CA 125: a clinically useful tumor marker in the management of colorectal carcinoma metastatic to the liver in patients with normal carcinoembryonic antigen.

Two patients with colon carcinoma metastatic to the liver had normal plasma carcinoembryonic antigen (CEA) levels (<1.0 ng/ml) but elevated CA 125 levels. Treatment of the metastatic disease with chemotherapy, plus surgery in one case, led to declines in the CA 125 levels. These decreases were associated with tumor regression, as confirmed by clinical and radiologic evidence. These findings lead us to conclude that the measurement of CA 125 for patients with normal CEA levels is useful in the management of colorectal carcinoma.

Secondary drug resistance in breast cancer: failure to reverse with oral nifedipine.

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 < or = 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.

A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix.

A Phase I study of the novel angiogenesis inhibitor TNP-470 was performed. Patients with inoperable recurring or metastatic squamous cell cancer of the cervix with evaluable disease, no coagulopathy, and adequate renal, hepatic, and hematological function were eligible. One course of treatment consisted of an i.v. infusion of TNP-470 over 60 min every other day for 28 days, followed by a 14-day rest period. The starting dose was 9.3 mg/m2. Eighteen evaluable patients were treated, with a median age of 48 years (range 27-55) and performance status Zubrod 1 (range 0-2). Grade 3 neurotoxicities consisting of weakness, nystagmus, diplopia, and ataxia were encountered in two patients receiving the 71.2 mg/m2 dose. An intermediate dose level of 60 mg/m2 was evaluated and found to be well tolerated by three patients. Only one patient experienced grade 3 nausea on the 60 mg/m2 dose level. No myelosuppression, retinal hemorrhage, weight loss, or significant alopecia were observed. One patient had a complete response, which continues for 26 months, and three patients with initially progressive disease stage had stable disease for 5, 7.7, and 19+ months. Other Phase I studies, including over 200 patients, were performed concurrently with this study. Based on this experience, the dose of TNP-470 recommended for further studies is 60 mg/m2 as a 60-min i.v. infusion every Monday, Wednesday, and Friday. Neurotoxicity was dose limiting, but appears to be reversible. Otherwise, the treatment was well tolerated. The drug may be active in squamous cell cancer of the cervix. Further studies of TNP-470 in squamous cell cancer of the cervix are warranted.

Treatment of uveal melanoma metastatic to the liver: a review of the M. D. Anderson Cancer Center experience and prognostic factors.

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 restrospectively reviewed the cases and compared the results of systemic therapies, hepatic intra-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.

Elevated plasma thrombopoietic activity in patients with metastatic cancer-related thrombocytosis.

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-mI) 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, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and IL-1 beta protein using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Expression of platelet-specific cell-surface 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-1 beta and IL-3 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.

Hepatic arterial infusion of recombinant platelet factor-4 suppresses metastases to the lungs from tumors implanted into the livers of rabbits.

BACKGROUND: This study evaluated the toxicity (Part I) and antitumor effects (Part II) associated with hepatic arterial infusion of recombinant platelet factor-4 (rPF4), an antiangiogenic protein. METHODS: Healthy rabbits (Part I) and rabbits with tumors implanted in their livers (Part II) received saline or rPF4 via hepatic arterial infusion. Three saline-receiving and four rPF4-receiving animals died 2-3 days postinfusion from gastroduodenal thromboembolism. The remaining animals were necropsied 3, 7, 10, or 14 days postinfusion. Blood analyses and hepatic angiography were performed before infusion and at the time of sacrifice. RESULTS: In Part I, focal coagulation necrosis of the hepatic parenchyma was observed in 1 of 11 rabbits that received saline and in 6 of 10 that received rPF4. In Part II, hepatic arterial infusion of rPF4 had no effect on growth of the implanted liver tumors. However, the protein significantly reduced the incidence of lung metastasis. CONCLUSIONS: Intraarterial infusion of rPF4 significantly reduced the incidence of lung metastasis. Nonheparin systemic anticoagulation may be needed during catheterization and infusion procedures to prevent thromboemboli.

Gastrointestinal leiomyosarcoma metastatic to the liver. Durable tumor regression by hepatic chemoembolization infusion with cisplatin and vinblastine.

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/m2). 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.

