bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemotherapy for Human Immunodeficiency Virus–Associated Non-Hodgkin’s Lymphoma in Combination With Highly Active Antiretroviral Therapy
Authors: Ratner Lee , Lee Jeannette , Tang Shenghui , Redden David , Hamzeh Fayez , Herndier Brian , Scadden David , Kaplan Lawrence , Ambinder Richard , Levine Alexandra , Harrington William , Grochow Louise , Flexner Charles , Tan Benjamin , Straus David
Published: February 2017

PURPOSE: This study investigated the efficacy, toxicity, and pharmacokinetic interactions resulting from simultaneous combination chemotherapy and highly active antiretroviral therapy (HAART) for patients with human immunodeficiency virus (HIV)-associated non-Hodgkin’s lymphoma (NHL). In addition, the effects on viral load, CD4 counts, and opportunistic infections were examined with the use of combination chemotherapy combined with HAART.

PATIENTS AND METHODS: Sixty-five patients with previously untreated and measurable disease at any stage of HIV-associated NHL of intermediate or high grade were entered onto this study at 17 different centers. The first 40 patients entered onto the study received reduced doses of cyclophosphamide and doxorubicin, combined with vincristine and prednisone (modified CHOP [mCHOP]), whereas the subsequent 25 patients entered onto the study received full doses of CHOP combined with granulocyte colony-stimulating factor (G-CSF). All patients also received stavudine, lamivudine, and indinavir.

RESULTS: The complete response rates were 30% and 48% among patients who received mCHOP and full-dose CHOP combined with HAART, respectively. Grade 3 or 4 neutropenia occurred in 25% of patients receiving mCHOP and 12% of those receiving full-dose CHOP combined with G-CSF (25% v 12%). There were similar numbers of patients with grade 3 or 4 hyperbilirubinemia (12% and 17%), constipation and abdominal pain (18% and 17%), and transaminase elevation (48% and 52%) on the modified and full-dose arms of the study, respectively. Doxorubicin clearance and indinavir concentration curves were similar among patients on this study and historical controls, whereas cyclophosphamide clearance was 1.5-fold reduced as compared with control values. Human immunodeficiency virus (HIV) load declined from a median baseline value of 29,000 copies/mL to a median minimum value on therapy of 500 copies/mL.

CONCLUSION: Either modified-dose or full-dose CHOP chemotherapy for HIV-NHL, delivered with HAART, is effective and tolerable.
Results of a Pilot Study Involving the Use of an Antisense Oligodeoxynucleotide Directed Against the Insulin-Like Growth Factor Type I Receptor in Malignant Astrocytomas
Authors: Andrews David W. , Resnicoff Mariana , Flanders Adam E. , Kenyon Lawrence , Curtis Mark , Merli Gino , Baserga Renato , Iliakis George , Aiken Robert D.
Published: February 2017

PURPOSE: Preclinical animal experiments support the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor (IGF-IR/AS ODN) as an effective potential antitumor agent. We performed a human pilot safety and feasibility study using an IGF-IR/AS ODN strategy in patients with malignant astrocytoma.

PATIENTS AND METHODS: Autologous glioma cells collected at surgery were treated ex vivo with an IGF-IR/AS ODN, encapsulated in diffusion chambers, reimplanted in the rectus sheath within 24 hours of craniotomy, and retrieved after a 24-hour in situ incubation. Serial posttreatment assessments included clinical examination, laboratory studies, and magnetic resonance imaging scans.

RESULTS: Other than deep venous thrombosis noted in some patients, no other treatment-related side effects were observed. IGF-IR/AS ODN–treated cells, when retrieved and assessed, were ≤ 2% intact by trypan blue exclusion, and none of the intact cells were viable in culture thereafter. Parallel Western blots disclosed IGF-IR downregulation to ≤ 10% after ex vivo antisense treatment. At follow-up, clinical and radiographic improvements were observed in eight of 12 patients, including three cases of distal recurrence with unexpected spontaneous or postsurgical regression at either the primary or the distant intracranial site.

CONCLUSION: Ex vivo IGF-IR/AS ODN treatment of autologous glioma cells induces apoptosis and a host response in vivo without unusual side effects. Subsequent transient and sustained radiographic and clinical improvements warrant further clinical investigations.
Analysis of p53/BAX/p16ink4a/CDKN2 in Esophageal Squamous Cell Carcinoma: High BAX and p16ink4a/CDKN2 Identifies Patients With Good Prognosis
Authors: Sturm Isrid , Petrowsky Henrik , Volz Roland , Lorenz Matthias , Radetzki Silke , Hillebrand Timo , Wolff Gerhard , Hauptmann Steffen , Dörken Bernd , Daniel Peter T.
Published: February 2017

PURPOSE: We have previously shown that loss of BAX expression is a negative prognostic factor in metastatic colorectal cancer. In the present study, we addressed the prognostic relevance of BAX and its upstream regulator p53 in squamous cell carcinoma (SCC) of the esophagus. Analysis of p16ink4a/CDKN2 was included because p16ink4a/CDKN2 and p53 were shown previously to cooperate during induction of cell cycle arrest and apoptosis.

PATIENTS AND METHODS: Retrospective analysis of 53 patients with curative intended R0 resection of esophageal SCC was done. Protein expression of BAX, p53, and p16ink4a/CDKN2 was investigated by immunohistochemistry. In addition, tumor DNA was screened for BAX frameshift mutations by fragment length analysis and for p53 mutations by single-strand conformation polymorphism–polymerase chain reaction.

