bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I pharmacokinetic study of multicycle high-dose carboplatin followed by peripheral-blood stem-cell infusion in patients with cancer.
Authors: Johansen M J , Madden T , Mehra R C , Wood J G , Rondon G , Browne V , Newman R A , Champlin R E
Published: February 2017

PURPOSE

To examine the feasibility of escalating carboplatin area under the concentration-time curve (AUC), using dose predictions based on individual estimates of drug clearance, in a phase I trial of multicycle carboplatin, paclitaxel, and cyclophosphamide chemotherapy with peripheral-blood stem-cell (PBSC) replacement.

PATIENTS AND METHODS

Forty-four patients (37 breast, seven ovarian) received 165 courses. Initial target carboplatin AUC was 10 mg/ml x min, with interpatient escalation in increments of 25%. Initial carboplatin dose estimates used creatinine clearance (CrCl) to estimate carboplatin clearance. Subsequent clearance and dose estimates were determined using a model incorporating Bayesian estimation and two measured carboplatin plasma ultrafiltrate concentrations.

RESULTS

Median clearance was 80.5 mL/min/m2 (range, 41.6 to 131.8). Carboplatin doses up to 2,440 mg/m2 per course were administered without major extramedullary toxicity. Doses varied 2.6-fold at each exposure level. Using the Bayesian model, AUC was predicted with a mean accuracy of 101.2% (83% using CrCl). Ninety-six of 117 courses were within 25% of the target AUC. This model was less biased (0.15 v -2.35 mg/mL x min) and more precise (2.76 v 3.52) in predicting AUC compared with one using CrCl. Hematologic recovery was not prolonged with increasing exposure. The carboplatin maximum-tolerated systemic exposure (MTSE) was 13.3 mg/mL x min (level five). The dose-limiting toxicity was cardiac toxicity, which occurred at dose levels six and seven.

CONCLUSION

Results demonstrate that (1) CrCl is a poor estimator of carboplatin clearance in this population, and (2) the use of a model incorporating limited sampling and Bayesian estimation improves the precision of carboplatin clearance estimation and is suitable for targeting carboplatin exposure in an ambulatory setting.
Hematopoietic recovery after allogeneic blood stem-cell transplantation compared with bone marrow transplantation in patients with hematologic malignancies.
Authors: Pavletic Z S , Bishop M R , Tarantolo S R , Martin-Algarra S , Bierman P J , Vose J M , Reed E C , Gross T G , Kollath J , Nasrati K , Jackson J D , Armitage J O , Kessinger A
Published: February 2017

PURPOSE

To compare hematopoietic recovery, duration of hospitalization, and 100-day survival in patients who received allogeneic-blood stem cells (BSC) or conventional allogeneic bone marrow transplantation (BMT).

PATIENTS AND METHODS

From December 1994 to August 1995, 21 patients participated in a phase II study of allogeneic BSC transplantation. Cells mobilized with granulocyte colony-stimulating factor (G-CSF; 5 micrograms/kg/ d) were collected from human leukocyte antigen (HLA)-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. G-CSF (10 micrograms/kg/d) was administered posttransplant. The outcomes were compared with 22 identically treated historical patients who received allogeneic BMT.

RESULTS

The median infused CD34+ cell and granulocyte-macrophage colony-forming unit (CFU-GM) content were 7.73 x 10(4)/kg and 41.6 x 10(4)/kg, respectively. The median time to a neutrophil count greater than 500/ microL was 11 days after BSC and 16.5 days after BMT (P = .0003). A trend toward faster platelet and RBC recovery after BSC was observed. BSC patients received fewer platelet transfusions: 10 versus 19 (P = .015). The median length of hospitalization was shorter after BSC transplantation: 25 versus 31.5 days (P = .0243). The 100-day survival rates were similar: 83% after BSC and 75% after BMT (P = .3585). The incidence of acute GVHD grade II to IV was 57% and 45% for BSC and BMT, respectively (P = .4654).

CONCLUSION

In comparison to BMT, allogeneic BSC transplantation may result in faster hematopoietic recovery, shorter hospital stay, and similar early survival. Whether allogeneic BSC are superior to bone marrow needs to be determined in randomized trials.
Treatment outcome and prognostic factors for primary mediastinal (thymic) B-cell lymphoma: a multicenter study of 106 patients.
Authors: Lazzarino M , Orlandi E , Paulli M , Sträter J , Klersy C , Gianelli U , Gargantini L , Rousset M T , Gambacorta M , Marra E , Lavabre-Bertrand T , Magrini U , Manegold C , Bernasconi C , Möller P
Published: February 2017

PURPOSE

To define clinicopathologic features, response to treatment, and prognostic factors of primary mediastinal B-cell lymphoma (MBL), a CD20+ tumor recognized as a distinct entity among non-Hodgkin's lymphomas (NHL).

PATIENTS AND METHODS

One hundred six patients presented with disease confined to thorax (86%), bulky mediastinum (73%), superior vena cava syndrome (47%), and contiguous infiltration (57%). Ninety-nine received doxorubicin-containing chemotherapy (CHT).

