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For several decades, providers have routinely restricted the diets of neutropenic cancer patients by eliminating foods that might harbor pathogenic microbes to reduce infection rates. These diets, known as neutropenic or low-bacteria diets, are prescribed across the country with little uniformity in the extent or content of prescription. These diets are difficult to follow and force patients to omit fresh fruits and vegetables and limit dairy and meat products from their diet. These dietary omissions compromise nutritional intake in patients who are already at high risk of malnutrition. Randomized trials have shown that these restrictive diets are not superior in preventing infections than more liberalized diets. Evidence shows that adherence to the Safe Food-Handling guidelines issued by the Food and Drug Administration, a mandate for all hospital kitchens, provides adequate protection against food-borne infection, precluding the need for the neutropenic diet. Thus, routine use of the neutropenic diet should be abandoned., (© 2018 Society of Hospital Medicine.)

Background: To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010., Objectives: To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival., Search Methods: We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations., Selection Criteria: We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment., Data Collection and Analysis: We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status., Main Results: We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low., Authors' Conclusions: Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.

Purpose: To improve image quality and reduce data requirements for spatial electron paramagnetic resonance imaging (EPRI) by developing a novel reconstruction approach using compressed sensing (CS)., Methods: EPRI is posed as an optimization problem, which is solved using regularized least-squares with sparsity promoting penalty terms, consisting of the l1 norms of the image itself and the total variation of the image. Pseudo-random sampling was employed to facilitate recovery of the sparse signal. The reconstruction was compared with the traditional filtered back-projection reconstruction for simulations, phantoms, isolated rat hearts, and mouse gastrointestinal (GI) tracts labeled with paramagnetic probes., Results: A combination of pseudo-random sampling and CS was able to generate high-fidelity EPR images at high acceleration rates. For three-dimensional (3D) phantom imaging, CS-based EPRI showed little visual degradation at nine-fold acceleration. In rat heart datasets, CS-based EPRI produced high quality images with eight-fold acceleration. A high resolution mouse GI tract reconstruction demonstrated a visual improvement in spatial resolution and a doubling in signal-to-noise ratio (SNR)., Conclusion: A novel 3D EPRI reconstruction using compressed sensing was developed and offers superior SNR and reduced artifacts from highly undersampled data., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: To improve the quality and speed of electron paramagnetic resonance imaging (EPRI) acquisition by combining a uniform sampling distribution with spinning gradient acquisition., Theory and Methods: A uniform sampling distribution was derived for spinning gradient EPRI acquisition (uniform spinning sampling, USS) and compared to the existing (equilinear spinning sampling, ESS) acquisition strategy. Novel corrections were introduced to reduce artifacts in experimental data., Results: Simulations demonstrated that USS puts an equal number of projections near each axis whereas ESS puts excessive projections at one axis, wasting acquisition time. Artifact corrections added to the magnetic gradient waveforms reduced noise and correlation between projections. USS images had higher SNR (85.9 ± 0.8 vs. 56.2 ± 0.8) and lower mean-squared error than ESS images. The quality of the USS images did not vary with the magnetic gradient orientation, in contrast to ESS images. The quality of rat heart images was improved using USS compared to that with ESS or traditional fast-scan acquisitions., Conclusion: A novel EPRI acquisition which combines spinning gradient acquisition with a uniform sampling distribution was developed. This USS spinning gradient acquisition offers superior SNR and reduced artifacts compared to prior methods enabling potential improvements in speed and quality of EPR imaging in biological applications., (Copyright © 2013 Wiley Periodicals, Inc.)

In vivo or ex vivo electron paramagnetic resonance imaging (EPRI) is a powerful technique for determining the spatial distribution of free radicals and other paramagnetic species in living organs and tissues. However, applications of EPRI have been limited by long projection acquisition times and the consequent fact that rapid gated EPRI was not possible. Hence in vivo EPRI typically provided only time-averaged information. In order to achieve direct gated EPRI, a fast EPR acquisition scheme was developed to decrease EPR projection acquisition time down to 10-20 ms, along with corresponding software and instrumentation to achieve fast gated EPRI of the isolated beating heart with submillimeter spatial resolution in as little as 2-3 min. Reconstructed images display temporal and spatial variations of the free-radical distribution, anatomical structure, and contractile function within the rat heart during the cardiac cycle., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Demographic factors and treatment regimens were evaluated in relation to differences in outcome between patients with advanced nonsmall cell lung cancer (NSCLC) who were diagnosed and treated on Eastern Cooperative Oncology Group Phase II and III trials from 1981 to 1990 and from 1991 to 2000., Methods: In this retrospective analysis, 6 advanced NSCLC trials were identified between 1981 and 1990, and 3 trials were identified after 1990. Patient characteristics (n = 3398 patients) and other clinical outcomes were analyzed, including progression-free survival (PFS) and overall survival (OS)., Results: Patients who entered on trials after 1990 more likely were women, received a cisplatin-containing regimen, had a performance status of 0 or 1, had Stage IIIB (vs. Stage IV) disease, had tumors with adenocarcinoma histology, had weight loss < or = 10%, and had pulmonary-only metastases (although more total metastases and brain metastases) compared with patients who were diagnosed before 1990. OS was longer post-1990 than pre-1990 (8.2 months vs. 5.8 months pre-1990), and PFS was longer post-1990 (3.5 months vs. 2.6 months pre-1990; P<.001 for both). In addition, the median interval from the date of disease progression to death increased by nearly 62% in the later decade., Conclusions: Improved survival in more recent NSCLC trials was explained in part by the enrollment of patients with more favorable prognostic factors. A change in the natural history of the disease was reflected by some of these changes, including increased numbers of women with the disease and changes in the patterns of metastases. Changes in eligibility criteria also accounted for some improvements in prognostic factors and improved second line therapies in the later decade. Thus, the survival improvements are likely to be multifactorial, with improved therapies also playing a major role., (Copyright 2006 American Cancer Society)

