Robert Wesley

The cardiovascular response of normal humans to the administration of endotoxin.

Marked abnormalities in cardiovascular function accompany septic shock, and bacterial endotoxin is believed to be one of the principal mediators of these abnormalities. To evaluate the cardiovascular effects of endotoxemia in humans, we measured hemodynamic variables in nine normal subjects given an intravenous bolus dose of endotoxin (Escherichia coli, 4 ng per kilogram of body weight) and in six normal subjects given a bolus dose of saline, before and three hours after administration. All the subjects then underwent volume loading with normal saline (mean, 2217 ml) during the fourth and fifth hours after administration of the bolus, and the measurements were repeated. Three hours after the administration of endotoxin and before volume loading, the cardiac index had increased by 53 percent and the heart rate by 36 percent (both changes were significant; P less than or equal to 0.008), and the systemic vascular-resistance index had decreased by 46 percent (P = 0.004). After volume loading (five hours after the administration of endotoxin), the left ventricular ejection fraction decreased by 1 percent of the base-line value in the subjects given endotoxin, but increased by 14 percent in the controls (P = 0.008). The left ventricular end-diastolic and end-systolic volume indexes increased by 18 percent (P = 0.07) and 24 percent (P = 0.042), respectively. Left ventricular performance, as measured by the ratio of the peak systolic pressure to the end-systolic volume index, was depressed (a decrease of 0.90 in the subjects given endotoxin vs. an increase of 0.76 in the controls; P = 0.024). We conclude that the administration of endotoxin to normal subjects causes a depression of left ventricular function that is independent of changes in left ventricular volume or vascular resistance. The changes in function are similar to those observed in septic shock and suggest that endotoxin is a major mediator of the cardiovascular dysfunction in this condition.

The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy.

Between May 1975 and April 1981, 43 adult patients with high-grade soft tissue sarcomas of the extremities were prospectively randomized to receive either amputation at or above the joint proximal to the tumor, including all involved muscle groups, or to receive a limb-sparing resection plus adjuvant radiation therapy. The limb-sparing resection group received wide local excision followed by 5000 rads to the entire anatomic area at risk for local spread and 6000 to 7000 rads to the tumor bed. Both randomization groups received postoperative chemotherapy with doxorubicin (maximum cumulative dose 550 mg/m2), cyclophosphamide, and high-dose methotrexate. Twenty-seven patients randomized to receive limb-sparing resection and radiotherapy, and 16 received amputation (randomization was 2:1). There were four local recurrences in the limb-sparing group and none in the amputation group (p1 = 0.06 generalized Wilcoxon test). However, there were no differences in disease-free survival rates (71% and 78% at five years; p2 = 0.75) or overall survival rates (83% and 88% at five years; p2 = 0.99) between the limb-sparing group and the amputation treatment groups. Multivariate analysis indicated that the only correlate of local recurrence was the final margin of resection. Patients with positive margins of resection had a higher likelihood of local recurrence compared with those with negative margins (p1 less than 0.0001) even when postoperative radiotherapy was used. A simultaneous prospective randomized study of postoperative chemotherapy in 65 patients with high-grade soft-tissue sarcomas of the extremities revealed a marked advantage in patients receiving chemotherapy compared with those without chemotherapy in three-year continuous disease-free (92% vs. 60%; p1 = 0.0008) and overall survival (95% vs. 74%; p1 = 0.04). Thus limb-sparing surgery, radiation therapy, and adjuvant chemotherapy appear capable of successfully treating the great majority of adult patients with soft tissue sarcomas of the extremity.

A Randomized Trial Comparing Ceftazidime Alone with Combination Antibiotic Therapy in Cancer Patients with Fever and Neutropenia

To assess the efficacy of single-agent therapy relative to standard combination antibiotic therapy for the initial management of fever and neutropenia in cancer patients, we conducted a randomized trial comparing ceftazidime alone with a combination of cephalothin, gentamicin, and carbenicillin. Of 550 evaluable episodes of fever and neutropenia, 282 were treated with ceftazidime alone and 268 with the combination. All episodes were evaluated for responses at 72 hours after the start of treatment and at resolution of the neutropenia. Of the patients with unexplained fever who were given ceftazidime alone, 99 percent were alive at 72 hours and 98 percent were alive when the neutropenia resolved, as compared with 100 percent and 98 percent, respectively, of those given combination therapy. Of the patients with documented infection who were given ceftazidime alone, 98 percent were alive at 72 hours and 89 percent when the neutropenia resolved, as compared with 98 percent and 91 percent, respectively, of those given combination therapy. The majority of episodes of documented infection in both treatment groups necessitated additional antimicrobial treatment or other modifications of the initial regimen, as compared with only 22 percent of the episodes of unexplained fever. We conclude that initial single-agent therapy with certain beta-lactam antibiotics is a safe alternative to standard combination antibiotic therapy, although patients with documented infection or protracted neutropenia are likely to require additional or modified treatment.

Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use

Context Clinical studies of vitamin C as a potential anticancer agent have produced inconsistent results despite in vitro evidence that high concentrations kill cancer cells. Contribution Pharmacokinetic studies in healthy persons, using a depletion-repletion design, show that intravenous administration can achieve 70-fold higher blood levels of vitamin C than the highest tolerated oral dose. Cautions Although this study provides better understanding of the pharmacokinetic issues involved in research on vitamin C, it provides no evidence that vitamin C has any effect on cancer cells and cannot be used to support its clinical use for therapeutic purposes. The Editors Vitamin C in gram doses is taken orally by many people and administered intravenously by complementary and alternative medicine practitioners to treat patients with advanced cancer (1, 2). After oral intake, vitamin C plasma concentrations are tightly controlled at 70 to 85 mol/L for amounts (as much as 300 mg daily) that can be obtained from food (3, 4). However, concentrations achieved by higher pharmacologic doses are uncertain. Despite poor rationale, vitamin C in gram doses was proposed as an anticancer agent decades ago (5). Unblinded studies with retrospective or nonrandom controls reported clinical benefit from oral and intravenous vitamin C administered to patients with terminal cancer at a dosage of 10 g daily (1, 6, 7). Placebo-controlled trials in patients with cancer reported no benefit from oral vitamin C at a dosage of 10 g daily (8, 9), and vitamin C treatment was judged ineffective (10). However, in vitro evidence showed that vitamin C killed cancer cells at extracellular concentrations higher than 1000 mol/L (11, 12), and its clinical use by some practitioners continues. We recognized that oral or intravenous routes could produce substantially different vitamin C concentrations (13). We report here that intravenous doses can produce plasma concentrations 30- to 70-fold higher than the maximum tolerated oral doses. These data suggest that the role of vitamin C in cancer treatment should be reexamined, and insights from vitamin C pharmacokinetics can guide its clinical use. Methods Pharmacokinetic Studies in Healthy Persons The study was approved by the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. After we obtained written informed consent, 17 healthy volunteers (7 men, 10 women; age, 19 to 27 years) were studied as inpatients by using a depletion-repletion study design (3, 4). Participants were hospitalized for 3 to 6 months and consumed a vitamin C-deficient diet containing less than 0.005 g of vitamin C per day. At plasma vitamin C concentrations less than 8 mol/L, persons were depleted without signs of scurvy. Vitamin C, 0.015 g twice daily, was then administered orally until participants achieved a steady state for this dose (0.03 g daily). Participants received successive oral daily vitamin C doses of 0.03 g, 0.06 g, 0.1 g, 0.2 g, 0.4 g, 1.0 g, and 2.5 g until a steady state was achieved for each dose. Bioavailability sampling was conducted at a steady state for vitamin C doses of 0.015 g, 0.03 g, 0.05 g, 0.1 g, 0.2 g, 0.5 g, and 1.25 g. For each bioavailability sampling, vitamin C was administered in the fasting state. After oral administration, blood samples were collected at 0, 15, and 30 minutes and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 19, 22, and 24 hours (3, 4). After intravenous administration at 250 mg/min, blood samples were collected at 0, 2.5, 5, 10, 15, and 30 minutes and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, and 10 hours. Data obtained from bioavailability samplings were used to determine peak plasma and urine vitamin C concentrations. Pharmacokinetic Modeling We used data from 7 men to construct a unique 3-compartment vitamin C pharmacokinetic model with parameters describing saturable absorption, tissue distribution, and renal excretion and reabsorption (14). This model was used to predict peak plasma and urine vitamin C concentrations attained when pharmacologic doses of the vitamin are administered. For intravenous administration, it was assumed that vitamin C was infused at a rate of 1 g/min, and urine output was 100 mL/h. Vitamin C Assay Vitamin C was measured by using high-performance liquid chromatography with coulometric electrochemical detection (3, 4, 15). Statistical Analysis We compared plasma vitamin C concentration curves (against either dose or time) by repeated-measures analyses of variance (ANOVA). In addition to the repeating factor (dose or time), other factors considered were sex and route of administration. In the comparison of routes of administration at multiple doses, in which sex not only was an important factor itself but also had an important interaction with route, separate ANOVA were determined for men and women to assess the importance of route of administration. Analyses