bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of undiluted or diluted high-dose etoposide with or without busulfan administered to patients with hematologic malignancies.
Authors: Mross K , Bewermeier P , Krüger W , Stockschläder M , Zander A , Hossfeld D K 
Published: February 2017

PURPOSE We used two different methods to administer high-dose etoposide (VP-16) during a myeloablative conditioning chemotherapy regimen before bone marrow transplantation (BMT). VP-16 was administered either diluted (0.5 mg/mL) or undiluted (20 mg/mL), with or without busulfan. PATIENTS AND METHODS Blood samples were drawn from 17 patients during the infusion (6 hours) and thereafter daily until 2 days after BMT. VP-16 concentrations were measured in all plasma samples by high-performance liquid chromatography (HPLC) and electrochemical detection, and the results were analyzed with a pharmacokinetic data analysis system. RESULTS All calculated pharmacokinetic parameters in the two patient groups (VP-16 administered diluted or undiluted) were similar. There were no statistically significant differences in half-lives, mean residence time (MRT), volume of distribution, total clearance, or area under the curve (AUC). VP-16 was found in blood samples from eight of 17 patients at the time of BMT. Significant differences in systemic drug exposure and systemic clearance were found when patients were grouped according to treatment with busulfan or with total-body irradiation (TBI). CONCLUSION The two administration modes for VP-16, either diluted or undiluted, are bioequivalent in pharmacokinetic terms. The terminal half-lives were longer than expected and resulted in significant VP-16 plasma levels at the time of BMT. The biologic significance remains unclear. Busulfan and/or concomitant medication with phenytoin influence plasma clearance (clp) and systemic drug exposure significantly.
Prognostic factors and outcome of incompletely resected invasive thymoma following radiation therapy.
Authors: Ciernik I F , Meier U , Lütolf U M 
Published: February 2017

BACKGROUND Stage III and stage IV thymomas with significant macroscopic infiltration to the neighboring structures are rarely completely resectable. It therefore remains unclear to what extent tumors must be surgically debulked to improve prognosis. PATIENTS AND METHODS We reviewed the cases of 31 patients with incompletely resected invasive thymoma and residual macroscopic disease who were referred to postoperative irradiation. Survival and local tumor control were analyzed. All patients were treated between 1958 and 1990 with megavoltage irradiation at doses ranging from 42 to 66 Gy. The shortest follow-up time for living patients was more than 5 years. RESULTS The overall median 5-year survival rate was 45%. Eighteen stage III patients had a 5-year survival rate of 61% and a 10-year survival rate of 57%. Thirteen patients had stage IV disease and 5- and 10-year survival rates of 23% and 8%, respectively. Univariate and multivariate analyses confirmed a worse prognosis for stage IV disease. Epithelial or spindle-cell thymoma was associated with stage IV disease. Twenty-two percent of patients with stage III disease had epithelial or spindle-cell thymoma, versus 69% of patients with stage IV disease (P = .02 for univariate and P = .05 for multivariate analysis). Initial tumor diameter greater than 10 cm correlated with poor prognosis in the univariate analysis (P = .05). However, more importantly, debulking of tumor did not significantly improve outcome when compared with patients who received biopsy only. The median survival rate of patients with stage IVa disease did not differ from that of those with stage IVb disease. Mediastinal control was achieved in 23 patients (74%). Stage IV disease did not correlate with an increase in local treatment failure after irradiation, although epithelial or spindle-cell thymoma predisposed for local treatment failure (46% v 11%; P = .04 in univariate and P = .055 in multivariate analysis). CONCLUSION Tumor debulking leaving macroscopic residual thymoma, as opposed to biopsy alone, does not improve prognosis when followed by radiation. Radiation therapy for local tumor control is most effective in nonepithelial-predominant thymomas.
Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: a phase II study.
Authors: Abratt R P , Bezwoda W R , Falkson G , Goedhals L , Hacking D , Rugg T A 
Published: February 2017

