bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I Study of a Decision Aid for Patients With Locally Advanced Non–Small-Cell Lung Cancer
Authors: Brundage M. D. , Feldman-Stewart D. , Cosby R. , Gregg R. , Dixon P. , Youssef Y. , Davies D. , Mackillop W. J.
Published: February 2017

PURPOSE: Many patients with locally advanced non–small-cell lung cancer (LA-NSCLC) are eligible for combined-modality therapy (CMT; chemotherapy and radiotherapy). Although CMT offers slightly higher chances of survival than radiotherapy alone (RT), it also carries a higher probability of toxicity, raising the possibility that some patients may prefer to decline CMT. We report a pilot study of a decision aid designed for patients in this setting.

PATIENTS AND METHODS: The aid included a structured description of the treatment options and trade-off exercises designed to help clarify the patient’s values for the relevant outcomes by determining the patient’s survival advantage threshold (SAT; the increase in survival conferred by CMT over RT that the patient deemed necessary for choosing CMT). Additional outcome measures included each patient’s strength of treatment preference, decisional conflict, objective understanding of survival information, and decisional role preference.

RESULTS: Twenty-seven patients met the eligibility criteria for the study. Of these, seven declined the decision aid because they had a clear treatment preference. The remaining 20 participants completed the decision aid; 18 chose CMT, and two chose RT. All 20 patients wished to participate in the decision to some extent. All patients reported that using the decision support was useful to them and recommended its use for others. No patient or physician reported that the aid interfered with the physician-patient relationship. Patients’ 3-year SATs and median SATs were each strongly correlated with their strengths of treatment preference (ρ = 0.83, P < .001 and ρ = 0.67, P = .02, respectively). For all but one patient, either their 3-year or median survival threshold was consistent with their final treatment choice. Ten patients reported a stronger treatment preference after using the decision aid.

CONCLUSION: We conclude that implementing the decision-aid for patients with LA-NSCLC is feasible, that it demonstrates convergent validity, and that it is favorably evaluated by patients and their physicians. The aid seems to help patients understand the benefits and risks of treatment and to choose the treatment that is most consistent with their values. Further evaluation of the aid is warranted.
Image-Aided Estimate of Tumor Burden in Hodgkin’s Disease: Evidence of Its Primary Prognostic Importance
Authors: Gobbi Paolo G. , Ghirardelli Maria L. , Solcia Marco , Di Giulio Giuseppe , Merli Francesco , Tavecchia Luisa , Bertè Raffaella , Davini Ottavio , Levis Alessandro , Broglia Chiara , Maffè Gabriella Carnevale , Ilariucci Fiorella , Dore Roberto , Ascari Edoardo
Published: February 2017

PURPOSE: To explore a more direct method for evaluating tumor burden (TB) in Hodgkin’s disease (HD) and to verify its prognostic importance.

PATIENTS AND METHODS: The volume of TB at diagnosis was directly and retrospectively measured in 121 HD patients through images of the lesions recorded by computed tomographic (CT) scan of the thorax, abdomen, and pelvis for all deep sites of involvement and many superficial ones, and by ultrasonography (US) for the remaining superficial lesions.

RESULTS: The TB, which was obtained from the sum of the volumes of all the lesions measured on CT scans and US and normalized to body-surface area (relative TB [rTB]), showed a median value of 102.6 cm3/m2 (range, 2.2 to 582.8). At multivariate analysis for prognostic value, rTB was the parameter that statistically correlated best with time to treatment failure (P = 2.2 × 10-6), followed by erythrocyte sedimentation rate (ESR) (P = .0003), and serum fibrinogen (P = .0112). The prognostic discrimination allowed by rTB alone proved to be clearly superior to that obtained with the score of the International Prognostic Factor Project. The rTB was found to be correlated with many clinical staging parameters (bulky disease, number of involved lymph node regions, serum lactate dehydrogenase, ESR, hemoglobin, Karnofsky index), but its predictability from these variables was low (R2 = .668).

CONCLUSION: Relative TB is emerging as a strong prognostic factor in HD, more powerful than and largely independent of those hitherto known and used. Further studies are needed to confirm these results and exploit their clinical value, particularly the relationship among rTB, drug doses, and response.
Pharmacokinetic Evaluation of N-[2-(Dimethylamino)Ethyl]Acridine-4-Carboxamide in Patients by Positron Emission Tomography
Authors: Saleem Azeem , Harte Robert J. , Matthews Julian C. , Osman Safiye , Brady Frank , Luthra Sajinder K. , Brown Gavin D. , Bleehen Norman , Connors Tom , Jones Terry , Price Pat M. , Aboagye Eric O.
Published: February 2017

PURPOSE: To evaluate tumor, normal tissue, and plasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA). The study aimed to determine the pharmacokinetics of carbon-11–labeled DACA ([11C]DACA) and evaluate the effect of pharmacologic doses of DACA on radiotracer kinetics.

PATIENTS AND METHODS: [11C]DACA (at 1/1,000 phase I starting dose) was administered to 24 patients with advanced cancer (pre–phase I) or during a phase I trial of DACA in five patients. Positron emission tomography (PET) was performed to assess pharmacokinetics and tumor blood flow. Plasma samples were analyzed for metabolite profile of [11C]DACA.