RESULTS: Overall median survival was 13.7 months. Patients with high BAX protein expression had a median survival of 19.5 months versus 8.0 months with low BAX expression (P < .005). High p16ink4a/CDKN2 protein expression was associated with a median survival of 23.8 months versus 9.7 months with low p16ink4a/CDKN2 (P = .011). The best survival (median, 45.8 months) was seen in a subgroup of 12 patients whose tumors bore the combination of both favorite phenotypes (ie, high BAX and high p16ink4a/CDKN2 protein expression).

CONCLUSION: In this retrospective investigation, the combined analysis of BAX and p16ink4a/CDKN2 shows subgroups in SCC of the esophagus with favorable (p16ink4a/CDKN2/BAX high expressing) or poor prognosis (loss of p16ink4a/CDKN2/loss of BAX). We suggest that such a multimarker analysis of apoptosis pathways could be useful for individualization of therapeutic strategies in the future, and suggest prospective studies to confirm these results.
Patterns of Intellectual Development Among Survivors of Pediatric Medulloblastoma: A Longitudinal Analysis
Authors: Palmer Shawna L. , Goloubeva Olga , Reddick Wilburn E. , Glass John O. , Gajjar Amar , Kun Larry , Merchant Thomas E. , Mulhern Raymond K.
Published: February 2017

PURPOSE: To examine two competing hypotheses relating to intellectual loss among children treated for medulloblastoma (MB): Children with MB either: (1) lose previously learned skills and information; or (2) acquire new skills and information but at a rate slower than expected compared with healthy same-age peers.

PATIENTS AND METHODS: Forty-four pediatric MB patients were evaluated who were treated with postoperative radiation therapy (XRT) with or without chemotherapy. After completion of XRT, a total of 150 examinations were conducted by use of the child version of the Wechsler Intelligence Scales. These evaluations provided a measure of intellectual functioning called the estimated full-scale intelligence quotient (FSIQ). Changes in patient performance corrected for age (scaled scores) as well as the uncorrected performance (raw scores) were analyzed.

RESULTS: At the time of the most recent examination, the obtained mean estimated FSIQ of 83.57 was more than one SD below expected population norms. A significant decline in cognitive performance during the time since XRT was demonstrated, with a mean loss of 2.55 estimated FSIQ points per year (P = .0001). An analysis for the basis of the intelligence quotient (IQ) loss revealed that subtest raw score values increased significantly over time since XRT, but the rate of increase was less than normally expected, which resulted in decreased IQ scores.

CONCLUSION: These results support the hypothesis that MB patients demonstrate a decline in IQ values because of an inability to acquire new skills and information at a rate comparable to their healthy same-age peers, as opposed to a loss of previously acquired information and skills.
High-Dose Interferon Alfa-2b Significantly Prolongs Relapse-Free and Overall Survival Compared With the GM2-KLH/QS-21 Vaccine in Patients With Resected Stage IIB-III Melanoma: Results of Intergroup Trial E1694/S9512/C509801
Authors: Kirkwood John M. , Ibrahim Joseph G. , Sosman Jeffrey A. , Sondak Vernon K. , Agarwala Sanjiv S. , Ernstoff Marc S. , Rao Uma
Published: February 2017

PURPOSE: Vaccine alternatives to high-dose interferon alfa-2b therapy (HDI), the current standard adjuvant therapy for high-risk melanoma, are of interest because of toxicity associated with HDI. The GM2 ganglioside is a well-defined melanoma antigen, and anti-GM2 antibodies have been associated with improved prognosis. We conducted a prospective, randomized, intergroup trial to evaluate the efficacy of HDI for 1 year versus vaccination with GM2 conjugated to keyhole limpet hemocyanin and administered with QS-21 (GMK) for 96 weeks (weekly × 4 then every 12 weeks × 8).

PATIENTS AND METHODS: Eligible patients had resected stage IIB/III melanoma. Patients were stratified by sex and number of positive nodes. Primary end points were relapse-free survival (RFS) and overall survival (OS).

RESULTS: Eight hundred eighty patients were randomized (440 per treatment group); 774 patients were eligible for efficacy analysis. The trial was closed after interim analysis indicated inferiority of GMK compared with HDI. For eligible patients, HDI provided a statistically significant RFS benefit (hazard ratio [HR] = 1.47, P = .0015) and OS benefit (HR = 1.52, P = .009) for GMK versus HDI. Similar benefit was observed in the intent-to-treat analysis (RFS HR = 1.49; OS HR = 1.38). HDI was associated with a treatment benefit in all subsets of patients with zero to ≥ four positive nodes, but the greatest benefit was observed in the node-negative subset (RFS HR = 2.07; OS HR = 2.71 [eligible population]). Antibody responses to GM2 (ie, titers ≥ 1:80) at days 29, 85, 365, and 720 were associated with a trend toward improved RFS and OS (P2= .068 at day 29).

CONCLUSION: This trial demonstrated a significant treatment benefit of HDI versus GMK in terms of RFS and OS in melanoma patients at high risk of recurrence.
Testicular Disease in Childhood B-Cell Non-Hodgkin’s Lymphoma: The French Society of Pediatric Oncology Experience
Authors: Dalle Jean-Hugues , Mechinaud Françoise , Michon Jean , Gentet Jean-Claude , de Lumley Lionel , Rubie Hervé , Schmitt Claudine , Patte Catherine
Published: February 2017

PURPOSE: To investigate whether testicular disease in childhood B-cell lymphoma should continue to be considered a sanctuary site, as it is with other lymphoid malignancies such as acute lymphoblastic leukemia.