PURPOSE The aim of this study was to evaluate the efficacy and toxicity of gemcitabine at higher doses than had been used previously in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Eighty-four patients (65 men, 19 women; age range, 35 to 75 years; mean age, 59 years) with locally advanced or metastatic pathologically documented NSCLC were enrolled. Patients had bidimensionally measurable disease, as defined by computed tomographic (CT) scan or chest x-ray. A total of 28.6% had previously been surgically treated, while 9.5% had received radiotherapy. Fifty-three patients commenced at a dose of 1,000 mg/m2, and 31 at a dose of 1,250 mg/m2. Patients were to receive two dose escalations of 25%, provided that overall toxicity was no worse than World Health Organization (WHO) grade 1 or WHO grade 0 for platelets. Responding patients were reviewed and validated by a blinded oncology review board (ORB) of experts not involved with the study. Of the original 84 patients enrolled, 76 were assessable. RESULTS The overall response rate was 20% (95% confidence interval [CI], 11.6% to 30.8%). There were two complete responses (3%) and 13 partial responses (17%). Hematologic toxicity was negligible. WHO grade 3 WBC toxicity occurred in 0.9% of doses and WHO grade 4 in 0.1%. WHO grade 3 and 4 thrombocytopenia occurred in 0.1% and 0.1% of all doses, respectively. Nonhematologic toxicity was minor and easily controlled. Common side effects included peripheral edema, asthenia, and transient malaise. CONCLUSION The single-agent efficacy of gemcitabine is equivalent to other agents commonly used to treat NSCLC. Gemcitabine has an unusually mild side effect profile for such an active agent. The nausea and vomiting experienced with gemcitabine are mild and generally well controlled with standard antiemetics; 5-HT3 receptor antagonists are typically not required. The use of gemcitabine does not cause significant alopecia, and hematologic toxicity is modest and unlikely to require hospitalization. Gemcitabine may have a role as monotherapy in patients with inoperable NSCLC.
Role of radiotherapy in combined modality treatment of locally advanced non-small-cell lung cancer.
Authors: Kubota K , Furuse K , Kawahara M , Kodama N , Yamamoto M , Ogawara M , Negoro S , Masuda N , Takada M , Matsui K 
Published: February 2017

PURPOSE For patients with locally advanced (stage III) non-small-cell lung cancer (NSCLC), radiotherapy (RT) has been used conventionally for many years. Few prospective trials have determined the role of RT. Recently, chemotherapy (CT) has been shown to produce excellent responses in regionally advanced disease. We therefore conducted a randomized trial using cisplatin (P)-based CT regimens with or without thoracic irradiation. PATIENTS AND METHODS We randomly assigned 92 patients with locally advanced NSCLC to receive one of three arms of P-based combination chemotherapy: vindesine (V) plus P, mitomycin (M) plus V plus P, or etoposide (E) plus P alternating with V plus M. After two cycles of CT, patients were reevaluated and those with stage III were again randomized to receive RT or not. RT consisted of 50 to 60 Gy in 5 to 6 weeks; 2 Gy was delivered once daily in conventional fractions. RESULTS Sixty-three patients were included in the second randomization. The patients in the CT/RT group (n = 32) and CT-alone group (n = 31) were comparable in terms of age, sex, performance status, histologic features, stage of disease, and induction CT regimen. The median durations of survival were similar for the two groups (461 days in CT/RT group and 447 days in CT-alone group). The survival rate in the CT/RT group was 58% at 1 year, 36% at 2 years, and 29% at 3 years, as compared with 66%, 9%, and 3% at 1, 2, and 3 years, respectively, in the CT-alone group. One patient in the CT/RT group died of pneumonitis, but there were no CT-related deaths. CONCLUSION In locally advanced NSCLC, P-based combination CT followed by chest irradiation significantly increases the number of long-term survivors as compared with CT alone. RT to bulky disease in the thorax is thus an important part of combined modality therapy, and a necessary part of further studies in locally advanced disease.
Multiinstitutional phase II trial of intensive combination chemoimmunotherapy for metastatic melanoma.
Authors: Atkins M B , O'Boyle K R , Sosman J A , Weiss G R , Margolin K A , Ernest M L , Kappler K , Mier J W , Sparano J A , Fisher R I 
Published: February 2017

