M. Valdivieso

A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin.

One hundred fifty-eight patients receiving Adriamycin underwent 226 transjugular biopsy procedures. The specimens were evaluated by electron microscopy for evidence of drug-related cardiotoxicity. Ejection fraction determinations using echocardiographic or nuclear techniques at rest were available for 69% and 81% of the patients, respectively. Analysis of the data revealed a correlation between cumulative Adriamycin dose and biopsy grade (p less than 0.02). No similar relationship existed between cumulative Adriamycin dose and ejection fractions obtained at rest or between biopsy grades and ejection fractions. In patients who underwent serial endomyocardial biopsies and serial ejection fraction determinations, the correlation between changes in biopsy grade and ejection fraction was poor. A change in resting ejection fraction detected by either method did not reliably predict a change in biopsy grade. The poor correlation between ejection fractions and biopsy grades could be due in part to the sensitivity and specificity of the Adriamycin-related structural changes in contrast to the wider range of disease processes that can affect myocardial function, and to the fact that structural changes often precede the ejection fraction abnormalities. The greater sensitivity and specificity of the biopsy grade should prove useful in reducing the risks associated with evaluating new anthracyclines and potential myocardial protectors of Adriamycin toxicity.

A randomized comparative trial of three aminoglycosides-comparison of continuous infusions of gentamicin, aaikacin and sisomicin combined with carbenicillin in the treatment of infections in neutropenic patients with malignancies

Continuous infusions of gentamicin, amikacin or sisomicin combined with carbenicillin were compared in a randomized study in the treatment of 572 febrile episodes in 281 patients with cancer. The three treatments (C+A, C+A and C+S) were equally effective with no significant differences in response rate overall (67%, 68%, 67%) or in any infection, except septicemia where C+G had a significantly lower response rate than the other two groups. Pneumonia, the most common infection, had the lowest response rate for all three groups (45-50%). Klebsiella spp. were the most common pathogens and showed a lower response rate than other gram-negative bacilli (P = 0.003). Patients with persistent severe neutropenia had a response rate of 56%. Azotemia was significantly less common in patients with documented infection treated with C+A than in the C+S group. Combinations of carbenicillin plus an aminoglycoside antibiotic are effective for the treatment of infections in neutropenic patients.

Natural history study of gallbladder cancer: a review of 36 years experience at M. D. Anderson Hospital and Tumor Institute.

Seventy‐five patients with gallbladder cancer referred to our institution over a 36‐year period were studied. They represented 0.08% of all hospital admissions over the period of study. The disease was most common in older females (median age, 62 years). Ninety‐seven percent of patients had a pre‐existing clinical history of recurrent right upper quadrant pain suggestive of cholecystitis for a median duration of 3 years (range, 4 days to 25 years). Ninety‐eight percent of patients whose records had adequate clinical, surgical or postmortem information had gallstones. Laparotomy was diagnostic in 100% of the patients. The cell type in all patients was adenocarcinoma. Surgery was curative in only 5% of patients. Results of chemotherapy, mainly 5‐fluorouracil, were poor. The median survival for all patients was 5.2 months. Survival was slightly better for males, for patients younger than 62 years of age, and for patients with good performance status. At postmortem, most patients had metastases to the liver (91%) and intraabdominal lymph nodes (82%). Metastases to extraabdominal organs were infrequent.

Percutaneous Hepatic Arterial Infusion (HAI) of Mitomycin C and Floxuridine (FUDR): An Effective Treatment for Metastatic Colorectal Carcinoma in the Liver

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 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. Chemotherapyrelated 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.

Therapeutic trials with tobramycin

Tobramycin, a new aminoglycoside, was utilized in the treatment of 82 infectious episodes in 73 cancer patients. Forty-four episodes (54 per cent) responded to this antibiotic. Pneumonia and septicemia were the most common infections treated (62 per cent) and the response rates were 47 and 33 per cent, respectively. Tobramycin was most effective against the 11 urinary tract infections, producing a 91 per cent response rate. Gram-negative organisms were responsible for 92 per cent of the identified infections and 58 per cent of these infections responded to tobramycin. Klebsiella spp., E. coli, and Pseudomonas spp. were the most common gram-negative bacilli causing infection. Sixty per cent of Klebsiella infections responded to tobramycin, compared to only 36 per cent of E. coll and 40 per cent of Pseudomonas infections. Only 24 per cent of infections occurring in patients with an initial neutrophil count of less than 1007mm3 responded, whereas 69 per cent of infections occurring in patients with more than 1000 neutrophils/mm3 responded to tobramycin. Nephrotoxicity was the only side effect of tobramycin and occurred during 17 per cent of the courses of therapy. However, in only 6 per cent was the drug exclusively responsible for the nephrotoxicity, Tobramycin has a spectrum of antibacterial activity similar to gentamicin and appears to be as effective in the therapy of gram-negative infections. This drug may be less nephrotoxic than gentamicin.

Increased therapeutic index of weekly doxorubicin in the therapy of non-small cell lung cancer: a prospective, randomized study.

One hundred patients with non-small cell lung cancer were entered into a randomized evaluation of two schedules of doxorubicin combined with ftorafur, cyclophosphamide, and cisplatin (FACP). Doxorubicin was given either weekly at 20 mg/m2, or every three weeks (standard) at 60 mg/m2. Fifty-two patients were randomized to the FACP/weekly doxorubicin arm and 48 patients to the FACP/standard doxorubicin arm. The FACP/weekly doxorubicin regimen was associated with higher complete and partial remission rates (31% versus 19%), longer response duration (median, 33 versus 21 weeks), and longer survival duration for responders (median, 58 versus 50 weeks). These differences were not significant. Less neutropenia (p = 0.01) and less infectious morbidity (p = 0.05) were observed in the FACP/weekly doxorubicin arm. Twenty-eight patients underwent 35 endomyocardial biopsies to assess doxorubicin-induced cardiotoxicity. Sixteen biopsies were performed in 12 patients receiving cumulative doxorubicin doses ranging from 250 to 1,190 mg/m2 within the FACP/weekly doxorubicin arm. Nineteen biopsies were performed in 16 patients receiving cumulative doxorubicin doses ranging from 250 to 540 mg/m2 within the FACP/standard doxorubicin regimen. The FACP/weekly doxorubicin regimen was associated with significantly lower cardiotoxicity scores (p = 0.01). This study indicates that weekly administered doxorubicin is as effective and less cardiotoxic than the standard schedule.

