Advanced Malignant Disease Research Articles

Efficacy and pharmacokinetics of a new controlled-release morphine sulfate 200-mg tablet

Nineteen of 25 patients (14 female) with advanced malignant disease completed a randomized controlled trial of a new high-dose (200 mg) tablet formulation of controlled-release morphine. Compared with the currently available 100-mg tablets there were no differences in pain severity or adverse effects with the new formulation.. In four patients, full 12-hr plasma morphine concentration profiles at steady state were obtained and showed no significant differences between the same dose provided as 100-mg and 200-mg tablets in C max , t max , or other pharmacokinetic indices.

Corticosteroids and peptic ulceration

The relationship between corticosteroids and peptic ulceration, together with the major complications of gastrointestinal haemorrhage and perforation, remains an area of clinical concern. This paper reviews the literature regarding peptic ulceration and corticosteroids. Risk factors related to an increased incidence of peptic ulceration in patients prescribed corticosteroids are discussed. These include: total dose of corticosteroid, previous history of peptic ulceration, advanced malignant disease and concurrent prescribing of nonsteroidal anti-inflammatory drugs (NSAIDs). It is suggested that prophylaxis should be considered for those patients with two or more risk factors. Choice and efficacy of prophylaxis is also considered.

Phase I Trial of Combined Recombinant Interleukin-2 with Levamisole in Patients with Advanced Malignant Disease

A Phase I study of rIL-2 and levamisole was performed to evaluate the activity, toxicity, and effect on immune parameters of this combination of agents in patients with advanced malignancy. Twelve patients with advanced cancer were included and begun on therapy with rIL-2, 1 x 10(6) U/m2 subcutaneously (SQ) daily for 5 days and levamisole beginning at 25 mg/m2 orally three times daily for 5 days. The dose of levamisole was increased to 50 mg/m2 thrice daily during this study. Immune parameter analysis included the percentages of lymphocyte subsets in peripheral blood, cellular cytotoxicity assays versus K562 and Daudi cells, and lymphocyte blastogenesis to the recall antigens tetanus toxoid and Candida albicans. The dose-limiting toxicities were pruritus, nausea, and facial edema. There were no indications of significant hematologic or hepatorenal toxicities. No patient fulfilled the traditional criteria for an objective response. In 8 of 9 patients with immune parameter data available there was an increase in cellular cytotoxicity and in the percentage of lymphocytes with the natural killer phenotype (CD3-, CD16/56+). This regimen can be given as an outpatient with acceptable toxicity. For Phase II investigations the doses of rIL-2, 1 x 10(6) U/m2 SQ daily x 5 days and levamisole, 50 mg/m2 three times daily x 5 days is recommended.

Electron beam intraoperative radiation therapy for pediatric neoplasms.

Intraoperative radiation therapy (IORT) has potential advantages over conventional external beam radiation in that a single large dose is delivered to the tumor and its regional bed at the time of surgical exploration. The therapeutic ratio is enhanced by direct tumor visualization, precise treatment volume, and exclusion of normal organs. In childhood, local tumor control is critical for lesions that cannot be totally excised or residual disease not ablated by systemic therapy. During the past decade, the authors evaluated IORT in pediatric patients with unresectable or recurrent tumors. Fifty-nine patients were treated, 48 for advanced malignant disease and 11 for histologically benign but locally aggressive tumors. Sixty-four operations were performed, during which 84 separate radiation fields were used. High energy electrons at 5-11 MeV were delivered at a dose of 1000-1700 cGy to a tissue depth of 0.5-3 cm. Of 25 children with advanced neuroblastoma, 15 were alive 14-104 months (mean, 51 months) after treatment. The survival of all patients with solid malignancies was 63%. Local tumor control was achieved in 75% of children with cancer and 91% of those with benign tumors. Complications of IORT at the doses used were trivial. Electron beam therapy can be safely and efficiently delivered to young patients during operations intended to treat the primary tumor. The outcome achieved for overall survival and local control of the primary tumor is encouraging, and an acceptable complication rate during intermediate to long-term follow-up has been noted.

