bluuebunny/crossref_metadata_2025 huggingface dataset:
High- and Low-Dose Interferon Alfa-2b in High-Risk Melanoma: First Analysis of Intergroup Trial E1690/S9111/C9190
Authors: Kirkwood John M. , Ibrahim Joseph G. , Sondak Vernon K. , Richards Jon , Flaherty Lawrence E. , Ernstoff Marc S. , Smith Thomas J. , Rao Uma , Steele Mary , Blum Ronald H.
Published: February 2017

PURPOSE: Pivotal trial E1684 of adjuvant high-dose interferon alfa-2b (IFNα2b) therapy in high-risk melanoma patients demonstrated a significant relapse-free and overall survival (RFS and OS) benefit compared with observation (Obs).

PATIENTS AND METHODS: A prospective, randomized, three-arm, intergroup trial evaluated the efficacy of high-dose IFNα2b (HDI) for 1 year and low-dose IFNα2b (LDI) for 2 years versus Obs in high-risk (stage IIB and III) melanoma with RFS and OS end points.

RESULTS: A total of 642 patients were enrolled (608 patients eligible), of whom a majority (75%) had nodal metastasis (50% had nodal recurrence). Unlike E1684, E1690 allowed entry of patients with T4 (> 4 mm) deep primary tumors, regardless of nodal dissection, and 25% of the patients entered onto this trial had deep primary tumors (compared with 11% in E1684). At 52 months’ median follow-up, HDI demonstrated an RFS benefit exceeding that of LDI compared with Obs. The 5-year estimated RFS rates for the HDI, LDI, and Obs arms were 44%, 40%, and 35%, respectively. The hazards ratio for the intent-to-treat analysis of HDI versus Obs was 1.28 (P2 = .05); for LDI versus Obs, it was 1.19 (P2 = .17). By Cox analysis, the impact of HDI on RFS achieved significance (P2 = .03). The RFS benefit was equivalent for node-negative and node-positive patients. Neither HDI nor LDI has demonstrated an OS benefit compared with Obs at this time. A major improvement in the median OS of patients in the E1690 Obs arm was noted in comparison with E1684 (6 years v 2.8 years). An analysis of salvage therapy for patients who relapsed on E1690 demonstrated that a significantly larger proportion of patients in the Obs arm received IFNα-containing salvage therapy compared with the HDI arm; this therapy was unavailable to patients during E1684, and patients with undissected regional nodes were not included in E1684. This study did not specify therapy at recurrence. Analysis of treatments received at recurrence demonstrated significantly more frequent use of IFNα2b at relapse from Obs than from HDI, which may have confounded interpretation of the survival benefit of assigned treatments in E1690.

CONCLUSION: The results of the intergroup E1690 trial demonstrate an RFS benefit of IFNα2b that is dose-dependent and significant for HDI by Cox multivariable analysis.
Phase I and Pharmacokinetic Study of Oral Paclitaxel
Authors: Malingré Mirte M. , Terwogt Jetske M. Meerum , Beijnen Jos H. , Rosing Hilde , Koopman Franciska J. , van Tellingen Olaf , Duchin Ken , Huinink Wim W. Ten Bokkel , Swart Martha , Lieverst Jan , Schellens Jan H. M.
Published: February 2017

PURPOSE: To investigate dose escalation of oral paclitaxel in combination with dose increment and scheduling of cyclosporine (CsA) to improve the systemic exposure to paclitaxel and to explore the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT).

PATIENTS AND METHODS: A total of 53 patients received, on one occasion, oral paclitaxel in combination with CsA, coadministered to enhance the absorption of paclitaxel, and, on another occasion, intravenous paclitaxel at a dose of 175 mg/m2 as a 3-hour infusion.

RESULTS: The main toxicities observed after oral intake of paclitaxel were acute nausea and vomiting, which reached DLT at the dose level of 360 mg/m2. Dose escalation of oral paclitaxel from 60 to 300 mg/m2 resulted in significant but less than proportional increases in the plasma area under the concentration-time curve (AUC) of paclitaxel. The mean AUC values ± SD after 60, 180, and 300 mg/m2 of oral paclitaxel were 1.65 ± 0.93, 3.33 ± 2.39, and 3.46 ± 1.37 μmol/L·h, respectively. Dose increment and scheduling of CsA did not result in a further increase in the AUC of paclitaxel. The AUC of intravenous paclitaxel was 15.39 ± 3.26 μmol/L·h.

CONCLUSION: The MTD of oral paclitaxel was 300 mg/m2. However, because the pharmacokinetic data of oral paclitaxel, in particular at the highest doses applied, revealed nonlinear pharmacokinetics with only a moderate further increase of the AUC with doses up to 300 mg/m2, the oral paclitaxel dose of 180 mg/m2 in combination with 15 mg/kg oral CsA is considered most appropriate for further investigation. The safety of the oral combination at this dose level was good.
Chemotherapy in Neuroendocrine/Merkel Cell Carcinoma of the Skin: Case Series and Review of 204 Cases
Authors: Tai Patricia T. H. , Yu Edward , Winquist Eric , Hammond Alex , Stitt Larry , Tonita Jon , Gilchrist Jim
Published: February 2017

PURPOSE: To study the use of chemotherapy for Merkel cell carcinoma (MCC) of the skin.

PATIENTS AND METHODS: Twenty-five cases of MCC were treated at the London Regional Cancer Center between 1987 and 1997. Thirteen cases treated with chemotherapy were reviewed with 191 cases from the literature.

