bluuebunny/crossref_metadata_2025 huggingface dataset:
Trauma History as a Predictor of Psychologic Symptoms in Women With Breast Cancer
Authors: Green Bonnie L. , Krupnick Janice L. , Rowland Julia H. , Epstein Steven A. , Stockton Patricia , Spertus Ilyse , Stern Nicole
Published: February 2017

PURPOSE: To identify predictors of psychiatric problems in women with early-stage breast cancer.

PATIENTS AND METHODS: One hundred sixty women with early-stage breast cancer were recruited from three treatment centers. They filled out self-report questionnaires, including a medical history and demographic survey, the Trauma History Questionnaire, Life Event Questionnaire, Brief Symptom Inventory, Beck Depression Inventory, and Duke-UNC Functional Social Support Questionnaire, and were evaluated using the Structured Clinical Interview for DSM-III-R.

RESULTS: Hierarchical regression analyses indicated that four of five variable sets made a significant incremental contribution to outcome prediction, with 35% to 37% of the variance explained. Outcomes were predicted by demographic variables, trauma history variables, precancer psychiatric diagnosis, recent life events, and perceived social support. Cancer treatment variables did not predict outcome.

CONCLUSION: The findings highlight the important roles of trauma history and recent life events in adjustment to cancer and have implications for screening and treatment.
Matrix Metalloproteinases: Biologic Activity and Clinical Implications
Authors: Nelson Amy R. , Fingleton Barbara , Rothenberg Mace L. , Matrisian Lynn M.
Published: February 2017

ABSTRACT: Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in specific steps of the metastatic cascade. As scientific understanding of the MMPs has advanced, therapeutic strategies that capitalize on blocking the enzymes have rapidly developed. The preclinical and clinical evolution of the synthetic MMP inhibitors (MMPIs) is also examined, with the discussion encompassing important methodologic issues associated with determining clinical efficacy of MMPIs and other novel therapeutic agents.
Sequential Dose-Intensive Paclitaxel, Ifosfamide, Carboplatin, and Etoposide Salvage Therapy for Germ Cell Tumor Patients
Authors: Motzer Robert J. , Mazumdar Madhu , Sheinfeld Joel , Bajorin Dean F. , Macapinlac Homer A. , Bains Manjit , Reich Lilian , Flombaum Carlos , Mariani Tania , Tong William P. , Bosl George J.
Published: February 2017

PURPOSE: To evaluate the efficacy and toxicity of sequential, dose-intensified chemotherapy with paclitaxel/ifosfamide and carboplatin/etoposide administered plus peripheral blood–derived stem-cell (PBSC) support for patients with germ cell tumors (GCT) who have unfavorable prognostic features in response to conventional-dose salvage programs. Carboplatin was dose escalated by target area under the curve (AUC; in [milligrams per milliliter] × minutes) among patient cohorts, and pharmacokinetic studies were performed for comparison.

PATIENTS AND METHODS: Thirty-seven previously treated patients who had cisplatin-resistant GCT and unfavorable prognostic features for response to conventional-dose salvage therapy were treated. Two cycles of paclitaxel 200 mg/m2 plus ifosfamide 6 g/m2 were given 2 weeks apart with leukapheresis, followed by three cycles of carboplatin plus etoposide given 14 to 21 days apart with reinfusion of PBSCs. The dose of etoposide was 1,200 mg/m2, and the carboplatin target AUC ranged among cohorts from 12 to 32 (mg/mL) × min. Pharmacokinetic studies of carboplatin were performed for comparison of target to measured AUC.

RESULTS: Twenty-one patients (57%) achieved a complete response and an additional two patients (5%) achieved a partial response with normal tumor markers; therefore, 23 (62%) achieved a favorable response. Eight patients relapsed, and 15 (41%) of the favorable responses remained durable at a median follow-up of 30 months. Myelosuppression was the major toxicity; 58% of carboplatin/etoposide cycles were associated with hospitalization for nadir fever. The AUC of carboplatin measured in serum was lower than the target AUC; this may be related to underestimation of the glomerular filtration rate used in the dosing formula.

CONCLUSION: Dose-intense therapy with sequential, accelerated chemotherapy of paclitaxel/ifosfamide and carboplatin/etoposide administered with PBSC support was relatively well tolerated. The durable complete response proportion was substantial in patients with unfavorable prognostic features for achieving durable complete response to conventional-dose salvage programs. Optimal dosing of carboplatin in the high-dose setting warrants further investigation.
Results of Treatment After Relapse From High-Dose Chemotherapy in Germ Cell Tumors
Authors: Porcu Pierluigi , Bhatia Sumeet , Sharma Matt , Einhorn Lawrence H.
Published: February 2017

PURPOSE: To identify therapy-related or patient-related characteristics that predict response and long-term survival after failure of high-dose chemotherapy (HDCT) for germ cell tumors (GCT).

PATIENTS AND METHODS: Between 1986 and 1997, 101 GCT patients relapsed after high-dose carboplatin and etoposide (VP-16) at Indiana University (Indianapolis, IN). Median time to relapse was 10 months (range, 1 to 17 months). HDCT was the first salvage treatment in 29 patients and second or later salvage treatment in 72 patients.

