bluuebunny/crossref_metadata_2025 huggingface dataset:
Duration of Hospitalization as a Measure of Cost on Children’s Cancer Group Acute Lymphoblastic Leukemia Studies
Authors: Gaynon Paul S. , Bostrom Bruce C. , Hutchinson Raymond J. , Lange Beverly J. , Nachman James B. , Steinherz Peter G. , Sensel Martha G. , Lee Mei K. , Stram Daniel O. , Sather Harland N.
Published: February 2017

PURPOSE: We used duration of hospitalization as a surrogate for cost and event-free survival as a measure of effectiveness to estimate the cost-effectiveness ratios of various treatment regimens on Children’s Cancer Group trials for acute lymphoblastic leukemia.

PATIENTS AND METHODS: The analyses included 4,986 children (2 to 21 years of age) with newly diagnosed acute lymphoblastic leukemia enrolled onto risk-adjusted protocols between 1988 and 1995. Analyses were based on a model of 100 patients. The marginal cost-effectiveness ratio (hospital days per additional patient surviving event-free) was the difference in total duration of hospitalization divided by the difference in number of event-free survivors at 5 years for two regimens. Relapse-adjusted marginal cost of frontline therapy was the difference in total duration of hospitalization for frontline therapy plus relapse therapy divided by the difference in number of event-free survivors at 5 years on the frontline therapy for two regimens.

RESULTS: One or two delayed intensification (DI) phases, augmented therapy, and dexamethasone all improved outcome. Marginal cost-effectiveness of these regimens compared with the control regimens was 133 days per patient for DI, 117 days per patient for double DI, and 41 days per patient for augmented therapy. Dexamethasone resulted in 17 fewer days per patient. Relapse-adjusted marginal costs were 68 days per patient for DI and 52 days for double DI. Augmented therapy and dexamethasone-based therapy resulted in 16 and 82 fewer hospital days, respectively. The estimated cost-effectiveness for treating any first relapse was 250 days per patient.

CONCLUSION: DI, double DI, augmented therapy, and dexamethasone-based therapy are cost-effective strategies compared with current treatment of first relapse.
Congestive Heart Failure After Treatment for Wilms’ Tumor: A Report From the National Wilms’ Tumor Study Group
Authors: Green Daniel M. , Grigoriev Yevgeny A. , Nan Bin , Takashima Janice R. , Norkool Pat A. , D’Angio Giulio J. , Breslow Norman E.
Published: February 2017

PURPOSE: We determined the frequency of and risk factors for congestive heart failure following treatment for Wilms’ tumor that included doxorubicin.

PATIENTS AND METHODS: Flow sheets and medical records were reviewed to identify cases of congestive heart failure in a cohort of patients treated on National Wilms’ Tumor Studies (NWTS)-1, -2, -3, and -4. The frequency of congestive heart failure was estimated using the Kaplan-Meier method. A case-control study was conducted to determine the relationship among cumulative doxorubicin dose, site(s), total dose of abdominal and thoracic irradiation, sex, and the frequency of congestive heart failure.

RESULTS: The cumulative frequency of congestive heart failure was 4.4% at 20 years after diagnosis among patients treated initially with doxorubicin and 17.4% at 20 years after diagnosis among those treated with doxorubicin for their first or subsequent relapse of Wilms’ tumor. The relative risk (RR) of congestive heart failure was increased in females (RR = 4.5; P = .004) and by cumulative doxorubicin dose (RR = 3.3/100 mg/m2; P < .001), lung irradiation (RR = 1.6/10 Gy; P = .037), and left abdominal irradiation (RR = 1.8/10 Gy; P = .013).

CONCLUSION: We conclude that congestive heart failure is a risk of treatment with doxorubicin for Wilms’ tumor. Additional follow-up of those children treated on NWTS-4 will be necessary to determine if the decrease in dose to 150 mg/m2 significantly reduces this risk.
Patients With Cancer Referred to Hospice Versus a Bridge Program: Patient Characteristics, Needs for Care, and Survival
Authors: Casarett David , Abrahm Janet L.
Published: February 2017

PURPOSE: The purpose of this study was to compare the characteristics and needs of patients with advanced cancer who were referred to hospice with those referred to a prehospice “bridge” program that is staffed by hospice nurses.

PATIENTS AND METHODS: Data were gathered through retrospective review of computerized clinical records using precoded data fields of 284 patients with cancer enrolled in a bridge program and 1,000 who enrolled in a hospice program. Patient characteristics, needs for supportive care at the time of enrollment, and survival were assessed.

RESULTS: Bridge patients were less likely to have Medicare or Medicaid (43% v 72%; odds ratio, 0.30; P < .001) and were younger (69 v 73 years, rank sum test; P < .001), more likely to be married (59% v 43%; odds ratio, 1.90; P < .001), and more likely to be in the highest income category (14% v 10%; odds ratio, 1.77; P = .009). Bridge patients had at least as many needs for care as did patients in hospice. Bridge patients lived significantly longer (median, 46 v 19 days; log-rank test of survivor functions, P < .001).

CONCLUSION: Patients referred to this bridge program had prognoses that are significantly better than those of patients who enter hospice, but they have needs for supportive care that are at least as great. These findings underscore the importance of initiatives to extend some of the benefits of hospice care to a wider population of patients and should encourage the analysis of similar programs’ ability to meet these needs.
Phase I Clinical and Pharmacokinetic Study of Rebeccamycin Analog NSC 655649 Given Daily for Five Consecutive Days
Authors: Dowlati Afshin , Hoppel Charles L. , Ingalls Stephen T. , Majka Susan , Li Xiaolin , Sedransk Nell , Spiro Timothy , Gerson Stanton L. , Ivy Percy , Remick Scot C.
Published: February 2017

PURPOSE: Rebeccamycin analog (NSC 655649) is active against a variety of both solid and nonsolid tumor cell lines. We performed a phase I trial to determine the maximum-tolerated dose (MTD) of rebeccamycin analog when given on a daily × 5 schedule repeated every 3 weeks, characterize the toxicity profile using this schedule, observe patients for antitumor response, and determine the pharmacokinetics of the agent and pharmacodynamic interactions.