RESULTS: At presentation, 24 patients had localized skin lesions (stage I) and one had locoregional involvement (stage II). Among the nine cases with recurrent nodal disease, six had chemotherapy as a component of salvage treatment. They were all free of disease at a median of 19 months (range, 12 to 37 months). In contrast, two patients who had salvage radiotherapy alone died of disease. Overall survival (OS) and disease-free survival (DFS) were 59% and 43%, respectively, at two years. Median OS and DFS were 29 months (range, 1 to 133 months) and 9 months (range, 1 to 133 months), respectively. Nodal disease developed in 12 (50%) of 24 patients with stage I disease, and distant metastases developed in six (25%) of 24. Including those from the literature, there were 204 cases treated with chemotherapy. Cyclophosphamide/doxorubicin (or epirubicin)/vincristine combination ± prednisone was the most commonly used chemotherapy regimen (47 cases), with an overall response rate of 75.7% (35.1% complete, 35.1% partial, and 5.4% minor responses). Etoposide/cisplatin (or carboplatin) was the next most commonly used regimen (27 cases), with an overall response rate of 60% (36% complete and 24% partial responses). The difference in response rate was not statistically significant (P = .19). Among the 204 cases, there were seven (3.4%) toxic deaths.

CONCLUSION: Chemoradiation for locally recurrent or advanced disease may be an option for patients with a good performance status.
Gemcitabine Plus Vinorelbine Versus Vinorelbine Alone in Elderly Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Frasci Giuseppe , Lorusso Vito , Panza Nicola , Comella Pasquale , Nicolella Gianpaolo , Bianco Andrea , De Cataldis Giuseppe , Iannelli Annunziato , Bilancia Domenico , Belli Mario , Massidda Bruno , Piantedosi Francovito , Comella Giuseppe , De Lena Mario
Published: February 2017

PURPOSE: To evaluate whether the addition of gemcitabine (G) to vinorelbine (V) improves survival and quality of life (QoL) among elderly patients with advanced non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Patients with NSCLC aged ≥ 70 years with advanced disease were randomly allocated to receive V 30 mg/m2 on days 1 and 8 every 3 weeks or G 1,200 mg/m2 + V 30 mg/m2 on days 1 and 8 every 3 weeks. The estimated sample size was 120 patients per arm, but an interim analysis of survival was planned based on the first 60 patients per arm.

RESULTS: In May 1999, the survival data were analyzed of 120 eligible patients (V group = 60; G + V group = 60) who had been randomized from June 1997 to February 1999. Forty-nine patients had stage IIIB disease, and 71 had stage IV. At a median potential follow-up of 14 months (range, 3 to 22 months), 93 patients had died (G + V group = 41; V group = 52). In the G + V group, median survival time was 29 weeks and projected 1-year survival was 30%; these values were 18 weeks and 13% in the V group. According to multivariate Cox analysis, the risk of death in the G + V arm compared with the V arm was 0.48 (95% confidence interval, 0.29 to 0.79; P < .01). Combination therapy was also associated with a clear delay in symptom and QoL deterioration. The overall response rates were 22% and 15% in the G + V and V groups, respectively.

CONCLUSION: In elderly patients with NSCLC, G + V treatment is associated with significantly better survival than is V alone.
Gemcitabine in Combination With Doxorubicin in Advanced Breast Cancer: Final Results of a Phase II Pharmacokinetic Trial
Authors: Pérez-Manga G. , Lluch A. , Alba E. , Moreno-Nogueira J.A. , Palomero M. , García-Conde J. , Khayat D. , Rivelles N.
Published: February 2017

PURPOSE: Gemcitabine has promising single-agent activity in advanced breast disease. The aim of this phase II study was to determine the efficacy, toxicity, and pharmacokinetic profile of gemcitabine administered with doxorubicin as first-line treatment in patients with metastatic breast cancer.

PATIENTS AND METHODS: Of the 42 women with metastatic breast cancer (age 33 to 74 years; mean age, 55 years), 13 were chemotherapy-naive and 29 had received adjuvant chemotherapy. Gemcitabine (800 or 1,000 mg/m2) and doxorubicin (25 mg/m2) were administered intravenously on days 1, 8, and 15 of each 28-day cycle. Blood samples were drawn on day 8 of cycles 1, 2, and 3 and of subsequent odd cycles for gemcitabine pharmacokinetic determinations and before and after the first dose of cycle 1 or 2 for doxorubicin determinations.

RESULTS: There were three complete and 20 partial responses, for an overall response rate of 55% (95% confidence interval [CI], 40% to 70%) and a complete response rate of 7%. The median survival time for all 42 patients was 27 months (95% CI, 13.4 to 30.0 months) and the 1-year survival rate was 80%. Toxicity was mainly hematologic. The disposition of both drugs was unchanged when they were administered on the same day compared with when they were given singly.

CONCLUSION: The combination of gemcitabine (800 mg/m2) and doxorubicin (25 mg/m2) can be safely administered using a weekly schedule. The disposition of both drugs is unchanged when they are administered on the same day. This combination shows promising activity with acceptable toxicity compared with other combination therapies.
Tandem High-Dose Therapy in Rapid Sequence for Children With High-Risk Neuroblastoma
Authors: Grupp Stephan A. , Stern Julie W. , Bunin Nancy , Nancarrow Cheryl , Ross Amy A. , Mogul Mark , Adams Roberta , Grier Holcombe E. , Gorlin Jed B. , Shamberger Robert , Marcus Karen , Neuberg Donna , Weinstein Howard J. , Diller Lisa
Published: February 2017

PURPOSE: Advances in chemotherapy and supportive care have slowly improved survival rates for patients with high-risk neuroblastoma. The focus of many of these chemotherapeutic advances has been dose intensification. In this phase II trial involving children with advanced neuroblastoma, we used a program of induction chemotherapy followed by tandem high-dose, myeloablative treatments (high-dose therapy) with stem-cell rescue (HDT/SCR) in rapid sequence.

