bluuebunny/crossref_metadata_2025 huggingface dataset:
Striking Regression of Chronic Radiotherapy Damage in a Clinical Trial of Combined Pentoxifylline and Tocopherol
Authors: Delanian Sylvie , Balla-Mekias Saida , Lefaix Jean-Louis
Published: February 2017

PURPOSE: Radiation-induced fibrosis (RIF) remains the most morbid complication of radiotherapy because of the absence of spontaneous regression and the difficulty of patient management. RIF treatment with combined pentoxifylline (PTX) and tocopherol (Vit E) was prompted by recent advances in cellular and molecular biology that have improved researchers' understanding of radiation-induced late-injury mechanisms and by the excellent results from our previous human and animal studies.

PATIENTS AND METHODS: Forty-three patients (mean [± SD] age, 59 ± 10 years) presenting with 50 symptomatic RIF areas involving the skin and underlying tissues were treated from April 1995 to September 1997. Patients had had radiotherapy for head and neck or breast cancer a mean period of 8.5 ± 6.5 years previously. RIF developed in the first year after irradiation and gradually worsened, without spontaneous regression. The mean measurable surface area of RIF ([S]) at the time of this study ([S0]) was 42 ± 34 cm2. The initial Subjective Objective Medical management and Analytic (SOMA) injury evaluation score was 13.2 ± 5.9 and included evidence of edema, plexitis, restricted movement, and local inflammatory signs. A combination of PTX (800 mg/d) and Vit E (1,000 IU/d) was administered orally for at least 6 months.

RESULTS: Treatment was well tolerated. All assessable injuries exhibited continuous clinical regression and functional improvement. Mean RIF surface area and SOMA scores improved significantly (P < .0001) at 3 months ([S3], −39%; [SOMA3], −22%), 6 months ([S6], −53%; [SOMA6], −35%), and 12 months ([S12], −66%; [SOMA12], −48%), and mean linear dimensions ([D]) diminished from the start of the study ([D0], 6.5 ± 2.5 cm) to the end of treatment 12 months later ([D12], 4 ± 2 cm). At the time of the treatment, we did not attempt to achieve the maximum effect, and the study was continued.

CONCLUSION: The PTX-Vit E combination reversed human chronic radiotherapy damage and, because no other treatment is presently available for RIF, should be considered as a therapeutic measure.
Liposomal Doxorubicin and Conventionally Fractionated Radiotherapy in the Treatment of Locally Advanced Non–Small-Cell Lung Cancer and Head and Neck Cancer
Authors: Koukourakis M. I. , Koukouraki S. , Giatromanolaki A. , Archimandritis S. C. , Skarlatos J. , Beroukas K. , Bizakis J. G. , Retalis G. , Karkavitsas N. , Helidonis E. S.
Published: February 2017

PURPOSE: Stealth (ALZA Corporation, Palo Alto, CA) liposomal drug formulation allows a higher intratumoral accumulation and a prolonged plasma half-life of the encapsulated drugs. In the study presented here, we evaluated the feasibility of Stealth liposomal doxorubicin (Caelyx; ALZA Corporation) administered concurrently with conventionally fractionated radiotherapy in the treatment of non–small-cell lung cancer (NSCLC) and head and neck cancer (HNC).

PATIENTS AND METHODS: Fifteen patients with NSCLC and 15 with squamous-cell HNC were recruited in two phase I dose-escalation trials. The starting dose of Caelyx was 10 mg/m2 every 2 weeks (for three cycles during radiotherapy) and was increased by 5 mg/m2 dose increments for every three patients.

RESULTS: The maximum tolerated dose of Caelyx was 20 mg/m2 for HNC and 25 mg/m2 in NSCLC patients. Oral/pharyngeal mucositis was the dose-limiting toxicity for HNC patients. “In field” radiation skin toxicity was slightly increased. Hematologic toxicity was minimal. Single photon emission computed tomographic evaluation of Caelyx distribution, using technetium-99m–diethylenetriamine pentaacetic acid labeling, revealed a high intratumoral accumulation of the drug. The tumor to thoracic vessel area count ratio in the NSCLC cases ranged from 0.6 to 1.6 (mean ± SD, 1.01 ± 0.29), whereas this ratio was higher (0.8 to 1.85; mean ± SD, 1.35 ± 0.39) in HNC cases (P = .049). The complete response rate was 21% in the NSCLC cases and 75% in the HNC cases. NSCLC cases with higher Caelyx tumor accumulation responded better to the regimen. The tumor microvessel density assessed with the anti-CD31 monoclonal antibody directly correlated with the degree of the Caelyx accumulation (P = .007; r = .92).

