bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter, randomized, double-blind, placebo-controlled, dose-titration study of oral pilocarpine for treatment of radiation-induced xerostomia in head and neck cancer patients.
Authors: LeVeque F G , Montgomery M , Potter D , Zimmer M B , Rieke J W , Steiger B W , Gallagher S C , Muscoplat C C 
Published: February 2017

PURPOSE To determine the efficacy and safety of pilocarpine hydrochloride for symptomatic relief of postradiation xerostomia symptoms and for saliva production in patients with head and neck cancer. PATIENTS AND METHODS One hundred sixty-two head and neck cancer patients who had received at least 40 Gy of radiation (117 patients had received > 60 Gy) with clinically significant xerostomia were enrolled onto a randomized, double-blind, placebo-controlled, multi-center clinical investigation. Patients received 2.5-mg tablets for the first 4 weeks, 5.0-mg tablets for the second 4 weeks, and 10.0-mg tablets for the last 4 weeks of the 12-week study. Patients were allowed to titrate pilocarpine or placebo for improvement in symptoms or to reduce side effects. Patients were evaluated for symptomatic relief by questionnaires and visual analog scales (VAS), and for saliva production by sialometry. RESULTS Pilocarpine produced a significant improvement (P = .035) in overall global assessments compared with placebo. There was a statistically significant (P = .020) decreased use of oral comfort agents such as artificial saliva, hard candy, and water. Values for symptomatic improvement in dryness approached significance (P = .057). There were statistically significant postdose improvements in whole and parotid salivary flow in pilocarpine treatment groups versus placebo. All pilocarpine dosages tested were judged to be safe. Adverse experiences were primarily sweating, rhinitis, headache, nausea, and urinary frequency, with the most common side effect being mild to moderate sweating. There were no serious drug-related adverse experiences in any of the pilocarpine treatment groups. CONCLUSION It is concluded that pilocarpine produces clinically significant benefits for the symptomatic treatment of postradiation xerostomia. Best results were obtained with continuous treatment for 8 to 12 weeks with doses greater than 2.5 mg three times per day.
Rapid administration of multiple cycles of high-dose myelosuppressive chemotherapy in patients with metastatic breast cancer.
Authors: Crown J , Kritz A , Vahdat L , Reich L , Moore M , Hamilton N , Schneider J , Harrison M , Gilewski T , Hudis C 
Published: February 2017

PURPOSE To determine the feasibility and safety of a rapidly cycled sequence of high-dose myelosuppressive chemotherapy courses. PATIENTS AND METHODS Seventeen patients with metastatic breast cancer were treated with two courses of cyclophosphamide (CPA; 3.0 g/m2) supported by granulocyte colony-stimulating factor (G-CSF). Following the first CPA treatment, peripheral-blood leukaphereses commenced when the leukocyte count recovered to 1.0 x 10(9)/L. After hematologic recovery from the second dose of CPA, patients were treated with carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and CPA 5.0 g/m2 administered over 3 days. The peripheral-blood progenitors (PBPs) were reinfused 3 days later, and G-CSF was recommenced. RESULTS All patients received the three courses. The median interval between treatments was 14 days (range, 13 to 21). Sixteen of the 34 courses of CPA resulted in admissions for fever. Following the third course, neutrophil counts recovered to 0.5 x 10(9)/L at a median of 9 days (range, 8 to 18) after PBP reinfusion and platelets recovered to 50 x 10(9)/L at a median of 12 days (range, 9 to 102). There were no treatment-related deaths. Flow-cytometric analysis was performed on the leukapheresis collections of eight patients. Seven patients with at least 2.0 x 10(6) CD34+ CD33- cells per kilogram body weight exhibited prompt hematologic recovery. One patient with 0.03 x 10(6) CD34+ CD33- cells was still cytopenic on day 21, and required reinfusion of her back-up marrow. Among seven patients with measurable or assessable disease, there were two complete responses (CRs) and four partial responses (PRs). CONCLUSION These preliminary results suggest that multiple, rapidly cycled courses of high-dose myelosuppressive chemotherapy can be administered. PBPs, harvested during the G-CSF-augmented rebound from CPA-induced cytopenia, produce rapid hematologic recovery in patients undergoing high-dose chemotherapy (HDC). Further follow-up will be necessary to assess the efficacy of this specific regimen in the treatment of metastatic breast cancer.
Impact of cyclophosphamide on relationships between carboplatin exposure and response or toxicity when used in the treatment of advanced ovarian cancer.
Authors: Reyno L M , Egorin M J , Canetta R M , Jodrell D I , Swenerton K D , Pater J L , Burroughs J N , Novak M J , Sridhara R 
Published: February 2017