Octreotide in relieving gastrointestinal symptoms due to bowel obstruction.

Gastrointestinal obstruction is a common problem in advanced malignant disease, but its management remains controversial. In those patients for whom surgery is not appropriate, medical intervention is the only remaining option. We present a series of 14 patients with intestinal obstruction who were managed with subcutaneous injections of octreotide, a somatostatin analogue which reduces the volume of gastrointestinal secretions. Good control of vomiting was achieved in 12 patients, and no major side effects were observed. Octreotide would appear to be a useful drug in this clinical situation.

Importance of Serum Sialic Acid and Lactate Dehydrogenase in Diagnosis and Treatment Monitoring of Cervical Cancer Patients

In an attempt to establish a blood-based biochemical index for diagnosis of cervical cancer and treatment monitoring of patients suffering from the disease, serum levels of total sialic acid (TSA), lipid-bound sialic acid (LSA), and lactate dehydrogenase were estimated by highly specific spectrophotometric methods. Serum concentrations of the markers in 108 untreated cervical cancer patients were compared with the levels of the biomarkers in 125 healthy, age-matched female individuals (controls). The alterations in serum levels of the markers after radiotherapy in cervical cancer patients were also observed. The levels of all markers were significantly higher (P < 0.001) in untreated cervical cancer patients compared to the controls. TSA was found to be the most sensitive (90.74%) marker for diagnosis of cervical cancer. Combined use of the markers revealed maximum (100%) sensitivity. In comparison between early (stage I + II) and advanced (stage III + IV) malignant disease, the markers showed insignificant changes. TSA and LSA values in patients who did not respond to radiotherapy were significantly higher (P < 0.05 and P < 0.001, respectively) than those of the responders. The results suggest that combined evaluation of the markers is helpful for diagnosis as well as for treatment monitoring of cervical carcinoma patients.

Upper limb venous gangrene, a lethal condition

Venous gangrene of the upper extremity is rare. It was the mode of presentation in a 41-year-old woman who died 10 days later of heart failure due to acute myocardial infarction. There is evidence from this and previous publications that patients with this condition tend to have characteristics in common. Most have either advanced malignant disease or seriously impaired myocardial function and venous gangrene usually occurs as a pre-terminal event. Treatment should be directed primarily at the underlying illness but there may be a case for early amputation if permitted by the general condition of the patient.

Flavone acetic acid (FAA) with recombinant interleukin-2 (rIL-2) in advanced malignant melanoma. IV: Pharmacokinetics and toxicity of flavone acetic acid and its metabolites.

Flavone acetic acid (FAA) was administered at a dose of 4.8 g m-2 over 1 h to patients with advanced malignant disease in combination with Interleukin II. A new high performance liquid chromatography method is described to determine both the parent compound and eight drug-related products, and the conditions required to determine these components in plasma are discussed. The half-life over the first 8 h was 2.3 h, but the terminal clearance of the drug was extremely slow. Severe (WHO Grade 4) hypotension was observed in some patients. However, incidence of this did not appear to be associated with any differences in FAA plasma concentrations, nor were there differences in FAA clearance between those patients whose tumour responded to the drug combination and those who did not.

A double blind placebo controlled trial of medroxyprogesterone acetate (MPA) in cancer cachexia

Patients with breast cancer treated with MPA often report an improvement in appetite. Similar appetite stimulation is seen in patients treated with some corticosteroids, but MPA has a potential advantage over these drugs in that it does not exert a catabolic effect. MPA (100 mg tds orally) has therefore been compared with placebo in 60 patients with advanced malignant disease. Twenty-one patients in the MPA group and 20 in the placebo group were receiving chemotherapy. Patients were treated for 6 weeks and were assessed at weeks 0, 3 and 6 for appetite, energy, mood and pain using visual analogue scales. Nutritional status was assessed by the measurement of serum proteins and anthropometrics. Karnofsky score was recorded as a measure of performance status. There was a significant improvement in appetite in the MPA group between weeks 0 (pre-study) and 3 (P = 0.0002) and 0 and 6 (P = 0.015). There was no significant improvement in appetite in the placebo group. Supporting this finding was the significant increase in serum thyroid binding pre-albumin and retinol binding protein in the MPA group between weeks 0 and 3 and 0 and 6 (P = 0.023 and P = 0.039 respectively). These two parameters showed no significant change in the placebo group. There was no change in anthropometric measurements, weight, performance status, energy, mood or pain in either group. These data indicate that there was a significant increase in appetite in anorexic patients with advanced cancer treated with MPA which was reflected in increases in rapid turnover proteins reported to reflect nutritional status. However, this apparent increase in appetite did not result in improved weight, performance status, energy levels, mood or relief of pain. Further studies to investigate the effect of higher doses of MPA are indicated.