RESULTS: There was rapid systemic clearance of [11C]DACA over 60 minutes (1.57 and 1.46 L·min-1·m-2in pre–phase I and phase I studies, respectively) with the production of several radiolabeled plasma metabolites. Tumor, brain, myocardium, vertebra, spleen, liver, lung, and kidneys showed appreciable uptake of 11C radioactivity. The area under the time-versus-radioactivity curves (AUC) showed the highest variability in tumors. Of interest to potential toxicity, maximum radiotracer concentrations (Cmax) in brain and vertebra were low (0.67 and 0.54 m2·mL-1, respectively) compared with other tissues. A moderate but significant correlation was observed for tumor blood flow with AUC (r = 0.76; P = .02) and standardized uptake value (SUV) at 55 minutes (r = 0.79; P = .01). A decrease in myocardial AUC ( P = .03) and splenic and myocardial SUV ( P = .01 and .004, respectively) was seen in phase I studies. Significantly higher AUC, SUV, and Cmax were observed in tumors in phase I studies.

CONCLUSION: The distribution of [11C]DACA and its radiolabeled metabolites was observed in a variety of tumors and normal tissues. In the presence of unlabeled DACA, pharmacokinetics were altered in myocardium, spleen, and tumors. These data have implications for predicting activity and toxicity of DACA and support the use of PET early in drug development.
Detection of Occult Melanoma Cells in Paraffin-Embedded Histologically Negative Sentinel Lymph Nodes Using a Reverse Transcriptase Polymerase Chain Reaction Assay
Authors: Palmieri Giuseppe , Ascierto Paolo A. , Cossu Antonio , Mozzillo Nicola , Motti Maria L. , Satriano Sabrina M.R. , Botti Gerardo , Caracò Corrado , Celentano Egidio , Satriano Rocco A. , Lissia Amelia , Tanda Francesco , Pirastu Mario , Castello Giuseppe
Published: February 2017

PURPOSE: Detection of occult metastasis before the development of clinical disease could allow more accurate staging, appropriate follow-up procedures, and adjuvant therapies in patients with malignant melanoma (MM). The sentinel lymph node (SLN) has been proposed as a reliable predictor of metastatic disease in the lymphatic basin draining the primary melanoma. In this study, we screened both paraffin-embedded SLNs and peripheral-blood (PB) samples from MM patients at various stage of disease using a multimarker reverse transcriptase polymerase chain reaction (RT-PCR) assay. The prognostic significance of the presence of PCR-positive markers was also evaluated.

PATIENTS AND METHODS: Total RNA was obtained from paraffin-embedded SLN sections and PB samples of 75 MM patients. RT-PCR was performed using tyrosinase and MelanA/MART1 as melanoma-associated markers. Radiolabeled PCR products were analyzed on denaturing polyacrylamide gels.

RESULTS: Good sensitivity of the RT-PCR assay on archival tissues was demonstrated after comparison of RT-PCR results on frozen and paraffin-embedded SLNs from 16 MM patients. Significant correlation between the disease stage and marker expression in both PB and SLN samples was observed; the highest value was for patients who were positive for both markers in SLN (P = .006). Progression of disease was significantly associated with the total number of PCR-positive markers in both PB (P = .034) and SLN (P = .001) samples.

CONCLUSION: Although sensitivity is lowered by the use of paraffin-embedded specimens, our data indicate that RT-PCR analysis of serial sections from archival SLNs may be helpful in improving detection of occult micrometastases, thus improving staging of patients with melanoma.
Comparative Analysis of Micrometastasis to the Bone Marrow and Lymph Nodes of Node-Negative Breast Cancer Patients Receiving No Adjuvant Therapy
Authors: Braun Stephan , Cevatli B. Semeni , Assemi Cyamak , Janni Wolfgang , Kentenich Christina R.M. , Schindlbeck Christian , Rjosk Dorothea , Hepp Florian
Published: February 2017

PURPOSE: In node-negative patients, of whom up to 30% will recur within 5 years after diagnosis, markers are still needed that identify patients at high enough risk to warrant further adjuvant treatment. In the present study we analyzed whether a correlation exists between microscopic tumor cell spread to bone marrow and to lymph nodes and attempted to determine which route is clinically more important.

PATIENTS AND METHODS: According to a prospective design, bone marrow aspirates and axillary lymph nodes of level I (n = 1,590) from 150 node-negative patients with stage I or II breast cancer were analyzed immunocytochemically with monoclonal anticytokeratin (CK) antibodies. We investigated associations with prognostic factors and the effect of micrometastasis on patients’ prognosis.

RESULTS: CK-positive cells in bone marrow aspirates were present in 44 (29%) of 150 breast cancer patients, whereas only 13 patients (9%) had such positive findings in lymph nodes; simultaneous microdissemination to bone marrow and lymph nodes was seen in merely two patients. No correlation of bone marrow micrometastases with other risk factors was assessed. Reduced 4-year distant disease-free and overall survival were each associated with a positive bone marrow finding (P = .032 and P = .014, respectively) but not with lymph node micrometastasis. Multivariate analysis revealed an independent prognostic effect of bone marrow micrometastasis on survival, with a hazards ratio of 6.1 (95% confidence interval, 1.2 to 31.3) for cancer-related death (P = .031) in our series.

CONCLUSION: Immunocytochemical detection of micrometastatic cells in bone marrow but not in lymph nodes is an independent prognostic risk factor in node-negative breast cancer that may have implications for surgery and stratification into adjuvant therapy trials.
Platelet Transfusion for Patients With Cancer: Clinical Practice Guidelines of the American Society of Clinical Oncology*
Authors: Schiffer Charles A. , Anderson Kenneth C. , Bennett Charles L. , Bernstein Steven , Elting Linda S. , Goldsmith Miriam , Goldstein Michael , Hume Heather , McCullough Jeffery J. , McIntyre Rosemary E. , Powell Bayard L. , Rainey John M. , Rowley Scott D. , Rebulla Paolo , Troner Michael B. , Wagnon Alton H.
Published: February 2017

OBJECTIVE: To determine the most effective, evidence-based approach to the use of platelet transfusions in patients with cancer.

