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Significant increments in measurable plasma CEA were effected by 2.5 M MgCl2 elution from putative circulating CEA–anti-CEA complexes in 11 of 15 patients with disseminated colorectal cancer and in five of ten patients with a high probability of having subclinical disease (Dukes' C category). Following 2.5 M MgCl2 elution, IgG from a patient with a high CEA increment effected a higher specific binding to 125I-CEA than a similar IgG eluate from a patient with a negligible increment in measurable CEA. These data suggest that CEA is autoimmunogenic and may result in circulating CEA–anti-CEA complex formation. The clinical implications of such complexes in the diagnosis and monitoring of patients with colorectal cancer remain to be determined. Cancer 52:146-149, 1983.

The in vitro restorative effect of aqueous extracts from two traditional Chinese medicinal herbs were studied in 19 cancer patients and in 15 normal healthy donors. Using the local graft versus host (GVH) reaction as a test assay for T-cell function, the extract from astragalus membranaceus (10 microgram/ml) induced a restored reaction in nine of ten patients with an increase in local GVH reaction from 18.2 plus/minus 15.8 mm3 to 112.9 plus/minus 94.2 mm3 (P less than 0.01). The extract from ligustrum lucidum, likewise effected an immune restoration in nine of 13 cancer patients with an increase in local GVH reaction from 32.3 plus/minus 36.1 mm3 to 118 plus/minus 104.9 mm3 (P less than 0.01). This degree of immune restoration appears to be complete as it equals the local GVH reaction observed among untreated mononuclear cells from normal healthy donors (82.8 plus/minus 41.1 mm3, P greater than 0.1). These results suggest that both extracts of the traditional Chinese medicinal herbs contain potent immune stimulants which may provide the rational basis for their therapeutic use as biological response modifiers.

Fifty-eight patients with Dukes' C classification of carcinoma of the large bowel were placed on adjuvant immuno- or chemoimmunotherapy with Bacillus calmette guerin (BCG) or combination of 5-fluorouracil (5-FU) plus BCG following primary and definitive surgery, and were followed for up to 21 months. Of twenty-six patients receiving BCG alone by scarification, five have relapsed with 75% of freedom from disease estimated at 15.1 months compared with 10.1 months in a group of carefully selected historical controls who had surgery alone (p = 0.12). The survival of all patients receiving BCG alone has not reached the 75 percentile yet, and the difference from controls is currently estimated at the 18% level. The combination of 5-FU plus BCG (studied in 32 patients) may be superior to BCG alone at this time, in that it appears to more effectively protect against tumor recurrence (75 percentile not yet reached compared to control, (p = 0.08). The survival of patients on 5-FU plus BCG also appears to be improved (p = 0.09). No patients have expired compared to a 75 percentile survival of 16.6 months in the control. Serial determination of plasma CEA was crucial in the clinical follow-up of these patients. Frequent CEA detetminations have led to early detection of clinical relapse. In the elevation of CEA suggests tumor recurrence with a high degree of probability in patients with past history of cancer of the large bowel.

Patients with colorectal cancer commonly succumb to the sequelae of hepatic metastases. Response to systemic therapy is inadequate. Hepatic arterial infusion (HAI) exposes liver metastases to high local concentrations of drug. Herein, we review the randomized trials of HAI in colorectal cancer. Data for this review were identified by searches of MEDLINE and references from relevant articles using the search terms "infusion intra-arterial" and "colorectal cancer." Abstracts and reports from meetings were included only when they related directly to previously published work. Only papers published in English between 1966 and 2003 were included. Randomized trials (5-fluorouracil- (5-FU-) or fluordeoxyuridine- (FUDR-) based regimens) often demonstrated superior response rates for HAI as compared to systemic chemotherapy (primary treatment or post-resection). Enhanced survival has, however, shown only when HAI was combined with systemic chemotherapy in the post-resection setting. For 5-FU-based and perhaps other regimens, randomized trials of combined regional and systemic therapy versus systemic treatment alone may be needed in order to determine whether or not there is a survival advantage after HAI in unresectable patients, as has been recently demonstrated in resectable patients. A variety of agents other than 5-FU have also been given by HAI to patients with liver metastases from diverse cancers. Such regional therapy often yields encouraging response rates and impact on survival therefore merits investigation.

background and purpose High platelet counts are occasionally seen in patients suffering from progressive malignant disorders. While granulocyte colony-stimulating factor (G-CSF) has been implicated in paraneoplastic leukemoid reactions, the stimulus for thrombocytosis is unknown. Our purpose in this study was to determine if plasma from cancer patients with thrombocytosis contains a factor or factors with thrombopoietic activity. methods We tested the effects of plasma obtained from 5 individuals with advanced tumors and high platelet counts and from 4 patients with advanced cancer and normal platelet counts on megakaryocytic differentiation of two megakaryoblastic cell lines (Dami and HEL). Differentiation was evaluated by assessing the expression of the platelet-specific cell-surface antigens CD41 (HUPL-ml) and glycoprotein IIb-IIIa using an immunocytochemical staining score. In addition, plasma samples from 7 of the 9 patients and from 5 additional cancer patients with thrombocytosis were assayed for the levels of interleukin (IL)-3, IL6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and IL-1β protein using an enzyme-linked immunosorbent assay (ELISA). results Expression of platelet-specific cellsurface antigen was increased in HEL cells after exposure to plasma from all 5 of the cancer patients with thrombocytosis, and in Dami cells after exposure to plasma from 4 of the 5. Similar, but less significant, results were found when these cells were incubated with control combinations of recombinant GM-CSF plus IL-6 or of IL-3 plus IL-6. Platelet-specific cell-surface-antigen expression was not increased in HEL or Dami cells after exposure to the plasma from the 4 cancer patients with normal platelet counts or to normal control plasma. ELISA revealed elevated levels of IL-6 in the plasma from 4 patients with thrombocytosis (38, 40, 63, and 99 pg/mL). In addition, GM-CSF concentration was high in 3 of these 4 patients (33, 47, and 127 pg/mL), and the G-CSF level was elevated in 1 (543 pg/mL). IL-1β and IL3 levels were undetectable. conclusions Our data suggest that the thrombocytosis observed in individuals with advanced malignant disease is mediated by a humoral mechanism. Levels of IL-6, GM-CSF, and G-CSF are elevated in some of these patients, but the plasma concentrations are generally lower than those required for in vitro induction of megakaryocytic differentiation. Plasma from patients with paraneoplastic thrombocytosis may therefore contain thrombopoietins that have not yet been identified, and which might have clinical usefulness.