PATIENTS AND METHODS: Thirty assessable patients received a total of 153 cycles according to the following dose escalation schema: 60, 80, 106, 141, and 188 mg/m2/d × 5 days.

RESULTS: Grade 2 phlebitis occurred in all patients before the use of central venous access, placed at dose level 4 and higher. Dose-limiting toxicity (DLT), grade 4 neutropenia, occurred at 188 mg/m2/d × 5 days in both previously treated and chemotherapy-naive patients. Pharmacokinetic analysis revealed a three-compartmental model of drug elimination and a long terminal half-life (154 ± 55 hours). The percentage drop in absolute neutrophil count correlates with the area under the curve∞. The presence of a second peak during the elimination phase as well as a high concentration of NSC 655649 in biliary fluid compared with the corresponding plasma measurement (one patient) is suggestive of enterohepatic circulation. Two partial responses, two minor responses, and six prolonged (> 6 months) cases of stable disease were observed. Of these, three patients with gallbladder cancer and one patient with cholangiocarcinoma experienced either a minor response or a significant period of freedom from progression.

CONCLUSION: The recommended phase II dose for NSC 665649 on a daily × 5 every 3 weeks schedule is 141 and 165 mg/m2/d for patients with prior and no prior therapy, respectively, with DLT being neutropenia. During this phase I trial, encouraging antitumor activity was been observed.
Addition of Oxaliplatin to Continuous Fluorouracil, l-Folinic Acid, and Concomitant Radiotherapy in Rectal Cancer: The Lyon R 97-03 Phase I Trial
Authors: Freyer Gilles , Bossard Nadine , Romestaing Pascale , Mornex Françoise , Chapet Olivier , Trillet-Lenoir Véronique , Gérard Jean-Pierre
Published: February 2017

PURPOSE: Oxaliplatin could increase the efficacy of fluorouracil (5-FU)/folinic acid chemoradiotherapy in rectal cancer. We tested three dose levels to identify a feasible oxaliplatin dose for combination therapy.

PATIENTS AND METHODS: Between February 1998 and April 2000, we included 17 rectal adenocarcinoma patients in a single-center phase I study. Patients had T4 rectal carcinoma, T1-T3 disease with colostomy refusal, or potentially operable T2/T3 M1 requiring local treatment. Pelvic radiotherapy was 45 Gy over 5 weeks, 1.8 Gy/fraction, with concomitant chemotherapy weeks 1 and 5. Chemotherapy was oxaliplatin 80, 100, or 130 mg/m2 2-hour infusion on day 1 followed by l-folinic acid 100 mg/m2/d intravenous bolus, and 5-FU 350 mg/m2/d continuous infusion on days 1 to 5 (FolfoR1). Six patients refusing surgery received additional contact radiotherapy +/− brachytherapy. Dose escalation proceeded if less than two of six patients had dose-limiting toxicity (DLT) at a given dose-level.

RESULTS: All except two patients completed treatment; patients at level 1 (prolonged grade 1 thrombocytopenia) and level 3 (prolonged cold-related dysesthesia) had no second chemotherapy course. Median follow-up is 14 months (range, 2 to 28 months). One elderly patient at dose level 1 had DLT asthenia, severe diarrhea and vomiting, and more than 10% weight loss. There were no other DLTs and no severe rectitis or gastrointestinal toxicity. There were objective responses at all doses and no progressions. Eight patients underwent radical surgery after chemoradiotherapy. Two had complete pathologic responses.

CONCLUSION: FolfoR1 seems feasible and effective. Dose escalation did not increase toxicity. Although the MTD was not reached in this study, we recommend oxaliplatin 130 mg/m2 for phase II studies because it is the dose determined from studies in metastatic patients with no toxicity when given concurrently with radiation.
Melanoma Information on the Internet: Often Incomplete—A Public Health Opportunity?
Authors: Bichakjian Christopher K. , Schwartz Jennifer L. , Wang Timothy S. , Hall Janette M. , Johnson Timothy M. , Sybil Biermann J.
Published: February 2017

PURPOSE: To assess the accuracy and completeness of information regarding melanoma on the Internet, retrieved by use of search engines.

METHODS: The first 30 uniform/universal resource locators (URLs) from each of eight search engines using the search term “melanoma” were retrieved for evaluation of accuracy and completeness using a 35-point checklist rating system instrument. Four reviewers independently rated each of 35 sites, and one reviewer rated all 74 assessable sites. Kappa statistics were used to evaluate interrater variability.

RESULTS: A total of 74 assessable Web sites were evaluated. The remainder were inaccessible, link pages only, or duplicates. Thirty-five Web sites were each independently rated by four reviewers. The remaining 39 Web sites were each rated by one reviewer. The mean kappa statistic for all variables and all rater pairs for which a kappa could be calculated was 0.824, indicating excellent overall inter-rater reliability. The majority of Web sites failed to include complete information on general information, risk factors, diagnosis, treatment, prevention, and prognosis. Ten Web sites (14%) contained a total of 13 inaccuracies, most relatively minor.