Background: Survivin, which is a member of the inhibitor of apoptosis protein gene family, regulates both programmed cell death and mitosis. It has been shown that survivin expression and its subcellular localization both have prognostic value for patients with malignant disease. In this study, the authors investigated whether nuclear or cytoplasmic staining of survivin was a prognostic marker for patients with lung carcinoma., Methods: Paraffin-embedded tissue blocks from 144 patients with Stage I and II resected nonsmall cell lung carcinoma (NSCLC) were obtained for immunohistochemical staining. Three specimens from each patient were prepared and stained with a survivin-specific antibody. Nuclear and cytoplasmic staining was graded from 1 to 3 based on intensity., Results: Patients who had nuclear staining for survivin had a significantly increased risk of disease recurrence (hazard ratio, 2.95; P = 0.0046) and death (hazard ratio, 2.74; P = 0.0086)., Conclusions: The nuclear presence of survivin may be an independent biomarker for disease recurrence and overall survival in patients with resected Stage I and II NSCLC., ((c) 2005 American Cancer Society.)

Background: To determine the changes in clinical trials and outcomes of patients with limited-stage small cell lung carcinoma (SCLC) treated on Phase III randomized trials initiated in North America between 1972 and 1992., Methods: Phase III trials from 1972 to 1992 for patients with limited-stage SCLC were identified. Patients with limited-stage SCLC treated during a similar time interval were also evaluated in the Surveillance, Epidemiology, and End Results (SEER) database. Trends were tested in the number of trials, in the number and gender of patients entered on trial, and in survival duration over time., Results: Thirty trials involving 6564 patients were eligible for analyses. Nineteen trials (61%) involving 3626 patients were initiated within the first half of this time period (1972-1981). The median of median survival times of all patients treated on the control arms of the Phase III trials initiated between 1972 and 1981 and between 1982 and 1992 were 12.0 months (range, 10-16 months) and 17.0 months (range, 11-20 months), respectively (P < 0.001). Of 26 studies available for survival analysis, 5 (19%) showed a statistically significant survival prolongation in the experimental arm compared with the control arm with a median prolongation of 3.4 months (range, 1-5.2 months). All five evaluated some aspect of thoracic radiation therapy. Over a similar time period, there was a 6.4-month increase in the median survival of limited-stage SCLC patients listed in the SEER database (P < 0.0001) and a more than doubling of the 5-year survival from 5.2% to 12.1% (P = 0.0001)., Conclusions: Analyses of the patients with limited-stage SCLC treated on Phase III trials in North America initiated between 1972 and 1992 and those listed in the SEER database show significant improvements in median survivals. Furthermore, the 5-year survival of patients with limited-stage SCLC listed in the SEER database has more than doubled over the last 25 years. Further research will be needed to determine the relative contribution of improved therapy, supportive care, and stage migration to this prolongation in survival., (Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10841)