RESULTS: Fifty-four of 101 patients received post-HDCT treatment. Of these, 47 received chemotherapy, alone (n = 35) or in combination with surgery (n = 12). Seven patients underwent surgery alone. There were only 12 objective responses (three complete and nine partial responses) for 66 chemotherapy regimens given to 47 patients, for an overall response rate of 18.2%. Fifteen patients received platinum-based chemotherapy, with only one objective response. Chemotherapy was discontinued in 17% of cases because of toxicity. A longer interval between HDCT and post-HDCT treatment was the only variable that was associated with response. Five patients (4.9%) are disease-free at 30, 53, 57, 85, and 93 months after relapse. Of these, three responded to oral VP-16 and underwent resection of residual mediastinal, retroperitoneal, and inguinal cancer, respectively. One had resection of residual mediastinal yolk sac tumor, followed by oral VP-16. One relapsed with teratoma and received thoracoabdominal resection without chemotherapy.

CONCLUSION: Patients who experience disease progression after HDCT often receive further chemotherapy and/or surgery. Chemotherapy resulted in a response rate of less than 20%, with only three complete responses. All of the long-term survivors (4.9%) had surgery as a component of their post-HDCT regimen.
Oxaliplatin or Paclitaxel in Patients With Platinum-Pretreated Advanced Ovarian Cancer: A Randomized Phase II Study of the European Organization for Research and Treatment of Cancer Gynecology Group
Authors: Piccart Martine J. , Green John A. , Lacave Angel Jimenez , Reed Nick , Vergote Ignace , Benedetti-Panici Pierluigi , Bonetti Andrea , Kristeller-Tome Vera , Fernandez Cesar Mendiola , Curran Desmond , Van Glabbeke Martine , Lacombe Denis , Pinel Marie-Claire , Pecorelli Serge
Published: February 2017

PURPOSE: This was a multicentric, open, randomized, phase II study of single-agent paclitaxel and oxaliplatin to evaluate the efficacy of oxaliplatin in a relapsing progressive ovarian cancer patient population and to analyze the safety profile and impact of both agents on quality of life, time to progression, and survival.

PATIENTS AND METHODS: Eighty-six patients with platinum-pretreated advanced ovarian cancer were randomly assigned to two arms: 41 received paclitaxel at 175 mg/m2 over 3 hours every 3 weeks, and 45 received oxaliplatin at 130 mg/m2 over 2 hours every 3 weeks. For inclusion, patients had to have a performance status of 0 to 2 and to have received at least one and no more than two prior cisplatin- and/or carboplatin-containing chemotherapy regimens within the last 12 months.

RESULTS: Seven confirmed responses were observed in each arm, for an overall response rate in the total treated population of 17% (95% confidence interval [CI], 7% to 32%) in the paclitaxel arm and 16% (95% CI, 7% to 29%) in the oxaliplatin arm. Median time to progression was 14 weeks and 12 weeks, and overall survival was 37 weeks and 42 weeks in the paclitaxel and oxaliplatin arms, respectively. Among 63 patients with a 0- to 6-month progression-free, platinum-free interval, there were five objective responses with paclitaxel in 31 patients and two objective responses with oxaliplatin in 32 patients. Nine patients (22%) in the paclitaxel arm had grade 3 or 4 neutropenia (National Cancer Institute of Canada [NCIC] Common Toxicity Criteria). Two patients (4%) experienced grade 3 thrombocytopenia in the oxaliplatin arm. Maximum grade (grade 3) NCIC neurosensory toxicity was experienced by three patients (7%) in the paclitaxel arm and by four patients (9%) in the oxaliplatin arm.

CONCLUSION: Single-agent oxaliplatin at 130 mg/m2 every 3 weeks is active with moderate toxicity in patients with cisplatin-/carboplatin-pretreated advanced ovarian cancer.
Factors That Predict the Referral of Breast Cancer Patients Onto Clinical Trials by Their Surgeons and Medical Oncologists
Authors: Siminoff Laura A. , Zhang Amy , Colabianchi Natalie , Sturm Christina M. Saunders , Shen Quansheng
Published: February 2017

PURPOSE: To improve understanding of physicians’ reluctance to refer patients to clinical trials.

METHODS: This study was conducted in a large metropolitan region from 1993 to 1995 using a two-staged population-based sampling strategy. A total of 147 physicians discussed 245 patient cases and their own knowledge, attitudes, and practices toward clinical trials.

RESULTS: Ninety-three patients (38.0%) were offered a trial, and 49 (52.7%) of them agreed to participate. Forty-five patients (18.4%) actually received their adjuvant therapy on trial. Older patients and those with a poorer prognosis were less likely to be referred. Patients who delayed their decision were more than three times as likely to participate in a trial and more than eight times as likely to participate when they were reported to be actively involved in making the decision. Generally, physicians in university settings and who had formal support from a cooperative group were more likely to refer patients to trials. More specifically, surgeons referred more patients to trials when they felt comfortable explaining trials or believed that treatment should not stray from protocol. Oncologists were less likely to make referrals if they perceived the paperwork to be onerous or entry requirements to be too stringent. Surgeons’ participation in recommending adjuvant therapy to patients resulted in more trial referrals unless they treated their patients with tamoxifen.

CONCLUSION: (1) Physicians still need to overcome attitudinal and practical barriers to trial participation, (2) more support for physicians is needed, (3) surgeons may play a pivotal role in the recruitment of patients to adjuvant therapy trials, and (4) garnering patient enthusiasm for trial participation and involving them in the choice of adjuvant therapy may be key components to increasing trial enrollment.
Multicenter Phase II Study of Iodine-131 Tositumomab for Chemotherapy-Relapsed/Refractory Low-Grade and Transformed Low-Grade B-Cell Non-Hodgkin’s Lymphomas
Authors: Vose Julie M. , Wahl Richard L. , Saleh Mansoor , Rohatiner Ama Z. , Knox Susan J. , Radford John A. , Zelenetz Andrew D. , Tidmarsh George F. , Stagg Robert J. , Kaminski Mark S.
Published: February 2017

PURPOSE: This multicenter phase II study evaluated the efficacy, dosimetry methodology, and safety of iodine-131 tositumomab in patients with chemotherapy-relapsed/refractory low-grade or transformed low-grade non-Hodgkin’s lymphoma (NHL).