PURPOSE To determine (1) the impact of cyclophosphamide 600 mg/m2 on previously defined relationships between carboplatin area under the plasma concentration versus time curve (AUC) and indices of toxicity and response in women with advanced ovarian cancer; and (2) the relationships between indices of cumulative drug exposure and clinical outcomes. METHODS Carboplatin AUC = dose/(creatinine clearance [CCr] + 25) and was calculated in 224 women who received carboplatin 300 mg/m2 and cyclophosphamide 600 mg/m2. The likelihood of grade 3 or greater myelotoxicity at any carboplatin AUC was compared with the likelihood of myelotoxicity at the same single-agent carboplatin AUC. The nadir count predicted using the University of Maryland single-agent carboplatin dosing formula was compared with the nadir count observed. Received and relative-received dose-intensity were calculated. Carboplatin exposure-intensity was defined by substituting cumulative carboplatin exposure for total dose. Relationships were sought between these indices and therapeutic outcomes. RESULTS The incidence of leukopenia and thrombocytopenia at any carboplatin AUC was greater for the two-drug combination than for single-agent carboplatin. The platelet nadir in 83% of patients was less than or equal to the nadir predicted for the same single-agent carboplatin AUC. Despite a narrow range of received dose-intensities, carboplatin exposure-intensity was distributed over a twofold range. There were no relationships between received and relative-received dose-intensity or carboplatin exposure-intensity and time to progression or survival. CONCLUSION Any carboplatin AUC when administered with cyclophosphamide 600 mg/m2 produces greater myelotoxicity than the same AUC of single-agent carboplatin. Received carboplatin dose-intensity underestimates the range of plasma drug exposure resulting from a fixed carboplatin dosing regimen. Whether higher carboplatin exposures can improve outcome requires prospective validation.
Pharmacodynamics of prolonged oral etoposide in patients with advanced non-small-cell lung cancer.
Authors: Miller A A , Tolley E A , Niell H B , Griffin J P , Mauer A M 
Published: February 2017

PURPOSE This study was undertaken to investigate the pharmacodynamic relationship between etoposide drug levels on 21-day oral treatment courses and hematologic toxicities in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Thirty-two patients with stage IIIB or IV NSCLC were treated with oral etoposide 50 mg/m2/d for 21 consecutive days in combination with cisplatin 100 mg/m2 on day 1. Treatment was repeated every 28 days for up to six courses. Patients had not received previous chemotherapy and had a performance status of 0 to 2. Patients were monitored weekly while on treatment for compliance with oral etoposide and toxicity, including complete blood cell counts, and a blood sample before the daily etoposide dose (drug trough levels). Etoposide concentrations were measured in the plasma by high-performance liquid chromatography (HPLC). RESULTS Three patients achieved a complete response (CR) and 10 patients a partial response for an objective response rate of 41% (95% confidence interval, 24% to 58%). The median survival was 4 months (range, 1 to 23). Neutropenia was dose-limiting, and two patients died of neutropenic sepsis. Pharmacodynamic correlations for drug concentrations and hematologic toxicities were available for 27 patients and a total of 76 treatment courses, and correlations were significant for graded hematologic toxicity and nadir counts of leukocytes, neutrophils, hemoglobin, and platelets. The grade of infection (77 courses) was also related to drug levels. Using data from 27 initial courses, a pharmacodynamic model was developed to estimate the nadir leukocyte or neutrophil count (WBCn, ANCn) based on the pretreatment count (WBCp, ANCp) and the etoposide concentration (Ec) as follows: WBCn = 0.35 (1 + WBCp x e-1.12 x Ec) and ANCn = 0.32 (1 + ANCp x e-2.47 x Ec). CONCLUSION Etoposide concentrations are related to the resulting hematologic toxicities. It is possible to predict nadir counts in the first course by a pharmacodynamic model. The above equations need to be validated prospectively and may be useful in future studies of prolonged oral etoposide.
Phase II study of weekly edatrexate as first-line chemotherapy for metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group study.
Authors: Vandenberg T A , Pritchard K I , Eisenhauer E A , Trudeau M E , Norris B D , Lopez P , Verma S S , Buckman R A , Muldal A 
Published: February 2017