Background. Gastrointestinal leiomyosarcoma metastatic to the liver is considered most resistant to any combination of systemic chemotherapy containing doxorubicin and/or ifosphamide. Methods. Fourteen patients with gastrointestinal leiomyosarcoma metastatic to the liver were treated with hepatic chemoembolization infusion consisting of polyvinyl alcohol sponge particles mixed with cisplatin powder (150 mg) followed by an intrahepatic arterial infusion of vinblastine (10 mg/m 2 ). Results. Ten major (>50% regression) tumor responses were observed (70%) in patients lasting from 8 to 31 + months (median, 12 months) after an average of two hepatic chemoembolization procedures, usually 4 weeks apart. Transient side effects included right upper quadrant pain requiring narcotics, significant hepatic enzyme elevation, particularly of lactic dehydrogenase with a minimal increase in bilirubin, paralytic ileus requiring nasogastric suction up to 72 hours, urinary electrolyte losses (potassium + , magnesium ++ , sodium + ) requiring supplements, and occasionally mild but transient leukopenia and thrombocytopenia. Conclusions. Hepatic chemoembolization infusion appears to induce a high rate of durable tumor response in patients with notoriously chemoresistant gastrointestinal leiomyosarcoma metastatic to the liver. Cancer 1995 :75 :2083-8.

Background. Islet cell carcinoma of the pancreas is a neuroendocrine tumor often presenting with left upper quadrant mass and radiographic evidence of liver metastases. Because survival among these patients is determined largely by the pace of metastatic events in the liver, significant palliation may be achieved by regional hepatic therapy. Methods. Five patients with islet cell carcinoma of the pancreas metastatic to the liver (four nonfunctional, one gastrin producing), were treated by hepatic arterial chemoembolization-infusion consisting of a mixture of polyvinyl alcohol sponge (150 mg) and cisplatin (150 mg) followed by 2-hour intraarterial infusion of vinblastine (10 mg/m2). Each patient received two such treatments, 1 month apart, requiring 3 to 6 days of hospital admission. Results. Significant tumor regression (> 50%) was observed in four of five patients, lasting from 8 to 44 months. Toxicity was limited to right upper quadrant pain, paralytic ileus requiring nasogastric suction for 24 to 72 hours, transient, mild bilirubinemia and liver enzyme elevation, hypomagnesemia and hypokalemia, and occasionally, moderate, self-limiting granulocytopenia. Conclusions. This preliminary, albeit limited, experience with hepatic chemoembolization-infusion in patients with islet cell carcinoma metastatic to the liver emphasizes the high incidences of durable tumor regression that can be achieved with minimal iatrogenic intervention.

Twenty-two chemotherapy-resistant patients with liver metastases received 46 courses of recombinant human tumor necrosis factor (rhTNF) administered by 5-day continuous infusion through percutaneously inserted hepatic arterial catheters. The maximum tolerated daily dose of rhTNF was 150 micrograms/m2. This is six times the maximum tolerated daily dose of rhTNF that could be given systemically (intravenous) on the same schedule. The dose-limiting toxicity resulted in severe, although transient, hypophosphatemia (less than 1.0 mg/dl) associated with myocardial dysfunction. Objective tumor response (partial tumor response or greater) was observed in 2 of 14 patients (14%) with colorectal cancer and lasted as long as 3 months. Three additional minor responses occurred among these patients with colorectal cancer. Plasma carcinoembryonic antigen levels also decreased significantly (greater than 25%) in 7 of the 14 (50%) patients with colorectal cancer. Regional biologic therapy with rhTNF as a sole modality has definite antitumor activity in colorectal cancer metastatic to the liver and warrants additional study in previously untreated patients.

Eight of 28 (28%) cancer patients with liver metastases treated by either splenic (four) or hepatic (four) arterial infusion of recombinant interleukin-2 (rIL-2) developed hypersensitivity reactions to iodine-containing radiographic contrast media. These reactions consisted of fever, chills, malaise, nausea and vomiting, skin rash, diarrhea, and occasionally, hypotension. Reactions usually occurred 1 month after the initial arteriographic procedure and rIL-2 infusion, with 1-hour to 4-hour intervals between procedure and reexposure of the patient to the iodine-containing contrast medium (used in conjunction with computerized tomography or repeated arteriography for subsequent courses of rIL-2 infusions) and the onset of symptoms. Prompt administration of corticosteroids during the reaction and premedication of patients who were known to have had a reaction in the past were very effective in stopping reactions or preventing them from reoccurring. The high incidence (28%) of hypersensitivity reactions, the temporal relationship (4 hours) between the arteriographic procedure (utilizing iodine-containing contrast medium) and the initial infusion of rIL-2 (while some of the contrast medium was still present), and the absence of such hypersensitivity reactions among patients receiving systemic (intravenous) rIL-2 (not requiring the use of concomitant iodine-containing contrast medium) provide additional evidence that in the presence of a potentially immunogenic moiety, rIL-2, a potent stimulant of the human immune system, can produce an initial sensitization followed by subsequent anamnestic reaction upon reexposure of the patient to the immunogen (even without the additional rIL-2).