CONCLUSION: Medical information retrieved with the search term melanoma was likely to lack complete basic melanoma information and contained inaccuracies in 14% of sites. Health care providers can help patients by recommending comprehensive and accurate Web sites for patient review, by working to create accurate and thorough Web-based health information material, and by educating patients and the public about the variability in completeness and accuracy.
Cooperative Role of Telomerase Activity and p16 Expression in the Prognosis of Non–Small-Cell Lung Cancer
Authors: González-Quevedo Rosa , Iniesta Pilar , Morán Alberto , de Juan Carmen , Sánchez-Pernaute Andrés , Fernández C. , Torres Antonio , Díaz-Rubio E. , Balibrea Jose-Luis , Benito Manuel
Published: February 2017

PURPOSE: Telomerase activity and p16 expression can be considered two of the most important molecular markers implicated in tumorigenesis. Our main aim was to study the cooperative role of both molecular alterations in the prognosis of patients surgically resected for non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: We have determined telomerase activity and p16 expression in a series of 98 prospectively collected NSCLC specimens obtained from patients who had undergone surgery without other treatment. Telomerase activity was investigated by a telomeric repeat amplification protocol enzyme-linked immunosorbent assay–based procedure, and p16 expression was examined by Western blot. Associations with survival were evaluated.

RESULTS: Positive results for telomerase activity were found in 82% of the cases, and this variable correlated with poor differentiation and recurrence of tumors. Lack of p16 expression was observed in 61% of tumors, and a significant association with tumor recurrence was also observed. By univariate analysis, both negative telomerase activity and p16-positive expression were significantly correlated with a better prognosis. Moreover, statistics for equality of survival distributions for telomerase, adjusted for p16, indicated a positive interaction between both parameters. For telomerase-positive tumors, p16 expression emerged as a significant independent protective variable, as indicated by Cox multivariate analysis (relative risk [RR], 0.214; P = .014). This protective effect was maintained only for stage I and II tumors (RR, 0.108; P = .046).

CONCLUSION: These results suggest that the combined telomerase activity and p16 expression analyses may be of prognostic importance in NSCLC, especially for patients affected by stage I and II tumors.
Outcomes and Cost-Effectiveness of Alternative Staging Strategies for Non–Small-Cell Lung Cancer
Authors: Esnaola Nestor F. , Lazarides Sophia N. , Mentzer Steven J. , Kuntz Karen M.
Published: February 2017

PURPOSE: To identify the optimal strategy for staging the mediastinum of patients with known non–small-cell lung cancer (NSCLC), stratified by tumor (T) classification.

METHODS: We used a decision-analytic model to compare the health outcomes and cost-effectiveness of three staging strategies: (1) chest computed tomography alone, (2) selective mediastinoscopy, and (3) routine mediastinoscopy. The overall effectiveness and cost of each strategy was a function of the proportion of patients accurately staged and the risks, benefits, and costs of the diagnostic tests and treatments used. Probability estimates and costs were derived from primary data and the literature. We adopted a societal perspective and calculated incremental cost-effectiveness ratios (ICERs) as cost per quality-adjusted life year (QALY) gained.

RESULTS: Both mediastinoscopy strategies correctly identified more patients with mediastinal involvement (N2/N3 disease) and assigned them to multimodal regimens. Routine mediastinoscopy maximized quality-adjusted life expectancy in all patients, irrespective of T classification, and this result was robust to varying the model estimates over their reported ranges. In T1 patients, selective mediastinoscopy cost $24,500 per QALY gained, compared with $78,800 per QALY gained for routine mediastinoscopy. In T2 and T3 patients, the ICER of routine mediastinoscopy was more favorable ($42,800 and $53,400 per QALY gained, respectively).

CONCLUSION: Routine mediastinoscopy maximizes quality-adjusted life expectancy in patients with known NSCLC, and its ICER compares favorably with other currently accepted medical technologies. The survival benefit and cost-effectiveness of this strategy are greater in patients with T2 and T3 tumors and are likely to improve with advances in multimodal therapy.
Interferon-Alfa as a Comparative Treatment for Clinical Trials of New Therapies Against Advanced Renal Cell Carcinoma
Authors: Motzer Robert J. , Bacik Jennifer , Murphy Barbara A. , Russo Paul , Mazumdar Madhu
Published: February 2017

PURPOSE: To define outcome data and prognostic criteria for patients with metastatic renal cell carcinoma (RCC) treated with interferon-alfa as initial systemic therapy. The data can be applied to design and interpretation of clinical trials of new agents and treatment programs against this refractory malignancy.

PATIENTS AND METHODS: Four hundred sixty-three patients with advanced RCC administered interferon-α as first-line systemic therapy on six prospective clinical trials were the subjects of this retrospective analysis. Three risk categories for predicting survival were identified on the basis of five pretreatment clinical features by a stratified Cox proportional hazards model.

RESULTS: The median overall survival time was 13 months. The median time to progression was 4.7 months. Five variables were used as risk factors for short survival: low Karnofsky performance status, high lactate dehydrogenase, low serum hemoglobin, high corrected serum calcium, and time from initial RCC diagnosis to start of interferon-α therapy of less than one year. Each patient was assigned to one of three risk groups: those with zero risk factors (favorable risk), those with one or two (intermediate risk), and those with three or more (poor risk). The median time to death of patients deemed favorable risk was 30 months. Median survival time in the intermediate-risk group was 14 months. In contrast, the poor-risk group had a median survival time of 5 months.

CONCLUSION: Progression-free and overall survival with interferon-α treatment can be compared with new therapies in phase II and III clinical investigations. The prognostic model is suitable for risk stratification of phase III trials using interferon-α as the comparative treatment arm.
Phase II Trial of Thalidomide for Patients With Advanced Renal Cell Carcinoma
Authors: Motzer Robert J. , Berg William , Ginsberg Michelle , Russo Paul , Vuky Jacqueline , Yu Richard , Bacik Jennifer , Mazumdar Madhu
Published: February 2017

PURPOSE: To assess efficacy and toxicity of thalidomide in patients with advanced renal cell carcinoma (RCC).

