bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular pathologic substaging in 244 stage I non-small-cell lung cancer patients: clinical implications.
Authors: Kwiatkowski D J , Harpole D H , Godleski J , Herndon J E , Shieh D B , Richards W , Blanco R , Xu H J , Strauss G M , Sugarbaker D J
Published: February 2017

PURPOSE

To retrospectively construct a comprehensive multivariate model of cancer recurrence and to design a molecular pathologic substaging system in stage I non-small-cell lung cancer (NSCLC).

METHODS

All patients with stage I NSCLC resected at Brigham and Women's Hospital (Boston, MA) between 1984 and 1992 with adequate clinical follow-up were studied. The importance of three demographic characteristics, surgical extent, 11 pathologic features, and seven molecular factors on cancer-free survival was examined.

RESULTS

Two hundred forty-four patients were studied, with 25 noncancer deaths and 80 patients with recurrent disease. Significant univariate predictors (P < .05) of cancer recurrence were age older than 60 years, male sex, wedge resection, World Health Organization (WHO) adenocarcinoma subtype solid tumor with mucin, lymphatic invasion, and p53 expression. Multivariate analysis identified nine independent predictors of recurrence: solid tumor with mucin, a wedge resection, tumor diameter of 4 cm or greater, lymphatic invasion, age older than 60 years, male sex, p53 expression, K-ras codon 12 mutation, and absence of H-ras p21 expression. Multivariate cancer-free survival (CFS) analysis in the 180 patients who underwent lobectomy or pneumonectomy led to the elimination of sex and age, which left six independent factors.

CONCLUSION

Lobectomy or pneumonectomy should be performed in stage I NSCLC. Using the six independent factors for recurrent disease, we propose a pathologic molecular substaging system. Patients with two factors or less are graded Ia, with a 5-year CFS rate of 87%; those with three factors are graded Ib, with a 5-year CFS rate of 58%; and those with four factors or more are graded Ic, with a 5-year CFS rate of 21%.
Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.
Authors: Langevin A M , Casto D T , Thomas P J , Weitman S D , Kretschmar C , Grier H , Pratt C , Dubowy R , Bernstein M , Blaney S , Vietti T
Published: February 2017

PURPOSE

A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity.

PATIENTS AND METHODS

A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD.

RESULTS

Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition.

CONCLUSION

The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.
Cancer gene therapy: connecting basic research with clinical inquiry.
Authors: Dranoff G
Published: February 2017

Molecular genetics has spawned an impressive outpouring of insights into the biology of neoplastic transformation and the host-tumor relationship. This deeper understanding of cancer pathogenesis presents a rich opportunity to develop novel therapeutic agents with improved selectivity for cancer cells. One promising approach involves gene therapy, which is the introduction of genetic material into a patient's tissues with the intent to achieve therapeutic benefit. A number of gene transfer systems have been designed that enable the genetic modification of relevant target cells, albeit with varying strengths and limitations. Several strategies to exploit gene transfer as a tool to target specific molecular defects intrinsic to cancer cells, enhance tumor chemosensitivity, and augment tumor immunogenicity are under intensive investigation. A number of these approaches have entered initial clinical testing and already provide intriguing new information about the biology of cancer in patients. In this review, I will highlight the critical issues and controversies that underscore preclinical experiments in cancer gene therapy, discuss some of the preliminary findings from the first wave of clinical trials, and speculate about the prospects that cancer gene therapy will change the way that cancer medicine is practiced.
Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment.
Authors: Pegram M D , Lipton A , Hayes D F , Weber B L , Baselga J M , Tripathy D , Baly D , Baughman S A , Twaddell T , Glaspy J A , Slamon D J
Published: February 2017

PURPOSE

To determine the toxicity, pharmacokinetics, response rate, and response duration of intravenous (i.v.) administration of recombinant, humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) plus cisplatin (CDDP) in a phase II, open-label, multicenter clinical trial for patients with HER2/neu-overexpressing metastatic breast cancer.

PATIENTS AND METHODS

The study population consisted of extensively pretreated advanced breast cancer patients with HER2/neu overexpression and disease progression during standard chemotherapy. Patients received a loading dose of rhuMAb HER2 (250 mg i.v.) on day 0, followed by weekly doses of 100 mg i.v. for 9 weeks. Patients received CDDP (75 mg/m2) on days 1, 29, and 57.

RESULTS

Of 37 patients assessable for response, nine (24.3%) achieved a PR, nine (24.3%) had a minor response or stable disease, and disease progression occurred in 19 (51.3%). The median response duration was 5.3 months (range, 1.6-18). Grade III or IV toxicity was observed in 22 of 39 patients (56%). The toxicity profile reflected that expected from CDDP alone with the most common toxicities being cytopenias (n = 10), nausea/vomiting (n = 9), and asthenia (n = 5). Mean pharmacokinetic parameters of rhuMAb HER2 were unaltered by coadministration of CDDP.

CONCLUSION

The use of rhuMAb HER2 in combination with CDDP in patients with HER2/neu-overexpressing metastatic breast cancer results in objective clinical response rates higher than those reported previously for CDDP alone, or rhuMAb HER2 alone. In addition, the combination results in no apparent increase in toxicity. Finally, the pharmacology of rhuMAb HER2 was unaffected by coadministration with CDDP.
Infiltrating ductal carcinoma of the breast: the survival impact of race.
Authors: Edwards M J , Gamel J W , Vaughan W P , Wrightson W R
Published: February 2017

PURPOSE

Breast cancer has a poorer prognosis among black women than among white women. This review was conducted to determine whether this disparity reflects the direct impact of race on likelihood of cure or on time to death from breast cancer or stems from the interaction of race with tumor stage and patient age.