PURPOSE To evaluate the activity and toxicity of combined high-dose cisplatin, dacarbazine (DTIC), and tamoxifen chemotherapy and high-dose bolus interleukin-2 (IL-2) in patients with metastatic melanoma. PATIENTS AND METHODS Patients with metastatic melanoma, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and normal organ function were enrolled onto this multiinstitutional Cytokine Working Group trial. Patients received intensive chemoimmunotherapy consisting of cisplatin (50 mg/m2) and DTIC (350 mg/m2) intravenously (IV) on days 1 to 3 and 43 to 45, IL-2 600,000 IU/kg IV every 8 hours on days 12 to 16 and 26 to 30 (maximum, 28 doses), and tamoxifen 20 mg orally each day. Patients were evaluated for response at day 63 of each cycle, and responding patients were given a second cycle of therapy beginning on day 71 to 85. RESULTS Thirty-eight patients were entered onto this study. Toxicities were as expected for the chemotherapy and immunotherapy components of this regimen. Overlapping toxicity consisted primarily of thrombocytopenia (76% of patients required platelet transfusions), neutropenia, anemia, fatigue, and weight loss. Despite these cytopenias, bleeding and infectious complications were rare. There were no treatment-related deaths. Three patients achieved a complete response (CR; 8%), and 13 achieved a partial response (PR). The overall objective response rate was 42% (95% confidence interval [CI], 26% to 58%). Six additional patients had greater than 50% tumor reduction at day 63, which did not persist until a subsequent evaluation. The median duration of response was 5 months (range, 2 to 20+), and the median survival duration was 11 months. CONCLUSION This intensive treatment regimen appears to possess activity in metastatic melanoma comparable, but not superior, to that of other less intensive cisplatin- and IL-2-based chemoimmunotherapy regimens. Although the toxicity and complexity of this regimen make it unsuitable for phase III testing and impractical for more widespread use, the results of this study support a potential favorable interaction between IL-2 and chemotherapy in this disease and highlight the need for appropriately designed phase III trials.
Phase I/II study of iodine 131-labeled monoclonal antibody A33 in patients with advanced colon cancer.
Authors: Welt S , Divgi C R , Kemeny N , Finn R D , Scott A M , Graham M , Germain J S , Richards E C , Larson S M , Oettgen H F 
Published: February 2017

PURPOSE A phase I/II study was designed to determine the maximum-tolerated dose (MTD) of iodine 131-labeled monoclonal antibody (mAb) A33 (131I-mAb A33) administered intravenously, its limiting organ toxicity, and its radioisotope retention in tumors, and to develop preliminary evidence of antitumor activity. PATIENTS AND METHODS Patients (N = 23) with colorectal cancer who had failed to respond to conventional chemotherapy but had not received prior radiotherapy were treated with escalating doses of 131I-mAb A33. Three or more patients were entered at each dose level, starting at 30 mCi/m2, with increments of 15 mCi/m2 to a maximal dose of 90 mCi/m2. Radiolabeling was performed to maintain a specific activity of 30 mCi/m2/4 mg mAb A33 (projected maximum, 15 mCi/mg). Patients were under strict isolation precautions until whole-body radiation levels decreased to less than 5 mrem/h at 1 m. Serial radioimmunoscintigrams were performed in some cases for up to 3 weeks after 131I-mAb A33 administration. RESULTS All 20 patients with radiologic evidence of disease showed localization of radioisotope to sites of disease. Two patients with elevated carcinoembryonic antigen (CEA) levels and negative radiologic tests did not have positive antibody scans. One patient with a small-bowel cancer also had a negative antibody scan. The major toxicity was hematologic and was more pronounced in patients with compromised bone marrow due to prior chemotherapy. Of five patients who received 78 to 84 mCi/m2 131I-mAb A33, one had grade 3 and one grade 4 toxicity; of six patients treated with 86 to 94 mCi/m2 131I-mAb A33, two had grade 4 and one grade 1 toxicity. The MTD was determined to be 75 mCi/m2 in these heavily pretreated patients. Although the isotope showed variable uptake in the normal bowel, gastrointestinal symptoms were mild (n = 8) or absent. No major responses were observed; however, three patients had evidence of mixed responses, and CEA levels decreased in two patients without clinical or radiologic measurable disease. Immunoreactivity of radiolabeled mAb A33 decreased at the highest dose levels in preparations in which specific activity exceeded 18 mCi/mg. CONCLUSION The A33 antigen appears to be a promising target for radioimmunotherapy of colon cancer. The modest antitumor activity of 131I-mAb A33 in heavily pretreated patients is encouraging because of its lack of toxicity in the bowel, the only antigen-positive normal tissue.
Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report.
Authors: Yang J C , Topalian S L , Parkinson D , Schwartzentruber D J , Weber J S , Ettinghausen S E , White D E , Steinberg S M , Cole D J , Kim H I 
Published: February 2017