were performed by using DataDesk, version 5 (1995) (Data Description, Inc., Ithaca, New York). Role of the Funding Source The funding source had no role in the design, conduct, and reporting of the study or in the decision to submit the manuscript for publication. Results When 1.25 g of vitamin C was given intravenously, plasma concentrations were significantly higher than when the vitamin was given orally (P < 0.001 by repeated-measures ANOVA) (Figure 1). In addition, plasma concentrations were significantly higher over all doses (P < 0.001 by repeated-measures ANOVA) with intravenous compared with oral administration (Figure 1, inset). At the highest dose of 1.25 g, mean peak values from intravenous administration were 6.6-fold higher than mean peak values from oral administration. When all doses were considered, peak plasma vitamin C concentrations increased with increasing intravenous doses, whereas peak plasma vitamin C concentrations seemed to plateau with increasing oral doses. Urine vitamin C concentrations were higher for the same dose given intravenously compared with that administered by the oral route. At the highest dose of 1.25 g, peak urine concentrations from intravenous administration were approximately 3.5 times higher than from oral administration (data not shown). Figure 1. Plasma vitamin C concentrations in healthy volunteers after intravenous or oral administration of vitamin C. Inset: The 3-compartment vitamin C pharmacokinetic model that we developed predicted that a single oral dose of 3 g, the maximum tolerated single dose, produced a peak plasma concentration of 206 mol/L (Figure 2, top). Peak predicted concentration after a single 1.25-g oral dose was slightly lower at 187 mol/L. For 200 mg, an amount obtained from vitamin C-rich foods, peak predicted concentration was approximately 90 mol/L. Plasma concentrations for all of these amounts returned to steady-state values, approximately 70 to 85 mol/L, after 24 hours. With 3 g given orally every 4 hours, the maximum tolerable (6), peak predicted plasma concentration was approximately 220 mol/L (Figure 2, top). By contrast, after intravenous administration, predicted peak plasma vitamin C concentrations were approximately 1760 mol/L for 3 g, 2870 mol/L for 5 g, 5580 mol/L for 10 g, 13 350 mol/L for 50 g, and 15 380 mol/L for 100 g (Figure 2, bottom). Doses of 60 g given intravenously are used for cancer treatment by complementary and alternative medicine practitioners (2). Predicted peak urine vitamin C concentrations were as much as 140-fold higher after intravenous administration compared with oral administration (data not shown). Figure 2. Predicted plasma vitamin C concentrations in healthy persons after oral ( top ) or intravenous ( IV ) ( bottom ) administration of vitamin C. Discussion Our data show that vitamin C plasma concentrations are tightly controlled when the vitamin is taken orally, even at the highest tolerated amounts. By contrast, intravenous administration bypasses tight control and results in concentrations as much as 70-fold higher than those achieved by maximum oral consumption. Both findings have clinical relevance. Vitamin C oral supplements are among the most popular sold, and gram doses are promoted for preventing and treating the common cold, managing stress, and enhancing well-being (1). Our data show that single supplement gram doses produce transient peak plasma concentrations that at most are 2- to 3-fold higher than those from vitamin C-rich foods (200 to 300 mg daily). In either case, plasma values return to similar steady-state concentrations in 24 hours. Because differences in plasma concentrations from supplements and from food intake are not large, supplements would be expected to confer little additional benefit, a finding supported by available evidence (16, 17). However, consumption of fruits and vegetables, which contain vitamin C, is beneficial for unknown reasons (16, 17). On the basis of current knowledge and the pharmacokinetics presented here, physicians should advise their patients to consume fruits and vegetables, not vitamin C supplements, to obtain potential benefits. Just as important, our data show that intravenous administration of vitamin C produces substantially higher plasma concentrations than can be achieved with oral administration of vitamin C. This difference was previously unrecognized and may have treatment implications. Case series published by Cameron, Campbell, and Pauling (l, 6, 7) have been controversial. In these series, several hundred patients with terminal cancer treated with 10 g of vitamin C intravenously for 10 days and then 10 g orally indefinitely were compared with more than 1000 retrospective and prospective controls. Patients treated with vitamin C survived 150 to 300 days longer than controls (1, 6, 7). Other researchers reported benefit consisting of increased survival, improved well-being, and reduced pain (1). All of these studies

