bluuebunny/crossref_metadata_2025 huggingface dataset:
Corticosteroid-induced magnetic resonance imaging changes in patients with recurrent malignant glioma.
Authors: Watling C J , Lee D H , Macdonald D R , Cairncross J G
Published: February 2017

PURPOSE

We studied corticosteroid-induced magnetic resonance (MR) scan changes in patients with recurrent malignant glioma to determine if corticosteroid therapy started concurrently with investigational treatment might yield false-positive responses.

PATIENTS AND METHODS

Ten symptomatic patients not on corticosteroids when malignant glioma recurred had a baseline MR scan performed before corticosteroid treatment, followed by serial scans at weekly intervals for 1 month while on dexamethasone (16 mg/d). The maximum cross-sectional areas and volumes of the gadolinium-enhancing regions (tumor) and T2-weighted abnormalities (tumor plus edema) were compared quantitatively and qualitatively for each series of scans.

RESULTS

Nine of 10 patients (90%) had a measurable reduction in the size of the gadolinium-enhancing region or T2-weighted abnormality with corticosteroid treatment. The maximum cross-sectional area and volume of the gadolinium-enhancing region decreased by at least 25% in three of 10 patients (30%). The maximum cross-sectional area and volume of the T2-weighted abnormality decreased by at least 25% in five of 10 patients (50%). Maximum measurable radiologic improvement was evident within 2 weeks in most patients. MR scans were judged improved by the reporting neuroradiologist in seven of 10 (70%). These subjective visual improvements were also evident within 2 weeks, but generally described as slight or modest.

CONCLUSION

Corticosteroid-induced MR scan reductions in tumor size may confound the assessment of response of recurrent malignant gliomas to investigational agents. For patients who start corticosteroids for symptom control, investigational treatment should be delayed until a new baseline MR image is established 2 weeks later. Response is then judged by comparing subsequent MR scans with the new corticosteroid-influenced baseline image.
Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity.
Authors: Stewart C F , Baker S D , Heideman R L , Jones D , Crom W R , Pratt C B
Published: February 2017

PURPOSE

Topotecan pharmacokinetics and pharmacodynamics were studied following a 72-hour continuous infusion in 20 children with cancer (median age, 8 years; range, 3.5 to 18).

METHODS

Serial plasma and urine samples were collected during the infusion and for up to 6 hours following the end of infusion. Topotecan (lactone) and total (lactone plus hydroxy acid) concentrations were determined by a sensitive and specific high-performance liquid chromatography (HPLC) assay with fluorescence detection. Using maximum a posteriori-Bayesian modeling, lactone and total plasma concentrations were described separately by a two-compartment model. Hematologic toxicity was expressed as the percent decrease in absolute neutrophil count (ANC) and platelet count. The relation between systemic exposure (SE) and hematologic toxicity was modeled using a sigmoid maximum-effect model.

RESULTS

Systemic clearance rates for lactone and total topotecan were (mean +/- SD) 18.5 +/- 7.0 and 6.5 +/- 2.4 L/h/m2, respectively. Urinary recovery of total topotecan was (mean +/- SD) 67.5% +/- 25.2% (n = 12 patients). SE (area under the concentration-time curve from zero to infinity [AUC] or steady-state plasma concentration [Cpss]) to either topotecan lactone or total topotecan was significantly correlated to hematologic toxicity (P < .05). Overall, patients with a higher SE to topotecan experienced greater hematologic toxicity.

CONCLUSION

These data demonstrate a relation between systemic exposure to topotecan and clinical effect (myelosuppression). Moreover, these data provide the basis for development of individualized topotecan administration schedules.
Phase I trial of continuous infusion carboplatin and etoposide in children with refractory acute leukemia: a Pediatric Oncology Group study.
Authors: Sadowitz P D , Dubowy R , Souid A , Pollock B H , Weinstein H , Parmley R T , Bowman W P , Land V , Vats T , Pratt C
Published: February 2017

PURPOSE

The purpose of this phase I study was to determine the toxicities and response to continuous infusion carboplatin in combination with a fixed dose of etoposide (VP-16) in children with refractory acute leukemia.

PATIENTS AND METHODS

From January 1989 to February 1992, 20 patients received 28 courses of treatment. Each course of treatment consisted of a 1-hour intravenous (IV) infusion of VP-16 100 mg/m2/d for 5 days, followed by a 23-hour IV infusion of carboplatin each day. The initial, total 5-day dose of carboplatin (1,000 mg/m2) was escalated by 250- to 375-mg increments to a final, total dose of 1,875 mg/m2 over 5 days.

RESULTS

Significant marrow suppression was observed in all patients, with prolonged marrow aplasia at the 1,875-mg/m2 dose level. Grade III diarrhea occurred in three patients; 10 patients experienced life-threatening infection and three had severe thrombocytopenic bleeding. Major marrow responses (two complete remissions and two partial remissions) occurred in four patients (20%).

CONCLUSION

In view of the apparent antileukemic efficacy and minimal extramedullary toxicity, carboplatin deserves further study in a phase II trial.
Chronic lymphocytic leukemia: an updated review.
Authors: Faguet G B
Published: February 2017

PURPOSE

To review recent advances in the pathogenesis, biology, diagnosis, and management of chronic lymphocytic leukemia (CLL).