PATIENTS AND METHODS: Seven hundred forty-two children with B-cell non-Hodgkin’s lymphoma were included in the LMB protocols of the French Society of Pediatric Oncology from February 1981 to May 1994. Thirty patients (5.3%) had testicular involvement at diagnosis. We describe the clinical presentation and outcome of these 30 patients, who were treated without local radiation therapy.

RESULTS: Five patients underwent diagnostic orchidectomy. The median patient age was 8.5 years (range, 2 to 14 years), and their cancers were stage III (18 patients), stage IV (five patients), and B-cell acute lymphoblastic leukemia (seven patients). Five patients had central nervous system involvement. Twenty-eight patients (95%) achieved complete remission. Twenty-six patients are alive without progressive disease (median follow-up, 6.5 years).

CONCLUSION: Testicular disease does not seem to confer a poor prognosis, and it is curable with intensive combination chemotherapy alone. Local treatment (surgery or radiation) is avoidable; therefore, gonadal function can be preserved.
Phase II Study of Oral Capecitabine in Patients With Advanced or Metastatic Pancreatic Cancer
Authors: Cartwright Thomas H. , Cohn Allen , Varkey Jerry A. , Chen Yin-Miao , Szatrowski Ted P. , Cox John V. , Schulz Joseph J.
Published: February 2017

PURPOSE: To determine the safety and efficacy of capecitabine (Xeloda; Roche Laboratories, Nutley, NJ) in patients with metastatic or unresectable, locally advanced pancreatic cancer.

PATIENTS AND METHODS: Forty-two patients were treated with oral capecitabine 1,250 mg/m2 administered twice daily (2,500 mg/m2/d) as intermittent therapy in 3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment. Tumor lesions were assessed by computed tomography scan or physical examination at 6-week intervals (after every two cycles). Adverse events were monitored continuously during treatment and for 28 days after the last dose of study drug.

RESULTS: Ten (24%) of 42 patients experienced a clinical benefit response (95% confidence interval [CI], 12.1% to 39.5%) as evidenced by improvement in pain intensity, analgesic consumption, and/or Karnofsky performance status. Three (7.3%) of the 41 patients with measurable disease had an objective response (partial). The median time to objective response was 85 days (range, 47 to 91 days) and duration of response was 208, 260, and 566 days for the three responding patients. One patient with nonmeasurable but assessable disease had improved residual disease with a positive clinical benefit response, for a total of four responses among the 42 assessable patients, for an overall response rate of 9.5% (90% CI, 3.3% to 20.5%). Capecitabine was generally well tolerated.

CONCLUSION: Treatment with capecitabine resulted in clinically significant beneficial effects on tumor-related symptoms and yielded objective response activity in patients with metastatic or locally advanced pancreatic cancer. These results together with its generally tolerable safety profile and the added advantage of oral administration provide the basis for further evaluating capecitabine as a single agent or in combination with other treatment modalities in this patient population.
Randomized Multicenter Phase II Trial of Oxaliplatin Plus Irinotecan Versus Raltitrexed as First-Line Treatment in Advanced Colorectal Cancer
Authors: Scheithauer Werner , Kornek Gabriela V. , Raderer Markus , Ulrich-Pur Herbert , Fiebiger Wolfgang , Gedlicka Claudia , Schüll Birgit , Brugger Stefan , Schneeweiss Bruno , Lang Fritz , Lenauer Alfred , Depisch Dieter
Published: February 2017

PURPOSE: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting.

PATIENTS AND METHODS: Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m2 plus irinotecan 175 mg/m2 or raltitrexed 3 mg/m2 given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected.

RESULTS: Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P = .0025) and longer progression-free survival (median, 7.1 v 5.0 months; P = .0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P = .3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m2, tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%).

CONCLUSION: Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.
Variations in the Use of Chemotherapy for Elderly Patients With Advanced Ovarian Cancer: A Population-Based Study
Authors: Sundararajan Vijaya , Hershman Dawn , Grann Victor R. , Jacobson Judith S. , Neugut Alfred I.
Published: February 2017

PURPOSE: Since 1986, the recommended therapy for patients with ovarian cancer has included surgery and chemotherapy with a platinum compound (cisplatin or carboplatin). The purpose of this study is to assess the use of chemotherapy in elderly patients with advanced ovarian cancer.

METHODS: The Surveillance, Epidemiology, and End Results–Medicare database represents approximately 14% of the United States population and provides clinical and demographic information on cancer patients covered by Medicare, along with health care–utilization data from Medicare claims files. We analyzed the association of demographic and clinical factors with treatment among patients diagnosed from 1992 to 1996 with stage III or IV ovarian cancer, who survived ≥ 120 days beyond diagnosis, and were ≥ 65 years of age (N = 1,775).

RESULTS: Approximately 83% of elderly patients received some form of chemotherapy within 4 months of diagnosis. In a multiple logistic regression model with patients aged 65 to 69 years as the reference, the odds ratios of receiving chemotherapy were 0.96 (95% confidence interval [CI], 0.63 to 1.46) for ages 70 to 74, 0.65 (95% CI, 0.43 to 1.00) for 75 to 79, 0.24 (95% CI, 0.15 to 0.37) for 80 to 84, and 0.12 (95% CI, 0.07 to 0.19) for 85+. Hispanic patients were less likely to receive chemotherapy than non-Hispanic white patients. Since 1992, paclitaxel has gradually replaced cyclophosphamide as the drug most commonly used with platinum.