PURPOSE The National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a phase II study to assess the efficacy and toxicity of edatrexate, a folate antagonist, in 35 patients with metastatic breast cancer. PATIENTS AND METHODS The planned dose of edatrexate was 80 mg/m2/wk administered intravenously as first-line therapy. Prior adjuvant chemotherapy was allowed provided at least 12 months had elapsed from the completion of treatment to the development of recurrence. RESULTS Mucositis was the dose-limiting toxicity in 34 assessable patients, resulting in a mean delivered dose-intensity of 57 mg/m2/wk. Other toxicities included myelosuppression, rash, pneumonitis, and increased AST. Side effects were generally mild to moderate. The complete plus partial remission rate (13 patients; 41%) was impressive. CONCLUSION Edatrexate is an active agent against metastatic breast cancer, with acceptable toxicity. A lower than planned delivered dose-intensity was mainly due to mucositis.
Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy.
Authors: Robertson J M , Lawrence T S , Dworzanin L M , Andrews J C , Walker S , Kessler M L , DuRoss D J , Ensminger W D 
Published: February 2017

PURPOSE To develop more effective regional therapy for patients with unresectable primary hepatobiliary cancer using concurrent conformal radiation therapy and intraarterial hepatic (IAH) fluorodeoxyuridine (FdUrd). PATIENTS AND METHODS Twenty-six patients with unresectable, nonmetastatic primary hepatobiliary cancer were treated with concurrent IAH FdUrd (0.2 mg/kg/d) and conformal hepatic radiation therapy (1.5 to 1.65 Gy per fraction twice per day). The total dose of radiation administered to the tumor depended on the fraction of normal liver excluded from the high-dose volume. All patients were assessed for toxicity, hepatobiliary relapse, and survival; 17 patients were assessable for response (eight had cholangiocarcinoma not assessable by computed tomographic [CT] scan and one progressed distantly during treatment). The median potential follow-up duration was 27 months. RESULTS Whole-liver radiation was administered to six patients with diffuse hepatocellular carcinoma (HCC). Eleven patients with localized HCC and nine with cholangiocarcinoma received focal radiation to a dose of 48 to 72.6 Gy. An objective response for assessable patients was observed in 11 of 11 patients treated with focal radiation, but only one of six patients treated with whole-liver radiation. Whole-liver radiation accounted for five of seven patients with > or = grade 3 toxicity and four of six local treatment failures. Two patients had nonfatal radiation hepatitis. The median survival duration for patients with localized hepatobiliary cancer was 19 months, while patients with diffuse HCC had a median survival duration of 4 months. The rate of actuarial freedom from hepatobiliary progression in patients with localized disease was 72% at 24 months. CONCLUSION These findings suggest that three-dimensional planned focal liver radiation and IAH FdUrd can produce a high, durable response rate and an encouraging median survival duration in patients with nondiffuse, unresectable primary hepatobiliary cancer.
Phase II study of goserelin for patients with postmenopausal metastatic breast cancer.
Authors: Saphner T , Troxel A B , Tormey D C , Neuberg D , Robert N J , Pandya K J , Edmonson J H , Rosenbluth R J , Abeloff M D 
Published: February 2017

PURPOSE To determine the response rate of postmenopausal breast cancer patients to the gonadotropin-releasing hormone (GN-RH) agonist, Zoladex (goserelin; ICI Pharma, Wilmington, DE). PATIENTS AND METHODS A multi-institutional single-agent trial in postmenopausal patients was conducted. Serum levels of follicle-stimulating hormone (FSH), testosterone, and estradiol were requested before and after Zoladex treatment. RESULTS For estrogen receptor-positive (ER+) patients, the response rate was 11%, with one complete response (CR) and three partial responses (PRs) among 36 eligible patients. Responses were of short duration. There were no responses among 16 estrogen receptor-negative (ER-) patients. CONCLUSION GN-RH agonists have activity in ER+ postmenopausal patients, but response rates are not as high as with other available endocrine therapies and the duration of response is short.
Phase I clinical and pharmacokinetic study of a 14-day infusion of etoposide in patients with lung cancer.
Authors: Minami H , Shimokata K , Saka H , Saito H , Ando Y , Senda K , Nomura F , Sakai S 
Published: February 2017