PATIENTS AND METHODS: Twenty-six patients with RCC were treated with thalidomide at a starting dose of 200 mg daily. Thalidomide was increased by 200 mg every 2 weeks until a maximum dose of 800 mg or prohibitive toxicity was reached. Fifteen patients had prior nephrectomy, 11 patients had no prior systemic therapy, and 15 had received one prior systemic regimen.

RESULTS: A maximum dose of 800 mg, 600 mg, 400 mg, and 200 mg was reached in five, 10, eight, and three patients, respectively. Grade 2 and 3 dyspnea occurred in four and three patients, respectively. Grade 2 and 3 neurologic toxicity was observed in five and two patients, respectively. Of the 25 assessable patients, the best response was stable disease in 16 (95% confidence interval [CI], 43% to 82%) patients. The 6-month progression-free survival rate was 32% (95% CI, 14% to 50%). Three patients achieved prolonged stable disease of 16, 16+, and 18+ months, including two patients who were refractory to previous cytokine therapy. Fifty-seven percent were alive at 1 year (95% CI, 37% to 76%).

CONCLUSION: This trial does not support the routine use of thalidomide to induce partial response for metastatic RCC. Because disease stabilization occurs as a part of the natural history of metastatic RCC, the potential effect of thalidomide on progression-free and overall survival for patients with advanced RCC is being addressed in a randomized phase III trial. New immunomodulatory analogs of thalidomide that have shown potentially greater antitumor effects in preclinical models warrant study in metastatic RCC.
STI571: A Paradigm of New Agents for Cancer Therapeutics
Authors: Mauro Michael J. , O’Dwyer Michael , Heinrich Michael C. , Druker Brian J.
Published: February 2017

ABSTRACT: STI571 exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of Bcr-Abl as a therapeutic target in chronic myelogenous leukemia and the steps in the development of an agent to specifically inactivate this abnormality. Issues related to clinical trials of molecularly targeted agents are discussed, including dose selection, optimizing therapy, and predicting response, as are possible mechanisms of resistance to STI571. Lastly, the potential use of STI571 in other malignancies and the translation of this paradigm to other malignancies are explored.
Phase II Trial of Biweekly Administration of Vinorelbine and Gemcitabine in Pretreated Advanced Breast Cancer
Authors: Stathopoulos George P. , Rigatos Sotiris K. , Pergantas Nikos , Tsavdarides Dimitris , Athanasiadis Ilias , Malamos Nikos A. , Stathopoulos John G.
Published: February 2017

PURPOSE: To determine the efficacy of gemcitabine (GEM) plus vinorelbine (VRL) administered biweekly in pretreated patients with advanced breast cancer.

PATIENTS AND METHODS: Advanced breast cancer patients without response, with stable disease, or with recurrence within 6 months of prior treatment were given GEM 1,000 mg/m2 and VRL 25 mg/m2, once every 2 weeks for at least six cycles.

RESULTS: Of the 51 patients enrolled, 50 (median, age 58 years; range, 34 to 76 years) were assessable. All patients had prior chemotherapy with an anthracycline-related regimen that included taxanes in 50% of the cases. Four patients (8%) had a complete response (CR) and 23 (46%) had a partial response (PR), for an overall response rate of 54%; 16 (32%) had stable disease and 7 (14%) experienced disease progression. Response occurred mainly in patients with soft tissue (83.3%) and lung metastasis (66.7%). Response duration was 4 to 8+, 4 to 9+, and 4 to 9 months for those with CR, PR, and stable disease, respectively. The regimen was well tolerated, with grade 1 to 2 myelotoxicity and asthenia reported. No patient required a dose reduction. Gastrointestinal side effects were negligible. Patients received 99.7% (range, 93.0% to 100.0%) of the planned dose-intensity of each drug.

CONCLUSION: GEM in combination with VRL is an active regimen for advanced breast cancer patients, and biweekly administration significantly reduces myelotoxicity.
Troxacitabine, an l-Stereoisomeric Nucleoside Analog, on a Five-Times-Daily Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Malignancies
Authors: de Bono Johann S. , Stephenson Joseph , Baker Sharyn D. , Hidalgo Manuel , Patnaik Amita , Hammond Lisa A. , Weiss Geoffrey , Goetz Andrew , Siu Lillian , Simmons Cecelia , Jolivet Jacques , Rowinsky Eric K.
Published: February 2017

PURPOSE: To assess the feasibility of administering troxacitabine, a unique l-nucleoside that is not a substrate for deoxycytidine deaminase–mediated catabolism, as a 30-minute intravenous (IV) infusion daily for 5 days.

PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of troxacitabine as a 30-minute IV infusion daily for 5 days. Plasma and urine sampling was performed to characterize the pharmacokinetics and pharmacodynamics of troxacitabine.

RESULTS: Thirty-nine patients received 124 courses of troxacitabine at eight dose levels ranging from 0.12 to 1.8 mg/m2/d. Severe neutropenia that was protracted (> 5 days) and/or associated with fever, and skin rashes were consistently experienced by heavily (HP) and minimally pretreated (MP) patients at doses exceeding 1.2 and 1.5 mg/m2/d, respectively. At troxacitabine doses ≥ 1.2 mg/m2/d, treatment was often delayed 1 additional week for complete resolution of hematologic effects, resulting in lengthening of the treatment interval from every 3 to 4 weeks. Skin rash, palmar-plantar erythrodysesthesia, and thrombocytopenia were also observed and were occasionally severe, particularly at the highest doses. A patient with metastatic ocular melanoma experienced a partial response. Pharmacokinetics of troxacitabine were dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance (Cls) were 60 (32) L and 161 (33) mL/min, respectively, on day 1. After treatment on the fifth day, terminal half-life values averaged 39 (63) hours, and Cls was reduced by approximately 20%, averaging 127 (27) mL/min. The principal mode of drug elimination was renal.

