Pulmonary toxicity of high-dose chemotherapy for breast cancer: a non-invasive approach to diagnosis and treatment

Drug-induced pulmonary toxicity is one of the most frequent non-hematologic toxicities in breast cancer patients receiving high-dose chemotherapy with cyclophosphamide, cisplatin and BCNU (CY/CDDP/BCNU). A non-invasive clinical scoring system was utilized in an attempt to diagnose and treat early lung toxicity in 64 consecutive breast cancer patients undergoing CY/CDDP/BCNU supported by peripheral blood progenitor cells. Following hospital discharge, patients who developed symptoms suggestive of lung toxicity were evaluated with physical examination, DLCO, 2-min walking oximetry and a chest radiograph. Clinically weighted scores were assigned as follows: crackles on lung exam, 2; decrease in corrected DLCO by > 10% from baseline, 3; decrease in O2 saturation by > or = 4% with a 2-min walk, 3; and interstitial infiltrates on chest radiograph, 3. Patients with scores > or = 6 were treated with prednisone (60 mg p.o. twice a day followed by a 2-month taper). Treatment was instituted in 37 patients (58%) a median of 56 days after high-dose chemotherapy. Steroid therapy was associated with rapid clinical improvement in most patients. No fatal complications or chronic pulmonary fibrosis was seen. This non-invasive clinical scoring system can be utilized as a model for the early diagnosis of lung toxicity. Further investigation is warranted for the development of preventative measures against this syndrome.     

Anticancer chemotherapy. Prevention of toxicity

A MAJOR CHALLENGE: Prevention of short and long term toxicity of chemotherapy is an important challenge in oncology in order to maintain the dose/intensity of protocols and to increase patient comfort. AVAILABLE CHEMOPROTECTORS: Amifostine protects against the blood, kidney and nerve toxicity of cisplatin. Protection is less evident for carboplatin and should be further evaluated for alkylating agents, anthracyclines and taxans. Dexrazoxane protects against the cumulative cardiotoxicity of anthracyclines without reduction of antitumor efficacy. It must be used beyond a cumulative dose of 300 mg/m2 doxorubicin (or equivalent) in responsive patients. Its use in the curative treatment of lymphoma should be assessed by further clinical trials. Mesna must be widely used to prevent the urotoxicity of cyclophosphamide and ifosfamide. An oral preparation is now available for outpatients. Protection of the gonadic function could be achieved by LH-FH analogs in young women. PERSPECTIVES: Due to their high cost and the risk of diminishing the antitumor efficacy in curable diseases, a precise evaluation of present and future chemoprotectors is necessary before wider use.     

Delayed pulmonary toxicity syndrome following high-dose chemotherapy and bone marrow transplantation for breast cancer

We have intensely followed 45 consecutive women who underwent high-dose chemotherapy (cyclophosphamide/cisplatin/BCNU) and autologous bone marrow transplant (HDC/ABMT) for primary breast cancer with pulmonary function testing and computed tomography at regular intervals up to 126 wk (median follow-up, 72 wk). Our results show a high incidence of interstitial pneumonitis requiring steroids (64%), but no deaths due to pulmonary toxicity. The DL(CO) reaches a nadir of 58.2 +/- SEM 3.4 (expressed as a percent of baseline value) 15-18 wk following HDC/ABMT, and marginally improves with time. To a much lesser extent, vital capacity is reduced with a parallel drop in FEV1, suggesting mild restrictive changes without significant obstruction. Patients who develop pulmonary symptoms of cough or dyspnea have a corresponding significantly greater and earlier decline in DL(CO). Chest computed tomography was neither sensitive nor specific for diagnosing pulmonary toxicity. For patients who received steroids for pulmonary toxicity, there was a subsequent improvement in DL(CO) of 17.1% (p = 0.0001). Because our patients do not fit with the recent definition of idiopathic pulmonary syndrome (IPS), we propose the term delayed pulmonary toxicity syndrome (DPTS) to better describe the milder form of lung toxicity seen in our patient population. We were unable to correlate the severity of DPTS with age, tobacco use, baseline pulmonary function, or systemic exposure to BCNU, cyclophosphamide, or cisplatin. These data suggest that factor(s) other than, or in addition to, chemotherapy systemic exposure can contribute to DPTS. Furthermore, early identification and institution of systemic corticosteroids may improve lung function.     

