Combined modalities in the treatment of small cell carcinoma of the lung. A review of current standings.
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Carcinoma, Small Cell↗
Biomedical subjects
J Aisner
Publications and source records attributed to J Aisner.
A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation.
Twenty patients with extravasation of anthracyclines were treated on a single-arm pilot study with topical 99% dimethyl sulfoxide (DMSO) and observed for 3 months with regular examinations and photographs. DMSO was applied to approximately twice the area affected by the extravasation and allowed to air dry. This was repeated every six hours for 14 days. The initial signs of extravasation included swelling in 17 patients, erythema in 15, and pain in 12. The median area of damage was 8.25 cm2 and a median of 25 minutes elapsed between extravasation and application of DMSO with one patient not treated until seven days postextravasation. Sixteen patients were observed for 3 months, two died of disease earlier after receiving 2 weeks of DMSO and three days of DMSO, respectively, and two were lost to follow-up having received one day and five days of DMSO. In no patient did extravasation progress to ulceration or require surgical intervention, suggesting with 95% confidence a true ulceration rate of between 1% and 17%. At 3 months there was no sign of residual damage in six patients, while a pigmented indurated area remained in ten. Two patients had a recall reaction with increased pain at the extravasation site when further intravenous (IV) doxorubicin was administered. The only toxicities of DMSO included a burning feeling on application subsequently associated with itch, erythema, and mild scaling. Blisters occurred in four patients. Six patients reported a characteristic breath odor associated with DMSO. Topical DMSO appears to be a safe and effective treatment for anthracycline extravasation.
Administration, Topical↗
Megestrol acetate-induced differentiation of 3T3-L1 adipocytes in vitro.
We recently observed significant weight gain in patients with advanced breast cancer treated with high-dose megestrol acetate. However, the mechanisms of this effect are completely unknown. As the analysis of the action of steroids in vivo is complex, we chose to examine the effects of megestrol acetate on the differentiation of a preadipocyte clone (L1) of the Swiss 3T3 mouse fibroblast cell line. Addition of insulin, fetal bovine serum, dexamethasone, and methyl-isobutylxanthine to confluent 3T3-L1 cells induced adipocyte differentiation, as verified by morphologic studies and analysis of the activity of the enzyme glycerol-3-phosphate dehydrogenase (G-3-PD), a specific and sensitive indicator of lipocyte function. Substitution of megestrol acetate for dexamethasone also resulted in greatly increased lipocyte differentiation. Tumor necrosis factor (TNF) alpha blocked the adipocyte differentiation induced by the combination of insulin, dexamethasone, and methyl-isobutylxanthine. Addition of megestrol acetate failed to reverse the inhibitory effect of TNF. Thus, megestrol acetate, in vitro, is a potent inducer of lipocyte differentiation. Further studies on the regulation of adipocyte differentiation and function in this model system may be important to clarify megestrol acetate's mechanism of action.
1-Methyl-3-isobutylxanthine↗
Staging, prognostic factors, and special considerations in small cell lung cancer.
New treatment approaches in the fight against SCLC are clearly on the horizon and some are already in clinical trials. With this in mind, several comments concerning future directions in staging this disease can be made: 1. Staging is important and complete staging is needed in order to continue to build meaningful information. 2. Limited/Extensive disease categories are in use and remain important; yet this system is not completely adequate. There are subsets within each group that do better: minimal disease versus bulky disease in limited stage, extraabdominal v intraabdominal in extensive disease, and single organ versus multiple organ involvement. Therefore, a new staging system is needed. The TNM system is designed primarily to define surgical resectability and will thus not adequately address the issues for SCLC unless the N and M categories are markedly enlarged. A staging symposium was recently held in Europe to begin to address potential approaches to staging and an American staging conference is planned. 3. Biomarkers: In the broad range of possible markers, most are not sufficiently sensitive or specific to supplant clinical exam and routine testing. But newer tests such as NSE, CK-BB and tumor surface antigen expression and recognition may impact on staging in the near future. 4. Finally, as the biology of SCLC is further understood, much of the derived understanding will likely change the staging and prognostic factors.