PATIENTS AND METHODS

We analyzed data from 115,838 patients with localized (node-negative) and regionally metastatic (node-positive) breast cancer from the Surveillance, Epidemiology, and End-Results (SEER) Program of the National Cancer Institute. Parametric analysis was used to determine the independent prognostic value of age, stage, and race. Linear regression and distribution analyses were also used to examine the interaction of these covariates.

RESULTS

The prevalence of regionally metastatic disease, relative to localized disease, declined with increased age among white patients and those classified as "other," but remained relatively constant among black patients. Parametric analysis showed a smaller cured fraction and shorter time to death when patients with regional disease were compared with those with localized disease. A similar disparity was found when black patients were compared with those classified as white or other.

CONCLUSION

Age and race have a significant association with tumor stage. In addition, our data show that race has an independent impact on the clinical course of breast cancer and diminishes both the likelihood of cure and time to death among uncured patients.
Enhanced myelotoxicity due to granulocyte colony-stimulating factor administration until 48 hours before the next chemotherapy course in patients with small-cell lung carcinoma.
Authors: Tjan-Heijnen V C , Biesma B , Festen J , Splinter T A , Cox A , Wagener D J , Postmus P E
Published: February 2017

PURPOSE

To evaluate the impact of granulocyte colony-stimulating factor (G-CSF) priming on peripheral-blood cell counts during standard-dose chemotherapy.

PATIENTS AND METHODS

Twelve patients with relapsed small-cell lung carcinoma (SCLC) were treated with two chemotherapy courses. Six patients received G-CSF priming only before the first course (group A) and the other six patients only before the second course (group B). Each patient served as his own control. Patients were treated with cyclophosphamide, epirubicin, and etoposide (CEE), or with vincristine, ifosfamide, mesna, and carboplatin (VIMP) every 4 weeks. G-CSF was administered subcutaneously 5 microg/kg/d for 6 days until 48 hours before the first or second chemotherapy course.

RESULTS

Priming caused a lowering of the WBC nadir, with a median value of 0.95 x 10(9)/L (P = .004), and of absolute neutrophil nadir, with a median value of 0.48 x 10(9)/L (P = .03). There was a trend for a lower platelet (PLT) nadir after G-CSF priming (P = .09). G-CSF priming resulted in a prolonged duration of WBC count less than 3.0 x 10(9)/L of +4.25 days (P = .04), and of WBC count less than 1.0 x 10(9)/L of +0.50 days (P = .03). The duration of neutropenia less than 0.5 x 10(9)/L seemed longer in primed courses (+3.75 days, P = .18). The duration of PLT counts less than 100 x 10(9)/L was prolonged by 1.5 days (P = .04). Hemoglobin (Hgb) levels were not influenced by G-CSF priming.

CONCLUSION

G-CSF administration until 48 hours before the next chemotherapy course increases chemotherapy-associated leukocytopenia and thrombocytopenia. This may be of special concern when G-CSF is administered during dose-densified chemotherapy.
Treatment of patients with transitional-cell carcinoma of the urothelial tract with ifosfamide, paclitaxel, and cisplatin: a phase II trial.
Authors: Bajorin D F , McCaffrey J A , Hilton S , Mazumdar M , Kelly W K , Scher H I , Spicer J , Herr H , Higgins G
Published: February 2017

PURPOSE

A phase II trial of ifosfamide, paclitaxel, and cisplatin (ITP) was conducted in previously untreated patients with advanced transitional-cell carcinoma (TCC) to assess its efficacy and toxicity.

PATIENTS AND METHODS

Thirty patients with metastatic or unresectable TCC were treated with ifosfamide 1.5 g/m2/d for 3 days with paclitaxel 200 mg/m2 over 3 hours and cisplatin 70 mg/m2 on day 1 of each 28-day treatment cycle. Therapy was continued for a maximum of six cycles. Prophylactic hematopoietic growth factor (recombinant human granulocyte colony-stimulating factor [rhG-CSF]) was given on days 6 to 17 of each cycle.

RESULTS

Twenty-three of 29 assessable patients (79%; 95% confidence interval [CI], 60% to 92%) demonstrated a major response (six complete [CR] and 17 partial [PR]) with response durations that ranged from 5 to 24+ months. Five patients with T4 bladder primary tumors had a major response, two with pathologic CR. At a median follow-up duration of 17.9 months, nine (31%) patients remain disease-free (range, 10+ to 24+). Hematologic toxicity included anemia, thrombocytopenia, and neutropenia; febrile neutropenia was observed in 17% of patients and 4% of cycles. No grade 4 nonhematologic toxicity was observed. Grade 3 nonhematologic toxicity included alopecia, allergy (3%), renal insufficiency (13%), and neuropathy (10%). Dose reductions or drug omissions were necessary for adverse events in seven (23%) patients.