PURPOSE A phase I study was conducted to determine the maximum-tolerated dose (MTD) of a 14-day continuous infusion of etoposide, and to evaluate the pharmacokinetics in patients with lung cancer. PATIENTS AND METHODS Etoposide was administered continuously through a central venous catheter using a pump. The starting dose level was 300 mg/m2 over 14 days, with dose escalations of 100 mg/m2 over 14 days until unacceptable toxicities occurred. Pharmacokinetic studies were performed in all patients. RESULTS Twenty-one patients, 20 with non-small-cell lung cancer and one with refractory small-cell lung cancer, received 37 courses. No World Health Organization (WHO) grade III or greater toxicity occurred at doses up to 400 mg/m2 over 14 days. At 700 mg/m2 over 14 days, all four patients experienced grade III or IV leukocytopenia, and two developed grade III stomatitis. No cumulative toxicity was observed. A steady concentration of etoposide was achieved 24 hours after the start of chemotherapy, and it was significantly correlated with surviving fractions of leukocytes (r = -.64, P = .001) and platelets (r = -.68, P < .001). The leukocyte count at the termination of chemotherapy predicted the nadir count (r = .93, P < .001). CONCLUSION Steady blood levels of etoposide were maintained for prolonged periods, during 14-day continuous infusions. Leukocytopenia and stomatitis were dose-limiting. Nadir counts and surviving fractions of leukocytes were predicted by the leukocyte count at the end of chemotherapy and the concentration of etoposide, respectively. The recommended dose for phase II trials is 600 mg/m2 over 14 days.
Assessment of estrogenic recruitment before chemotherapy in advanced breast cancer: a double-blind randomized study. European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group.
Authors: Paridaens R , Heuson J C , Julien J P , Veyret C , Van Zyl J , Klijn J G , Sylvester R , Mignolet F 
Published: February 2017

PURPOSE In the present phase III study, the specific effect of estrogenic recruitment was assessed by comparing two groups of patients with advanced breast cancer receiving either ethinylestradiol (EE2) or placebo (PL) before chemotherapy (CT). PATIENTS AND METHODS The therapeutic regimen consisted of (1) estrogen suppression by aminoglutethimide (AGL) 1 g/d plus hydrocortisone (HC) 40 mg/d, with surgical castration performed on premenopausal patients; (2) fluorouracil (5-FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide (CPA) 500 mg/m2 (FAC) intravenously (IV) every 3 weeks; (3) following randomization, patients were double-blinded to receive either PL or EE2 50 micrograms exactly 24 hours before receiving FAC. All patients had advanced breast cancer presumably sensitive to endocrine therapy (estrogen receptor-positive [ER+] and/or progesterone receptor-positive [PgR+] status) with measurable lesions; none had received prior systemic antineoplastic therapy for metastatic disease; prior adjuvant hormonal therapy (HT) or CT (without anthracyclines) was allowed if interval since completion was longer than 1 year. RESULTS Among 154 patients treated according to the protocol, tolerance, response rates, time to progression, and median survival duration were identical in the PL and EE2 groups. Only performance status, dominant metastatic site, and menopausal status seemed to influence response (overall response, 64%), with the highest levels of partial remission (PR) and complete remission (CR) being achieved in premenopausal women (CR plus PR, 26% plus 55%) and in those with dominant soft tissue lesions (CR plus PR, 45% plus 28%). CONCLUSION We conclude that the validity of the hormonal recruitment concept has not yet been established in clinical practice so that this approach remains experimental. The results achieved by combining (near) complete estrogenic suppression and cyclical FAC chemotherapy are not significantly different from those to be expected with the more conventional use of HT followed by CT in presumably hormone-responsive (ER+) patients.
Intraoperative lymphatic mapping and selective cervical lymphadenectomy for early-stage melanomas of the head and neck.
Authors: Morton D L , Wen D R , Foshag L J , Essner R , Cochran A 
Published: February 2017

