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.

Immunogenicity of chemically induced murine colon cancers.

The antigenicity and immunogenicity of three colorectal carcinomas induced in BALB/c mice by 1,2-dimethylhydrazine or N-methyl-N-nitrosourethan were studied. All tumors were readily transplantable. Two of these tumors metastasized when transplants reached sufficient size. All tumors were found to be immunogenic in the strain of origin, and all tumors were shown to contain unique tumor-specific transplantation antigens in cross-protection experiments. The use of these tumors as an animal model for studies of adjuvant immunotherapy and chemoimmunotherapy is suggested.

In vivo effects of delta 1-testololactone on peripheral aromatization.

To evaluate the in vivo effect of delta 1-testololactone on peripheral aromatization, studies were performed on seven postmenopausal women with metastatic breast cancer. Analysis of variance indicated that there were significant increases of circulating androstenedione (p less than 0.05) and estradiol (p less than 0.001) during administration of different doses of testololactone. Androstenedione levels were increased with all doses of testololactone tested (50, 100, 250, and 500 mg every 6 hr for 14 days each), while estradiol rose with only the 250- and 500-mg dosages. With administration, there was a significant decrease of estrone (p less than 0.001) with the mean level falling from 26 +/- 3 (S.E.) to 11 +/- 2 pg/ml. The addition of adrenal suppression (dexamethasone, 1 mg nightly at 11 p.m.) significantly lowered androstenedione (p less than 0.05) but had no effect on estrone or estradiol levels. Long-term therapy (up to 6 months) with the 250-mg dosage showed continual suppression of estrone with no escape being observed. Studies to determine the reason for the increase of estradiol with testololactone suggested cross-reactivity of the antibody with in vivo metabolites of the drug. However, these possible metabolites did not bind to uterine cytosol estrogen receptors. The decrease in estrone with testololactone administration presumably explains its antitumor properties.

Inhibition of peripheral aromatization of androstenedione to estrone in postmenopausal women with breast cancer using delta 1-testololactone.

To determine if delta 1-testololactone can inhibit the peripheral aromatization of androstenedione (delta), nine postmenopausal women with metastatic breast cancer were studied before and after 2 weeks of therapy with 250 mg of the drug, given every 6 h by mouth. The conversion ratio of delta to estrone (E1) was significantly reduced (P less than 0.005) from a mean (+/-SE) of 0.0098 +/- 0.0025 before to 0.0009 +/- 0.0005 after treatment. The drug's effect on the metabolism of delta seemed to be specific since significant changes in the MCR of delta and in the conversion ratio to testosterone were not observed. That this inhibition of peripheral aromatization had an effect on E1 metabolism was shown by the significant decrease (P less than 0.01) of mean serum E1 levels from 22 +/- 3 pg/ml before to 12 +/- 1 pg/ml after treatment. Serum estradiol levels rose slightly from 8 +/- 0.8 to 12 +/- 4 pg/ml. Serum delta and testosterone levels were unchanged by therapy. These data are consistent with the concept that delta 1-testololactone is a potent inhibitor of peripheral aromatization of delta to E1. This mechanism could explain the antitumor properties of this compound.

Reconstruction after total gastrectomy: construction of a Hunt-Lawrence pouch using Auto Suture staples.

A simple gastric reservoir using autosuture staples can be constructed rapidly after total gastrectomy. The importance of both a reservoir capacity and delayed evacuation was supported by the clinical course of most of the patients. All 18 patients had improved nutrition. Patients resected for cure tended to have greater weight gain and less abdominal discomfort. Occasionally patients who underwent only palliative resection were long-term survivors with a clinical course similar to that of patients resected for cure. On the basis of these results, it is unfair not to consider this type of reconstruction in patients who have undergone a total gastrectomy because it adds little to the operating time, yet it provides better palliation in terms of nutrition and abdominal comfort on both a short- and long-term basis.

Treatment with combined intra-arterial 5-FUdR infusion and whole-liver radiation for colon carcinoma metastatic to the liver. Preliminary results.

Twenty-eight patients with colon carcinoma metastatic to the liver were treated with continuously infused intra-arterial 5-fluorouracil deoxyriboside (5-FUdR) and cyclical whole-liver radiation (2000-3000 rad). Survivorship ranged from 25 days to almost 4 years and was a clear function of the extent of liver dysfunction at the time of initiation of this treatment. Difficulties in establishing the objective complete response rates in patients with minor imaging abnormalities were frequently noted. Both extracorporeal and permanently implanted arterial infusion devices have been employed, the results favoring the internal infusion units. Under ideal circumstances (early treatment, disease limited to the liver, and a permanent indwelling pump), a median survivorship of approximately 2 years can be projected with a significant number of patients rendered free of progressive cancer in the liver for months to years. The dose-limiting feature of this approach is treatment-related to hepatitis, which proved lethal in one of 28 patients thus far treated. Preclinical studies on the original and reduction of drug- and x-ray-induced liver toxicity should have high research priority.