Background: Eastern Cooperative Oncology Group (ECOG) Study E1594 compared paclitaxel and cisplatin with three newer chemotherapy doublets in the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC). The accrual of patients with an ECOG performance status (PS) of 2 was discontinued due to a perceived rate of unacceptable toxicity., Methods: Patients were stratified by PS and randomized to one of the following treatments: 1) paclitaxel (135 mg/m2) over 24 hours with cisplatin (75 mg/m2) on a 21-day cycle; 2) cisplatin (100 mg/m2) with gemcitabine (1 g/m2) on Days 1, 8, and 15 on a 28-day cycle; 3) cisplatin (75 mg/m2) with docetaxel (75 mg/m2) on a 21-day cycle; and 4) paclitaxel (225 mg/m2) over 3 hours with carboplatin (area under the curve, 6). All tests of statistical significance were two-sided., Results: Sixty-eight patients with an ECOG PS of 2 were enrolled, and 64 patients were evaluable for toxicity and response. Fifty-six percent of 64 evaluable patients were male, and 81% had Stage IV disease. Grade 3-4 hematologic toxicities occurred in > 50% of the patients in each treatment group. Nonhematologic Grade 3-4 toxicities occurred significantly less often in the paclitaxel and carboplatin arm (P = 0.0032). The overall rate of toxicity did not differ significantly from the rate of toxicity in the PS-0 or PS-1 cohorts. There were 5 deaths (7.35%) among 68 patients with a PS of 2 during therapy; however, only 2 of those deaths were attributed to therapy. The overall response rate for the 64 evaluable patients was 14%. The overall median survival of all 68 patients with a PS of 2, as determined by an intent-to-treat analysis, was 4.1 months., Conclusions: Patients with advanced NSCLC and a PS of 2 experienced a large number of adverse reactions and overall poor survival. A comparison with patients with a PS of 0-1 suggests that these events and the shorter survival were related to disease process rather than treatment. Alternative strategies need to be explored with therapy specifically tailored for this group of patients., (Copyright 2001 American Cancer Society.)

Background: Patients with thymic tumors (thymoma and thymic carcinoma) are known to respond to a variety of chemotherapeutic agents, including single-agent ifosfamide and cisplatin with etoposide. The purpose of this trial was to evaluate the response rate, progression free survival, overall survival, and toxicity of combined etoposide, ifosfamide, and cisplatin (VIP) in patients with advanced thymoma and thymic carcinoma., Methods: From July 1995 through February 1997, 34 patients with advanced thymoma or thymic carcinoma were entered on trial to receive etoposide (75 mg/m2 on Days 1-4) ifosfamide (1.2 g/m2 on Days 1-4), and cisplatin (20 mg/m2 on Days 1-4). Cycles were repeated every 3 weeks for four total cycles., Results: Among 28 evaluable patients (pathology review excluded 6 patients), there were no complete responses and 9 partial responses (complete and partial responses combined, 32%; 95% confidence interval, 16-52%). The median follow-up was 43 months (range, 12.8-52.3 months), the median duration of response was 11.9 months (range, < 1-26 months), and the median overall survival was 31.6 months. Based on Kaplan-Meier estimates, the 1-year and 2-year survival rates were 89% and 70%, respectively. The toxicity was predominantly myelosuppression., Conclusions: The VIP regimen has moderate activity in patients with advanced thymic malignancies. However, with limited follow-up, the results of this trial appear to be inferior to other chemotherapy regimens reported in large Phase II trials performed in patients with this disease., (Copyright 2001 American Cancer Society.)

Background: Current therapy for patients with carcinoma of an unknown primary site (CUP) is inadequate. To develop less toxic and more effective therapies for patients with CUP, a multicenter, randomized, Phase II study was conducted. Patients with CUP received either carboplatin and etoposide (CE) or a combination of paclitaxel, 5-fluorouracil, and leucovorin (TFL)., Methods: Patients randomized to Arm A received paclitaxel, 175 mg/m(2), intravenously over 3 hours on Day 1 followed by leucovorin, 300 mg, over 30-60 minutes and 5-fluorouracil, 350 mg/m(2), both intravenously on Days 1-3. Patients randomized to Arm B received etoposide, 100 mg/m(2), intravenously on Days 1-3 and carboplatin at an area under the curve of 6 on Day 1 only. The cycles in both treatment arms were repeated every 28 days. Patients were followed for tumor response, survival, and toxicity., Results: Thirty-four patients were enrolled, 32 of whom were evaluable for response. An identical overall response rate of 19% (95% confidence interval, 4-45%) was noted in each treatment arm. The median survival for the entire study population was 194 days. The median survivals observed in Arm A and Arm B were 251 days and 194 days, respectively (P = 0.91 [difference not significant]). Hematologic toxicity on Arm B was considerable with 29% of the patients developing neutropenia and fever. Toxicity on Arm A was modest., Conclusions: In this randomized Phase II trial, CE and TFL appeared to have modest activity in CUP patients, with response rates similar to those reported with previously described chemotherapy regimens. Toxicity with CE was more severe than expected, although TFL was found to be well tolerated., (Copyright 2001 American Cancer Society.)