Na +-dependent glutamine transport in the liver of tumour-bearing rats

In rats with advanced malignant disease, the liver extracted circulating glutamine at a ratio three times faster than the liver of control non-tumour-bearing animals. This augmented uptake occurred in spite of a fall in circulating glutamine levels, implying an increase in hepatocyte plasma membrane transport. Na +-dependent glutamine transport activity (System N) was increased nearly two-fold in hepatocyte plasma membrane vesicles from tumour-bearing rats; this increase in System N activity was proportional to tumour size and was due to an increase in carrier V max with no change in carrier affinity. Measurement of System N activity in isolated hepatocytes incubated with serum from tumour-bearing rats demonstrated a significant increase in glutamine transport compared with cells incubated with serum from control rats. These data indicate that the liver of rats with advanced malignant disease displays accelerated glutamine consumption. This increased uptake is due, in part, to enhanced carrier-mediated transport activity, and is mediated by a circulating factor(s) that is not present (or inactive) in non-tumour-bearing controls.

Clinical significance of cellular resistance in tumours to cytotoxic chemotherapy and radiotherapy.

Cellular resistance is a significant component of tumour treatment failure. More detailed understanding of resistance mechanisms has enabled us to plan circumvention strategies, though these are not yet in routine clinical use. Such resistance is, however, only one of several factors which render cure of advanced malignant disease difficult. It is important for researchers in this field to see not only therapeutic opportunities but also limitations of these approaches. It is hoped that increased cooperation between clinicians and scientists in the field of cellular resistance will yield further improvement in tumour response rates and cure.

Endoscopic therapy for biliary obstruction.

Endoscopic management of biliary obstruction is feasible in most patients and has emerged as standard treatment. Aside from the removal of bile duct stones, placement of a biliary stent is the most commonly employed modality of management. In experienced hands, this is successful in over 90% of patients. Lower procedure-related complications and the relative non-invasive nature of endoscopic treatment has relegated surgical management to a subsidiary role. Hospitalization time rarely exceeds 1-2 days. In most patients with advanced malignant disease and short life expectancy, stenting affords effective palliation. For the majority of patients endoscopic management is preferable to the percutaneous transhepatic approach due to lower overall mortality and morbidity. Stent occlusion necessitating replacement remains a problem, but improvements in this area can be expected. New plastic stent designs are undergoing investigation. Expandable metallic stents are promising but controlled comparative trials with conventional plastic prostheses are needed. Use of expandable stents should be judicious since these cannot be removed. In the future we can look forward to advances in peroral cholangioscopic technology which may permit targeted treatment of intraductal biliary malignancies.

Acute graft-versus-host disease: analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate [see comments

