bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluorouracil: biochemistry and pharmacology.
Authors: Pinedo H M , Peters G F
Published: February 2017

Fluorouracil (5FU) is still considered the most active antineoplastic agent in the treatment of advanced colorectal cancer. The drug needs to be converted to the nucleotide level in order to exert its effect. It can be incorporated into RNA leading to interference with the maturation of nuclear RNA. However, its conversion to 5-fluoro-2'deoxy-5' monophosphate (FdUMP) leading to inhibition of thymidylate synthase (TS) and subsequently of DNA synthesis, is considered to be its main mechanism of action. In the presence of a folate cofactor a covalent ternary complex is formed, the stability of which is the main determinant of the action of 5FU. Resistance against 5FU can be mainly attributed to aberrations in its metabolism or to alterations of TS, eg, gene amplification, altered kinetics in respect to nucleotides or folates. Biochemical modulation of 5FU metabolism can be applied to overcome resistance against 5FU. A variety of normal purines, pyrimidines, and other antimetabolites have been studied in this respect, but only some of them have been clinically successful. Delayed administration of uridine has recently been shown to "rescue" mice and patients from toxicity, while pretreatment with leucovorin is the most promising combination to enhance the therapeutic efficacy. 5FU is frequently administered in an intravenous (IV) injection, and shows a rapid distribution and a triphasic elimination. The nonlinearity of 5FU pharmacokinetics is related to saturation of its degradation. Continuous infusion of 5FU led to different kinetics. Regional administration, such as hepatic artery infusion, offers a way to achieve higher drug concentrations in liver metastases and is accompanied by lower systemic concentration. The current status of the biochemical and pharmacokinetic data is reviewed.
Acute toxicities associated with radiation in the second National Wilms' Tumor Study.
Authors: Thomas P R , Tefft M , D'Angio G J , Norkool P
Published: February 2017

Twenty-three of 303 patients (7.6%) entered into National Wilms' Tumor Study Number 2 (NWTS-2) with groups II, III, and IV disease experienced 26 toxic events thought to be related to radiotherapy (RT). The randomization between vincristine (VCR) plus dactinomycin (AMD) and the same two drugs plus doxorubicin (ADR) had a minimal effect on RT toxicity. Five (1.6%) fatalities were recorded and the surviving 18 patients recovered without discernible residua. Sixteen patients had hepatic, four had pulmonary, and three had cardiac toxicity. Hepatic toxicity was significantly more common when the right side of the abdomen or the whole abdomen was irradiated than when the left side was treated (P = .01). We conclude that acute RT-related toxicity in NWTS-2 was very similar to that in NWTS-1, in which 26 (7.2%) of 359 randomized patients developed RT-related toxicity and three died. This acceptable rate was maintained despite more intensive chemotherapy (CT) in NWTS-2.
Computerized telephone assessment of the "concrete" needs of chemotherapy outpatients: a feasibility study.
Authors: Siegel K , Mesagno F P , Chen J Y , Klein L , Bowles M E , McKenna M , Peyser S , Christ G
Published: February 2017

The feasibility of using a computer-automated telephone outreach system to routinely assess the needs of chemotherapy outpatients was evaluated. The automated intervention was designed as a cost-efficient strategy for assessing patients' needs on a periodic basis so that emerging needs could be identified in a timely way. Ninety-seven chemotherapy outpatients were surveyed at least once over the telephone by a computer in a high-quality, digitally stored voice asking 12 questions regarding the patients' "concrete" needs. Early results of this larger ongoing study, in which patients are scheduled to be called every 4 to 6 weeks for approximately four months, indicated that computer-automated surveys had broad-based acceptance among our outpatients and that patients were able to comply accurately with the survey's instructions. Furthermore, the speech recognition system was found to be reliable, and patients' response patterns to the automated surveys valid. Nonparticipation in this study (28.0%) was not substantially higher than in our previous research within this patient population and neither nonparticipation nor attrition appeared significantly attributable to the automation itself. This method offers the potential for cost-efficient, universal, and ongoing assessment of patient needs, facilitating timely intervention, and efficient use of professional staff.
Photodynamic therapy.
Authors: Manyak M J , Russo A , Smith P D , Glatstein E
Published: February 2017

Photodynamic therapy (PDT) is an experimental cancer treatment modality that selectively destroys cancer cells by an interaction between absorbed light and a retained photosensitizing agent. This review discusses the basic components of photodynamic activity and examines the clinical applications of photodynamic therapy in cancer treatment. Treatment of superficial and early-stage malignancies is encouraging. Technologic advancement and further elucidation of the fundamental basis of photodynamic action should permit treatment of more advanced malignancies.
A prospective randomized trial of fluorouracil versus fluorouracil plus cisplatin in the treatment of metastatic colorectal cancer: a Hoosier Oncology Group trial.
Authors: Loehrer P J , Turner S , Kubilis P , Hui S , Correa J , Ansari R , Stephens D , Woodburn R , Meyer S
Published: February 2017