Background: Elderly patients comprise a significant portion of patients with limited stage small cell lung carcinoma. However, the prognostic importance of age has been controversial, and concern for toxicity often hinders enthusiasm for offering full dose therapy., Methods: In this retrospective analysis of Intergroup Trial 0096, the authors compared the outcome of patients 70 years or older to those younger than 70 years. Patients received cisplatin 60 mg/m(2), Day 1 and etoposide 120 mg/m(2), Days 1-3 for 4 cycles and either once or twice daily concurrent thoracic radiotherapy to 45 grays., Results: Of 381 patients, 50 (13%) were age 70 years or older. The elderly group did not differ significantly from those younger than 70 years with respect to gender distribution, performance status, or weight loss. Severe hematologic toxicity (Grade 4-5: 61% vs. 84%; P < 0.01) and fatal toxicity (1% vs. 10%; P = 0.01) occurred more often among older patients. There were no differences in the frequency of nonhematologic toxicities. Response rate (88% vs. 80%; P = 0.11), event free survival rate (5 year, 19% vs. 16%; P = 0.18), time to local failure, and duration of response did not differ between groups. Overall survival rates (5 year, 22% vs. 16%; P = 0.05) favored those younger than 70 years. Much of the difference in overall survival rates between age groups occurred within the first 6 months on study., Conclusions: Elderly patients had similar response and survival rates compared with those younger than 70 years. However, toxicity, particularly hematologic, was greater among the elderly. Selected older patients, such as those with a good performance status, should be considered for optimum treatment approaches., (Copyright 2000 American Cancer Society.)

Background: Nonsmall cell lung carcinoma comprises approximately 75% of all lung carcinoma cases in the U.S. Newly evolving strategies have created considerable controversy regarding the optimal treatment for patients diagnosed with this disease., Methods: A 17-item survey was designed to collect demographic data and information regarding practice patterns for nonsmall cell lung carcinoma, including patient assessment, treatment approaches, and roles of chemotherapy and radiotherapy. Surveys were mailed in the summer of 1997 to approximately 9200 oncologists of all types throughout the U.S. Practice settings included private office, private hospital, academic, university-affiliated office, government, and Veterans Administration institutions., Results: Approximately 10% of the oncologists responded (n = 979), including 499 medical oncologists (51%), 464 radiation oncologists (47%), and 16 others (2%). For the adjuvant treatment of surgically resected N1-2 disease, combined modality treatment was preferred over radiation therapy alone by medical oncologists (48% vs. 16%; P<0.001) and radiation therapy alone was preferred over combined modality treatment by radiation oncologists (55% vs. 38%; P<0.001). The combination of paclitaxel and carboplatin was the preferred first-line regimen for all stages of nonsmall cell lung carcinoma by the majority of medical oncologists (55%), whereas the majority of radiation oncologists (58%) chose the combination of etoposide and platinum. With regard to the optimal combined modality approach, respondents were divided evenly between concurrent chemoradiotherapy (34%) and sequential chemoradiotherapy (31%). Overall, respondents reported basing treatment decisions largely on published literature (55%) compared with personal experience (19%), seminars and colleagues (16%), and clinical trial availability (10%) (P<0.001)., Conclusions: This survey confirms many differences in practice patterns among medical oncologists and radiation oncologists in the treatment of patients with nonsmall cell lung carcinoma and suggests the need for the multidisciplinary management of this entity. In addition, the current study demonstrates that reliance on the medical literature as a basis for treatment steadily declines the longer the physician has been in practice., (Copyright 2000 American Cancer Society.)

Background: The dysregulation of both myc gene expression and retinoid signaling pathways commonly occurs in small cell lung carcinoma (SCLC). Because preclinical data showed that all-trans-retinoic acid (RA) inhibited SCLC growth, altered myc expression, and blocked transition to a treatment-resistant phenotype, a Phase II trial was designed to determine the effects of the combination of RA, cisplatin, and etoposide in patients with SCLC., Methods: Patients with untreated, extensive stage SCLC were treated with up to 8 cycles of cisplatin, 60 mg/m2, intravenously (i.v.) on Day 1 and etoposide, 120 mg/m2, i.v. on Days 1-3 in addition to up to 1 year of oral RA, 150 mg/m2/day., Results: Of 22 assessable patients 1 had a complete response and 9 had a partial response, for an overall response rate of 45% (95% confidence interval, 24-68%). The median survival was 10.9 months and the 1-year survival was 41%. The median duration of chemotherapy was 6 cycles and the median duration of RA treatment was 2.8 months. Thirteen patients discontinued RA prematurely due to toxicity and only 4 responders were receiving RA at the time of recurrence. Toxicity-limiting RA treatment mainly was comprised of mucocutaneous changes and headaches., Conclusions: RA at a dose of 150 mg/m2/day was tolerated poorly in combination with cisplatin plus etoposide, leading to early discontinuation of RA in the majority of patients. The hematologic toxicity, response rate, and survival were similar to those associated with cisplatin and etoposide in prior trials. Further studies with more active and less toxic agents will be required to determine the role of retinoids in the treatment of SCLC.

A case involving a 27-year-old woman who ingested an overdose of acebutolol is presented. Extracorporeal membrane oxygenation was initiated to stabilize the patient's condition before commencing hemodialysis. S-diacetolol (the N-acetelation product of acebutolol) was cleared with hemodialysis. It is suggested that extracorporeal membrane oxygenation may be of short-term benefit in the treatment of overdoses with beta-adrenergic agents such as acebutolol when accelerated clearance with hemodialysis is anticipated.