RESULTS

Thirty-five of 99 patients were primarily CHT-resistant, and 64 responded: 23 achieved complete response (CR) and 41 achieved response with residual mediastinal abnormality. Seventy-seven percent of responders received mediastinal radiotherapy (RT). Of 64 responders, 18 (28%) relapsed: none of 23 CR patients and 18 of 41 (44%) with residual mediastinal abnormality. Relapse-free survival rate of responders was 71% at 3 years. Actuarial 3-year survival rate was 52% for all patients and 82% for responders. Predictive factors of poor outcome were identified by logistic regression; Cox survival analysis was performed on death and relapse. Pericardial effusion (P < .001) and Eastern Cooperative Oncology Group (ECOG) performance status > or = 2 (P = .009) predicted nonresponse (NR) and affected survival. Less than partial midway response to CHT predicted NR to subsequent therapies. Bulky disease was related to persistent mediastinal abnormality and risk of relapse (P = .025).

CONCLUSION

MBL is an aggressive NHL with unique clinicopathologic aspects, often refractory to current CHT designed for high-grade NHL. Poor performance status and pericardial effusion predict NR and poor survival. Inadequate response after the first courses of front-line CHT predicts failure of subsequent treatment. Responders with bulky mediastinum or residual mediastinal abnormality after CHT are at risk of relapse. These factors should help to select high-risk patients for intensive treatments.
Deletions of p15 and/or p16 genes as a poor-prognosis factor in adult T-cell leukemia.
Authors: Yamada Y , Hatta Y , Murata K , Sugawara K , Ikeda S , Mine M , Maeda T , Hirakata Y , Kamihira S , Tsukasaki K , Ogawa S , Hirai H , Koeffler H P , Tomonaga M
Published: February 2017

PURPOSE

To determine the frequency of the deletions of p15/p16 genes in adult T-cell leukemia (ATL) cells and to evaluate their value in the diagnosis of clinical subtypes of ATL patients and the prediction of their clinical outcome.

MATERIALS AND METHODS

Peripheral-blood samples from 114 patients with ATL were examined by Southern blot analysis. In five chronic-type patients who showed disease progression to acute type, serial samples also were examined.

RESULTS

Among 114 patients, 28 (24.6%) showed the deletions of p15 and/or p16 genes. The results were well correlated with the clinical subtypes. Patients with deleted p15 and/or p16 genes had significantly shorter survival times than the patients in whom both genes were preserved (P < .0001). A similar decline in survival time was observed in the analyses within the same subtypes. In multivariate analysis using the Cox proportional hazard model, the deletions of p15 and/or p16 genes emerged as an independent prognostic indicator. Moreover, three of the five chronic-type patients who progressed to acute type lost the p16 gene alone or both the p15 and p16 genes at their exacerbation phase.

CONCLUSION

The results suggest the following: (1) that the deletions of p15 and/or p16 genes play a key role in the progression of ATL; and (2) that these deletions are reliable prognostic factors that predict shortened survival times.
Asymptomatic recurrence detection with surveillance scanning in children with medulloblastoma.
Authors: Shaw D W , Geyer J R , Berger M S , Milstein J , Lindsley K L
Published: February 2017

PURPOSE

To assess the utility of surveillance neuroimaging in detecting recurrent disease in patients treated for medulloblastoma.

PATIENTS AND METHODS

Records and scans of 59 consecutive patients treated for medulloblastoma between 1984 and 1993 in one institution were retrospectively reviewed.

RESULTS

Nineteen of 59 patients had recurrence of tumor, of which 17 were available for this study. Eleven of the 17 recurrent patients were asymptomatic at the time of detection. The median time to recurrence was 13 months (range, 3 to 90).

CONCLUSION

Surveillance scanning detected a majority of recurrences before onset of symptoms. Although the outcome of those with recurrent disease remains poor, early detection with minimum disease provides the best setting in which to test newer therapies. Patients and their parents also were more likely to elect pursuing further treatment when relapse was detected asymptomatically.
Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma.
Authors: Kelly K M , Womer R B , Sorensen P H , Xiong Q B , Barr F G
Published: February 2017

PURPOSE

We evaluated the clinical features of the common PAX3-FKHR and variant PAX7-FKHR gene fusions observed in rhabdomyosarcoma.

PATIENTS AND METHODS

Reverse-transcriptase polymerase chain reaction (RT-PCR) assays were used to detect the gene fusions in 34 cases of rhabdomyosarcoma. Clinical data were obtained retrospectively and compared with the molecular results.

RESULTS

The PAX3-FKHR and PAX7-FKHR gene fusions were present in tumors from 18 and 16 patients, respectively. The group with a PAX7-FKHR fusion was younger (P = .01) and presented more often with an extremity lesion (82% v 22%; P = .001). PAX7-FKHR tumors were more often localized than PAX3-FKHR tumors (P = .03). In patients with metastatic disease at diagnosis, the patterns were different: PAX7-FKHR patients had metastatic disease that involved only bone (n = 2) and distant nodes (n = 2), while the PAX3-FKHR group had multiple sites involved, including bone (n = 7), marrow (n = 7), lungs (n = 3), distant nodes (n = 2), skin (n = 1), and brain (n = 1). No significant difference in relapse rate was observed. A trend toward improved overall survival in the PAX7-FKHR group was noted (P = .09). Event-free survival for this PAX7-FKHR group was significantly longer (P = .04).