Durable hepatic tumor regression after arterial chemoembolization-infusion in patients with islet cell carcinoma of the pancreas metastatic to the liver.

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.

Regional biologic therapy. Hepatic arterial infusion of recombinant human tumor necrosis factor in patients with liver metastases.

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.

The prevalence and location of metastases from ocular melanoma: imaging study in 110 patients.

Ocular melanoma is characterized by an unpredictable clinical course, during which fulminant metastatic disease may occur after a prolonged disease-free interval. The purpose of this study was to determine the pattern of metastatic involvement in this disease. The clinical and radiologic findings in 110 patients with metastatic ocular melanoma were reviewed. The 54 men and 56 women were 24-79 years old (mean, 50 years) when the primary tumor was first diagnosed. Metastases were present in three patients at the time of first diagnosis and occurred in 107 patients 2 months to 36 years later (mean, 52 months). One hundred five patients died between 1 and 38 months after the onset of metastatic disease. Hepatic metastases developed in 101 patients (92%), and in 60 (55%) of these, the liver was the only organ involved initially. Pulmonary parenchymal metastases developed in 34 patients (31%), but in only four of them were metastases confined to the lungs. Twenty-five patients (23%) had bone involvement, mostly affecting the spine. Nineteen patients (17%) had skin or subcutaneous metastases, but in only two of them was this the initial finding. Nodal involvement was shown in 15 patients (14%), almost always associated with extensive hepatic metastases. Brain and adrenal metastases were seen in five and three patients, respectively. Hepatic involvement occurs in almost all patients who develop metastatic ocular melanoma, and the liver is the most common initial site of metastatic involvement. Metastases may develop after a long disease-free interval.

Arterial chemotherapy in the management of colorectal cancer: an overview.

We have discussed the role of arterial therapy in patients with various stages and types of colon cancer. Arterial therapy is probably not useful as an adjuvant therapy for Dukes' C colon cancer. It may, however, play a role among patients with incomplete resection of liver metastases (positive margins). A randomized trial is needed to determine the role of arterial therapy in patients who have undergone complete resection of liver metastasis. Arterial therapy does not seem justified for patients with recurrent pelvic tumors. For nonresectable liver metastases, hepatic arterial therapy induces a higher response rate than does intravenous treatment. It may also improve performance status and offer additional palliation to patients who have failed systemic chemotherapy. are refractory to systemic chemotherapy may be candidates for palliative hepatic arterial chemotherapy even out of the context of a clinical trial. Asymptomatic patients with nonresectable liver metastasis who are refractory to systemic chemotherapy should be enrolled in phase I-II arterial chemotherapy trials designed to identify optimal treatment regimens. Previously untreated asymptomatic patients wishing treatment may be enrolled in a new multi-institutional phase III trial being designed to compare contemporary systemic chemotherapy with less toxic arterial therapy and combined arterial and systemic therapy. Such a new trial will have to avoid any cross-over between arms to determine the true impact of arterial therapy on survival. Regional arterial chemotherapy tries to extract the "extra mile" from marginally active drugs that have a steep dose response curve by increasing tumor drug exposure. Increased drug concentrations in the tumor may be accomplished by means of the blood vessel-to-tumor concentration gradient. The technology to achieve such a gradient has involved percutaneous hepatic arterial catheters, implantable infusion pumps or ports, and external pumps. The most economic hepatic arterial delivery system for protracted arterial FUdR is an infusion pump. Despite good pharmacological rationale, an improved response rate, and good evidence for effective palliation in advanced disease, hepatic arterial therapy has not improved survival when compared with systematic intravenous treatment. Possible explanations include the following: (1) poor study design that allowed patients to cross over between arms: (2) inadequate arterial chemotherapy combination; (3) inadequate arterial chemotherapy schedule; (4) hepatobiliary toxicity levels that required cessation of hepatic arterial therapy and allowed the emergence of resistant tumor clones; and (5) systemic progression of disease. Only time will tell whether improved chemotherapy and the design of a new phase III trial will establish a beneficial role for upfront hepatic arterial therapy in asymptomatic patients with colon cancer metastatic to the liver.

Regression of hepatic metastases from gastrointestinal leiomyosarcoma after hepatic arterial chemoembolization.

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.