From May 1984 through December 1986, 141 patients with metastatic adenocarcinoma of the colon or rectum were entered on this Hoosier Oncology Group (HOG) trial evaluating the role of cisplatin in systemic therapy. Patients were stratified by the presence or absence of hepatic metastases and by performance status, and were subsequently randomized to receive fluorouracil (5-FU) (15 mg/kg/wk) alone or the same dose of 5-FU plus cisplatin (60 mg/m2 every 3 weeks). The total duration of treatment was six cycles (18 weeks). In 132 fully evaluable patients the objective response rates were 19% for 5-FU and 22% for 5-FU plus cisplatin. Statistically, the median survival times of 40 and 39 weeks were not significantly different (P = .62). However, the median duration of remission (MDR) was superior (P = .05) for 5-FU alone. This study fails to confirm clinically significant synergy of 5-FU plus cisplatin in the treatment of metastatic colorectal cancer.
Preradiation high-dose intravenous methotrexate with leucovorin rescue for untreated primary childhood brain tumors.
Authors: Allen J C , Walker R , Rosen G
Published: February 2017

Although high-dose intravenous (IV) methotrexate (MTX) with leucovorin rescue (HDMTX) is effective for certain recurrent primary brain tumors, concern for inducing leukoencephalopathy has restrained its use as adjuvant therapy following therapeutic brain irradiation (RT). We have conducted a phase I to II clinical trial using four biweekly courses of HDMTX (8 g/m2) in a neoadjuvant setting in ten patients with newly diagnosed high-risk pediatric primary brain tumors. Four patients experienced an objective response after two to four courses of HDMTX alone (medulloblastoma, one; pineoblastoma, one; malignant cerebral astrocytoma, two). All ten patients subsequently received a course of therapeutic RT, and in seven cases, adjuvant chemotherapy with other agents. One patient acquired an acute transient encephalopathy before RT that completely resolved, and another developed a seizure disorder following RT associated with white matter abnormalities on a magnetic resonance imaging (MRI) scan. Five patients have survived a minimum of 33+ months, and four remain in continuous remission. The acute and delayed neurotoxicity of neoadjuvant HDMTX is acceptable, and we favor further use of this neoadjuvant approach in the context of a phase III trial.
Dose-ranging evaluation of the serotonin antagonist GR-C507/75 (GR38032F) when used as an antiemetic in patients receiving anticancer chemotherapy.
Authors: Kris M G , Gralla R J , Clark R A , Tyson L B
Published: February 2017

GR-C507/75 (GR38032F) antagonizes the 5-HT3 (serotonin) receptor and prevents cisplatin-induced emesis in animals. In this dose-ranging trial, 44 patients with cancer receiving chemotherapy known to produce nausea and vomiting (including cisplatin, cyclophosphamide, and doxorubicin) received three intravenous (IV) infusions of GR-C507/75 every two hours beginning 30 minutes before chemotherapy. Ten dosage levels were explored, ranging from 0.04 mg/kg to 0.35 mg/kg in each of the three infusions. Toxicities were mild and included sedation, dizziness, headache, transient elevations of SGOT or alanine aminotransferase (ALT), and dry mouth. No akathisia or acute dystonic reactions were observed. Antiemetic effects were seen in patients receiving cisplatin at 120 mg/m2. GR-C507/75 can be safely administered on this schedule at IV dosages up to 0.35 mg/kg in patients receiving chemotherapy. Further studies of this agent at higher dosages and by different schedules are appropriate.
A phase I trial of intraperitoneal recombinant gamma-interferon in advanced ovarian carcinoma.
Authors: D'Acquisto R , Markman M , Hakes T , Rubin S , Hoskins W , Lewis J L
Published: February 2017

The interferons are a class of biological agents that have demonstrated antineoplastic activity in a variety of tumors both in vitro and in vivo. Previous reports have suggested that interferons can be safely administered by the intraperitoneal (IP) route with a pharmacokinetic advantage for peritoneal cavity exposure compared with the systemic circulation and with objective antitumor activity being demonstrated. On the basis of these reports and laboratory data suggesting activity for recombinant gamma-interferon (r-GIFN) against several malignant cell lines, we treated 27 refractory ovarian carcinoma patients, including six with very-small-volume residual disease, with this agent delivered by the IP route. While r-GIFN was found to be remarkably well tolerated, with a 150- to 200-fold pharmacokinetic advantage for peak levels achieved in the peritoneal cavity compared with the plasma, no objective responses were observed. Despite the lack of demonstrated activity for single-agent IP-administered r-GIFN in this clinical setting, there remains considerable interest in this agent when delivered by the IP route because of in vitro data suggesting concentration-dependent synergy between r-GIFN and other biological agents.
Phase I/pharmacokinetic study of thioguanine administered as a 48-hour continuous intraperitoneal infusion.
Authors: Zimm S , Cleary S M , Horton C N , Howell S B
Published: February 2017