Prevention and treatment of hepatic venocclusive disease after high-dose cytoreductive therapy

Venocclusive disease of the liver (VOD) is one of the most common and serious complications following stem cell transplantation. High-dose chemotherapy or chemoradiotherapy injures the structures of Zone 3 of the liver acinus and produces the clinical syndrome of hepatomegaly or right upper quadrant pain, jaundice, and fluid retention. VOD occurs in up to 54% of stem cell transplant recipients and is fatal in 25-50% of them. While the clinical signs of VOD usually manifest during the first post-transplant week, late presentation can occur. The purpose of this review is to discuss the manifestations and pathophysiology of VOD and the options for prevention and treatment.     

The relationship between high-dose treatment and combination chemotherapy: the concept of summation dose intensity

The most important variables for the clinical use of antitumor agents (AAs) are dose and combination chemotherapy. The objectives of this study were to analyze the relationship between these two variables and to propose a unified conceptual framework for the construct and interpretation of clinical trials. Definitions and variables with respect to dose include potency, therapeutic index, standard dose, efficacy, relative efficacy, dose-limiting toxicity (DLT), dose rate, dose density, dose intensity, and fractional dose intensity. Our overarching concept, that is, summation dose intensity (SDI), was calculated in several ways, depending upon the nature of the data, and included the relative efficacy method, the unit regimen method, and the high dose method. The SDI concept was then applied to disease categories and strategies to determine its usefulness and effectiveness in integrating dose and combinations. The tumors and settings were: mustargen-vincristine-procarbazine-prednisone in Hodgkin's disease, combination chemotherapy for acute lymphocytic leukemia in children, metastatic breast cancer including dose and combinations, selected other solid tumors, alternating chemotherapy, and high dose studies in the leukemias and lymphomas. SDI was effective in integrating and quantifying dose and combination chemotherapy. For classical AAs, the implication of SDI for the construct and analysis of clinical trials was emphasized. In addition to new drug development, emphasis should be given to reducing or eliminating DLTs, such as those of the marrow, now and, in the future, those of the gastrointestinal tract toxicity and other DLTs. The above was derived from and applies to the classical AAs. Whether they will apply to, with appropriate adjustment, agents with significantly different dose-response curves, such as biotherapeutics and hormonal agents, remains to be determined.     

Glutamine and vitamin E in the treatment of hepatic veno-occlusive disease following high-dose chemotherapy

PURPOSE: To analyze the nonfatal adverse events (AE) associated with a first episode of status epilepticus (SE). METHODS: We performed a population-based retrospective cohort study to determine the morbidity of SE. Participants included 184 residents of Rochester, Minnesota who experienced nonfebrile SE between 1965 and 1984. RESULTS: The etiology of SE was acute symptomatic in 100 patients and unprovoked in 84 patients. The most common seizure-types were continuous partial (n=56, 30%), generalized convulsive (n=52, 28%), and generalized with focal features (n=32, 17%). Morbidity related to SE was noted in 5 of the 146 patients (3.4%) surviving 30 days. The AE included hemiparesis (n=3), encephalopathy (n=2), mental retardation (n=1), and aphasia (n=1). All patients with morbidity had an acute symptomatic (n=4) or remote symptomatic (n=1) etiology. Thirty-four patients (18.5%) had a second episode of SE. CONCLUSIONS: Based on this retrospective study, significant morbidity related to SE is uncommon and is associated with the underlying etiology.     

Neurotrophic factors in the treatment of neurotoxicity: an overview

In recent years, major advances have been made in our understanding of neurotrophic factors and the role they play in the development and maintenance of the nervous system. This knowledge, combined with major advances in molecular biology, have enabled investigators to begin considering their applications to clinical problems. The toxic neuropathies may prove to be one of the simplest and most practical clinical settings for the early use of neurotrophic factors. In this brief review, we provide an overview of some of the most important neurotrophic factors, and summarize the major preclinical studies which suggest that they may be useful in the treatment of toxic neuropathy.     