CONCLUSION

ITP is an active, well-tolerated regimen in previously untreated patients with TCC of the urothelial tract. Further study of this regimen in patients with both TCC and non-transitional-cell urothelial tumors is ongoing.
Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers.
Authors: Bécouarn Y , Ychou M , Ducreux M , Borel C , Bertheault-Cvitkovic F , Seitz J F , Nasca S , Nguyen T D , Paillot B , Raoul J L , Duffour J , Fandi A , Dupont-André G , Rougier P
Published: February 2017

PURPOSE

To evaluate the objective tumor response rate and safety profile of oxaliplatin when administered to patients with previously untreated metastatic colorectal adenocarcinoma.

PATIENTS AND METHODS

A total of 39 patients were entered onto this phase II trial. One patient was excluded for having had a second cancer, so the study was based on 38 patients. Patients were treated with oxaliplatin 130 mg/m2 as a 2-hour infusion on day 1, every 21 days. Patients were assessed for response every three courses. All clinical and radiologic data were reviewed by an external panel of experts, with their assessment being considered definitive.

RESULTS

Nine partial responses (PRs) were observed (response rate, 24.3%; 95% confidence interval, 11.8% to 41.2%). The median duration of response was 216+ days. Fifteen patients (40.5%) had stable disease and 13 (35.2%) had progressive disease. The median progression-free survival time for all patients was 126+ days (range, 21 to 447+). The main toxicity was peripheral sensory neuropathy. Grade 3 neurotoxicity (National Cancer Institute common toxicity criteria [NCI-CTC]) was reported in 13%. Hematologic and gastrointestinal toxicities were mild. The incidence of grade 3 neutropenia was 5.2%, while that of grade 3 or 4 thrombopenia was 7.9%. Vomiting (grade 3 or 4) occurred in 7.9% of patients and grade 3 diarrhea in 2.6%.

CONCLUSION

This phase II study provides clear evidence of the safety and efficacy of oxaliplatin monotherapy at this dose and schedule in patients with previously untreated metastatic colorectal carcinoma.
Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea in patients with advanced colorectal cancer: a prospective assessment.
Authors: Saliba F , Hagipantelli R , Misset J L , Bastian G , Vassal G , Bonnay M , Herait P , Cote C , Mahjoubi M , Mignard D , Cvitkovic E
Published: February 2017

PURPOSE

Irinotecan (CPT-11), a camptothecin derivative, has shown efficacy against colorectal cancer. Delayed-onset diarrhea is its main limiting toxicity. The aim of this study was to determine the pathophysiology of CPT-11-induced delayed-onset diarrhea and assess the efficacy of combined antidiarrheal medication in a phase II, prospective, successive-cohorts, open study.

PATIENTS AND METHODS

Twenty-eight patients with advanced colorectal cancer refractory to fluorouracil (5-FU) therapy received CPT-11 350 mg/m2 every 3 weeks. The first cohort of 14 consecutive patients explored for the mechanism of diarrhea received acetorphan (a new enkephalinase inhibitor) 100 mg three times daily; the second 14-patient cohort received, in addition to acetorphan, loperamide 4 mg three times daily. Before treatment, and if late diarrhea occurred, patients underwent colon mucosal biopsies for CPT-11 and topoisomerase I levels; intestinal transit time; fecalogram; fat and protein excretion; alpha1-antitrypsin clearance; D-xylose test; blood levels for vasoactive intestinal polypeptide, glucagon, gastrin, somatostatin, prostaglandin E2, and carboxylesterase; CPT-11/SN-38 and SN-38 glucuronide pharmacokinetics; and stool cultures.

RESULTS

Delayed-onset diarrhea occurred during the first three treatment cycles in 23 patients (82%). Electrolyte fecal measurements showed a negative or small osmotic gap in nine of nine patients and an increased alpha1-antitrypsin clearance in six of six patients. There were no modifications in stool cultures or hormonal dysfunction. Four of 11 patients (36%) with delayed-onset diarrhea in the first cohort responded to acetorphan, whereas nine of 10 patients (90%) responded to the combination of acetorphan and loperamide (P < .02).

CONCLUSION

CPT-11-induced delayed-onset diarrhea is caused by a secretory mechanism with an exudative component. Early combined treatment with loperamide and acetorphan seems effective in controlling the diarrheal episodes.
Phase I trial of anti-CD3-stimulated CD4+ T cells, infusional interleukin-2, and cyclophosphamide in patients with advanced cancer.
Authors: Curti B D , Ochoa A C , Powers G C , Kopp W C , Alvord W G , Janik J E , Gause B L , Dunn B , Kopreski M S , Fenton R , Zea A , Dansky-Ullmann C , Strobl S , Harvey L , Nelson E , Sznol M , Longo D L
Published: February 2017

PURPOSE

We performed a phase I trial to determine whether in vivo expansion of activated CD4+ T cells was possible in cancer patients. 111Indium labeling was used to observe trafficking patterns of the infused stimulated CD4+ T cells. The influence of cyclophosphamide (CTX) dosing on immunologic outcome was also examined.

PATIENTS AND METHODS

Patients with advanced solid tumors or non-Hodgkin's lymphoma received CTX at 300 or 1,000 mg/m2 intravenously (i.v.). Leukapheresis was performed to harvest peripheral-blood mononuclear cells (PBMCs) either just before the CTX dose, or when the patient was either entering or recovering from the leukocyte nadir induced by CTX. An enriched population of CD4+ T cells was obtained by negative selection. The CD4+ T cells were activated ex vivo with anti-CD3, cultured with interleukin-2 (IL-2) for 4 days, and adoptively transferred. After adoptive transfer, patients received IL-2 (9.0 x 10(6) IU/m2/d) by continuous infusion for 7 days.