OUTCOMES: Outcomes of interest included prevention of morbidity and mortality from hemorrhage, effects on survival, quality of life, toxicity reduction, and cost-effectiveness.

EVIDENCE: A complete MedLine search was performed of the past 20 years of the medical literature. Keywords included platelet transfusion, alloimmunization, hemorrhage, threshold and thrombocytopenia. The search was broadened by articles from the bibliographies of selected articles.

VALUES: Levels of evidence and guideline grades were rated by a standard process. More weight was given to studies that tested a hypothesis directly related to one of the primary outcomes in a randomized design.

BENEFITS/HARMS/COST: The possible consequences of different approaches to the use of platelet transfusion were considered in evaluating a preference for one or another technique producing similar outcomes. Cost alone was not a determining factor.

RECOMMENDATIONS: Appendix A summarizes the recommendations concerning the choice of particular platelet preparations, the use of prophylactic platelet transfusions, indications for transfusion in selected clinical situations, and the diagnosis, prevention, and management of refractoriness to platelet transfusion.

VALIDATION: Five outside reviewers, the ASCO Health Services Research Committee, and the ASCO Board reviewed this document.

SPONSOR: American Society of Clinical Oncology
Postmastectomy Radiotherapy: Clinical Practice Guidelines of the American Society of Clinical Oncology*
Authors: Recht Abram , Edge Stephen B. , Solin Lawrence J. , Robinson David S. , Estabrook Alison , Fine Richard E. , Fleming Gini F. , Formenti Silvia , Hudis Clifford , Kirshner Jeffrey J. , Krause David A. , Kuske Robert R. , Langer Amy S. , Sledge George W. , Whelan Timothy J. , Pfister David G.
Published: February 2017

OBJECTIVE: To determine indications for the use of postmastectomy radiotherapy (PMRT) for patients with invasive breast cancer with involved axil-lary lymph nodes or locally advanced disease who receive systemic therapy. These guidelines are intended for use in the care of patients outside of clinical trials.

POTENTIAL INTERVENTION: The benefits and risks of PMRT in such patients, as well as subgroups of these patients, were considered. The details of the PMRT technique were also evaluated.

OUTCOMES: The outcomes considered included freedom from local-regional recurrence, survival (disease-free and overall), and long-term toxicity.

EVIDENCE: An expert multidisciplinary panel reviewed pertinent information from the published literature through July 2000; certain investigators were contacted for more recent and, in some cases, unpublished information. A computerized search was performed of MEDLINE data; directed searches based on the bibliographies of primary articles were also performed.

VALUES: Levels of evidence and guideline grades were assigned by the Panel using standard criteria. A “recommendation” was made when level I or II evidence was available and there was consensus as to its meaning. A “suggestion” was made based on level III, IV, or V evidence and there was consensus as to its meaning. Areas of clinical importance were pointed out where guidelines could not be formulated due to insufficient evidence or lack of consensus.

RECOMMENDATIONS: The recommendations, suggestions, and expert opinions of the Panel are described in this article.

VALIDATION: Seven outside reviewers, the American Society of Clinical Oncology (ASCO) Health Services Research Committee members, and the ASCO Board of Directors reviewed this document.
Lung Cancer After Hodgkin’s Disease: A Nested Case-Control Study of the Relation to Treatment
Authors: Swerdlow A. J. , Schoemaker M. J. , Allerton R. , Horwich A. , Barber J. A. , Cunningham D. , Lister T. A. , Rohatiner A. Z.S. , Vaughan Hudson G. , Williams M. V. , Linch D. C.
Published: February 2017

PURPOSE: To investigate the causes of the raised risk of lung cancer in patients who have had Hodgkin’s disease, and in particular the relationship to treatment.

PATIENTS AND METHODS: A nested case-control study was conducted within a cohort of 5,519 patients with Hodgkin’s disease treated in Britain during 1963 through 1993. For 88 cases of lung cancer and 176 matched control subjects, information on treatment and other risk factors was extracted from hospital case-notes, and odds ratios for lung cancer in relation to these factors were calculated.

RESULTS: Risk of lung cancer was borderline significantly greater in patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy than those who did not receive this treatment (relative risk [RR] = 1.66; 95% confidence interval [CI], 0.99 to 2.82), and increased with number of cycles of MOPP (P = .07). Exclusion of lung cancers for which histologic confirmation was not available strengthened these associations (RR = 2.41; 95% CI, 1.33 to 4.51; P = .004 for any MOPP and P = .007 for trend with number of cycles of MOPP). Risks were not raised, however, after chlorambucil, vinblastine, procarbazine, and prednisone treatment. There was evidence that the raised risk of lung cancer occurring in relation to radiotherapy was restricted to histologies other than adenocarcinoma.

CONCLUSION: The results suggest that MOPP chemotherapy may lead to elevated risk of lung cancer, at least in certain subgroups of patients. The role of chemotherapy in the etiology of lung cancer after Hodgkin’s disease deserves further investigation.
Improved Prognostication of Renal Cell Carcinoma Using an Integrated Staging System
Authors: Zisman Amnon , Pantuck Allan J. , Dorey Fredrick , Said Jonathan W. , Shvarts Oleg , Quintana Deanna , Gitlitz Barbara J. , deKernion Jean B. , Figlin Robert A. , Belldegrun Arie S.
Published: February 2017

PURPOSE: To integrate stage, grade, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) into a clinically useful tool capable of stratifying the survival of renal cell carcinoma (RCC) patients.

