bluuebunny/crossref_metadata_2025 huggingface dataset:
Matched-Pair Analysis of Conformal High–Dose-Rate Brachytherapy Boost Versus External-Beam Radiation Therapy Alone for Locally Advanced Prostate Cancer
Authors: Kestin Larry L. , Martinez Alvaro A. , Stromberg Jannifer S. , Edmundson Gregory K. , Gustafson Gary S. , Brabbins Donald S. , Chen Peter Y. , Vicini Frank A.
Published: February 2017

PURPOSE: We performed a matched-pair analysis to compare our institution’s experience in treating locally advanced prostate cancer with external-beam radiation therapy (EBRT) alone to EBRT in combination with conformal interstitial high–dose-rate (HDR) brachytherapy boosts (EBRT + HDR).

MATERIALS AND METHODS: From 1991 to 1998, 161 patients with locally advanced prostate cancer were prospectively treated with EBRT + HDR at William Beaumont Hospital, Royal Oak, Michigan. Patients with any of the following characteristics were eligible for study entry: pretreatment prostate-specific antigen (PSA) level of ≥ 10.0 ng/mL, Gleason score ≥ 7, or clinical stage T2b to T3c. Pelvic EBRT (46.0 Gy) was supplemented with three (1991 through 1995) or two (1995 through 1998) ultrasound-guided transperineal interstitial iridium-192 HDR implants. The brachytherapy dose was escalated from 5.50 to 10.50 Gy per implant.

Each of the 161 EBRT + HDR patients was randomly matched with a unique EBRT-alone patient. Patients were matched according to PSA level, Gleason score, T stage, and follow-up duration. The median PSA follow-up was 2.5 years for both EBRT + HDR and EBRT alone.

RESULTS: EBRT + HDR patients demonstrated significantly lower PSA nadir levels (median, 0.4 ng/mL) compared with those receiving EBRT alone (median, 1.1 ng/mL). The 5-year biochemical control rates for EBRT + HDR versus EBRT-alone patients were 67% versus 44%, respectively (P < .001). On multivariate analyses, pretreatment PSA, Gleason score, T stage, and the use of EBRT alone were significantly associated with biochemical failure. Those patients in both treatment groups who experienced biochemical failure had a lower 5-year cause-specific survival rate than patients who were biochemically controlled (84% v 100%; P < .001).

CONCLUSION: Locally advanced prostate cancer patients treated with EBRT + HDR demonstrate improved biochemical control compared with those who are treated with conventional doses of EBRT alone.
p27kip1 Protein Expression Correlates With Survival in Myxoid and Round-Cell Liposarcoma
Authors: Oliveira Andre M. , Nascimento Antonio G. , Okuno Scott H. , Lloyd Ricardo V.
Published: February 2017

PURPOSE: The p27kip1 protein (p27) is a cyclin-dependent kinase inhibitor that has been shown to be an independent prognostic factor in a variety of human neoplasms. Low expression of p27 tends to occur in more aggressive neoplasms. The role of p27 as an independent prognostic factor in the spectrum of myxoid and round-cell liposarcomas has not been examined.

MATERIALS AND METHODS: Forty-seven cases of myxoid and round-cell liposarcomas were examined. Clinicopathologic features and immunohistochemical expression of p27 and Ki-67 antigen were studied in all cases. Survival analysis was performed using the log-rank test and the Cox multivariate regression model.

RESULTS: The male:female ratio was 1.4:1, and the mean age at diagnosis was 45 years. The tumors were located in the lower extremities (94%) and retroperitoneum (6%). The median tumor size was 13.5 cm. The median follow-up was 6.3 years, and the overall 5- and 10-year survival rates were 76% and 67%, respectively. Low expression of p27 was identified in 34 cases (72%) and correlated with decreased metastasis-free (P = .026) and overall survival (P = .008). In a multivariate analysis, only round-cell differentiation and low expression of p27 independently predicted decreased metastasis-free and overall survival.

CONCLUSION: p27 expression predicts the clinical behavior of myxoid and round-cell liposarcomas, even in neoplasms with few or no round-cell differentiation.
Primary Cutaneous T-Cell Lymphoma: Review and Current Concepts
Authors: Siegel Richard S. , Pandolfino Tomi , Guitart Joan , Rosen Steven , Kuzel Timothy M.
Published: February 2017

PURPOSE: Primary cutaneous T-cell lymphomas (CTCLs) encompass a wide variety of lymphomas that are characterized by the localization of the malignant lymphocytes to the skin at presentation. Advances in molecular biologic techniques, including immunophenotyping and gene rearrangement studies to determine clonality, have led to more frequent diagnosis of CTCL as well as more consistent subclassification of these entities. However, there continues to be confusion in the classification, prognosis, and management of patients with CTCL. The purpose of this review is to present a summary of the diagnosis, prognosis, and treatment of CTCL, with specific emphasis on mycosis fungoides (MF) and Sézary syndrome (SS). We also present a detailed discussion of the entities that make up the differential diagnosis of CTCL.

DESIGN: We reviewed the medical literature on CTCL and other diseases that make up the differential diagnosis of CTCL.