PATIENTS AND METHODS: Patients received a dosimetric dose that consisted of 450 mg of anti-B1 antibody followed by 35 mg (5 mCi) of iodine-131 tositumomab. Serial total-body gamma counts were then obtained to calculate the patient-specific millicurie activity required to deliver the therapeutic dose. A therapeutic dose of 75 cGy total-body dose (attenuated to 65 cGy in patients with platelet counts of 101,000 to 149,000 cells/mm3) was given 7 to 14 days after the dosimetric dose.

RESULTS: Forty-five of 47 patients were treated with a single dosimetric and therapeutic dose. Twenty-seven patients (57%) had a response. The response rate was similar in patients with low-grade (57%) or transformed low-grade (60%) NHL. The median duration of response was 9.9 months. Fifteen patients (32%) achieved a complete response (CR; 10 CRs and five clinical CRs), including five patients (50%) with transformed low-grade NHL. The median duration of CR was 19.9 months, and six patients have an ongoing CR. Treatment was well tolerated, with the principal toxicity being hematologic. The most common nonhematologic toxicities that were considered to be possibly related to the treatment included mild to moderate fatigue (32%), nausea (30%), fever (26%), vomiting (15%), infection (13%), pruritus (13%), and rash (13%). Additionally, one patient developed human-antimouse antibodies.

CONCLUSION: Iodine-131 tositumomab produced a high overall response rate, and approximately one third of patients had a CR despite having chemotherapy-relapsed or refractory low-grade or transformed low-grade NHL.
Concomitant Chemoradiotherapy as Primary Therapy for Locoregionally Advanced Head and Neck Cancer
Authors: Vokes Everett E. , Kies Merrill S. , Haraf Daniel J. , Stenson Kerstin , List Marcy , Humerickhouse Rod , Dolan M. Eileen , Pelzer Harold , Sulzen Laura , Witt Mary Ellyn , Hsieh Yi-Ching , Mittal Bharat B. , Weichselbaum Ralph R.
Published: February 2017

PURPOSE: To achieve locoregional control of head and neck cancer, survival, and organ preservation using intensive concomitant chemoradiotherapy.

PATIENTS AND METHODS: This study was a phase II trial of chemoradiotherapy with cisplatin 100 mg/m2 every 28 days, infusional fluorouracil 800 mg/m2/d for 5 days, hydroxyurea 1 g orally every 12 hours for 11 doses, and radiotherapy twice daily at 1.5 Gy/fraction on days 1 through 5 (total dose, 15 Gy). Five days of treatment were followed by 9 days of rest, during which time patients received granulocyte colony-stimulating factor. Five cycles (three with cisplatin) were administered over 10 weeks (total radiotherapy dose, ≤ 75 Gy). Adjuvant chemoprevention with retinoic acid and interferon alfa-2A was offered.

RESULTS: Seventy-six patients were treated (stage IV, 93%; N2, 54%; N3, 21%). At a median follow-up of 38 months, the 3-year progression-free survival is 72%, locoregional control 92%, systemic control 83%, and overall survival 55%. Toxicities included mucositis (grade 3, 45%; grade 4, 12%), neutropenia (grade 4, 39%), and thrombocytopenia (grade 4, 53%). Surgery at the primary site was performed in 13 patients, and 39 had neck dissection. A majority of patients declined adjuvant chemoprevention. Pharmacokinetic parameters were not prognostic of tumor control. Quality of life declined during treatment but returned from good to excellent by 12 months after treatment.

CONCLUSION: Intensive concomitant chemoradiotherapy leads to high locoregional control and survival rates with organ preservation and a reversal of the historical pattern of failure (distant > locoregional). Surgery after concomitant chemoradiotherapy is feasible. Compliance with adjuvant chemoprevention is poor. Identification of less toxic regimens and improved distant disease control emerge as important future research goals.
Phase II Trial of Up-Front Accelerated Thoracic Radiotherapy Combined With Chemotherapy and Optional Up-Front Prophylactic Cranial Irradiation in Limited Small-Cell Lung Cancer
Authors: Hügli A. , Moro D. , Mermillod B. , Bolla M. , Alberto P. , Bonnefoi H. , Miralbell R. ,   for the Groupe d’Oncologie Thoracique des Régions Alpines
Published: February 2017

PURPOSE: To investigate the feasibility and outcome of bifractionated, up-front thoracic radiotherapy (TR) (45 Gy in 30 fractions of 1.5 Gy twice daily over 3 weeks) combined with chemotherapy (CT) (six cycles of cisplatin and etoposide) and optional low-dose, up-front prophylactic cranial irradiation (18 Gy in 10 fractions of 1.8 Gy twice daily over 5 days) in limited small-cell lung cancer.

PATIENTS AND METHODS: CT (etoposide 100 mg/m2 for 3 days and cisplatin 25 mg/m2 for 3 days) was started on day 8 or 15 after the first TR treatment. In the five subsequent cycles, cisplatin was given as a single 100-mg/m2 dose on day 1 every 4 weeks. A total of 52 patients were entered (41 men and 11 women); the median age was 55 years (range, 33 to 67 years). World Health Organization performance status was 0 in 34 patients, 1 in 16 patients, and 2 in two patients. Thirty-six patients (69%) received the full planned six cycles of CT.