Biomarkers, Tumor↗
Studies of high-dose megestrol acetate: potential applications in cachexia.
Cachexia can be a severe problem in the management of patients with cancer and other illnesses because it produces an ever-increasing spiral of anorexia, undernutrition, loss of tissue mass, muscle wasting, and increased susceptibility to infection and treatment toxicity. Megestrol acetate has been observed to produce weight gain in patients with hormone-sensitive tumors and has recently been noted to produce a similar degree of weight gain in those with hormone insensitive tumors. A review of our experience in a phase I-II study of escalating doses of megestrol acetate for advanced breast cancer revealed that weight gain occurred in more than 80% of all treated patients and in 90% of those patients who received treatment for 6 or more weeks. The median maximum weight gain was 5.5 kg, with a range of -5.6 to 44 kg. Subjective improvement in appetite occurred in most patients. These data provided the impetus for a series of further studies of the role of megestrol acetate in the control of cachexia, including a randomized study in cancer cachexia, AIDS cachexia, and anorexia nervosa. In addition, a number of laboratory trials seeking the mechanism of action have been initiated, as well as whole-animal studies to define the compartment of increased weight. Our data and the preliminary observation of weight gain in patients with hormone insensitive tumors suggest that megestrol acetate has a potential role in producing a possibly dose-related subjective improvement and an increase in appetite and weight. Further research is necessary to understand the mechanism of appetite stimulation and anabolic effect.
Body Weight↗
High-dose megestrol acetate in the treatment of advanced breast cancer.
A dose-response relationship has long been suspected for progestin compounds in the treatment of breast cancer, but only recently have trials been implemented to investigate this issue. In 1985, we began a phase I-II study of high-dose megestrol acetate in dosages of 480 mg/d to 1,600 mg/d in heavily pretreated postmenopausal patients with advanced breast cancer. After establishing the safety of this therapy, we expanded our trial, which now includes 47 patients, 34 of whom have measurable disease. Of these 34 patients, 30 had disease progression on prior hormonal therapy and 29 had progression on chemotherapy. Six of the 34 patients had complete response and six had partial response for a median time on study of 10 months (range, 8 to 30 months). Ten patients had stabilization and 12 had progression. Thirteen patients had evaluable but nonmeasurable disease, and of these, ten had improvement or stabilization for a median period of 6 months (range, 2 to 18 months) and three had progression. Of 17 patients who had experienced disease progression while receiving standard-dose megestrol acetate, 13 (76%) achieved objective remissions or stabilization with high-dose therapy. The main side effects were weight gain and appetite enhancement, which were beneficial in 13 underweight patients. These data indicate that high-dose megestrol acetate is well tolerated and effective in patients with advanced breast cancer refractory to multiple previous therapies. While optimal dose levels for clinical use remain to be established by ongoing studies, our data suggest that doses higher than the standard dose may be more effective.
Adult↗
High-dose megestrol acetate. A possible treatment for cachexia.
Weight loss and anorexia are significant complications of a variety of disorders and add morbidity to the underlying process. We observed marked weight gain (median, 5.1 kg; range, 0.9 to 20.1 kg) and appetite enhancement in 27 of the 28 patients with breast cancer receiving treatment consisting of high doses of oral megestrol acetate (480 to 1600 mg/d). Weight gain occurred regardless of pretreatment weight, extent of metastases, or response to therapy. Our results suggest a possible role for megestrol acetate in reversing anorexia and weight loss, thereby improving the quality of life of patients with cachexia. Further research is needed to establish the mechanism of weight gain and potential clinical applications.
Body Weight↗
Phase I clinical and pharmacokinetic study of hexamethylene bisacetamide (NSC 95580) administered as a five-day continuous infusion.
Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was tested in patients with refractory, solid tumors. Twenty patients received 25 evaluable courses. HMBA was given by continuous i.v. infusion for 5 consecutive days with courses repeated every 4 wk, provided there was acceptable, reversible toxicity. The starting dose was 4.8 g/m2/day for 5 days with escalations in subsequent cohorts of patients to 43.2 g/m2/day for 5 days. The patients included 12 females and eight males with median age of 56 yr (range 35 to 75 yr) and a median performance status of 80% (range, 60 to 100%). All except two patients had received prior chemotherapy, radiation therapy, or both. Metabolic acidosis and neurotoxicity, consisting of agitation, hallucinations, confusion, and alteration of consciousness, were dose dependent and dose limiting. The one patient treated with 43.2 m/m2/day became acidotic, agitated, and disoriented but recovered to his previous mental and electrolyte status by 8 days after the end of the HMBA infusion. One patient treated with 33.6 g/m2/day became severely acidotic (pH 7.07) and obtunded and also developed myocardial and cerebral infarctions during the HMBA infusion. The other two patients treated with 33.6 g/m2/day became mildly agitated during drug infusion. Six patients were treated at 24 g/m2/day without neurotoxicity. Transient renal insufficiency was seen in the two patients with severe neurotoxicity and in three other patients. Dose-related, mild to moderate nausea and vomiting were observed in ten patients. Four patients developed cutaneous herpes infections during treatment. White blood cell depression was not dose related, and at 24 g/m2/day, the median white blood cell nadir was 4,500/microliter (range, 2,000 to 7,900/microliter). Thrombocytopenia was dose related. At 24 g/m2/day, the median platelet count nadir was 207,000/microliter (range, 66,000 to 542,000/microliter). No objective tumor regressions were noted. HMBA pharmacokinetics was studied at all dosages. Plasma and urine samples from 20 patients were analyzed by gas-liquid chromatography for parent compound. HMBA plasma steady-state concentrations (Css) were achieved in all patients by 12 to 24 h into infusion. Once Css was achieved, daily variation was generally less than or equal to 10% from the mean Css. HMBA plasma Css increased linearly with dose, but there was variation in the Css achieved in individual patients at each dose. Doses of 24 to 33.6 g/m2/day consistently produced plasma HMBA Css of 1 to 2 mM matching concentrations required for differentiation in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)
Acetamides↗
Surgery in acute leukemia: a review of 167 operations in thrombocytopenic patients.
Of 435 consecutive patients with acute leukemia, 95 patients had 167 operations with a platelet count of less than 100 X 10(9)/L and 130 operations with platelet counts of less than 50 X 10(9)/L. Only 7% of operations had intraoperative blood loss of greater than 500 ml, and 7% required greater than 4 units of red cells transfused in the perioperative period. No patient died of bleeding attributable to surgery within 1 month of the operation. Granulocyte count was less than 0.5 X 10(9)/L in 66% of operations with 57% febrile preoperatively. However, no patient developed infection within the surgical field in the postoperative month. Logistic regression analyses were used to assess preoperative factors, which identified those operations at risk for excessive bleeding or postoperative surgical complications. Major (group 1) operations, preoperative fever, and preoperative coagulation abnormalities were associated with operations with an intraoperative blood loss greater than 500 ml and/or perioperative red blood cell RBC transfusions greater than 4 units (P less than .001). Surgery in cytopenic patients with acute leukemia is safe provided optimal supportive care is available.
Acute Disease↗
Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. Cancer and Leukemia Group B.