Severe, symptomatic, dose-limiting hypophosphatemia induced by hepatic arterial infusion of recombinant tumor necrosis factor in patients with liver metastases.

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.

Increased incidence of hypersensitivity to iodine-containing radiographic contrast media after interleukin-2 administration.

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).

Splenic versus hepatic artery infusion of interleukin-2 in patients with liver metastases.

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.

[F3, a fractionated extract of Astragalus membranaceus, potentiates lymphokine-activated killer cell cytotoxicity generated by low-dose recombinant interleukin-2].

Success with rIL-2 immunotherapy of human cancer appears to depend on the administration of high doses which are frequently associated with excessive toxicity. Future use of rIL-2 will require certain modifications based on the use of lower doses of rIL-2 without significant loss of antitumor efficacy. The authors tested in vitro the possibility of potentiating the activity of rIL-2 in terms of LAK cell generation. The authors hypothesized that co-incubation of LAK cell precursors with a Chinese herbal extract (F3) of Astragalus membranaceus (an immune modulator currently under study in the authors' laboratory), along with a low concentration of rIL-2 would generate levels of LAK cell activity equivalent to those generated by high concentrations of rIL-2 alone. The authors found: (1) a 10-fold potentiation of rIL-2 activity manifested by tumor cell killing activity of 80% resulting from LAK cell generation with F3 plus 100 u/ml of rIL-2 versus 76% generated by 1000 u/ml of rIL-2 alone; (2) a significant reduction in the number of effector LAK cells required for equicytotoxic reaction following LAK cell generation with F3 plus rIL-2 compared to rIL-2 alone. The authors conclude that potentiation of antitumor activity mediated by rIL-2 in low concentrations is possible by the concomitant use of another immune modulator such as Astragalus membranaceus.

Hepatic arterial infusion of human recombinant tumor necrosis factor-alpha. An experimental study in dogs.

Local and systemic toxicities associated with hepatic arterial infusion of human recombinant tumor necrosis factor (rTNF) were studied in healthy adult mongrel dogs. The animals received saline containing human serum albumin with or without rTNF (0.02, 0.2, or 2.0 mg/m2). Arteriograms were made, and blood samples were collected for hematologic and biochemical analyses at regular intervals. The dogs were killed at 1, 3, and 7 days postinfusion and complete necropsies were performed. Specimens were obtained from various tissues for histopathologic evaluation. Results indicated that all but the highest dose of rTNF were well tolerated. Severe histopathologic changes were found in the liver, spleen, and kidneys of the animals receiving 2.0 mg/m2 rTNF. In addition, focal tubular degeneration was found in one dog administered 0.2 mg/m2 rTNF. These data suggest that the upper dose limit for hepatic arterial infusion of rTNF is between 0.2 and 2.0 mg/m2 and that renal function should be closely monitored after infusion.

Interferon-induced organic mental disorders associated with unsuspected pre-existing neurologic abnormalities.

Eleven patients ranging in age from 52 to 80 years, undergoing treatment for cancer with various preparations of interferon received neurobehavioral evaluations after experiencing unexpectedly severe organic mental disorders. The reactions ranged from delirium to extrapyramidal symptoms, mania, and neurasthenia with catatonic episodes. Computed tomographic (CT) scans of the brain disclosed unsuspected pre-existing neurologic abnormalities in all patients, including cerebral atrophy (6/11), brain metastases (4/11), and evidence of head injury incurred 40 years earlier (1/11). These findings suggest that cancer patients with pre-existing neurologic dysfunctions are at increased risk for severe interferon neurotoxicity.

Regression of ocular melanoma metastatic to the liver after hepatic arterial chemoembolization with cisplatin and polyvinyl sponge.

Thirty patients with ocular melanoma metastatic to the liver were treated by hepatic arterial chemoembolization using an admixture of cisplatin and polyvinyl sponge. Tumor regression was complete in one patient and partial (greater than 50%) in 13 patients. The total response rate was 46%. The median survival for the entire group was 11 months (95% confidence interval, nine to 18 months). Treatment-related morbidity was short-lived and included primarily severe upper right quadrant abdominal pain, transient paralytic ileus, and nonicteric hepatitis. Hepatic arterial chemoembolization provided effective palliation, with good-quality survival among 46% of patients with ocular melanoma metastatic to the liver.