CONCLUSION: We conclude that combination of radiotherapy with Stealth liposomal doxorubicin is feasible. The potential role of such a regimen in the treatment of highly angiogenic tumors requires further investigation.
Placebo-Controlled Trial of 13-cis-Retinoic Acid Activity on Retinoic Acid Receptor-Beta Expression in a Population at High Risk: Implications for Chemoprevention of Lung Cancer
Authors: Ayoub J. , Jean-François R. , Cormier Y. , Meyer D. , Ying Y. , Major P. , Desjardins C. , Bradley W.E.C.
Published: February 2017

PURPOSE: To establish the incidence of abnormalities in the expression of retinoic acid receptor-beta (RARβ) in bronchial cells and determine the capacity of 13-cis-retinoic acid (13-CRA) to correct such abnormalities.

PATIENTS AND METHODS: One hundred eighty-eight smokers had a medical indication for bronchoscopy and were studied with bronchial brushings. Bronchial brushing samples were obtained for cytology analysis and for molecular analysis. After RNA was extracted, RARβ sequences were amplified by reverse transcriptase polymerase chain reaction and Southern blots were performed to assess RARβ expression. Forty-four eligible individuals with diminished RARβ expression consented to double-blind randomization to receive a placebo or 13-CRA 30 mg orally daily for 6 months. A second bronchoscopy was performed at the end of the treatment period. An analysis of variance was used to analyze changes in RARβ expression before and after treatment.

RESULTS: The 6-month treatment course was completed by 27 patients, and results were obtained for a total of 18 patients (eight patients treated with 13-CRA and ten treated with the placebo). In the placebo group, there was no difference between the results of RARβ expression before and after treatment (P = .43). In the 13-CRA group, there was an upregulation of RARβ expression at the end of 13-CRA treatment (P = .001). Cytologic changes were uncommon. Toxicities were primarily of grade 1. Palatal brushings were compared with bronchial brushings in 40 smokers. A perfect correlation of the results of RARβ expression was obtained from 27 patients.

CONCLUSION: RARβ expression is frequently decreased in the bronchial epithelium of smokers and is upregulated at the end of 13-CRA treatment. These results support undertaking a phase III chemoprevention trial of 13-CRA treatment for lung cancer.
Patients With t(8;21)(q22;q22) and Acute Myeloid Leukemia Have Superior Failure-Free and Overall Survival When Repetitive Cycles of High-Dose Cytarabine Are Administered
Authors: Byrd John C. , Dodge Richard K. , Carroll Andrew , Baer Maria R. , Edwards Colin , Stamberg Judith , Qumsiyeh Mazin , Moore Joseph O. , Mayer Robert J. , Davey Frederick , Schiffer Charles A. , Bloomfield Clara D.
Published: February 2017

PURPOSE: To examine the effect of single compared with repetitive (at least three) cycles of high-dose cytarabine after induction therapy for patients with acute myeloid leukemia (AML) who have the t(8;21)(q22;q22) karyotype.

PATIENTS AND METHODS: Patients entered onto the study had AML and t(8;21) and attained a complete remission on four successive Cancer and Leukemia Group B studies. In these studies, either ≥ three cycles of high-dose cytarabine or one cycle of high-dose cytarabine was administered, followed by sequential cyclophosphamide/etoposide and mitoxantrone/diaziquone with or without filgrastim support. Outcomes of these two groups of t(8;21) patients were compared.

RESULTS: A total of 50 patients with centrally reviewed AML and t(8;21) were assigned to receive one (n = 29) or ≥ three cycles (n = 21) of high-dose cytarabine as postinduction therapy. The clinical features of these two groups of patients were similar. Initial remission duration for t(8;21) patients assigned to one cycle of high-dose cytarabine was significantly inferior (P = .03), with 62% of patients experiencing relapse with a median failure-free survival of 10.5 months, compared with the group of patients who received ≥ three cycles, in which only 19% experienced relapse and failure-free survival is estimated to be greater than 35 months. Furthermore, overall survival was also significantly compromised (P = .04) in patients assigned to one cycle of high-dose cytarabine, with 59% having died as a consequence of AML, compared with 24% of those who received ≥ three cycles of high-dose cytarabine.