CONCLUSION: Despite its proven efficacy in treating ovarian cancer, chemotherapy seems to be used less among patients over age 65, especially those who are nonwhite and/or in the oldest age groups. Further research is needed to elucidate to what degree this represents appropriate clinical judgment and to what degree other factors, such as patient choice, play a role.
Neoadjuvant Chemotherapy and Radical Surgery Versus Exclusive Radiotherapy in Locally Advanced Squamous Cell Cervical Cancer: Results From the Italian Multicenter Randomized Study
Authors: Benedetti-Panici Pierluigi , Greggi Stefano , Colombo Alessandro , Amoroso Mariangela , Smaniotto Daniela , Giannarelli Diana , Amunni Gianni , Raspagliesi Francesco , Zola Paolo , Mangioni Costantino , Landoni Fabio
Published: February 2017

PURPOSE: Neoadjuvant chemotherapy (NACT) and radical surgery (RS) have emerged as a possible alternative to conventional radiation therapy (RT) in locally advanced cervical carcinoma. In 1990, a phase III trial was undertaken to verify such a hypothesis in terms of survival and treatment-related morbidity.

PATIENTS AND METHODS: Patients with squamous cell, International Federation of Gynecology and Obstetrics stage IB2 to III cervical cancer were eligible for the study. They received cisplatin-based NACT followed by RS (type III to V radical hysterectomy plus systematic pelvic lymphadenectomy) (arm A) or external-beam RT (45 to 50 Gy) followed by brachyradiotherapy (20 to 30 Gy) (arm B).

RESULTS: Of 441 patients randomly assigned to NACT+RS or RT, eligibility was confirmed in 210 and 199 patients, respectively. Treatment was administered according to protocol in 76% of arm A patients and 72% of arm B patients. Adjuvant treatment was delivered in 48 operated patients (29%). There was no evidence for any significant excess of severe morbidity in one of the two arms. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 58.9% and 55.4% for arm A and 44.5% and 41.3% for arm B (P = .007 and P = .02), respectively. Subgroup survival analysis shows OS and PFS rates of 64.7% and 59.7% (stage IB2-IIB, NACT+RS), 46.4% and 46.7% (stage IB2-IIB, RT) (P = .005 andP = .02), 41.6% and 41.9% (stage III, NCAT+RS), 36.7% and 36.4% (stage III, RT) (P = .36 and P = .29), respectively. Treatment had a significant impact on OS and PFS.

CONCLUSION: Although significant only for the stage IB2 to IIB group, a survival benefit seems to be associated with the NACT+RS compared with conventional RT.
New Prognostic Score Based on Treatment Outcome of Patients With Relapsed Hodgkin’s Lymphoma Registered in the Database of the German Hodgkin’s Lymphoma Study Group
Authors: Josting Andreas , Franklin Jeremy , May Michael , Koch Peter , Beykirch Maria K. , Heinz Juergen , Rudolph Christian , Diehl Volker , Engert Andreas
Published: February 2017

PURPOSE: To evaluate salvage treatment outcome of patients with relapsed Hodgkin’s disease (HD) and to distinguish different risk groups using identified prognostic factors.

PATIENTS AND METHODS: From 4,754 patients registered in the German Hodgkin’s Lymphoma Study Group (GHSG) database between 1988 and 1999, 422 patients with early (n = 170) or late (n = 252) relapsed HD were identified. One hundred seven patients (25%) relapsed after radiotherapy (RT) for early stages, 133 patients (32%) after combined-modality therapy for intermediate stages, and 182 patients (43%) after chemotherapy (CT) and RT to initial bulky disease or residual lymphoma for advanced stages. At relapse, characteristics of these 422 patients (median age, 38 years; range, 17 to 77) were stage III/IV, 45%; B symptoms, 24%; elevated erythrocyte sedimentation rate, 29%; anemia, 13%; and Karnofsky performance score, less than 90 in 13%. At first relapse, salvage treatment was RT in 13%, CT in 54%, and high-dose chemotherapy (HDCT) with autologous stem-cell transplantation (ASCT) in 33%.

RESULTS: Median follow-up time after relapse was 45 months. Freedom from second failure (FF2F) and overall survival (OS) were 81% and 89% for relapse after RT, 33% and 46% for early relapse after CT, and 43% and 71% for late relapse after CT, respectively. In multivariate analysis, independent risk factors were time to relapse, clinical stage at relapse, and anemia at relapse. Four subgroups with significantly different FF2F and OS were identified. The prognostic score was predictive for patients who relapsed after RT, CT with conventional CT salvage, and CT with HDCT/ASCT.

CONCLUSION: In the GHSG database, time to relapse and clinical stage and anemia at relapse are relevant factors and can be used to form a prognostic score for HD patients at relapse.
Importance of Radiotherapy in the Outcome of Patients With Primary CNS Lymphoma: An Analysis of the CHOD/BVAM Regimen Followed by Two Different Radiotherapy Treatments
Authors: Bessell E. M. , López-Guillermo A. , Villá S. , Verger E. , Nomdedeu B. , Petit J. , Byrne P. , Montserrat E. , Graus F.
Published: February 2017

PURPOSE: To assess the effect of a reduced dose of radiotherapy (RT) in patients with primary CNS lymphoma (PCNSL) responding to the cyclophosphamide, doxorubicin, vincristine, and dexamethasone (CHOD)/carmustine, vincristine, methotrexate, and cytarabine (BVAM) regimen.

PATIENTS AND METHODS: Patients received one cycle of CHOD and two of BVAM. In the first trial, all 31 patients received 45-Gy whole-brain RT (CHOD/BVAM I). In the second, with 26 patients, RT dose was reduced to 30.6 Gy if there was a complete response (CR) after chemotherapy (CHOD/BVAM II).