Thioguanine (TG) is an antimetabolite with established antileukemic activity. The most pharmacologically rational manner of TG administration is continuous infusion. Intraperitoneal (IP) delivery of TG provides the opportunity to definitively test the concept of high-dose, long-term antimetabolite administration. The high systemic clearance and in vitro activity of TG against ovarian carcinoma suggested that it would be an excellent candidate for IP administration as a prolonged infusion. TG was administered as a 48-hour continuous IP infusion in this phase I/pharmacokinetic study. TG infusions were administered using a portable, programmable pump (Pancretec Provider Model 2000; Pancretec, Inc, San Diego). Twenty-five patients were treated. At a dose of 900 mg/m2/48 h, TG produced unacceptably severe myelosuppression. The dose-limiting toxicity was granulo-cytopenia. Other toxicities were mild: emesis, alopecia, skin rashes, and photosensitivity reactions. IP TG did not produce chemical peritonitis, hepatotoxicity, or mucositis. The pharmacokinetics of IP TG were determined in 16 patients. TG levels were measured by reverse-phase high-performance liquid chromatography (HPLC). At steady state, the mean peritoneal to plasma TG ratio was 1,800 at the maximum tolerated dose (MTD). Steady-state TG levels in the peritoneal cavity and plasma were 2 mmol/L and 1.1 mumol/L, respectively, at a dose of 744 mg/m2. The elimination half-life of TG from the peritoneal cavity was one hour. TG exhibited linear pharmacokinetics over the dosage range investigated. Encouraging clinical activity was seen with IP TG. There was one partial response (PR) and four minor responses (MR). TG can be safely administered by the IP route. The recommended dose for phase II testing is 744 mg/m2/48 h. IP TG has a favorable pharmacokinetic advantage and has demonstrated encouraging clinical activity. Further studies of IP TG infusions are warranted.
Cellular pharmacokinetics of daunorubicin: relationships with the response to treatment in patients with acute myeloid leukemia.
Authors: Kokenberg E , Sonneveld P , Sizoo W , Hagenbeek A , Löwenberg B
Published: February 2017

In an attempt to identify pharmacokinetic factors that determine the response of acute myeloid leukemia (AML) patients to induction chemotherapy, we determined the concentrations of daunorubicin (DNR) and the main metabolite daunorubicinol (DOL) in vivo and particularly evaluated the concentrations in blood and bone marrow nucleated cells. Cell measurements were obtained in 37 evaluable patients during their first remission induction treatment with DNR and cytarabine (ara-C) and directly compared with the plasma distribution kinetics of DNR. We show that (1) plasma DNR concentrations do not correlate with DNR concentrations in bone marrow nucleated cells; but (2) plasma area under the curve (AUC) values of DNR correlate inversely (P less than .01) with AUC values of DNR in WBCs; (3) concentrations of DNR in WBCs correlate positively (P less than .01) with DNR concentrations in bone marrow nucleated cells; and (4) the concentrations of DNR in WBCs show a negative correlation (P less than .01) with the numbers of peripheral blast cells at diagnosis. We then tested whether the pharmacokinetic parameters had predictive value for the clinical outcome of therapy, but none of the plasma levels or WBC and bone marrow concentrations of DNR predicted treatment outcome. The inverse correlation between the concentrations of DNR in WBC and the numbers of peripheral blast cells suggests that the effective DNR concentrations achieved intracellularly are mainly a function of the tumor load so that lesser amounts of DNR accumulate intracellularly when the AML cell numbers in blood are higher.
Adjuvant chemotherapy following surgical resection for small-cell carcinoma of the lung.
Authors: Shepherd F A , Evans W K , Feld R , Young V , Patterson G A , Ginsberg R , Johansen E
Published: February 2017

Surgery alone is inadequate therapy for limited small-cell lung cancer (SCLC), resulting in less than 5% long-term survival. Since 1976, we treated patients undergoing surgery for SCLC with adjuvant chemotherapy in an attempt to prolong survival and increase cure. Seventy-seven patients who underwent surgery as their primary treatment were identified, and of these 63 (46 male and 17 female) received chemotherapy. Fifteen patients had a pneumonectomy, 46 a lobectomy, and two had wedge resections. Six patients had positive microscopic resection margins. Pathologic staging showed tumor, node, metastasis (TNM) involvement as follows: T1N0, eight; T2N0, ten; T1N1, six; T2N1, 18; T1N2, five; T2N2, nine; T3N0, three; T3N1, one; and T3N2, three. All patients received cyclophosphamide, Adriamycin (doxorubicion; Adria Laboratories, Mississauga, Ontario), and vincristine; four also received etoposide (VP-16) and cisplatin, one VP-16, and four methotrexate, procarbazine, and lomustine (CCNU). Forty-nine patients received prophylactic cranial irradiation, and 35 received radiotherapy to the mediastinum and primary site. The overall median survival of the 63 patients is 83 weeks, and the projected 5-year survival is 31%. Patients with T1 or T2 tumors without nodal involvement had a median survival of 191 weeks, and projected 5-year survival of 48%. Stage II (T1N1, T2N1) and stage III (any T3 or T1-2N2) patients had median survivals of 72 weeks and 65 weeks, and projected 5-year survivals of 24.5% and 24%, respectively. Thirty-three patients have relapsed and died of disease. Only two patients had an isolated relapse at the primary site. Seven other patients have died without recurrent disease. Adjuvant chemotherapy after surgery results in prolonged survival and cure for a significant number of patients with stage I SCLC, although nodal involvement at any level is associated with shorter survival.
Management of refractory myeloma: a review.
Authors: Buzaid A C , Durie B G
Published: February 2017