BACKGROUND. Approximately 25% of patients with metastatic breast carcinoma develop hepatic involvement during the course of their disease that further affects their survival. Systemic paclitaxel is safe and has demonstrated good antitumor activity against breast carcinoma. The objective of this prospective study was to determine the safety and antitumor activity of hepatic intra-arterial paclitaxel therapy. METHODS. Ten patients with breast carcinoma and dominant liver metastases received monthly, inpatient, 24-hour, continuous hepatic infusions of paclitaxel at 200 mg/m2 through an intra-arterial catheter, which was placed using a percutaneous transfemoral approach. RESULTS. The mean patient age at the time of treatment was 51 years. Fifty-six courses of paclitaxel were delivered. The most common treatment-related toxicities were leukopenia, fatigue, nausea, and vomiting. No procedure-related complications were observed. Three patients (30%) attained partial responses that lasted for 6 months, 7 months, and 48 months; and 4 other patients had stable disease for 5 months to 9 months. One patient underwent liver resection after receiving hepatic arterial infusions of paclitaxel and remained disease free for 48 months. Eight patients had received prior systemic taxane therapy alone or with other cytotoxic agents. However, no association between previous taxane exposure and the efficacy of the current regimen was established. CONCLUSIONS. Hepatic intra-arterial therapy with paclitaxel at the dose level and on the schedule used in this study was safe and well tolerated and had reasonable antitumor activity against breast carcinoma involving the liver. Previous taxane exposure did not hamper the potential benefit of this approach. This regimen alone or in combination with targeted therapies deserves further investigation in patients with dominant liver metastases from breast carcinoma. Cancer 2007. © 2007 American Cancer Society.

We tested the efficacy of nifedipine to reverse acquired resistance to chemotherapy regimens containing doxorubicin or vinblastine or both in 12 patients with metastatic breast cancer. All patients had been receiving one or both of these drugs, had had a prior partial response (median duration 5 months, range 2–10) and subsequently progressed. Immediately after drug resistance was documented by tumor progression, eligible patients with measurable or evaluable disease were treated with nifedipine beginning 3 days before restarting the same chemotherapy. The initial dose of nifedipine was 20 mg TID, escalating daily to 40 mg TID on day 3 if the patient had no serious side effects. Nifedipine was continued at the highest tolerable dose during and for 2 days after completion of the chemotherapy. Most patients had ≤2 prior chemotherapy regimens and a median Zubrod performance status of 1. Twelve patients received a total of 23 courses preceded by nifedipine. No objective tumor responses were observed. The expected toxic effects attributable to nifedipine occurred, but nifedipine did not increase the toxicity caused by the chemotherapy. Nifedipine, given in this dose and schedule, did not reverse acquired drug resistance in patients with breast cancer. Int. J. Cancer 73:184–186, 1997. © 1997 Wiley-Liss, Inc.

Two patients with colon carcinoma metastatic to the liver had normal plasma carcinoembryonic antigen (CEA) levels (

Two patients with gastrointestinal leiomyosarcoma metastatic to the liver were treated by hepatic chemoembolization with cisplatin and polyvinyl sponge followed by hepatic arterial infusion of vinblastine. Effective palliation in terms of durable tumor regression was achieved in both patients after two chemoembolization-infusion procedures. These results suggest that regional therapy may offer new hope for the subset of sarcoma patients who have liver metastases resistant to combination systemic chemotherapy.

Twenty-two patients with liver metastases received 45 courses of recombinant tumor necrosis factor (rTNF) by hepatic arterial infusion in doses ranging from 12.5 to 175 micrograms/m2/d for 5 days by continuous infusion. The induction of statistically significant, dose-related, severe, albeit transient, hypophosphatemia (less than 1.0 mg/dl) associated with clinically significant, right-sided myocardial dysfunction and severe lassitude was observed. These side effects were promptly reversed after rTNF was stopped and intravenous phosphate supplementation was started. As no significant or consistent increase in urinary phosphate excretion was detected, the rTNF-induced hypophosphatemia probably resulted from an intracellular shift of phosphate. Since tumor regression was clearly associated with the lowest levels of serum phosphate, hypophosphatemia may be important in the antitumor effects of rTNF.

In an attempt to improve the therapeutic index of recombinant interleukin-2 (rIL-2) by generating or activating lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TIL) regionally and/or in situ, we randomly assigned 28 patients with liver metastases to receive rIL-2 by continuous infusion for 5 days via either the splenic artery or the hepatic artery. Clinically significant and lasting tumor regression was observed only in two of 28 patients (7%), one in each of the two treatment arms. The maximum-tolerated daily dosage of rIL-2 was 3 x 10(6) U/m2; beyond this dosage, toxicity was excessive. Peripheral LAK cell activity measured in vitro and clinical tumor regression did not correlate. This observation, coupled with the equal distribution of regressions between the two treatment arms, raises the possibility that tumor regression, rare though it may be in response to rIL-2 administration, is largely mediated by TIL activation and not by LAK cell generation.

10626 Background: Approximately 50% of pts with metastatic breast carcinoma develop hepatic involvement during the course of their disease. Their median survival is 1–14 months (mo). Systemic paclitaxel has good anti-tumor activity against breast carcinoma and is safe. We sought to prospectively determine the safety and anti-tumor activity of HIA paclitaxel therapy. Methods: Ten pts with breast carcinoma and dominant liver metastases received monthly inpatient 24 hr-continuous HIA infusions of paclitaxel at 200 mg/m2 through intra-arterial catheters placed via percutaneous transfemoral approach. WHO tumor assessment guidelines were used. Results: Nine pts enrolled in this study had infiltrating ductal carcinoma and their median age at the time of treatment was 51 years. The group had received a mean of 3.8 previous treatment regimens including adjuvant regimens. Therapy was well tolerated. Fifty-six courses were delivered. Mean hospital stay was 3 days. No procedure related complications were observed. Most common treatment related toxicities included leukopenia, fatigue, nausea, and vomiting. Three pts attained partial responses (50% decrease in tumors) lasting 6, 7, and 48 months whereas in 4 others disease stabilization lasted 5 to 9 mo. One pt underwent liver resection and remained NED for 48 mo. Eight pts had received prior systemic taxane therapy alone or in combination with other cytotoxics (3 adjuvant; 5 palliative). However, no association between previous taxane exposure and clinical efficacy of this regimen was not established. Conclusions: Hepatic arterial therapy with paclitaxel at this dose and schedule is safe and well tolerated and has reasonable anti-tumor activity against breast carcinoma involving the liver. Previous taxane exposure does not hamper the potential benefit of this approach. This regimen deserves further investigation alone or in combination with targeted strategies in patients with dominant liver involvement from breast carcinoma. No significant financial relationships to disclose.