DESIGN

A literature search restricted to English-language articles, abstracts, book chapters, and reports published between 1975 and 1993 was conducted both electronically using MEDLINE and CANCERLIT and manually using the bibliographies of the electronically retrieved data base. Of approximately 1,000 publications identified for analysis, 233 were selected as representative of important advances in CLL.

RESULTS

The last 10 years have witnessed renewed interest in the biology and treatment of CLL, a disease long viewed by clinicians as following an indolent course and perceived by investigators as uninspiring. This interest, based on advances in understanding the lineage and biology of CLL and on the advent of new and more efficacious chemotherapeutic agents, has led to improvements in patient survival and, for the first time, to complete remissions (CRs) in large subsets of patients. As we learn to use these agents better, especially in combination chemotherapy, alternative therapeutic modalities, are being vigorously pursued, including high-dose ablative chemotherapy with allogeneic or autologous bone marrow transplantation (BMT) rescue and the use of powerful tumor-cell target-specific immunoreagents. These therapeutic advances, coupled with the recent availability of molecular probes to ascertain objectively minimal remnant disease posttreatment, provide a basis for developing and assessing ever more efficacious and potentially curative treatment strategies for the management of this disease.

CONCLUSION

For the first time since the original 1924 monograph by Minot and Isaacs, the cure of subsets of patients with CLL appears not to be an unreasonable goal.
Timed sequential chemotherapy for previously treated patients with acute myeloid leukemia: long-term follow-up of the etoposide, mitoxantrone, and cytarabine-86 trial.
Authors: Archimbaud E , Thomas X , Leblond V , Michallet M , Fenaux P , Cordonnier C , Dreyfus F , Troussard X , Jaubert J , Travade P
Published: February 2017

PURPOSE

To confirm and extend encouraging preliminary results of timed sequential chemotherapy (TSC) in patients with previously treated acute myelogenous leukemia (AML).

PATIENTS AND METHODS

We report the results of the regimen of mitoxantrone on days 1 to 3, etoposide on days 8 to 10, and cytarabine on days 1 to 3 and 8 to 10 (EMA) in 133 patients, with a median follow-up of 40 months.

RESULTS

Sixty percent of patients, with a 95% confidence interval (CI) ranging from 51% to 68%, achieved complete remission (CR), including 44% (CI, 32% to 57%) of refractory patients and 76% (CI, 64% to 86%) of late first-relapse patients (P = .0002). Twenty-nine percent of patients did not respond to therapy, and 11% died from toxicity. Median duration of neutropenia and thrombocytopenia was 31 days and 29 days, respectively. Severe nonhematologic toxicity included sepsis in 54% of patients and mucositis in 23%. Postinduction therapy included a second course of EMA in 27 patients, maintenance in 10, autologous bone marrow transplantation (BMT) in 12, and allogeneic BMT in 13. Median survival of patients who did not have transplantation performed is 7 months, with 11% (CI, 4% to 18%) survival at 5 years. Median disease-free survival (DFS) is 8 months with 20% (CI, 8% to 32%) DFS at 5 years. Twenty-eight percent (CI, 15% to 44%) of nontransplanted patients who achieved CR had an inversion of CR duration. Previous refractoriness was the main factor associated with poor prognosis for CR achievement, DFS, and survival.

CONCLUSION

These results confirm initial reports on TSC and show that approximately 20% of patients with first relapse after therapy can enjoy prolonged DFS using chemotherapy only.
Monotherapy for fever and neutropenia in cancer patients: a randomized comparison of ceftazidime versus imipenem.
Authors: Freifeld A G , Walsh T , Marshall D , Gress J , Steinberg S M , Hathorn J , Rubin M , Jarosinski P , Gill V , Young R C
Published: February 2017

PURPOSE

To compare the efficacy of ceftazidime and imipenem monotherapy for fever and neutropenia, and to determine whether fewer antimicrobial modifications (additions or changes) are required by the broader-spectrum agent, imipenem.

PATIENTS AND METHODS

Adult and pediatric patients undergoing chemotherapy for solid tumors, leukemias, or lymphomas were randomized to receive open-label ceftazidime or imipenem on presentation with fever and neutropenia. Success with or without modifications of the initial antibiotic was defined as survival through neutropenia; failure was death due to infection. Comparisons were based on numbers of modifications made to each monotherapy during the course of neutropenia, in patients stratified as having unexplained fever or a documented infection.

RESULTS

Among 204 ceftazidime and 195 imipenem recipients, the overall success rate with or without modification was more than 98%, regardless of initial antibiotic regimen. Modifications occurred in half of all episodes, primarily in patients with documented infections on either monotherapy. Antianaerobic agents were more frequently added to ceftazidime (P < .001), but addition of other antibiotics, including vancomycin and aminoglycosides, was similar between the two monotherapy groups. Imipenem therapy was associated with significantly greater toxicity, manifested by Clostridium difficile-associated diarrhea and by nausea and vomiting, which required discontinuation of imipenem in 10% of recipients.

CONCLUSION

Ceftazidime and imipenem are both effective in the management of fever and chemotherapy-related neutropenia, provided that modifications are made in response to clinical and microbiologic data that emerge during the course of neutropenia. Imipenem, despite its broader antimicrobial spectrum, does not significantly decrease the overall need for antibiotic modifications and is more often complicated by gastrointestinal toxicity.
Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans.
Authors: Gianni L , Kearns C M , Giani A , Capri G , Viganó L , Lacatelli A , Bonadonna G , Egorin M J
Published: February 2017

PURPOSE

To characterize and model the disposition of paclitaxel in humans and define a pharmacodynamic relationships between paclitaxel disposition and its toxicity and efficacy.