Management of refractory myeloma represents a common and challenging clinical problem. Approximately 30% to 50% of patients with multiple myeloma do not respond to first-line therapy, and those who initially achieve a remission will eventually relapse. Surprisingly, there is no routinely accepted approach to patients with refractory disease. Therefore, we review the literature in an attempt to provide an overview of the published results and outline our treatment recommendations for such patients. We suggest the following: (1) for truly resistant patients (ie, those who clearly progress with initial therapy), administration of high-dose or pulsed glucocorticosteroids is the best treatment, with an expected response of 40% (defined as a greater than or equal to 50% reduction in monoclonal [M]-protein concentration); (2) for patients who relapse during therapy or relapse within 6 months of stopping the initial treatment, the VAD regimen (vincristine, doxorubicin, and dexamethasone) is one of the most effective salvage therapies, resulting in an approximately 75% response rate (greater than or equal to 50% reduction in M-protein concentration); (3) for patients who relapse within more than 6 months of stopping therapy (unmaintained remission), reinitiation of the initial therapy represents an excellent alternative, leading to recontrol in 60% to 70% of patients (greater than or equal to 50% reduction in M-protein concentration). If progression is observed or if there is response and then relapse in this setting, VAD chemotherapy can be administered again. (4) Patients who fail second-line salvage therapies should enter well-designed clinical trials to evaluate new treatment modalities. If this is not feasible, alpha-interferon or "systemic" radiotherapy are recommended in selected cases.
Clinical use of a standard kit-preparation of radiolabeled monoclonal antibody 96.5 in the diagnostic imaging of metastatic melanoma.
Authors: Saleh M N , Miller D M , Peterson L , Russell C D , Unger M W , Urist M M , Wheeler R H , LoBuglio A F
Published: February 2017

We studied the efficiency of a standard-kit preparation using 1 mg 111In-labeled 96.5 monoclonal antibody in combination with 19 mg of unlabeled antibody in the diagnostic imaging of 27 patients with documented metastatic melanoma. Twenty-three of 26 patients (88%) demonstrated immunoscintigraphic localization of tumor. Of 104 metastatic sites previously documented by conventional studies, 62 (60%) were identified by immunoscintigraphy. A total of 77 sites demonstrated localization of radiolabeled antibody. Fifty-four (70%) corresponded to known sites of disease; eight sites (10%) were "discovered" by immunoscintigraphy and subsequently confirmed by conventional studies; 15 imaged sites (20%) could not be confirmed by conventional studies. Size and location of metastasis appear to be important features that influence imaging efficiency. Tumor size (greater than or equal to 2 cm v less than 2 cm) appears to be the statistical dominant determinant. The feasibility and potential clinical use of radioimmune imaging of tumors is discussed.
Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy.
Authors: Fowble B , Gray R , Gilchrist K , Goodman R L , Taylor S , Tormey D C
Published: February 2017

Risk factors for isolated local-regional (LR) recurrence following mastectomy for breast cancer were analyzed in a review of 627 women entered into Eastern Cooperative Oncology Group (ECOG) adjuvant chemotherapy trials between 1978 and 1982. Premenopausal patients were randomized to cyclophosphamide, methotrexate, and fluorouracil (5-FU) (CMF), cyclophosphamide, methotrexate, 5-FU, and prednisone (CMFP), or cyclophosphamide, methotrexate, 5-FU, prednisone, and tamoxifen (CMFPT). Postmenopausal patients were randomized to observation, CMFP, or CMFPT. Median follow-up time was 4.5 years. At 3 years, 225 patients relapsed and in 70 (31% of failures, 11% of all patients) the initial site was LR without distant metastases. In a multivariate analysis, the risk of an isolated LR recurrence significantly correlated with the number of positive axillary nodes, the primary tumor size, the presence of tumor necrosis, and the number of axillary nodes examined. Factors that significantly discriminated between an isolated LR recurrence and distant metastasis were the number of positive nodes and primary tumor size. Patients with four to seven positive nodes or tumor size greater than or equal to 5 cm had a chance of developing an isolated LR recurrence almost equal to the risk of distant metastases. These findings suggest a potential for improved survival in this subset of patients with the addition of postmastectomy radiation to chemotherapy, and continue to emphasize the presence of a group of patients at high risk for isolated LR recurrence despite adjuvant chemotherapy.
Significance of pulmonary computed tomography at diagnosis in Wilms' tumor.
Authors: Wilimas J A , Douglass E C , Magill H L , Fitch S , Hustu H O
Published: February 2017

Pulmonary lesions were found by computed tomography (CT) despite normal chest roentgenograms (CXR) at diagnosis in 11 of 124 patients with Wilms' tumor. All patients were entered on a treatment protocol at St Jude Children's Research Hospital from 1978 to 1986. The 11 patients all had favorable histology Wilms' tumor. Staging and therapy were based on interpretation of the CXR and abdominal findings. Excluding CT findings, one patient had stage I disease, two stage II, seven stage III, and one stage IV on the basis of multiple liver metastases. Four patients have relapsed: one with stage II and three with stage III. All relapses have been pulmonary. Overall, 4/11 (36%) relapsed. This relapse rate is considerably greater than the 20% overall relapse rate of patients treated according to this protocol though not statistically significant. These relapses suggest that such patients may be at increased risk for pulmonary recurrence. The results also indicate that small lesions initially noted only on CT scans of the chest in children with Wilms' tumor frequently represent metastatic tumor. Further studies of larger numbers of patients will be necessary to confirm these findings.
Effects of interleukin-2 immunotherapy on renal function.
Authors: Kozeny G A , Nicolas J D , Creekmore S , Sticklin L , Hano J E , Fisher R I
Published: February 2017