The grading of soft tissue sarcomas results of a clinicohistopathologic correlation in a series of 163 cases

A multidisciplinary study of 163 patients treated at the NCI for soft tissue sarcomas allowed the correlation of a number of histologic features (histologic type, mitosis, necrosis, pleomorphism, cellularity, and matrix) of the primary lesion to time to recurrence and overall survival of the patients. The results of the stratified analyses show that necrosis is the single best histopathologic parameter to predict the time to recurrence (P = 0.025) and the overall survival of the patients (P = 0.002). Necrosis in the primary lesion is also of value in predicting survival after the first recurrence has taken place (P = 0.001). The value of necrosis in the primary lesions predicting the clinical course after recurrence appears to be independent of age, sex, location, and size of the tumor. The authors propose a grading system based on histologic typing and histologic parameters to identify a group of lesions with minimal metastatic potential (Grade 1), and on the use of necrosis to distinguish between aggressive lesions with good patient survival (Grade 2) and aggressive lesions with poor patient survival (Grade 3).

CD4 Counts as Predictors of Opportunistic Pneumonias in Human Immunodeficiency Virus (HIV) Infection

STUDY OBJECTIVE To determine if circulating CD4+ lymphocyte counts are predictive of specific infectious or neoplastic processes causing pulmonary dysfunction. DESIGN Retrospective, consecutive sample study. SETTING Referral-based clinic and wards. PATIENTS We studied 100 patients infected with human immunodeficiency virus (HIV) who had had 119 episodes of pulmonary dysfunction within 60 days after CD4 lymphocyte determinations. MEASUREMENTS AND MAIN RESULTS Circulating CD4 counts were less than 0.200 X 10(9) cells/L (200 cells/mm3) before 46 of 49 episodes of pneumocystis pneumonia, 8 of 8 episodes of cytomegalovirus pneumonia, and 7 of 7 episodes and 19 of 21 episodes of infection with Cryptococcus neoformans and Mycobacterium avium-intracellulare, respectively. In contrast, circulating CD4 counts before episodes of nonspecific interstitial pneumonia were quite variable: Of 41 episodes, 11 occurred when CD4 counts were greater than 0.200 X 10(9) cells/L. The percent of circulating lymphocytes that were CD4+ had a predictive value equal to that of CD4 counts. Serum p24 antigen levels had no predictive value. CONCLUSIONS Pneumocystis pneumonia, cytomegalovirus pneumonia, and pulmonary infection caused by C. neoformans or M. avium-intracellulare are unlikely to occur in HIV-infected patients who have had a CD4 count above 0.200 to 0.250 X 10(9) cells/L (200 to 250 cells/mm3) or a CD4 percent above 20% to 25% in the 60 days before pulmonary evaluation. Patients infected with HIV who have a CD4 count below 0.200 X 10(9) cells/L (or less than 20% CD4 cells) are especially likely to benefit from antipneumocystis prophylaxis.

Systematic Review: The Effect of Preventive Lamivudine on Hepatitis B Reactivation during Chemotherapy