Background. Liver metastasis develops in approximately two-thirds of patients with recurrent uveal melanoma. Despite therapy, the median survival of those with liver metastasis is 5 to 7 months. The recognition of a grave prognosis associated with liver metastasis has led to evaluation of new modalities of therapy, including the use of regional therapies such as intrahepatic arterial chemotherapy and either embolization or chemoembolization of hepatic metastases. In this study, the results of an institutional experience over the past 2 decades are reviewed and prognostic factors that affect survival from the time the liver metastasis is diagnosed are assessed. Methods. In this study of 201 patients with uveal melanoma involving the liver who were treated at M. D. Anderson Cancer Center between 1968 and 1991, the authors retrospectively reviewed the cases and compared the results of systemic therapies, hepatic infra-arterial chemotherapies, and chemoembolization of liver metastases. Cox's multivariate analysis and stepwise logistic regression were then computed to determine significant prognostic variables. Results. The systemic therapies produced a response rate of less than 1%. Chemoembolization was the most effective treatment, inducing responses in 36% of patients. Survival curves were calculated using the life-table method of Kaplan and Meier. Patient-and tumor-related characteristics were examined and their relation to on survival from the time of diagnosis of liver metastasis was determined. Levels of serum alkaline phosphatase, total bilirubin, and lactic dehydrogenase plus response to treatment showed a strong relation to survival. In contrast, univariate analysis showed that patient age and gender, metastasis free interval, presence of extrahepatic metastasis, and type of therapy for liver metastasis did not influence survival. Multivariate stepwise regression analysis identified serum alkaline phosphatase and metastasis free interval as the main independent prognostic factors for survival after liver metastasis diagnosis. Conclusions. Of the three modalities of therapy used for choroidal melanoma metastatic to the liver, only chemoembolization using cisplatin-based regimens produced a meaningful response rate. Information from this analysis can be used to predict the outcome of patients with uveal melanoma metastatic to the liver. Patients with metastatic ocular melanoma confined to the liver should be treated with chemoembolization and should not be included in chemotherapy trials designed for cutaneous melanoma. Cancer 1995; 76:1665–70.

Fifty-two untreated patients with colorectal cancer were randomized to receive 5-fluorouracil (5-FU) alternating either with methotrexate (MTX) or Baker's Antifol (BAF) with or without the immunostimulant, levamisole (Program I). Fifty-five patients who had received prior treatment were randomized to receive methyl-CCNU (Me) with MTX or BAF (Program 11). Fifteen of these patients had failed to respond to initial therapy with 5-FU plus MTX or BAF and subsequently received Me plus the alternate antifol. Overall response rate for each of programs I and I1 was 10%. The responses were 1/11 with 5-FU-MTX plus levamisole, 2/12 with 5-FU-MTX, 1/8 with 5-FU-BAF plus levamisole, 0/8 with 5-FU-BAF, 2/20 with Me-MTX and 2/21 with Me-BAF. The median survival times (MST) for patients receiving Programs I and I1 were 10 and 5 months, respectively. The MST for all patients receiving MTX was significantly longer than that of patients receiving BAF. Survival was not influenced by levamisole administration. Both chemotherapy programs were well tolerated. The sequential administration of 4 active agents failed to improve the results of treatment of colorectal cancer. Cancer 42:2169-2176, 1978.

The current status of treatment for patients with colorectal cancer is suboptimal. Although approximately 80% of patients are amenable to surgery, cure is only possible for 40%. Survival of patients is closely related to disease staging at the time of surgery, being poorer for patients presenting with locally advanced disease or with distant metastases. Patients who undergo curative resections and are categorized as having a high risk of developing recurrence, such as those with regionally involved lymph nodes, should be subjected to studies of adjuvant therapy. Although the definite role of such studies is still under evaluation, there already exist studies of chemotherapy with 5FU, chemoimmunotherapy with 5FU-BCG, and radiation therapy, suggesting the beneficial effect of these treatment modalities based on prolongation of the disease-free interval and survival of patients. The status of available treatments for patients with advanced disease is poor. There exists no single or multidrug regimen capable of producing significant tumor regression to improve the patient's quality of life and survival. Accordingly, the active clinical investigation of newer and potentially effective chemotherapeutic agents should continue. The role of present immunotherapy is not fully determined, although several studies suggest its potential usefulness in the adjuvant and the advanced situations. Serial determinations of CEA are extremely helpful in the postsurgical monitoring of patients receiving adjuvant treatments and also in the follow-up of patients undergoing therapy for overt metastatic disease.

The administration of two chemoimmunotherapy programs to 103 consecutive patients with metastatic colorectal cancer resulted in improved survival for patients who achieved either objective tumor regressions or disease stabilization for more than 8 weeks. Objective tumor regression was observed in 47% of patients treated with the Ftorafur-methyl-CCNU-methotrexate-Bacillus Calmette-Guerin (FTOR-MeM-BCG) program and in 34% of patients treated with the 5-~uorouracil-methotrexate-Baker’s antifol (FU-M-BAF) f Levamisole progra’m. The combined median duration of survival for patients who achieved objective tumor regression and disease stabilization with FTOR-MeM-BCG was 13 months compared with 6 months for patients who had progression of disease (p = 0.001). The corrcsponding values for patients treated with FU-M-BAF f levamisole were 11 months and seven months, respectively (p = 0,001). While the role of BCG immunotherapy in these results remains speculative, the administration of levamisole immunotherapy did not appear to have influenced results significantly. Patients who presented at diagnosis with Dukes A, B and C lesions, and therefore had longer disease-free intervals, responded more frequently to chemoimmunotherapy and survived longer than patients who presented at diagnosis with Dukes D lesions. Similarly, greater antitumor effect was observed in patients with lower pretreatment plasma CEA levels. Evaluation of these pretreatment characteristics may have significant implications for the design of future clinical trials. Canccr 40: 2 73 1 -2 739, 1 9 77.

