Identification of a macromolecule containing an anticarcinoembryonic antigen-reactive substance and immunoglobulin M in human pancreatic cancer.

Ascitic fluid from a patient with carcinoma of the pancreas was fractionated by ammonium sulfate precipitation. The fraction precipitated between 25 and 50% saturation of ammonium sulfate was sequentially chromatographed on Sephadex G-200 and Sepharose 6B. A macromolecular fraction (greater than 10(6) daltons) obtained was found to react with both antihuman IgM and antiserum to carcinoembryonic antigen (CEA). This fraction was further purified by adsorption with protein A-Sepharose CL-4B and chromatography on DEAE-Sephacel. The purified macromolecular fraction had a sedimentation value of 28S as determined by ultracentrifugation. Upon dissociation of the purified macromolecule at pH 2.3 and purification of the dissociated components on Sepharose CL-2B and BioGel A 1.5M, a 19S protein and a 5S protein were recovered. The 19S protein showed a complete line of identity with a reference human IgM when reacted with antihuman IgM in gel diffusion, whereas the 5S protein showed a partial immunologic identity with colon CEA against anti-CEA. These results indicated the existence of an IgM-containing macromolecular complex with an anti-CEA cross-reactive substance in the extracellular fluid of human pancreatic cancer.

Isolation of glycoprotein antigen from ascites fluid of pancreatic carcinoma.

A glycoprotein antigen from the ascites fluid of pancreatic carcinoma has been isolated with the use of perchloric acid extraction and chromatographies on Sepharose 4B, DEAE-Sephadex, and DE52, followed by Sephadex G-200. The purified glycoprotein was found to be homogenous by sodium dodecyl sulfate polyacrylamide gel electrophoresis. A molecular weight of 185,000 dattons was determined by gel filtration. The molecule contained 55% protein and 45% carbohydrate. Both the amino acid and carbohydrate compositions were different from those of carcinoembryonic antigen. This glycoprotein antigen of pancreatic cancer cross-reacted with anticarcinoembryonic antigen; however, the antiserum prepared from this antigen did not react with carcinoembryonic antigen. The biological significance of this glycoprotein in pancreatic cancer is being studied.

Simultaneous evaluation of a pancreas-specific antigen and a pancreatic cancer-associated antigen in pancreatic carcinoma.

A pancreas cancer-associated antigen (PCAA) and a pancreas-specific antigen (PaA) were simultaneously quantitated by enzyme-linked immunosorbent assays in serum specimens from 51 normal controls, 76 pancreatic cancers, 194 nonpancreatic cancers, and 22 benign pancreatic diseases. Primary immunological reagents used in the enzyme-linked immunosorbent assays were our polyclonal antibodies produced in rabbits against purified PCAA and PaA. Results revealed discordance of these two markers in pancreatic cancer, suggesting that the presence of these two biochemically and immunologically distinct pancreas proteins in patients' serum may reflect different biological aspects of cancer. The combination test resulted in a better sensitivity and specificity for pancreatic cancer, 90 and 85%, respectively, than either PCAA or PaA assay alone. This study demonstrated that the combination of serum PCAA and PaA tests yields an additive clinical value and may be a useful adjunctive aid for the immunodiagnosis of the pancreatic cancer.

An Eastern Cooperative Oncology Group evaluation of combinations of methyl-CCNU, mitomycin C, Adriamycin, and 5-fluorouracil in advanced measurable gastric cancer (EST 2277).

In a prospectively randomized trial, patients with advanced locally recurrent or metastatic gastric adenocarcinoma were randomized to receive 5-fluorouracil (5-FU) and methyl-CCNU; 5-FU, Adriamycin (Adria Laboratories, Columbus, Ohio), and methyl-CCNU; 5-FU, Adriamycin, and mitomycin C; or Adriamycin and mitomycin C alone. One hundred eighty-three previously untreated evaluable patients were randomized among the four arms. An additional 39 patients previously treated with 5-FU, were assigned to treatment directly to Adriamycin and mitomycin C. Response rates were 14%, 29%, 39%, and 29%, respectively, among previously untreated patients and 21% for Adriamycin and mitomycin C among previously treated patients. 5-Fluorouracil, Adriamycin, and mitomycin C, the arm containing the largest number of responders (18), was the combination associated with the longest median survival. A larger proportion of patients in this arm survived one year or more. In addition, the 5-FU, Adriamycin, and mitomycin C program had the lowest rate of severe or worse toxicity of any of the treatments and was effective in patients who were less than fully ambulatory and in those who had lost weight. 5-Fluorouracil, Adriamycin, and mitomycin C appear to be a likely combination to be considered in a surgical adjuvant program.

Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor.

EST 5275 is a phase II and III study of fluorouracil plus streptozocin (5-FU plus STZ) or doxorubicin in patients with measurable progressive carcinoid tumor. Among one hundred seventy-two cases with no prior chemotherapy and no heart disease, the response rate was 22% for 5-FU plus STZ and 21% for doxorubicin, while the median response duration and median survival were 31 weeks and 64 weeks for the combination and 26 weeks and 48 weeks for doxorubicin. Thirty-three patients who failed 5-FU plus STZ crossed over to doxorubicin and achieved an 18% response. Of the thirty-five patients who failed on doxorubicin, 29% responded to 5-FU plus STZ. Hematologic toxicity was similar for both treatments; however, the 5-FU plus STZ patients experienced more vomiting but acceptable renal toxicity. Both chemotherapy regimens have antitumor activity in carcinoid tumors.

Phase I and pharmacologic studies of intraperitoneal leucovorin and 5-fluorouracil in patients with advanced cancer.

Many patients with gastrointestinal (GI) tumors develop extensive peritoneal and serosal metastasis and/or malignant ascites which respond poorly to available treatments. Twelve patients with tumors confined primarily to the intraabdominal cavity were treated with intraperitoneal (IP) 5-fluorouracil (5-FU) in escalating concentrations (2 to 4 mmol/L) in combination with leucovorin (dl-5-formyltetrahydrofolic acid or folinic acid; dl-CF) in a 2-L volume, either by eight consecutive four-hour dwells or once daily for five days. CF dose was 20.8 or 104 mumol/L. Nine of the patients had pancreatic carcinoma, one had stomach carcinoma, and two had hepatobiliary neoplasms. Median age was 62.5 years and median Eastern Cooperative Oncology Group (ECOG) performance status was 3. Toxicity included mucositis, diarrhea, nausea and vomiting, leucopenia, skin rash, and abdominal pain, and was similar to that previously reported for IP 5-FU used as a single agent. Four episodes of peritonitis occurred, but all patients responded to antibiotics. At the 20.8 mumol/L dose, dl-CF concentration in the peritoneal fluid declined from 10.4 +/- 3.0 3.0 mumol/L at one hour to 4.9 +/- 2.2 mumol/L at four hours, corresponding to a mean absorption half-life of 127 +/- 49 minutes and a mean peritoneal clearance of 13.0 +/- 4.5 mL/min. Decline was biphasic in all but five of the 19 exchanges evaluated. The levels of l-CF (biologically active isomer of dl-CF) were 2.8 +/- 2.5 mumol/L after 60 minutes and 1.2 +/- 0.7 mumol/L after four hours. The peritoneal area under the concentration v time curve (AUC) for 5-FU increased proportionally with dose. For example, the AUC at 2.0 and 3.5 mmol/L was 129 +/- 25 and 201 +/- 23 mmol/L X minute, respectively. However, the maximal peritoneal to plasma AUC ratio was 461 at the 2 mmol/L dose, but decreased with increasing doses as systemic clearance decreased. This regimen was well tolerated in patients with advanced cancer, but must be evaluated further to determine its clinical efficacy.

A phase II trial of 5-fluorouracil and high-dose intravenous leucovorin in gastric carcinoma.

Twenty-eight patients with advanced measurable gastric carcinoma were treated with leucovorin (dl-CF; folinic acid; dl-5-formyltetrahydrofolic acid) 500 mg/m2 administered as a two-hour infusion and 5-fluorouracil (5-FU) 600 mg/m2 intravenous (IV) push midinfusion. Treatment was administered weekly for 6 weeks followed by a 2-week rest. Twenty-five patients were evaluable for response. Twelve of them had received previous combination chemotherapy that included 5-FU. Median age was 59 years, and median Eastern Cooperative Oncology Group (ECOG) performance status was 2. Three patients had partial responses and two of them had been treated previously with 5-FU. Twelve patients had stable disease. Five of these patients had subjective improvement with improved performance status and/or decreased dysphagia. The 95% confidence interval for response is 3% to 32%. Median survival time for all 28 patients enrolled in the study was 22 weeks. Toxicity was moderate and consisted primarily of diarrhea. Myelosuppression, skin rash, and increased lacrimation also occurred. Plasma concentrations of the active reduced folates, I-CF and 5-methyltetrahydrofolic acid (5-CH3FH4), were greater than the 10 mumol/L levels that potentiate 5-FU activity in in vitro models, for more than four hours in all five patients in whom pharmacokinetics were studied. 5-FU and high-dose dl-CF has activity in patients with gastric carcinoma including patients who had previously progressed on 5-FU-containing combinations. Further study in a larger patient population is necessary to determine the usefulness of this regimen in gastric carcinoma.