RESULTS: All treated patients were assessable for response. Thirty-one patients (60%) achieved a complete response, and 16 (30%) had a partial response. One-, 3-, and 4-year survival rates were 74% (95% confidence interval [CI], 60% to 84%), 34% (95% CI, 21% to 49%), and 32% (95 CI, 16% to 46%), respectively. The median survival time was 18 months. Event-free survival at 1 year was 45% (95% CI, 32% to 58%) and at 3 years, 30% (95% CI, 18% to 44%). The main radiation-related acute toxicity was esophageal: 38% of the patients experienced grade 3 or 4 acute toxicity. CT was well tolerated. Although grade 3/4 neutropenia was observed in 86% of the patients, only 4% presented with associated fever. Grade 3/4 nausea and vomiting was seen in 35% of patients.

CONCLUSION: This trial demonstrates that up-front accelerated TR associated with CT is feasible, has acceptable toxicity, and shows considerable long-term survival potential.
Outcome at 8 Years After Breast-Conserving Surgery and Radiation Therapy for Invasive Breast Cancer: Influence of Margin Status and Systemic Therapy on Local Recurrence
Authors: Park Catherine C. , Mitsumori Michihide , Nixon Asa , Recht Abram , Connolly James , Gelman Rebecca , Silver Barbara , Hetelekidis Stella , Abner Anthony , Harris Jay R. , Schnitt Stuart J.
Published: February 2017

PURPOSE: To examine the relationship between pathologic margin status and outcome at 8 years after breast-conserving surgery and radiation therapy.

PATIENTS AND METHODS: The study population comprised 533 patients with International Union Against Cancer/American Joint Committee on Cancer clinical stage I or II breast cancer who had assessable margins, who received at least 60 Gy to the primary tumor bed, and who had more than 8 years of potential follow-up. Each margin was scored (according to the presence of invasive or in situ disease that touched the inked surgical margin) as one of the following: negative, close, focally positive, or extensively positive. Outcome at 8 years was calculated using crude rates of first site of failure. A polychotomous logistic regression analysis was performed. Median follow-up time was 127 months.

RESULTS: At 8 years, patients with close margins and those with negative margins both had a rate of local recurrence (LR) of 7%. Patients with extensively positive margins had an LR rate of 27%, whereas patients with focally positive margins had an intermediate rate of LR of 14%. In the polychotomous logistic regression model, margin status and the use of systemic therapy were the only two variables that had significant effects on the risk ratio of LR to remaining alive and free of disease. Among the 45 patients with focally positive margins who received systemic therapy, the crude LR rate was 7% at 8 years (95% confidence interval, 1% to 20%).

CONCLUSION: Pathologic margin status and the use of adjuvant systemic therapy are the most important factors associated with LR among patients treated with breast-conserving surgery and radiation therapy.
Biology of the Adenomatous Polyposis Coli Tumor Suppressor
Authors: Goss Kathleen Heppner , Groden Joanna
Published: February 2017

ABSTRACT: The adenomatous polyposis coli (APC) gene was first identified as the gene mutated in an inherited syndrome of colon cancer predisposition known as familial adenomatous polyposis coli (FAP). Mutation of APC is also found in 80% of all colorectal adenomas and carcinomas and is one of the earliest mutations in colon cancer progression. Similar to other tumor suppressor genes, both APC alleles are inactivated by mutation in colon tumors, resulting in the loss of full-length protein in tumor cells. The functional significance of altering APC is the dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, which include cell cycle progression, migration, differentiation, and apoptosis. Roles for APC in some of these processes are in large part attributable to its ability to regulate cytosolic levels of the signaling molecule beta-catenin and to affect the transcriptional profile in cells. This article summarizes numerous genetic, biochemical, and cell biologic studies on the mechanisms of APC-mediated tumor suppression. Mouse models of FAP, in which the APC gene has been genetically inactivated, have been particularly useful in testing therapeutic and chemopreventive strategies. These data have significant implications for colorectal cancer treatment approaches as well as for understanding other disease genes and cancers of other tissue types.
Twelve-Year Experience With Two Courses of Adjuvant Single-Agent Carboplatin Therapy for Clinical Stage I Seminoma
Authors: Reiter Werner J. , Brodowicz Thomas , Alavi Saeid , Zielinski Christoph C. , Kozak Walter , Maier Ulrich , Nöst Gerald , Lipsky Herbert , Marberger Michael , Kratzik Christian
Published: February 2017

PURPOSE: During the past 30 years, radiation therapy with 28 to 30 Gy for para-aortic and ipsilateral iliac node areas was the standard adjuvant treatment for clinical stage I seminoma after orchiectomy. However, late effects of radiotherapy prompted a search for alternative adjuvant treatment approaches, including surveillance and application of carboplatin. In this retrospective analysis, we evaluated the efficacy and toxicity of two adjuvant single-agent carboplatin courses in 107 patients who were diagnosed with clinical stage I seminoma at our study centers between 1988 and 1999.

PATIENTS AND METHODS: All 107 patients (median age, 39 years; range, 24 to 63 years) received two postoperative adjuvant cycles of carboplatin (400 mg/m2). The pathologic tumor stage was pT1 in 84 patients, pT2 in 18 patients, and pT3 in five patients. Whole blood count and serum chemistry were evaluated weekly during treatment to assess hematologic and nonhematologic toxicity.