RESULTS

The absolute number of CD4+, CD4+/DR+, and CD4+/CD45RO+ T cells increased in a statistically significant fashion in all cohorts after the first course of therapy. The degree of CD4 expansion was much greater than CD8 expansion, which resulted in a CD4:CD8 ratio that increased in 26 of 31 patients. The greatest in vivo CD4 expansion occurred when cells were harvested as patients entered the CTX-induced nadir. One complete response (CR), two partial responses (PRs), and eight minor responses were observed. Trafficking of 111Indium-labeled CD4 cells to subcutaneous melanoma deposits was also documented.

CONCLUSION

CD4+ T cells can be expanded in vivo in cancer patients, which results in increased CD4:CD8 ratios. The timing of pheresis in relation to CTX administration influences the degree of CD4 expansion. Tumor responses with this regimen were observed in a variety of tumors, including melanoma and non-Hodgkin's lymphoma; a high percentage of patients had at least some tumor regression from the regimen that produced the greatest CD4+ T-cell expansion.
New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project.
Authors: Armitage J O , Weisenburger D D
Published: February 2017

Increasing knowledge about the biology of the non-Hodgkin's lymphomas has led to new approaches in classification. Rather than grouping lymphomas simply based on cell size, cell shape, and growth pattern, it is now possible to identify distinctive clinicopathologic entities. In many cases, the existence of specific immunologic and/or genetic features has confirmed the existence of these distinctive types of lymphoma. Since patients will be given these diagnoses by pathologists, it is important that clinicians be knowledgeable with regard to their clinical characteristics. The findings for the 13 most common lymphoma types that will be encountered in clinical practice are presented here.
Consolidation therapy with antimetabolite-based therapy in standard-risk acute lymphocytic leukemia of childhood: a Pediatric Oncology Group Study.
Authors: Harris M B , Shuster J J , Pullen D J , Borowitz M J , Carroll A J , Behm F G , Land V J
Published: February 2017

PURPOSE

To develop antimetabolite-based consolidation regimens that minimize acute and long-term toxicities and improve the survival rate of children with standard-risk B-lineage acute lymphocytic leukemia (ALL).

PATIENTS AND METHODS

Seven hundred twenty-seven eligible patients with standard-risk early pre-B ALL were registered onto the study. Seven hundred sixteen patients attained a complete remission (CR) after induction therapy. Of these, 114 patients were randomized to a different regimen and were the subject of a separate report. Six hundred two patients were randomized to receive one the following regimens: intermediate-dose methotrexate (IDMTX) with leucovorin rescue on weeks 7, 10, 13, 16, 19, and 22 (regimen A); regimen A plus asparaginase (ASP) administered intramuscularly (i.m.) weekly for 24 weeks (regimen B); or regimen A plus a 24-hour infusion of cytarabine (AraC) with each IDMTX (regimen C). After consolidation, patients were placed on maintenance therapy through week 156. Regimens A and C were opened in February 1986, and regimen B in May 1987. Comparisons are based on concurrently randomized patients (May 1987 to January 1991 between regimens A and B, and February 1986 to January 1991 between regimens A and C).

RESULTS

The 5-year continuous CR (CCR) rates were not significantly different: A versus B, 78.1% (3.9 +/- SE) versus 83.3% +/- 3.5% and A versus C, 79.4% +/- 3.2% versus 83.5% +/- 2.9%; P by one-sided log-rank tests were .27 and .34, respectively. Significant treatment differences were not found with regard to sex, rate of testicular and CNS relapse, or CNS complications. During consolidation, regimen C had significantly more bacterial infections (P = .0032) and days spent in the hospital (P < .001) compared with regimen A.

CONCLUSION

We were unable to show a statistical advantage of adding either ASP or AraC to IDMTX in terms of improvement in event-free survival (EFS).
Uracil-tegafur in gastric carcinoma: a comprehensive review.
Authors: Takiuchi H , Ajani J A
Published: February 2017

PURPOSE

The second-generation oral anticancer agent UFT, a combination of uracil and tegafur (TGF), results in a higher fluorouracil (5-FU) concentration in the tumor tissues than is achieved by TGF or comparable doses of intravenous 5-fluorouracil. UFT has been extensively studied in Japan and has been in use in the Orient for many years, particularly for patients with gastric carcinoma. UFT has recently entered extensive investigations in North America and Europe.

METHODS

Relevant studies that have chronicled the establishment of UFT, its mechanism of action, preclinical toxicology, human pharmacokinetics, phase I studies, and activity against gastric carcinoma are described in detail.

RESULTS

The uracil in UFT slows degradation of 5-FU by dihydropyrimidine dehydrogenase (DPD), which results in sustained concentrations of 5-FU in blood and tumor tissues. UFT is well tolerated, but such toxic effects as nausea, vomiting, and diarrhea are dose- and schedule-dependent. In phase I pharmacokinetic studies, UFT given orally on a 28-day schedule resulted in blood concentrations comparable to those following low-dose continuous intravenous infusion of 5-FU. In patients with gastric carcinoma, UFT alone has a response rate of approximately 20%. In the adjuvant setting, UFT plus mitomycin appears superior to TGF plus mitomycin. In Japan, UFT is part of the standard adjuvant chemotherapy for gastric carcinoma.