Results and

CONCLUSION: MF and SS are the most common forms of CTCL. The etiology of this disease is still unknown. Patients may go for months to years with skin abnormalities before being diagnosed. MF/SS is an indolent disease and patients with T1 disease have a normal life expectancy. Patients who undergo transformation to large-cell lymphoma (8% to 23% of patients) have a poor prognosis, with mean survival ranging from 2 to 19 months. Treatment for MF/SS continues to be palliative. There are many new therapies that are currently being investigated in clinical trials, and the DAB389IL-2 fusion protein was recently approved for the treatment of refractory MF/SS.
Natural Course of Neuroblastoma Detected by Mass Screening: A 5-Year Prospective Study at a Single Institution
Authors: Nishihira Hirokazu , Toyoda Yasunori , Tanaka Yukichi , Ijiri Rieko , Aida Noriko , Takeuchi Maho , Ohnuma Kei , Kigasawa Hisato , Kato Keisuke , Nishi Toshiji
Published: February 2017

PURPOSE: To describe various favorable courses of neuroblastoma (NBL) detected by mass screening and to present our observation program as a temporary treatment option, to be used until a final decision is made regarding the mass screening program for 6-month-old infants.

PATIENTS AND METHODS: Between October 1993 and November 1999, 26 of 51 patients with NBL detected by mass screening were enrolled in our observation program. The criteria for observation included urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels less than 50 μg/mg creatinine, smaller tumor size (< 5.0 cm), preoperative status, and granted informed consent. Patients were divided into four groups according to changes in urinary VMA and HVA values and tumor size. Patients who no longer fulfilled criteria underwent surgery.

RESULTS: The observation period ranged from 4 to 73 months. Urinary VMA and HVA levels decreased in 19 of 26 patients, often by age 16 months. Eighteen patients had regressing tumors, and in 10 of these cases, the tumor was undetectable or barely detectable by imaging techniques. Four patients younger than 12 months had increased tumor marker levels and tumor volume, histologically reflecting neuroblastic proliferation. The remaining three patients, all older than 18 months, had varied tumor marker levels but increased tumor volume, histologically reflecting an increase in Schwann cells. No upgrading of tumor stage or unfavorable biologic factor was noted in any patient.

CONCLUSION: None of our patients showed evidence of transition from favorable to unfavorable prognosis, a finding that points to a reduction in the significance of screening as a public health measure. Until results of ongoing screening trials involving older patients have been evaluated, the observation program can be used as a temporary measure to avoid, with little risk, unnecessary surgical intervention.
Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Advanced or Metastatic Bladder Cancer: Results of a Large, Randomized, Multinational, Multicenter, Phase III Study
Authors: von der Maase H. , Hansen S.W. , Roberts J.T. , Dogliotti L. , Oliver T. , Moore M.J. , Bodrogi I. , Albers P. , Knuth A. , Lippert C.M. , Kerbrat P. , Sanchez Rovira P. , Wersall P. , Cleall S.P. , Roychowdhury D.F. , Tomlin I. , Visseren-Grul C.M. , Conte P.F.
Published: February 2017

PURPOSE: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium.

PATIENTS AND METHODS: Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8, and 15; cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles.

RESULTS: Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI, 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively) and thrombocytopenia (57% v 21%, respectively). On both arms, the RBC transfusion rate was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1%, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue.

CONCLUSION: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.
Prognostic Factors in Ewing’s Tumor of Bone: Analysis of 975 Patients From the European Intergroup Cooperative Ewing’s Sarcoma Study Group
Authors: Cotterill S.J. , Ahrens S. , Paulussen M. , Jürgens H.F. , Voûte P.A. , Gadner H. , Craft A.W.
Published: February 2017

PURPOSE: To further elaborate on prognostic factors for Ewing’s sarcoma of bone and to document improvements in relapse-free survival (RFS) and trends in local therapy over the study period (1977 to 1993).

PATIENTS AND METHODS: A retrospective analysis was performed on a combined Gesellschaft Für Pädiatrische Onkologie und Hämatologie/Cooperative Ewing Sarcoma Study and United Kingdom Children’s Cancer Study Group/Medical Research Council data set of 975 patients registered with the respective trial offices before the current collaborative European Intergroup Cooperative Ewing’s Sarcoma Study trial. Both groups independently undertook studies with similar chemotherapy during the period.

RESULTS: The key adverse prognostic factor is metastases at diagnosis (5-year RFS, 22% of patients with metastases at diagnosis v 55% of patients without metastases at diagnosis; P < .0001). For the group with metastases, there was a trend for better survival for those with lung involvement compared with those with bone metastases or a combination of lung and bone metastases (P < .0001). In the group of patients with no metastases at diagnosis, multivariate analysis demonstrated that site (axial v other), age-group (< 15 v ≥ 15 years), and period of diagnosis had significant influence on RFS (all P < .005). RFS was superior in the period after 1985 compared with the period before 1985 for nonmetastatic patients (45% v 60%, respectively; P < .0001) and for metastatic patients (16% v 30%, respectively; P = .016). Patients who relapsed within 2 years of diagnosis had a less favorable prognosis than patients who relapsed later (5-year survival after relapse, 4% v 23%, respectively; P < .0001). There were other changes over the period; in particular, radiotherapy or amputation were more common in the period before 1986, whereas endoprosthetic surgery was widely used in the later period.

CONCLUSION: Survival and RFS improved over the period. Prognostic factors are metastases at diagnosis, primary site, and age.
Systematic Overview of Cost-Utility Assessments in Oncology
Authors: Earle C.C. , Chapman R.H. , Baker C.S. , Bell C.M. , Stone P.W. , Sandberg E.A. , Neumann P.J.
Published: February 2017

PURPOSE: Cost-utility analyses (CUAs) present the value of an intervention as the ratio of its incremental cost divided by its incremental survival benefit, with survival weighted by utilities to produce quality-adjusted life years (QALYs). We critically reviewed the CUA literature and its role in informing clinical oncology practice, research priorities, and policy.