CONCLUSION: Recommended doses for phase II studies of troxacitabine as a 30-minute infusion daily for 5 days every 4 weeks are 1.5 and 1.2 mg/m2/d for MP and HP patients, respectively. Broad disease-directed evaluations of troxacitabine on this schedule and possibly less frequent schedules are warranted.
Phase II and Biologic Study of Interferon Alfa, Retinoic Acid, and Cisplatin in Advanced Squamous Skin Cancer
Authors: Shin Dong M. , Glisson Bonnie S. , Khuri Fadlo R. , Clifford John L. , Clayman Gary , Benner Steven E. , Forastiere Arlene A. , Ginsberg Lawrence , Liu Diane , Lee J. Jack , Myers Jeffrey , Goepfert Helmuth , Lotan Reuben , Hong Waun Ki , Lippman Scott M.
Published: February 2017

PURPOSE: The purpose of this study was to test interferon alfa (IFNα), 13-cis-retinoic acid (13cRA), and cisplatin biochemotherapy in advanced squamous cell carcinoma (SCC) of the skin.

PATIENTS AND METHODS: Patients with advanced skin SCC received IFNα (5 × 106 IU/m2, subcutaneous injection, three times a week), 13cRA (1 mg/kg, orally, daily), and cisplatin (20 mg/m2, intravenous injection, weekly) in a phase II trial. The growth inhibition, cell-cycle, and apoptosis activity of these agents was evaluated in two skin SCC cell lines (SRB1-m7 and SRB12-p9).

RESULTS: Thirty-nine patients were enrolled. All were assessable for survival, 35 for response and toxicity (median follow-up was 38 months). The overall and complete response rates were 34% and 17%, respectively, with median durations of 9 and 35.4 months, respectively. The response rate was higher in locally advanced (67%) than metastatic (17%) disease (P = .007). Median survival was 14.6 months. One-, 2-, and 5-year survival rate estimates were 58%, 32%, and 21%, respectively. Toxicity included generally mild to moderate fatigue and mucocutaneous dryness, moderate to severe neutropenia (38%), and neutropenic fever (6%). There were no treatment-related deaths. In vitro growth inhibition and apoptosis effects of cisplatin were differential and inversely associated with those of retinoic acid and especially IFNα in two skin SCC lines.

CONCLUSION: The rising incidence, morbidity, and mortality of advanced skin SCC are a major challenge for clinical oncologists. Combined 13cRA, IFNα, and cisplatin was clinically active in extensive locally advanced disease. Each agent had independent, non–cross-resistant biologic effects in vitro, which may account for the combination’s clinical activity.
Beneficial Effects of Adenosine Triphosphate on Nutritional Status in Advanced Lung Cancer Patients: A Randomized Clinical Trial
Authors: Agteresch Hendrik J. , Rietveld Trinet , Kerkhofs Leon G.M. , van den Berg J. Willem O. , Wilson J. H. Paul , Dagnelie Pieter C.
Published: February 2017

PURPOSE: In a randomized clinical trial in patients with advanced non–small-cell lung cancer (NSCLC), infusion with adenosine 5′-triphosphate (ATP) inhibited loss of body weight and quality of life. In the present article, the effects of ATP on body composition, energy intake, and energy expenditure as secondary outcome measures in the same patients are reported.

PATIENTS AND METHODS: Patients with NSCLC, stage IIIB or IV, were randomized to receive either 10 intravenous, 30-hour ATP infusions every 2 to 4 weeks or no ATP. Fat mass (FM), fat-free mass (FFM), and arm muscle area were assessed at 4-week intervals for 28 weeks. Food intake, body cell mass (BCM), and resting energy expenditure (REE) were assessed at 8-week intervals for 16 weeks. Between-group differences were tested for statistical significance by repeated-measures analysis of covariance.

RESULTS: Fifty-eight patients were randomized (28 ATP, 30 control). No change in body composition over the 28-week follow-up period was found in the ATP group, whereas, per 4 weeks, the control group lost 0.6 kg of FM (P = .004), 0.5 kg of FFM (P = .02), 1.8% of arm muscle area (P = .02), and 0.6% of BCM/kg body weight (P = .054) and decreased 568 KJ/d in energy intake (P = .0001). Appetite also remained stable in the ATP group but decreased significantly in the control group (P = .0004). No significant differences in REE between the ATP and control groups were observed.

CONCLUSION: The inhibition of weight loss by ATP infusions in patients with advanced NSCLC is attributed to counteracting the loss of both metabolically active and inactive tissues. These effects are partly ascribed to maintenance of energy intake.
Clinical Value of Iodine-123-Alpha-Methyl-l-Tyrosine Single-Photon Emission Tomography in the Differential Diagnosis of Recurrent Brain Tumor in Patients Pretreated for Glioma at Follow-Up
Authors: Samnick Samuel , Bader Jochen B. , Hellwig Dirk , Moringlane Jean Richard , Alexander Christof , Romeike Bernd F.M. , Feiden Wolfgang , Kirsch Carl-Martin
Published: February 2017

PURPOSE: To assess the clinical potential of iodine-123-alpha-methyl-l-tyrosine (IMT) and single-photon emission tomography (SPET) in the differential diagnosis of recurrences in patients pretreated for gliomas at follow-up.