PATIENTS AND METHODS: The medical records of 661 patients undergoing nephrectomy at University of California Los Angeles between 1989 and 1999 were evaluated. Median age was 61 years, male-to-female ratio was 2.2:1, and median follow-up was 37 months. Survival time was the primary end point assessed. Sixty-four possible combinations of stage, grade, and ECOG PS were analyzed and collapsed into distinct groups. The internal validity of the categoriesd was challenged by a univariate analysis and a multivariate analysis testing for the accountability of each UCLA Integrated Staging System (UISS) category against independent variables shown to have impact on survival.

RESULTS: Combining and stratifying 1997 tumor-node-metastasis stage, Fuhrman’s grade and ECOG PS resulted in five survival stratification groups designated UISS, and numbered I to V. The projected 2- and 5-year survival for the UISS groups are as follows for the groups: I, 96% and 94%; II, 89% and 67%; III, 66% and 39%; IV, 42% and 23%; and V, 9% and 0%, respectively. UISS accounted for the significant variables in the variate analysis.

CONCLUSION: A novel system for staging and predicting survival for RCC integrating clinical variables is offered. UISS is simple to use and is superior to stage alone in differentiating patients’ survival. Our data suggests that UISS is an important prognostic tool for counseling patients with various stages of kidney cancer. Further prospective large-scale validation with external data is awaited.
Comparison of Methods of Measuring HER-2 in Metastatic Breast Cancer Patients Treated With High-Dose Chemotherapy
Authors: Harris Lyndsay N. , Liotcheva Vlayka , Broadwater Gloria , Ramirez Michael J. , Maimonis Peter , Anderson Steven , Everett Tajuana , Harpole David , Moore Mary Beth , Berry Donald A. , Rizzeri David , Vredenburgh James J. , Bentley Rex C.
Published: February 2017

PURPOSE: HER-2 is overexpressed in 20% to 30% of human breast cancer and is associated with poor outcome. Studies suggest an association between HER-2 overexpression and resistance to alkylating agents. To further evaluate this relationship, we assessed the interaction of HER-2, measured by different methods, and outcome after dose intensification with alkylating agents in metastatic breast cancer.

PATIENTS AND METHODS: From 1988 to 1995 at Duke University, 425 patients with metastatic breast cancer were enrolled in a study of high-dose alkylating agents (HDC) with autologous cellular support after doxorubicin-based therapy (AFM). HER-2 was measured in serum for shed extracellular domain (ECD) and in tissue by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH).

RESULTS: HER-2 ECD was positive in 29% (19 of 65) of patients pre-AFM and in 11.7% (34 of 290) pre-HDC. Higher pre-AFM and higher pre-HDC HER-2 ECD predicted worse overall survival (P = .045 and P = .0096, respectively). HER-2 overexpression by IHC and FISH showed no correlation with worse disease-free survival or overall survival. FISH and ECD were highly specific for IHC (97.3% and 97.7% respectively). However, ECD had a low sensitivity for IHC—only 22% of patients with HER-2 in the primary tumor shed ECD into the serum.

CONCLUSION: These data suggest that the method of measuring HER-2 is important in predicting clinical outcome. HER2 ECD may identify a poor prognosis subgroup of HER-2–positive tumors. Lack of association of HER2 by IHC/FISH with worse outcome suggests that therapy with AFM and/or HDC therapy may be able to overcome the effect of this prognostic factor or it may not be a prognostic factor in this setting.
Adenovirus-Mediated Wild-Type p53 Gene Transfer in Patients Receiving Chemotherapy for Advanced Non–Small-Cell Lung Cancer: Results of a Multicenter Phase II Study
Authors: Schuler Martin , Herrmann Richard , De Greve Jacques L.P. , Stewart A. Keith , Gatzemeier Ulrich , Stewart David J. , Laufman Leslie , Gralla Richard , Kuball Jürgen , Buhl Roland , Heussel Claus P. , Kommoss Friedrich , Perruchoud André P. , Shepherd Frances A. , Fritz Mary Ann , Horowitz Jo Ann , Huber Christoph , Rochlitz Christoph
Published: February 2017

PURPOSE: To study the additional benefit from adenoviral p53 gene therapy in patients undergoing first-line chemotherapy for advanced non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Twenty-five patients with nonresectable NSCLC were enrolled in an open-label, multicenter phase II study of three cycles of regimen A, carboplatin (area under the curve, 6; day 1) plus paclitaxel (175 mg/m2, day 1), or regimen B, cisplatin (100 mg/m2, day 1) plus vinorelbine (25 mg/m2, days 1, 8, 15, and 22) in combination with intratumoral injection of 7.5 × 1012 particles of SCH 58500 (rAd/p53, day 1). Responses of individual tumor lesions were assessed after each cycle, and gene transfer was examined in posttreatment tumor biopsies using reverse transcriptase polymerase chain reaction.

RESULTS: There was no difference between the response rate of lesions treated with p53 gene therapy in addition to chemotherapy (52% objective responses) and lesions treated with chemotherapy alone (48% objective responses). Subgroup analysis according to the chemotherapy regimens revealed evidence for increased mean local tumor regressions in response to additional p53 gene therapy in patients receiving regimen B, but not in patients receiving regimen A. There was no survival difference between the two chemotherapy regimens, and the median survival of the cohort was 10.5 months (1-year survival, 44%). Transgene expression was confirmed in tumor samples from 68% of patients, and toxicities attributable to gene therapy were mild to moderate.