METHODS: The English-language literature was searched between 1975 and1997 for CUAs. Two readers abstracted from each article descriptions of the clinical situation and patients, the methods used, study perspective, the measures of effectiveness, costs included, discounting, and whether sensitivity analyses were performed. The readers then made subjective quality assessments. We also extracted utility values from the reviewed papers, along with information on how and from whom utilities were measured.

RESULTS: Our search yielded 40 studies, which described 263 health states and presented 89 cost-utility ratios. Both the number and quality of studies increased over time. However, many studies are at variance with current standards. Only 20% of studies took a societal perspective, more than a third failed to discount both the costs and QALYs, and utilities were often simply estimates from the investigators or other physicians.

CONCLUSION: The cost-utility literature in oncology is not large but is rapidly expanding. There remains much room for improvement in the methodological rigor with which utilities are measured. Considering quality-of-life effects by incorporating utilities into economic studies is particularly important in oncology, where many therapies obtain modest improvements in response or survival at the expense of nontrivial toxicity.
Cost-Effectiveness of Adding an Electron-Beam Boost to Tangential Radiation Therapy in Patients With Negative Margins After Conservative Surgery for Early-Stage Breast Cancer
Authors: Hayman James A. , Hillner Bruce E. , Harris Jay R. , Pierce Lori J. , Weeks Jane C.
Published: February 2017

PURPOSE: Electron-beam boosts (EBB) are routinely added after conservative surgery and tangential radiation therapy (TRT) for early-stage breast cancer. We performed an incremental cost-utility analysis to evaluate their cost-effectiveness.

METHODS: A Markov model examined the impact of adding an EBB to TRT from a societal perspective. Outcomes were measured in quality-adjusted life years (QALYs). On the basis of the Lyon trial, the EBB was assumed to reduce local recurrences by approximately 2% at 10 years but to have no impact on survival. Patients’ utilities were used to adjust for quality of life. Given the small absolute benefit of the EBB, baseline utilities were assumed to be the same with or without it, an assumption evaluated by Monte Carlo simulation. Direct medical, time, and travel costs were considered.

RESULTS: Adding the EBB led to an additional cost of $2,008, an increase of 0.0065 QALYs and, therefore, an incremental cost-effectiveness ratio of over $300,000/QALY. In a sensitivity analysis, the ratio was moderately sensitive to the efficacy and cost of the EBB and highly sensitive to patients’ utilities for treatment without it. Even if patients do value a small risk reduction, the mean cost-effectiveness ratio estimated by the Monte Carlo simulation remains high, at $70,859/QALY (95% confidence interval, $53,141 to $105,182/QALY).

CONCLUSION: On the basis of currently available data, the cost-effectiveness ratio for the EBB is well above the commonly cited threshold for cost-effective care ($50,000/QALY). The EBB becomes cost-effective only if patients place an unexpectedly high value on the small absolute reduction in local recurrences achievable with it.
Impact of Young Age on Outcome in Patients With Ductal Carcinoma-In-Situ Treated With Breast-Conserving Therapy
Authors: Vicini Frank A. , Kestin Larry L. , Goldstein Neal S. , Chen Peter Y. , Pettinga Jane , Frazier Robert C. , Martinez Alvaro A.
Published: February 2017

PURPOSE: We reviewed our institution’s experience treating patients with ductal carcinoma-in-situ (DCIS) with breast-conserving therapy (BCT) to determine the impact of patient age on outcome.

PATIENTS AND METHODS: From 1980 to 1993, 146 patients were treated with BCT for DCIS. All patients underwent excisional biopsy, and 64% underwent re-excision. All patients received whole-breast irradiation to a median dose of 45 Gy. Ninety-four percent of patients received a boost to the tumor bed, for a median total dose of 60.4 Gy. All slides on every patient were reviewed by one pathologist. The median follow-up period was 7.2 years.

RESULTS: Seventeen patients developed an ipsilateral local recurrence, for 5- and 10-year actuarial rates of 10.2% and 12.4%, respectively. The 10-year rate of ipsilateral failure was 26.1% in patients younger than 45 years of age versus 8.6% in older patients (P = .03). On multivariate analysis, young age was independently associated with recurrence of the index lesion (true recurrence/marginal miss [TR/MM] failures), regardless of how it was analyzed (eg, < 45 years of age or as a continuous variable). In addition, young patients had a dramatically higher 10-year rate of invasive TR/MM failures (19.9% v 3.2%). In a separate multivariate analysis for the development of invasive TR/MM failures, only patient age and predominant nuclear grade were independently associated with recurrence. The relationship between excision volume and outcome was analyzed in the 95 patients who underwent re-excision. The 5-year actuarial rate of TR/MM failure was significantly worse only in young patients with smaller (< 40 mL) re-excision volumes (33.3% v 9.1%; P = .02). In a separate multivariate analysis of only these 95 patients (25 of whom were < 45 years of age), the volume of re-excision had the strongest association with outcome (P = .05). Patient age was no longer associated with local recurrence.

CONCLUSION: These findings suggest that young patients with DCIS have a significantly greater risk of local recurrence after BCT that is independent of other previously defined risk factors. Our data also suggest that the extent of resection may in part be related to the less optimal results that are observed in these patients.
p53 Gene Status as a Predictor of Tumor Response to Induction Chemotherapy of Patients With Locoregionally Advanced Squamous Cell Carcinomas of the Head and Neck
Authors: Temam Stéphane , Flahault Antoine , Périé Sophie , Monceaux Guy , Coulet Florence , Callard Patrice , Bernaudin Jean-François , St Guily Jean Lacau , Fouret Pierre
Published: February 2017

PURPOSE: To determine whether p53 gene status predicts tumor responses to platinum- and fluorouracil-based induction chemotherapy in locoregionally advanced squamous cell carcinomas of the head and neck.