Inhibition of human lymphoma cell-line colony formation (ICF) was induced by peripheral blood lymphocytes (PBL) from patients with lymphoma and apparently healthy cancer hospital personnel. PBL from patients with non-lymphoma neoplasms and from normal blood bank donors did not elicit ICF. ICF was most marked when PBL were cocultivated for 24 hours in a ratio of 1000:I with target lymphoma cells that had been cultured for 24 hours before exposure. No significant ICF was observed when target cells consisted of human neurogenic sarcoma, melanoma, colon adenocarcinoma, or Chinese hamster cells. It is possible that ICF is elicited by PBL sensitized to a cross-reacting antigen present on the membrane of cultured lymphoma cells. This antigen may be synthesized by a transmissible etiologic factor.

Cisplatin (CDDP) was combined with floxuridine (FUDR) and delivered into the hepatic arteries of 29 patients as induction therapy for colorectal cancer metastatic to the liver. Mitomycin C and FUDR combination was substituted after progression or when response had peaked. Chemotherapy was delivered with an Infusaid pump (Infusaid Corp; Norwood, Mass; 14 patients), Medtronic programmable drug administration device (Medtronic, Inc, Minneapolis; two patients), or percutaneously placed catheters (13 patients). Complete disappearance of liver metastases was observed in four patients and 11 additional patients had a partial remission as determined by computed tomography (CT) scan and substantiated at times by angiography, for a total response rate of 52%. Response as determined by imaging techniques coincided with a concurrent decrease in carcinoembryonic antigen (CEA) and improvement in performance status. The severity of tumor burden was correlated with the response to therapy and survival. Among those patients who responded to arterial chemotherapy, differences in disease severity did not significantly influence survival. Median survival among responders with greater than 25% liver replacement by tumor was 14 months (P = .28), compared with 28 months for those patients with less than 25% liver replacement. In contrast, differences in tumor burden significantly affected survival among patients who failed to respond to chemotherapy; median survival among nonresponding patients with greater than 25% liver replacement was 4 months, compared with 8 months for those who had less than 25% liver replacement (P = .01). The presence of minimal extrahepatic disease at the time of initiation of intraarterial treatment did not seem to have a significant detrimental effect on survival. The study suggests that hepatic tumor response to arterial administration of CDDP and FUDR and mitomycin C and FUDR is clinically significant because it overrides the effect of tumor burden on survival among patients who have colorectal cancer with liver metastases and may offer effective palliation.

83 patients with colorectal carcinoma of the Dukes' C class were randomised to receive postoperative adjuvant therapy with B.C.G. alone or in combination with oral doses of 5-fluorouracil (5-F.U.), and have been followed for up to thirty months. Results were compared with carefully selected historical controls who were treated by surgery alone. A statistically significant prolongation of both disease-free interval and overall survival was observed in 50 patients receiving the combination of B.C.G. and 5-F.U. (P=0.03, P=0.01 respectively) as well as in 33 patients receiving B.C.G. alone (P=0.03, P=0.05 respectively). The efficacy of B.C.G.+5-F.U. was independent of the number of tumour-involved lymph-nodes in the surgical specimen. In contrast, B.C.G. given alone appears to be highly effective among 10 patients with 6 or more positive lymph-nodes (P less than 0.04) and ineffective (as yet) among 23 patients with 5 or less positive lymph-nodes. These results suggest that adjuvant immunotherapy, with or without chemotherapy, can improve the prognosis of surgically treated patients with colorectal carcinoma of the Dukes' C class.

Sixty adult patients with disseminated melanoma refractory to DTIC or Dacarbazine were given chemoimmunotherapy with intermittent high single dose Actinomycin-D and Levamisole. Actinomycin-D was given at a dose of 1.5-2.0 mg/m2 intravenously every 3 to 4 weeks. Levamisole was given in a dose of 150 mg/day for two consecutive days each week (50 patients) and in a dose of 200 mg every other day (10 patients). Antitumor responses consisted of 2% complete remissions (CR), 2% partial remissions (PR), and 33% disease improvement less than PR or stabilization (S). Comparison of these patients who received Actinomycin-D + Levamisole with those on an immediately preceding study in a similar population where Actinomycin-D was given as a single agent revealed no difference in response rates. Patients who responded to Actinomycin-D + Levamisole (CR + PR + S) survived significantly longer (35 weeks) than nonresponders (12 weeks, p less than 0.01). Survival was not longer (p less than .05) in responding patients (CR + PR + S) receiving Actinomycin-D + Levamisole (35 weeks) compared to those responding to Actinomycin-D alone (18 weeks, p = 0.09). Hematologic toxicity was tolerable with median lowest granulocyte counts of 1.6 x 10(3)/microliter and platelet counts of 134,000/microliter. Other toxic effects were predominantly nausea, vomiting, and mucositis. In those patients who received alternate day Levamisole there was greater gastrointestinal upset as well as fever, rash and central nervous system toxicity which was unacceptable.

Tumor-induced blastogenesis was detected in vitro in autologous lymphocytes from 19 of 29 patients with solid tumors. The blastogenic response was dose related, and maximum response required a tumor cell-lymphocyte ratio of 1:1. The intensity of response correlated inversely with the extent of disease. Tumor cells from patients with widespread disease seem to have a lower stimulatory capacity regardless of their site of origin (primary or metastatic lesion). The effect of serum from cancer patients on the blastogenic response was mostly nonspecific, and could be both inhibitory or facilitory. It did not correlate with the extent of disease.

Eighty-nine patients with disseminated malignant melanoma were treated with a combination of dimethyl triazeno imidazole carboxamide (DTIC) administered intravenously and bacillus Calmette–Guerin (BCG) administered by scarification. The results were compared to those in a comparable retrospective group of 111 patients treated with DTIC alone. Metastatic areas regional to BCG immunization showed an augmented response to chemotherapy. Thus, chemoimmunotherapy-treated patients with lymph-node metastasis had a remission rate of 55 per cent compared to one of 18 per cent for patients treated with chemotherapy alone (p = 0.025). The duration of remissions and survival was significantly longer for patients (both nonvisceral and visceral metastases) treated with chemoimmunotherapy than for those treated with chemotherapy alone (p = 0.05, 0.001, respectively). A good prognosis was associated with immunocompetence before treatment or an increase in immunocompetence during treatment. Chemoimmunotherapy was ...