Previous studies of risk factors for acute graft-versus-host disease (GVHD) involved patients receiving predominantly single-agent prophylaxis. Therefore, a retrospective analysis was performed on 446 patients, from a single institution, who received transplants of marrow from HLA-identical siblings and the combination of cyclosporine (CSP) and methotrexate (MTX) to determine risk factors for acute GVHD associated with this more effective form of GVHD prophylaxis. The incidences of Grades II-IV and Grades III-IV (severe) acute GVHD were 35% and 16%, respectively. Increased clinical grades of acute GVHD in patients without advanced malignant disease were associated with a decreased survival. In a multivariate Cox regression analysis, risk factors associated with the onset of Grades II-IV acute GVHD were sex mismatch and donor parity (P = .001), increased dose of total body irradiation (TBI) (P = .001), and reduction to less than 80% of the scheduled dose of MTX (P = .02) or CSP (P = .02). The multivariate analysis indicated a relative risk of 1.37 for acute GVHD in a group defined as having advanced malignant disease at transplant; however, this difference failed to reach conventional levels of statistical significance (P = .07). Reduction of MTX and CSP occurred in up to 36% and 44% of patients, respectively, primarily because of renal or hepatic dysfunction. The periods of increased risk for the onset of acute GVHD were up to 1 week after a reduction of MTX and 2 weeks after a reduction in CSP. When only patients who developed Grades II-IV acute GVHD were considered, the more severe acute GVHD of Grades III-IV was associated with increased patient age of 40 years or greater (P = .05) and dose reductions of CSP (P = .008). Serologic status of patient and donor for cytomegalovirus (CMV), HLA antigens in the A and B loci, and isolation in a laminar air flow room during marrow transplantation, all previously identified as risk factors for acute GVHD, were not confirmed as risk factors in this study population. The toxicity of MTX and CSP and the development of acute GVHD from inadequate immunosuppression because of dose reduction warrants further trials with potentially less toxic immunosuppressive agents. Risk factors for acute GVHD should be considered in clinical management and in the design of clinical trials.

Acute Graft-Versus-Host Disease: Analysis of Risk Factors After Allogeneic Marrow Transplantation and Prophylaxis With Cyclosporine and Methotrexate

Abstract Previous studies of risk factors for acute graft-versus-host disease (GVHD) involved patients receiving predominantly single-agent prophylaxis. Therefore, a retrospective analysis was performed on 446 patients, from a single institution, who received transplants of marrow from HLA-identical siblings and the combination of cyclosporine (CSP) and methotrexate (MTX) to determine risk factors for acute GVHD associated with this more effective form of GVHD prophylaxis. The incidences of Grades II-IV and Grades III-IV (severe) acute GVHD were 35% and 16%, respectively. Increased clinical grades of acute GVHD in patients without advanced malignant disease were associated with a decreased survival. In a multivariate Cox regression analysis, risk factors associated with the onset of Grades II-IV acute GVHD were sex mismatch and donor parity (P = .001), increased dose of total body irradiation (TBI) (P = .001), and reduction to less than 80% of the scheduled dose of MTX (P = .02) or CSP (P = .02). The multivariate analysis indicated a relative risk of 1.37 for acute GVHD in a group defined as having advanced malignant disease at transplant; however, this difference failed to reach conventional levels of statistical significance (P = .07). Reduction of MTX and CSP occurred in up to 36% and 44% of patients, respectively, primarily because of renal or hepatic dysfunction. The periods of increased risk for the onset of acute GVHD were up to 1 week after a reduction of MTX and 2 weeks after a reduction in CSP. When only patients who developed Grades II-IV acute GVHD were considered, the more severe acute GVHD of Grades III-IV was associated with increased patient age of 40 years or greater (P = .05) and dose reductions of CSP (P = .008). Serologic status of patient and donor for cytomegalovirus (CMV), HLA antigens in the A and B loci, and isolation in a laminar air flow room during marrow transplantation, all previously identified as risk factors for acute GVHD, were not confirmed as risk factors in this study population. The toxicity of MTX and CSP and the development of acute GVHD from inadequate immunosuppression because of dose reduction warrants further trials with potentially less toxic immunosuppressive agents. Risk factors for acute GVHD should be considered in clinical management and in the design of clinical trials.

Terminal restlessness in patients with advanced malignant disease

So-called 'terminal restlessness' may have many causes often difficult to diagnose but with specific treatment for a minority of cases. Some of the possible causes and their management are reviewed, including motor restlessness and mental unrest.