PATIENTS AND METHODS: Tumor responses of 105 patients were measured at the primary tumor site. Objective response and major response were defined by a 50% and 80% reduction in tumor size, respectively. All coding parts of p53 gene were directly sequenced. p53 expression in tumor cells was determined by immunohistochemistry. Human papillomavirus infection was detected by polymerase chain reaction. Odd ratios were adjusted by stepwise logistic regression analysis.

RESULTS: p53 mutations, p53 expression, and tumor stage were sufficient to explain the variation in tumor responses to chemotherapy in multivariate models. p53 mutation was the only variable to significantly predict objective response (odds ratio, 0.23; 95% confidence interval, 0.10 to 0.57; P = .002) and was the strongest predictor of major response (odds ratio, 0.29; 95% confidence interval, 0.11 to 0.74; P = .006). p53 expression (odds ratio, 0.39; 95% confidence interval, 0.16 to 0.98) and tumor stage (odds ratio, 0.31; 95% confidence interval, 0.10 to 0.96) also predicted major response. Specific mutations (contact mutations) accounted for much of the reduction in the risk of major response associated with overall mutations. In complementary analyses, p53 expression was weakly predictive of major response in the subgroup with wild-type p53, and p53 mutations also predicted histologic response.

CONCLUSION: p53 gene mutations are strongly associated with a poor risk of both objective and major responses to chemotherapy. Contact mutations are associated with the lowest risk of major response to chemotherapy.
Sentinel Lymph Node Biopsy Is Accurate After Neoadjuvant Chemotherapy for Breast Cancer
Authors: Breslin Tara M. , Cohen Lisa , Sahin Aysegul , Fleming Jason B. , Kuerer Henry M. , Newman Lisa A. , Delpassand Ebrahim S. , House Rosalyn , Ames Frederick C. , Feig Barry W. , Ross Merrick I. , Singletary S. Eva , Buzdar Aman U. , Hortobagyi Gabriel N. , Hunt Kelly K.
Published: February 2017

PURPOSE: Sentinel lymph node (SLN) biopsy has proved to be an accurate method for detecting nodal micrometastases in previously untreated patients with early-stage breast cancer. We investigated the accuracy of this technique for patients with more advanced breast cancer after neoadjuvant chemotherapy.

PATIENTS AND METHODS: Patients with stage II or III breast cancer who had undergone doxorubicin-based neoadjuvant chemotherapy before breast surgery were eligible. Intraoperative lymphatic mapping was performed with peritumoral injections of blue dye alone or in combination with technetium-labeled sulfur colloid. All patients were offered axillary lymph node dissection. Negative sentinel and axillary nodes were subjected to additional processing with serial step sectioning and immunohistochemical staining with an anticytokeratin antibody to detect micrometastases.

RESULTS: Fifty-one patients underwent SLN biopsy after neoadjuvant chemotherapy from 1994 to 1999. The SLN identification rate improved from 64.7% to 94.1%. Twenty-two (51.2%) of the 43 successfully mapped patients had positive SLNs, and in 10 of those 22 patients (45.5%), the SLN was the only positive node. Three patients had false-negative SLN biopsy; that is, the sentinel node was negative, but at least one nonsentinel node contained metastases. Additional processing revealed occult micrometastases in four patients (three in sentinel nodes and one in a nonsentinel node).

CONCLUSION: SLN biopsy is accurate after neoadjuvant chemotherapy. The SLN identification improved with experience. False-negative findings occurred at a low rate throughout the series. This technique is a potential way to guide the axillary treatment of patients who are clinically node negative after neoadjuvant chemotherapy.
Routine Chest Roentgenography Is Unnecessary in the Work-Up of Stage I and II Breast Cancer
Authors: Chen E. Alexandra , Carlson Gregory A. , Coughlin Bret F. , Reed William P. , Garb Jane L. , Frank James L.
Published: February 2017

PURPOSE: Clinical practice guidelines of many professional societies call for routine staging chest x-rays (SCXR) for all patients with invasive cancer. Given the estimated 157,000 patients annually for whom this recommendation pertains, this screening examination represents a considerable health care expenditure. If it were shown that SCXR rarely changed the management of low-risk subsets of this population, it might be possible to selectively omit this practice from the care of these patients with substantial resultant cost savings.

PATIENTS AND METHODS: All patients with clinical stage I and II breast cancer presenting to the Baystate Medical Center from 1989 through 1997 were identified through the Tumor Registry. Their hospital records were reviewed for clinical presentation and documentation of SCXR.

RESULTS: One thousand four hundred ninety-four patients were identified with clinical stage I and II disease. SCXR were available for review on 1,003 patients. Only one asymptomatic patient was upstaged to stage IV based on a SCXR. Two patients with primary lung tumors were also identified. These data demonstrate an asymptomatic pulmonary metastasis detection rate of 0.099% (95% confidence interval, 0.0% to 0.6%). The total charges of SCXR for this group approached $180,000.