CONCLUSION

Our results suggest that the common PAX3-FKHR and the variant PAX7-FKHR fusions are associated with distinct clinical phenotypes. Identification of fusion gene status may be a useful diagnostic tool in rhabdomyosarcoma.
Survival of differentiated thyroid carcinoma studied in 500 patients.
Authors: Lerch H , Schober O , Kuwert T , Saur H B
Published: February 2017

PURPOSE

To analyze the factors that influence survival of patients with differentiated thyroid carcinoma treated by surgical thyroidectomy, radioactive iodine, and early surgical reintervention with compartment-oriented lymphadenectomy in the case of locoregional recurrence.

METHODS

The survival of 500 patients with differentiated thyroid carcinoma was analyzed retrospectively with regard to mortality and survival rate (Kaplan-Meier). A total of 301 patients had papillary and 199 follicular thyroid carcinoma. The mean age of the 380 women and 120 men was 46.8 +/- 16.4 years at presentation. All patients were treated by surgical thyroidectomy, high-dose radioactive iodine, and early surgical reintervention with compartment-oriented lymphadenectomy in cases of locoregional recurrence, without routine adjuvant external radiotherapy of the neck. Patients were monitored up to 23 years, with a median follow-up time of 5.6 years.

RESULTS

Twenty-nine of 500 patients died, 19 of thyroid cancer. The corrected overall 5-year survival rate (Kaplan-Meier) was 0.92. Among patients with tumor stage pT1-3NO-1MO (low risk), none died of thyroid carcinoma (5-year survival rate, 0.97); in patients with tumor stage pT4 and/or M1 (high risk), the 5-year survival rate was 0.83. The cause of death was locoregional recurrence in eight and metastatic disease in 11. Using multivariate analysis, risk factors that significantly influence survival were local invasion (pT4), metastatic disease (M1), and age.

CONCLUSION

In differentiated thyroid carcinoma, the use of total surgical thyroidectomy followed by high-dose radioiodine therapy and early surgical reintervention in case of locoregional recurrence yields high survival rates, even without adjuvant external radiotherapy of the neck.
Hereditary cancer risk notification and testing: how interested is the general population?
Authors: Andrykowski M A , Lightner R , Studts J L , Munn R K
Published: February 2017

PURPOSE

Great interest in predictive testing for hereditary cancer syndromes has been reported. Prior research has focused on testing for specific hereditary syndromes and/or among individuals at high risk for positive carrier status. Given anticipated expansion of both the range of hereditary syndromes for which testing will be available, as well as the clinical settings in which testing will occur, assessment of interest in hereditary cancer risk testing and notification in the general public is warranted.

METHODS

As part of an annual statewide telephone survey, adults' (N = 654) interest in hereditary cancer risk testing and notification was assessed.

RESULTS

Interest in both risk testing (82%) and risk notification (87%) was high. Logistic regression analyses indicated that disinterest in risk notification was associated with female sex, performance of fewer health protective behaviors, and better perceptions of personal health. Disinterest in risk testing was associated with these same variables as well as older age, less concern over developing cancer, and a more extensive history of cancer in first degree relatives.

CONCLUSION

In the absence of risk-reducing behaviors with demonstrable efficacy, hereditary risk testing programs may have difficulty attracting the interest of those at greatest risk for carrier status. In contrast, many individuals at low risk for positive carrier status might seek testing, perhaps as a means of seeking reassurance regarding their low hereditary risk.
Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemic blasts: a Children's Cancer Group study.
Authors: Uckun F M , Gaynon P S , Sensel M G , Nachman J , Trigg M E , Steinherz P G , Hutchinson R , Bostrom B C , Sather H N , Reaman G H
Published: February 2017

PURPOSE

Leukemic cells from T-lineage acute lymphoblastic leukemia (ALL) patients are thought to originate from T-lymphocyte precursors corresponding to discrete stages of T-cell ontogeny. Here we sought to determine the influence of leukemic cell apparent maturational stage on treatment outcomes in pediatric T-lineage ALL.

PATIENTS AND METHODS

From 1983 through 1993, 407 pediatric T-lineage ALL patients were enrolled onto two sequential series of risk-adjusted treatment protocols of the Children's Cancer Group. In the current analysis, T-lineage ALL patients were immunophenotypically classified as follows: CD7+ CD2- CD5- pro-thymocyte leukemia (pro-TL), CD7+ (CD2 or CD5)+ CD3- immature TL, and CD7+ CD2+ CD5+ CD3+ mature TL.

RESULTS

Similar induction outcomes of 91.4%, 97.1%, and 98.3% were obtained by the pro-, immature, and mature TL groups, respectively. Four-year event-free survival (EFS) was lower for pro-TL patients (57.1%; SD = 8.4%,) compared with immature and mature TL patients (68.5%; SD = 3.5%; and 77.1%; SD = 4.0%, respectively) with an overall significance of .05 (log-rank test) or .04 (log-rank trend test). Relative hazards rates (RHR) were 2.11 and 1.22 for pro-TL and immature TL versus mature TL, respectively. Highly significant differences were found for overall survival (P = .005, log-rank test; P = .009, log-rank trend test). Multivariate analysis confirmed that the prognostic influence of ontogeny grouping was independent of that of other prognostic factors.