The toxicity of radiotherapy following high-dose chemotherapy with peripheral blood stem cell support in high-risk breast cancer: a preliminary analysis

High-dose chemotherapy with autologous bone marrow and/or peripheral blood stem cell (PBSC) support is increasingly employed in the adjuvant treatment of high-risk breast cancer. Subsequent radiotherapy has been reported to be associated with morbidity and mortality resulting from pulmonary toxicity. In addition, the course of radiation therapy may be hampered by excess myelosuppression. The aim of this study was to investigate the contribution to radiation-induced toxicity of a high-dose chemotherapy regimen (CTC) that incorporates cyclophosphamide, thiotepa and carboplatin, in patients with high-risk breast cancer. In two randomised single institution studies, 70 consecutive patients received anthracycline-containing adjuvant chemotherapy (FEC: 5-fluorouracil, epirubicin and cyclophosphamide) followed by radiotherapy to achieve maximal local control. Of these patients, 34 received high-dose CTC with autologous PBSC support. All patients tolerated the full radiation dose in the planned time schedule. Radiation pneumonitis was observed in 5 patients (7%), 4 of whom had undergone high-dose chemotherapy (P = 0.38). All 5 responded favourably to prednisone. Fatal toxicities were not observed. Myelosuppression did not require interruption or untimely discontinuation of the radiotherapy, although significant reductions in median nadir platelet counts and haemoglobin levels were observed in patients who had received high-dose chemotherapy (P = 0.0001). The median nadir of WBC counts was mildly but significantly decreased during radiotherapy (P = 0.01). Red blood cell or platelet transfusions were rarely indicated. Adequate radiotherapy for breast cancer can be safely administered after high-dose CTC with autologous PBSC support. Radiation-induced myelotoxicity is clearly enhanced following CTC, but this is of little clinical significance. Radiation pneumonitis after high-dose therapy may occur more often in patients with a history of lung disease or after a relatively high radiation dose to the chest wall. Other high-dose regimens, particularly those incorporating drugs with known pulmonary toxicity (such as BCNU), may predispose patients to radiation pneumonitis.     

Principles of treatment of malignant gliomas in adults: an overview

The cornerstone of conventional treatments of malignant gliomas in adults has been surgical debulking, radiation therapy and chemotherapy. Almost always a combination of these treatments is used. With these conventional treatments the outcome, as measured by survival and quality of life, has remained universally dismal. Novel treatments, which are at different stages of laboratory and clinical trials, may offer a ray of hope for treatment of malignant gliomas. Development of these methods are directly related to the discoveries, over the past two decades, of cellular and molecular mechanisms involved in the genesis of brain tumors. Understanding of the mechanisms of tumor genesis may open new avenues of effective treatments for this devastating cancer.     

Androgenetic alopecia in men and women: an overview of cause and treatment

Hair loss is a cause of anxiety and distress in both men and women. New understanding of the causes of androgenetic alopecia is leading to potential new medical therapies. Pathophysiology, clinical presentations, diagnosis, current and future treatments are discussed.     

Prevention and treatment of hypotension during spinal anesthesia

Spinal and epidural anaesthesias alter self-regulation of arterial pressure as they lead to a sympathetic blockade. The extent and the speed of appearance of this blockade conditions the magnitude of the decrease of arterial pressure. So, epidural or spinal anaesthesias may only be performed on hemodynamically stable patients for a non hemorrhagic surgery. The routine fluid preloading is illogical and poorly efficient. Correcting a deep arterial hypotension demands first of all the use of vasoconstricting agents the choice of which depends on the site of the anaesthesia and on the cardiovascular condition of the patient. The occurrence of bradycardia more often indicates a hypovolaemic state.     

Trovafloxacin: an overview

Trovafloxacin, a new synthetic naphthyridine fluoroquinolone antibiotic, is a broad-spectrum agent available orally and intravenously. It was recently approved by the Food and Drug Administration for the treatment of selected pulmonary, surgical, intraabdominal, gynecologic, pelvic, skin, and urinary tract infections. Its spectrum of activity includes aerobic gram-positive and gram-negative organisms as well as anaerobic pathogens. It is rapidly absorbed after oral administration, achieves good tissue and cerebrospinal fluid penetration, and has a half-life that allows once-daily dosing. It is hepatically metabolized, and dosage adjustments are necessary for patients with severe hepatic dysfunction but not for those with mild or moderate dysfunction or renal dysfunction. The drug has a favorable safety profile, and a high tendency for transient first-dose dizziness and/or lightheadedness in young women. Similar to other quinolones, trovafloxacin should not be taken with antacids that contain aluminum or magnesium, sucralfate, or ferrous sulfate. Trovafloxacin may prove beneficial as it allows for oral or intravenous monotherapy against indicated infections that normally require multidrug, broad-spectrum antibiotic coverage.     