CONCLUSION: These data demonstrate the low diagnostic yield and high cost of routine SCXR in the management of asymptomatic patients with clinical stage I and stage II breast cancer. Because other studies have shown that SCXR changes neither quality of life nor overall survival, SCXR should be limited to symptomatic patients in whom metastatic disease is suspected.
Phase I Trial of 6-Hour Infusion of Glufosfamide, a New Alkylating Agent With Potentially Enhanced Selectivity for Tumors That Overexpress Transmembrane Glucose Transporters: A Study of the European Organization for Research and Treatment of Cancer Early Clinical Studies Group
Authors: Briasoulis Evangelos , Judson Ian , Pavlidis Nicholas , Beale Philip , Wanders Jantien , Groot Yvonne , Veerman Gijbert , Schuessler Martina , Niebch Georg , Siamopoulos Konstantinos , Tzamakou Eleftheria , Rammou Dimitra , Wolf Lisa , Walker Ruth , Hanauske Axel
Published: February 2017

PURPOSE: To determine the maximum-tolerated dose (MTD), the principal toxicities, and the pharmacokinetics of 6-hour infusion of glufosfamide (beta-d-glucosylisophosphoramide mustard; D-19575), a novel alkylating agent with the potential to target the glucose transporter system.

PATIENTS AND METHODS: Twenty-one patients (10 women and 11 men; median age, 56 years) with refractory solid tumors were treated with doses ranging from 800 to 6,000 mg/m2. Glufosfamide was administered every 3 weeks as a two-step (fast/slow) intravenous infusion over a 6-hour period. All patients underwent pharmacokinetic sampling at the first course.

RESULTS: The MTD was 6,000 mg/m2. At this dose, two of six patients developed a reversible, dose-limiting renal tubular acidosis and a slight increase in serum creatinine the week after the second and third courses of treatment, respectively, whereas three of six patients experienced short-lived grade 4 neutropenia/leukopenia. Other side effects were generally mild. Pharmacokinetics indicated linearity of area under the time–versus-concentration curve against dose over the dose range studied and a short elimination half-life. There was clear evidence of antitumor activity, with a long-lasting complete response of an advanced pancreatic adenocarcinoma and minor tumor shrinkage of two refractory colon carcinomas and one heavily pretreated breast cancer.

CONCLUSION: The principal toxicity of 6-hour infusion of glufosfamide is reversible renal tubular acidosis, the MTD is 6,000 mg/m2, and the recommended phase II dose is 4,500 mg/m2. Close monitoring of serum potassium and creatinine levels is suggested for patients receiving glufosfamide for early detection of possible renal toxicity. Evidence of antitumor activity in resistant carcinomas warrants further clinical exploration of glufosfamide in phase II studies.
Prognostic Factors in Metastatic Melanoma: A Pooled Analysis of Eastern Cooperative Oncology Group Trials
Authors: Manola Judith , Atkins Michael , Ibrahim Joseph , Kirkwood John
Published: February 2017

PURPOSE: To identify factors that are prognostic for survival in patients with metastatic melanoma treated in eight Eastern Cooperative Oncology Group (ECOG) trials conducted over the past 25 years.

METHODS: We identified common, significant patient characteristics collected at baseline on 1,362 eligible patients for inclusion in a pooled analysis. Proportional hazards models were used to examine simultaneously the effects of multiple covariates on survival.

RESULTS: Median survival was 6.4 months (95% confidence interval, 6.1 to 6.9 months.) Factors conferring the greatest increased risk of death included number of metastatic sites (relative risk [RR] = 1.12), ECOG performance status of 1 or more (RR = 1.49), or metastatic disease in the gastrointestinal (GI) tract (RR = 1.49), liver (RR = 1.44), pleura (RR = 1.35), or lung (RR = 1.19). Prior immunotherapy (RR = 0.84) and female sex (RR = 0.87) were associated with prolonged survival. Although only 12% of patients responded to protocol treatment, landmark analysis showed this to be a significant prognostic factor (RR = 0.57). A model based on three recent studies in which baseline values for alkaline phosphatase, lactate dehydrogenase (LDH), and platelets were available identified an increased number of sites of metastasis (RR = 1.30), abnormal LDH (RR = 1.89), abnormal alkaline phosphatase (RR = 1.76), abnormal platelets (RR = 1.63), and GI metastases (RR = 1.66) as prognostic for poorer survival. Response to treatment, when examined by landmark analysis of studies with laboratory parameters, was associated with decreased risk of death (RR = 0.47).

CONCLUSION: This study demonstrates the importance and utility of laboratory parameters as prognostic factors for survival and confirmed the deleterious effects of multiple metastatic sites. Prior immunotherapy and female sex were associated with improved prognosis. Prognostic factors identified in this analysis are consistent with the findings of prior published studies and argue for the adoption of laboratory findings in the staging systems that are used for entry and stratification of clinical trials in the future.
The United Kingdom Children’s Cancer Study Group’s Second Germ Cell Tumor Study: Carboplatin, Etoposide, and Bleomycin Are Effective Treatment for Children With Malignant Extracranial Germ Cell Tumors, With Acceptable Toxicity
Authors: Mann J.R. , Raafat F. , Robinson K. , Imeson J. , Gornall P. , Sokal M. , Gray E. , McKeever P. , Hale J. , Bailey S. , Oakhill A.
Published: February 2017

PURPOSE: To evaluate carboplatin, etoposide, and bleomycin (JEB) in children with malignant extracranial germ cell tumors (GCTs).