The local xenogeneic graft-versus-host reaction (GVHR) assay has been used clinically to evaluate cellular immune competence and experimentally to monitor the immunomodulatory effects of several drugs. By employing a computerized radioisotope imaging (CRI) technique, we were able to perform the assay with smaller numbers of mononuclear cells (MNC) and to rid it entirely of any bias. Measuring the local GVHR by CRI compares well with the conventional measurement of the volume (correlation coefficient r = 0.619; P less than 0.001). A clear-cut distinction was documented between normal donors and cancer patients (P less than 0.001) when 10 X 10(6) or more MNC were used in the assay. This is an improvement over the previous, conventional testing of local GVHR which required injection of 20 X 10(6) MNC in order to achieve a similar resolution. The indications for the presence of immune competence have therefore been redefined using the local GVHR index as determined by CRI according to the scale of MNC injected. Thus, immunocompetence is considered present if the CRI index is greater than or equal to 1.2 for 10 X 10(6) MNC, greater than or equal to 2.0 for 15 X 10(6) MNC and greater than or equal to 2.6 for 20 X 10(6) MNC.

Immunological factors are involved in all aspects of the lymphomas and leukaemias. The aetiology of these diseases is related at least in some cases to immunodeficiency, immunostimulation, autoimmunity and a dysregulation of the immune system. The majority of lymphomas and leukaemias are monoclonal proliferations of the B-lymphocyte series at different stages of maturation while some are derived from T lymphocytes and others have no recognisable B or T-cell markers. Each of the lymphoid malignancies has a characteristic and unique pattern of immunological deficiency, suggesting a unique aetiology. Hodgkin's disease and histiocytic lymphoma, the acute leukaemias and chronic myelogenous leukaemia have predominantly cell-mediated immune deficiencies, while lymphocytic lymphoma, chronic lymphocytic leukaemia, multiple myeloma, and the plasma cell dyscrasias have predominantly humoral immune deficiencies. There is a relationship between immunocompetence and prognosis and between immunocompetence and extent of disease in the lymphomas and leukaemias. Immunocompetent patients have a better prognosis and more limited disease than immunoincompetent patients. Therapy for these diseases profoundly suppresses host defence mechanisms, particularly those which are cell-mediated. Ability to resist or recover from this immunosuppression is also associated with an improved prognosis. Lymphoma and leukaemia also induce a tumour-specific immune response in the tumour-bearing host and this also correlates with prognosis. These factors form a rational basis for immunotherapy and indeed lymphomas and leukaemias respond to active nonspecific immunotherapy with BCG and active specific immunotherapy with tumor cells resulting in prolongation of remission duration and survival.

A study was conducted to determine some of the potential applications of a human leukocyte culture supernatant or “lymphokine” preparation in cancer patients. The application evaluated in this study was the use of this preparation as a skin test reagent for evaluation of the inflammatory response following intradermal injection. The preparation was derived from the supernatant of a long-term cultured lymphoblastoid cell line with migration inhibition factor (MIF) and other lymphokine activities. Dose response, histology and toxicity studies were done in 53 patients with malignant melanoma stage IIIB and IV. A dose response curve was observed for both erythema and induration at 12 and 24 hours, but not at 48 hours. An optimal intradermal dose for eliciting inflammation was determined and found to be five units. Histopathological evaluation of biopsy specimens showed a mixed cell reaction including granulocytes, eosinophils, lymphocytes and monocytes differing in lymphocyte content from the classical delayed type hypersensitivity (DTH) reaction in man. Compared with the response to recall antigens, only a weak correlation with the DTH response to the recall antigens was found. Our results support the conclusion that lymphokines may be used in the future to evaluate the ability to develop nonspecific inflammation in cancer patients, and that this inflammatory response can be obtained in a number of patients no longer capable of responding to recall antigens.

The response rate of metastatic colorectal carcinoma confined to the liver to HAI of FUDR alone is at the range of 50% and to mitomycin C by hepatic arterial infusion (HAI) at the range of 35%. Mitomycin C was added to FUDR by continuous infusion and given by HAI to 12 patients with colorectal cancer confined to the liver. Catheters were placed subselectively in the hepatic artery, and infusion continued for five to six days when the catheter was removed. Cycles were repeated every 30 days. Chemotherapy consisted of mitomycin C 15 mg/m2 administered on day 1 followed by FUDR 100 mg/m2 by continuous infusion daily for five days. Response to treatment was evaluated by serial determinations of plasma CEA and by imaging techniques consisting of a computerized tomography, sonography, and radionuclide scanning of liver as well as by angiography. In 2 patients, complete remission was achieved; in 4 patients a 75% and in another 4 patients a 50% decrease in liver metastasis was observed, while 2 patients had stable disease. Thus, a response rate of 83% with a median duration of six to seven months was achieved. The median survival of the these patients was 16 months. Eight of the 12 patients have failed previous, i.v. 5-FU containing regimens. Complications related to 45 treatment cycles were the following: catheter displacement in 11.1%, an intimal tear, usually in the hepatic artery in 4.4%, gastric ulcerations in 5.4%, and septicemia in 2.7% of the cycles. In addition, aneurysmal dilation of the hepatic artery occurred in 4 patients (8.8% of the treatment cycles), all of whom continued treatment. Chemotherapy-related complications included primarily thrombocytopenia and stomatitis. Mitomycin C + FUDR by hepatic arterial infusion is an effective treatment for colorectal carcinoma metastatic to the liver. The high response rate justifies the adjuvant treatment of Dukes class C colon cancer patients with this treatment.