Adjuvant adriamycin and cisplatin in newly diagnosed, nonmetastatic osteosarcoma of the extremity.

Twenty-two patients with newly diagnosed nonmetastatic osteosarcoma of the extremity were treated with an adjuvant chemotherapeutic regimen consisting of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin. Fourteen of the 22 patients remain continuously disease free for 65+ to 113+ months, with a median time on study of 70+ months. The 72-month disease-free survival estimate is 64%. Pulmonary metastases occurred in six patients, an isolated stump recurrence was seen in one patient, and one patient had a local recurrence following a limb-salvage procedure. For those patients in whom pulmonary metastases developed, the onset was late in three of six, and the number of metastases was three or fewer in all patients. Two patients with pulmonary metastases and one with a stump recurrence have apparently been salvaged, thus resulting in a 77% 72-month survival. Toxicity observed in patients treated with this regimen was in keeping with previous reports. This chemotherapeutic regimen is effective in the adjuvant therapy of nonmetastatic osteosarcoma of the extremity. It should be incorporated into other adjuvant protocols in an effort to continue to improve the outcome in patients with osteosarcoma.

Neocarzinostatin versus m-AMSA or doxorubicin in hepatocellular carcinoma.

Sixty-one of 76 patients entered on a prospective randomized trial of neocarzinostatin ( NCZ ) versus m-AMSA or doxorubicin were eligible for analysis. Among these 61 patients at least one episode of severe toxicity was documented in 39% of patients on NCZ and 58% on m-AMSA. Fifty-one of the 61 patients were previously untreated with chemotherapy. Among these 51 patients objective response was documented in two of 25 patients treated with NCZ , none of 17 treated with m-AMSA, and one of nine treated with doxorubicin. Among previously untreated North American and European (NA/E) patients the median survival times were: NCZ 11 weeks and m-AMSA 12 weeks. The data on South African (SA) patients with similar entrance criteria entered on earlier Eastern Cooperative Oncology Group trials were analyzed with that from the randomized trial and show that for SA patients the median survival times were: NCZ , 11 weeks (31 patients); m-AMSA, 13 weeks (33 patients); and doxorubicin, 15 weeks (29 patients).

Etoposide pharmacokinetics in patients with normal and abnormal organ function.

Precise guidelines for dose modification of etoposide in patients with hepatic dysfunction have not been determined. Etoposide pharmacokinetics were determined in 17 patients. Nine patients had bilirubin less than or equal to 1 mg/dL and eight had bilirubin ranging from 1.9 to 23 mg/dL. Twelve patients received etoposide 100 mg/m2 days 1, 3, and 5, in combination with cisplatin 70 mg/m2 or iproplatin 225 mg/m2 on day 1. Five patients received only one dose of etoposide. Etoposide was measured using a published high pressure liquid chromatography (HPLC) method which also quantitates picro etoposide and its hydroxy acid. Systemic clearance, Vdss and t1/2 beta averaged (+/- SD) 21.4 (+/- 7.4) mL/min/m2, 10.7 (+/- 4.1) L/m2, and 8.1 (+/- 2.8) hours in the nine patients with bilirubin less than or equal to 1 mg/dL, and 22.4 (+/- 9.6) mL/min/m2, 13.6 (+/- 11.3) L/m2, and 8.4 (+/- 3.9) hours in the eight patients with bilirubin 1.9 to 23.0 mg/dL. Stepwise multiple linear regression analysis of liver and renal function tests and other patient-specific variables identified creatinine clearance as the strongest predictor of etoposide systemic clearance (r2 = 40.8). Serum albumin was identified as the next strongest predictor, improving the r2 to 57.3%. Cumulative biliary excretion of unchanged etoposide and glucuronide or sulfate conjugates over 48 hours accounted for less than 3% of the dose in six patients studied. Toxicity occurred in patients with normal and abnormal bilirubin and was unrelated to etoposide clearance. Patients with total bilirubin 1.9 to 23 mg/dL, but creatinine clearance greater than 30 mL/min/m2 had etoposide clearance within the range for patients with normal liver function (16.8 to 35 mL/min/m2). Although these patients did not have reduced etoposide clearance, the major routes of etoposide non-renal elimination remain to be clearly defined. Additional patients should be evaluated to establish more precise guidelines for dosing etoposide in patients with abnormal liver function.