Background: The authors evaluated a high-intensity inpatient regimen using augmented but subtransplantation doses of multiple agents in patients with metastatic breast cancer. Two high-dose courses were given in an attempt to improve the efficacy of high-dose regimens using a single course., Methods: Forty women received treatment between October 1988 and October 1991. The median age was 38 years (range, 24-56 years). Twenty-five patients were receiving their first chemotherapy for metastatic disease; 15 patients had received one or more prior regimens. The patients received two courses of chemotherapy, which consisted of the following: cyclophosphamide 1500 mg/m2 intravenously (i.v.) on days 1 and 2; doxorubicin 45 mg/m2 i.v. on days 1 and 2; cisplatin 20 mg/m2 i.v. on days 1, 2, 3, 8, 9, and 10; 5-fluorouracil 1000 mg/m2 on days 8, 9, and 10 (continuous infusion); methotrexate 100 mg/m2 i.v. on days 15 and 22; leucovorin 15 mg/m2 i.v. or by mouth for four doses beginning 24 hours after methotrexate. Etoposide 400 mg/m2 i.v. on days 1, 2, and 3 was substituted for doxorubicin in 14 patients who had received prior doxorubicin., Results: Twenty-nine of 40 patients (73%) had objective response to therapy, with 10 (25%) complete responses. Four patients who obtained a complete response remain disease-free at 14, 21, 28, and 32 months, respectively; all of these patients received this regimen as first-line therapy for metastatic disease. Myelosuppression was severe, with median durations of leukocytes less than 1000/microliters and platelets less than 50,000/microliters of 15 days (range, 7-48 days) and 13 days (range, 3-49 days), respectively. Moderate or severe mucositis occurred in 56 of 68 courses. Four patients (10%) had treatment-related deaths., Conclusions: This regimen produced high overall response and complete response rates compared with standard regimens. However, only 15% of patients who received this therapy as first-line treatment for metastatic breast cancer remain disease-free, and median response duration was shorter than that reported using high-dose therapy with bone marrow support. Toxicity with this regimen was greater than anticipated, although myelosuppression and stomatitis would be reduced by the use of cytokines. This regimen does not improve results achieved with standard therapy sufficiently to justify its toxicity and expense.

Etoposide is a schedule-dependent agent with greater activity against small cell lung cancer (SCLC) when a given dose is administered over several days compared with a 1-day administration of the same dose. In an attempt to capitalize on the schedule dependency of etoposide, 22 previously untreated extensive-stage SCLC patients were given cisplatin (100 mg/m2 on day 1) plus 21 days of low-dose, oral etoposide (50 mg/m2/d). Chemotherapy was repeated every 28 days for four cycles. Complete blood counts were monitored weekly, and etoposide was discontinued if either the leukocyte or platelet count dropped below 2000/microliters or 75,000/microliters, respectively. All 22 patients were evaluable for response; 18 had either a complete (9%) or partial response (73%), an overall response rate of 82% (95% confidence interval, 62% to 93%). The median response duration was 7 months, and the median survival was 9.9 months (range, 1 to 17+ months). Sixteen (73%) patients received all planned cycles of etoposide. In Cycle 1 of chemotherapy, the median leukocyte nadir was 2700/microliters (range, 100 to 6300/microliters), and median platelet nadir was 180,000/microliters (range, 51,000 to 397,000/microliters). Life-threatening leukopenia (less than 1000/microliters) was rare (3 of 74 cycles). There were three treatment-related deaths, only one of which was associated with neutropenia. One patient had mild renal insufficiency that resolved after discontinuation of therapy. Alopecia was observed in all patients, but other nonhematologic toxicities were uncommon. A randomized study is necessary to determine if this schedule of cisplatin and etoposide administration is superior to more standard methods. However, these data do not indicate a major survival benefit will be derived from increasing the duration of etoposide administration when used in combination with cisplatin given every 28 days.

Twenty-eight patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) received neoadjuvant chemotherapy with cisplatin (120 mg/m2 on days 1 and 29) and vinblastine (4 mg/m2 weekly for 6 weeks). At the completion of induction chemotherapy, all patients were assessed for resectability. Those patients judged to be resectable underwent thoracotomy. All remaining patients received thoracic radiation therapy (5500 cGy) followed by additional chemotherapy in those patients responding to neoadjuvant treatment. There were 15 partial responses to neoadjuvant chemotherapy for an overall response rate of 54% (95% confidence interval, 36% to 71%). Only five partially responding patients (18%) were thought to have had sufficient tumor regression to allow for a potentially curative resection. However, a complete resection was done in only two patients. Overall median survival was 12 months (range, 4 to 72 months) with 1-year, 2-year, and 3-year survival rates of 54%, 39%, and 11%, respectively. The primary toxicity associated with neoadjuvant chemotherapy was moderate to severe (Eastern Cooperative Oncology Group Grade 3 or 4) nausea and emesis in 25% of patients. Hematologic toxicity was relatively modest; only one patient had Grade 4 leukopenia (less than 1000/microliter). Fever and neutropenia were uncommon, and there were no documented septic episodes or treatment-related deaths. Compared with historic controls treated with radiation therapy alone, cisplatin-based neoadjuvant chemotherapy appeared to improve the median and long-term survival of Stage III NSCLC patients modestly.