PATIENTS AND METHODS

Paclitaxel pharmacokinetics were studied in 55 courses of therapy in 30 patients. Paclitaxel was administered at 135 mg/m2 or 175 mg/m2 by either a 3- or a 24-hour infusion schedule to patients with advanced ovarian cancer (n = 15), or at 225 mg/m2 by 3-hour infusion to patients with advanced breast cancer (n = 15). Paclitaxel and 6 alpha-hydroxylpaclitaxel were quantified by high-performance liquid chromatography (HPLC). Pharmacokinetics were assessed by noncompartmental and model-dependent methods. Pharmacodynamic correlations were evaluated statistically and by regression models.

RESULTS

Paclitaxel disposition is nonlinear in humans and, on the 3-hour schedule, 6 alpha-hydroxylpaclitaxel was identified in the plasma of all patients treated. The plasma disposition of paclitaxel and 6 alpha-hydroxylpaclitaxel was well described by a model that featured multiple nonlinear processes. Neutropenia was not related to the areas under the curves (AUCs) of paclitaxel or 6 alpha-hydroxylpaclitaxel, or to palitaxel peak concentrations (Cmax). Neutropenia was related to the duration that plasma concentrations were > or = 0.05 mumol/L, a relationship that is well described by a sigmoid maximum response (Emax) model.

CONCLUSION

The disposition of paclitaxel in humans is nonlinear. Paclitaxel metabolism to 6 alpha-hydroxylpaclitaxel is likely an important detoxification pathway. Myelosuppression is related to the duration that plasma paclitaxel concentrations are > or = 0.05 mumol/L. Trials of new doses and schedules of paclitaxel should take into account its nonlinear disposition to rule out adverse clinical consequences, especially if the drug is administered by short infusion. Our pharmacokinetic model should prove to be a powerful tool in predicting paclitaxel disposition, regardless of dose and schedule, and should facilitate further pharmacodynamic investigations.
Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients.
Authors: Abigerges D , Chabot G G , Armand J P , Hérait P , Gouyette A , Gandia D
Published: February 2017

PURPOSE

A phase I study was undertaken to determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacokinetics of the novel topoisomerase I inhibitor irinotecan (CPT-11).

PATIENTS AND METHODS

Sixty-four patients meeting standard phase I eligibility criteria were included (24 women, 40 men; median age, 51 years; primary sites: colon, head and neck, lung, pleura; 60 of 64 had been previously treated). Pharmacokinetics was determined by high-performance liquid chromatography (HPLC).

RESULTS

One hundred ninety CPT-11 courses were administered as a 30-minute intravenous (IV) infusion every 3 weeks (100 to 750 mg/m2). Grade 3 to 4 nonhematologic toxicities included diarrhea (16%; three hospitalizations), nausea and vomiting (9%), asthenia (14%), alopecia (53%), elevation of hepatic transaminases (8%), and one case of skin toxicity. An acute cholinergic syndrome was observed during CPT-11 administration. Diarrhea appeared dose-limiting at 350 mg/m2, but this was circumvented by using a high-dose loperamide protocol that allowed dose escalation. Dose-dependent, reversible, noncumulative granulocytopenia was the dose-limiting toxicity (nadir, days 6 to 9; median recovery time, 5 days). Grade 3 to 4 anemia was observed in 9% of patients. One patient died during the study, 8 days after CPT-11 treatment. Two complete responses (cervix, 450 mg/m2; head and neck, 750 mg/m2) and six partial responses in fluorouracil (5-FU)-refractory colon cancer were observed (260 to 600 mg/m2). Pharmacokinetics of CPT-11 and active metabolite SN-38 were performed in 60 patients (94 courses). CPT-11 plasma disposition was bi- or triphasic, with a mean terminal half-life of 14.2 +/- 0.9 hours (mean +/- SEM). The mean volume of distribution (Vdss) was 157 +/- 8 L/m2, and total-body clearance was 15 +/- 1 L/m2/h. The CPT-11 area under the plasma concentration versus time curves (AUC) and SN-38 AUC increased linearly with dose. SN-38 plasma decay had an apparent half-life of 13.8 +/- 1.4 hours. Both CPT-11 and SN-38 AUCs correlated with nadir leukopenia and granulocytopenia, with grade 2 diarrhea, and with nausea and vomiting.

CONCLUSION

The MTD of CPT-11 administered as a 30-minute IV infusion every 3 weeks is 600 mg/m2, with granulocytopenia being dose-limiting. At 350 mg/m2, diarrhea appeared dose-limiting, but high-dose loperamide reduced this toxicity and allowed dose escalation. For safety reasons, the recommended dose is presently 350 mg/m2 every 3 weeks; more experience must be gained to establish the feasibility of a higher dose in large multicentric phase II studies. However, when careful monitoring of gastrointestinal toxicities is possible, a higher dose of 500 mg/m2 could be recommended in good-risk patients. The activity of this agent in 5-FU-refractory colorectal carcinoma makes it unique and mandates expedited phase II testing.
Phase I trial of the somatostatin analog octreotide acetate in the treatment of fluoropyrimidine-induced diarrhea.
Authors: Wadler S , Haynes H , Wiernik P H
Published: February 2017

PURPOSE

Diarrhea is one of the dose-limiting toxicities for administration of fluorouracil (5FU) in patients with gastrointestinal malignancies and can result in severe morbidities or mortality. The somatostatin analog octreotide acetate has been used in the treatment of 5FU-induced diarrhea with promising results. A phase I trial was initiated to determine the maximum-tolerated dose of octreotide acetate that could be administered in this setting.