CONCLUSION: Intratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.
Polymorphisms of the Repeated Sequences in the Enhancer Region of the Thymidylate Synthase Gene Promoter May Predict Downstaging After Preoperative Chemoradiation in Rectal Cancer
Authors: Villafranca Elena , Okruzhnov Yury , Dominguez Miguel A. , García-Foncillas Jesús , Azinovic Ignacio , Martínez Enrique , Illarramendi Jose J. , Arias Fernando , Martínez-Monge Rafael , Salgado Esteban , Angeletti Silvia , Brugarolas Antonio
Published: February 2017

PURPOSE: Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. TS gene promoter possesses regulatory tandemly repeated (TR) sequences that are polymorphic in humans, depending on ethnic factors. These polymorphisms have been reported to influence TS expression. TS expression levels affect tumor downstaging after preoperative fluoruracil (5-FU)–based chemoradiation. Tumor downstaging correlates with improved local control and disease-free survival. The aim of this study is to correlate TR polymorphisms with downstaging and disease-free survival.

PATIENTS AND METHODS: Sixty-five patients with rectal cancer underwent tumor resection after preoperative 5-FU–based chemoradiation. Tumor downstaging was evaluated by comparing the pretreatment T stage with the pathologic stage observed in the surgical specimen. TS polymorphism genotype was determined by polymerase chain reaction amplification of the corresponding TS promoter region, and products of amplification were electrophoresed, obtaining products of 220 bp (2/2), 248 bp (3/3), or both (2/3). The TS polymorphism genotype results were subsequently compared with the downstaging observed and with disease-free survival.

RESULTS: Patients who were homozygous for triple TR (3/3) had a lower probability of downstaging than patients who were homozygous with double TR or heterozygous patients (2/2 and 2/3): 22% versus 60% (P = .036; logistic regression). Furthermore, a trend toward improved 3-year disease-free survival was detected in the 2/2 and 2/3 groups, compared with that in the 3/3 group (81% v 41%; P = .17).

CONCLUSION: This preliminary study suggests that TS repetitive-sequence polymorphisms are predictive for tumor downstaging. TR sequences in TS promoter may be useful as a novel means of predicting response to preoperative 5-FU–based chemoradiation.
Clinical Trial Designs for the Early Clinical Development of Therapeutic Cancer Vaccines
Authors: Simon Richard M. , Steinberg Seth M. , Hamilton Michael , Hildesheim Allan , Khleif Samir , Kwak Larry W. , Mackall Crystal L. , Schlom Jeffrey , Topalian Suzanne L. , Berzofsky Jay A.
Published: February 2017

ABSTRACT: There are major differences between therapeutic tumor vaccines and chemotherapeutic agents that have important implications for the design of early clinical trials. Many vaccines are inherently safe and do not require phase I dose finding trials. Patients with advanced cancers and compromised immune systems are not good candidates for assessing either the toxicity or efficacy of therapeutic cancer vaccines. The rapid pace of development of new vaccine candidates and the variety of possible adjuvants and modifications in method of administration makes it important to use efficient designs for clinical screening and evaluation of vaccine regimens. We review the potential advantages of a wide range of clinical trial designs for the development of tumor vaccines. We address the role of immunological endpoints in early clinical trials of tumor vaccines, investigate the design implications of attempting to use disease stabilization as an end point and discuss the difficulties of reliably utilizing historical control data. Several conclusions for expediting the clinical development of effective cancer vaccines are proposed.
2000 Update of Recommendations for the Use of Tumor Markers in Breast and Colorectal Cancer: Clinical Practice Guidelines of the American Society of Clinical Oncology*
Authors: Bast Robert C. , Ravdin Peter , Hayes Daniel F. , Bates Susan , Fritsche Herbert , Jessup John M. , Kemeny Nancy , Locker Gershon Y. , Mennel Robert G. , Somerfield Mark R.
Published: February 2017

OBJECTIVE: To update the 1997 clinical practice guidelines for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast and colorectal cancers. These guidelines are intended for use in the care of patients outside of clinical trials.

OPTIONS: Six tumor markers for colorectal cancer and eight for breast cancer were considered. They could be recommended or not for routine use or for special circumstances. In addition to carcinoembryonic antigen (CEA) and CA 15-3, CA 27.29 was also considered among the serum tumor markers for breast cancer.

OUTCOMES: In general, the significant health outcomes identified for use in making clinical practice guidelines (overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness) were used.

EVIDENCE: A computerized literature search from 1994 to March 1999 was performed.

VALUES: The same values for use, utility, and levels of evidence were used by the committee.

BENEFITS, HARMS, AND COSTS: The same benefit, harms, and costs were used.

RECOMMENDATION: Changes were recommended (see Appendix).

VALIDATION: The updated recommendations were validated by external review by the American Society of Clinical Oncology’s (ASCO’s) Health Services Research Committee and by ASCO’s Board of Directors.

SPONSOR: American Society of Clinical Oncology.
Value of High-Dose Cytarabine During Interval Therapy of a Berlin-Frankfurt-Munster–Based Protocol in Increased-Risk Children With Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma: Results of the European Organization for Research and Treatment of Cancer 58881 Randomized Phase III Trial
Authors: Millot F. , Suciu S. , Philippe N. , Benoit Y. , Mazingue F. , Uyttebroeck A. , Lutz P. , Mechinaud F. , Robert A. , Boutard P. , Marguerite G. , Ferster A. , Plouvier E. , Rialland X. , Behard C. , Plantaz D. , Dresse M. F. , Philippet P. , Norton L. , Thyss A. , Dastugue N. , Waterkeyn C. , Vilmer E. , Otten J. ,   for the Children’s Leukemia Cooperative Group of the European Organization for Research and Treatment of Cancer
Published: February 2017

PURPOSE: The European Organization for Research and Treatment of Cancer 58881 study was designed to test in a prospective multicentric randomized trial the value of high-dose (HD) intravenous (IV) cytarabine (Ara-C) added to HD IV methotrexate (MTX) to reduce the incidence of CNS and systemic relapses in children with increased-risk acute lymphoblastic leukemia (ALL) or stage III and IV lymphoblastic lymphoma treated with a Berlin-Frankfurt-Munster (BFM)–based regimen.