RESULTS: Six patients died from tumor-unrelated causes. The remaining 101 patients are currently alive and free of disease after a median follow-up of 74 months (range, 5 to 145 months). A detailed analysis of hematologic toxicity showed only World Health Organization (WHO) grade 1 leukocytopenia in 10.7% of all cycles and WHO grade 2 leukocytopenia in 2.1% of all cycles.

CONCLUSION: Regarding the absence of tumor recurrences in our retrospective analysis and the favorable toxicity profile with no episodes of long-term toxicity, we suggest that two adjuvant courses of single-agent carboplatin for clinical stage I seminoma patients might be equivalent to radiotherapy.
Novel Allogeneic Granulocyte-Macrophage Colony-Stimulating Factor–Secreting Tumor Vaccine for Pancreatic Cancer: A Phase I Trial of Safety and Immune Activation
Authors: Jaffee Elizabeth M. , Hruban Ralph H. , Biedrzycki Barbara , Laheru Daniel , Schepers Karen , Sauter Patricia R. , Goemann Marti , Coleman Joanne , Grochow Louise , Donehower Ross C. , Lillemoe Keith D. , O’Reilly Seamus , Abrams Ross A. , Pardoll Drew M. , Cameron John L. , Yeo Charles J.
Published: February 2017

PURPOSE: Allogeneic granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting tumor vaccines can cure established tumors in the mouse, but their efficacy against human tumors is uncertain. We have developed a novel GM-CSF–secreting pancreatic tumor vaccine. To determine its safety and ability to induce antitumor immune responses, we conducted a phase I trial in patients with surgically resected adenocarcinoma of the pancreas.

PATIENTS AND METHODS: Fourteen patients with stage 1, 2, or 3 pancreatic adenocarcinoma were enrolled. Eight weeks after pancreaticoduodenectomy, three patients received 1 × 107 vaccine cells, three patients received 5 × 107 vaccine cells, three patients received 10 × 107 vaccine cells, and five patients received 50 × 107 vaccine cells. Twelve of 14 patients then went on to receive a 6-month course of adjuvant radiation and chemotherapy. One month after completing adjuvant treatment, six patients still in remission received up to three additional monthly vaccinations with the same vaccine dose that they had received originally.

RESULTS: No dose-limiting toxicities were encountered. Vaccination induced increased delayed-type hypersensitivity (DTH) responses to autologous tumor cells in three patients who had received ≥ 10 × 107 vaccine cells. These three patients also seemed to have had an increased disease-free survival time, remaining disease-free at least 25 months after diagnosis.

CONCLUSION: Allogeneic GM-CSF–secreting tumor vaccines are safe in patients with pancreatic adenocarcinoma. This vaccine approach seems to induce dose-dependent systemic antitumor immunity as measured by increased postvaccination DTH responses against autologous tumors. Further clinical evaluation of this approach in patients with pancreatic cancer is warranted.
Recovery After Stem-Cell Transplantation for Hematologic Diseases
Authors: Lee Stephanie J. , Fairclough Diane , Parsons Susan K. , Soiffer Robert J. , Fisher David C. , Schlossman Robert L. , Antin Joseph H. , Weeks Jane C.
Published: February 2017

PURPOSE: Although the number of autologous and allogeneic stem-cell transplantations (SCT) is increasing, relatively little information about recovery after transplantation is available. Quantitative information appropriate for patient counseling is difficult to discern from the literature. We sought to suggest reasonable expectations for recovery and symptoms after SCT for hematologic malignancies and other disorders using the following measures: (1) objective measures of health status, such as frequency of clinic visits, need for rehospitalization, medication usage, work status, and overall and event-free survival; (2) qualitative assessment of quality of life, such as returning to a normal life, resumption of normal activities, satisfaction with appearance, and whether recovery has occurred; and (3) quantification of specific bothersome symptoms.

PATIENTS AND METHODS: Autologous and allogeneic SCT recipients at a tertiary-care transplant center participated in the prospective, longitudinal questionnaire study.

RESULTS: Three hundred twenty patients were studied. Questionnaire response rates at 6, 12, and 24 months range from 85% to 88% among survivors. Although autologous patients had better event-free and overall survival, fewer symptoms, and more complete recovery at 6 months, these advantages had largely equalized by 12 months. Specific bothersome symptoms were reported by less than 24% of patients after transplantation, except for fatigue and financial and sexual difficulties, which were more prevalent.

CONCLUSION: These findings may help counsel patients considering transplantation and educate them about reasonable expectations for recovery. Overall, the low level of bothersome symptoms and continued recovery through the first year after transplantation are encouraging.
Paclitaxel, Estramustine Phosphate, and Carboplatin in Patients With Advanced Prostate Cancer
Authors: Kelly William Kevin , Curley Tracy , Slovin Susan , Heller Glenn , McCaffrey John , Bajorin Dean , Ciolino Allison , Regan Kevin , Schwartz Morton , Kantoff Philip , George Daniel , Oh William , Smith Matthew , Kaufman Donald , Small Eric J. , Schwartz Lawrence , Larson Steve , Tong William , Scher Howard
Published: February 2017

PURPOSE: To determine the safety and activity of weekly paclitaxel in combination with estramustine and carboplatin (TEC) in patients with advanced prostate cancer.

PATIENTS AND METHODS: In a dose-escalation study, patients with advanced prostate cancer were administered paclitaxel (weekly 1-hour infusions of 60 to 100 mg/m2), oral estramustine (10 mg/kg), and carboplatin (area under the curve, 6 mg/mL-min every 4 weeks). Paclitaxel levels were determined 0, 30, 60, 90, and 120 minutes and 18 hours after infusion, and a concentration-time curve was estimated. Once a safe dose was established, a multi-institutional phase II trial was conducted in patients with progressive androgen-independent disease.