RESULTS: Age, performance status, and chemotherapy received were similar in both protocols. CR rate at the end of all treatment was 68% for CHOD/BVAM I and 77% and for CHOD/BVAM II. Treatment modality was the only predictor of relapse, with 3-year relapse risks of 29% and 70% for CHOD/BVAM I and II, respectively. This was specifically important in the 25 patients less than 60 years old (3-year relapse risk, 25% v 83%; P = .01). The 5-year overall survival (OS) was 36%. Age (< 60 v ≥ 60 years) was the only predictor for OS in the multivariate analysis (relative risk, 2.1; 95% confidence interval, 1.4 to 2.8). RT dose was the only predictor of OS in patients younger than 60 years old who achieved CR at the end of all treatment (3-year OS, 92% v 60% for patients receiving 45 or 30.6 Gy, respectively; P = .04).

CONCLUSION: Reduction of the RT dose from 45 Gy to 30.6 Gy in patients younger than 60 years old with PCNSL who achieved CR resulted in an increased risk of relapse and lower OS.
Preoperative Chemotherapy Followed by Surgery Compared With Primary Surgery in Resectable Stage I (Except T1N0), II, and IIIa Non–Small-Cell Lung Cancer
Authors: Depierre Alain , Milleron Bernard , Moro-Sibilot Denis , Chevret Sylvie , Quoix Elisabeth , Lebeau Bernard , Braun Denis , Breton Jean-Luc , Lemarié Etienne , Gouva Sylvie , Paillot Nadine , Bréchot Jeanne-Marie , Janicot Henri , Lebas François-Xavier , Terrioux Philippe , Clavier Jean , Foucher Pascal , Monchâtre Michel , Coëtmeur Daniel , Level Marie-Claude , Leclerc Pascal , Blanchon François , Rodier Jean-Michel , Thiberville Luc , Villeneuve Anne , Westeel Virginie , Chastang Claude ,   from the French Thoracic Cooperative Group
Published: February 2017

PURPOSE: To evaluate whether preoperative chemotherapy (PCT) could improve survival in resectable stage I (except T1N0), II, and IIIA non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: A randomized trial compared PCT to primary surgery (PRS). PCT consisted of two cycles of mitomycin (6 mg/m2, day 1), ifosfamide (1.5 g/m2, days 1 to 3) and cisplatin (30 mg/m2, days 1 to 3), and two additional postoperative cycles for responding patients. In both arms, patients with pT3 or pN2 disease received thoracic radiotherapy.

RESULTS: Three hundred fifty-five eligible patients were randomized. Overall response to PCT was 64%. There were two preoperative toxic deaths. Postoperative mortality was 6.7% in the PCT arm and 4.5% in the PRS arm (P = .38). Median survival was 37 months (95% confidence interval [CI], 26.7 to 48.3) for PCT and 26.0 months (95% CI, 19.8 to 33.6) for PRS (P = .15). Survival differences between both arms increased from 3.8% (95% CI, 1.3% to 25.1%) at 1 year to 8.6% (95% CI, 2.64% to 24.4%) at 4 years. A quantitative interaction between N status and treatment was observed, with benefit confined to N0 to N1 disease (relative risk [RR], 0.68; 95% CI, 0.49 to 0.96; P = .027). After a nonsignificant excess of deaths during treatment, the effect of PCT was significantly favorable on survival (RR, 0.74; 95% CI, 0.56 to 0.99; P = .044). Disease-free survival time was significantly longer in the PCT arm (P = .033).

CONCLUSION: Although impressive differences in median, 3-year, and 4-year survival were observed, they were not statistically significant, except for stage I and II disease.
Palliative Uses of Methylphenidate in Patients With Cancer: A Review
Authors: Rozans Mark , Dreisbach Albert , Lertora Juan J.L. , Kahn Marc J.
Published: February 2017

PURPOSE: Cancer is, unfortunately, often a terminal disease. The goal of therapy for many patients with cancer is palliation of symptoms common at the end of life, including pain, depression, and cognitive dysfunction. Methylphenidate is a psychostimulant most commonly used in the treatment of attention deficit hyperactivity disorder. In this report, we review the use of methylphenidate in the palliative care of patients with cancer.

METHODS: This review was written on the basis of a computerized literature search of Medline. We considered all English language publications from 1966 to present using the following key words: methylphenidate, palliative care, and cancer. Forty-nine articles were identified as being relevant for this review.

RESULTS: On the basis of this review, we came to the conclusion that methylphenidate is used to ameliorate opioid-induced somnolence, to augment the analgesic effects of opioids, to treat depression, and to improve cognitive function in patients with cancer.

CONCLUSION: The medical literature supports the palliative use of methylphenidate in the care of patients with cancer. Further placebo-controlled trials are needed to elucidate the precise role that methylphenidate will have in providing symptom relief to dying patients.
Survey of Modalities of Toxicity Assessment and Reporting in Noncomparative Prospective Studies of Chemotherapy in Breast Cancer
Authors: Perrone Francesco , De Maio Ermelinda , Maione Paolo , Di Maio Massimo , Ottaiano Alessandro , Pensabene Matilde , Di Lorenzo Giuseppe , Vernaglia Lombardi Alessandra , Gallo Ciro
Published: February 2017

PURPOSE: To review how toxicity, a main end point of phase II studies, is assessed and reported in published phase II chemotherapy trials in breast cancer.