PATIENTS AND METHODS: Seventy-eight patients were examined after primary therapy over 36 months. Histopathologic diagnoses of all patients was known at first treatment; magnetic resonance and/or computed tomography examination was performed in addition to IMT-SPET. Cerebral SPET images were acquired 20 minutes after intravenous application of 190 ± 10 MBq of IMT. SPET images were classified as positive or negative for recurrent tumor visually and by calculating the ratios between tracer accumulation in the lesion and the unaffected contralateral regions of reference using region of interest. Final diagnoses were based on prospective clinicopathologic findings obtained independently of IMT-SPET.

RESULTS: IMT-SPET detected all high-grade recurrent gliomas (grade 4; sensitivity, 100%). A difference could be demonstrated in grade 2 and 3 recurrences (sensitivity, 84% and 92%, respectively). Moreover, benign posttherapeutic lesions (postoperative scars, radiation necrosis) were correctly diagnosed as negative for tumor recurrence. In general, IMT uptake in grade 2 (1.45 ± 0.24) was significantly lower than that in grades 3 (1.70 ± 0.41) and 4 (1.88 ± 0.32). However, it was difficult to evaluate tumor grade only from the IMT accumulation in individual cases.

CONCLUSION: IMT-SPET seems highly useful for detecting and delineating recurrent gliomas and differentiating between benign posttherapeutic lesions and malignant tumor tissue. It may be a valuable clinical tool to diagnose recurrences in patients pretreated for gliomas at follow-up. However, it showed limitations in determining histologic tumor grade.
Prospective Trial of Chemotherapy and Donor Leukocyte Infusions for Relapse of Advanced Myeloid Malignancies After Allogeneic Stem-Cell Transplantation
Authors: Levine John E. , Braun Thomas , Penza Samuel L. , Beatty Patrick , Cornetta Kenneth , Martino Rodrigo , Drobyski William R. , Barrett A. John , Porter David L. , Giralt Sergio , Leis Jose , Holmes Houston E. , Johnson Matthew , Horowitz Mary , Collins Robert H.
Published: February 2017

PURPOSE: Patients with advanced myeloid malignancies who experience relapse after allogeneic bone marrow transplantation (BMT) have a poor prognosis. Long-term survival after chemotherapy alone, second myeloablative transplant, or donor leukocyte infusions (DLIs) alone is unusual. DLIs may have minimal effectiveness in advanced disease because adequate cellular responses are not able to develop in the presence of bulky, fast-growing disease. A chemotherapy strategy was used to debulk disease before administration of granulocyte colony-stimulating factor (G-CSF)–primed DLIs.

PATIENTS AND METHODS: Sixty-five patients experiencing hematologic relapse of myeloid malignancy after HLA-matched sibling BMT were prospectively treated with cytarabine-based chemotherapy, then G-CSF–primed DLIs. No prophylactic immunosuppression was provided.

RESULTS: Twenty-seven of 57 assessable patients experienced a complete response. Graft-versus-host disease (GVHD) was observed in 56% of the patients. Treatment-related mortality was 23%. Overall survival at 2 years for the entire cohort was 19%. Patients with a complete response were more likely to survive, with 1- and 2-year survival rates of 51% and 41%, respectively, with a median follow-up of more than 2 years. The 1-year survival for nonresponders was 5%. A posttransplant remission lasting more than 6 months before relapse was associated with a higher likelihood of response. GVHD was not required for durable remission.

CONCLUSION: Salvage treatment with chemotherapy before DLI can help some patients with advanced myeloid relapse and is not dependent on GVHD. Patients with short remissions after BMT are unlikely to benefit from this approach, and the approach is associated with significant treatment-related mortality. Modifications of this approach or entirely different approaches will be required for most patients with this difficult clinical problem.
Effect of BRCA Mutations on the Length of Survival in Epithelial Ovarian Tumors
Authors: Ben David Y. , Chetrit A. , Hirsh-Yechezkel G. , Friedman E. , Beck B.D. , Beller U. , Ben-Baruch G. , Fishman A. , Levavi H. , Lubin F. , Menczer J. , Piura B. , Struewing J.P. , Modan B.
Published: February 2017

PURPOSE: To study the role of BRCA mutations in ovarian cancer survival.

PATIENTS AND METHODS: Blood samples and specimens of ovarian tumors (whenever blood samples were not available) at the time of the primary surgery were obtained in the course of a nationwide case-control study of women with ovarian cancer in Israel. The three common BRCA mutations in Israel (185delAG, 5382insC, and 6174delT) were analyzed with a multiplex polymerase chain reaction to amplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms. Patients were followed for up to 5 years (range, 20 to 64 months). Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. Stepwise Cox regression analysis was used for determination of independent prognostic factors.

RESULTS: This report is based on 896 blood or tumor specimens analyzed for the presence of the BRCA mutations. Of these, 234 women (26.1%) were found to be positive. A significant difference in survival pattern was found between BRCA1/BRCA2 carriers and noncarriers among the women with invasive ovarian cancer (median survival, 53.4 months v 37.8 months; 3-year survival, 65.8% v 51.9%, respectively). These differences were independent of age at diagnosis or stage of the disease.