Adenocarcinoma occurring in association with a chronic sinus tract and biliary fistula.

Malignant change can occur in various types of fistulae, draining sinuses, chronic inflammatory tracts, scars, and old wounds. An unusual case of an adenocarcinoma arising in association with a chronic sinus tract and biliary-cutaneous fistula of twenty years' duration is presented. Literature review reveals this to be the first reported case.

Conservative management without alkylating agents of squamous cell anal cancer using cyclical 5-FU alone and x-ray therapy.

We have treated 11 patients with squamous cell anal carcinoma using a regimen of repeated cycles of 120-hour infused 5-FU (25 mg/kg/24 hours) and x-rays. Total radiation doses were between 3000 (palliative) and 4750 (curative) rads. Unlike all other equivalent combined-modality studies, no alkylating agent or drug other than 5-FU was used. With follow-up between 1 and 4 years, there has been only one local recurrence (coincident with terminal disseminated disease in a stage III patient treated palliatively). All other patients have maintained local control. Inclusion of alkylating agents (eg, mitomycin) in this approach can be questioned if the patient is willing to accept somewhat greater acute but reversible toxic effects.

Pharmacologic studies of intra-hepatic artery chemotherapy with degradable starch microspheres.

The effect of degradable starch microspheres (DSM) on the pharmacokinetics of 4 drugs administered via the hepatic artery was studied in 5 patients with colon carcinoma metastatic to the liver. The 4 drugs were 99m-technetium diethylenetriamine pentaacetic acid (99mTc-DTPA), an agent which is not metabolized in the liver, and floxuridine, doxorubicin, and mitomycin, agents which undergo hepatic metabolism to varying extents. DSM transiently decreased arterial blood flow to normal liver an average of 64% and to hepatic tumor an average of 78%. DSM increased tumor exposure to DTPA by a mean of 1.71-fold, and increased hepatic exposure by 1.46-fold, but did not affect total plasma exposure. In contrast, DSM did reduce total plasma exposure to floxuridine by a mean of 34%, and to mitomycin by 20%. No information was available on the effect of DSM on plasma doxorubicin levels which never exceeded the limits of detection. Variation in the injection rate of DSM did not appear to influence the relative advantages produced in tumor or plasma AUCs. The estimated increase in tumor exposure produced by DSM was 3.8-fold for floxuridine, and 3.0-fold for mitomycin. These results reflect the differences in extent of hepatic metabolism of these agents, and agree closely with predictions made from mathematical models. Although DSM improved the therapeutic index, the increase in tumor exposure was insufficient to produce significant tumor regression.

Peritoneal tumor: MR imaging with dilute oral barium and intravenous gadolinium-containing contrast agents compared with unenhanced MR imaging and CT.

PURPOSE: To compare fat-suppressed, gadolinium-enhanced, breath-hold magnetic resonance (MR) imaging after administration of dilute oral barium solution with unenhanced MR imaging and computed tomography (CT) in the detection of peritoneal tumors. MATERIALS AND METHODS: In 24 patients in whom peritoneal tumor was known or suspected, double-contrast MR imaging and CT were performed prospectively. MR imaging included T1-weighted, fast spin-echo T2-weighted, and immediate and delayed gadolinium-enhanced, breath-hold, fast multiplanar sequences with fat saturation. Helical and conventional dynamic CT were performed with intravenously and orally administered contrast media. MR images and CT scans were reviewed independently and prospectively by different pairs of radiologists for presence of peritoneal tumor in 17 anatomic sites. Imaging findings were compared with surgical and histopathologic results. RESULTS: Of the 24 patients, 18 had peritoneal tumor confirmed at surgery. Detection of tumor sites was superior with double-contrast MR images (mean sensitivity, specificity, and accuracy, 84%, 87%, and 86%, respectively) compared with CT scans (mean sensitivity, specificity, and accuracy, 54%, 91%, and 74%, respectively). Double-contrast MR imaging enabled better detection of carcinomatosis and tumors less than 1 cm in diameter (75%-80%) than CT (22%-33%; P < .0001). CONCLUSION: Double-contrast MR imaging demonstrated more peritoneal tumors than CT or unenhanced spin-echo MR imaging.

Intra-arterial chemotherapy using an implantable infusion pump and liver irradiation for the treatment of hepatic metastases.