CONCLUSION: These data demonstrate that failure-free survival and overall survival of patients with t(8;21)(q22;q22) may be compromised by treatment approaches that do not include sequential high-dose cytarabine therapy.
Phase II Trial of Paclitaxel and Cisplatin in Metastatic and Recurrent Carcinoma of the Uterine Cervix
Authors: Papadimitriou Christos A. , Sarris Kyrillos , Moulopoulos Lia A. , Fountzilas George , Anagnostopoulos Athanassios , Voulgaris Zannis , Gika Dimitra , Giannakoulis Nikolaos , Diakomanolis Emmanuel , Dimopoulos Meletios A.
Published: February 2017

PURPOSE: Both paclitaxel and cisplatin have moderate activity in patients with metastatic or recurrent cancer of the cervix, and the combination of these two agents has shown activity and possible synergism in a variety of solid tumors. We administered this combination to patients with metastatic or recurrent cervical cancer to evaluate its activity.

PATIENTS AND METHODS: Thirty-four consecutive patients were treated on an outpatient basis with paclitaxel 175 mg/m2 administered intravenously over a 3-hour period followed by cisplatin 75 mg/m2 administered intravenously with granulocyte colony-stimulating factor support. The chemotherapy was administered every 3 weeks for a maximum of six courses.

RESULTS: Sixteen patients (47%; 95% confidence interval, 30% to 65%) achieved an objective response, including five complete responses and 11 partial responses. Responses occurred in 28% of patients with disease within the radiation field only and in 57% of patients with disease involving other sites. The median duration of response was 5.5 months, and the median times to progression and survival for all patients were 5 and 9 months, respectively. Grade 3 or 4 toxicities included anemia in 18% of patients and granulocytopenia in 15% of patients. Fifty-three percent of patients developed some degree of neurotoxicity; 21% of cases were grade 2 or worse.

CONCLUSION: The combination of paclitaxel with cisplatin seems relatively well tolerated and moderately active in patients with metastatic or recurrent cervical cancer. The significant incidence of neurotoxicity is of concern, and alternative methods of administration of the two agents could be evaluated. Then, further study of this combination, alone or with the addition of other active agents, is warranted.
Additional Value of Whole-Body Positron Emission Tomography With Fluorine-18-2-Fluoro-2-deoxy-d-glucose in Recurrent Colorectal Cancer
Authors: Flamen Patrick , Stroobants Sigrid , Van Cutsem Eric , Dupont Patrick , Bormans Guy , De Vadder Nancy , Penninckx Freddy , Van Hoe Lieven , Mortelmans Luc
Published: February 2017

PURPOSE: To assess the additional value of the whole-body [18F]-2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan as a staging modality complementing conventional diagnostic methods (CDM) in patients suspected of having recurrent colorectal adenocarcinoma.

PATIENTS AND METHODS: In 103 patients, the discordances between FDG-PET and CDM results were identified and related to the final diagnosis obtained by histopathology or clinical follow-up (> 1 year). All FDG-PET studies were reviewed with full knowledge of the CDM findings.

RESULTS: In a region-based analysis, discordances between CDM and FDG-PET findings were found in 40 of 412 regions (10%). In these, FDG-PET had additional diagnostic value in 14 of 16 locoregional, six of seven hepatic, seven of eight abdominal, and eight of nine extra-abdominal regions. In a patient-based analysis, CDM categorized a subgroup of 60 patients as having resectable recurrent disease limited to the liver (n = 37) or locoregional region (n = 23). In 13 of these patients, there were discordant FDG-PET findings, detecting additional tumor sites in nine patients and excluding disease in three patients and yielding an additional diagnostic value in 20% of the patients. A second subgroup consisted of 13 patients with inconclusive CDM findings (n = 5) or with elevated plasma carcinoembryonic antigen levels and an otherwise negative conventional work-up (n = 8). In these patients, FDG-PET results were correct in eight of nine discordances, yielding a positive additional diagnostic value in 62% of the patients.

CONCLUSION: Whole-body FDG-PET can have a clear impact on the therapeutic management in the follow-up of patients with colorectal cancer.
Prognostic Factors in Children With Localized Malignant Nonseminomatous Germ Cell Tumors
Authors: Baranzelli M. C. , Kramar A. , Bouffet E. , Quintana E. , Rubie H. , Edan C. , Patte C.
Published: February 2017

PURPOSE: Prognostic factors were studied in children older than 1 year who were treated with chemotherapy for extracranial localized malignant non seminomatous germ cell tumors.