The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group.

A total of 343 patients with previously untreated metastatic measurable colorectal carcinoma were studied to evaluate the impact on toxicity, response, and survival of leucovorin-modulated fluorouracil (5-FU). A maximally tolerated intravenous bolus loading course regimen of 5-FU alone (500 mg/m2 x 5 days every 4 weeks with 25 mg/m2 escalation) was compared with a high-dose leucovorin regimen (600 mg/m2 of 5-FU with 500 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest) and with a similar low-dose leucovorin regimen (600 mg/m2 of 5-FU with 25 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest). The dose-limiting toxicity for the two 5-FU and leucovorin regimens was gastrointestinal, specifically diarrhea; severe diarrhea was seen frequently, and treatment-related toxicity was implicated in the demise of 11 of the patients (5%). Significant improvements in response rates were observed with a response rate of 33 of 109 (30.3%) on the high-dose leucovorin regimen (P less than .01 v control); 13 of 107 (12.1%) on the 5-FU control; and 21 of 112 (18.8%) on the low-dose leucovorin regimen. A trend toward longer survival in the 5-FU plus high-dose leucovorin regimen was observed. In this study, leucovorin was shown to significantly enhance the therapeutic effect of 5-FU in metastatic colorectal carcinoma.

Unusual gastrointestinal complications of interleukin-2 therapy.

Minor and reversible gastrointestinal side effects are common when patients receive interleukin-2 (IL-2) with or without lymphokine-activated killer (LAK) cells. We treated 42 cancer patients with IL-2 therapy and 3 patients developed serious gastrointestinal problems during treatment. Complications included sigmoid colon perforation, ischemic necrosis of the small and large intestine, and diffuse bowel ulceration. These were not associated with tumor implants or hypotension. Two patients died as a direct result of these problems despite aggressive surgical and medical management. The incidence of major gastrointestinal complications with IL-2 therapy may be greater than previously reported and a heightened awareness of potential gastrointestinal problems may circumvent considerable morbidity and mortality.

Is taste related to anorexia in cancer patients?

Intensity and pleasantness of five suprathreshold concentrations each of citric acid, NaCl, urea, and sucrose in beverages were scaled by 62 patients with primary tumors in upper gastrointestinal or thoracic areas, 22 of whom had chemotherapy within the month before testing. Mean intensity scores directly correlated with concentration of sour, salty, bitter, and sweet stimuli and indicated no abnormalities of taste perception among patients grouped by tumor site, therapy, or appetite. In contrast, mean hedonic functions differed among individuals and groups. Patients on chemotherapy were less likely to display a distinct preference for any of the five concentrations of sucrose, particularly high levels, than those not on chemotherapy. Anorectics were more likely to prefer lower sweetness levels than nonanorectics, but sweet foods constituted a greater percentage of their daily caloric intake. Current theories for regulation of hunger and satiety were examined to elucidate the pathogenesis of anorexia in cancer patients.

Gastric cancer: overview of current therapies.

The worldwide results of surgical adjuvant therapy for gastric cancer are reviewed. Studies from Japan suggest that earlier initiation of chemotherapy results in significantly improved survival, even in advanced resectable disease. Sites of cancer recurrence were evaluated. Transperitoneal and lymph node metastases were the major causes of treatment failure. It is suggested that these sites of recurrence be targeted in future surgical adjuvant therapy trials through preoperative, intraoperative, and early postoperative systemic and intraperitoneal therapy to control microscopic residual disease at a time when the tumor burden is the smallest.

Gastric adenocarcinoma--management of the primary disease.