CONCLUSION: Our data indicate that the survival of patients with ovarian cancer is affected by BRCA germline mutation, at least in the early years after diagnosis.
Comprehensive Geriatric Assessment Adds Information to Eastern Cooperative Oncology Group Performance Status in Elderly Cancer Patients: An Italian Group for Geriatric Oncology Study
Authors: Repetto Lazzaro , Fratino Lucia , Audisio Riccardo A. , Venturino Antonella , Gianni Walter , Vercelli Marina , Parodi Stefano , Dal Lago Denise , Gioia Flora , Monfardini Silvio , Aapro Matti S. , Serraino Diego , Zagonel Vittorina
Published: February 2017

PURPOSE: To appraise the performance of Comprehensive Geriatric Assessment (CGA) in elderly cancer patients (≥ 65 years) and to evaluate whether it could add further information with respect to the Eastern Cooperative Oncology Group performance status (PS).

PATIENTS AND METHODS: We studied 363 elderly cancer patients (195 males, 168 females; median age, 72 years) with solid (n = 271) or hematologic (n = 92) tumors. In addition to PS, their physical function was assessed by means of the activity of daily living (ADL) and instrumental activities of daily living (IADL) scales. Comorbidities were categorized according to Satariano’s index. The association between PS, comorbidity, and the items of the CGA was assessed by means of logistic regression analysis.

RESULTS: These 363 elderly cancer patients had a good functional and mental status: 74% had a good PS (ie, lower than 2), 86% were ADL-independent, and 52% were IADL-independent. Forty-one percent of patients had one or more comorbid conditions. Of the patients with a good PS, 13.0% had two or more comorbidities; 9.3% and 37.7% had ADL or IADL limitations, respectively. By multivariate analysis, elderly cancer patients who were ADL-dependent or IADL-dependent had a nearly two-fold higher probability of having an elevated Satariano’s index than independent patients. A strong association emerged between PS and CGA, with a nearly five-fold increased probability of having a poor PS (ie, ≥ 2) recorded in patients dependent for ADL or IADL.

CONCLUSION: The CGA adds substantial information on the functional assessment of elderly cancer patients, including patients with a good PS. The role of PS as unique marker of functional status needs to be reappraised among elderly cancer patients.
Factors Affecting Workload of Cancer Clinical Trials: Results of a Multicenter Study of the National Cancer Institute of Canada Clinical Trials Group
Authors: Roche Kathyrn , Paul Nancy , Smuck Bobbi , Whitehead Marlo , Zee Benny , Pater Joseph , Hiatt Mary-Anne , Walker Hugh
Published: February 2017

PURPOSE: Increasingly, cancer treatment centers need to be able to estimate specific costs and resources associated with clinical trials. Because the time requirements of trial coordination and data collection are not well known, the Clinical Research Associates (CRA) Committee of the National Cancer Institute of Canada Clinical Trials Group carried out a multicenter study to measure trials’ task times and evaluate the effects of certain factors.

METHODS: A data collection instrument was designed and validated before its implementation in the study. Eighty-three CRAs from 24 cancer treatment institutions across Canada collected timing observations of 41 tasks (156 subtasks). Information from all stages of trials activity (protocol management, eligibility and entry, treatment, and follow-up and final stage) was obtained, from initial negotiations to follow-up after study closure.

RESULTS: After controlling for stage, phase and sponsor were found to be significant independent factors. Analysis within the stages showed similar patterns. New drug inclusion as a factor was confounded with phase. Industry-sponsored studies had significantly higher overall mean times than did local and cooperative group studies. Early-phase studies required more time than did phase III trials. External sponsorship of any kind increased CRA time more than that necessary for locally coordinated studies, except during the protocol management stage. The burden of a phase I study increased to greater than average once underway and accruing patients.

CONCLUSION: Our data demonstrated that sponsor and study phase are important factors to be taken into consideration when estimating clinical trial costs and resource use.
Dronabinol Versus Megestrol Acetate Versus Combination Therapy for Cancer-Associated Anorexia: A North Central Cancer Treatment Group Study
Authors: Jatoi Aminah , Windschitl Harold E. , Loprinzi Charles L. , Sloan Jeff A. , Dakhil Shaker R. , Mailliard James A. , Pundaleeka Sarode , Kardinal Carl G. , Fitch Tom R. , Krook James E. , Novotny Paul J. , Christensen Brad
Published: February 2017

PURPOSE: To determine whether dronabinol administered alone or with megestrol acetate was more, less, or equal in efficacy to single-agent megestrol acetate for palliating cancer-associated anorexia.

PATIENTS AND METHODS: Four hundred sixty-nine assessable advanced cancer patients were randomized to (1) oral megestrol acetate 800 mg/d liquid suspension plus placebo, (2) oral dronabinol 2.5 mg twice a day plus placebo, or (3) both agents. Eligible patients acknowledged that loss of appetite or weight was a problem and reported the loss of 5 pounds or more during 2 months and/or a daily intake of less than 20 calories/kg of body weight.

RESULTS: Groups were comparable at baseline in age, sex, tumor type, weight loss, and performance status. A greater percentage of megestrol acetate-treated patients reported appetite improvement and weight gain compared with dronabinol-treated patients: 75% versus 49% (P = .0001) for appetite and 11% versus 3% (P = .02) for ≥ 10% baseline weight gain. Combination treatment resulted in no significant differences in appetite or weight compared with megestrol acetate alone. The Functional Assessment of Anorexia/Cachexia Therapy questionnaire, which emphasizes anorexia-related questions, demonstrated an improvement in quality of life (QOL) among megestrol acetate–treated and combination-treated patients. The single-item Uniscale, a global QOL instrument, found comparable scores. Toxicity was also comparable, with the exception of an increased incidence of impotence among men who received megestrol acetate.