SummaryA rapid method for the establishment of short-term primary cultures of human tumor cells obtained from fresh surgical biopsies is described. The method consists of the separation of the viable fraction of tumor cells by differential flotation on ficoll-hypaque density solution and its subsequent seeding into culture flasks. Tumor cell growth is established within 2–3 days. The incidence of overgrowth with fibroblasts is apparently reduced and usually delayed for 4–5 weeks, but cannot be prevented by this method.This study was supported by Grant NOI-CB-33888 from the National Cancer Institute, Bethesda, Maryland 20014. Dr. Mavligit and Gutterman are the recipients of Career Development Awards (I KO4 CA 00130 and 5 KO4 CA 71007, respectively) from the Department of Health, Education, and Welfare, National Institutes of Health, Bethesda, Maryland 20014.

The in vitro blastogenic responses of lymphocytes from peripheral blood leukocytes (PBL) and lymph-node leukocytes (LNL) of cancer patients were examined simultaneously in paired studies. The lymph nodes were obtained at the time of surgical tumor extirpation from the area draining or adjacent to the tumor, but were determined to be tumor-free. There was an inverse relationship between the responses of PBL and LNL to tumor cells (TC). In those subjects where the PBL responses to TC were positive (stimulation index >3), the responses of LNL were usually negative and significantly lower. In those subjects where the LNL responses to TC were positive, the PBL responses were usually negative and significantly lower. A positive response by LNL to TC correlated with a significantly higher mixed lymphocyte culture response among LNL than among PBL. There was no correlation of these responses to TC with the PBL or LNL responses to phytohemagglutinin. There was a trend for the PBL response to TC to be higher than that of the LNL in patients with gastrointestinal cancer and melanoma and lower than that of LNL in patients with breast and squamous cell carcinoma. Stage of disease and age also influenced these results.

The effect of a single high dose of Levamisole (200 mg/M2) on delayed-type hypersensitivity (DTH) in vivo and on lymphocyte blastogenesis to mitogens and antigens in vitro was studied in 26 patients with carcinoma. Similar studies were conducted in 24 control patients. Levamisole had a moderate but significant enhancing effect on DTH to Dermatophytin detectable no earlier than eight hours and still present at 48 hours after the drug administration. A moderate but significant enhancing effect on lymphocyte blastogenesis to mitogens and antigens was also demonstrated during the same time sequence. Further clinical trials with Levamisole should be conducted with more attention paid to schedule of drug administration.

Summary Five severely immunocompromised patients with progressive mucocutaneous manifestations of culture-proven herpes simplex virus infection were treated with cimetidine—1200 mg per day by mouth (four patients) or by i.v. infusion (one patient). Treatment resulted in rapid improvement as evidenced by decreased local pain and crusting of lesions within 24–48 h. Complete resolution was observed within 3–13 days. These encouraging, albeit preliminary, findings suggest that cimetidine warrants further, large-scale trials in patients with herpes virus infections.

The immunorestorative effect of Isoprinosine (ISO) in vivo on T-cell-induced local graft-versus-host reaction (GVHR) was analyzed in 60 cancer patients randomized into three groups: 20 patients received 1 g/day ISO orally for 7 days, 20 patients received 4 g/day ISO for 7 days, and 20 patients received no treatment for 7 days. The local GVHR was assessed before and after the 7 days of treatment (or no treatment). A significant augmentation of the local GVHR was observed among the ISO-treated patients (44.1 +/- 19.1 vs 61 +/- 37.1 for 1 g ISO, P less than 0.05; 42.1 +/- 20.1 vs 58.9 +/- 23.8 for 4 g of ISO, P less than 0.01). This was not so for patients who received no treatment (38.5 +/- 20.4 vs 38.3 +/- 21.2; P greater than 0.1). Nine patients treated with 1 g of ISO and 5 treated with 4 g of ISO/day, who were initially characterized by a negative local GVHR (less than 50 mm3), converted to a positive reaction (greater than or equal to 50 mm3) compared to none of the patients who received no treatment. Two patients treated with 1 g of ISO and 2 patients treated with 4 g, who initially had a positive GVHR, demonstrated further augmentation (greater than or equal to 50% increase) in the GVHR after 7 days of treatment. In 2 patients (one in each treated group) the ISO induced a suppression of the GVHR from positive to negative. Incubation of the patients' lymphocytes in vitro with ISO (100 micrograms/ml X 1 hr) failed to induce augmentation of the GVHR and did not correlate with the in vivo effect in the same patients. These results demonstrate an immunomodulatory effect of ISO in cancer patients and lend further support to the use of this drug as an immunomodulating therapy among cancer patients.

Twenty-one patients with inoperable colon cancer in the pelvis were treated with intra-arterial 5-fluorouracil (5-FU) and mitomycin C, given bilaterally into the internal iliac arteries. Seventeen of the 21 patients had failed previous radiation therapy and 15 had also failed systemic intravenous chemotherapy. Eighteen of the 21 patients received intra-arterial treatments because of pelvic pain. Effect of this treatment on the pain could be evaluated in 16 patients. A measurable decrease in pain medication occurred in 8 of 16, whereas a subjective feeling of pain relief was observed in 12 of 16 patients for a mean period of 3.5 months. However, objective tumor response was considered definite only if associated with a greater than 50% decline of an elevated plasma carcinoembryonic antigen level; this was observed in 5 of 11 patients (45%). Reduction in tumor mass as measured by imaging techniques was observed in two of ten patients in whom it was evaluable. Improvement in hydronephrosis was observed in five of seven evaluable patients. Hematuria was present in 12 patients and improved in 10 of those patients. The most significant side effect of chemotherapy was perineal and gluteal skin erythema, which was observed in 36% of the patients after the first course and in 24% during the second course. This frequently escalated to cutaneous vesiculation and desquamation. This side effect was prevented by concurrent administration of steroids. Pelvic arterial infusion of 5-FU and mitomycin C can offer temporary pain relief to patients who have failed other means of therapy. Objective antitumor effects may have also resulted but were much harder to assess in this group of patients.