PATIENTS AND METHODS

Patients were required to have National Cancer Institute Common Toxicity Criteria > or = grade 2 diarrhea or watery diarrhea secondary to treatment with 5FU or a modulated 5FU regimen. At least three patients were treated at each dose level; after satisfactory completion of this dose level (zero of three or one of six patients with < or = grade 2 toxicity), additional patients were added at the next dose level. Doses of octreotide acetate studied were 50 to 2,500 micrograms subcutaneously three times daily for 5 days.

RESULTS

A total of 35 patients received 49 courses of therapy. The only significant toxicities occurred at 2,500 micrograms. At this dose level, one patient developed an allergic reaction with flushing, nausea, and dizziness after each of the first two injections. A second patient developed asymptomatic hypoglycemia with a serum glucose level of 26 mg/dL. The maximum-tolerated dose was 2,000 micrograms. The efficacy of the treatment correlated significantly (P = .01) with the dose of octreotide administered, and more patients completed the course of therapy at the higher doses.

CONCLUSION

Octreotide acetate can be safely administered for the treatment of fluoropyrimidine-induced diarrhea in patients with gastrointestinal malignancies. The dose-limiting toxicities were allergic (nausea, rash, and light-headedness) and endocrine (hypoglycemia). There was a significant correlation between complete response to therapy and octreotide dose.
Ciprofloxacin versus trimethoprim/sulfamethoxazole for prophylaxis of bacterial infections in bone marrow transplant recipients: a randomized, controlled trial.
Authors: Lew M A , Kehoe K , Ritz J , Antman K H , Nadler L , Kalish L A , Finberg R
Published: February 2017

PURPOSE

To compare the efficacy and safety of ciprofloxacin (CIP) and trimethoprim/sulfamethoxazole (TMS) for the prevention of bacterial infections in patients who received bone marrow transplantation (BMT) for the treatment of solid and hematopoietic neoplasms.

PATIENTS AND METHODS

Adult inpatients about to undergo BMT for lymphoma, leukemia, or solid tumors were enrolled onto a prospective, randomized, double-blinded, controlled trial that compared CIP (750 mg orally twice per day) with TMS (160 mg trimethoprim and 800 mg sulfamethoxazole orally twice per day). Subjects were stratified before randomization according to tumor and BMT type. Prophylaxis was begun within 96 hours of initiation of the BMT preparative regimen and continued until the onset of fever, signs or symptoms of infection, serious adverse effects, or recovery of the absolute granulocyte count (AGC) to > or = to 400/microL.

RESULTS

Seventy-five CIP recipients and 71 TMS recipients were assessable for efficacy. No difference was noted between the two groups in occurrence of fever during neutropenia, time to onset of first fever, or overall infection rates. Ten bacteremias occurred in CIP recipients versus six in TMS recipients (P = .43). Ten episodes of Clostridium difficile enterocolitis occurred in TMS recipients versus no episodes in CIP recipients (P = .001). Four infections caused by gram-negative bacilli, including one bacteremia, occurred in TMS recipients versus none in CIP recipients (P = .06). No differences were noted in the incidence of rash or organ toxicity. TMS recipients had longer durations of granulocytopenia at AGC levels < or = to 500/microL and < or = to 100/microL than did CIP recipients (P = .08 for both comparisons). Mean peak and trough serum levels of CIP decreased significantly between weeks 1 and 2 of prophylaxis.

CONCLUSION

CIP and TMS were equally safe and effective in the prevention of bacterial infections in BMT patients when the overall infection rate was used as the principal end point. TMS prophylaxis was associated with a higher incidence of C difficile enterocolitis and infections caused by gram-negative bacilli, as well as a trend toward prolongation of granulocytopenia.
Are axillary recurrence and overall survival affected by axillary extranodal tumor extension in breast cancer? Implications for radiation therapy.
Authors: Leonard C , Corkill M , Tompkin J , Zhen B , Waitz D , Norton L , Kinzie J
Published: February 2017

PURPOSE

To determine the overall survival and local recurrence significance of axillary lymph node extranodal tumor extension (ETE) and whether axillary/chest-wall irradiation influenced any of these outcomes.

MATERIALS AND METHODS

The records of 81 breast cancer patients treated with radical or modified radical mastectomy at a single surgical practice were eligible for study. Thirty-four patients had ETE: 17 with focal ETE (< 10 x high-power field) and 17 with extensive ETE (> 10 x high-power field).

RESULTS

With a median follow-up duration of 92 months, only two patients had an axillary recurrence (2%): one had focal ETE and one had no ETE. Neither of these patients received axillary radiation therapy. Overall survival and recurrence-free survival were significantly decreased with ETE in patients whether axillary radiation therapy had been administered or not. Analysis showed that the age of the patient correlated significantly with extensive ETE (P = .04) and that the number of positive lymph nodes (< or = three v > three) correlated significantly with ETE (whether focal or extensive) (P = .0001). A multivariate analysis of extranodal tumor extension and number of positive lymph nodes showed that ETE was associated with decreased survival (P = .05), although to a lesser degree than number of positive lymph nodes (P = .003).