CONCLUSION

UFT is one of the first second-generation oral 5-FU prodrugs under investigation in North America and Europe. The literature suggests UFT is well tolerated and has cellular pharmacokinetic superiority over the first-generation 5-FU prodrug TGF. UFT has a more favorable toxicity profile than intravenous 5-FU. The issues of efficacy, patient convenience, and quality of life need to be studied in controlled randomized trials.
Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients.
Authors: Keilholz U , Conradt C , Legha S S , Khayat D , Scheibenbogen C , Thatcher N , Goey S H , Gore M , Dorval T , Hancock B , Punt C J , Dummer R , Avril M F , Bröcker E B , Benhammouda A , Eggermont A M , Pritsch M
Published: February 2017

PURPOSE

In patients with stage IV melanoma, durable responses have been reported with treatment regimens that involve high-dose interleukin-2 (IL-2). We analyze long-term results of 631 melanoma patients from 12 institutions who had received IL-2 alone, in combination with interferon alfa 2a or 2b (IFNalpha), or with cytotoxic drugs.

METHODS

Case records that contained pretreatment parameters, response data, and updated survival information were collected. After univariate analysis, the multivariate evaluation of the impact of pretreatment parameters on response and survival was performed by logistic regression and Cox's regression, respectively.

RESULTS

Patients were divided into four groups according to treatment: IL-2 alone (n=117), IL-2 and chemotherapy (n=49), IL-2 and IFNalpha (n=153), and IL-2, chemotherapy, and IFNalpha (n=312). The median survival of all patients was 10.5 months and the 2- and 5-year survival rates were 19.9% and 10.4%, respectively. Independent prognostic factors for response and survival were entirely different, treatment group being the only significant factor for response, and serum lactate dehydrogenase (LDH), metastatic site, and performance predicting survival. The addition of IFNalpha to IL-2 was associated with prolonged survival, but the effect of additional chemotherapy was less obvious.

CONCLUSION

Serum LDH, metastatic site, and performance status are useful stratification factors for randomized trials in metastatic melanoma. The improved long-term survival rates observed in melanoma patients treated with IL-2/IFNalpha-containing regimens are notable in contrast to the reported 5-year survival rates of 2% to 6% achieved with chemotherapy, but because selection bias cannot be ruled out, the impact of IL-2, as well as all other components of the treatment regimens, on survival needs to be confirmed in prospective randomized trials.
Granulocyte-macrophage colony-stimulating factor in patients with neutropenic fever is potent after low-risk but not after high-risk neutropenic chemotherapy regimens: results of a randomized phase III trial.
Authors: Ravaud A , Chevreau C , Cany L , Houyau P , Dohollou N , Roché H , Soubeyran P , Bonichon F , Mihura J , Eghbali H , Tabah I , Bui B N
Published: February 2017

PURPOSE

A randomized unblinded phase III trial was designed to determine the ability of granulocyte-macrophage colony-stimulating factor (GM-CSF) to accelerate recovery from febrile neutropenia induced by chemotherapy.

PATIENTS AND METHODS

A total of 68 patients with febrile neutropenia following chemotherapy defined as axillary temperature greater than 38 degrees C and absolute neutrophil count (ANC) less than 1 x 10(9)/L were included. After stratification for high- and low-risk chemotherapy to induce febrile neutropenia, treatment was randomized between GM-CSF at 5 microg/kg/d or control, both being associated with antibiotics.

RESULTS

GM-CSF significantly reduced the median duration of neutropenia from 6 to 3 days for ANC less than 1 x 10(9)/L(P < .001) and from 4 to 3 days for ANC less than 0.5 x 10(9)/L (P=.024), days of hospitalization required for febrile neutropenia, and duration of antibiotics during hospitalization. The greatest benefit with GM-CSF appeared for patients who had received low-risk chemotherapy, for which the median duration of ANC less than 1 x 10(9)/L was reduced from 7 to 2.5 days (P < .001) and from 4 to 2 days for ANC less than 0.5 x 10(9)/L (P=.0011), the duration of hospitalization during the study from 7 to 4 days (P=.003), and the duration on antibiotics during hospitalization from 7 to 3.5 days (P < .001). A multivariate analysis, using Cox regression, showed that variables predictive for recovery from neutropenia were GM-CSF (P=.0010) and time interval between the first day of chemotherapy and randomization (P=.030). There was no benefit for GM-CSF when high-risk chemotherapy was considered.

CONCLUSION

GM-CSF significantly shortened duration of neutropenia, duration of neutropenic fever-related hospitalization, and duration on antibiotics during hospitalization when febrile neutropenia occurred after low-risk chemotherapy, but not high-risk chemotherapy.
Anti-G(D2) antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age.
Authors: Cheung N K , Kushner B H , Cheung I Y , Kramer K , Canete A , Gerald W , Bonilla M A , Finn R , Yeh S J , Larson S M
Published: February 2017

PURPOSE

To eradicate minimal residual disease with anti-G(D2) monoclonal antibody 3F8 in stage 4 neuroblastoma (NB) diagnosed at more than 1 year of age.

PATIENTS AND METHODS

Thirty-four patients were treated with 3F8 at the end of chemotherapy. Most had either bone marrow (n=31) or distant bony metastases (n=29). Thirteen patients were treated at second or subsequent remission (group I) and 12 patients in this group had a history of progressive/persistent disease after bone marrow transplantation (BMT); 21 patients were treated in first remission following N6 chemotherapy (group II).