Three combination chemotherapy regimens each with or without the methanol-extracted residue of bacillus Calmette-Guérin (BCG) (MER) were compared for efficacy. After stratification for disease-free interval and dominant sites of disease, patients were randomized to either CMF (cyclophosphamide [CYC], 100 mg/m2 orally, days 1 through 14; methotrexate [MTX], 40 mg intravenously [IV], days 1 and 8; 5-fluorouracil [5-FU], 500 mg/m2 IV, days 1 and 8), or CAF (CYC, 100 mg/m2 orally, days 1 through 14; doxorubicin [DOX], 25 mg/m2 IV, days 1 and 8; 5-FU, 500 mg/m2 IV, days 1 and 8), or CAFVP (CAF as above plus vincristine [VCR], 1.0 mg/m2 IV, days 1 and 8; and prednisone [PRED], 40 mg/m2 orally, days 1 through 14). Nonspecific immunotherapy with MER was administered in five sites at 100 micrograms or at the lowest tenfold dilution that produced a 1-cm indurated lesion. A total of 432 patients were entered, but 37 were disqualified, leaving 395 evaluable for treatment results and toxicities. One hundred thirty-five evaluable patients were randomized to chemoimmunotherapy until October 28, 1978. One hundred twenty-six evaluable patients were randomized to chemotherapy alone in the same time period. For the entire study, a total of 260 evaluable patients were randomized to chemotherapy. Chemoimmunotherapy patients were compared with the initial 126 chemotherapy patients. Chemotherapy regimens were compared among all 260 patients. Patient characteristics were similar between regimens and between chemotherapy and chemoimmunotherapy treatment groups. For patients on chemotherapy plus MER, there was no significant differences between the regimens for response frequencies: 43%, 41%, and 32%, respectively for CMF, CAF, and CAFVP. The comparable chemotherapy alone group had 36%, 58%, and 63% response, respectively. The response rates, adjusted for chemotherapy regimen, were 52% and 38% (P = .02) for chemotherapy and chemoimmunotherapy, respectively. MER was associated with painful ulcers and fevers. Thus, MER produced toxicity without response or survival benefit and further randomization after October 28, 1978 was to chemotherapy alone. For 260 evaluable patients on chemotherapy alone, the complete (CR) and partial responses (PR) were 37%, 55%, and 58%, respectively for CMF, CAF, and CAFVP. These response rates for CAF and CAFVP were significantly better than CMF (P = .01 and P less than .01, respectively). These comparisons were consistent within subgroupings such as dominant sites of disease.(ABSTRACT TRUNCATED AT 400 WORDS)
Antineoplastic Combined Chemotherapy Protocols↗
Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081.
In a prospective, randomized trial Cancer and Leukemia Group B (CALGB) evaluated CAF chemotherapy (cyclophosphamide + doxorubicin + 5-fluorouracil [5-FU]) v CAF plus tamoxifen (TCAF) in advanced breast cancer. Patients were stratified by estrogen receptor (ER) status, dominant site of metastatic disease, menopausal status, and prior adjuvant therapy. Regardless of ER status or menopausal status, the addition of tamoxifen conferred no significant advantage in response rate, response duration, time to treatment failure (TTF) or survival over CAF alone. A secondary objective was to compare the response to CAF of ER positive (ER+) and ER negative (ER-) patients to determine if there was a differential response to cytotoxic chemotherapy. Response rates of ER+ and ER- patients to CAF were identical (56%), but the response duration, time to treatment failure, and survival of ER+ patients were significantly longer than ER- patients. This lack of differential response implies that chemotherapy and hormonal therapy may compete for the same pool of ER+ cells. It also suggests that chemotherapy kills breast cancer cells indiscriminately, regardless of ER status.
Adult↗
Abdominal CT in the staging of small-cell carcinoma of the lung: incidence of metastases and effect on prognosis.
CT studies of the abdomen performed on 72 patients with small-cell carcinoma of the lung were retrospectively reviewed to assess the role of abdominal CT in staging. Forty-four of the 72 patients had extensive disease, defined as disease extending beyond the confines of one hemithorax, plus or minus mediastinal or ipsilateral supraclavicular disease or ipsilateral pleural effusion. Initial-staging abdominal CT revealed one or more sites of metastatic disease in 26 (59%) of these 44 patients, while 18 patients had normal initial CT examinations. Statistical analysis of patients with extensive disease revealed a significant increase in complete therapeutic response (p = .0054) and in the length of survival (p = .001) among those who had extensive disease without abdominal metastases as compared with those who had abdominal metastases on their initial abdominal CT examination. The development of new or recurrent abdominal metastases in general or in specific organs on follow-up scans obtained in 35 patients did not significantly decrease their survival time as compared with that of patients without such metastases. Our findings suggest that CT of the abdomen is beneficial in the initial staging of patients with small-cell carcinoma of the lung and provides prognostic information concerning response to therapy and length of survival.
Abdominal Neoplasms↗
Phase II study of caracemide in advanced or recurrent non-small cell lung cancer.
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Adult↗
Identification of new drugs in small cell lung cancer: phase II agents first?