PURPOSE We developed intraoperative lymphatic mapping with selective lymphadenectomy (SLND) to identify micrometastatic spread of cutaneous melanoma to regional lymph nodes. This study was undertaken to assess the sensitivity and specificity of our technique in patients with clinical stage I (CS-I) melanoma of the head or neck. PATIENTS AND METHODS Seventy-two CS-I melanoma patients underwent intraoperative lymphatic mapping of primary cutaneous melanomas located on the head, neck, or upper chest/back draining to the neck. Key (sentinel) cervical lymph nodes in the regional lymphatic drainage basin were identified, selectively excised during SLND, and examined for microscopic evidence of tumor cells. If these sentinel nodes were tumor-negative, the surgery was concluded; if the sentinel nodes were tumor-positive, all nodes in the drainage basin were removed during en bloc lymphadenectomy (LND). RESULTS Intraoperative lymphatic mapping identified sentinel nodes in 90% of the regional drainage basins. Fifteen percent of these nodes were tumor-positive, indicating the need for LND. There were no false-negative sentinel nodes, and extended follow-up showed no local nodal recurrences in patients whose sentinel-node histology did not indicate the need for LND. CONCLUSION Intraoperative lymphatic mapping and SLND is a minimally invasive and highly accurate screening technique for determining which patients with CS-I head and neck melanomas have subclinical node metastases and therefore might benefit from cervical LND.
Intravenous mercaptopurine: life begins at 40.
Authors: Pinkel D 
Published: February 2017

PURPOSE This review is intended to provide a concise portrayal of the background, rationale, and current use of intravenous infusions of mercaptopurine (6MP) in patients with acute leukemia. DESIGN After a brief description of the mode of action of 6MP and the formulation, pharmacokinetics, and history of its intravenous administration, the rationale for current use of intravenous 6MP infusion is explained. Subsequently, the review summarizes and discusses clinical experience with intravenous 6MP alone and in combination with intravenous methotrexate (Mtx) and cytarabine (Ara-C). RESULTS Although still an investigative drug, intravenous 6MP has been used for 40 years and currently is being administered extensively to children with previously untreated acute lymphoid leukemia (ALL) in frontline protocol studies. The reasons are the better and more consistent bioavailability of intravenous versus oral MP, higher blood and CSF levels, compliance, and preliminary evidence suggesting superior remission experience for intravenous Mtx and 6MP than for Mtx alone. The apparent lack of late adverse sequelae with 6MP as compared with other antileukemia drugs adds to this interest. CONCLUSION The new life of intravenous 6MP at age 40 years illustrates the need for continued investigation of significant anticancer drugs as insights and technology progress.
Erratum
Authors: Gray James R. , Bridges James D. , Sobczak Mark L. 
Published: February 2017

Response Migration: Area Versus Volume for Tumor Response Assessment To the Editor: A correction is necessary regarding the method of assessing tumor response as put forward by Drs Clamon and Clamon. They stated that tumor volume is a stricter criterion than tumor area in determining a partial response (PR, 50% reduction) for use in clinical trials. In fact, just the opposite is true. A PR by measuring tumor area is a more dramatic reduction in tumor bulk than a PR or 50% reduction by measuring tumor volume. Let us demonstrate by example. If a spherical tumor mass originally measures 8 cm across, its initial area calculation is (π)*(r)2 = 50.26 cm2. To be scored as a PR, the area must decrease to 25.13 cm2. This corresponds to a mass measuring 5.6 cm across (note, not 4 cm). However, the initial volume of this mass is (4/3)*(π)*(r) = 268.08 cm3. To be scored as a PR by the volume criterion the volume must decrease to 134.04 cm3. This corresponds to a mass measuring 6.3 cm across. A mere loss of 1.7 cm from the original tumor dimension results in a PR! If area of the tumor is used, the measurement must decrease by 2.4 cm, obviously a more stringent criterion. Trials that require a 50% reduction in tumor area for a PR have in essence demanded a 65% reduction in volume, not a 35% reduction as stated by Clamon and Clamon. If future clinical trials are to use computed tomography or magnetic resonance imaging data to calculate tumor volumes as a measurement of response, and the definition of a PR becomes a 50% reduction in volume, treatment regimens may seemingly become more effective with a higher overall response rate. The corresponding required area reduction in this case would be only 38%, not 50%. Just as more complete staging information can lead to stage migration with fewer malignancies labeled as early stage (the Will Rogers phenomenon2), a change to volume determination for response assessment could lead investigators to conclude erroneously that newer therapies are more successful than those in the past. We must be careful to judge all therapeutic maneuvers on an even playing field to determine truly what is best for our patients.