Context Does lamivudine prevent hepatitis B virus (HBV) reactivation among patients with cancer who test positive for hepatitis B surface antigen (HBsAg) and are undergoing chemotherapy? Contribution This systematic review of 14 studies found that, compared with no preventive lamivudine, lamivudine reduced HBV reactivation, HBV-related hepatitis, and HBV-related hepatic failure. Caution Studies were small and heterogeneous. Only 2 were randomized trials, and none compared lamivudine with other, newer anti-HBV agents. Implication Preventive lamivudine may reduce risk for HBV reactivation and associated death in HBsAg-positive patients with cancer who are undergoing chemotherapy. The Editors More than 350 million persons worldwide have hepatitis B virus (HBV) (1). Chronic infection with HBV is a major public health problem and is the leading cause of liver cancer in Asia and Africa (1). In the United States, the prevalence of HBV infection, defined as the presence of hepatitis B surface antigen (HBsAg) in the blood, is less than 1% but may be as high as 5% to 15% in immigrants from Asia, Africa, the Middle East, and Eastern Europe (2, 3). Infection with HBV can lead to chronic liver disease, cirrhosis, and liver cancer (4). However, many persons who continue to harbor HBV in serum and hepatocytes for many years have few (if any) clinical sequelae. These persons are considered to have the inactive HBsAg carrier state and have little evidence of liver disease, despite low levels of HBV replication in hepatocytes (5). In such individuals, immunosuppressive agents can precipitate an increase in HBV replication followed by a flare of hepatitis B that can be severe and even fatal (6). Prompt recognition and institution of anti-HBV therapy are desirable, but therapy may fail if substantial damage has already occurred (7). Because chemotherapy is highly immunosuppressive, it may cause flares of HBV in persons who carry HBsAg in their serum (7). Flares can occur despite normal serum alanine aminotransferase (ALT) levels and low levels of circulating virus before chemotherapy is started (7, 8) and may lead to high HBV-related morbidity and mortality (9). Because cancer is the second leading cause of death in the United States, a large proportion of the population may undergo chemotherapy during their lifetime (10). Therefore, even with a relatively low prevalence of the HBsAg carrier state, prevention of chemotherapy-induced HBV reactivation is an important medical problem and a public health concern. The problem is more critical in areas of the world where HBV infection is endemic (1). Lamivudine, a nucleoside analogue (11), effectively suppresses HBV replication, reduces levels of HBV DNA in serum, and improves liver injury in patients with chronic hepatitis B. Lamivudine also has an excellent long-term safety profile and is generally well tolerated (12). Several studies reported a beneficial effect of lamivudine in preventing HBV reactivation and HBV-related death in patients who tested positive for HBsAg and are undergoing chemotherapy (8, 13, 14). However, the quantitative benefits of preventive therapy with lamivudine have not been carefully defined. The magnitude of response to lamivudine for preventing morbidity and mortality in this clinical setting has direct implications for both clinicians and health policymakers. The research synthesis discussed here explored the following question: Does preventive lamivudine therapy reduce the risk for HBV reactivation, HBV-related hepatitis, acute hepatic failure due to HBV, or HBV-related death in patients who test positive for HBsAg and are undergoing chemotherapy? Methods Data Sources and Searches We searched the following databases in all languages until June 2007: MEDLINE from 1966, Ovid MEDLINE from 1950, TOXNET from 1965, Scopus from 1966, Web of Science from 1955, and the Cochrane Central Register of Controlled Trials from January 1997. Index terms included hepatitis B virus or HBV in combination with reactivation. Figure 1 shows our prespecified protocol. We also did a manual review of the bibliographies for seminal primary and review articles to identify additional relevant studies. Furthermore, we manually searched the 2006 and 2007 American Gastroenterological Association annual meeting abstracts. To maximize data requisition, we contacted authors whose articles contained inadequate information. In addition, we contacted authors of included studies to request information about long-term efficacy and safety outcomes, including cancer-related or all-cause mortality, adverse effects of lamivudine, and any new or unpublished data or relevant meeting abstracts. Figure 1. Study flow diagram. Study Selection The 4 criteria for analyzing studies in this research synthesis were randomized, controlled trials, or retrospective or prospective cohort studies with a control (concurrent or historical) group that allowed assessment of the rate of reactivation of hepatitis B after the start of chemotherapy with or without lamivudine therapy; a report of HBV reactivation, HBV-related hepatitis, acute hepatic failure due to HBV, or HBV-related death; a clear definition of the baseline population in terms of HBsAg positivity; and more than 5 participants per treatment group. Trials were excluded if relevant data could not be extracted. Case reports or series and studies that included posttransplantation patients or those with rheumatologic diseases or HIV were also excluded. The primary outcome measure of this research synthesis was reactivation of hepatitis B, defined as at least a 10-fold increase in serum HBV DNA levels with an accompanying increase in serum ALT compared with baseline. Secondary outcome measures included HBV-related hepatitis, defined as an increase in serum ALT that was 2 or more times greater than baseline levels and a 10-fold increase in serum HBV DNA levels; HBV-related hepatic failure, defined as elevated serum ALT level and prolonged prothrombin time or other evidence of coagulopathy with jaundice with or without encephalopathy after starting chemotherapy in patients who met criteria for HBV-related hepatitis; and HBV-related death, defined as death of a patient who had documented HBV reactivation that was reported by the authors as an HBV-related death and who had no other apparent cause of death. Data Extraction and Study Quality Two investigators independently screened titles and abstracts and extracted data from eligible studies. The independently identified articles that met the initial screening criteria were collectively reviewed in their entirety by these 2 investigators and were verified for the extracted data. Subsequently, 2 additional investigators confirmed whether eligible studies met the inclusion criteria and independently assessed the accuracy of data extraction. When necessary, conflict was resolved by consensus of all 4 investigators. The Appendix Table summarizes the methodological characteristics of the 14 studies eligible for this research synthesis. We considered randomized, controlled trials as high-quality evidence, prospective cohort studies with a concurrent control group as intermediate-quality evidence, and retrospective cohort studies and studies with a historical control group as low-quality evidence. Appendix Table. Methodological Characteristics of Clinical Trials Assessing the Efficacy of Preventive Lamivudine Data Synthesis and Statistical Analysis For each eligible study, relative risk (RR) and the exact 2-sided 95% CI were computed for the primary (HBV reactivation) and secondary (HBV-related hepatitis, HBV-related hepatic failure, and HBV-related death) outcomes by using StatXact PROCs (Cytel, Cambridge, Massachusetts). An RR less than 1.00 indicates risk reduction in the intervention group (lamivudine) over the control group (no or deferred lamivudine use). Graphics were created by using Comprehensive Meta Analysis Software (Biostat, Englewood, New Jersey). Because of the heterogeneity of patient populations, study designs, and other study methods, we considered it inappropriate to compute pooled estimates. Instead, we present study-specific estimates of effect and qualitatively describe the patterns of results overall. Role of the Funding Source This project was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases and the Clinical Center, National Institutes of Health. The funding sources had no role in conducting the study and have no potential conflicts of interest. Results Characteristics and Quality of Studies Fourteen studies met the specified criteria for assessment of HBV reactivation (Figure 1). Of these, 12 studies were conducted in East Asia (8, 13, 1523) and 1 each in Turkey (24) and Israel (25) (Table 1). All studies were in English except for 1 in Chinese (20). There were 2 randomized, controlled trials (8, 21); 8 prospective cohort studies (13, 15, 20, 2226), including 3 with concurrent control groups and 5 with historical control groups (13, 15, 22, 23, 26); and 4 retrospective cohort studies (1619) (Table 1). In addition, we identified 1 study (27) that compared lamivudine versus control in a similar patient population, but it did not report any of the outcomes of interest. The authors were contacted but did not provide further information, and thus we did not include the study. The Appendix Table describes the methodological characteristics and other quality indicators of the studies included in this review. The studies were generally small and did not consistently provide primary and secondary outcomes stratified by age, sex, ethnicity or race, baseline serum ALT levels, serum HBV DNA levels, or HBsAg status. On the other hand, patients included in both the treatment and the control groups were derived from similar patient populations at the same treatment center and received similar chemotherapeutic regimens. Furthermore, few patients