PURPOSE A randomized prospective study was performed to compare the efficacy and toxicity of high-dose intravenous bolus interleukin-2 (IL-2) and a lower-dose intravenous bolus regimen for the treatment of metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS Between March 1991 and April 1993, 125 patients with metastatic RCC were randomized to receive IL-2 by intravenous bolus every 8 hours at either 720,000 IU/kg (high-dose) or 72,000 IU/kg (low-dose) to the maximum-tolerated number of doses (or a maximum of 15 doses). After approximately 7 to 10 days, both treatment groups were re-treated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5 to 6 weeks later went on to receive re-treatment with another course (two cycles) of therapy. Response rates and toxicity were determined for the two treatment arms. RESULTS One hundred twenty-five patients received a total of 208 courses of therapy. Sixty patients were randomized to receive low-dose, and 65 to receive high-dose IL-2. There were no treatment-related deaths in either arm. There was a greater incidence of grade III or IV thrombocytopenia, malaise, and hypotension in patients who received high-dose IL-2, while patients who received low-dose IL-2 had significantly more infections. Three percent of treatment courses with low-dose IL-2 required vasopressor support, compared with 52% of courses with high-dose IL-2. Patients who received low-dose IL-2 had a 7% complete response (CR) and an 8% partial response (PR) rate, and patients who received high-dose IL-2 had a 3% CR and a 17% PR rate. CONCLUSION Low-dose intravenous bolus IL-2 represents an effective regimen for the treatment of metastatic RCC, with preliminary results comparable to those observed with high-dose IL-2. Low-dose IL-2 can be administered with significantly fewer complications, reduced use of vasopressor support, and fewer admissions to an intensive care unit (ICU).
Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group.
Authors: Spaulding M B , Fischer S G , Wolf G T 
Published: February 2017

PURPOSE In 1984, the Department of Veterans Affairs Cooperative Studies Program began a trial in which patients with resectable squamous cell carcinoma of the larynx were randomized to receive standard surgery followed by radiation therapy or to receive neoadjuvant therapy with cisplatin and fluorouracil (5-FU) followed by radiation therapy for those achieving a greater than 50% tumor response to chemotherapy. This analysis reviews the tumor responses, toxicity, compliance, and long-term survival for those patients randomized to the chemotherapy arm. PATIENTS AND METHODS One hundred sixty-six patients were randomized to the chemotherapy arm. Standard tumor response data, chemotherapy toxicity, and survival have been examined using standard statistical methods. RESULTS The high response rates and acceptable toxicity to cisplatin and 5-FU of previously untreated patients were confirmed. Long-term disease-free survival was more likely to occur in patients who achieved a complete response to chemotherapy, particularly in those who had a confirmed histologic response to chemotherapy. Pretreatment histologic growth patterns were highly predictive of responses to chemotherapy. CONCLUSION Neoadjuvant chemotherapy was well tolerated and did not negatively affect the definitive treatment that followed. The survival of nonresponding patients who underwent prompt salvage surgery was also not impaired. The role of organ preservation should be explored in other head and neck sites.
Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion.
Authors: Wilson W H , Berg S L , Bryant G , Wittes R E , Bates S , Fojo A , Steinberg S M , Goldspiel B R , Herdt J , O'Shaughnessy J 
Published: February 2017