METHODS: A survey was performed by hand-searching studies published in seven distinguished journals between 1995 and 1999. All selected articles were independently evaluated by two investigators using an ad hoc study report form. Descriptive statistics, contingency tables, and the χ2 test were applied.

RESULTS: Overall, 122 articles were found; 65.6% lacked a statistical study design. Planned modalities for assessment of toxicity were inadequately reported in 20.5% of the studies. The scheduling of assessment of hematologic toxicity varied greatly. Toxicity was predominantly summarized per patient (69.7%). Although overall the World Health Organization scale was adopted more frequently (45.9%), the Common Toxicity Criteria (in different versions) were used more frequently in studies published in journals with a high impact factor (P = .001), in more recently initiated studies (P = .03), in sponsored studies (P = .0006), and in studies with an identifiable statistical design (P = .006).

CONCLUSION: The wide diversity in modalities of toxicity assessment and reporting observed in this study suggests that the reliability of the body of published data on the toxicity of chemotherapy in breast cancer may be questionable. Current standards should be revised and harmonized to improve the reliability of such data. A checklist is proposed to help editorial evaluation of assessment and reporting of toxicity in phase II studies.
Reinfusion of Autologous Lymphocytes With Granulocyte-Macrophage Colony-Stimulating Factor Induces Rapid Recovery of CD4+ and CD8+ T Cells After High-Dose Chemotherapy for Metastatic Breast Cancer
Authors: de Gast G. C. , Vyth-Dreese F. A. , Nooijen W. , van den Bogaard C. J.C. , Sein J. , Holtkamp M. M.J. , Linthorst G. A.M. , Baars J. W. , Schornagel J. H. , Rodenhuis S.
Published: February 2017

PURPOSE: Repeated high-dose chemotherapy (HDCT) followed by peripheral-blood progenitor cell (PBPC) transplantation can induce a complete remission in patients with metastatic breast cancer sensitive to standard chemotherapy (CT), but the majority of patients relapse within 1 to 2 years. The immune system is seriously compromised after HDCT, which precludes the development of effective immunotherapy. We investigated whether autologous lymphocytes, reinfused after HDCT, could induce a rapid recovery of T cells.

PATIENTS AND METHODS: Three patients were monitored for immune recovery without reinfusion of lymphocytes. In the next 11 patients, stem cells were harvested after CT + granulocyte colony-stimulating factor (G-CSF) and lymphocytes were harvested after CT + granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2. These patients received stem cells and G-CSF after the first HDCT; stem cells, G-CSF, and lymphocytes after the second; and stem cells, GM-CSF, and lymphocytes after the third HDCT.

RESULTS: Patients not receiving lymphocyte reinfusion had a very slow recovery of lymphocytes. In particular, CD4 counts remained low (< 200/μL for 9 months). Lymphocyte reinfusion had a significant effect on the recovery of lymphocytes, T cells, and CD8+ T cells (normalized on day 25). Recovery of CD4+ T cells was significantly accelerated by lymphocyte reinfusion and GM-CSF, leading to counts of 500/μL at 25 days.

CONCLUSION: Lymphocyte reinfusion with G-CSF had a significant effect on the recovery of CD8+ T cells, whereas rapid recovery of CD4+ T cells required lymphocyte reinfusion and GM-CSF, which possibly acts as a survival factor through activation of antigen presenting cells. Whether the rapid recovery of CD4+ and CD8+ T cells prevents or delays relapse of the disease should be further investigated.
Phase I Study of Combination Topotecan and Carboplatin in Pediatric Solid Tumors
Authors: Athale Uma H. , Stewart Clinton , Kuttesch John F. , Moghrabi Albert , Meyer William , Pratt Charles , Gajjar Amar , Heideman Richard L.
Published: February 2017

PURPOSE: We conducted a phase I trial of escalating doses of topotecan (TOPO) in association with a fixed systemic exposure of carboplatin (CARBO) with or without granulocyte colony-stimulating factor (G-CSF) in children.

PATIENTS AND METHODS: Two separate cohorts of patients (pts) with solid tumors were studied: (A) pts with refractory or recurrent disease and (B) pts with no prior myelosuppressive therapy or newly diagnosed tumors for which there was no standard chemotherapy. CARBO was given on day 1 at an area under the curve of 6.5, followed by TOPO as a continuous infusion for 3 days; the starting dose of TOPO was 0.50 mg/m2/d. Cycles were repeated every 21 days. G-CSF was given at a dose of 5 μg/kg/d starting on day 4.

RESULTS: Forty-eight of 51 pts were assessable for toxicity. In group A, dose-limiting myelosuppression persisted despite de-escalation of TOPO to 0.3 mg/m2/d and use of G-CSF. In group B, the maximum-tolerated dose of TOPO was 0.5 mg/m2/d for 3 days, and 0.6 mg/m2/d for 3 days with G-CSF. No significant nonhematologic toxicities were observed. Among 46 pts assessable for response, one had complete response, five had partial response, and 18 had stable disease.

CONCLUSION: Although this combination possesses antineoplastic activity in pediatric solid tumors, hematologic toxicity precluded any meaningful TOPO dose escalation. The addition of G-CSF did not alter this. The potential for preservation of activity and diminution of toxicity with alternative sequences and schedules of administration (topoisomerase followed by alkylating or platinating agents) should be evaluated.
Value of Positron Emission Tomography With [F-18]Fluorodeoxyglucose in Patients With Colorectal Liver Metastases: A Prospective Study
Authors: Ruers T.J.M. , Langenhoff B.S. , Neeleman N. , Jager G. J. , Strijk S. , Wobbes Th. , Corstens F. H.M. , Oyen W. J.G.
Published: February 2017

PURPOSE: To assess prospectively the value of fluor-18-deoxyglucose (FDG) positron emission tomography (PET), in addition to conventional diagnostic methods (CDM), as a staging modality in candidates for resection of colorectal liver metastases.