Recombinant interleukin-2 (IL-2) infusions have recently been evaluated as a new form of immunotherapy for the treatment of malignancies. This form of therapy has been complicated by the development of fluid retention, azotemia, and hypophosphatemia. To evaluate the effects of IL-2 on renal function, we prospectively studied eight patients who received IL-2 (10(5) micron/kg every eight hours intravenously [IV]) for five days as the initial phase of a treatment protocol using IL-2 plus lymphokine activated killer (LAK) cells. Dopamine and fluids were used to maintain blood pressure and all patients received indomethacin (100 mg/d). IL-2 therapy produced a syndrome similar to endotoxemia with the development of respiratory alkalosis (pH = 7.44 +/- .2, pCO2 = 30 +/- 2) and hypotension (mean BP, 71.3 mm Hg). These changes were accompanied by marked sodium avidity, edema formation, and mild elevations of BUN and creatinine. Hypophosphatemia, hypocalcemia, and hypomagnesemia were commonly seen. No defects in renal calcium, magnesium, phosphorous, net acid excretion, or glycosuria were demonstrated. We conclude: (1) IL-2 induces an increase in vascular permeability causing the development of edema, sodium avidity, and prerenal azotemia as occurs during endotoxemia; (2) IL-2 therapy induces respiratory alkalosis with the subsequent intracellular shift of phosphorous accompanied by increased renal phosphorous reabsorption; and (3) there is no evidence of renal tubular dysfunction (renal tubular acidosis [RTA], renal leak of glucose, phosphorous, or magnesium).
Improved tumor localization with increasing dose of indium-111-labeled anti-carcinoembryonic antigen monoclonal antibody ZCE-025 in metastatic colorectal cancer.
Authors: Patt Y Z , Lamki L M , Haynie T P , Unger M W , Rosenblum M G , Shirkhoda A , Murray J L
Published: February 2017

Monoclonal antibodies (MoAbs) against carcinoembryonic antigen (CEA) react with human colorectal cancer cells, and when labeled with a gamma-emitting radioisotope, may help to localize known and occult metastatic disease. We tested ZCE-025 (Hybritech, Inc, San Diego), a high-affinity immune gamma globulin1 (IgG1) MoAb anti-CEA that does not react with normal granulocyte glycoproteins in a phase I/II trial to determine the reagent's toxicity and its maximum efficacy in detecting metastatic colorectal cancer. Increasing doses of unlabeled ZCE-025 were mixed with 1 mg of Indium-111 (111In)-radiolabeled MoAb and administered intravenously (IV) to 34 patients who had metastatic colorectal cancer. Planar nuclear or single photon emission computed tomographic (SPECT) scans were performed 48 to 72 and 120 to 144 hours later. Total dose of MoAb and scanning sensitivity (number of imaged lesions/number of known lesions) were correlated up to 80 mg. At doses of 2.5 to 20 mg, a mean of 22% of the lesions were imaged; at 40 mg, 77% were imaged (P less than .01). Liver metastases were detected as areas of increased activity ("hot") at the 40 mg dose but showed decreased MoAb uptake at lower doses. At the 40 mg dose normal liver parenchymal uptake of the labeled MoAb was lower with respect to blood pool compared with the other doses. At 80 mg, however, sensitivity of detection declined to 21%. One milligram of 111In-labeled ZCE-025 antibody coinfused with 39 mg of unlabeled antibody appeared optimal for detecting metastatic colorectal cancer, particularly in the liver. Although the exact mechanism(s) for this dose effect is currently unknown, a partial "blocking" effect of unlabeled antibody with a change in MoAb biodistribution may be occurring.
A phase I trial of intravenously-administered recombinant tumor necrosis factor-alpha in cancer patients.
Authors: Feinberg B , Kurzrock R , Talpaz M , Blick M , Saks S , Gutterman J U
Published: February 2017

We report a phase I clinical investigation of 30-minute and four-hour intravenous (IV) infusions of recombinant tumor necrosis factor (rTNF)-alpha. Thirty-nine patients with disseminated cancer received escalating doses of rTNF-alpha for five consecutive days every 2 weeks for a total duration of 8 weeks. Dose escalations followed a modified Fibonacci scale with a minimum of four patients entered at each dose level: 5, 10, 25, 50, 75, 100, 150, 200, and 250 micrograms/m2/d. Toxicities consisted mainly of constitutional symptoms including fever, chills, headache, and fatigue, increasing in severity with dose escalation. No significant differences in dose-limiting toxicities were seen between the two rates of IV infusion. The maximum tolerated dose (MTD) was 200 micrograms/m2 with dose limiting toxicity being constitutional symptoms and hypotension. Hematologic changes included median decrease in both granulocyte and platelet counts of 38% and 41%, respectively (range, 16% to 85%), although clinically significant granulocytopenia and thrombocytopenia were not observed. Hematological parameters returned to baseline within 72 hours after rTNF-alpha was stopped. rTNF-alpha induced changes in lipid metabolism were manifested by median fasting triglyceride elevations above baseline (median, 103 micrograms/dL) of 157% (range, 16% to 389%) after five days of therapy with doses greater than 75 micrograms/m2, associated with a median increase in very-low-density lipoprotein (VLDL) of 80%. Serum rTNF peak levels exceeding 10 ng/mL were observed 30 minutes following rTNF-alpha infusions at MTD dose. Twelve of 34 patients had no change in their evaluable disease for a median duration of 18 weeks (range, 8 to 30 weeks), and 22 patients showed progressive disease. This study forms the framework for phase II trials of IV administered rTNF-alpha.
Prognostic factors in adult chronic myelomonocytic leukemia: an analysis of 107 cases.
Authors: Fenaux P , Beuscart R , Lai J L , Jouet J P , Bauters F
Published: February 2017