PATIENTS AND METHODS: Malignant GCTs in children aged 0 to 16 years were excised without major morbidity or otherwise biopsied. Stage I testicular and some ovarian GCTs were resected and monitored with alpha-fetoprotein (AFP) (“watch-and-wait” approach). Patients with recurrent stage I disease and all other patients received JEB (etoposide 120 mg/m2 on days 1 through 3, carboplatin 600 mg/m2 on day 2, and bleomycin 15 mg/m2 on day 3). Courses were administered every 3 to 4 weeks until remission, and then two more courses were given. Chemotherapy toxicities were assessed using World Health Organization or Brock grading.

RESULTS: Between January 1989 and December 1997, 192 patients were registered. Eight were excluded because either there was no histologic diagnosis (n = 3) or chemotherapy was given off-study (n = 5). The remaining 184 patients had germinoma (n = 20), malignant teratoma (n = 55), embryonal carcinoma (n = 1), yolk sac tumor (n = 107), or choriocarcinoma (n = 1). Forty-seven patients were treated with surgery alone, and 137 patients received JEB. The 5-year survival rate in March 1999 for all 184 patients was 93.2% (95% confidence interval [CI], 87.9% to 96.3%); for the 137 JEB-treated patients, it was 90.9% (95% CI, 83.9% to 95.0%), with an event-free survival rate of 87.8% (95% CI, 81.1% to 92.4%). The median follow-up after JEB treatment was 53 months (range, 0 to 109 months); the median number of courses was five (range, three to eight). Site, stage, and AFP level had prognostic significance. Nonfatal hematologic toxicity was common, but deafness and pulmonary and renal toxicities were rare. One child died of a thoracic tumor and bronchopulmonary dysplasia, and another died of acute myeloid leukemia.

CONCLUSION: Conservative surgery, a watch-and-wait approach after complete excision, and JEB for those requiring chemotherapy produced high cure rates and few serious complications.
Phase I Study of Chimeric Human/Murine Anti–Ganglioside GD2Monoclonal Antibody (ch14.18) With Granulocyte-Macrophage Colony-Stimulating Factor in Children With Neuroblastoma Immediately After Hematopoietic Stem-Cell Transplantation: A Children’s Cancer Group Study
Authors: Ozkaynak M. Fevzi , Sondel Paul M. , Krailo Mark D. , Gan Jacek , Javorsky Brad , Reisfeld Ralph A. , Matthay Katherine K. , Reaman Gregory H. , Seeger Robert C.
Published: February 2017

PURPOSE: Ganglioside GD2is strongly expressed on the surface of human neuroblastoma cells. It has been shown that the chimeric human/murine anti-GD2monoclonal antibody (ch14.18) can induce lysis of neuroblastoma cells by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The purposes of the study were (1) to determine the maximum-tolerated dose (MTD) of ch14.18 in combination with standard dose granulocyte-macrophage colony-stimulating factor (GM-CSF) for patients with neuroblastoma who recently completed hematopoietic stem-cell transplantation (HSCT), and (2) to determine the toxicities of ch14.18 with GM-CSF in this setting.

PATIENTS AND METHODS: Patients became eligible when the total absolute phagocyte count (APC) was greater than 1,000/μL after HSCT. ch14.18 was infused intravenously over 5 hours daily for 4 consecutive days. Patients received GM-CSF 250 μg/m2/d starting at least 3 days before ch14.18 and continued for 3 days after the completion of ch14.18. The ch14.18 dose levels were 20, 30, 40, and 50 mg/m2/d. In the absence of progressive disease, patients were allowed to receive up to six 4-day courses of ch14.18 therapy with GM-CSF. Nineteen patients with neuroblastoma were treated.

RESULTS: A total of 79 courses were administered. No toxic deaths occurred. The main toxicities were severe neuropathic pain, fever, nausea/vomiting, urticaria, hypotension, mild to moderate capillary leak syndrome, and neurotoxicity. Three dose-limiting toxicities were observed among six patients at 50 mg/m2/d: intractable neuropathic pain, grade 3 recurrent urticaria, and grade 4 vomiting. Human antichimeric antibody developed in 28% of patients.

CONCLUSION: ch14.18 can be administered with GM-CSF after HSCT in patients with neuroblastoma with manageable toxicities. The MTD is 40 mg/m2/d for 4 days when given in this schedule with GM-CSF.
LMCE3 Treatment Strategy: Results in 99 Consecutively Diagnosed Stage 4 Neuroblastomas in Children Older Than 1 Year at Diagnosis
Authors: Frappaz D. , Michon J. , Coze C. , Berger C. , Plouvier E. , Lasset C. , Bernard J.L. , Stephan J.L. , Bouffet E. , Buclon M. , Combaret V. , Fourquet A. , Philip T. , Zucker J.M.
Published: February 2017

PURPOSE: To tailor postinduction therapy for stage 4 neuroblastoma in children who are older than 1 year at diagnosis according to status after induction.

PATIENTS AND METHODS: From March 1987 to December 1992, 99 patients who were consecutively admitted were included in the Lyon-Marseille-Curie East of France (LMCE)3 strategy. After induction with the French Society of Pediatric Oncology NB87 regimen and surgery, patients who were in complete remission immediately proceeded to consolidation therapy with vincristine, melphalan, and fractionated total-body irradiation (VMT). All other patients underwent a postinduction strategy before VMT, either an additional megatherapy regimen or further chemotherapy with etoposide/carboplatin.