While it will be another decade before the results are apparent, the past decade has sown the seeds of new generation of concepts regarding the initial management of gastric adenocarcinoma. Those seeds will come to flower when we fully utilize the management tools that have been developed. Endoscopy provides the opportunity for earlier diagnosis of gastric cancer. More liberal use of gastroscopy and cytology when x-rays are not completely diagnostic should identify the still surgically curable tumor. An improved understanding of the routes of tumor spread--by invasion and metastases--have identified a number of practical alterations to the surgical procedures for the removal of gastric adenocarcinoma arising from various sites in the stomach. Suggestions for effective adjuvant therapies, based on the realization that most gastric cancer has become a systemic disease by the time of diagnosis, are apparent from the clinical trials to date: Local control of microscopic disease with radiotherapy and treatment of transperitoneal tumor spread by the intraperitoneal route are logical additions to systemic therapy. More careful and thorough pathologic examination of resected tissues, with adjuvant treatment planning based on the results of that examination, should alter what has in the past been the grim prognosis of this disease. Careful follow-up evaluation and attention to nutrition can improve the quality of the patient's life, just as carefully planned antineoplastic therapy can improve its duration.

Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group.

The prognostic effect of weight loss prior to chemotherapy was analyzed using data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group. The frequency of weight loss ranged from 31 percent for favorable non-Hodgkin's lymphoma to 87 percent in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Chemotherapy response rates were lower in the patients with weight loss, but only in patients with breast cancer was this difference significant. Decreasing weight was correlated with decreasing performance status except for patients with pancreatic and gastric cancer. Within performance status categories, weight loss was associated with decreased median survival. The frequency of weight loss increased with increasing number of anatomic sites involved with metastases, but within categories of anatomic involvement, weight loss was associated with decreased median survival. These observations emphasize the prognostic effect of weight loss, especially in patients with a favorable performance status or a limited anatomic involvement with tumor.

Combined chemoradiotherapy vs. radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group.

Squamous carcinoma of the thoracic esophagus has an extremely poor prognosis. This study, EST-1282, was undertaken by the Eastern Cooperative Oncology Group (ECOG) to determine whether the combined use of 5-fluorouracil (5-FU), mitomycin C, and radiation therapy improved the disease-free survival and overall survival of patients with carcinoma of the esophagus, compared to those who received radiation therapy alone. Two- and 5-year survivals were 12% and 7% in the radiation alone arm and 27% and 9% in the chemoradiation arm. Patients treated with chemoradiation had a longer median survival (14.8 months), compared to patients receiving radiation therapy alone (9.2 months). This difference was statistically significant. The same pattern of survival was noted in almost all subgroups independent of whether surgical resection was performed.

Microplate leukocyte adherence inhibition assay in pancreatic cancer. Effect of chemotherapy on the specific antitumor response.

This study evaluated the effect of adriamycin and 5-fluorouracil (5-FU) on the host's tumor specific immune response monitored by a microplate leukocyte adherence inhibition assay (LAI) in patients with pancreatic ductal adenocarcinoma. Sixteen previously LAI positive patients were treated with adriamycin. The previously positive LAI responses were abrogated in 11 of the 16 patients. This effect of adriamycin on the hosts' tumor specific immune response lasted for a period of 4 weeks following therapy. Seventeen LAI reactive patients were treated with 5-FU. In contrast to the effect of adriamycin, 13 of these 17 patients remained LAI reactive following administration of 5-FU.

Abdominal wall replacement with plastic mesh in ablative cancer surgery.

Planned excisions of tumors involving the abdominal or chest wall should not be compromised because of lack of tissue for wound closure. Reconstruction with an inert polypropylene mesh provides a strong and stable covering for the defect. Mobilization of adjacent skin flaps to provide covering for the mesh is desirable and results in reduced morbidity. When this is not possible the mesh may be left to granulate and later be grafted. Nine illustrative cases are presented.

Chylous ascites and lymphocyst management by peritoneovenous shunt.

Although lymphocyst (retroperitoneal lymphocele) is not an uncommon complication after retroperitoneal surgery, with a reported incidence ranging from 0.6% to 48%, the occurrence of chylous ascites is a rare phenomenon. Most reports are anecdotal, and hospital records list the incidence of diagnosis as 0.001% of admissions. Diagnosis of chylous ascites is usually not difficult, inasmuch as aspiration and chemical analysis of the fluid yield the answer. Visualization of retroperitoneal fluid collection by computerized tomography or ultrasonography, however, does always raise the possibility of recurrence of tumor in cases where the primary operation was for cancer. Treatment of smaller lesions can be expectant. Respiratory exercises causing an increase in negative intrathoracic pressure may aid in the movement of fluid through the lymphatics. For larger collections, elemental diets and total parenteral nutrition are also often enough, but surgery is sometimes required. Simple insertion of a peritoneovenous shunt, as in this patient, can be as effective as major operations such as identification and ligation of the offending lymphatic or marsupialization of the cyst.