CONCLUSION: In the doses and schedules we studied, megestrol acetate provided superior anorexia palliation among advanced cancer patients compared with dronabinol alone. Combination therapy did not appear to confer additional benefit.
Comparative Pharmacokinetics of Unbound Paclitaxel During 1- and 3-Hour Infusions
Authors: Gelderblom Hans , Mross Klaus , ten Tije Albert J. , Behringer Dirk , Mielke Stephan , van Zomeren Desirée M. , Verweij Jaap , Sparreboom Alex
Published: February 2017

PURPOSE: The paclitaxel vehicle Cremophor EL (CrEL) profoundly influences the cellular distribution of paclitaxel in human blood in vitro by a concentration-dependent decrease of the unbound drug fraction. Because CrEL clearance increases by extending the infusion duration from 3 to 24 hours, we hypothesized that exposure to unbound paclitaxel might also be schedule-dependent.

PATIENTS AND METHODS: CrEL and unbound paclitaxel pharmacokinetics were prospectively analyzed in 29 patients with advanced solid tumors treated with paclitaxel 100 mg/m2given as a 1-hour (n = 15) or 3-hour (n = 14) intravenous infusion.

RESULTS: The systemic exposure (area under the curve [AUC]) to CrEL was significantly higher with the 1-hour as compared with the 3-hour schedule (80.2 ± 24.2 v 48.5 ± 24.1 μL·h/mL; P = .002). In contrast, the AUC of unbound paclitaxel was substantially reduced after the 1-hour infusion (0.50 ± 0.10 v 0.62 ± 0.12 μmol/L·h; P = .009). Similarly, clearance and volume of distribution were significantly dependent on infusion duration (P < .005). A trend was observed toward more severe hematologic toxicity with the 3-hour schedule (P = .053), consistent with increased exposure to unbound drug.

CONCLUSION: Overall, these findings explain, at least in part, previous observations that short-infusion schedules of paclitaxel lack significant myelotoxicity, whereas potentially CrEL-related side effects, including peripheral neuropathy, are augmented.
Phase I Evaluation of Prolonged-Infusion Gemcitabine With Mitoxantrone for Relapsed or Refractory Acute Leukemia
Authors: Rizzieri David A. , Bass Adam J. , Rosner Gary L. , Gockerman Jon P. , DeCastro Carlos M. , Petros William P. , Adams David J. , Laughlin Mary J. , Davis Patti , Foster Traci , Jacobson Robert , Hurwitz Herbert , Moore Joseph O.
Published: February 2017

PURPOSE: To ascertain the maximum tolerated duration of infusion of gemcitabine at 10 mg/m2/min in combination with mitoxantrone at 12 mg/m2 daily for 3 days in the treatment of acute leukemia.

PATIENTS AND METHODS: Thirty-four patients were enrolled. Stratum I consisted of 26 patients, median age 50 years (range, 25 to 71 years), with relapsed or refractory leukemia. Stratum II contained eight patients, median age 62.5 years (range, 38 to 83 years), who had received fewer than three cycles of myelotoxic therapy for chronic myeloid leukemia or myelodysplasia that had evolved into leukemia. Patients received mitoxantrone at 12 mg/m2 daily for 3 days. After the first mitoxantrone dose, gemcitabine was provided intravenously at 10 mg/m2/min with the duration adjusted by following a continuous reassessment model.

RESULTS: Severe myelosuppression, and stomatitis or esophagitis were the most common hematologic and nonhematologic dose-limiting toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours (7,200 mg/m2). The mean steady-state concentration of gemcitabine was 24.72 μmol/L and varied over a fivefold range among patients. Overall response rates in this phase I trial for strata I and II were 42% and 63%, respectively.

CONCLUSION: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m2/min for 12 hours with 12 mg/m2/d mitoxantrone for 3 days is a tolerable induction regimen and achieves plasma concentrations sufficient for maximal intracellular activation. Stomatitis or esophagitis should be anticipated; however, this regimen may induce significant responses in patients with difficult-to-treat leukemias.
Prognostic Model for Relapse After High-Dose Chemotherapy With Autologous Stem-Cell Transplantation for Stage IV Oligometastatic Breast Cancer
Authors: Nieto Yago , Nawaz Samia , Jones Roy B. , Shpall Elizabeth J. , Cagnoni Pablo J. , McSweeney Peter A. , Barón Anna , Razook Carrington , Matthes Steve , Bearman Scott I.
Published: February 2017

PURPOSE: To study prognostic factors after high-dose chemotherapy (HDC) for patients with stage IV oligometastatic breast cancer.

PATIENTS AND METHODS: Sixty patients with minimal metastatic disease amenable to local therapy enrolled onto a prospective HDC trial were analyzed for potential prognostic factors. Tumor blocks were retrospectively collected from referring institutions.

RESULTS: Median follow-up was 62 months (range, 4 to 120 months). Median relapse-free survival (RFS) and overall survival (OS) times were 52 and 80 months, respectively. Five-year RFS and OS rates were 52% (95% confidence interval [CI], 39% to 64%) and 62% (95% CI, 49% to 74%), respectively. HER-2 expression, number of tumor sites, primary axillary nodal ratio (number of positive nodes divided by number of sampled nodes), number of positive axillary nodes, and delivery or omission of radiotherapy to metastases correlated with RFS. HER-2 overexpression and more than one site were independent adverse risk factors for RFS. HER-2 and the axillary nodal ratio were independent predictors of OS. The following prognostic categories for RFS were established (RFS rate, median RFS): good risk, no factors (77%, 80 months); intermediate risk, one factor (41%, 28 months); and poor risk, both factors (10%, 10 months).

CONCLUSION: Long-term results in patients with oligometastatic breast cancer are encouraging but need validation in prospective randomized studies. HER-2 expression, number of sites, and primary nodal ratio are independent outcome predictors. Confirmation of these observations in this selected population would imply the need for reevaluation of the current tenet that early detection of metastatic breast cancer recurrence is of no benefit.