A novel chemotherapeutic approach was designed for the treatment of intermediate and high-grade histology non-Hodgkin's lymphoma using augmented (but subtransplantation) doses of chemotherapy administered at frequent intervals in the inpatient setting. For the initial evaluation of this regimen, poor prognosis patients were treated with a projected long-term survival rate of less than 25% in response to standard therapy. Between March 1982 and May 1988, 56 previously untreated patients were entered into this study; all patients had either high-grade histology (20 patients) or predominantly large cell lymphoma (36 patients). Median age was 41.5 years (range, 18 to 69 years). Poor prognosis features included: Stage IV, 71%; poor performance status (Eastern Cooperative Oncology Group scale, 2 to 4), 55%; multiple extranodal sites of disease, 52%; elevated lactic dehydrogenase (greater than 300 IU/l), 43%; and bulky (greater than 10 cm) tumor masses, 30%. Thirty-three of 56 patients (59%) were in Shipp's Category 3. During the 6-year study, the chemotherapy regimen was modified in an attempt to improve efficacy and reduce toxicity. However, most patients received a 2-month course of therapy as follows: cyclophosphamide 1500 mg/m2 intravenously (IV) on days 1, 2, and 29; etoposide 400 mg/m2 IV on days 1, 2, and 3 and 100 mg/m2 on days 29, 30, 31; doxorubicin 45 mg/m2 IV on days 29, 30; vincristine 1.4 mg/m2 IV on days 8, 22, 36, and 50; bleomycin 10 units/m2 IV on days 8, 22, 36, and 50; methotrexate 200 mg/m2 IV on days 15 and 43 followed 24 hours later by leucovorin 15 mg/m2 IV every 6 hours for six doses; and prednisone 60 mg/m2 orally on days 1 to 7 and 29 to 35. The complete response (CR) rate was 77% (95% confidence interval, 64% to 86%). There were ten relapses, only one of which occurred after 18 months of follow-up. Overall event-free survival (EFS) was 52% (95% confidence interval, 36% to 68%), with a median follow-up of 36 months. Eleven of 13 patients with small noncleaved lymphoma had CR; actuarial EFS in this subgroup was 61%. Myelosuppression occurred in all patients, with severe leukopenia (less than 1000/microliters) lasting a median of 12 days (range, 3 to 29 days); toxic deaths occurred in five patients (9%; 95% confidence interval, 4% to 19%). This intensive approach improved the response and survival of very poor risk non-Hodgkin's lymphoma patients.

Curative combination chemotherapy is available for many patients with aggressive non-Hodgkin's lymphoma (NHL); however, treatment of elderly patients with these regimens is difficult due to excessive toxicity. From 1983 to 1988 the authors treated 26 patients 65 years and older with aggressive NHL with a novel 8-week chemotherapy regimen containing bleomycin, etoposide, cyclophosphamide, doxorubicin, methotrexate with leucovorin, and prednisone (BECALM), designed to preserve dose intensity and minimize toxicity. Median age was 75 years. Histologic types included the following: 20 intermediate grade (16 large noncleaved cell; two large cleaved cell; one intermediate grade, unspecified); six high grade (four small noncleaved cell; one immunoblastic sarcoma B-cell; one high grade, unspecified). Twenty-one patients were Stage III or IV. Twenty-two of 26 patients had one or more of the following: tumor greater than 10 cm; multiple extranodal sites; lactate dehydrogenase (LDH) 400 IU/l or greater; small noncleaved cell histologic type. Chemotherapy consisted of bleomycin 20 U intravenously (IV) weeks 1 and 7; etoposide 75 mg/m2 IV every day x 3 days on week 4; cyclophosphamide 600 mg/m2 IV weeks 1, 4, 7; doxorubicin 40 mg/m2 IV weeks 1, 7; methotrexate 50 mg/m2 IV weeks 1, 2, 4, 5, 7, 8 with oral leucovorin rescue; prednisone 60 mg orally for 10 days on weeks 1, 4, 7. Eighteen patients completed the 8-week treatment course. There were 13 complete responses (CR); seven patients remain in continuous CR at a median follow-up of 37.5 months. There have been five relapses, including one late relapse; and one patient died of an intercurrent illness in CR. Overall and actual event-free survivals are 38% and 27%, respectively. The major toxicities were neutropenic fever and mucositis. There were four treatment-related deaths. The authors conclude that BECALM chemotherapy can be administered to elderly patients with aggressive NHL. Although neurotoxicity and cumulative toxicity from bleomycin and anthracycline are avoided, the regimen remains moderately toxic, particularly with respect to myelosuppression. Treatment results compare favorably with other reported regimens in this group of patients with multiple poor prognostic features.