RESULTS: Fifty-six patients with progressive androgen-independent disease were treated for a median of four cycles. The dose of paclitaxel was escalated from 60 to 100 mg/m2 without the occurrence of DLT. Posttherapy decreases in serum prostate-specific antigen levels of 50%, 80%, and 90% were seen in 67%, 48%, and 39% (95% confidence interval, 55% to 79%, 35% to 61%, 26% to 52%) of the patients, respectively. Of the 33 patients with measurable disease, two (6%) had a complete response and 13 (39%) had a partial response. The overall median time to progression was 21 weeks, and the median survival time for all patients was 19.9 months. Major grade 3 or 4 adverse effects were thromboembolic disease (in 25% of patients), hyperglycemia (in 38%), and hypophosphatemia (in 42%). Significant leukopenia, thrombocytopenia, and peripheral neuropathy were not observed.

CONCLUSION: TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer.
Living With Treatment Decisions: Regrets and Quality of Life Among Men Treated for Metastatic Prostate Cancer
Authors: Clark Jack A. , Wray Nelda P. , Ashton Carol M.
Published: February 2017

PURPOSE: To examine variation in men’s long-term regret of treatment decisions, ie, surgical versus chemical castration, for metastatic prostate cancer and its associations with quality of life.

METHODS: Survey of previously treated patients to assess treatment decisions and quality of life, supplemented with focus groups. Two items addressing whether a patient wished he could change his mind and the belief that he would have been better off with the treatment not chosen were combined in classifying survey respondents as either satisfied or regretful. χ2 and t tests were used to test associations between regret and treatment history, complications, and quality of life.

RESULTS: Survey respondents included 201 men aged 45 to 93 years (median, 71 years), who had begun treatment (71% chemical castration, 29% orchiectomy) a median of 2 years previously. Most reported complications: hot flashes (70%), nausea (34%), and erectile dysfunction (81%). Most were satisfied with the treatment decision, but 23% expressed regret. Regretful men more frequently reported surgical (43%) versus chemical (36%) castration (P = .030) and nausea in the past week (54% v 32%; P = .010) but less frequently reported erectile dysfunction (56% v 72%; P = .048). Regretful men indicated poorer scores on every measure of generic and prostate cancer–related quality of life. Qualitative analyses revealed substantial uncertainty about the progress of their disease and the quality of the decisions in which patients participated.

CONCLUSION: Regret was substantial and associated with treatment choice and quality of life. It may derive from underlying psychosocial distress and problematic communication with physicians when decisions are being reached and over subsequent years.
Viable Malignant Cells After Primary Chemotherapy for Disseminated Nonseminomatous Germ Cell Tumors: Prognostic Factors and Role of Postsurgery Chemotherapy—Results From an International Study Group
Authors: Fizazi Karim , Tjulandin Sergei , Salvioni Roberto , Germà-Lluch José R. , Bouzy Jeannine , Ragan David , Bokemeyer Carsten , Gerl Arthur , Fléchon Aude , de Bono Johann S. , Stenning Sally , Horwich Alan , Pont Jörg , Albers Peter , De Giorgi Ugo , Bower Mark , Bulanov Anatoly , Pizzocaro Giorgio , Aparicio Jorge , Nichols Craig R. , Théodore Christine , Hartmann Jörg Thomas , Schmoll Hans-Joachim , Kaye Stanley B. , Culine Stéphane , Droz Jean-Pierre , Mahé Cedric
Published: February 2017

PURPOSE: To assess the value of postsurgery chemotherapy in patients with disseminated nonseminomatous germ-cell tumors (NSGCTs) and viable residual disease after first-line cisplatin-based chemotherapy.

PATIENTS AND METHODS: The outcome of 238 patients was reviewed. Tumor markers had normalized in all patients before resection. A multivariate analysis of survival was performed on 146 patients.

RESULTS: The 5-year progression-free survival (PFS) rate was 64% and the 5-year overall survival (OS) rate was 73%. Three factors were independently associated with both PFS and OS: complete resection (P < .001), < 10% of viable malignant cells (P = .001), and a good International Germ Cell Consensus Classification (IGCCC) group (P = .01). Patients were assigned to one of three risk groups: those with no risk factors (favorable group), those with one risk factor (intermediate group), and those with two or three risk factors (poor-risk group). The 5-year OS rate was 100%, 83%, and 51%, respectively (P < .001). The 5-year PFS rate was 69% (95% confidence interval [CI], 62% to 76%) and 52% (95% CI, 40% to 64%) in postoperative chemotherapy recipients and nonrecipients, respectively (P < .001). No significant difference was detected in 5-year OS rates. After adjustment on the three prognostic factors, postoperative chemotherapy was associated with a significantly better PFS (P < .001) but not with better OS. Patients in the favorable risk group had a 100% 5-year OS, with or without postoperative chemotherapy. Postoperative chemotherapy appeared beneficial in both PFS (P < .001) and OS (P = .02) in the intermediate-risk group but was not statistically beneficial in the poor-risk group.