CONCLUSION

Leukemic cells of the pro-TL maturation stage identify a small subgroup of T-lineage ALL patients who have a significantly worse EFS outcome than patients whose cells are of a more mature stage of development.
Adjuvant chemotherapy in colorectal cancer with high-dose leucovorin and fluorouracil: impact on disease-free survival and overall survival.
Authors: Zaniboni A
Published: February 2017

PURPOSE

The rationale for using adjuvant chemotherapy in colorectal cancer is to achieve better disease control and thus reduce the high rates of tumor recurrence and mortality in patients who undergo curative surgery. The current literature, including relevant abstracts, on clinical trials of fluorouracil (5-FU) in combination with high-dose leucovorin as adjuvant chemotherapy for colorectal cancer is reviewed. The intent is not to present new data, but to present the reader with a broad perspective and larger patient experience on which to base well-reasoned treatment decisions.

DESIGN

Published clinical trials and abstracts presented at the 1996 American Society of Clinical Oncology (ASCO) meeting that assessed 5-FU in combination with high-dose leucovorin as adjuvant chemotherapy for colorectal cancer were surveyed. End points of interest were disease-free survival (DFS), overall survival, and toxicity.

RESULTS

In randomized trials that used high-dose leucovorin at doses that ranged from daily-times-five 200 mg/m2 to weekly 500 mg/m2 in combination with 5-FU, significant improvements in both DFS and overall survival were observed over surgery alone (control). In patients treated with high-dose leucovorin/5-FU, DFS rates ranged from 71% to 77% compared with control (58% to 64%). A similar trend was seen in overall survival, with a range of 75% to 84% compared with control (63% to 77%). Toxicities observed for high-dose leucovorin administered on a weekly or daily-times-five schedule were diarrhea, stomatitis, myelosuppression, and nausea.

CONCLUSION

Overall, the results of these randomized trials support the use of high-dose leucovorin/5-FU as adjuvant therapy for colorectal cancer. Longer follow-up studies are needed to compare the benefits of these different regimens in terms of survival and to characterize adverse effects, especially those that may not be immediately evident. Adjuvant therapy with high-dose leucovorin/5-FU is an effective regimen that is well tolerated by many patients with colorectal cancer.
Randomized trial of CVPP for three versus six cycles in favorable-prognosis and CVPP versus AOPE plus radiotherapy in intermediate-prognosis untreated Hodgkin's disease.
Authors: Pavlovsky S , Schvartzman E , Lastiri F , Magnasco H , Corrado C , Raslawski E , Cancela M E , Ardaiz M C , Cerutti I , Rosso A , Bruno S , Aranguren P N , Salvarezza A , Donato H , Dibar E , Zirone S
Published: February 2017

PURPOSE

To evaluate in a randomized trial the impact of three versus six cycles of cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP) chemotherapy in favorable-prognosis and CVPP versus doxorubicin, vincristine, prednisone, and etoposide (AOPE) plus involved-field radiotherapy (RT) in intermediate-prognosis previously untreated Hodgkin's disease.

PATIENTS AND METHODS

Of 256 patients evaluated, 80 with a favorable prognosis according to a prognostic index designed by the Grupo Argentina de Tratamiento de Leucemia Aguda (GATLA) were randomized to three versus six cycles of CVPP without RT and 176 with intermediate risk to CVPP versus AOPE, both for six cycles with RT between the third and fourth cycles of 30 Gy to the involved areas at diagnosis. CVPP consisted of intravenous (I.V.) cyclophosphamide and vinblastine on days 1 and 8, and oral procarbazine and prednisone on days 1 to 14, every 28 days. AOPE consisted of I.V. doxorubicin and vincristine on day 1, oral prednisone on days 1 to 5, and I.V. etoposide on days 1 and 3, every 28 days.

RESULTS

Complete remission was obtained in 39 of 41 (95%) patients treated with three cycles of CVPP and 36 of 39 (92%) treated with six cycles in the favorable-risk group (difference not significant [NS]). In the intermediate-risk group, 89 of 92 (97%) treated with CVPP plus RT versus 75 of 84 (89%) treated with AOPE plus RT achieved a complete remission (P = .05). At 60 months, the event-free survival (EFS) and overall survival rates in the favorable-risk group were 80% and 91% for CVPP x 3 and 84% and 97% for CVPP x 6, respectively (P = NS). In the intermediate-risk group, 60-month EFS rate for CVPP plus RT was 85%, compared with 66% for AOPE plus RT (P = .009). The overall survival rate was 95% versus 87% respectively (P = .157).

CONCLUSION

Three cycles of CVPP without RT are equally effective as six cycles in the favorable-risk group. However, in the intermediate-group, CVPP plus RT is superior to AOPE plus RT, with significantly fewer events before and after induction (P = .009), without a difference in overall survival.
Tumor-Cell Number and Viability as Quality and Efficacy Parameters of Autologous Virus-Modified Cancer Vaccines in Patients With Breast or Ovarian Cancer
Authors: Ahlert T. , Sauerbrei W. , Bastert G. , Ruhland S. , Bartik B. , Simiantonaki N. , Schumacher J. , Hacker B. , Schumacher M. , Schirrmacher V.
Published: February 2017

The April 1997 article entitled, "Tumor-Cell Number and Viability as Quality and Efficacy Parameters of Autologous Virus-Modified Cancer Vaccines in Patients With Breast or Ovarian Cancer" by Ahlert et al (J Clin Oncol 15:1354–1366, 1997) contained several errors. On page 1354, the affiliation should have read: from the Universität-Frauenklinik Heidelberg; Deutsches Krebsforschungszentrum Heidelberg, Abteilung 710; Forschungspraxis Technologiepark Heidelburg; Institute für medizinische Biometrie und Informatik, Universität Freiburg, Freiburg, Germany. Reference number 36 on page 1365 should have read:

36. Pomer S, Schirrmacher V, Thiele R, et al: Tumor response and 4-year survival data of patients with advanced renal cell carcinoma treated with autologous tumor vaccine and subcutaneous r-IL-2 and IFN-alpha 2b. Int J Oncol 6:941–954, 1995

In addition, Table 5 is reprinted here correctly in its entirety: Please see the PDF for table 5.
Effective chemotherapy for advanced CNS embryonal tumors in adults.
Authors: Galanis E , Buckner J C , Schomberg P J , Hammack J E , Raffel C , Scheithauer B W
Published: February 2017

PURPOSE

Embryonal tumors of the CNS include, among others, medulloblastoma, cerebral neuroblastoma, pineoblastoma, and primitive neuroectodermal tumors (PNETs). Almost all data on the treatment of embryonal CNS tumors are derived from the pediatric population, since these tumors are uncommon in adulthood. The purpose of this study was to examine the rate and duration of response to chemotherapy of advanced embryonal CNS tumors in adults.

PATIENTS AND METHODS

We retrospectively studied all adult (> 18 years of age) patients with advanced embryonal tumors of the CNS who received chemotherapy at our institution between 1976 and 1994. Seventeen consecutive patients were treated with regimens that contained either nitrosourea or cisplatin or both sequentially, with no patients having received the combination of nitrosourea and cisplatin concurrently.

RESULTS

In patients who received cisplatin-based chemotherapy, responses were observed in 84.5% (26% complete response [CR] rate), 10.5% remained stable, and 5% progressed. The median time to progression was 18 months for patients who had a CR, 6 months for those with partial response (PR), and 10 months for stable patients. Among patients who received nitrosourea-based chemotherapy, PR was observed in 27%, 36.5% remained stable, and 36.5% progress. The median time to progression was 6 months for patients who had a PR and 6.5 months for stable patients.

CONCLUSION

In adults with advanced embryonal CNS tumors, conventional-dose intravenous cisplatin-based chemotherapy regimens are able to produce responses in the majority of the patients (84.5%), even as second- or third-line regimens. Nitrosourea-based regimens less frequently produce responses (27%).
Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients.
Authors: Ellison N , Loprinzi C L , Kugler J , Hatfield A K , Miser A , Sloan J A , Wender D B , Rowland K M , Molina R , Cascino T L , Vukov A M , Dhaliwal H S , Ghosh C
Published: February 2017

PURPOSE

A minority of cancer survivors develops long-term postsurgical neuropathic pain. Based on evidence that capsaicin, the pungent ingredient in hot chili peppers, might be useful for treating neuropathic pain, we developed the present clinical trial.

PATIENTS AND METHODS

Ninety-nine assessable patients with postsurgical neuropathic pain were entered onto this study. After stratification, patients were to receive 8 weeks of a 0.075% capsaicin cream followed by 8 weeks of an identical-appearing placebo cream, or vice versa. A capsaicin/placebo cream was to be applied to the painful site four times daily. Treatment evaluation was performed by patient-completed weekly questionnaires.

RESULTS

During the first 8-week study period, the capsaicin-cream arm was associated with substantially more skin burning, skin redness, and coughing (P < .0001 for each). Nonetheless, treatment was stopped for patient refusal or toxicity just as often while patients were receiving the placebo as compared with the capsaicin. The capsaicin cream arm had substantially more pain relief (P = .01) after the first 8 weeks, with an average pain reduction of 53% versus 17%. On completion of the 16-week study period, patients were asked which treatment period was most beneficial. Of the responding patients, 60% chose the capsaicin arm, 18% chose the placebo arm, and 22% chose neither (P = .001).

CONCLUSION

A topical capsaicin cream decreases postsurgical neuropathic pain and, despite some toxicities, is preferred by patients over a placebo by a three-to-one margin among those expressing a preference.
Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer. Aarhus Lung Cancer Group.
Authors: Work E , Nielsen O S , Bentzen S M , Fode K , Palshof T
Published: February 2017

PURPOSE

To evaluate if the timing of chest irradiation with respect to chemotherapy would influence survival and local and distant control in patients with limited-stage small-cell lung cancer (LSCLC).

PATIENTS AND METHODS

From 1981 to 1989, 199 consecutive patients with LSCLC were randomly allocated to receive initial chest irradiation (ICI; n = 99) or late chest irradiation (LCI; n = 100) given 18 weeks delayed. Both groups received the same nine cycles of combination chemotherapy: three cycles of cisplatin and etoposide and six cycles of cyclophosphamide, doxorubicin, and vincristine. In the first part of the study, prophylactic cranial irradiation (PCI) was only given to patients randomized to ICI, but after inclusion of 42 patients in the LCI arm, the protocol was changed, so that all patients received PCI independent of the timing of the chest irradiation (CI). A total of 157 patients received PCI with a radiation dose of 25 Gy in 11 fractions.

RESULTS

The timing of radiotherapy had no significant effect on the 2-year overall survival rate (20% after ICI v 19% after LCI, P = .4) or the 2-year in-field recurrence rate (72% after ICI v 68% after LCI, P = .2). Median survival durations were 10.5 (ICI) and 12.0 (LCI) months. Similarly, no difference in the 2-year incidence of CNS recurrences was found between the 2 arms in patients who received PCI (19% after ICI v 13% after LCI, P = .24). Bone marrow toxicity was acceptable, as 15% developed World Health Organization (WHO) grade 4 leukocytopenia and 4% grade 4 thrombocytopenia. Grade 4 leukocytopenia was more pronounced in the ICI group. There was no difference in the frequency and severity of other toxicities between the 2 groups.