Etoposide is a schedule-dependent drug with excellent activity against small cell lung cancer (SCLC). Single-agent etoposide achieves overall response rates ranging from 15% to 84%, depending on the schedule of drug administration and the characteristics of the treated population. The route of etoposide administration (intravenous versus oral) has little impact on response rate, provided appropriate dose adjustments are made for oral therapy. In combination with other active agents, etoposide has proven particularly effective in the management of SCLC. Etoposide can be substituted for doxorubicin or vincristine in the cyclophosphamide, doxorubicin, and vincristine (CAV) regimen without loss of efficacy. The etoposide and cisplatin (EP) combination is thought to be synergistic and has proven to be an effective salvage regimen for CAV failures. A regimen that alternates CAV and EP has been found by some investigators to be modestly more effective against SCLC than CAV alone; however, EP alone may be as useful as an alternating regimen. Most studies to date have demonstrated that EP induction is at least as effective as any other standard induction regimen. However, EP has the potential advantage of being more easily integrated with thoracic radiation therapy (RT). This is particularly important in limited-disease patients: two recent pilot studies employing EP induction with hyperfractionated thoracic RT yielded 2-year survival rates of greater than 50%. These promising results are being evaluated further in an ongoing Phase III trial in the United States. The available data indicate that etoposide is one of the most active agents against SCLC and therefore should be included as a component of induction therapy in all patients. New schedules of etoposide administration warrant further study.

Etoposide is an important drug that has been recently incorporated with other agents in the curative treatment of patients with advanced neoplasms, including germ cell tumors, non-Hodgkin's lymphomas (NHL), and small cell lung cancer (SCLC). Etoposide demonstrates remarkable schedule dependency. A randomized comparison has shown an impressive survival difference for patients with extensive SCLC receiving a 5-day course versus those receiving a 1-day course. Because of these and previous clinical and laboratory data, etoposide is now given intravenously or orally in a 3-day to 5-day schedule. It is generally accepted that approximately 50% of the orally administered drug is absorbed. The authors have initiated several etoposide studies using an extended administration schedule, believing that a prolonged schedule may be superior to the standard 3-day to 5-day schedule. This was initially tested in a Phase I study. Results showed that etoposide (50 mg/m2/d) given over 21 days was feasible and was associated with only moderate toxicity. Several Phase II studies have been completed or are nearing completion, including studies in patients with SCLC, NHL, germ cell tumors, soft tissue sarcoma, renal carcinoma, and ovarian carcinoma. Responses have been seen in all of these groups, particularly in patients with SCLC, lymphoma, and germ cell tumors. In these groups we saw responses in patients who were clearly resistant to etoposide plus cisplatin given in a standard schedule or in some patients who were resistant to high-dose etoposide with bone marrow transplantation. Investigators at Indiana University Medical Center who studied oral etoposide in a similar fashion in patients with advanced germ cell tumors and SCLC achieved results similar to those reported here. The authors have initiated a number of combination chemotherapy programs using the chronic oral form of etoposide. These include patients with SCLC, non-small cell lung cancer, and elderly patients with high-grade and intermediate forms of NHL. In addition, chronic intravenous oral etoposide is being used in salvage approaches for patients with acute myelocytic leukemia and recurrent resistant intermediate-grade and high-grade NHL. Preliminary pharmacokinetic data suggest that a 50-mg/m2 oral dose is highly bioavailable (91% to 96%). Therefore, during a prolonged oral course at 50 mg/m2, many patients maintain a minimum plasma concentration of 1 microgram/ml. Further studies of multiple dose or continuous infusion etoposide to maintain a potentially critical plasma level are in progress. Etoposide administered in this way could represent a "new" drug because many of its features are different, and its activity spectrum may be broader.