PATIENTS AND METHODS: Patients underwent induction chemotherapy during which peripheral-blood stem and progenitor cells were collected and local control measures undertaken. Patients then received tandem courses of HDT/SCR, 4 to 6 weeks apart. Thirty-nine patients (age 1 to 12 years) were assessable, and 70 cycles of HDT/SCR were completed.

RESULTS: Pheresis was possible in the case of all patients, despite their young ages, with an average of 7.2 × 106 CD34+ cells/kg available to support each cycle. Engraftment was rapid; median time to neutrophil engraftment was 11 days. Four patients who completed the first HDT course did not complete the second, and there were three deaths due to toxicity. With a median follow-up of 22 months (from diagnosis), 26 of 39 patients remained event-free. The 3-year event-free survival rate for these patients was 58%.

CONCLUSION: A tandem HDT/SCR regimen for high-risk neuroblastoma is a feasible treatment strategy for children and may improve disease-free survival.
Telomerase Activity and Telomerase Subunits Gene Expression Patterns in Neuroblastoma: A Molecular and Immunohistochemical Study Establishing Prognostic Tools for Fresh-Frozen and Paraffin-Embedded Tissues
Authors: Poremba Christopher , Scheel Christina , Hero Barbara , Christiansen Holger , Schaefer Karl-Ludwig , Nakayama Jun-ichi , Berthold Frank , Juergens Heribert , Boecker Werner , Dockhorn-Dworniczak Barbara
Published: February 2017

PURPOSE: We have recently demonstrated that telomerase activity (TA) is an independent prognostic factor in neuroblastomas. In the present study, the prognostic impact of TA and gene expression of the three major telomerase subunits is evaluated by molecular and immunohistochemical techniques in fresh-frozen and paraffin-embedded tissues.

PATIENTS AND METHODS: One hundred thirty-three neuroblastomas of all stages were analyzed for TA. The TA levels of 75 neuroblastoma cases were correlated with gene expression of telomerase subunits hTRT, human telomerase RNA (hTR), and telomerase protein 1 (TP1) by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), using an innovative approach on the LightCycler instrument (Roche Diagnostics, Mannheim, Germany). For selected cases, the applicability of RT-PCR and immunohistochemistry for hTRT expression analysis was investigated in paraffin-embedded tissues. TA and subunit expression patterns were correlated with traditional prognostic indicators and disease outcome.

RESULTS: TA was present in a total of 39 (29.3%) of 133 neuroblastomas and in 31 (29.8%) of 104 initial neuroblastomas without cytotoxic pretreatment. TA was significantly correlated with both event-free and overall survival (P < .0001). Furthermore, we found a significant correlation between expression levels of TA and hTRT (P < .0001) as well as hTR (P < .001). Multivariate analysis revealed only TA and tumor stage but not serum lactate dehydrogenase, MYCN amplification, or age at diagnosis as independent prognostic factors.

CONCLUSION: The significant correlation with clinical outcome strongly recommends that analysis of TA be incorporated into the clinical investigation of each individual neuroblastoma at the time of diagnosis. Because the mere presence or absence of TA without further quantification is sufficient basis for predicting disease outcome, the telomeric repeat amplification protocol assay could be complemented with but not replaced by analysis of hTRT or hTR expression.
Activity of Thalidomide in AIDS-Related Kaposi’s Sarcoma
Authors: Little Richard F. , Wyvill Kathleen M. , Pluda James M. , Welles Lauri , Marshall Vickie , Figg William D. , Newcomb Fonda M. , Tosato Giovanna , Feigal Ellen , Steinberg Seth M. , Whitby Denise , Goedert James J. , Yarchoan Robert
Published: February 2017

PURPOSE: To assess the toxicity and activity of oral thalidomide in Kaposi’s sarcoma (KS) in a phase II dose-escalation study.

PATIENTS AND METHODS: Human immunodeficiency virus (HIV)–seropositive patients with biopsy-confirmed KS that progressed over the 2 months before enrollment received an initial dose of 200 mg/d of oral thalidomide in a phase II study. The dose was increased to a maximum of 1,000 mg/d for up to 1 year. Anti-HIV therapy was maintained during the study period. Toxicity, tumor response, immunologic and angiogenic factors, and virologic parameters were assessed.

RESULTS: Twenty patients aged 29 to 49 years with a median CD4 count of 246 cells/mm3(range, 14 to 646 cells/mm3) were enrolled. All patients were assessable for toxicity, and 17 for response. Drowsiness in nine and depression in seven patients were the most frequent toxicities observed. Eight (47%; 95% confidence interval [CI], 23% to 72%) of the 17 assessable patients achieved a partial response, and an additional two patients had stable disease. Based on all 20 patients treated, the response rate was 40% (95% CI, 19% to 64%). The median thalidomide dose at the time of response was 500 mg/d (range, 400 to 1,000 mg/d). The median duration of drug treatment was 6.3 months, and the median time to progression was 7.3 months.

