this been done because of CEA rises alone. The use of the CEA nomogram merely eliminated laboratory variation as a cause of the CEA rise. It did not, however, rule out biologic causes of CEA rises, other than that of cancer, especially benign liver disease. We were unable to differentiate benign from malignant rises on the basis of CEA changes alone. Preoperative CEA values helped to separate the two rises. Transient rises usually began earlier. Malignant CEA rises were more likely to be exponential. The rate of rise alone did not discriminate between the two rises. Thus, although serial CEA levels were helpful in making the decision for reexploration, they did not substitute for complete clinical assessment.

Early postoperative intraperitoneal chemotherapy as an adjuvant therapy to surgery for peritoneal carcinomatosis from gastrointestinal cancer: pharmacological studies.

Gastrointestinal malignancy may spread to peritoneal surfaces in the absence of lymphatic or hematogenous metastases. To treat peritoneal carcinomatosis, a uniformly lethal disease process, extensive cytoreductive surgery and i.p. chemotherapy were combined. Early postoperative i.p. chemotherapy was instilled in the first few days after the surgical procedure in an attempt to treat anatomic sites that would be sealed off by postoperative adhesions. Mitomycin C was given on the first postoperative day at two doses, 10 and 12 mg/m2. 5-Fluorouracil was given on postoperative days 2-5 at 15 and 20 mg/kg, respectively. Median area under the curve ratio i.p./i.v. was 117 for 5-fluorouracil and 21.6 for mitomycin C. Elevated intraportal levels of drug were observed for i.p. 5-fluorouracil but not for mitomycin C. The marked pharmacokinetic advantage of postoperative i.p. suggests that this treatment strategy should be considered in a clinical trial in patients at risk for progression of peritoneal carcinomatosis.