In a randomized multi-center study, 83 patients with small cell lung cancer were randomly assigned to treatment with cisplatin 100 mg/m2 intravenously (IV) day 1 and etoposide 120 mg/m2 IV days 1, 2, and 3 or cisplatin 100 mg/m2 IV day 1 and etoposide 120 mg/m2 IV day 1 and 240 mg/m2 orally days 2 and 3. Both regimens were repeated every 4 weeks. Prior to randomization, patients were stratified by extent of disease, performance status, and gender. A total of 41 patients were randomly assigned to the parenteral treatment only regimen, and 42 patients received cisplatin and IV/oral etoposide therapy. Both treatment arms were comparable regarding patient characteristics. Limited disease (LD) patients constituted 52% and 49% of the patient population for the oral and IV etoposide regimens, respectively. The overall complete response (CR) and partial response (PR) rate was 50% (95% confidence interval [CI] 35% to 65%) for the oral etoposide regimen and 59% (95% CI 44% to 74%) for the IV etoposide regimen (P = 0.438). For both regimens, 55% of the LD patients achieved either CR or PR. Time to progression and survival were comparable for both treatment arms. Hematologic toxicity was comparable in both treatment arms, with 80% of patients experiencing grade 3 or 4 neutropenia or thrombocytopenia. Moderate to severe anemia and weight loss were more predominant with the IV than with the oral regimen.

Patients with poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA) of unknown primary site comprise 25% to 35% of the patients with carcinoma of unknown primary site. Some of these patients have neoplasms that are highly responsive to combination chemotherapy, and a minority have potentially curable tumors. Between 1978 and 1982, 68 patients were treated with combination chemotherapy (most received cisplatin, vinblastine, and bleomycin [PVB] with or without doxorubicin). Thirty-eight patients (56%) responded to treatment, with 15 (22%) complete responder (CR) and 9 (13%) long-term, disease-free survivors. Since that time, we have incorporated etoposide into the treatment of these patients because of its synergism with cisplatin and its great activity against several other neoplasms, including germ cell tumors. Seventeen patients with PDC of unknown primary site received salvage therapy with etoposide and cisplatin after failing PVB. Ten of these patients had partial responses (PR), with a median response duration of 5 months (range, 2 to 12 months). Thirty-two previously untreated patients with PDC received etoposide and cisplatin combinations as initial treatment. Eighteen of 30 evaluable patients (60%) responded to therapy, and 11 patients (37%) had CR. Seven patients remain disease-free 39 to 63 months after the completion of therapy. Etoposide is an active drug in the treatment of PDC of unknown primary site. Preliminary results indicate that initial treatment with etoposide and cisplatin combinations produces results equivalent to or superior to those achieved with PVB.

Two patients with metastatic adrenal cortical carcinoma were treated with cisplatin and etoposide. Both achieved a partial remission after only one cycle. One patient had a "nonfunctioning" tumor that had previously regressed on mitotane whereas the second patient presented with classical Cushing's syndrome. Although the latter patient's urinary 17-ketosteroids normalized while receiving mitotane, the tumor itself failed to regress objectively. Cisplatin plus etoposide appears to be an active combination for the treatment of metastatic adrenal cortical carcinoma.

Fifteen patients with breast cancer who had skeletal metastases already present at the time the primary breast lesion was detected, were retrospectively identified. The majority were postmenopausal, estrogen receptor-positive, and had large (often neglected) primary lesions. Eleven patients were asymptomatic with respect to their skeletal metastases, although bone scans and bone roentgenograms revealed multiple areas of involvement in all patients. The median survival from the time of diagnosis was 33 months (range, 1-74 months); the 5-year actuarial survival was 45%. Systemic therapy with hormones or chemotherapy was effective in producing subjective responses; radiotherapy to painful bony areas was also an effective palliative treatment. Median survival in this group of patients was significantly improved when compared to our breast cancer patients who had extraskeletal metastases at initial diagnosis (33 versus 9 months, respectively), and to previously reported series of breast cancer patients with metastases at initial diagnosis. Since patients with Stage IV breast cancer and metastases limited to the skeleton often have prolonged survival, complications from bone metastases (e.g. pathologic fracture, epidural spinal cord compression) and other intercurrent illnesses should be managed aggressively.

Patients with germ cell neoplasms who are in complete remission 2 years after treatment have a very high probability of cure, and reports of recurrences occurring after 2 years are rare. Of 81 testicular cancer patients treated for advanced disease at Vanderbilt University between 1970 and 1985, five developed a recurrent or metachronous germinal tumor 58 to 195 months after the initial treatment. Only two of these patients had received prior cisplatin-based combination chemotherapy. Four patients had unfavorable prognostic features when tumor recurrence was diagnosed. All five patients responded to salvage chemotherapy, although there were only two complete responses. The extent of disease was a significant factor in predicting response to salvage therapy. The possible mechanisms of development of a late recurrence of germinal neoplasms include the following: (1) malignant degeneration of mature teratoma to germinal malignancy; (2) growth of an occult testicular tumor not eliminated by chemotherapy due to the presence of a blood-testicular barrier; (3) development of a second primary germ cell neoplasm; or (4) late relapse due to persistent microscopic viable tumor with an atypical less aggressive biologic behavior. "Cured" germ cell tumor patients need careful follow-up beyond 2 years. At a minimum, these patients should be seen annually. Patients found to have teratomas following cisplatin-based chemotherapy should probably undergo more frequent evaluations.