CONCLUSION: Oral thalidomide was tolerated in this population at doses up to 1,000 mg/d for as long as 12 months and was found to induce clinically meaningful anti-KS responses in a sizable subset of the patients. Additional studies of this agent in KS are warranted.
Role of Telomerase in Normal and Cancer Cells
Authors: Meyerson Matthew
Published: February 2017

ABSTRACT: Shortening of the telomeric DNA at chromosome ends is postulated to limit the lifespan of human cells. In contrast, activation of telomerase, the enzyme that synthesizes telomeric DNA, is proposed to be an essential step in cancer cell immortalization and cancer progression. This review discusses the structure and function of telomeres and telomerase, the role of telomerase in cell immortalization, and the effects of telomerase inactivation on normal and cancer cells. Moreover, data on the experimental use of telomerase assays for cancer detection and diagnosis are reviewed. Finally, the review considers the evidence regarding whether telomerase inhibitors could be used to treat human cancers.
Gemcitabine and Cisplatin as Induction Regimen for Patients With Biopsy-Proven Stage IIIA N2 Non–Small-Cell Lung Cancer: A Phase II Study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group (EORTC 08955)
Authors: Van Zandwijk N. , Smit E.F. , Kramer G.W. P. , Schramel F. , Gans S. , Festen J. , Termeer A. , Schlosser N.J. J. , Debruyne C. , Curran D. , Giaccone G.
Published: February 2017

PURPOSE: Our objective was to better define the activity/feasibility of gemcitabine/cisplatin (GC) as induction chemotherapy in patients with stage IIIA N2 non–small-cell lung cancer (NSCLC) followed by surgery or radiotherapy within a large, ongoing comparative study (EORTC 08941).

PATIENTS AND METHODS: Forty-seven chemotherapy-naive patients with NSCLC, median age of 58 years, stage IIIA N2 disease, World Health Organization performance status of 0 or 1, and the ability to tolerate a pneumonectomy received gemcitabine 1,000 mg/m2 on days 1, 8, and 15 and cisplatin 100 mg/m2 on day 2, every 4 weeks. Patients received induction chemotherapy (three cycles) before re-evaluation and randomization to surgery or radiotherapy.

RESULTS: Grade 3/4 thrombocytopenia, the main hematologic toxicity, occurred in 60% of patients but was not associated with bleeding. Full-dose gemcitabine was given in 48% of the courses. Severe nonhematologic toxicity was uncommon. Two patients with preexisting, autoimmune pulmonary fibrosis had deterioration of pulmonary function after radiotherapy. Thirty-three (70.2%; 95% confidence interval, 55.1% to 82.7%) of the 47 eligible patients had objective responses (three complete responses and 30 partial responses). Mediastinal nodes were tumor-free after induction therapy in 53% of cases. Resections were considered complete in 71% of the patients who underwent thoracotomy after induction therapy. Median survival for all recruited patients (N = 53) was 18.9 months, with an estimated 1-year survival rate of 69%.

CONCLUSION: In patients with N2 stage IIIA NSCLC, GC is a highly active and well-tolerated induction regimen. GC should be explored in combination with surgery or radiotherapy in stage I and II patients.
Phase II Evaluation of Thalidomide in Patients With Metastatic Breast Cancer
Authors: Baidas Said M. , Winer Eric P. , Fleming Gini F. , Harris Lyndsay , Pluda James M. , Crawford Jeanette G. , Yamauchi Hideko , Isaacs Claudine , Hanfelt John , Tefft Mariella , Flockhart David , Johnson Michael D. , Hawkins Michael J. , Lippman Marc E. , Hayes Daniel F.
Published: February 2017

PURPOSE: To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer.

PATIENTS AND METHODS: Twenty-eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg. Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated.

RESULTS: No patient had a true partial or complete response. On the 800-mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200-mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose-limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia. Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy.

CONCLUSION: Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels.
Survival Advantage From Higher-Dose Radiation Therapy for Clinically Localized Prostate Cancer Treated on the Radiation Therapy Oncology Group Trials
Authors: Valicenti Richard , Lu Jiandong , Pilepich Miljenko , Asbell Sucha , Grignon David
Published: February 2017

PURPOSE: We evaluated the effect of external-beam radiation therapy on disease-specific survival (death from causes related to prostate cancer) and overall survival in men with clinically localized prostate cancer.

METHODS: From 1975 to 1992, 1,465 men with clinically localized prostate cancer received radiation therapy on four Radiation Therapy Oncology Group phase III randomized trials and were pooled for this analysis. No one received androgen-deprivation therapy with his initial treatment. All original histology had central pathologic review for grading using the Gleason classification system. Total delivered radiation dose ranged from 60 to 78 Gy (median, 68.4 Gy). The median follow-up time was 8 years.

RESULTS: A Cox regression model revealed that Gleason score was an independent predictor of disease-specific survival and overall survival. The 10-year disease-specific survival rates by Gleason score were as follows: score of 2 through 5, 85%; score of 6, 79%; score of 7, 62%; and score of 8 through 10, 43%. Stratifying outcome by this important prognostic factor revealed that higher radiation dose was a significant predictor for improved disease-specific survival and overall survival only for those patients whose cancers had Gleason scores of 8 through 10 (P < .05). After adjusting for clinical T stage, nodal status, and age, treating with a higher radiation dose was associated with a 29% lower relative risk of death from prostate cancer and 27% reduced mortality rate (P < .05).

CONCLUSION: These data demonstrate that higher-dose radiation therapy can significantly reduce the risk of dying from prostate cancer in men with clinically localized disease. This survival benefit is restricted to men with poorly differentiated cancers.
Evaluating the Financial Impact of Clinical Trials in Oncology: Results From a Pilot Study From the Association of American Cancer Institutes/Northwestern University Clinical Trials Costs and Charges Project
Authors: Bennett Charles L. , Stinson Tammy J. , Vogel Victor , Robertson Lyn , Leedy Donald , O’Brien Patrick , Hobbs Jane , Sutton Tamara , Ruckdeschel John C. , Chirikos Thomas N. , Weiner Roy S. , Ramsey Marguerite M. , Wicha Max S.
Published: February 2017

PURPOSE: Medical care for clinical trials is often not reimbursed by insurers, primarily because of concern that medical care as part of clinical trials is expensive and not part of standard medical practice. In June 2000, President Clinton ordered Medicare to reimburse for medical care expenses incurred as part of cancer clinical trials, although many private insurers are concerned about the expense of this effort. To inform this policy debate, the costs and charges of care for patients on clinical trials are being evaluated. In this Association of American Cancer Institutes (AACI) Clinical Trials Costs and Charges pilot study, we describe the results and operational considerations of one of the first completed multisite economic analyses of clinical trials.