Oral carriage of yeasts, coliforms and staphylococci in patients with advanced malignant disease

Many patients with advanced cancer have oral problems, some of which may have a microbiologic basis. The oral flora in such patients has not, however, been characterized. This study has assessed the prevalence of yeasts, coliforms and coagulase positive staphylococci in the oral flora of 197 patients with advanced cancer. Both imprint cultures (n = 197) and oral rinses (n = 161) were collected. Yeasts were isolated from the mouths of 83% of the patients, coliforms from 49.1% and coagulase-positive staphylococci from 28%. All these percentages are considerably in excess of reported levels for healthy individuals. The results indicate a loss of colonization resistance of the oral mucosa in terminal cancer, with potential implications for the development of mouth care regimes for such patients.

Autologous blood stem cell transplantation in pediatric cancer patients - the austrian experience (1986-1991)

Autologous blood stem cell transplantation (ABSCT) was applied in 29 children with advanced malignant disease (generalised solid tumors or hematologic malignancies). The median age was 12 years. We observed up to median 40fold increases in the myeloid committed progenitors (CFU-GM) and numbers of hematopoietic progenitors obtained after myeloablative therapy. The determination of CD34 positive cells by flow cytometry appeared to be helpful to determine the optimal days for leukaphereses. Granulocyte recovery was rapid after ABSCT with 11 days (8–17) to reach 0.1×109/1 granulocytes and 23 days (11–214) to 1×109/1 circulating lymphocytes. Eleven of 29 children are alive in complete remission for median 27 months (range 3–57) after ABSCT.

Breast disease evaluation with fat-suppressed magnetic resonance imaging

Thirty patients with a variety of pathologically confirmed malignant and benign pathologic lesions of the breast were evaluated with a spectrally selective fat suppression imaging technique to obtain fat-suppressed images of the breast. The technique, a selective partial inversion-recovery (SPIR) method, demonstrated the architectural relationship of malignant and benign tumors with respect to the normal water-containing elements of the breast. These relationships included signs of advanced malignant disease such as tissue retraction, invasive growth, and multicentricity, which appeared on the fat-suppressed images. Fat-suppressed imaging provided useful information for assessing the breasts of both pre- and postmenopausal women, especially in the latter group, where fatty involution of the breast is common. Microcysts, which are normally not visualized by conventional methods, were demonstrated and associated with patients having confirmed fibrocystic disease of the breast. As expected, the SPIR technique did not improve the ability to distinguish between tissues having similar T 1 and T 2 relaxation time values, such as malignant tumors and normal breast parenchymal tissues. The technique was able to demonstrate that the intense lipid signal, known to be responsible for obscuring the borders of water-fat interfaces and small tumors, could be eliminated in a variety of pathological settings.

Superselective Embolization of Superior Gluteal Artery Pseudoaneurysms Following Intramuscular Injection:

Two bleeding superior gluteal artery pseudoaneurysms occurred in a patient with advanced malignant disease following an intramuscular injection. This was diagnosed by angiography and successfully managed by superselective embolization. This avoided further surgery and no additional complication from the pseudoaneurysm occurred up to the time of the patient's demise.

Phase I Trial of ImmTher, a New Liposome-Incorporated Lipophilic Disaccharide Tripeptide

A phase I clinical trial was conducted to evaluate the toxicology and biological activity of a new liposome-incorporated lipophilic disaccharide tripeptide, ImmTher. Twelve patients with advanced nonhematological malignant disease received 13 courses of therapy at dose levels of 200-1,200 micrograms/m2. A course of therapy consisted of once-weekly administration of the drug for 2-12 weeks. The major clinical toxicities observed were chills and hypotension. No renal, hepatic, cardiac, or hematological toxicity was observed. A small decrease in pulmonary diffusion capacity was observed. Biological activity was demonstrated by changes in plasma cytokine levels, changes in in vitro monocyte cytotoxicity, and by a decrease in tumor size. Improvement was observed in three of three patients with metastatic disease to the liver. Response in these three patients correlated with an increase in their tumor necrosis factor and neopterin levels compared with nonresponders. These preliminary indications of biological and clinical activity of a liposome-incorporated lipophilic disaccharide tripeptide in patients with advanced metastatic hepatic disease suggest a potential new therapeutic approach to this common problem.