PATIENTS AND METHODS: Data from two consecutive protocols were pooled. The TGM 85 (1985-1989) protocol consisted of alternating courses of cyclophosphamide, dactinomycin and vinblastine, bleomycin, and cisplatin at a dose of 100 mg/m2 per course. The TGM 90 (1990-1994) protocol was initiated with carboplatin 400 mg/m2 substituted for cisplatin as the only modification to the previous protocol.

RESULTS: We examined alpha-fetoprotein (AFP) levels, disease stage, and primary site and identified three prognostic groups. Patients with a poor prognosis had either an AFP level ≥ 10,000 ng/mL or stage III disease and a sacrococcygeal or mediastinal primary site; such patients represented 46% of the patient population and experienced a 43% 3-year failure-free survival rate and a 77% overall survival rate. Patients with a good prognosis had an AFP level less than 10,000 ng/mL, stage I or II disease, and a testicular, ovarian, perineal, or retroperitoneal primary site; such patients represented 22% of the patient population and experienced no treatment failures. The other patients were classified in the intermediate prognosis group and represented 37% of the patient population, with an 81% 3-year failure-free survival rate and a 92% overall survival rate.

CONCLUSION: Initial AFP level, disease stage, and primary site are the most important prognostic factors in this analysis. Prognostic models for pediatric germ cell tumors should allow the stratification of patients for a risk-adapted approach to treatment.
Safety and Efficacy of Using a Single Agent or a Phase II Agent Before Instituting Standard Combination Chemotherapy in Previously Untreated Metastatic Breast Cancer Patients: Report of a Randomized Study—Cancer and Leukemia Group B 8642
Authors: Costanza Mary E. , Weiss Raymond B. , Henderson I. Craig , Norton Larry , Berry Donald A. , Cirrincione Constance , Winer Eric , Wood William C. , Frei III Emil , McIntyre O. Ross , Schilsky Richard L.
Published: February 2017

PURPOSE: We undertook a prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients.

PATIENTS AND METHODS: A total of 365 women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide, carboplatin, or elsamitrucin, followed by CAF.

RESULTS: The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates for the single agent followed by CAF were not statistically different from those of CAF alone (44% v 52%; P = .24). However, in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the phase II agent plus CAF arm (P = .078). Although survival and response duration also were not statistically significantly different between the two study arms (P = .074 and P = .069, respectively), there was a suggestion of benefit for the CAF-only arm.

CONCLUSION: The brief use of a phase II agent, regardless of its efficacy, followed by CAF resulted in response rates, toxicities, durations of response, and survival statistically equivalent to those seen with the use of CAF alone. These findings support the use of a new paradigm for the evaluation of phase II agents in the treatment of patients with metastatic breast cancer.
Is Axillary Lymph Node Dissection Indicated for Early-Stage Breast Cancer? A Decision Analysis
Authors: Parmigiani Giovanni , Berry Donald A. , Winer Eric P. , Tebaldi Claudia , Iglehart J. Dirk , Prosnitz Leonard R.
Published: February 2017

PURPOSE: Axillary lymph node dissection (ALND) has been a standard procedure in the management of breast cancer. In a patient with a clinically negative axilla, ALND is performed primarily for staging purposes, to guide adjuvant treatment. Recently, the routine use of ALND has been questioned because the results of the procedure may not change the choice of adjuvant systemic therapy and/or the survival benefit of a change in adjuvant therapy would be small. We constructed a decision model to quantify the benefits of ALND for patients eligible for breast-conserving therapy.

METHODS: Patients were grouped by age, tumor size, and estrogen receptor (ER) status. The model uses the Oxford overviews and three combined Cancer and Leukemia Group B studies. We assumed that patients who did not undergo ALND received axillary radiation therapy and that the two procedures are equally effective. All chemotherapy combinations were assumed to be equally efficacious.

RESULTS: The largest benefits from ALND are seen in ER-positive women with small primary tumors who might not be candidates for adjuvant chemotherapy if their lymph nodes test negative. Virtually no benefit results in ER-negative women, almost all of whom would receive adjuvant chemotherapy. When adjusted for quality of life (QOL), ALND may have an overall negative impact. In general, the benefits of ALND increase with the expected severity of adjuvant therapy on QOL.