RESULTS

Before 3F8 treatment, 23 patients were in complete remission CR, eight in very good partial remission (VGPR), one in partial remission (PR), and two had microscopic foci in marrow. Twenty-five had evidence of NB by at least one measurement of occult/minimal tumor (iodine 131[(131)I]-3F8 imaging, marrow immunocytology, or marrow reverse-transcriptase polymerase chain reaction [RT-PCR]). Acute self-limited toxicities of 3F8 treatment were severe pain, fever, urticaria, and reversible decreases in blood counts and serum complement levels. There was evidence of response by immunocytology (six of nine), by GAGE RT-PCR (seven of 12), and by (131)I-3F8 scans (six of six). Fourteen patients are alive and 13 (age 1.8 to 7.4 years at diagnosis) are progression-free (40 to 130 months from the initiation of 3F8 treatment) without further systemic therapy, none with late neurologic complications. A transient anti-mouse response or the completion of four 3F8 cycles was associated with significantly better survival.

CONCLUSION

Despite high-risk nature of stage 4 NB, long-term remission without autologous (A)BMT can be achieved with 3F8 treatment. Its side effects were short-lived and manageable. The potential benefits of 3F8 in consolidating remission warrant further investigations.
Patient-reported short-term and long-term physical and psychologic symptoms: results of the continuous hyperfractionated accelerated [correction of acclerated] radiotherapy (CHART) randomized trial in non-small-cell lung cancer. CHART Steering Committee.
Authors: Bailey A J , Parmar M K , Stephens R J
Published: February 2017

PURPOSE

The randomized multicenter trial of continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy for patients with non-small-cell lung cancer (NSCLC) showed a significant survival benefit to CHART (29% v 20% at 2 years, P=.004). However, an assessment of the effect on physical and psychologic symptoms is vital to balance the costs and benefits of the two treatments.

METHODS

A total of 356 patients in the United Kingdom completed the Rotterdam Symptom Checklist (RSCL) and the Hospital Anxiety and Depression Scale (HADS) at 10 time points. The principal aim of the analyses was to keep the methods simple, so as to allow the presentation and interpretation of the results to be as clear as possible. This was achieved by (1) considering individual symptoms rather than symptom subscales or domains, (2) assessing short-term effects (up to 3 months) and long-term effects (at 1 and 2 years) separately, and (3) for the short-term analyses, (a) splitting the data randomly into an exploratory data set and a confirmatory data set, and (b) using two different methods of analysis: a subject-specific approach, which used the area under the curve (AUC) as a summary measure, and a group-based method, which plotted the percent of patients with moderate or severe symptoms over time.

RESULTS

The results indicate that apart from CHART causing transient pain on swallowing and heartburn, there was little difference between the regimens in the short or long-term.

CONCLUSION

Combining the results of the patient-assessed symptom comparisons with the clinical results indicates that CHART confers a major benefit without serious morbidity.
Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients.
Authors: Eppenberger U , Kueng W , Schlaeppi J M , Roesel J L , Benz C , Mueller H , Matter A , Zuber M , Luescher K , Litschgi M , Schmitt M , Foekens J A , Eppenberger-Castori S
Published: February 2017

PURPOSE

To compare the prognostic impact of tumor angiogenesis factors (vascular endothelial growth factor [VEGF], angiogenin, and basic fibroblast growth factor [bFGF]), tumor proteolysis factors (urokinase-type plasminogen activator [uPA] and plasminogen activator inhibitor-1 [PAI-1]), and conventional tumor markers (stage, grade, and steroid receptors) in early breast cancer.

PATIENTS AND METHODS

In the primary clinical study, tumor angiogenesis and other factors were detected in frozen biopsies from 305 primary breast tumors. VEGF expression was assessed by chemiluminescence immunosorbent assay (ICMA); angiogenin, bFGF, uPA, and PAI-1 by enzyme-linked immunosorbent assay (ELISA); and steroid receptors (estrogen receptor [ER] and progesterone receptor [PgR]) by enzyme immunoassay (EIA). In the validating clinical study, another set of 190 node-negative primary breast tumor samples were collected at a separate institution.

RESULTS

Univariate analysis of the primary study showed that VEGF levels were positively correlated with recurrence (P < .001). Angiogenin levels were positively correlated with disease relapse (P < .005) for the overall collective group, but not within the node-negative subset. No significant correlations were found between tumor bFGF levels and patient survival. In multivariate regression analysis, the only independent predictors of relapse-free survival (RFS) were VEGF, uPA, and lymph node status. In the validation set, the distribution of VEGF and uPA values were similar to those in the primary study; low expression of both VEGF and uPA identified patients with a < or = 20% likelihood of recurrence within 7 years.

CONCLUSION

Separate primary and validating clinical studies concur that tumor VEGF level is the most important prognostic parameter among several markers of tumor angiogenesis and proteolysis.
Recommended guidelines for the treatment of chemotherapy-induced diarrhea.
Authors: Wadler S , Benson A B , Engelking C , Catalano R , Field M , Kornblau S M , Mitchell E , Rubin J , Trotta P , Vokes E
Published: February 2017

PURPOSE

Management of chemotherapy-induced diarrhea (CID) has customarily involved symptomatic treatment with opioids in conjunction with supportive care. Alternatively, patients refractory to conventional therapy have been given octreotide, a somatostatin analogue. Although this agent has been effective against CID, no widely accepted treatment guidelines that incorporate its use currently exist. An expert multidisciplinary panel was convened to formulate clinical practice guidelines for the treatment of CID.