Adult chronic myelomonocytic leukemia (CMML), as defined by the French-American-British (FAB) group, is associated with a variable survival, ranging from a few weeks to several years. From 1971 to 1986, we made the diagnosis of CMML in 107 cases, according to FAB criteria (except for patients with 20% to 30% bone marrow [BM] blasts who were also included). Median survival was 30 months (range 1 to 81 months) and life expectancy did not seem to be influenced by treatment modalities other than supportive care. Eighteen patients (17%) progressed to acute nonlymphoblastic leukemia (ANLL). In a Cox regression model, main factors associated with short survival were: an excess of marrow blasts (P = 10(-6], anemia (P = .17 x 10(-5], high peripheral blood (PB) monocytosis (P = .26 x 10(-5], presence of PB blasts (P = .49 x 10(-4], and to a lesser extent hyperleukocytosis (P = .001), presence of PB immature granulocytes, thrombopenia, and splenomegaly. Survival (less than 1 year v greater than 1 year) could be predicted at diagnosis in a multivariate stepwise discriminant analysis using two parameters only (percentage of BM blasts and hemoglobin level), with 82% accuracy. Among patients surviving greater than 1 year, initial PB leukocyte count was higher in patients with intermediate survival (12 to 42 months) than in long survivors (greater than 42 months) and was the only discriminating factor between these two subgroups in multivariate analysis. Abnormal cytogenetic findings and increased lysozymuria were also poor prognostic factors, but could not be analyzed in the multivariate models, as they were determined in a minority of patients. Parameters associated with subsequent progression to ANLL included younger age at diagnosis, thrombopenia, increased BM blasts, and splenomegaly. Our study allows for the identification of subgroups with different prognoses in CMML, on the basis of a small number of hematologic parameters, particularly initial percentage of BM blasts, hemoglobin level, and leukocytosis. These subgroups probably require different therapeutic approaches.
The effect of initial management of hyperleukocytosis on early complications and outcome of children with acute lymphoblastic leukemia.
Authors: Maurer H S , Steinherz P G , Gaynon P S , Finklestein J Z , Sather H N , Reaman G H , Bleyer W A , Hammond G D
Published: February 2017

Data were collected from 124 patients with newly diagnosed acute lymphoblastic leukemia (ALL) and WBC greater than 200,000/microL seen at institutions affiliated with the Children's Cancer Study Group (CCSG) from April 1981 to May 1983. The presenting characteristics, initial management, early complications, and outcome were reviewed. All the children received vigorous intravenous (IV) hydration, alkalinization of the urine, and allopurinol. Thirty-two patients were started on full therapy with no additional measure. One or more special measures believed to reduce the complications of leukostasis and blast cell lysis were administered to 92 patients as follows: small initial doses of prednisone, 63; emergency cranial irradiation, 26; exchange transfusion, 21; and leukopheresis, 19. The incidence of CNS hemorrhage was only 3% (4/124). Seven patients expired during induction and four failed to achieve a remission by day 28. Nineteen patients (15%) had documented bacterial or fungal sepsis. Mild to moderate electrolyte abnormalities occurred in 29 patients: three patients required renal dialysis. Pretreatment with small doses of prednisone did not decrease the incidence of electrolyte abnormalities in those patients when compared with patients who received full chemotherapy. The event-free survival (EFS) for the 106 patients treated on one of the three intensive pilot studies is 55% at 36 months. On multivariate analysis the two significant adverse prognostic factors were massive splenomegaly (P = .02) and WBC count greater than 600,000/microL (P = .05). In conclusion, in patients with hyperleukocytosis the complications of blast cell lysis and leukostasis were manageable with acceptable morbidity and minimal mortality in a group of patients treated with vigorous hydration, allopurinol, and alkalinization of the urine before beginning chemotherapy. Selected patients with severe hyperuricemia and renal dysfunction may benefit from leukopheresis. No beneficial role was demonstrated for the use of small initial doses of prednisone or emergency cranial irradiation.
Advanced epithelial ovarian cancer: salvage whole abdominal irradiation for patients with recurrent or persistent disease after combination chemotherapy.
Authors: Schray M F , Martinez A , Howes A E , Podratz K C , Ballon S C , Malkasian G D , Sikic B I
Published: February 2017

Between 1979 and 1984, 53 patients received whole abdominal irradiation in a curative salvage effort for residual (32 patients) or recurrent (21 patients) epithelial ovarian cancer after combination chemotherapy (cisplatin-based in 48 patients). Residual cancer less than or equal to 2 cm in diameter was confirmed at operation in all patients before irradiation consisting of 2,550 to 3,000 rad to the whole abdomen with partial liver/kidney shielding and boosting of the dose to the diaphragmatic/paraaortic nodal regions and pelvis to approximately 4,000 and 5,000 rad, respectively. Twelve patients (23%) did not complete therapy as a result of hematologic intolerance. Actuarial overall and disease-free survival at 3 years are 35% and 30%, respectively, with follow-up for disease-free patients ranging from 30 to 79 months (median, 43 months). Twenty-seven of 36 relapses (75%) occurred within the irradiated abdomen alone. At 3 years, 70% of patients with well- or moderately-differentiated tumors were disease-free v 10% of those with poorly differentiated tumors (P less than .001). Among prognostic factors evaluated, including grade, initial residual disease before chemotherapy, residual disease at time of irradiation, age, chemotherapy response v progression, and completion of irradiation, only grade and initial residual disease before chemotherapy were statistically significant in multivariate analysis (both P less than .01). Patients with the combination of high-grade tumor, initial residual disease greater than 2 cm before chemotherapy, and macroscopic disease after "second-look" laparotomy do not benefit from irradiation. Eleven patients (21%) developed an apparent treatment-related bowel obstruction after completion of irradiation. Selected subsets of patients do well; however, the role of irradiation in this setting can be confirmed only with randomized clinical study.
Bacillus Calmette-Guérin therapy alters the progression of superficial bladder cancer.
Authors: Herr H W , Laudone V P , Badalament R A , Oettgen H F , Sogani P C , Freedman B D , Melamed M R , Whitmore W F
Published: February 2017