CONCLUSION

Timing of CI did not significantly influence the incidence of in-field recurrences, CNS recurrences, or overall survival.
Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer.
Authors: Bruno R , Hille D , Riva A , Vivier N , ten Bokkel Huinnink W W , van Oosterom A T , Kaye S B , Verweij J , Fossella F V , Valero V , Rigas J R , Seidman A D , Chevallier B , Fumoleau P , Burris H A , Ravdin P M , Sheiner L B
Published: February 2017

PURPOSE

The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome.

PATIENTS AND METHODS

PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models.

RESULTS

PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication.

CONCLUSION

First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.
Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors.
Authors: Mason W P , Grovas A , Halpern S , Dunkel I J , Garvin J , Heller G , Rosenblum M , Gardner S , Lyden D , Sands S , Puccetti D , Lindsley K , Merchant T E , O'Malley B , Bayer L , Petriccione M M , Allen J , Finlay J L
Published: February 2017

PURPOSE

To evaluate a strategy that avoids radiotherapy in children less than 6 years of age with newly diagnosed malignant brain tumors, by administering myeloablative consolidation chemotherapy with autologous bone marrow reconstitution (ABMR) after maximal surgical resection and conventional induction chemotherapy.

PATIENTS AND METHODS

Between March 1991 and April 1995, 62 children (median age, 30 months) with newly diagnosed malignant brain tumors were enrolled onto this trial. Children received conventional induction chemotherapy with vincristine, cisplatin, cyclophosphamide, and etoposide, repeated every 3 weeks for five cycles. Children without disease progression on induction chemotherapy were offered consolidation with myeloablative chemotherapy that incorporated carboplatin, thiotepa, and etoposide followed by ABMR. Irradiation was used only for residual tumor at consolidation or for progressive/recurrent disease.

RESULTS

Induction chemotherapy was well tolerated by most patients; however, progression was noted in 17 children (27%) and four (6%) died of treatment complications. Of 37 children who received consolidation chemotherapy with ABMR, 15 are free of disease progression (median post-ABMR without further treatment, >44 months). The remaining 22 all progressed within 15 months of ABMR; three of 37 (8%) died of treatment-related complications. The 3-year overall survival (OS) and event-free survival (EFS) rates from diagnosis for all children are 40% (95% confidence interval [CI], 28% to 52%) and 25% (95% CI, 13% to 37%), respectively. Radiotherapy was administered to 19 of 62 children: 17 for progressive disease (PD) and two for residual disease at the time of ABMR.

CONCLUSION

A significant proportion of children with malignant brain tumors can avoid radiotherapy and prolonged maintenance chemotherapy yet still achieve durable remission with this brief intensive chemotherapy regimen.
High-dose chemotherapy for relapsed and refractory diffuse large B-cell lymphoma: mediastinal localization predicts for a favorable outcome.
Authors: Popat U , Przepiork D , Champlin R , Pugh W , Amin K , Mehra R , Rodriguez J , Giralt S , Romaguera J , Rodriguez A , Preti A , Andersson B , Khouri I , Claxton D , de Lima M , Donato M , Anderlini P , Gajewski J , Cabanillas F , van Besien K
Published: February 2017

PURPOSE

This study was performed to evaluate the outcome of high-dose chemotherapy and autologous transplantation in patients with diffuse B-cell large-cell lymphoma, and, specifically, to evaluate the impact of primary mediastinal localization on the outcome of high-dose chemotherapy.

PATIENTS AND METHODS

A retrospective review was performed of all patients with diffuse large B-cell lymphoma who underwent autologous marrow or peripheral-blood stem-cell transplantation at our institution between January 1 986 and December 1995.

RESULTS

Ninety patients were identified, of whom 31 (34%) had a primary mediastinal B-cell large-cell lymphoma (PML). Cumulative probabilities of disease-free survival, overall survival, and disease progression are 40% (95% confidence interval [CI], 29 to 51), 42% (95% CI, 31 to 53), and 52% (95% CI, 40 to 64), respectively. By univariate analysis, low lactate dehydrogenase (LDH) level and low Ann Arbor stage at transplant were associated with improved survival and disease-free survival. There was a trend for improved disease-free survival and survival for patients with PML. Multivariate stepwise Cox regression analysis showed that LDH level, Ann Arbor stage, and primary mediastinal localization were independent favorable prognostic factors for disease-free survival and survival. LDH level and Ann Arbor stage were also predictive for the risk of disease progression.

CONCLUSION

Our results indicate that patients with PML may display an increased susceptibility to high-dose chemotherapy compared with other types of B-cell large-cell lymphoma. These findings, if confirmed, may have implications for the initial management of patients with PML.
Increased mortality after successful treatment for Hodgkin's disease.
Authors: Hudson M M , Poquette C A , Lee J , Greenwald C A , Shah A , Luo X , Thompson E I , Wilimas J A , Kun L E , Crist W M
Published: February 2017

PURPOSE

To determine the impact of treatment toxicity on long-term survival in pediatric Hodgkin's disease.