CONCLUSION

These results show that ETE is associated with decreased survival and increased recurrence rates regardless of the extent of the radiation therapy field. Also, ETE does not necessarily indicate a significantly increased incidence of axillary recurrence. Therefore, axillary irradiation based on this pathologic finding may not be indicated.
Pubertal growth in young adult survivors of childhood leukemia.
Authors: Didcock E , Davies H A , Didi M , Ogilvy Stuart A L , Wales J K , Shalet S M
Published: February 2017

PURPOSE

To determine the effect of cranial irradiation (18 Gy and 24 Gy) on pubertal growth in young adult survivors of childhood acute lymphoblastic leukemia (ALL).

PATIENTS AND METHODS

Final height (FH) and pubertal growth were retrospectively examined in 142 young adult survivors of childhood ALL. All were in first remission and had received either 18 or 24 Gy of cranial irradiation. Eighty-four children (48 girls) were treated with 24 Gy and 58 (35 girls) with 18 Gy. None had received either testicular or spinal irradiation. Timing and duration of puberty were studied in 110 patients.

RESULTS

Significant reduction in height standard deviation score (SDS) from diagnosis to FH was seen in both sexes and in both dose groups. In girls, in both dose groups, mean age at peak height velocity (PHV) and mean age at menarche occurred significantly earlier than in the normal population. In boys, there was a normal timing of PHV. The amplitude of PHV was significantly reduced in both sexes and in both dose groups. Parameters of pubertal duration (PHV to menarche, PHV to FH, and menarche to FH) were not significantly different from normal population values.

CONCLUSION

In conclusion, puberty occurred early in girls, but not in boys. Amplitude of PHV was reduced in both sexes, with no reduction in the duration of puberty. It is likely that disturbances of both timing and quality of growth during puberty contribute to the loss of standing height and body disproportion seen in these children.
Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer.
Authors: Seidman A D , Tiersten A , Hudis C , Gollub M , Barrett S , Yao T J , Lepore J , Gilewski T , Currie V , Crown J
Published: February 2017

PURPOSE

To evaluate the efficacy and safety of paclitaxel administered by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer.

PATIENTS AND METHODS

Forty-nine patients with metastatic breast cancer received paclitaxel via 3-hour intravenous infusion after standard premedication. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used, and chemotherapy was cycled every 3 weeks. For 25 patients who received paclitaxel as initial therapy (group I), the starting dose was 250 mg/m2. Twenty-four patients who had received two or more prior regimens, including an anthracycline (group II), started at 175 mg/m2. Paclitaxel pharmacokinetics were evaluated in 23 patients in group I.

RESULTS

Grade 3 and 4 toxicities included (groups I/II) neutropenia (36%/33%), thrombocytopenia (0%/8%), anemia (0%/13%), neuropathy (8%/0%), arthralgia/myalgia (16%/4%), and mucositis (4%/4%). No significant hypersensitivity-type reactions or cardiac arrhythmias were seen. Six patients who received paclitaxel at > or = 250 mg/m2 experienced transient photopsia, without apparent chronic neuro-ophthalmologic sequelae. The mean peak plasma paclitaxel concentration was 5.87 mumol/L (range, 1.99 to 7.89) for these patients, and 6.08 mumol/L (range, 0.81 to 13.81) for 17 of 19 patients who did not experience visual symptoms. In 25 assessable patients in group I at a median follow-up time of 12 months, one complete response (CR) and seven partial responses (PRs) have been observed, for a total response rate of 32% (95% confidence interval [CI], 15% to 53%). In group II, five PRs were noted in 24 assessable patients (20.8%; 95% CI, 7% to 42%). Median response durations were 7 months for group I and 4 months for group II.

CONCLUSION

Paclitaxel via 3-hour infusion, without prophylactic G-CSF, is active and safe as initial and subsequent therapy for metastatic breast cancer. The transient visual symptoms noted at higher doses seem unrelated to peak plasma paclitaxel concentration. Further studies that compare 3- and 24 hour (or other) infusion schedules are necessary to determine the optimal administration of paclitaxel in metastatic breast cancer.
Serum cardiac troponin T levels during treatment of early-stage breast cancer.
Authors: Hughes-Davies L , Sacks D , Rescigno J , Howard S , Harris J
Published: February 2017

PURPOSE

To measure serum troponin T concentrations in patients with early-stage left breast cancer during breast-conserving radiation therapy. Troponin T has been introduced recently as a sensitive and specific marker for acute myocardial injury.

PATIENTS AND METHODS

We compared pretreatment and posttreatment serum troponin T values in 50 patients undergoing radiation therapy to the entire left breast following conservative surgery for stage I and II breast cancer.

RESULTS

No changes in troponin T concentrations were found after 45 to 46 Gy whole-breast irradiation. All women had undetectable or normal troponin T on the first and last day of treatment. There was no evidence of an upward trend during treatment.

CONCLUSION

Radiation therapy to the left breast does not affect serum cardiac troponin T levels, despite the fact that a portion of the myocardium lies within the high-dose region. This suggests that the acute effects of radiation on the myocardium are minor. Long-term evaluation of these patients is necessary to rule out the possibility of late cardiac morbidity due to accelerated atherosclerosis. This study also suggests that an elevated troponin T level during or shortly after left breast irradiation should not be attributed to treatment.
Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer: a Hoosier Oncology Group study.
Authors: Loehrer P J , Ansari R , Gonin R , Monaco F , Fisher W , Sandler A , Einhorn L H
Published: February 2017

PURPOSE

To determine whether the addition of ifosfamide to cisplatin plus etoposide improves the response rate, time to disease progression, or overall survival in previously untreated patients with extensive-stage small-cell carcinoma of the lung (SCLC).