METHODS: Our pilot effort included assessment of total direct medical charges for 6 months of care for 35 case patients who received care on phase II clinical trials and for 35 matched controls (based on age, sex, disease, stage, and treatment period) at five AACI member cancer centers. Charge data were obtained for hospital and ancillary services from automated claims files at individual study institutions. The analyses were based on the perspective of a third-party payer.

RESULTS: The mean age of the phase II clinical trial patients was 58.3 years versus 57.3 years for control patients. The study population included persons with cancer of the breast (n = 24), lung (n = 18), colon (n = 16), prostate (n = 4), and lymphoma (n = 8). The ratio of male-to-female patients was 3:4, with greater than 75% of patients having stage III to IV disease. Total mean charges for treatment from the time of study enrollment through 6 months were similar: $57,542 for clinical trial patients and $63,721 for control patients (1998 US$; P = .4)

CONCLUSION: Multisite economic analyses of oncology clinical trials are in progress. Strategies that are not likely to overburden data managers and clinicians are possible to devise. However, these studies require careful planning and coordination among cancer center directors, finance department personnel, economists, and health services researchers.
Preoperative Prediction of Surgical Margin Status in Patients With Prostate Cancer Treated by Radical Prostatectomy
Authors: Cheng Liang , Slezak Jeff , Bergstralh Erik J. , Myers Robert P. , Zincke Horst , Bostwick David G.
Published: February 2017

PURPOSE: We sought to determine the preoperative factors associated with surgical margin status in patients who underwent radical prostatectomy for prostate cancer.

PATIENTS AND METHODS: The study group consisted of 339 patients who were treated by radical retropubic prostatectomy and bilateral pelvic lymphadenectomy at the Mayo Clinic. None received preoperative adjuvant therapy. The mean age at the time of surgery was 66 years (range, 45 to 79 years). All specimens were totally embedded and whole-mounted. Positive surgical margin was defined as the presence of cancer cells at the inked margins. Numerous pathologic characteristics in needle biopsies and preoperative clinical findings were analyzed.

RESULTS: The overall margin positivity rate was 24%. In univariate analysis, preoperative serum prostate-specific antigen (PSA) level, Gleason score, perineural invasion, percentage of cancer in the biopsy specimens, and number and percentage of biopsy cores involved by cancer were all associated with positive surgical margins. In multivariate analysis, preoperative serum PSA level (odds ratio for a doubling of PSA levels, 1.9; 95% confidence interval, 1.5 to 2.4; P < .001) and percentage of cancer in the biopsy specimens (odds ratio for a 10% increase, 1.3; 95% confidence interval, 1.2 to 1.4; P < .001) were predictive of margin status in radical prostatectomy. With use of preoperative serum PSA level and percentage of cancer in the biopsy as predictors of surgical margins, the overall accuracy as measured by the area under the receiver operating characteristic curve was 0.74.

CONCLUSION: Preoperative serum PSA level and percentage of cancer in the biopsy specimens were independently associated with surgical margin status in patients who underwent radical prostatectomy for prostate cancer. The combination of these two factors provides a high level of predictive accuracy for margin status.
First-Line Chemotherapy With Local Treatment Can Prevent External-Beam Irradiation and Enucleation in Low-Stage Intraocular Retinoblastoma
Authors: Beck M. Nenadov , Balmer A. , Dessing C. , Pica A. , Munier F.
Published: February 2017

PURPOSE: To evaluate the efficacy of first-line chemotherapy (CT) in preventing external-beam radiotherapy (EBR) and/or enucleation in patients with retinoblastoma (Rbl).

PATIENTS AND METHODS: Twenty-four patients with newly diagnosed unilateral or bilateral Rbl received CT associated with local treatment (LT). Two to five courses of etoposide and carboplatin were administered at 3- to 4-week intervals, depending on tumor response, and were completed each time by LT.

RESULTS: Tumor response was observed in all eyes. Twenty-one of 24 patients showed a complete response (CR) that persisted at a median follow-up (FU) of 31 months (range, 4 to 41 months). Among the three patients who relapsed, two were lost to FU and one died of progressive disease. CR was achieved by CT and LT alone in 15 (71.4%) of 21 patients with less advanced disease (groups I to III). Six other patients with advanced disease (groups IV and V) experienced treatment failure and needed salvage treatment by EBR and/or enucleation. The difference between the two patient groups with regard to disease stage was statistically significant (P < .0001). EBR could be avoided in 13 (68.4%) of 19 patients, who presented with groups I to III (15 eyes) and group V (one eye) disease, whereas enucleation could be avoided in only two (40%) of five.