PURPOSE A phase I study of paclitaxel infused over 96-hours was performed to determine toxicity, maximum-tolerated dose (MTD), and pharmacokinetics in patients with incurable lymphomas and solid tumors. A phase II study was performed at the MTD of paclitaxel in patients with doxorubicin/mitoxantrone-refractory metastatic breast cancer. PATIENTS AND METHODS In the phase I study, paclitaxel dose levels ranged from 120 to 160 mg/m2, administered on a 21-day cycle. Patients with metastatic breast cancer who had either no response or a partial response (PR) to doxorubicin or mitoxantrone and had measurable disease were eligible for the phase I and II studies. Expression of the multidrug resistance (mdr-1) gene was determined in tumor biopsies by mRNA quantitative polymerase chain reaction. RESULTS Twelve patients received a total of 73 cycles of paclitaxel on the phase I study. Dose-limiting mucositis and/or grade IV granulocytopenia was reached at 160 mg/m2, and 140 mg/m2 was selected as the phase II dose. Thirty-six consecutive patients with metastatic breast cancer were treated, of whom three were not assessable. The median age was 49 years, with disease in the liver and/or lung in 76%. Patients received a median of two prior regimens for metastatic disease, and 73% had no response to prior doxorubicin or mitoxantrone. Of 33 patients treated with paclitaxel, 16 patients (48%) achieved a PR and five (15%) achieved a minor response (MR). With a median potential follow-up duration of 60 weeks, the median progression-free and overall survival durations were 27 and 43 weeks, respectively. No correlation was found between extent of prior treatment or prior response to doxorubicin/mitoxantrone, and response to paclitaxel. Paclitaxel pharmacokinetics showed a correlation between both granulocyte and mucosal toxicity, and serum steady-state concentrations (Css) more than 0.07 mumol/L. Patients with liver metastases had significantly decreased paclitaxel clearance and higher paclitaxel Css. Levels of mdr-1 were uniformly low in all tumor biopsies studied. CONCLUSION The recommended phase II dose of paclitaxel is 140 mg/m2 in patients without liver metastases and 105 mg/m2 in patients with liver metastases. Ninety-six-hour infusions of paclitaxel were effective and well tolerated in patients with doxorubicin/mitoxantrone-refractory breast cancer. Prolonged infusion schedules may be more effective than shorter schedules and deserve further study.
Salvage therapies in women who fail to respond to first-line treatment with fluorouracil, epirubicin, and cyclophosphamide for advanced breast cancer.
Authors: Porkka K , Blomqvist C , Rissanen P , Elomaa I , Pyrhönen S 
Published: February 2017

PURPOSE We studied all salvage therapies given until death or the end of follow-up evaluation in women who failed to respond to the same first-line cytotoxic therapy for metastatic breast cancer. PATIENTS AND METHODS The study cohort consisted of 140 women who had received the fluorouracil, epirubicin, and cyclophosphamide (FEC) regimen for metastatic breast cancer. Eight patients were excluded. No exclusions with respect to disease site, performance status, or biochemical abnormalities were made. The median follow-up time was 29 months for surviving patients. RESULTS Most patients (88%) died during the follow-up period. Patients received a median of three salvage therapies (range, zero to eight) during the course of disease. Most courses (52%) were not assessable for response. Fifty-percent of courses consisted of chemotherapy: 35% of hormonal and 15% of combination of cytotoxic and hormonal therapies. The median duration of therapy (DT) ranged from 4 to 1 months, and decreased with advancing stages of therapy. Similarly, median time to treatment failure (TTF) ranged from 3 to 0.5 months. For unknown causes, patients who received second-line hormonal therapy fared better than those who received other forms of therapy. Of 366 analyzed courses, only one complete response (CR) and 18 partial responses (PRs) were observed (response rate, 11% for assessable and 5% for all courses). Stable disease for at least 3 months was found in 20% to 25% of courses. Most responses (n = 10) occurred during first salvage therapy, and no responses were observed after third salvage therapy. CONCLUSIONS Response rates for salvage therapies were low, and median treatment times short. The value of offering more than two salvage chemotherapy regimens to an unselected group of patients is questionable.