PATIENTS AND METHODS: After completion of induction-consolidation phase, children with increased-risk (risk factor > 0.8 or T-lineage) ALL or stage III and IV lymphoblastic lymphoma were randomized to receive four courses of HD MTX (5 g/m2 over 24 hours every 2 weeks) and four intrathecal administrations of MTX (Arm A) or the same treatment schedule with additional HD IV Ara-C (1 g/m2 in bolus injection 12 and 24 hours after the start of each MTX infusion) (Arm B).

RESULTS: Between January 1990 and January 1996, 653 patients with ALL (593 patients) or lymphoblastic lymphoma (60 patients) were randomized: 323 were assigned to Arm A (without Ara-C) and 330 to Arm B (with Ara-C). A total of 190 events (177 relapses and 13 deaths without relapse) were reported, and the median follow up was 6.5 years (range, 2 to 10 years). The incidence rates of CNS relapse were similar in both arms whether isolated (5.6% and 3.3%, respectively) or combined (5.3% and 4.6%, respectively). The estimated 6-year disease-free survival (DFS) rate was similar (log-rank P = .67) in the two treatment groups: 70.4% (SE = 2.6%) in Arm A and 71.0% (SE = 2.5%) in Arm B. The 6-year DFS rate was similar for ALL and LL patients: 70.2% (SE = 1.9%) versus 76.3% (SE = 5.6%).

CONCLUSION: Prevention of CNS relapse was satisfactorily achieved with HD IV MTX and intrathecal injections of MTX in children with increased-risk ALL or stage III and IV lymphoblastic lymphoma treated with our BFM-based treatment protocol in which cranial irradiation was omitted. Disappointingly, with the dose schedule used in this protocol, HD Ara-C added to HD MTX, although well tolerated, failed to further decrease the incidence of CNS relapse or to improve the overall DFS.
Esophageal Cancer: The Mode of Lymphatic Tumor Cell Spread and Its Prognostic Significance
Authors: Hosch Stefan B. , Stoecklein Nikolas H. , Pichlmeier U. , Rehders Alexander , Scheunemann Peter , Niendorf Axel , Knoefel Wolfram T. , Izbicki Jakob R.
Published: February 2017

PURPOSE: Data on skip metastases and their significance are lacking for esophageal cancer. This issue is important to determine the extent of lymphadenectomy for esophageal resection. In this study we examined the lymphatic spread in esophageal cancer by routine histopathology and by immunohistochemistry.

PATIENTS AND METHODS: A total of 1,584 resected lymph nodes were obtained from 86 patients with resected esophageal carcinoma and evaluated by routine histopathology. Additionally, frozen tissue sections of 540 lymph nodes classified as tumor-free by routine histopathology were screened for micrometastases by immunohistochemistry with the monoclonal antibody Ber-EP4. The lymph nodes were mapped according to the mapping scheme of the American Thoracic Society modified by Casson et al.

RESULTS: Forty-four patients (51%) had pN1 disease, and 61 patients (71%) harbored lymphatic micrometastases detected by immunohistochemistry. Skip metastases detected by routine histopathology were present in 34% of pN1 patients. Skipping of micrometastases detected by immunohistochemistry was found in 66%. The presence of micrometastases was associated with a significantly decreased relapse-free and overall survival (56.0 v 10.0 months and > 64 v 15 months, P < .0001 and P = .004, respectively). Cox regression analysis revealed the independent prognostic influence of micrometastases in lymph nodes. Lymph node skipping had no significant independent prognostic influence on survival.

CONCLUSION: Histopathologically and immunohistochemically detectable skip metastases are a frequent event in esophageal cancer. Only extensive lymph node sampling, in conjunction with immunohistochemical evaluation, will lead to accurate staging. An improved staging system is essential for more individualized adjuvant therapy.
S-Phase Fraction and Urokinase Plasminogen Activator Are Better Markers for Distant Recurrences Than Nottingham Prognostic Index and Histologic Grade in a Prospective Study of Premenopausal Lymph Node–Negative Breast Cancer
Authors: Malmström P. , Bendahl P-O. , Boiesen P. , Brünner N. , Idvall I. , Fernö M.
Published: February 2017

PURPOSE: Histologic grade, Nottingham Prognostic Index (NPI), estrogen receptor (ER) and progesterone receptor (PgR) status, and tumor size have previously been shown to be important prognostic indicators for distant recurrence of breast cancer. The purpose of this study was to compare the prognostic value of these factors with flow cytometric S-phase fraction (SPF), urokinase plasminogen activator (uPA), and plasminogen activator inhibitor type 1 (PAI-1) in premenopausal patients with lymph node–negative breast cancer.

PATIENTS AND METHODS: In 237 consecutive premenopausal patients with lymph node–negative breast cancer and freshly frozen tumor material available, SPF, ER and PgR status, uPA and its inhibitor PAI-1, histologic grade, and NPI were evaluated.

RESULTS: SPF was univariately the most powerful prognostic factor for distant recurrence, followed by uPA, histologic grade, PgR, age, ER, NPI, and PAI-1, the latter being nonsignificant. Multivariate analysis revealed that neither NPI nor histologic grade was significant after adjustment for SPF, a fact that may be explained by the strong association between these factors. uPA was, however, an independent prognostic factor in addition to SPF, NPI, or histologic grade.