CONCLUSION: Our model quantifies the benefits of ALND and assists decision making by patients and physicians. The results suggest that the routine use of ALND in breast cancer patients should be reassessed and may not be necessary in many patients.
Effect of Tamoxifen on Sexual Functioning in Patients With Breast Cancer
Authors: Mortimer Joanne E. , Boucher Leslie , Baty Jack , Knapp Diana L. , Ryan Elizabeth , Rowland Julia H.
Published: February 2017

PURPOSE: To define the incidence of sexual dysfunction in a population of women with breast cancer treated with tamoxifen.

PATIENTS AND METHODS: Breast cancer patients with a performance status of 0 to 2 who had been treated with tamoxifen for 2 to 24 months completed the following measures: the Center for Epidemiologic Studies–Depression Scale, the Sexual History Form, and the Breast Cancer Prevention Trial Symptom Checklist. Forty-nine of the participants underwent gynecologic examinations with vaginal smears for determination of estrogen effect.

RESULTS: Fifty-seven women were entered onto the trial. Sexual desire, arousal, and ability to achieve orgasm were comparable to norms established in participants in the Tamoxifen Prevention Trial (National Surgical Adjuvant Breast and Bowel Project P-01). Pain, burning, or discomfort with intercourse was reported in 54% of patients and did not correlate with age, surgical treatment of the primary cancer, or chemotherapy. Estrogen effect was seen on the vaginal smears of 34 of 49 participants and was more common in older patients (P = .054). The presence of estrogen effect correlated with negative reactions during sex (P = .02) and vaginal dryness or tightness (P = .046).

CONCLUSION: Women treated with tamoxifen in the adjuvant setting experienced symptoms of sexual dysfunction. The individual contributions of chemotherapy and tamoxifen to sexual dysfunction warrant prospective study.
Randomized Trial of Low-Dose Chemotherapy Added to Tamoxifen in Patients With Receptor-Positive and Lymph Node–Positive Breast Cancer
Authors: Jakesz R. , Hausmaninger H. , Haider K. , Kubista E. , Samonigg H. , Gnant M. , Manfreda D. , Tschurtschenthaler G. , Kolb R. , Stierer M. , Fridrik M. , Mlineritsch B. , Steindorfer P. , Mittlböck M. , Steger G.
Published: February 2017

PURPOSE: To evaluate the outcome in patients with stage II hormone receptor–positive breast cancer treated or not treated with low-dose, short-term chemotherapy in addition to tamoxifen in terms of disease-free and overall survival.

PATIENTS AND METHODS: A total of 613 patients were randomized to receive either low-dose chemotherapy (doxorubicin 20 mg/m2 and vincristine 1 mg/m2 on day 1; cyclophosphamide 300 mg/m2; methotrexate 25 mg/m2; and fluorouracil 600 mg/m2 on days 29 and 36 intravenously) or no chemotherapy in addition to 20 mg of tamoxifen orally for 2 years. A third group without any treatment (postmenopausal patients only) was terminated after the accrual of 79 patients due to ethical reasons.

RESULTS: After a median follow-up period of 7.5 years, the addition of chemotherapy did not improve the outcome in patients as compared with those treated with tamoxifen alone, neither with respect to disease-free nor overall survival. Multivariate analysis of prognostic factors for disease-free survival revealed menopausal status, in addition to nodal status, progesterone receptor, and histologic grade as significant. Both untreated postmenopausal and tamoxifen-treated premenopausal patients showed identical prognoses significantly inferior to the tamoxifen-treated postmenopausal cohort. Prognostic factors for overall survival in the multivariate analysis showed nodal and tumor stage, tumor grade, and hormone receptor level as significant.

CONCLUSION: Low-dose chemotherapy in addition to tamoxifen does not improve the prognosis of stage II breast cancer patients with hormone-responsive tumors. Tamoxifen-treated postmenopausal patients show a significantly better prognosis than premenopausal patients, favoring the hypothesis of a more pronounced effect of tamoxifen in the older age groups.
Single-Agent Monoclonal Antibody Efficacy in Bulky Non-Hodgkin's Lymphoma: Results of a Phase II Trial of Rituximab
Authors: Davis T. A. , White C. A. , Grillo-López A. J. , Velásquez W. S. , Link B. , Maloney D. G. , Dillman R. O. , Williams M. E. , Mohrbacher A. , Weaver R. , Dowden S. , Levy R.
Published: February 2017

PURPOSE: A phase II trial was performed to evaluate the safety and efficacy of rituximab, a chimeric anti-CD20 monoclonal antibody, in patients with bulky (> 10-cm lesion) relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (NHL).