PATIENTS AND METHODS

Patients with extensive SCLC with a Karnofsky performance score (KPS) > or = 50 and adequate renal function and bone marrow reserve were eligible. Patients with CNS metastases were eligible and received concurrent whole-brain radiotherapy. Patients were randomized to receive cisplatin (20 mg/m2) plus etoposide (100 mg/m2) (VP) both given intravenously (i.v.) on days 1 to 4 or cisplatin (20 mg/m2), ifosfamide (1.2 g/m2), and etoposide (75 mg/m2) (VIP) all given i.v. on days 1 to 4. Cycles were repeated every 3 weeks for four cycles.

RESULTS

From May 1989 through March 1993, 171 patients were randomized (84 to VP and 87 to VIP). The median follow-up duration is 26 months. All patients were assessable for survival; 163 were fully assessable for response and 162 for toxicity. Myelosuppression was greater with VIP. Objective responses were observed in 55 of 82 (67%) and 59 of 81 (73%) assessable patients treated with VP and VIP, respectively (difference not significant). The difference in the median time to progression was statistically different (P = .039). The median survival times on VP and VIP were 7.3 months and 9.0 months, respectively (P = .045 for survival curves by stratified log-rank test) with 2-year survival rates of 5% versus 13%, respectively.

CONCLUSION

VIP combination chemotherapy is associated with an improved time to progression and overall survival over VP therapy in patients with extensive SCLC.
Docetaxel.
Authors: Cortes J E , Pazdur R
Published: February 2017

PURPOSE

We reviewed the preclinical and clinical profiles of the antineoplastic taxoid docetaxel (Taxotere, Rhône-Poulenc Rorer, Collegeville, PA).

DESIGN

From the literature and manufacturer's data, we detail docetaxel's activity, tolerability, and pharmacokinetics in preclinical and phase I studies and its activity and side effects in phase II trials in various neoplasms.

RESULTS

Docetaxel promotes the assembly of and stabilizes microtubules, preventing their depolymerization. In phase I studies in patients with solid tumors refractory to standard chemotherapy, docetaxel's major dose-limiting toxicity (DLT) was dose- but not schedule-dependent neutropenia; another major side effect was schedule-dependent grade 3 mucositis. Other, generally less severe effects included hypersensitivity reactions (HSRs), neurotoxicities, cutaneous reactions, alopecia, and asthenia. Responses were observed in breast, bronchial, and ovarian carcinomas. The recommended dose for phase II studies was 100 mg/m2 as a 1-hour intravenous (i.v.) infusion every 3 weeks. Preliminary phase II results confirmed docetaxel's activity against breast, non-small-cell and small-cell lung, ovarian, head and neck, and gastric cancers; melanoma; and soft tissue sarcomas. Neutropenia again was the principal dose-limiting side effect. Nonhematologic effects, usually grade 1 or 2, including HSRs, were common. HSRs were manageable with premedication. Corticosteroid premedication partially alleviated fluid retention seen after repeated docetaxel courses. Studies are evaluating docetaxel in various combination regimens in advanced breast cancer, non-small-cell lung cancer, and other solid tumors.

CONCLUSION

Multicenter and single-institution studies have demonstrated docetaxel's consistent significant activity in various cancers. Phase III and combination therapy trials are ongoing. Work is in progress to understand and prevent/resolve some of this drug's side effects.
Advanced breast cancer: a phase II trial with gemcitabine.
Authors: Carmichael J , Possinger K , Phillip P , Beykirch M , Kerr H , Walling J , Harris A L
Published: February 2017

PURPOSE

In this phase II study, the efficacy and tolerability of gemcitabine were studied in 44 patients with locally advanced or metastatic breast cancer.

PATIENTS AND METHODS

Of 40 patients assessable for response, 14 were chemotherapy-naive, seven had received adjuvant chemotherapy, and 19 had received one prior chemotherapy regimen for metastatic disease. Gemcitabine was administered as a 30-minute intravenous infusion once a week for 3 weeks followed by a 1-week rest every 4 weeks. The mean number of completed cycles administered was 2.7 and the mean dosage delivered was 725 mg/m2 per injection. Eighty-one percent of doses were delivered as scheduled.

RESULTS

There were three complete responses and seven partial responses, for an overall response rate of 25.0% (95% confidence interval [CI], 12.7% to 41.2%). Four patients were not assessable for efficacy (one had insufficient therapy, two had no bidimensionally measurable disease, and one had neither). All responses were independently validated by an external oncology review board. Responses were observed early in treatment, with a median time to response of 1.9 months. The median survival duration for all 40 assessable patients was 11.5 months. Hematologic toxicity was generally mild, with World Health Organization (WHO) grade 3 and 4 leukopenia occurring in 6.8% and 2.3% of patients and neutropenia in 23.3% and 7.0%, of patients, respectively. The only other grade 4 toxicities were infection and nausea and vomiting in one patient each. One patient was withdrawn due to shortness of breath, possibly drug-related. Flu-like symptoms, which were mild, transient, and treatable with acetominophen, were reported in 6.8% of patients. Only one patient developed alopecia of severity greater than WHO grade 2.