PATIENTS AND METHODS

We studied late events in 387 patients treated for pediatric Hodgkin's disease on four consecutive clinical trials at St Jude Children's Research Hospital from 1968 to 1990. Relative risks, actuarial risks, and absolute excess risks for cause-specific deaths were calculated.

RESULTS

As of April 1997, 316 (82%) of patients were alive, with a median follow-up of 15.1 (range, 2.9 to 28.6) years. In this cohort, which represented 5,623 person-years of follow-up, 71 fatal events resulted from Hodgkin's disease (n=36), second malignancies (n=14), infections (n=7), accidents (n=7), cardiac disease (n=6), and asphyxiation (n=1). The 5-year estimated event-free survival (EFS) for the entire cohort was 79.6%+/-2.1 %, which declined to 63.1%+/-4.4% by 20 years. Cumulative incidences of cause-specific deaths at 25 years were 9.8%+/-1.6% for Hodgkin's disease, 8.1%+/-2.6% for second malignancy, 4.0%+/-1.8% for cardiac disease, 3.9%+/-1.5% for infection, and 2.1%+/-0.8% for accidents. Standardized incidence ratios showed excess risk for all second malignancies (12; 95% confidence interval [CI], 8 to 17), acute myeloid leukemia (81; 95% CI, 16 to 237), solid tumors (11; 95% CI, 7 to 16), and breast cancer (33; 95% CI, 12 to 72). Standardized mortality ratios also showed excess mortality from cardiac disease (22; 95% CI, 8 to 48) and infection (18; 95% CI, 7 to 38).

CONCLUSION

Compared with age- and sex-matched control populations, survivors of pediatric Hodgkin's disease who were treated before 1990 face an increased risk of early mortality related to second cancers, cardiac disease, and infection.
Vinblastine for recurrent Hodgkin's disease following autologous bone marrow transplant.
Authors: Little R , Wittes R E , Longo D L , Wilson W H
Published: February 2017

PURPOSE

Bone marrow transplant (BMT) can cure recurrent Hodgkin's disease, but more than half of patients will progress and require additional treatment. When this occurs, there are no curative options and palliative therapy is usually indicated. In such patients, we have routinely used long-term vinblastine therapy because of its relatively low toxicity and high activity.

PATIENTS AND METHODS

We retrospectively reviewed the charts of all patients with Hodgkin's disease who relapsed after autologous BMT since 1991. Of 23 patients, 16 received vinblastine; we also include our index case, who began vinblastine following relapse in 1987. Patients received vinblastine 4 to 6 mg/m2 every 1 to 2 weeks, and continued until evidence of disease progression.

RESULTS

The 17 patients in this report had a median age of 31 years, performance status of 2, had received a median of three prior regimens, and 12 (71%) patients were advanced stage. Ten (59%) patients had objective responses, of which two (12%) were complete (CR) and eight (47%) were partial (PR). Two additional patients without measurable disease clinically improved for more than 6 months, and 1 patient had stable disease for more than 18 months. With a median follow-up of 20.4 months, the median event-free (EFS) and overall survival were 8.3 and 38.8 months, respectively. The two complete responders remain in remission at 4.6+ and 9+ years. Vinblastine was well tolerated with 3% of cycles associated with fever and neutropenia, and no cumulative or chronic toxicity.

CONCLUSION

Vinblastine provides effective palliation with low toxicity in recurrent Hodgkin's disease following transplant. These results suggest that long-term vinblastine therapy may be potentially curative and should be considered as initial therapy for such patients.
Improvement in the prognosis of breast cancer from 1965 to 1984.
Authors: Edwards M J , Gamel J W , Feuer E J
Published: February 2017

PURPOSE

The prognosis of breast cancer has improved over the past three decades. It is uncertain, however, whether this improvement results from an increase in the cure rate, extension of the life span of uncured patients, or some combination.

METHODS

From the Connecticut Tumor Registry, we obtained data on 25,091 patients with localized (node-negative) and regionally metastatic (node-positive) breast cancer who were diagnosed over the two decades between 1965 and 1984, with follow-up through 1993. The data for these patients were analyzed using a variety of parametric models to quantitate likelihood of cure and median survival time among uncured patients. These models incorporate the assumption that time to death from breast cancer follows a specific distribution.

RESULTS

For patients with node-negative disease, parametric analysis revealed no significant difference in cured-fraction or median survival time over the two decades studied. For patients with node-positive disease, however, a significant increase in median survival time (P < .001) was found during the second decade (1970 to 1979). There was also a trend toward a higher cured-fraction over time, but this was not statistically significant.

CONCLUSION

This study confirms that patients with node-positive disease had an improved prognosis over the two decades studied. Parametric analysis suggests that this improvement reflects primarily an increase in the median survival time for uncured patients, although there is a trend toward an increase in the likelihood of cure.
Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation given as a 24-hour continuous infusion weekly times four every 5 weeks.
Authors: Siu L L , Oza A M , Eisenhauer E A , Firby P S , Thiessen J J , Michael M , Wainman N , Manzo J , Feld R , Goldberg R A , Moore M J
Published: February 2017

PURPOSE

9-Aminocamptothecin (9-AC) is a water-insoluble camptothecin (CMP) derivative that inhibits normal topoisomerase I function. Schedule dependency was noted, with the greatest activity seen in the setting of greater than 24 hours exposure to lactone (L) concentrations > or = 10 nmol/L. In this phase I study, 9-AC was given by a continuous intravenous infusion over 24 hours once weekly times four every 5 weeks.