CONCLUSION: In this prospective study, SPF and uPA were found to be independent prognostic factors in premenopausal women with lymph node–negative breast cancer. We suggest that SPF, if performed under standardized conditions, can replace histologic grade as a selection instrument for adjuvant medical treatment. The value of the combination of SPF and uPA needs to be confirmed in an independent prospective trial.
Ondansetron Plus Metopimazine Compared With Ondansetron Plus Metopimazine Plus Prednisolone as Antiemetic Prophylaxis in Patients Receiving Multiple Cycles of Moderately Emetogenic Chemotherapy
Authors: Sigsgaard T. , Herrstedt J. , Handberg J. , Kjær M. , Dombernowsky P.
Published: February 2017

PURPOSE: To compare the antiemetic efficacy and tolerability of ondansetron plus metopimazine with ondansetron plus metopimazine plus prednisolone during nine cycles of moderately emetogenic chemotherapy.

PATIENTS AND METHODS: A total of 221 women with stage I or II breast cancer and no prior chemotherapy who were scheduled to receive adjuvant chemotherapy with intravenous cyclophosphamide, fluorouracil and methotrexate or cyclophosphamide, epirubicin, and fluorouracil given every 3 weeks were included in a double-blind parallel trial. Patients were randomized to 3 days of oral treatment with ondansetron plus metopimazine, or ondansetron plus metopimazine plus prednisolone. Ondansetron was administered as 8 mg bid, metopimazine as 30 mg qid, and prednisolone as 50 mg qd.

RESULTS: In all, 216 patients (97.7%) were assessable for efficacy during a total of 1,462 cycles. In cycle 1, complete protection from emetic episodes/nausea day 1, days 2 through 5, and days 1 through 5 was achieved in 84.4%/51.4%, 82.6%/41.3%, and 79.8%/34.9% with ondansetron plus metopimazine and in 84.1%/57.0%, 86.8%/53.8%, and 79.4%/43.0% with ondansetron plus metopimazine plus prednisolone, respectively. In cycle 1, the three-drug combination was superior only in the treatment of nausea on days 2 through 5 (P = .0497). The cumulative emetic protection rate after nine cycles was 0.52 with ondansetron plus metopimazine and 0.75 with ondansetron plus metopimazine plus prednisolone. Side effects were generally few and mild with both treatments. Constipation was the only adverse event significantly more frequent with the three-drug combination (P = .029).

CONCLUSION: Ondansetron plus metopimazine plus prednisolone is highly effective and superior to ondansetron plus metopimazine during nine cycles of moderately emetogenic chemotherapy.
Topotecan Versus Observation After Cisplatin Plus Etoposide in Extensive-Stage Small-Cell Lung Cancer: E7593—A Phase III Trial of the Eastern Cooperative Oncology Group
Authors: Schiller Joan H. , Adak Sudeshna , Cella David , DeVore Russell F. , Johnson David H.
Published: February 2017

PURPOSE: To determine the efficacy of topotecan in combination with standard chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer (SCLC), the Eastern Cooperative Oncology Group (ECOG) conducted a phase III trial.

PATIENTS AND METHODS: Eligible patients had measurable or assessable disease and an ECOG performance status of 0 to 2; stable brain metastases were allowed. All patients received four cycles of cisplatin and etoposide every 3 weeks (step 1; PE). Patients with stable or responding disease were then randomized to observation or four cycles of topotecan (1.5 mg/m2/d for 5 days, every 3 weeks; step 2). A total of 402 eligible patients were registered to step 1, and 223 eligible patients were registered to step 2 (observation, n = 111; topotecan, n = 112).

RESULTS: Complete and partial response rates to induction PE were 3% and 32%, respectively. A 7% response rate was observed with topotecan (complete response, 2%; partial response, 5%). The median survival time for all 402 eligible patients was 9.6 months. Progression-free survival (PFS) from date of randomization on step 2 was significantly better with topotecan compared with observation (3.6 months v 2.3 months; P < .001). However, overall survival from date of randomization on step 2 was not significantly different between the observation and topotecan arms (8.9 months v 9.3 months; P = .43). Grade 4 neutropenia and thrombocytopenia occurred in 50% and 3%, respectively, of PE patients in step 1 and 60% and 13% of topotecan patients in step 2. Grade 4/5 infection was observed in 4.6% of PE patients and 1.8% of topotecan patients. Grade 3/4 anemia developed in 22% of patients who received topotecan. No difference in quality of life between topotecan and observation was observed at any assessment time or for any of the subscale scores.

CONCLUSION: Four cycles of PE induction therapy followed by four cycles of topotecan improved PFS but failed to improve overall survival or quality of life in extensive-stage SCLC. Four cycles of standard PE remains an appropriate first-line treatment for extensive-stage SCLC patients with good performance status.
Prospective Study on Quality of Life Before and After Radical Radiotherapy in Non–Small-Cell Lung Cancer
Authors: Langendijk J. A. , Aaronson N. K. , de Jong J. M.A. , ten Velde G. P.M. , Muller M. J. , Lamers R. J. , Slotman B. J. , Wouters E. F.M.
Published: February 2017

PURPOSE: The purpose of this study was to investigate changes in respiratory symptoms and quality of life (QoL) in patients with non–small-cell lung cancer (NSCLC) receiving radical radiotherapy (60 Gy). Additionally, the association between the level of symptom relief and objective tumor response, as well as with radiation-induced pulmonary changes, was investigated.

PATIENTS AND METHODS: One hundred sixty-four patients were entered onto this prospective study. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and EORTC QLQ-LC13 were used to investigate changes in QoL. Assessments were performed before radiotherapy and 2 weeks, 6 weeks, 3 months, 6 months, and 12 months after the completion of radiotherapy.