Regulation of metabolism and growth during immune challenge: an overview of cytokine function

Commercially reared food animals encounter serial pathogenic and nonpathogenic immune challenges throughout production. Because of the diversion of nutrients away from growth in support of immune-related processes, immune challenge is considered a major obstacle to animals' achieving their genetic potential for growth or efficiency of gain. Scientists now recognize that many metabolic processes respond directly or indirectly to proinflammatory cytokines. This cytokine-mediated "reprogramming" of metabolism is a homeorhetic mechanism that ensures an adequate supply of nutrients for proliferation of lymphocyte and macrophage populations, antibody production, and hepatic synthesis of acute phase proteins. Proinflammatory cytokines have been linked to altered nutrient uptake and utilization. Anabolic processes are interrupted, and companion catabolic activities are amplified. Furthermore, cytokines may influence prenatal growth and development, and to the extent that postnatal proliferation and differentiation of myogenic and adipogenic cells contribute to postnatal growth, cytokine regulation of these events may ultimately influence growth. The following discussion is an overview of the impact of immune challenge and proinflammatory cytokines on metabolism and growth.     

Conditioned side effects induced by cancer chemotherapy: Prevention through behavioral treatment.

Cancer patients receiving chemotherapy often experience nausea and vomiting that develop as a result of classical conditioning. In order to determine whether this nausea and vomiting could be delayed or prevented, 24 cancer patients were randomized either to a group that received progressive muscle relaxation training (PMRT) plus guided imagery (GI), or to a no-treatment control group. Relaxation training sessions were held before the initiation of chemotherapy and during the first three chemotherapy treatments. Results indicated that patients receiving PMRT and GI had significantly less nausea and vomiting and significantly lower blood pressures, pulse rates, and dysphoria, especially anxiety, than did control patients. Nurse observations corroborated patient reports. These data suggest that early training in PMRT and GI can reduce and perhaps prevent the development of conditioned nausea and vomiting, and can alleviate high anxiety levels in cancer patients who receive emetogenic chemotherapy. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Adjuvant treatment of high-risk breast cancer using multicycle high-dose chemotherapy and filgrastim-mobilized peripheral blood progenitor cells

Women with primary breast cancer associated with extensive axillary node involvement or large primary tumors have a very poor prognosis despite treatment with standard-dose adjuvant chemotherapy. In an attempt to improve the outlook of these patients, we investigated the safety and feasibility of delivering three cycles of high-dose epirubicin and cyclophosphamide supported with filgrastim-mobilized peripheral blood progenitor cells (PBPC). Fifteen previously untreated women, median age 50 (range, 30-58) years, with poor prognosis early stage breast cancer received filgrastim (12 microgram/kg daily for 6 days) prior to chemotherapy to mobilize progenitor cells. Patients were then given three cycles of epirubicin (200 mg/m2) and cyclophosphamide (4 g/m2) at planned 28-day intervals, each followed by infusion of one third of the PBPC collected and daily administration of filgrastim (5 microgram/kg s.c.). Three leukaphereses collected a median of 114.9 (range, 22.7-273.5) x 10(4) granulocyte-macrophage-colony-forming cells/kg body weight. Hemopoietic recovery was rapid after each cycle, and there was no correlation between the rate of recovery and the number of granulocyte-macrophage-colony-forming cells infused. There was a small but significant progressive delay in recovery from hematological and nonhematological toxicities across the three cycles. Left ventricular ejection fraction fell to below 50% in eight (53%) patients, but none developed congestive cardiac failure. Two patients did not complete three cycles because of insufficient PBPC for a third cycle (n = 1) and 2-mercaptoethane sodium sulfonate- related drug reaction during the second cycle (n = 1). There were no deaths during the study or during the follow-up period (median, 70 weeks; range, 50-85 weeks), and no late toxicities occurred. Therefore, we concluded that the delivery of multiple cycles of nonmyeloablative, dose-intensive chemotherapy supported by PBPC and filgrastim is safe, and may be widely applicable to a variety of common chemosensitive cancers with a poor prognosis. The efficacy of three cycles of high-dose epirubicin and cyclophosphamide is to be compared with standard-dose chemotherapy in a randomized trial in patients with high-risk, operable stage II and III breast cancer.     