RESULTS: The progression-free survival (PFS) is 29% at 7 years from diagnosis, which compares favorably with that of a similar cohort of 72 patients previously reported by our group (LMCE1; PFS of 20% at 5 years and 8% at 14 years, P = .004). In the multivariate analysis, only age younger than 3 years at diagnosis (P = .0085) and achievement of complete or very good partial remission after NB87 and surgery (P = .00024) remained significant. The PFS of the 87 patients who were included in the postinduction strategy was significantly better than that of the comparable 62 patients on the LMCE1 study (32% v 11% at 7 years; P = .005).

CONCLUSION: The progressive improvements in the LMCE results over the last 10 years suggest that improvements in supportive care measures and increases in each component of this strategy (induction, postinduction, consolidation) may all contribute to increased survival rates.
Randomized Trial of Bone Marrow Versus Lenograstim-Primed Blood Cell Allogeneic Transplantation in Patients With Early-Stage Leukemia: A Report From the Société Française de Greffe de Moelle
Authors: Blaise Didier , Kuentz Mathieu , Fortanier Cecile , Bourhis Jean Henri , Milpied Noël , Sutton Laurent , Jouet Jean-Pierre , Attal Michel , Bordigoni Pierre , Cahn Jean-Yves , Boiron Jean-Michel , Schuller Marie-Pascale , Moatti Jean-Paul , Michallet Mauricette
Published: February 2017

PURPOSE: To compare hematologic recovery in patients receiving allogeneic blood cell transplantation (BCT) with those receiving allogeneic bone marrow transplantation (BMT).

PATIENTS AND METHODS: One hundred eleven patients with leukemia in the early stages and with HLA-matched sibling donors were randomized in this study. One hundred one underwent transplantation. Standard procedures for collection and transplantation were used. Patients did not receive prophylactic granulocyte colony-stimulating factor after undergoing transplantation. In addition to clinical end points being established, a prospective and comparative economic evaluation of the first 6 months after transplantation was performed.

RESULTS: Groups were balanced for patient, donor, and transplant characteristics. Blood cell collection led to the collection of a higher number of CD34+ and CD3+ cells than did bone marrow collection (P < 10−6) without reported side effects for the donor. Patients in the BCT group reached platelet counts of 25 and 50 × 109 platelets/L 8 and 11 days earlier than did the BMT group (P < 10−4 and P < 10−5), respectively. This resulted in fewer platelet transfusions during the first 180 days after transplantation (P = .002) for the former group. The time to reach neutrophil counts of 0.5 and 1 × 109 neutrophils/L was 6 and 7 days shorter, respectively, in the BCT group than in the BMT group (P < 10−5). This quicker hematologic recovery was associated with a shorter length of hospitalization and a decrease in total cost of procedure during the first 6 months.

CONCLUSION: This study establishes that allogeneic BCT results in quicker hematologic recovery but is associated with a higher occurrence of chronic graft-versus-host disease.
Comparison of Survival and Quality of Life in Advanced Non–Small-Cell Lung Cancer Patients Treated With Two Dose Levels of Paclitaxel Combined With Cisplatin Versus Etoposide With Cisplatin: Results of an Eastern Cooperative Oncology Group Trial
Authors: Bonomi Philip , Kim KyungMann , Fairclough Diane , Cella David , Kugler John , Rowinsky Eric , Jiroutek Michael , Johnson David
Published: February 2017

PURPOSE: Treatment with cisplatin-based chemotherapy provides a modest survival advantage over supportive care alone in advanced non–small-cell lung cancer (NSCLC). To determine whether a new agent, paclitaxel, would further improve survival in NSCLC, the Eastern Cooperative Oncology Group conducted a randomized trial comparing paclitaxel plus cisplatin to a standard chemotherapy regimen consisting of cisplatin and etoposide.

PATIENTS AND METHODS: The study was carried out by a multi-institutional cooperative group in chemotherapy-naive stage IIIB to IV NSCLC patients randomized to receive paclitaxel plus cisplatin or etoposide plus cisplatin. Paclitaxel was administered at two different dose levels (135 mg/m2 and 250 mg/m2), and etoposide was given at a dose of 100 mg/m2 daily on days 1 to 3. Each regimen was repeated every 21 days and each included cisplatin (75 mg/m2).

RESULTS: The characteristics of the 599 patients were well-balanced across the three treatment groups. Superior survival was observed with the combined paclitaxel regimens (median survival time, 9.9 months; 1-year survival rate, 38.9%) compared with etoposide plus cisplatin (median survival time, 7.6 months; 1-year survival rate, 31.8%; P = .048). Comparing survival for the two dose levels of paclitaxel revealed no significant difference. The median survival duration for the stage IIIB subgroup was 7.9 months for etoposide plus cisplatin patients versus 13.1 months for all paclitaxel patients (P = .152). For the stage IV subgroup, the median survival time for etoposide plus cisplatin was 7.6 months compared with 8.9 months for paclitaxel (P = .246).

With the exceptions of increased granulocytopenia on the low-dose paclitaxel regimen and increased myalgias, neurotoxicity, and, possibly, increased treatment-related cardiac events with high-dose paclitaxel, toxicity was similar across all three arms. Quality of life (QOL) declined significantly over the 6 months. However, QOL scores were not significantly different among the regimens.

CONCLUSION: As a result of these observations, paclitaxel (135 mg/m2) combined with cisplatin has replaced etoposide plus cisplatin as the reference regimen in our recently completed phase III trial.
Results of a Randomized Study of IM862 Nasal Solution in the Treatment of AIDS-Related Kaposi’s Sarcoma
Authors: Tulpule Anil , Scadden David T. , Espina Byron M. , Cabriales Suzanne , Howard Walter , Shea Kathleen , Gill Parkash S.
Published: February 2017

PURPOSE: Although advances have been made in the treatment of AIDS-related Kaposi’s sarcoma (AIDS-KS) with systemic chemotherapy, less toxic therapies are needed. IM862 is a naturally occurring peptide with antiangiogenic properties and was thus studied in patients with AIDS-KS.