The effectiveness of BCG in preventing disease progression in patients with superficial bladder cancer is evaluated. Long-term follow-up of high-risk patients treated in a previously reported randomized control trial of intravesical plus percutaneous BCG shows that progression occurred in 41/43 (95%) of control and 23/43 (53%) of BCG-treated patients. Muscle invasive and/or metastatic disease occurred with equal frequency in the two groups, but was significantly delayed by BCG treatment (P = .012). Cystectomies were required in 18/43 (42%) control and 11/43 (26%) BCG-treated patients. Median time to cystectomy was 8 months for control v 24 months for BCG-treated patients. Based on initial treatment, survival was improved by BCG therapy (P = .032) (median follow-up 6 years). These results suggest that in high-risk patients intravesical BCG can delay disease progression, prolong the period of bladder preservation, and increase overall survival.
Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis.
Authors: Sørensen J B , Hansen H H , Hansen M , Dombernowsky P
Published: February 2017

A consecutive group of 259 patients with inoperable adenocarcinoma of the lung (ACL) were observed to define risk groups for and frequency of brain metastases together with prognosis. All patients received chemotherapy in a three-armed randomized trial. Brain metastases were diagnosed in 25 patients before protocol entry and in 37 during treatment. Brain autopsy was performed in 87 patients and was positive in 38 (44%). Eleven of these (29%) were not diagnosed clinically. Patients younger than 60 years had a somewhat higher overall frequency of brain metastases than older patients. Patients with initial performance status above 60% and patients responding to chemotherapy had higher risk for developing brain metastasis during treatment than other patients, probably because of the increasing cumulated risk for this complication with prolonged survival. Median survival after onset of brain metastases was 73 days and survival was significantly shorter for these patients than for patients without this complication at days 0, 90, 180, and 365 after protocol entry. Thus, brain metastases is a frequent complication in ACL and the frequency increases with prolonged survival. Survival after development of brain metastases is short and it is questionable whether the inclusion of this subgroup of ACL patients into experimental cytostatic treatments is justified.
Leuprolide acetate in the treatment of refractory or persistent epithelial ovarian cancer.
Authors: Kavanagh J J , Roberts W , Townsend P , Hewitt S
Published: February 2017

Leuprolide acetate (Lupron, TAP Pharmaceuticals, North Chicago), a gonadotropin-releasing hormone analogue, was administered subcutaneously at a 1-mg dose for a minimum of 8 weeks to 23 patients with refractory epithelial ovarian cancer. Eighteen of these patients were evaluable. There were no complete responses. Four patients (17%) had a partial response, with a median duration of 52 weeks. Three of six patients with grade 1 carcinomas had a partial response and two had stabilized disease. There was only one response among 15 patients with grade 2 or 3 disease. Therapy was well tolerated, with three patients complaining of hot flashes and two of mild pedal edema. Leuprolide acetate thus shows evidence of antitumor activity against refractory grade 1 epithelial adenocarcinoma of the ovary. Further trials with larger numbers of patients should be conducted.
The use of bone marrow aspirations and lumbar punctures at the time of diagnosis of retinoblastoma.
Authors: Pratt C B , Meyer D , Chenaille P , Crom D B
Published: February 2017

Lumbar punctures (n = 115) and bone marrow aspirations (n = 114) were performed as part of the routine initial diagnostic evaluation of 115 children with retinoblastoma. Three spinal fluid examinations were positive for tumor cells, and bone marrow smears of three children demonstrated clumps of tumor cells. Five of the six positive studies were in patients with stage IV (extraglobar) disease. These results show that demonstrable CSF or bone marrow involvement is so infrequent an event at diagnosis in patients without symptoms, signs, or histologic evidence of tumor dissemination (stages I-II) as to support a recommendation that these studies need not be performed routinely in such patients. If, after enucleation, there is evidence of extraglobar extension, or if patients have symptoms or signs of CNS or systemic spread (stages III or IV), both procedures should be performed to accurately stage disease and provide baseline measurements of tumor involvement for monitoring of response to chemotherapy and/or irradiation. These results have importance in terms of justification of invasive work-up of most (greater than 85%) affected children, and cost containment.
Costs and benefits of adjuvant therapy in breast cancer: a quality-adjusted survival analysis.
Authors: Goldhirsch A , Gelber R D , Simes R J , Glasziou P , Coates A S
Published: February 2017