CONCLUSION: CT combined with intensive LT is effective in patients with groups I to III Rbl, permitting the avoidance of EBR in the majority of these young children and, thus, reducing the risk of long-term sequelae. This is in contrast with the disappointing results for patients with groups IV and V Rbl, in whom EBR and/or enucleation was needed.
CNS Involvement in Children With Newly Diagnosed Non-Hodgkin’s Lymphoma
Authors: Sandlund John T. , Murphy Sharon B. , Santana Victor M. , Behm Frederick , Jones Dana , Berard Costan W. , Furman Wayne L. , Ribeiro Raul , Crist William M. , Greenwald Carol , Chen Gang , Walter Andrew , Pui Ching-Hon
Published: February 2017

PURPOSE: To determine the frequency of CNS involvement at diagnosis of non-Hodgkin’s lymphoma (NHL), to characterize its pattern of presentation, and to determine its prognostic significance.

PATIENTS AND METHODS: We reviewed the records of 445 children (1975 through 1995) diagnosed with NHL (small noncleaved cell NHL/B-cell acute lymphoblastic leukemia [SNCC NHL/B-ALL], 201 patients; lymphoblastic, 113; large cell, 119; other, 12). Tumor burden was estimated by serum lactate dehydrogenase (LDH) measurement and reclassification of disease stage irrespective of CNS involvement (modified stage).

RESULTS: Thirty-six of 445 children with newly diagnosed NHL had CNS involvement (lymphoma cells in the CSF [n = 23], cranial nerve palsy [n = 9], both features [n = 4]), representing 13%, 7%, and 1% of small noncleaved cell lymphoma, lymphoblastic lymphoma, and large-cell cases, respectively. By univariate analysis, CNS disease at diagnosis did not significantly impact event-free survival (P = .095), whereas stage and LDH did; however, children with CNS disease at diagnosis were at 2.0 times greater risk of death than those without CNS disease at diagnosis. In a multivariate analysis, CNS disease was not significantly associated with either overall or event-free survival, whereas both serum LDH and stage influenced both overall and event-free survival. Among cases of SNCC NHL/B-ALL, CNS disease was significantly associated with event-free and overall survival (univariate analysis); however, in multivariate analysis, only LDH had independent prognostic significance. Elevated serum LDH or higher modified stage were associated with a trend toward poorer overall survival among children with CNS disease.

CONCLUSION: A greater tumor burden at diagnosis adversely influences the treatment outcome of children with NHL and CNS disease at diagnosis, suggesting a need for ongoing improvement in both systemic and CNS-directed therapy.
Survival Benefit of High-Dose Therapy in Poor-Risk Aggressive Non-Hodgkin’s Lymphoma: Final Analysis of the Prospective LNH87–2 Protocol—A Groupe d’Etude des Lymphomes de l’Adulte Study
Authors: Haioun Corinne , Lepage Eric , Gisselbrecht Christian , Salles Gilles , Coiffier Bertrand , Brice Pauline , Bosly André , Morel Pierre , Nouvel Christiane , Tilly Hervé , Lederlin Pierre , Sebban Catherine , Brière Josette , Gaulard Philippe , Reyes Félix
Published: February 2017

PURPOSE: To present the final analysis, with a median follow-up of 8 years, of the LNH87–2 randomized study, which compares consolidative sequential chemotherapy (ifosfamide plus etoposide, asparaginase, and cytarabine) with high-dose therapy (HDT) using cyclophosphamide, carmustine, and etoposide (CBV regimen) followed by stem-cell transplantation in patients with aggressive non-Hodgkin’s lymphoma in first complete remission after induction, focusing on high/intermediate- and high-risk patients identified by the age-adjusted international prognostic index.

PATIENTS AND METHODS: Among the 916 eligible patients, 451 presented with two (n = 318) or three (n = 133) risk factors. After reaching complete remission to induction therapy, 236 of these higher risk patients were assessable for the consolidation phase, with 125 patients in the HDT arm and 111 in the sequential chemotherapy arm.

RESULTS: Among these 451 higher risk patients, 277 (61%) achieved complete remission after induction treatment. In the population of 236 randomized patients, HDT was superior to sequential chemotherapy, with 8-year disease-free survival rates of 55% (95% confidence interval [CI], 46% to 64%) and 39% (95% CI, 30% to 48%), respectively (P = .02; relative risk, 1.56). The 8-year survival rate was significantly superior in the HDT arm (64%; 95% CI, 55% to 73%) compared with the sequential chemotherapy arm (49%; 95% CI, 39% to 59%) (P = .04; relative risk, 1.51).

CONCLUSION: On the basis of the final analysis of this prospectively treated series of patients, retrospectively analyzed on the basis of the International Prognostic Index, we hypothesize that HDT benefits patients at higher risk who achieve complete remission after induction treatment.
Donor Lymphocyte Infusions for Relapsed Multiple Myeloma After Allogeneic Stem-Cell Transplantation: Predictive Factors for Response and Long-Term Outcome
Authors: Lokhorst H.M. , Schattenberg A. , Cornelissen J.J. , van Oers M.H. J. , Fibbe W. , Russell I. , Donk N.W. C. J. v. d. , Verdonck L.F.
Published: February 2017

PURPOSE: To determine the efficacy, toxicity, and long-term outcome and prognostic factors of donor lymphocyte infusions (DLI) in patients with relapsed multiple myeloma (MM) after allogeneic stem-cell transplantation (AlloSCT).

MATERIALS AND METHODS: Twenty-seven patients received 52 DLI courses at a median of 30 months after the previous AlloSCT. Reinduction therapy was administered to 13 patients before DLI.