METHODS

The panel reviewed clinical data on the management of CID reported in the literature and analyzed currently available tools used to assess CID. Expert consensus was applied when published data were insufficient. Panel members also considered the effect of CID on quality of life and the cost-effectiveness and efficacy of different pharmacologic approaches. Effective resolution of CID and decreases in the need for supportive care or hospitalization were considered to be primary goals in the formulation of the guidelines.

RESULTS

The panel formulated suggested practice guidelines for the management of CID that detail recommendations for the assessment and evaluation of diarrhea and the sequence and duration of administration of specific pharmacologic agents.

CONCLUSION

The consensus of the panel was that standardized assessment and management of diarrhea is required to effectively control CID. The panel agreed that further data from a National Cancer Institute (NCI)-sponsored intergroup trial is required to determine the optimal dosage of octreotide and its cost in the treatment of cancer. The panel also agreed that further clinical research is warranted to address significant questions about the most effective way to assess and treat CID.
Treatment of Philadelphia Chromosome-Positive Early Chronic Phase Chronic Myelogenous Leukemia With Daily Doses of Interferon Alpha and Low-Dose Cytarabine
Authors: Kantarjian Hagop M. , O'Brien Susan , Smith Terry L. , Rios Mary Beth , Cortes Jorge , Beran Miloslav , Koller Charles , Giles Francis J. , Andreeff Michael , Kornblau Steven , Giralt Sergio , Keating Michael J. , Talpaz Moshe
Published: February 2017

PURPOSE: To evaluate the efficacy of the combination of interferon alpha (IFN-α) and daily low-dose cytarabine (ara-C) in the treatment of patients with early chronic-phase chronic myelogenous leukemia (CML) (within 1 year of diagnosis). Improving the degree of hematologic and cytogenetic response in patients with Philadelphia chromosome (Ph)-positive CML may improve prognosis. Both IFN-α and ara-C induce cytogenetic responses as single-agent therapy in CML.

PATIENTS AND METHODS: One hundred forty patients with Ph-positive early chronic-phase CML received subcutaneous injections of IFN-α 5 megaunits/m2 daily and ara-C 10 mg daily. Their median age was 46 years; 53% had good-risk disease, 33% had intermediate-risk disease, and 14% had poor-risk disease. Their results were compared with those of patients receiving IFN-α with or without intermittent ara-C (7 days/mo).

RESULTS: A complete hematologic response (CHR) was achieved in 92% of patients. A cytogenetic response was seen in 74%: it was major in 50% (Ph-positive < 35%) and complete in 31% (Ph-positive 0%). With a median follow-up of 42 months, the 4-year estimated survival rate was 70% (95% confidence interval, 61% to 79%). Significant side effects included fatigue (43%; grade 3/4, 11%), weight loss (19%; grade 3/4, 11%), muscle and bone aches (20%; grade 3/4, 7%), oral ulcers (4%), diarrhea (6%), and neurologic changes (27%, grade 3/4, 6%). The median dose of IFN-α was 3.7 megaunits/m2 daily, mainly because of reductions for myelosuppression (70% of cases); the median ara-C dose was 7.5 mg daily. Prognostic risk groups were predictive for response to the IFN-α plus ara-C combination. The incidence of CHR was higher with IFN-α plus daily ara-C compared with IFN-α plus intermittent ara-C and IFN-α alone (no ara-C) (92% v 84% v 80%, P = .01), as were the incidences of cytogenetic response (74% v 73% v 58%; P = .003) and major cytogenetic response (50% v 38% v 38%; P = .06). The median time to achievement of major cytogenetic response was significantly shorter than that for previous IFN-α regimens (7 v 10 v 12 months; P < .01). However, with the present follow-up, the survival and time to blastic transformation were similar.

CONCLUSION: The combination of IFN-α plus daily low-dose ara-C seems to be promising for the treatment of CML. High rates of CHR and cytogenetic response were observed with acceptable toxicity and a lower daily dose of IFN-α compared with our previous studies.
Decision Analysis as an Aid to Determining the Management of Early Low Rectal Cancer for the Individual Patient
Authors: Temple Larissa K.F. , Naimark David , McLeod Robin S.
Published: February 2017

PURPOSE: Because there are no data available from randomized controlled trials (RCT), a decision analysis was performed to aid in the decision of which option, a local excision with or without radiotherapy or an abdominal perineal resection (APR), should be offered to medically fit patients with early (suspected T1/T2) low (< 5 cm) rectal cancer.

METHODS: All clinically relevant outcomes, including complications of surgery and radiotherapy, cure, salvageability after local recurrence, distant disease, and death, were modeled for both options. The probabilities of complications and outcomes after radiotherapy and/or local excision were derived from weighted averages of results from studies conducted between 1969 and 1997. The probabilities for the APR option were extracted from relevant RCTs. Long- and short-term patient-centered utilities for each complication and outcome were extracted from the literature and from expert opinion.

RESULTS: The expected utility of local excision (EU = 0.81) for the base case was higher than the expected utility for APR (EU = 0.78). Although the result was sensitive to all variables, local excision was always favored over APR within the plausible ranges of the variables taken one, two, or three at a time. The model illustrated the tension between the patient's perception of a colostomy and the higher recurrence rates with local excision.