The use of adjuvant chemotherapy for postmenopausal patients with early breast cancer remains controversial because the potential benefits in terms of prolongation of disease-free survival (DFS) and overall survival (OS) must be balanced against the toxicity of treatment. Following mastectomy, 463 evaluable postmenopausal women with node-positive breast cancer were randomized to receive either chemoendocrine therapy for 1 year, or endocrine therapy alone for 1 year, or no adjuvant therapy (Ludwig Trial III). At 7-years median follow-up, OS was longer for the chemoendocrine-treated patients compared with controls (P = .04) and compared with the adjuvant endocrine therapy-alone group (P = .08). In order to balance this therapeutic advantage against the toxic effects of treatment, OS time was divided into time with toxicity (TOX), time without symptoms and toxicity (TWiST), and time after systemic relapse (REL). TOX and REL were weighted by coefficients of utility relative to TWiST and the results added to give a period of quality-adjusted survival (Q-TWiST). Benefits measured by Q-TWiST generally favored chemoendocrine therapy. For example, if TOX and REL were both given utility coefficients of 0.5 relative to 1.0 for TWiST, then by 7 years the average Q-TWiST for chemoendocrine therapy was 6.7 months longer than for no-adjuvant therapy (P = .05) and 4.1 months longer than for endocrine therapy alone (P = .20). Quality-adjusted survival analysis is recommended in assessing costs and benefits of toxic adjuvant therapy. In this example, it supports the use of chemoendocrine therapy in postmenopausal node-positive patients for a wide range of relative values assigned to periods with symptoms and toxicity.
A new serologic staging system for large-cell lymphomas based on initial beta 2-microglobulin and lactate dehydrogenase levels.
Authors: Swan F , Velasquez W S , Tucker S , Redman J R , Rodriguez M A , McLaughlin P , Hagemeister F B , Cabanillas F
Published: February 2017

We report results of our investigation of prognostic factors for patients with large-cell lymphoma who were entered on the same treatment protocol and who had known pretreatment serum beta 2-microglobulin (beta 2M) and lactate dehydrogenase (LDH) levels. beta 2M and LDH levels were the most significant and independent variables for predicting time to treatment failure (TTF) and survival. The serum level of beta 2M correlated with tumor burden. These two serum markers defined three significantly different prognostic groups. All 27 patients in the low-risk group remain alive and in remission; in contrast, 22 of the 27 patients (81%) in the high-risk group have failed treatment, and only seven (26%) remain alive. In comparison with the Ann Arbor staging system, serum levels of beta 2M and LDH may provide a more precise system for defining risk groups and thereby allow a more rational approach to the development and analysis of treatment strategies.
The association between high-dose cytarabine neurotoxicity and renal insufficiency.
Authors: Damon L E , Mass R , Linker C A
Published: February 2017

We reviewed the medical records of 110 consecutive patients at our institution who had acute leukemia and received high-dose cytarabine (Ara-C; HDAC) in order to analyze risk factors associated with HDAC neurotoxicity (NT). There were adequate records on 101 patients who received 147 courses of HDAC. Twenty-six treatment courses (18%) were complicated by NT. The median time of NT onset was 5 days (range, 1 to 10 days), and NT was reversible in 16 of 21 survivors (76%). Patients with severe NT (grades 3 to 4) were less likely to have complete reversal of their neurological deficit than those with mild NT (P less than .1). In our patients, there was no significant association between previously described risk factors (age over 49 years, male gender, CNS disorder, and cumulative HDAC dose greater than 48 g/m2) and incidence of NT. However, treatment courses involving HDAC given during renal insufficiency (serum creatinine greater than or equal to 1.5 mg/dL or an increase in serum creatinine greater than 0.5 mg/dL) were much more likely to be complicated by any degree of NT during administration of HDAC (62%) and severe NT (42%) than those given during normal renal function (8% and 3%, respectively; P less than .001). Of the treatment courses involving patients with estimated creatinine clearances less than 60 mL/min, 76% were complicated by NT compared with 8% of treatment courses involving patients with clearances greater than 60 mL/min (P less than .001). HDAC courses with neurotoxic patients had higher serum creatinines (2.1 +/- 1.4 v 1.1 +/- 0.6 mg/dL), greater increases in serum creatinine (+ 0.5 +/- 0.8 v + 0.07 +/- 0.3 mg/dL), and lower estimated creatinine clearances (61 +/- 35 v 91 +/- 29 mL/min) than those courses with nonneurotoxic patients (P less than .001, all parameters). Patients receiving HDAC during renal insufficiency are at high risk for developing NT. Dose reduction of HDAC should be considered for patients with renal insufficiency.
Autologous bone marrow transplantation for acute lymphoblastic leukemia.
Authors: Sallan S E , Niemeyer C M , Billett A L , Lipton J M , Tarbell N J , Gelber R D , Murray C , Pittinger T P , Wolfe L C , Bast R C
Published: February 2017

Forty-four children with acute lymphoblastic leukemia (ALL) who had relapsed (N = 43) or had refractory disease (N = 1) were intensively treated with combination chemotherapy, had remission bone marrow (BM) harvested and purged in vitro with monoclonal antibodies specific for leukemia-associated antigens, underwent postharvest ablative chemotherapy and radiotherapy and subsequently were infused with their autologous marrow. Of the 44 patients treated between November 1980 and January 1988, 19 relapsed, 10 died of complications, and 15 remained in complete remission for a median of 28.5 months (range, 10+ to 94+). Event-free survival (EFS) (+/- SE) at 5 years after autologous transplantation was 29 +/- 8%. For the 26 patients whose initial remission was greater than 2 years, event-free survival was 51 +/- 10%. These results compare favorably with allogeneic transplantation and chemotherapy trials for patients with relapsed ALL, and provide an alternative transplantation option for children without histocompatible donors.