CONCLUSION: A complete resection may be more critical than recourse to postoperative chemotherapy in the setting of postchemotherapy viable malignant NSGCT. Immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may be reasonable options depending on the completeness of resection, IGCCC group, and percent of viable cells. Validation is necessary.
Behavior of Borderline Tumors With Particular Interest to Persistence, Recurrence, and Progression to Invasive Carcinoma: A Prospective Study
Authors: Zanetta Gerardo , Rota Sonia , Chiari Stefania , Bonazzi Cristina , Bratina Giorgio , Mangioni Costantino
Published: February 2017

PURPOSE: Borderline tumors account for 10% to 20% of epithelial ovarian tumors, and their prognosis is outstanding; nevertheless, a mortality of up to 20% has been reported, particularly in earlier reports. There is a lack of information about the actual mortality and the rate of progression into invasive carcinoma in large and prospectively accrued populations.

PATIENTS AND METHODS: All women with borderline ovarian tumors undergoing primary surgery in our department or referred within 3 months from surgery performed elsewhere from 1982 to 1997 were prospectively accrued and observed.

RESULTS: We studied 339 women (83.4% stage I, 7.9% stage II, and 8.5% stage III). The median age at diagnosis was 39 years. A total of 150 women underwent radical surgery, and 189 underwent fertility-sparing surgery. After surgery, 13 women had macroscopic residual disease. With a median follow-up of 70 months, 317 women are alive with no clinical disease (eight with documented subclinical persistence of implants), three are alive with clinical disease, two died of disease, 10 died of other reasons, and seven women have been lost to follow-up. The recurrence of disease was higher after fertility-sparing surgery (35 of 189 cases) than after radical surgery (seven of 150 cases); nevertheless, all but one woman with recurrence of borderline tumor or progression to carcinoma after conservative surgery were salvaged. We observed seven progressions (2.0%) into invasive carcinoma, five in serous tumors (2.4%), and two in mucinous tumors (1.6%). The disease-free survival is 99.6% in stage I patients, 95.8% in stage II, and 89% in stage III.

CONCLUSION: The survival of patients with borderline tumors is higher than previously described in some retrospective studies. Conservative surgery is safe and may be proposed to several patients with early and disseminated disease after thorough discussion of all therapeutic options. Progression to carcinoma is approximately 2% and may be observed in both mucinous and serous tumors.
Improved Treatment Results in High-Risk Pediatric Acute Myeloid Leukemia Patients After Intensification With High-Dose Cytarabine and Mitoxantrone: Results of Study Acute Myeloid Leukemia–Berlin-Frankfurt-Münster 93
Authors: Creutzig U. , Ritter J. , Zimmermann M. , Reinhardt D. , Hermann J. , Berthold F. , Henze G. , Jürgens H. , Kabisch H. , Havers W. , Reiter A. , Kluba U. , Niggli F. , Gadner H. ,   for the Acute Myeloid Leukemia–Berlin-Frankfurt-Münster Study Group
Published: February 2017

PURPOSE: To improve outcome in high-risk patients, high-dose cytarabine and mitoxantrone (HAM) was introduced into the treatment of children with acute myelogenous leukemia (AML) in study AML-BFM 93. Patients were randomized to HAM as either the second or third therapy block, for the purpose of evaluation of efficacy and toxicity.

PATIENTS AND METHODS: A total of 471 children with de novo AML were entered onto the trial; 161 were at standard risk and 310 were at high risk. After the randomized induction (daunorubicin v idarubicin), further therapy, with the exception of HAM, was identical in the two risk groups and also comparable to that in study Acute Myeloid Leukemia–Berlin-Frankfurt-Münster (AML-BFM) 87.

RESULTS: Overall, 387 (82%) of 471 patients achieved complete remission, and 5-year survival, event-free survival (EFS), and disease-free survival rates were 60%, 51%, and 62%, respectively. Idarubicin induction resulted in a significantly better blast cell reduction in the bone marrow on day 15. Estimated survival and probability of EFS were superior in study AML-BFM 93 compared with study AML-BFM 87 (P = .01, log-rank test). This improvement, however, was restricted to the 310 high-risk patients (remission rate and probability of 5-year EFS in study AML-BFM 93 v study AML-BFM 87: 78% v 68%, P = .007; and 44% v 31%, P = .01, log-rank test). Probability of 5-year EFS among standard-risk patients in study AML-BFM 93 was similar to that in study AML-BFM 87 (65% v 63%, P = not significant). Whether HAM was placed as the second or third therapy block was of minor importance. However, patients who received the less intensive daunorubicin treatment during induction benefited from early HAM.

CONCLUSION: Improved treatment results in children with high-risk AML in study AML-BFM 93 must be attributed mainly to the introduction of HAM.
Prospective Evaluation of Early Cardiac Damage Induced by Epirubicin-Containing Adjuvant Chemotherapy and Locoregional Radiotherapy in Breast Cancer Patients
Authors: Meinardi M.T. , van Veldhuisen D.J. , Gietema J.A. , Dolsma W.V. , Boomsma F. , van den Berg M.P. , Volkers C. , Haaksma J. , de Vries E.G.E. , Sleijfer D.Th. , van der Graaf W.T.A.
Published: February 2017

PURPOSE: To evaluate prospectively the cardiotoxic effects of epirubicin-containing adjuvant chemotherapy in breast cancer patients.

PATIENTS AND METHODS: Patients (median age, 46 years; range, 28 to 55 years) were treated with five cycles of fluorouracil, epirubicin (90 mg/m2), and cyclophosphamide (FEC) (group I, n = 21) or with four cycles of FEC followed by high-dose chemotherapy consisting of cyclophosphamide, thiotepa, and carboplatin (group II, n = 19). Locoregional radiotherapy was applied subsequently. Cardiac evaluation was performed before chemotherapy (T0), 1 month after chemotherapy, 1 month after radiotherapy (T2), and 1 year after start of chemotherapy (T3). Left ventricular ejection fraction (LVEF) was determined by radionuclide ventriculography and diastolic function by echocardiography. Autonomic function was assessed by 24-hour ECG registration for heart rate variability (HRV) analysis. Time-corrected QT (QTc) was assessed and N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) were measured as biochemical markers of cardiac dysfunction.