Diffuse Aggressive Lymphomas: Increased Survival After Alternating Flexible Sequences of ProMACE and MOPP Chemotherapy

A new treatment program was developed in an attempt to increase the complete remission rate and survival of previously untreated patients with advanced stages of diffuse aggressive lymphomas. A flexible number of cycles of ProMACE chemotherapy (prednisone, methotrexate, doxorubicin, cyclophosphamide, and epipodophyllotoxin VP-16) was alternated with a flexible number of cycles of MOPP chemotherapy (mechlorethamine, vincristine sulfate, procarbazine, and prednisone), and finally late intensification with ProMACE therapy was given. The duration of each phase of treatment was determined by the patients rate of tumor response. Complete remissions were achieved in 55 of 74 patients (74%) with a median duration of follow-up exceeding 2 1/2 years. Only ten of the complete responders (18%) have had relapse. The dose-limiting toxicity is myelosuppression, and eight patients (10%) died from sepsis. Median survival for all patients has not been reached but is predicted to exceed 4 years with 65% of patients alive at 4 years. Previously we achieved a 46% complete remission rate with 38% of all patients alive at 4 years; relapse-free survival beyond 2 years was tantamount to cure. Therefore, ProMACE-MOPP chemotherapy represents a substantial improvement in treating patients with diffuse aggressive lymphomas.