PATIENTS AND METHODS: In 51 patients analyzed for resection of colorectal liver metastases, clinical management decisions were recorded after a complete work-up with CDM. Afterward, FDG-PET scans were performed and any change of clinical management according to FDG-PET results was carefully documented. Discordances between FDG-PET and CDM results were identified and related to the final diagnosis by histopathology, intraoperative findings, and follow-up.

RESULTS: In 10 (20%) out of 51 patients, clinical management decisions based on CDM were changed after FDG-PET findings were known. FDG-PET detected unresectable pulmonary (n = 5) and hepatic metastases (n = 1) and ruled out extrahepatic (n = 2) and hepatic disease (n = 2). Due to FDG-PET, eight patients were spared unwarranted liver resection or laparotomy and two other patients were identified as candidates for liver resection. When the results of FDG-PET were regarded as decisive in a retrospective analysis, potential change of management was 29% (15 patients). FDG-PET and CDM showed discordant extrahepatic results in 11 patients (22%) and discordant hepatic results in eight patients (16%). Compared with CDM, FDG-PET resulted in true upstaging (n = 11), true downstaging (n = 5), false upstaging (n = 1), and false downstaging (n = 2). The detection rate of liver metastases on a lesion basis was generally better for computed tomography than for FDG-PET (80% v 65%); this was related to tumor size.

CONCLUSION: FDG-PET as a complementary staging method improves the therapeutic management of patients with colorectal liver metastases, especially by detecting unsuspected extrahepatic disease.
Phase II/III Trial of Etoposide and High-Dose Ifosfamide in Newly Diagnosed Metastatic Osteosarcoma: A Pediatric Oncology Group Trial
Authors: Goorin Allen M. , Harris Michael B. , Bernstein Mark , Ferguson William , Devidas Meenakshi , Siegal Gene P. , Gebhardt Mark C. , Schwartz Cindy L. , Link Michael , Grier Holcombe E.
Published: February 2017

PURPOSE: The objectives of this trial were to estimate the response rate, progression-free survival, and overall survival of patients who received therapy with etoposide and high-dose ifosfamide, and to define the toxicity of this combination when provided with standard chemotherapy in patients with newly diagnosed metastatic osteosarcoma.

PATIENTS AND METHODS: Eligible patients received infusions of 100 mg/m2 per day of etoposide and 3.5 g/m2 per day of ifosfamide for 5 days. Therapy with granulocyte colony-stimulating factor was begun on day 6. This was repeated 3 weeks after therapy was begun. Response was determined at week 6 by both standard World Health Organization response criteria and by pathologic determination of tumor necrosis of the primary tumor.

RESULTS: Forty-three patients were registered; 39 were assessable for response and 41 for toxicity and survival. Twenty-eight (68%) of 41 had metastatic sites only in the lung; 12 (29%) had metastatic sites in other bones with or without lung involvement. Four patients (10%) experienced complete response, and 19 patients (49%) experienced partial response, for an overall response rate of 59% ± 8%. The projected 2-year progression-free survival (PFS) for the 28 patients with metastases to lungs was 39% ± 11%. The projected 2-year PFS for the 12 patients with metastases to other bones (with or without pulmonary metastases) was 58% ± 17%. Two patients died as a result of therapy toxicity. Eighty-three percent of patients had grade 4 neutropenia, and 29% had grade 4 thrombocytopenia. Ten patients (24%) had sepsis. Fanconi’s syndrome was observed in five patients.

CONCLUSION: The combination of etoposide and high-dose ifosfamide is effective induction chemotherapy for patients with metastatic osteosarcoma, despite significant associated myelosuppression sometimes complicated by infection and renal toxicity.
Neuropsychologic Impact of Standard-Dose Systemic Chemotherapy in Long-Term Survivors of Breast Cancer and Lymphoma
Authors: Ahles Tim A. , Saykin Andrew J. , Furstenberg Charlotte T. , Cole Bernard , Mott Leila A. , Skalla Karen , Whedon Marie B. , Bivens Sarah , Mitchell Tara , Greenberg E. Robert , Silberfarb Peter M.
Published: February 2017

PURPOSE: The primary purpose of this study was to compare the neuropsychologic functioning of long-term survivors of breast cancer and lymphoma who had been treated with standard-dose systemic chemotherapy or local therapy only.

PATIENTS AND METHODS: Long-term survivors (5 years postdiagnosis, not presently receiving cancer treatment, and disease-free) of breast cancer or lymphoma who had been treated with systemic chemotherapy (breast cancer: n = 35, age, 59.1 ± 10.7 years; lymphoma: n = 36, age, 55.9 ± 12.1 years) or local therapy only (breast cancer: n = 35, age, 60.6 ± 10.5 years; lymphoma: n = 22, age, 48.7 ± 11.7 years) completed a battery of neuropsychologic and psychologic tests (Center for Epidemiological Study–Depression, Spielberger State-Trait Anxiety Inventory, and Fatigue Symptom Inventory).

RESULTS: Multivariate analysis of variance, controlling for age and education, revealed that survivors who had been treated with systemic chemotherapy scored significantly lower on the battery of neuropsychologic tests compared with those treated with local therapy only (P < .04), particularly in the domains of verbal memory (P < .01) and psychomotor functioning (P < .03). Survivors treated with systemic chemotherapy were also more likely to score in the lower quartile on the Neuropsychological Performance Index (39% v 14%, P < .01) and to self-report greater problems with working memory on the Squire Memory Self-Rating Questionnaire (P < .02).