CONCLUSION: The results of this decision analysis suggest that local therapy for early low rectal cancer is the preferred method of treatment. However, there must be careful preoperative assessment, patient selection, and consideration of patient concerns. In addition, decision analysis may be useful in providing patient information and assisting in decision making.
Phase I Study in Cancer Patients of a Replication-Defective Avipox Recombinant Vaccine That Expresses Human Carcinoembryonic Antigen
Authors: Marshall John L. , Hawkins Michael J. , Tsang Kwong Y. , Richmond Ellen , Pedicano James E. , Zhu MingZhu , Schlom Jeffrey
Published: February 2017

PURPOSE: A phase I clinical trial in patients with advanced carcinoma was conducted, using a replication-defective avipox vaccine containing the gene for the human carcinoembryonic antigen (CEA). The canarypox vector, designated ALVAC, has the ability to infect human cells but cannot replicate.

PATIENTS AND METHODS: The recombinant vaccine, designated ALVAC-CEA, was administered intramuscularly three times at 28-day intervals. Each cohort of six patients received three doses of either 2.5 × 105, 2.5 × 106, or 2.5 × 107plaque-forming units of vaccine.

RESULTS: The vaccine was well tolerated at all dose levels and no significant toxicity was attributed to the treatment. No objective antitumor response was observed during the trial in patients with measurable disease. Studies were conducted to assess whether ALVAC-CEA had the ability to induce cytolytic T-lymphocyte (CTL) responses in patients with advanced cancer. Peripheral blood mononuclear cells (PBMCs) from patients with the MHC class I A2 allele were obtained before vaccine administration and 1 month after the third vaccination. Peripheral blood mononuclear cells were incubated with the CEA immunodominant CTL epitope carcinoembryonic antigen peptide-1 and interleukin 2 and quantitated using CTL precursor frequency analysis. In seven of nine patients evaluated, statistically significant increases in CTL precursors specific for CEA were observed in PBMCs after vaccination, compared with before vaccination.

CONCLUSION: These studies constitute the first phase I trial of an avipox recombinant in cancer patients. The recombinant vaccine ALVAC-CEA seems to be safe and has been demonstrated to elicit CEA-specific CTL responses. These studies thus form the basis for the further clinical exploration of the ALVAC-CEA recombinant vaccine in phase I/ II studies in protocols designed to enhance the generation of human T-cell responses to CEA.
Costs of Treating and Preventing Nausea and Vomiting in Patients Receiving Chemotherapy
Authors: Stewart David J. , Dahrouge Simone , Coyle Doug , Evans William K.
Published: February 2017

PURPOSE: To evaluate the effect of ondansetron availability on the costs of managing nausea and vomiting.

METHODS: We retrospectively assessed antiemetic costs (drug costs, nursing time, pharmacy time, physician's time, supplies, and facility “hotel” costs, in 1991 Canadian dollars) for all patients who received moderately or highly emetogenic chemotherapy from 6 months before to 6 months after ondansetron became commercially available in September 1991. We compared the costs for treating patients who received ondansetron versus those who received other antiemetic regimens, the costs for treating patients in the 6 months before versus the 6 months after ondansetron commercial availability, and the costs for treating patients in the first 4 months versus the last 4 months of the study period.

RESULTS: We found no cost differences for patients treated with ondansetron versus other antiemetic regimens. However, there was a significant reduction in emesis management costs for patients treated after versus before the availability of ondansetron: for patients treated in the last third versus first third of the study period, there was a decrease in cost per patient per month of treatment of $374 (95% confidence interval, $243 to $505). These savings were achieved through a reduction in hospital bed days and other costs associated with the prevention and more effective management of nausea and vomiting. At the same time, the number of patients who received emetogenic chemotherapy and their average age increased, presumably because of the better control of gastrointestinal toxicity.

CONCLUSION: Ondansetron availability has been associated with changes in the clinical management of cancer patients receiving chemotherapy and with overall cost savings compared with previously available antiemetic therapy.
Can 40 Seconds of Compassion Reduce Patient Anxiety?
Authors: Fogarty Linda A. , Curbow Barbara A. , Wingard John R. , McDonnell Karen , Somerfield Mark R.
Published: February 2017

PURPOSE: To use a standardized videotape stimulus to assess the effect of physician compassion on viewers' anxiety, information recall, treatment decisions, and assessment of physician characteristics.

PARTICIPANTS AND METHODS: One hundred twenty-three healthy female breast cancer survivors and 87 women without cancer were recruited for this study. A randomized pretest/posttest control group design with a standardized videotape intervention was used. Participants completed the State-Trait Anxiety Inventory (STAI), an information recall test, a compassion rating, and physician attribute rating scales.

RESULTS: Women who saw an “enhanced compassion” videotape rated the physician as warmer and more caring, sensitive, and compassionate than did women who watched the “standard” videotape. Women who saw the enhanced compassion videotape were significantly less anxious after watching it than the women in the other group. Nevertheless, information recall was relatively low for both groups, and enhanced compassion did not influence patient decisions. Those who saw the enhanced compassion videotape rated the doctor significantly higher on other positive attributes, such as wanting what was best for the patient and encouraging the patient's questions and involvement in decisions.

CONCLUSION: The enhanced compassion segment was short, simple, and effective in decreasing viewers' anxiety. Further research is needed to translate these findings to the clinical setting, where reducing patient anxiety is a therapeutic goal.