RESULTS: The QoL response rates were excellent for hemoptysis (83%); good for chest pain (68%), arm/shoulder pain (63%), and appetite loss (60%); and poor for dyspnea (37%), cough (31%), and fatigue (28%). The QoL response rates for the five functioning scales of the QLQ-C30 varied from 35% for physical and role functioning to 55% for social and cognitive functioning. The response rate for global QoL was 36%. A significant association was found between tumor response and palliation of chest pain, arm/shoulder pain, and physical functioning. During radiotherapy, a significant increase for most general symptoms and a deterioration in functioning and QoL were noted.

CONCLUSION: This study is the first to describe palliation and changes in QoL in radically irradiated patients with NSCLC. Radical radiotherapy offers palliation of respiratory symptoms and improved QoL in a substantial proportion of patients with NSCLC who have relatively good prognostic features. Although tumor reduction is associated with palliation of respiratory symptoms, it cannot serve as a surrogate for palliation.
Evaluation of the Combination of Nelarabine and Fludarabine in Leukemias: Clinical Response, Pharmacokinetics, and Pharmacodynamics in Leukemia Cells
Authors: Gandhi Varsha , Plunkett William , Weller Steve , Du Min , Ayres Mary , Rodriguez Carlos O. , Ramakrishna Prameen , Rosner Gary L. , Hodge Jeff P. , O’Brien Susan , Keating Michael J.
Published: February 2017

PURPOSE: A pilot protocol was designed to evaluate the efficacy of fludarabine with nelarabine (the prodrug of arabinosylguanine [ara-G]) in patients with hematologic malignancies. The cellular pharmacokinetics was investigated to seek a relationship between response and accumulation of ara-G triphosphate (ara-GTP) in circulating leukemia cells and to evaluate biochemical modulation of cellular ara-GTP metabolism by fludarabine triphosphate.

PATIENTS AND METHODS: Nine of the 13 total patients had indolent leukemias, including six whose disease failed prior fludarabine therapy. Two patients had T-acute lymphoblastic leukemia, one had chronic myelogenous leukemia, and one had mycosis fungoides. Nelarabine (1.2 g/m2) was infused on days 1, 3, and 5. On days 3 and 5, fludarabine (30 mg/m2) was administered 4 hours before the nelarabine infusion. Plasma and cellular pharmacokinetic measurements were conducted during the first 5 days.

RESULTS: Seven patients had a partial or complete response, six of whom had indolent leukemias. The disease in four responders had failed prior fludarabine therapy. The median peak intracellular concentrations of ara-GTP were significantly different (P = .001) in responders (890 μmol/L, n = 6) and nonresponders (30 μmol/L, n = 6). Also, there was a direct relationship between the peak fludarabine triphosphate and ara-GTP in each patient (r = 0.85). The cellular elimination of ara-GTP was slow (median, 35 hours; range, 18 to > 48 hours). The ratio of ara-GTP to its normal counterpart, deoxyguanosine triphosphate, was higher in each patient (median, 42; range, 14 to 1,092) than that of fludarabine triphosphate to its normal counterpart, deoxyadenosine triphosphate (median, 2.2; range, 0.2 to 27).

CONCLUSION: Fludarabine plus nelarabine is an effective, well-tolerated regimen against leukemias. Clinical responses suggest the need for further exploration of nelarabine against fludarabine-refractory diseases. Determination of ara-GTP levels in the target tumor population may provide a prognostic test for the activity of nelarabine.
Rituximab Dose-Escalation Trial in Chronic Lymphocytic Leukemia
Authors: O’Brien Susan M. , Kantarjian Hagop , Thomas Deborah A. , Giles Francis J. , Freireich Emil J. , Cortes Jorge , Lerner Susan , Keating Michael J.
Published: February 2017

PURPOSE: To conduct a dose-escalation trial of rituximab in patients with chronic lymphocytic leukemia (CLL) to define the maximum-tolerated dose (MTD), to evaluate first-dose reactions in patients with high circulating lymphocyte counts, and to assess the efficacy at higher versus lower doses.

PATIENTS AND METHODS: Fifty patients with CLL (n = 40) or other mature B-cell lymphoid leukemias (n = 10) were treated with four weekly infusions of rituximab. The first dose was 375 mg/m2 for all patients; dose- escalation began with dose 2 but was held constant for each patient. Escalated doses were from 500 to 2,250 mg/m2.

RESULTS: Toxicity with the first dose (375 mg/m2) was noted in 94% of patients but was grade 1 or 2 in most, predominantly fever and chills. Six patients (12%) experienced severe toxicity with the first dose, including fever, chills, dyspnea, and hypoxia in all six patients, hypotension in five, and hypertension in one. Toxicity on subsequent doses was minimal until a dose of 2,250 mg/m2 was achieved. Eight (67%) of 12 patients had grade 2 toxicity, including fever, chills, nausea, and malaise, although no patient had grade 3 or 4 toxicity. Severe toxicity with the first dose was significantly more common in patients with other B-cell leukemias, occurring in five (50%) of 10 patients versus one (2%) of 40 patients with CLL (P < .001). The overall response rate was 40%; all responses in patients with CLL were partial remissions. Response rates were 36% in CLL and 60% in other B-cell lymphoid leukemias. Response was correlated with dose: 22% for patients treated at 500 to 825 mg/m2, 43% for those treated at 1,000 to 1,500 mg/m2, and 75% for those treated at the highest dose of 2,250 mg/m2 (P = .007). The median time to disease progression was 8 months. Myelosuppression and infections were uncommon.

CONCLUSION: Rituximab has significant activity in patients with CLL at the higher dose levels. Severe first-dose reactions were uncommon in patients with CLL, even with high circulating lymphocyte counts, but were frequent in patients with other mature B-cell leukemias in which CD20 surface expression is increased. Efficacy of rituximab was also significant in this group of patients.