PATIENTS AND METHODS: IM862 was given as intranasal drops at a dose of 5 mg. Patients were randomized to two dosing schedules given in repeated cycles until disease progression or unacceptable toxicity: 5 days of therapy followed by 5 days off (n = 18) and every other day dosing (n = 26).

RESULTS: Forty-two male patients and two female patients with a median age of 38 years (range, 22 to 53 years) were accrued. Twenty-one patients (47%) had more than 50 mucocutaneous lesions, 14 (32%) had lymphedema, and none had visceral involvement. Thirty-three patients (75%) had received prior systemic chemotherapy. Twenty-four patients (55%) had CD4+ lymphocyte count ≤ 200/mm3. All but five patients were being treated with concurrent protease inhibitor(s), for a median of 10 months (range, 0 to 24 months). Major responses were documented in 36%, with five complete and 11 partial remissions, occurring after a median of 6 weeks (range, 3 to 26 weeks) and lasting a median of 33+ weeks (range, 12+ to 95+ weeks). Twenty-one patients had stable disease for periods of 7 to 72+ weeks. Adverse effects to IM862 were limited to mild and transient headache, fatigue, tingling, and nausea. No hematologic adverse effects attributed to treatment were reported.

CONCLUSION: IM862 given as intranasal drops is well tolerated and has antitumor activity in patients with AIDS-KS. A randomized double-blinded study to define the activity of IM862 in patients with AIDS-KS is in progress.
Management of Breast Cancer After Hodgkin’s Disease
Authors: Wolden Suzanne L. , Hancock Steven L. , Carlson Robert W. , Goffinet Don R. , Jeffrey Stefanie S. , Hoppe Richard T.
Published: February 2017

PURPOSE: To evaluate the incidence, detection, pathology, management, and prognosis of breast cancer occurring after Hodgkin’s disease.

PATIENTS AND METHODS: Seventy-one cases of breast cancer in 65 survivors of Hodgkin’s disease were analyzed.

RESULTS: The median age at diagnosis was 24.6 years for Hodgkin’s disease and 42.6 years for breast cancer. The relative risk for invasive breast cancer after Hodgkin’s disease was 4.7 (95% confidence interval, 3.4 to 6.0) compared with an age-matched cohort. Cancers were detected by self-examination (63%), mammography (30%), and physician exam (7%). The histologic distribution paralleled that reported in the general population (85% ductal histology) as did other features (27% positive axillary lymph nodes, 63% positive estrogen receptors, and 25% family history). Although 87% of tumors were less than 4 cm, 95% were managed with mastectomy because of prior radiation. Two women underwent lumpectomy with breast irradiation. One of these patients developed tissue necrosis in the region of overlap with the prior mantle field. The incidence of bilateral breast cancer was 10%. Adjuvant systemic therapy was well tolerated; doxorubicin was used infrequently. Ten-year disease-specific survival was as follows: in-situ disease, 100%; stage I, 88%; stage II, 55%; stage III, 60%; and stage IV, zero.

CONCLUSION: The risk of breast cancer is increased after Hodgkin’s disease. Screening has been successful in detecting early-stage cancers. Pathologic features and prognosis are similar to that reported in the general population. Repeat irradiation of the breast can lead to tissue necrosis, and thus, mastectomy remains the standard of care in most cases.
Neoadjuvant Chemotherapy for Peripheral Malignant Neuroectodermal Tumor of Bone: Recent Experience at the Istituto Rizzoli
Authors: Bacci Gaetano , Ferrari Stefano , Bertoni Franco , Donati Davide , Bacchini Patrizia , Longhi Alessandra , Brach del Prever Adalberto , Forni Cristiana , Rimondini Simonetta
Published: February 2017

PURPOSE: The results achieved in 44 patients with nonmetastatic peripheral neuroectodermal tumor (PNET) of bone treated with neoadjuvant chemotherapy are reported.

PATIENTS AND METHODS: A six-drug regimen of chemotherapy (vincristine, doxorubicin, dactinomycin, cyclophosphamide, ifosfamide, and etoposide) was administered to all patients. Local treatment consisted of surgery in 20 patients, surgery followed by radiotherapy in 13, and radiotherapy only in 11.

RESULTS: At a mean follow-up of 4.5 years (range, 2 to 7 years), 23 patients (52%) remain event-free, 20 have relapsed (45%), and one has died of chemotherapy-related toxicity. The 5-year event-free survival and overall survival were 54.2% and 62.7%, respectively. To assess the prognostic significance of neural differentiation in the family of Ewing’s sarcoma, these results have been compared with the outcomes of 138 concomitant patients with typical Ewing’s sarcoma (TES) who were treated according to the same protocol. Of these, 103 (75%) remained continuously event-free, 34 (24%) relapsed, and one died of chemotherapy-related toxicity. It follows that PNET patients treated with this chemotherapy regimen have a significantly worse prognosis than typical ES patients (5-year event-free survival, 54.2% v 70.6%, P < .012; 5-year overall survival, 62.7% v 78.3%, P < .002).

CONCLUSION: The authors conclude that studies into new adjuvant therapy for Ewing’s sarcoma modulated according to risk of relapse should also consider neural differentiation as a risk factor.