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Carcinoma, Small Cell↗
Small cell carcinoma of the lung: influence of age on treatment outcome.
Two hundred twenty-three patients between 29 and 78 years of age with small cell cancer of the lung were studied in serial protocols at the University of Maryland Cancer Center from 1975 to 1982. Each of these patients received chemotherapy consisting of doxorubicin, cyclophosphamide, and etoposide. In this paper we explore age and its interaction with the patient's extent of disease as it relates to clinical outcome variables such as the achievement of a complete response (CR), survival times, and various measures of toxicity. Preliminary evidence is found to suggest that an age-extent of disease interaction affects both the probability of obtaining a CR and the length of survival. Patients of all ages can benefit from treatment of small cell carcinoma of the lung, with CR as the treatment goal. However, increased toxicity and early death remain as barriers to successful treatment of the elderly.
Actuarial Analysis↗
Phase II trial of 4'-deoxydoxorubicin in advanced non-small cell lung cancer.
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Adult↗
High-dose megestrol acetate for the treatment of advanced breast cancer: dose and toxicities.
Endocrine maneuvers have considerable use in the management of advanced breast cancer, and progestins are hormonal agents with considerable antitumor activity. Sequential studies suggest a steep dose-response relationship for medroxyprogesterone. Megestrol acetate, (Megace, Bristol-Myers Oncology Division, Evansville, IN) an easily used progestin, has activity in advanced breast cancer, but dose response for this agent has not clearly been shown. This study was initiated to evaluate the tolerability and toxicity of escalating doses of megestrol acetate. Forty patients with advanced breast cancer who were not eligible for treatment with other conventional hormones or chemotherapy were entered into the study. All patients had disease progression on previous treatments, and all with visceral disease had disease progression while on one or more chemotherapy regimens. Using specially formulated 160-mg tablets (Bristol-Myers Oncology Division), three patients were entered at each of three dose levels: 480,800, and 1,280 mg/d. Thirty-one patients were entered at 1,600 mg/d. There were 39 postmenopausal women and one man; the median age was 58 years; the median performance status was 80%. Among 31 patients with measurable disease, there were six complete responses (CRs) and five partial responses (PRs); 11 of the 31 had stable disease. Fourteen patients had received previous megestrol acetate with disease progression on treatment: Six had had primary treatment failure. One of these 14 achieved CR, three achieved PR, and eight acheived stable disease on the high-dose regimens. Toxicities were mild (grade 0 to 1) and included mild BP elevation, weight gain, increased appetite, hyperglycemia, edema, dyspnea, congestive heart failure, and other mild problems.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Infections in patients with non-small-cell lung cancer treated with intensive induction chemotherapy.
The records of 65 consecutive patients with non-small-cell lung cancer (NSCLC) treated with intensive induction chemotherapy were reviewed to study the infectious complications during therapy and to analyze the relationship of the frequency of infections to various predisposing factors. A total of 44 infectious episodes were observed among 30 of the 65 patients. Of the 44 infections, 18 were microbiologically documented and 19 clinically. Seven (16%) infections were without microbiological or clinical documentation and were categorized as "possible" infections. Among the 18 microbiologically documented infections, fifteen (83%) were caused by bacteria and three by fungi. The most frequent bacteria identified in 11 (61%) of the 18 infections were gram-negative organisms, Escherichia coli and Klebsiella pneumoniae being the most frequent. Eight of the 44 infections were associated with bacteremia and three with microbiologically documented pneumonias. There were three drug-related infectious deaths, two associated with bacteremia and one with possible infections. All 44 infectious episodes presented with WBC counts of less than 1,000/microliter, and 34 (79%) had WBC counts of less than 500/microliter. We observed that during therapy, patients with poor performance status (less than 80%) are at a much higher risk to develop infectious complications than those with good performance status (greater than 80%; p less than .001). Although encouraging responses with intensive chemotherapy have been reported for NSCLC in several studies, a major impact of chemotherapy on the survival of patients with this disease has yet not been established. Thus, intensive chemotherapy for NSCLC should remain an experimental treatment modality and should be offered only to patients with good prognostic factors such as those defined by pretreatment performance status.
Adult↗