Amikacin therapy of infections in neutropenic patients.

Amikacin, a new aminoglycoside antibiotic, was utilized in the treatment of 49 cases of infection which occurred in 39 neutropenic cancer patients. Thirty-four patients (69 per cent) responded to this antibiotic. Pneumonia and septicemia were the most common types of infection treated and the response rates were 65 per cent and 75 per cent, respectively. Gram-negative bacilli were responsible for 93 per cent of the identified infections and 74 per cent responded. E. coli, Ps. aeruginosa, and organisms of the Klebsiella-Enterobacter- Serratia group were the most common gram-negative bacilli causing infection. Responses were more frequent among patients who maintained higher serum concentrations of antibiotic, but the differences were not statistically significant. Patients with severe neutropenia <100 neutrophils/mm3) had a response rate of 68 per cent. Toxicity was manifested as azotemia and hearing loss which occurred in 13 per cent and 6 per cent, respectively. However, toxicity was directly related to serum concentration and to the number of treatments with amikacin. This antibiotic is of potential importance because of its efficacy against gram-negative bacilli infections. Best results were obtained when sufficient drug was given as a continuous intravenous infusion to maintain serum concentrations of about 15μ g/ml.

Adriamycin, BCNU, ftorafur chemotherapy of pancreatic and biliary tract cancer

Twenty‐six evaluable patients with disseminated or locally unresectable pancreatic or biliary tract carcinoma received Ftorafur (4 g/m2 iv day 1 and 22 and 2 g/m2 iv day 4 and 26), Adriamycin (60 mg/m2 IV day 1 and 45 mg/m2 iv day 22) and BCNU (150 mg/m2 iv day 1) combination chemotherapy (FAB) repeated at 6–8 week intervals. Two (29%) complete and one (14%) partial remissions were observed in 7 patients with biliary carcinoma while 5 of 19 (26%) patients with pancreatic carcinoma achieved partial remissions. Median survival for responding patients was ∼11 months (range 7–16+) with median survivals of about 6 months (p < 0.05) and about 3 months (p < 0.05) for patients with stable and progressive disease. Major drug toxicity was myelosuppression with median lowest granulocyte counts of 1,000/μl and platelet counts of 88,000/μl. Approximately 25% of patients required antibiotic therapy for fever of unknown origin or documented infections. Other tolerable drug toxicities included nausea, vomiting and mucositis. The FAB regimen appears quite promising in biliary tract cancer and has efficacy in pancreatic carcinoma that warrants further clinical trials. Because of myelotoxicity observed with this regimen we now recommend a BCNU starting dose of 100 mg/m2 instead of 150 mg/m2.

Esophageal complications from combined chemoradiotherapy (cyclophosphamide + adriamycin + cisplatin + xrt) in the treatment of non-small cell lung cancer

Esophageal complications from combined chemoradiotherapy (CCRT) were analyzed in 55 patients with limited non-small cell lung cancer. CCRT consisted of chemotherapy (cyclophosphamide, doxorubicin (Adriamycin), and cisplatin: CAP) and chest irradiation (5000 rad in 25 fractions/5 weeks). Forty-five patients received two courses of CAP, followed by five weekly courses of low dose CAP and irradiation followed by maintenance courses of CAP (Group 1). Ten patients received concomitant CCRT from the onset of treatment (Group 2). Esophagitis occurred in 80% of all patients. Severe esophagitis occurred in 27% of patients of Group 1 and 40% of patients of Group 2. Esophageal stricture or fistula developed in 1 of 45 (2%) patients in Group 1, and 3 of 10 (30%) patients in Group 2 (p less than 0.025). Weekly low-dose chemotherapy administered concomitantly with chest irradiation (R) at the onset of treatment significantly increases esophageal complications. A review of the literature suggests that CCRT may be used safely with split courses of R. The duration between onset of chemotherapy either before or after R should be greater than one week.

Fungemia due to Torulopsis glabrata in the compromised host

Ten episodes of Torulopsis glabrata fungemia occurring in nine patients with terminal illnesses are described. Eight patients had underlying malignancies and one patient had aplastic anemia. Two episodes of fungemia were considered transient since they were clearly related to the administration of intravenous hyperalimentation (IVH). Most patients were adult women and had solid tumors of the genitourinary tract. Contributory factors were: antibiotic therapy (100%), immunosuppressive drugs (75%), abdominal surgery (63%), IVH (50%), neutropenia (38%), and diabetes mellitus (13%). The clinical course was indistinguishable from a severe bacterial infection. However, endotoxic shock was not observed. The infection was rapidly fatal in four patients. In the remaining five patients, the infection was altered favorably by the discontinuation of infected intravenous hyperalimentation catheters. However, tissue invasion by T. glabrata was found in two of these patients who died shortly thereafter from tumor progression. At autopsy, T. glabrata was identified in tissue sections of the lungs, kidneys, and mucosas of the gastrointestinal and genitourinary tracts. In all cases there was tissue necrosis with a minor inflammatory response consisting of mononuclear cells. To our knowledge, this is the single largest series of T. glabrata fungemia ever reported.