PATIENTS AND METHODS

Twenty patients, of whom 16 had fluorouracil-refractory colorectal cancer (CRC), entered the study. Dose levels were 0.7 mg/m2 (n = 4), 1.4 mg/m2 (n = 3), 1.9 mg/m2 (n = 6), and 1.65 mg/m2 (n = 7). Detailed pharmacokinetic (PK) measurements of 9-AC L and carboxylate (C) were performed on day 1 of cycles 1 and 2.

RESULTS

At 1.9 mg/m2, dose-limiting toxicity (DLT) was reached, with three of six patients having grade 4 neutropenia. At 1.65 mg/m2, one of seven patients had grade 4 neutropenia. Nonhematologic toxicity was modest, with diarrhea > or = grade 3 in two patients and lethargy > or = grade 3 in eight. PK/pharmacodynamic (PD) analyses showed marked interpatient variability. Steady-state concentrations (Css) of 9-AC L > or = 10 nmol/L (3.6 microg/L) were seen in five of seven patients at 1.65 mg/m2 and five of six patients at 1.9 mg/m2. Using the sigmoidal maximal effect (Emax) model, 9-AC L area under the concentration-time curve (AUC) and Css correlated with day 15 decrease in neutrophils (R2 = .47), but not platelets.

CONCLUSION

The recommended phase II dose of 9-AC colloidal dispersion (CD) given as a 24-hour continuous infusion weekly for 4 of every 5 weeks is 1.65 mg/m2.
Should bisphosphonates be part of the standard therapy of patients with multiple myeloma or bone metastases from other cancers? An evidence-based review.
Authors: Bloomfield D J
Published: February 2017

PURPOSE

To review objectively the evidence for the use of bisphosphonates for the reduction of skeletal events or the management of pain due to multiple myeloma or bone metastases from other types of cancer.

METHODS

MEDLINE was searched from 1976 onwards using the MeSH terms "exp diphosphonates/," "exp bone neoplasms/," "exp multiple myeloma/," and "bone metastases" as text words. Bibliographies of reports on these topics and major medical and scientific journals were searched. Experts in the field were approached. The question was defined and the evidence stratified in a hierarchical manner according to classification of study design. There were sufficient studies to enable the use of randomized trials only to address the questions. Effectiveness was defined and the evidence reviewed in a systematic manner.

RESULTS AND CONCLUSION

Eighteen randomized trials were identified. No meta-analyses are available. There is level I evidence (defined as an appropriately conducted randomized clinical trial with a statistically significant result) for the use of bisphosphonates to reduce both skeletal events and pain in multiple myeloma and in breast cancer patients with metastatic bone disease. There is also level I evidence for their use as part of a pain management program for bone metastases from carcinoma of the breast, lung, and prostate, and for symptomatic myeloma. The bisphosphonates appear to be well tolerated.
Double-alkylator non-total-body irradiation regimen with autologous hematopoietic stem-cell transplantation in pediatric solid tumors.
Authors: Ozkaynak M F , Matthay K , Cairo M , Harris R E , Feig S , Reynolds C P , Buckley J , Villablanca J G , Seeger R C
Published: February 2017

PURPOSE

To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered with fixed doses of carboplatin, etoposide, and melphalan (CEM) followed by autologous hematopoietic stem-cell transplantation (HSCT) in children with recurrent or high-risk solid tumors as a consolidation chemotherapy, and to make preliminary observations on efficacy.

PATIENTS AND METHODS

Twenty-seven patients with solid tumors between the ages of 2 and 21 years were enrolled. Twenty of 27 had recurrent disease, whereas seven were treated in first remission. Nine were treated with melphalan 50 mg/m2/d for 4 days, carboplatin 300 mg/m2/d for 4 days as a continuous infusion (CI), and etoposide 200 mg/m2/d for 4 days as a CI (level I). CTX 750 mg/m2/d for 4 days was added to this regimen for the next 18 patients (level II). Seven of nine patients at level I and four of 18 at level II received bone marrow (BM) only, while two of nine at level I and 14 of 18 at level II received BM plus peripheral-blood stem cells (PBSC).

RESULTS

The median time to reach an absolute neutrophil count (ANC) greater than 500/microl was 12.5 and 10 days for patients who received BM only and BM plus PBSC, respectively. Three cases of grade 3 mucositis, one Candida sepsis, and two transient hypoxemias were the main nonfatal toxicities. No toxic mortality was observed among level I patients. Three of 18 (16%) level II patients, all in second CR, died of transplant-related complications. Median follow-up is 29 months. Nine died of progressive disease (one second malignancy), six relapsed and are alive with disease, and nine are in continuous CR. Among the 15 PNET/Ewing's sarcoma patients, seven are in continuous CR (three of nine in second CR/VGPR, four of six in first CR/VGPR).

CONCLUSION

The addition of CTX 3 g/m2 to CEM followed by autologous HSCT as a consolidation therapy resulted in 16% toxic mortality in children with recurrent or high-risk solid tumors. Further CTX dose escalation was aborted. No common nonhematologic toxicity was identified. The event-free survival (EFS) of 66% +/- 19% at 3 years for patients with metastatic PNET/Ewing's sarcoma in first remission is encouraging. However, this is based on only six patients. Both level I and II need further exploration in high-risk pediatric solid tumors in first remission.