Carbohydrates and fertilization: an overview

Initial sperm-egg binding in mammals involves recognition of glycosylated proteins of egg zonae by glycosylated proteins on sperm surfaces. Egg zona protein structure is relatively simple, and has been strongly conserved. Species specificity must reside in the carbohydrate modifications on the egg surface, and in the co-ordinated assembly of a unique cohort of sperm proteins at capacitation. Fruitful advances have been made along four lines. Oligosaccharide structures capable of binding spermatozoa have been dissected by in-vitro synthesis and binding experiments, informed by the general advance of knowledge of protein glycosylation processes. Site-specific mutagenesis of zona proteins and their expression in tissue culture have identified glycosylation sites involved in species-specific sperm binding. Antibody and lectin labelling studies show a continuing process of remodeling of glycosylated sperm surface epitopes within a set of stable compartments during epididymal transit and capacitation of spermatozoa. Characterization of sperm-egg binding proteins from a variety of mammalian species shows that a different set of effectors induce acrosome reactions in each species, with each set including one or more sugar-recognizing proteins. Sequencing of some of these effectors suggests that each group may form a supermolecular complex to induce a species-specific acrosome reaction, with the functional activities distributed in a species limited or non-limited manner among the individual proteins.     

Acute porphyria and multiple organ failure during treatment with lamotrigine

A 38-year-old female suffered from an acute porphyric attack, multi-organ failure and disseminated intravascular coagulation (DIC) within two weeks of starting lamotrigine, a new antiepileptic drug. The porphyric attack was characterized by excess urinary excretion of aminolevulinic acid (ALA), porphobilinogen (PBG) and coproporphyrin III, a pattern similar to that seen in hereditary coproporphyria, however the diagnostic criteria for this specific porphyria were not fulfilled. We suggest that the observed clinical picture represents a rare adverse reaction to lamotrigine.     

Predicting etoposide toxicity: relationship to organ function and protein binding

PURPOSE: To investigate the effect of organ function on total and free etoposide pharmacokinetics and hematologic toxicity. PATIENTS AND METHODS: Seventy-two patients who received single-agent intravenous (i.v.) etoposide over 5 or 8 days (total dose, 500 mg/m2) were studied. Pharmacokinetic parameters were derived after analysis of total plasma etoposide by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection, and etoposide protein binding by ultrafiltration of an etoposide-spiked, pretreatment serum sample, followed by HPLC analysis. Free etoposide area under the concentration-time curve (AUC) was derived from the total AUC and protein binding. RESULTS: Patients with renal impairment (serum creatinine level > 130 mumol/L) had a lower plasma etoposide clearance (13.6 v 18.5 mL/min/m2; P = .016), resulting in an increased total-drug and free-drug AUC (total etoposide AUC 615 v 452 micrograms/mL.hr; P = .016; free etoposide AUC 26.0 v 17.6 micrograms/mL.hr; P = .026) and increased hematologic toxicity (nadir neutrophil count 0.3 v 1.9 x 10(9)/L; P = .005). Patients with albumin levels less than 35 g/L had no change in total etoposide kinetics but had an increase in unbound etoposide (5.2% v 4.1%; P = .01), resulting in an increase in free etoposide AUC (27.5 v 16.5 micrograms/mL.hr; P = .003) and more profound toxicity (nadir neutrophil count 0.6 v 1.9 x 10(9)/L; P = .004). In patients with normal albumin and creatinine, increased toxicity in those older than 65 years was associated with a reduced drug clearance, and in those with increased liver enzymes by a trend toward an increase in free etoposide AUC. CONCLUSION: Increased hematologic toxicity after etoposide in patients with abnormal organ function is mediated by an increase in free etoposide AUC. A reduction in dose is clearly indicated in such patients.