RESULTS: No patient developed overt congestive heart failure (CHF) and the mean LVEF declined from 0.61 at T0 to 0.54 at T3 (P = .001), resulting in an LVEF below 0.50 (range, 0.42 to 0.49) in 17% of the patients, whereas 28% had a decline of more than 0.10. Plasma NT-ANP levels increased gradually from 237 pmol/L at T0 to 347 pmol/L at T3 (P < .01), whereas plasma BNP levels increased from 2.9 pmol/L to 5.1 pmol/L (P = .04). Mean QTc increased from 406 msec at T0 to 423 msec at T3 (P < .01). No persistent alterations were found in diastolic function and HRV.

CONCLUSION: Relatively low doses of epirubicin in adjuvant chemotherapy for breast cancer results in mild subclinical myocardial damage demonstrated by a decline in LVEF, an increase in natriuretic peptide levels, and an increase in QTc, which may indicate a long-term risk of CHF.
Phase I Clinical Trial of Alitretinoin and Tamoxifen in Breast Cancer Patients: Toxicity, Pharmacokinetic, and Biomarker Evaluations
Authors: Lawrence Julia A. , Adamson Peter C. , Caruso Rafael , Chow Catherine , Kleiner David , Murphy Robert F. , Venzon David J. , Shovlin Margaret , Noone Marianne , Merino Maria , Cowan Kenneth H. , Kaiser Muriel , O’Shaughnessy Joyce , Zujewski JoAnne
Published: February 2017

PURPOSE: To determine the overall and dose-limiting toxicities (DLTs) of alitretinoin (9-cis-retinoic acid) in combination with tamoxifen and the pharmacokinetics of alitretinoin alone and when combined with tamoxifen in patients with metastatic breast cancer. The effect of tamoxifen and alitretinoin on MIB-1, a marker of proliferation, in unaffected breast tissue was explored.

PATIENTS AND METHODS: Eligible patients had metastatic breast cancer. Previous tamoxifen therapy was allowed. Planned dose levels for alitretinoin ranged from 50 to 140 mg/m2/d with 20 mg/d tamoxifen in all patients after 4 weeks of alitretinoin as a single agent. Plasma concentrations of alitretinoin and retinol were measured at baseline and after 1, 2, and 3 months. Breast core biopsies were obtained at baseline and after 2 months of therapy.

RESULTS: Twelve patients with metastatic breast cancer received a total of 86 cycles of therapy. At 90 mg/m2/d, three of five patients experienced a DLT: grade 3 headache, grade 3 hypercalcemia, and grade 3 noncardiogenic pulmonary edema. At 70 mg/m2/d, one of six patients experienced a DLT (headache), and this level was considered the maximal tolerated dose in this study. Three toxicities occurred that had not been reported previously with alitretinoin: an asymptomatic delay in dark adaptation, a marked decrease in high-density lipoprotein cholesterol, and the occurrence of enthesopathy. Two of the nine assessable patients had a durable clinical response: one partial response and stable disease for 18 months and one complete response in continuous remission for 48+ months. Both responding patients were estrogen receptor–positive and had had previous tamoxifen therapy. There was a high degree of interpatient variability of plasma alitretinoin concentrations, although a significant decline in alitretinoin plasma levels over time was observed. MIB-1 scores declined in four of the eight paired breast specimens obtained.

CONCLUSION: The combination of tamoxifen and alitretinoin is well tolerated and has antitumor activity in metastatic breast cancer. The recommended phase II dose is 70 mg/m2/d with 20 mg/d tamoxifen.
An On-Site Audit of the South African Trial of High-Dose Chemotherapy for Metastatic Breast Cancer and Associated Publications
Authors: Weiss Raymond B. , Gill Geraldine G. , Hudis Clifford A.
Published: February 2017

PURPOSE: The randomized study reported by Bezwoda et al of high-dose chemotherapy (HDC) for treatment of metastatic breast cancer was audited on site to verify the study results. Additional published studies were reviewed to determine whether they had been subject to the required institutional oversight.

PATIENTS AND METHODS: Ninety patients were reported to have been randomized and treated on this trial. A log of the names, hospital numbers, entry dates, and regimen received had been provided by the principal investigator. A search of more than 15,000 sets of medical records available from two Johannesburg hospitals was performed to locate records for as many of these 90 patients as possible. Standard auditing techniques were used. Additional clinical trials published by Bezwoda were compared against the minutes of the University of the Witwatersrand Committee for Research on Human Subjects to verify review and approval.

RESULTS: Records for only 61 of the 90 patients could be found. Of these 61, only 27 had sufficient records to verify eligibility for the trial by the published criteria. Of these 27, 18 did not meet one or more eligibility criteria. Only 25 patients appeared to have received their assigned therapy temporally associated with their enrollment date, and all but three of these 25 received HDC. The treatment details of individual patients were at great variance from the published data. Nine other trials reported by Bezwoda were not reviewed or approved by the appropriate institutional committee despite statements to the contrary in the publications.

CONCLUSION: The multiple publications of this study do not report verifiable data, and nine other publications coauthored by the principal investigator contain at least one major untrue statement.