CONCLUSION

In view of the single-agent activity seen in advanced breast cancer, modest toxicity profile, and novel mechanism of action, gemcitabine deserves evaluation in breast cancer and is an ideal candidate for combination therapy.
Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma.
Authors: Creagan E T , Dalton R J , Ahmann D L , Jung S H , Morton R F , Langdon R M , Kugler J , Rodrigue L J
Published: February 2017

PURPOSE

We conducted a randomized prospective trial in selected patients with fully resected high-risk stage I and II malignant melanoma.

PATIENTS AND METHODS

Interferon alfa-2a (IFN-alpha 2a) 20 x 10(6) U/m2 was administered three times each week for 12 weeks by the intramuscular route. Both the treatment group (n = 131) and the control group (n = 131) were evenly balanced with regard to relevant prognostic discriminants.

RESULTS

The median disease-free survival (DFS) time was 2.4 years for the IFN-alpha 2a group and 2.0 years for the observation group (log-rank P = 0.19). The median survival times were 6.6 years for IFN-alpha 2a and 5.0 years for observation (log-rank P = .40). For stage I patients (n = 102), there was no apparent therapeutic advantage from IFN-alpha 2a therapy. The DFS for stage II patients was a median of 10.8 months in the control group versus 17 months in the treatment group. The overall survival time was 4.1 years for the treatment group versus 2.7 years for the control group. The differences in DFS for stage II patient were significant in a Cox model. These results must be interpreted cautiously because of subset analysis. A severe flu-like toxicity occurred in 44% of patients, 13% lost at least 10% of their baseline weight, and 45% experienced a worsening of Eastern Cooperative Oncology Group (ECOG) performance score.

CONCLUSION

Our findings indicate trends that suggest a possible benefit for selected patients with high-risk malignant melanoma. The results will require further study in a larger patient population for confirmation.
Autologous bone marrow transplantation for advanced neuroblastoma using teniposide, doxorubicin, melphalan, cisplatin, and total-body irradiation.
Authors: McCowage G B , Vowels M R , Shaw P J , Lockwood L , Mameghan H
Published: February 2017

BACKGROUND

Disseminated neuroblastoma after infancy has a dismal prognosis; long-term survival with conventional therapy occurs in approximately 10% of cases.

PATIENTS AND METHODS

Between 1985 and 1992, we followed a strategy aimed to achieve remission with an induction combination of intensive chemotherapy, primary resection, and tumor-bed radiotherapy (TBRT). Patients who achieved remission proceeded to myeloablative chemoradiotherapy and unpurged autologous bone marrow transplant (ABMT). Twenty-eight patients older than 1 year presented with stage IV disease during the study period; six died of progressive disease and three died of complications of therapy. Nineteen patients achieved remission, two of whom did not receive ABMT. Seventeen patients proceeded to ABMT. Conditioning was with teniposide 130 mg/m2, doxorubicin 30 mg/m2, melphalan 120 mg/m2, cisplatin 80 mg/m2, and total-body irradiation 12 Gy in six fractions (modified VAMP-TBI).

RESULTS

Principal nonhematologic toxicities were mucositis and diarrhea. There were no ABMT-related deaths. Two patients relapsed at 8 and 26 months post-ABMT, respectively. Fifteen patients remain in complete remission (CR) at 24 to 102 months (median, 71) from ABMT and 30 to 114 months (median, 78) from diagnosis. Survival rates of all 28 patients are 61% and 50% at 2 and 5 years, respectively, and the disease-free survival (DFS) of the ABMT group is 94% and 87% at 2 and 5 years, respectively.

CONCLUSION

Modified VAMP-TBI appears to be an effective conditioning regimen, with 15 of 17 patients remaining disease-free, with no toxic deaths. This result compares favorably with that of other groups. Larger numbers of patients need to be treated to confirm the efficacy of this therapy.
Pulmonary thromboembolism in childhood leukemia: 8-years' experience in a pediatric hematology center.
Authors: Uderzo C , Faccini P , Rovelli A , Arosio M , Marchi P F , Riva A , Marraro G , Balduzzi A , Masera G
Published: February 2017

PURPOSE

To assess the occurrence and possible causes of pulmonary thromboembolism (PTE) in children with hematologic malignancies evaluated in a single pediatric hematology center.

PATIENTS AND METHODS

Four hundred fifty-two patients admitted for leukemia in different stages of disease were evaluated whenever they presented with PTE-related acute respiratory failure (ARF). Diagnosis was based on a perfusional lung scan and a digital pulmonary angiography in most cases. When necessary, patients with ARF were transferred to the pediatric intensive care unit (ICU) for cardiorespiratory monitoring and support. Thrombolytic treatment was usually performed with urokinase at a loading dose of 2,000 to 4,560 IU/kg as single bolus followed by 2,000 to 4,530 IU/kg/h for 12 to 42 hours. Before thrombolytic therapy was discontinued, heparin was started at a daily dose of 100 to 500 IU/kg as a continuous infusion and continued for 6 to 26 days.

RESULTS

Twelve of 452 children developed 17 PTE episodes, which were resolved completely after appropriate therapy in 15 cases. Univariate analysis showed a statistical correlation between PTE and the diagnosis of acute myeloid leukemia (AML) (P < .001). No major bleeding was observed after thrombolytic treatment.