Patterns of recurrence in patients with high-grade soft-tissue sarcomas.

From July 1975 to December 1982, 563 patients were referred to the Surgery Branch of the National Cancer Institute with the diagnosis of soft-tissue sarcoma. Three hundred and seven of these patients had fully resectable, localized high-grade soft-tissue sarcomas and were treated at the National Cancer Institute using standard protocols with surgery alone, or in combination with chemotherapy and/or radiotherapy. An aggressive surgical approach was undertaken in the management of patients who subsequently developed recurrent disease. These 307 cases have been reviewed, with a median duration of follow-up of 30 months, to determine the frequency of recurrent disease, the patterns of recurrence, and the impact of surgery on the survival of patients who developed recurrent disease. Disease recurred in one hundred seven patients (107/307, 35%), with a median disease-free interval of 18 months (range, 0.5 to 72.0 months). The frequency of recurrence by site of primary sarcoma was extremity, 31% (65/211); head and neck, 33% (4/12); trunk, 40% (17/42); retroperitoneum, 47% (17/36); and breast, 67% (4/6). Isolated pulmonary metastatic disease was the most common pattern of initial recurrence (56/107, 52%) followed by isolated local recurrence (21/107, 20%). Single other sites of recurrence and multiple concurrent sites of recurrence each accounted for 14% (15/107) of all initial recurrences. The relative frequency of each of these four patterns of recurrence varied with the site of the primary sarcoma. The outcome for patients with recurrent disease depended on the site of recurrence, rather than on the site of the primary sarcoma. Sixty-six patients (66/107, 62%) with recurrent disease were rendered surgically disease-free with the first recurrence, including 40 (40/56, 72%) patients with isolated pulmonary metastases, 20 patients (20/21, 96%) with isolated local recurrences, five patients (5/15, 33%), with isolated other sites of recurrence and one patient (1/15, 7%) with multiple sites of initial recurrence. Following surgical resection, the actuarial three-year survival for the 66 patients rendered disease-free was 51%. The median survival for the 41 patients not rendered surgically disease-free with the first recurrence was only 7.4 months. Thirty of the sixty-six patients (30/66, 45%) rendered disease-free with the first recurrence remained disease-free at follow-up, with a median follow-up of 28 months from the time of resection of the first recurrence. The remaining 36 patients (36/66, 55%) subsequently recurred, with a median disease-free interval of 7.3 months.(ABSTRACT TRUNCATED AT 400 WORDS)

Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults.

One hundred twenty-four children and young adults with recurrent tumors, predominantly sarcomas, were treated with the combination of ifosfamide, etoposide, and the uroprotector, mesna (2-mercaptoethane sulphonate), in a phase II trial. The treatment regimen consisted of 12 cycles of therapy administered every 3 weeks. After evaluation of the tumor response to chemotherapy alone, radiation or surgery was used to eradicate residual sites of metastatic disease where possible. At the present time, 77 patients are evaluable for response to the chemotherapy; 43 of the patients have experienced a significant reduction in the tumor size in response to the chemotherapy alone (39 partial responses [PR] and four complete responses [CR]). Sixteen of 17 patients with Ewings sarcoma, nine of 13 with rhabdomyosarcoma, four of eight with peripheral neuroepithelioma, three of eight with osteosarcoma, and 11 of 31 with other tumors have responded with a PR or CR. The toxicity of the regimen was acceptable. Moderate or severe toxicity evaluated on a per cycle basis included: neutropenia, 97%; thrombocytopenia, 32%; nephrotoxicity, less than 1%; mucositis, 1%; neurologic toxicity, 2%; nausea and vomiting, 13%; hemorrhagic cystitis, less than 1%. Fever was present after 33% of cycles and sepsis following 7%. One patient died due to sepsis and pancytopenia. At the present time, only seven of the 43 patients who responded to the chemotherapy regimen have relapsed, with a median follow-up of 10 weeks after the response. This drug combination is highly active in the treatment of recurrent sarcomas and other tumors in children and young adults.