Liver metastases are a common cause of death in colon carcinoma. The dual blood supply of the liver permits regional perfusion while hepatic catabolism fo 5-fluorouracil (FU), floxuridine (FUdR) permit higher drug exposures than systemic (IV) administration. We have studied the effect of continuous intra-arterial chemotherapy (FU: 5-10 mg/kg/day and FUdR: 0.2 mg/kg/day) and whole liver irradiation (1000 rad every 4 weeks, total dose of 3000 rad) for metastatic colon carcinoma to liver. Eighteen patients with metastases to liver only are reported using this combination therapy. Seven patients had percutaneous placement of a catheter via the brachial artery, two had operative placement of a catheter via the gastroduodenal artery, all of which were connected to the Cormed infusor system, nine had operative placement of the Infusaid implantable pump with catheter placement into the hepatic artery via the gastroduodenal artery. The median survival for the entire group was 241 days. In those patients whose liver function tests (bilirubin and alkaline phosphatase) were less than two times normal, the median survival was 770 days. The median survival of the patients with greater than two times normal LFT's was 178 days. Two patients died of complications of the treatment. One who developed irreversible radiation hepatitis but at autopsy had only two areas of microscopic tumor foci in the liver and another who had received only 15 days of infusion and 1000 rad to liver. This patient developed irreversible chemical enteritis secondary to chemotherapy infusion into the superior mesenteric artery. Three patients have undergone abdominal reexploration and one at autopsy, who were found to have no gross evidence of tumor in the liver despite previous pathologic confirmation. It appears that some patients with minimal tumor burdens can have sterilization of their tumors. There were three cases of reversible liver function abnormalities. Complications associated with conventional intra-arterial chemotherapy (artery thrombosis, catheter sepsis and dislodgement, pump infusion variation and pump failure) were not seen with the Infusaid delivery system. The pump is refilled every 2-3 weeks via percutaneous puncture. All therapy was given on an outpatient basis. Pump acceptance and tolerance was 100%. Intra-arterial chemotherapy can now be accomplished without the morbidity associated with it in the past. The combination of chemotherapy and liver irradiation may offer improved survival in selected patients.

Surgical adjuvant therapy in colon carcinoma: a human tumor spheroid model for evaluating radiation sensitizing agents.

HT-29 human colon tumor cells growing as spheroids have been evaluated as a model system for measuring the response of human colon tumor cell to antineoplastic agents. HT-29 cells have been capacity to form spheroids up to 1 mm or more in diameter when grown in spinner culture. The multicellular HT-29 spheroids develop hypoxic centers reflecting the cellular conditions found in human cancer treatment, i.e., nutritionally deficient hypoxic cells that are felt to be a significant source of both radiation and chemotherapy clinical treatment failures. Spheroids of increasing size were radiated and then dispersed into single cells for colony survival assay. Compared with irradiated single cell suspensions, the spheroid cells demonstrated a significant increase in radioresistance. Growing spheroids developed a complex radiation survival curve which was variable with respect to size of the spheroid. The drug 5-Fu was studied to examine in a preliminary fashion its interaction with these resistant cell fractions. In direct cytotoxicity assay, 5-fluorouracil (5-FU) exhibited both cytotoxic and cytostatic effects when the drug was present at a concentration greater than 0.4 microgram/ml. The interaction of 5-FU with x-rays in the HT-29 spheroids was complex and dependent on the type of assay employed (spheroid size versus clonogenicity). The effect of allopurinol, an agent that protects cells from 5-FU toxicity was examined. Allopurinol at a concentration of 100 microgram/ml was found to protect these human colonic carcinoma cells from the cytotoxic effects of 5-FU under conditions resembling those found in vivo. Overall, this HT-29 spheroid system appears to b an interesting model for studying a variety of drug/x-ray interactions in vitro and may prove capable of answering specific questions of preclinical and clinical relevance.

Treated ovarian cancer: comparison of MR imaging with serum CA-125 level and physical examination--a longitudinal study.

PURPOSE: To evaluate whether gadolinium-enhanced magnetic resonance (MR) imaging can demonstrate clinically occult tumors in women with treated ovarian cancer and to compare the diagnostic accuracy of MR imaging, serum CA-125 (ovarian cancer antigen) level, and physical examination. MATERIALS AND METHODS: From 1992 to 1997, a longitudinal study comparing MR imaging findings, CA-125 values, and physical examination results with eventual clinical outcome in 69 women with treated ovarian cancer was performed. Tumor presence was determined with surgery, by an elevated CA-125 value, or with follow-up of patients longitudinally to assess for tumor recurrence. Absence of tumor was accepted with a disease-free interval of at least 2 years. RESULTS: Twenty-three of 39 patients in clinical remission with a normal CA-125 level and physical examination result had subclinical tumor proved at laparotomy or clinical follow-up. Gadolinium-enhanced MR imaging correctly demonstrated residual tumor in 20 of 23 patients. In all 69 patients, MR images had a 91% sensitivity, 87% specificity, 90% accuracy, and 72% negative predictive value and were superior to serum CA-125 level (53%, 94%, 63%, and 38%, respectively) (P < .001) and physical examination (26%, 94%, 43%, and 29%, respectively) (P < .001) in the depiction of residual tumor. CONCLUSION: Gadolinium-enhanced MR imaging is a valuable clinical tool in patients with ovarian cancer. An abnormal MR examination with a normal CA-125 value is a strong indication of residual or recurrent tumor.