CONCLUSION

Our findings indicate that PTE is not an extremely rare event in children with leukemia and should be ruled out when sudden tachypnea develops in patients with risk factors such as previous tumor lysis, central venous catheter (CVC) malfunction, coagulation abnormalities, and drug-induced pulmonary toxicity. Complete resolution of PTE may be obtained in a high proportion of cases with early diagnosis and proper treatment.
Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation.
Authors: Rinaldi D A , Burris H A , Dorr F A , Woodworth J R , Kuhn J G , Eckardt J R , Rodriguez G , Corso S W , Fields S M , Langley C
Published: February 2017

PURPOSE

To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor.

PATIENTS AND METHODS

Patients with advanced solid tumors were administered LY231514 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients.

RESULTS

Twenty-five patients were administered 58 courses of LY231514 at doses that ranged from 10 to 40 mg/m2/wk. Reversible neutropenia was the dose-limiting toxicity. Inability to maintain the weekly treatment schedule due to neutropenia limited dose escalation on this schedule. Nonhematologic toxicities observed included mild fatigue, anorexia, and nausea. At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two patients with advanced colorectal cancer.

CONCLUSION

The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively.
Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study.
Authors: Bertelli G , Gozza A , Forno G B , Vidili M G , Silvestro S , Venturini M , Del Mastro L , Garrone O , Rosso R , Dini D
Published: February 2017

PURPOSE

To evaluate the activity and tolerability of dimethylsulfoxide (DMSO) in the prevention of soft tissue toxicity after extravasation of cytotoxic drugs.

PATIENTS AND METHODS

From June 1991 to December 1994, all patients who had an extravasation during intravenous (IV) infusion of cytotoxic drugs in our institution were considered for an open, prospective study of preventive treatment with 99% DMSO, applied topically on the extravasation site every 8 hours for 7 days. Intermittent local cooling (for 1 hour three times daily) on the first 3 days was also used.

RESULTS

One hundred forty-four patients with extravasations of doxorubicin (n = 11), epirubicin (n = 46), mitomycin (n = 5), mitoxantrone (n = 13), cisplatin (n = 44), carboplatin (n = 6), ifosfamide (n = 14), and fluorouracil (n = 5) entered the study; 127 were assessable. Only one patient suffered an ulceration. The treatment was well tolerated, with mild local burning and a characteristic breath odor being the only side effects of DMSO application, even in cases in which treatment continued for up to 6 weeks to obtain remission of the symptoms of extravasation.

CONCLUSION

Topical DMSO is an effective and safe antidote that may be used with local cooling after extravasations of vesicant drugs other than those drugs for which standard interventions are defined.
Pentoxifylline for treatment of cancer anorexia and cachexia? A randomized, double-blind, placebo-controlled trial.
Authors: Goldberg R M , Loprinzi C L , Mailliard J A , O'Fallon J R , Krook J E , Ghosh C , Hestorff R D , Chong S F , Reuter N F , Shanahan T G
Published: February 2017

PURPOSE

Based on evidence that suggests pentoxifylline can inhibit tumor necrosis factor, we set out to evaluate the activity and toxicity of this drug in patients with cancer-associated anorexia and/or cachexia.

PATIENTS AND METHODS

Seventy patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 with cancer anorexia and/or cachexia (defined by a weight loss of > or = 5 lb in the preceding 2 months or a caloric intake < 20 kcal/kg/d) were stratified and then randomly assigned to receive pentoxifylline or identical-appearing placebo tablets in a double-blind fashion. Patients' weights were monitored and patient questionnaires were used to assess appetite, toxicity, and perception of benefit.

RESULTS

Pentoxifylline failed to improve the appetites of study patients. Pentoxifylline did not appear to cause any toxicity.

CONCLUSION

This study failed to demonstrate any benefit of pentoxifylline at this dose and schedule as therapy for cancer anorexia and/or cachexia.
Phase II trial of docetaxel in patients with advanced cutaneous malignant melanoma previously untreated with chemotherapy.
Authors: Bedikian A Y , Weiss G R , Legha S S , Burris H A , Eckardt J R , Jenkins J , Eton O , Buzaid A C , Smetzer L , Von Hoff D D
Published: February 2017

PURPOSE

A phase II study was undertaken to determine the efficacy of docetaxel in patients with metastatic malignant melanoma.

PATIENTS AND METHODS

Between June 1992 and March 1994, 40 patients with metastatic malignant melanoma and no prior chemotherapy were treated with docetaxel 100 mg/m2 administered intravenously over 1 hour every 21 days. None of the patients had brain metastasis. Toxicity and follow-up data are provided.

RESULTS

One patient had a histologically confirmed complete response that lasted for 14+ months. Four patients had partial responses, bringing the overall response rate to 12.5% (95% confidence interval [CI], 6% to 30%). A patient with a partial response had a single chest-wall metastasis and was rendered free of disease surgically after a maximal response to docetaxel and remained free of tumor recurrence after 18+ months. Tumor was stabilized in 22 patients. The overall median survival time was 13 months. The main hematologic toxicity was neutropenia, which was severe but transient. Peripheral neuropathy was the limiting nonhematologic toxicity in three patients. Other important toxicities included cutaneous toxicity, fluid retention, oral mucositis, and hypersensitivity reactions. Preadministration of dexamethasone and diphenhydramine reduced the incidence of hypersensitivity reactions, cutaneous toxicities, and fluid retention.

CONCLUSION

Docetaxel has definite but low-level activity against malignant melanoma. Further investigation of this drug should be conducted in multidrug combination programs.