CONCLUSION: Data from this study support the hypothesis that systemic chemotherapy can have a negative impact on cognitive functioning as measured by standardized neuropsychologic tests and self-report of memory changes. However, analysis of the Neuropsychological Performance Index suggests that only a subgroup of survivors may experience long-term cognitive deficits associated with systemic chemotherapy.
When the Treatment Goal Is Not Cure: Are Cancer Patients Equipped to Make Informed Decisions?
Authors: Gattellari Melina , Voigt Katie J. , Butow Phyllis N. , Tattersall Martin H.N.
Published: February 2017

PURPOSE: Informed decision making now is considered the underpinning of ethical medical practice. We aimed to determine the extent to which patients with incurable cancer are adequately informed of their prognosis and treatment options and encouraged to participate in treatment decisions.

PATIENTS AND METHODS: One hundred eighteen cancer patients with incurable disease presenting for an initial consultation with one of nine oncologists at two Sydney tertiary referral hospitals participated in the study. Consultations were recorded on audiotape to permit a content analysis of doctor-patient interactions. We devised a coding system to assess disclosure of information and to evaluate doctor encouragement of patient participation in treatment decision making. Patient recall, satisfaction, anxiety, and perceptions of the decision-making process were assessed to determine the effects of informed decision making on patient outcomes.

RESULTS: Most patients were informed about the aim of anticancer treatment (84.7%), that their disease was incurable (74.6%), and about life expectancy (57.6%). An alternative to anticancer treatments was presented to 44.1%, 36.4% were informed about how anticancer treatment would affect quality of life, and 29.7% were offered a management choice. Oncologists checked patient understanding in only 10.2% of consultations. Although greater information disclosure did not seem to elevate anxiety levels, greater patient participation in the decision-making process was associated with increased anxiety levels (P = .0005), which persisted over a 2-week time span.

CONCLUSION: Most patients were well informed, but important gaps remain, especially concerning information about prognosis and alternatives to anticancer treatment. These gaps invite the question concerning whether patients are led toward anticancer treatment.
Identification and Referral of Families at High Risk for Cancer Susceptibility
Authors: Sweet Kevin M. , Bradley Terry L. , Westman Judith A.
Published: February 2017

PURPOSE: Obtainment of family history and accurate assessment is essential for the identification of families at risk for hereditary cancer. Our study compared the extent to which the family cancer history in the physician medical record reflected that entered by patients directly into a touch-screen family history computer program.

PATIENTS AND METHODS: The study cohort consisted of 362 patients seen at a comprehensive cancer center ambulatory clinic over a 1-year period who voluntarily used the computer program and were a mixture of new and return patients. The computer entry was assessed by genetics staff and then compared with the medical record for corroboration of family history information and appropriate physician risk assessment.

RESULTS: Family history information from the medical record was available for comparison to the computer entry in 69%. It was most often completed on new patients only and not routinely updated. Of the 362 computer entries, 101 were assigned to a high-risk category. Evidence in the records confirmed 69 high-risk individuals. Documentation of physician risk assessment (ie, notation of significant family cancer history or hereditary risk) was found in only 14 of the high-risk charts. Only seven high-risk individuals (6.9%) had evidence of referral for genetic consultation.

CONCLUSION: This study demonstrates the need to collect family history information on all new and established patients in order to perform adequate cancer risk assessment. The lack of identification of patients at highest risk seems to be directly correlated with insufficient data collection, risk assessment, and documentation by medical staff.
Tumor Hypoxia Has Independent Predictor Impact Only in Patients With Node-Negative Cervix Cancer
Authors: Fyles A. , Milosevic M. , Hedley D. , Pintilie M. , Levin W. , Manchul L. , Hill R. P.
Published: February 2017

PURPOSE: This prospective clinical study was begun in 1994 to validate the independent prognostic impact of tumor hypoxia in patients with cervix cancer treated with definitive radiation therapy.

PATIENTS AND METHODS: Between May 1994 and January 1999, 106 eligible patients with epithelial cervix cancer had tumor oxygen pressure (PO2) measured using the Eppendorf probe. Oxygenation data are presented as the hypoxic proportion, defined as the percentage of PO2 readings less than 5 mm/Hg (abbreviated as HP5) and the median PO2.

RESULTS: The median HP5 in individual patients was 48%, and the median PO2 was HP5. Progression-free survival (PFS) for patients with hypoxic tumors (HP5 > 50%) was 37% at 3 years versus 67% in those patients with better oxygenated tumors (P = .004). In multivariate analysis, only tumor size (risk ratio [RR], 1.33; P = .0003) and evidence of pelvic nodal metastases on imaging studies (RR, 2.52; P = .0065) were predictive of PFS. However, an interaction between nodal status and oxygenation was observed (P = .006), and further analysis indicated that HP5 was an independent predictor of outcome in patients with negative nodes on imaging (P = .007). There was a significant increase in the 3-year cumulative incidence of distant metastases in the hypoxic group (41% v 15% in those with HP5 < 50%; P = .0023), but not in pelvic relapse (37% v 27%; P = .12).

CONCLUSION: Tumor hypoxia is an independent predictor of poor PFS only in patients with node-negative cervix cancer, in addition to tumor size. Its impact appears to be related to an increased risk of distant metastases rather than to an effect on pelvic control.