RESULTS: Reinduction therapy was successful in eight of 13 patients. Fourteen patients (52%) responded to DLI, including six patients (22%) who achieved a complete remission (CR). Five patients responded after T-cell dose escalation in subsequent DLIs. Four patients experienced relapse or disease progression (three from partial response and one from CR). Five patients remain in remission more than 30 months after DLI. Major toxicity was acute and chronic graft-versus-host disease (GVHD), which was present in 55% and 26% of patients, respectively. Two patients died from bone marrow aplasia. Median overall survival of all patients was 18 months. Overall survival was 11 months for DLI-resistant patients and has not been reached for the responding patients. In two patients, sustained molecular remission was observed. The factors that were correlated with response to DLI were a T-cell dose of more than 1.108 cells/kg, response to reinduction therapy, and chemotherapy-sensitive disease before AlloSCT.

CONCLUSION: These data confirm the potential and durable graft-versus-myeloma effect of DLI in patients with relapsed MM after AlloSCT. Future studies should be aimed at increasing response rates, especially in patients with chemoresistant disease, and reducing toxicity by limiting GVHD. Adjuvant DLI seems an attractive and promising approach for patients who do not achieve a molecular remission after AlloSCT.
Exploratory Phase III Study of Paclitaxel and Cisplatin Versus Paclitaxel and Carboplatin in Advanced Ovarian Cancer
Authors: Neijt Jan P. , Engelholm Svend A. , Tuxen Malgorzata K. , Sørensen Peter G. , Hansen Mogens , Sessa Cristiana , de Swart Cees A. M. , Hirsch Fred R. , Lund Birthe , van Houwelingen Hans C.
Published: February 2017

PURPOSE: To determine the side effects and feasibility of cisplatin and carboplatin each in combination with paclitaxel as front-line therapy in advanced epithelial ovarian cancer.

PATIENTS AND METHODS: Patients were randomly allocated to receive paclitaxel 175 mg/m2 intravenously as a 3-hour infusion followed by either cisplatin 75 mg/m2 or carboplatin (area under the plasma concentration-time curve of 5), both on day 1. The schedule was repeated every 3 weeks for at least six cycles. Women allocated to paclitaxel-cisplatin were admitted to the hospital, whereas the carboplatin regimen was administered to outpatients.

RESULTS: A total of 208 eligible patients were randomized. Both regimens could be delivered in an optimal dose and without significant delay. Paclitaxel-carboplatin produced significantly less nausea and vomiting (P < .01) and less peripheral neurotoxicity (P = .04) but more granulocytopenia and thrombocytopenia (P < .01). The overall response rate in 132 patients with measurable disease was 64% (84 of 132 patients), and in patients with elevated CA 125 levels at start, it was 74% (132 of 178 patients). With a median follow-up time of 37 months, the median progression-free survival time of all patients was 16 months and the median overall survival time was 31 months. The small number of patients entered onto the study caused wide confidence intervals (CIs) around the hazards ratio for progression-free survival of paclitaxel-carboplatin compared with paclitaxel-cisplatin (hazards ratio, 1.07; 95% CI, 0.78 to 1.48) and did not allow conclusions about efficacy.

CONCLUSION: Paclitaxel-carboplatin is a feasible regimen for outpatients with ovarian cancer and has a better toxicity profile than paclitaxel-cisplatin.
Epirubicin-Based Chemotherapy in Metastatic Breast Cancer Patients: Role of Dose-Intensity and Duration of Treatment
Authors:   the French Epirubicin Study Group
Published: February 2017

PURPOSE: To determine whether the duration and the dose of epirubicin modify the long-term outcome of patients with metastatic breast cancer (MBC).

PATIENTS AND METHODS: Four hundred seventeen anthracycline-naive MBC patients were randomized to receive one of the following regimens: arm A: 11 cycles of fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2 (FEC 75) every 21 days; arm B: four cycles of FEC 100 (same regimen but with epirubicin 100 mg/m2) then eight cycles of FEC 50 (epirubicin 50 mg/m2); and arm C: four cycles of FEC 100 then restart the same regimen at disease progression in case of prior response or stabilization.

RESULTS: Hematologic toxicity was similar. Nausea/vomiting and stomatitis were significantly less frequent in arm A as was left ventricular ejection fraction decrease in arm C (A = six patients, B = five patients, and C = one patient). Six patients died of infections (A = four patients and C = two patients). After four cycles, the objective response rate (ORR) was better with FEC 100 than with FEC 75 (49.2% v 40%, respectively; P = .07). The ORR was better with the longer regimens (arm A, 56.9%; B, 64%; and C, 47.6%; P = .06) and was 41% after second-line FEC 100. After a median follow-up of 41 months, the response duration and time to progression (TTP) were significantly better with arm B, the longer regimen (P = .012 and P < 10−3, respectively). The median survival times for arms A, B, and C were similar (17.9, 18.9, and 16.3 months, respectively; P = .49).

CONCLUSION: In MBC, longer epirubicin-based regimens are better in terms of response duration and TTP. FEC 100 regimens improve the ORR. However, four initial cycles of FEC 100 and identical retreatment at disease progression yielded equivalent overall survival to longer regimens.
DX-8951f, a Hexacyclic Camptothecin Analog, on a Daily-Times-Five Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Malignancies
Authors: Rowinsky Eric K. , Johnson Thomas R. , Geyer Charles E. , Hammond Lisa A. , Eckhardt S. Gail , Drengler Ronald , Smetzer Leslie , Coyle John , Rizzo Jinee , Schwartz Garry , Tolcher Anthony , Von Hoff Daniel D. , De Jager Robert L.
Published: February 2017

PURPOSE: To assess the feasibility of administering DX-8951f (exatecan mesylate), a water-soluble, camptothecin analog, as a 30-minute intravenous infusion daily for 5 days every 3 weeks, determine the maximum-tolerated dose (MTD) and pharmacokinetic (PK) behavior of DX-8951f, and seek preliminary evidence of anticancer activity.

PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of DX-8951f. After three patients were treated at the first dose level, doses were to be escalated in increments of 100%, using a single patient at each dose level unless moderate toxicity was observed. The MTD, defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%, was calculated separately for minimally pretreated (MP) and heavily pretreated (HP) patients. The PK and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized.

RESULTS: Thirty-six patients were treated with 130 courses of DX-8951f at six dose levels ranging from 0.1 to 0.6 mg/m2/d. Brief, noncumulative neutropenia was the most common toxicity observed. Severe myelosuppression (neutropenia that was protracted and/or associated with fever and/or severe thrombocytopenia) was consistently experienced by HP and MP patients at doses exceeding 0.3 and 0.5 mg/m2/d, respectively. Nonhematologic toxicities (nausea, vomiting, and diarrhea) were also observed, but these effects were rarely severe. Objective antitumor activity included partial responses in one patient each with platinum-resistant extrapulmonary small-cell and fluoropyrimidine- and irinotecan-resistant colorectal carcinoma, and minor responses in patients with prostate, hepatocellular, thymic, primary peritoneal, and irinotecan-resistant colorectal carcinomas. The PKs of total DX-8951 were linear and well fit by a three-compartment model.

CONCLUSION: The recommended doses for phase II studies of DX-8951f as a 30-minute infusion daily for 5 days every 3 weeks are 0.5 and 0.3 mg/m2/d for MP and HP patients, respectively. The characteristics of the myelosuppressive effects of DX-8951f, paucity of severe nonhematologic toxicities, and antitumor activity against a wide range of malignancies warrant broad disease-directed evaluations of DX-8951f on this schedule.
Utilizing Predictions of Early Prostate-Specific Antigen Failure to Optimize Patient Selection for Adjuvant Systemic Therapy Trials
Authors: D’Amico Anthony V. , Whittington Richard , Malkowicz S. Bruce , Wu Yue Hui , Chen Ming-Hui , Hurwitz Mark , Kantoff Philip W. , Tomaszewski John E. , Renshaw Andrew A. , Wein Alan , Richie Jerome P.
Published: February 2017

PURPOSE: Prostate-specific antigen (PSA) failure within 2 years after radical prostatectomy (RP) has been shown to be a clinically significant predictor of distant failure. This study was performed to estimate 2-year PSA failure rates on the basis of readily available clinical and pathologic factors to identify patients for whom effective adjuvant systemic therapy is needed.

PATIENTS AND METHODS: A Cox regression multivariable analysis was used to determine whether the percentage of positive prostate biopsies, PSA level, and the pathologic findings at RP in 1,728 men provided clinically relevant information about PSA outcome after RP. A bootstrapping technique with 2,000 replications was used to provide 95% confidence intervals for the predicted 2-year PSA failure rates, which were determined on the basis of the independent clinical and pathologic predictors of PSA outcome.

RESULTS: The independent predictors of time to PSA failure included a percentage of positive prostate biopsies of greater than 34% (P ≤ .009), PSA level greater than 10 ng/mL (P ≤ .01), seminal vesicle invasion (P = .02), prostatectomy Gleason score of 8 to 10 (P = .04), and positive surgical margins (P = .0001). Predictions of 2-year PSA failure rates and bootstrap estimates of the 95% confidence intervals were arranged in a tabular format, stratified by independent clinical and pathologic predictors of PSA outcome.

CONCLUSION: Patients who are most likely to benefit from effective adjuvant systemic therapy after RP can be identified using readily available clinical and pathologic data.
Osteonecrosis as a Complication of Treating Acute Lymphoblastic Leukemia in Children: A Report From the Children’s Cancer Group
Authors: Mattano Leonard A. , Sather Harland N. , Trigg Michael E. , Nachman James B.
Published: February 2017

PURPOSE: To determine the incidence, risk factors, and morbidity for osteonecrosis (ON) in children with acute lymphoblastic leukemia (ALL) treated with intensive chemotherapy including multiple, prolonged courses of corticosteroid.

PATIENTS AND METHODS: The occurrence of symptomatic ON was investigated retrospectively in 1,409 children ages 1 to 20 years old receiving therapy for high-risk ALL on Children’s Cancer Group (CCG) protocol CCG-1882.

RESULTS: ON was diagnosed in 111 patients (9.3% ± 0.9%, 3-year life-table incidence). The incidence was higher for older children (≥ 10 years: 14.2% ± 1.3% v < 10 years: 0.9% ± 0.4%; P < .0001), especially females 10 to 15 years old and males 16 to 20 years old (19.2% ± 2.3% and 20.7% ± 4.7%, respectively). In patients 10 to 20 years old, the incidence of ON was higher for females versus males (17.4% ± 2.1% v 11.7% ± 1.6%, respectively; P = .03) and for patients randomized to receive two 21-day dexamethasone courses versus one course (23.2% ± 4.8% v 16.4% ± 4.3%, respectively; P = .27). Among ethnic groups, whites had the highest incidence and blacks the lowest, with other groups intermediate (16.7% ± 1.4% v 3.3% ± 2.3% v 6.7% ± 2.2%, respectively; P = .003). There was no difference in event-free survival in patients with or without ON. ON was diagnosed within 3 years of starting ALL therapy in all but one patient, involved weight-bearing joint(s) in 94% of patients, and was multifocal in 74% of patients. Symptoms of pain and/or immobility were chronic in 84% of patients, with 24% having undergone an orthopedic procedure and an additional 15% considered candidates for surgery in the future.

CONCLUSION: Children ages 10 to 20 years who receive intensive ALL therapy, including multiple courses of corticosteroid, are at significant risk for developing ON.