Thirty-five patients with malignant brain tumors (23 with primary brain tumors and 12 with brain metastases) progressing after cranial irradiation +/- chemotherapy received cisplatin, 60 to 120 mg/m2, into the internal carotid artery by a transfemoral approach. Courses of therapy were repeated every 4 weeks. Therapeutic evaluation was performed monthly using the CT scan of the brain and clinical neurologic examination. Thirty patients were evaluable for response. Of 20 evaluable patients with primary malignant brain tumors, 6 responded to therapy and 5 had stable disease. The median time to tumor progression for responding patients was 33 weeks, for stable patients 16 weeks, and 13 weeks for all patients. Five of 10 evaluable patients with brain metastases responded to intracarotid cisplatin, and 2 patients had stable disease. The estimated median time to progression for responding patients was 30+ weeks and 12+ weeks for patients with stable disease. Side effects included seizures in 5 courses, mental agitation and motor restlessness in 1, and transient hemiparesis in 7. One patient may have had a drug-related death, and one patient appeared to develop encephalopathy after treatment. Five patients had clinical deterioration in vision; in two patients it was bilateral. Intracarotid cisplatin has definite activity in patients with malignant primary brain tumors and in patients with brain metastases. The recommended starting dose for intracarotid cisplatin is 60 to 75 mg/m2. At this dose level side effects are uncommon, but includes the risk of neurologic and retinal toxicity.

Twenty patients with colon cancer metastatic to the liver underwent successful hepatic resection and adjuvant perioperative therapy that included hepatic arterial mitomycin C and floxuridine (FUDR). The median survival for all 20 patients was 51 months: 10 are still alive with a median postoperative follow-up of 49 months; 6 are disease-free with a median postoperative follow-up of 43 months. Among 10 patients in whom the surgical margins of the specimen contained tumor cells, the median survival was 52 months. This survival was comparable to that among 10 patients in whom the surgical margins were tumor free (P = 0.22). Neither the number of metastatic liver deposits nor the disease-free interval between the primary diagnosis of colorectal carcinoma and the development of liver metastases significantly affected survival. A transient chemical hepatitis which resolved before the next scheduled treatment was associated with 50% of arterial chemotherapy cycles (approximately 70% of the patients). Gastric or duodenal ulcerations occurred in 23% of the patients. Surgical complications were either pulmonary such as pleural effusion or atelectasis, or wound infections and subphrenic abscesses. Although these results compare favorably with the results in previously published series, this aggressive adjuvant chemotherapy appears to be particularly justified in patients with tumor positive surgical margins or those with multiple tumor masses and, therefore, are characterized by a poor prognosis.

The rapidly emerging therapeutic modality of cancer immunotherapy has been applied to a carefully selected group of patients with carcinoma of the large bowel. Patient selection was based on the extent of disease at the time of definitive surgery, and the strict provision that all discernible disease was removed. Thus, 20 consecutive patients who had mesenteric lymph node involvement were subsequently allocated to receive either BCG alone or the combination of 5-FU plus BCG as adjuvant treatment to surgery. After 10 months of patient accrual, all patients were clinically free of disease. Therapy was well tolerated without significant morbidity. Although general immunocompetence of these patients has improved on treatment, it is still too early to say whether immunotherapy will be clinically beneficial. Serial determination of plasma levels of CEA was useful in ruling out suspected recurrent disease. In contrast, preoperative plasma levels of CEA in patients with Dukes' C classification were elevated in only 40%. This indicates that its value in establishing the primary diagnosis is still doubtful.

The poor postsurgical prognosis in patients with colorectal cancer of the Dukes' C classification has prompted a clinical trial of adjuvant immunotherapy versus chemoimmunotherapy intended to prolong either the disease-free interval or the overall survival or both. One hundred and twenty-one patients have been entered on this study. Fifty-two patients received BCG alone and 69 patients received the combination of 5-FU and BCG. The disease-free interval and the overall survival were compared with similar parameters in a group of historical controls with similar prognostic characteristics who were operated on in our institution prior to the initiation of the current study. There was no difference as yet between BCG alone and the combination of 5-FU + BCG in terms of both the disease-free interval and the survival. Both treatments, however, had significantly better results than the surgical controls. Adjuvant therapy, especially with BCG is advocated for patients with colorectal carcinoma, Dukes' C class, following potentially curative surgery.

Forty-five patients with disseminated breast cancer were given a trial of combination chemotherapy consisting of fluorouracil, adriamycin, and cyclophosphamide (FAC) and immunotherapy with BCG given by scarification. The results were compared with those in a comparable group of 44 patients treated with FAC alone immediately before the chemoimmunotherapy study. The remission rates (73% and 76% for FAC and FAC-BCG respectively) were similar in both studies. The durations of remission for patients on FAC-BCG (medium 12 months) were longer than remissions achieved for patients given FAC alone (median 8 months) (P = 0.068). The most notable effect of BCG was on survival. Thus 21 out of 34 patients achieving remission on FAC-BCG were alive at the time of the last follow-up examination (median over 22 months) compared with 11 out of 32 patients achieving remission on FAC (median 15 months) (P = 0.01). Twenty-six of the 45 patients given FAC-BCG were alive at the time of the last follow-up examination (median over 22 months) compared with 12 of the 44 patients given FAC (median 15 months) (P = 0.005). Although the apparent benefit of BCG could be explained by a maldistribution of some prognostic factors, the data suggest that further trial of chemoimmunotherapy of breast cancer should be carried out.

The data reviewed in this paper indicate that immunotherapy is effective in prolonging remission and survival in acute and chronic leukemia. The acute lymphocytic leukemias may or may not respond to immunotherapy and further work is needed in this area. No studies of immunotherapy in chronic lymphocytic leukemia have been done, but this will be an important area for investigation, since there is often profound immunodeficiency in this disease. The malignant lymphomas are another fertile area for this type of research, since they have a high response rate, tumor-associated immunodeficiency, and at least differentiation antigens if not tumor-specific antigens. The scientific basis for the use of immunotherapy in leukemia includes the demonstration of a relationship of rate and duration of remission and survival to immunocompetence, the demonstration of unique tumor-associated antigens on leukemia cells, and the demonstration of immune responses to these antigens which can be boosted by immunization. At the present time, active nonspecific immunotherapy with BCG and MER and active specific immunotherapy have been proved effective in acute myelogenous leukemia. Careful attention should be given to dose, schedule, route, and so forth. Other types of immunotherapy remain to be explored.