PATIENTS AND METHODS: Thirty-one patients received intravenous infusions of rituximab 375 mg/m2weekly for four doses. All patients had at least one prior therapy (median, three; range, one to 13) and had progressive disease at study entry. Patients were a median of 4 years from diagnosis.

RESULTS: No patient had treatment discontinued because of an adverse event. No patient developed human antichimeric antibody. The overall response rate in 28 assessable patients was 43% with a median time to progression of 8.1 months (range, 4.5 to 18.6+ months) and median duration of response of 5.9 months (range, 2.8 to 12.1+ months). The average decrease in lesion size in patients who achieved a partial response was 76%, and patients with stable disease had a decrease in average lesion size of 26%. Median serum antibody concentration was higher in responders compared with nonresponders, and a negative correlation was shown between antibody concentration and tumor bulk at baseline.

CONCLUSION: Rituximab single-agent outpatient therapy is safe and shows significant clinical activity in patients with bulky relapsed or refractory low-grade or follicular B-cell NHL.
Outcomes of High-Dose Chemotherapy and Autologous Stem-Cell Transplantation in Stage IIIB Inflammatory Breast Cancer
Authors: Adkins D. , Brown R. , Trinkaus K. , Maziarz R. , Luedke S. , Freytes C. , Needles B. , Wienski D. , Fracasso P. , Pluard T. , Moriconi W. , Ryan T. , Hoelzer K. , Safdar S. , Rearden T. , Rodriguez G. , Khoury H. , Vij R. , DiPersio J.
Published: February 2017

PURPOSE: To evaluate the disease-free survival (DFS) and overall survival (OS), prognostic factors, and treatment-related mortality of women with stage IIIB inflammatory breast cancer (IBC) treated with combined modality therapy (CMT) and high-dose chemotherapy (HDCT) with autologous stem-cell transplantation.

PATIENTS AND METHODS: Between 1989 and 1997, 47 consecutive patients with stage IIIB IBC were treated with CMT and HDCT and were the subject of this retrospective analysis. Chemotherapy was administered to all patients before and/or after definitive surgery. Neoadjuvant and adjuvant chemotherapy was administered to 33 and 34 patients, respectively, and 20 patients received both. All patients received HDCT with autologous stem-cell transplantation, and 41 patients received locoregional radiation therapy. Tamoxifen was prescribed to patients with estrogen receptor (ER)–positive cancer.

RESULTS: The mean duration of follow-up from diagnosis was 30 months (range, 6 to 91 months) and from HDCT was 22 months (range, 0.5 to 82 months). At 30 months, the Kaplan-Meier estimates of DFS and OS from diagnosis were 57.7% and 59.1%, respectively. At 4 years, the Kaplan-Meier estimates of DFS and OS from diagnosis were 51.3% and 51.7%, respectively. In a multivariate analysis, the only factors associated with better survival were favorable response to neoadjuvant chemotherapy (P = .04) and receipt of tamoxifen (P = .06); however, the benefit of tamoxifen was only demonstrated in patients with ER-positive breast cancer. At last follow-up, 28 patients (59.6%) were alive and disease-free. Seventeen patients (36.2%) developed recurrent breast cancer. Seventeen patients died: 15 from disease recurrence and two (4.2%) from treatment-related mortality due to HDCT.

CONCLUSION: In this analysis, the early results of treatment with CMT and HDCT compare favorably with other series of patients with stage IIIB IBC treated with CMT alone. These outcomes must be confirmed with longer follow-up and controlled studies.
Phase I Clinical and Pharmacologic Study of 13-cis-Retinoic Acid, Interferon Alfa, and Paclitaxel in Patients With Prostate Cancer and Other Advanced Malignancies
Authors: DiPaola R. S. , Rafi M. M. , Vyas V. , Toppmeyer D. , Rubin E. , Patel J. , Goodin S. , Medina M. , Medina P. , Zamek R. , Zhang C. , White E. , Gupta E. , Hait W. N.
Published: February 2017

PURPOSE: Recent studies demonstrate that retinoids decrease expression of the anti-apoptotic protein bcl-2, enhance the effect of chemotherapy, and act synergistically with interferon alfa (IFNα) to inhibit tumor cell growth in vitro. A phase I trial of 13-cis-retinoic acid (CRA), IFNα, and paclitaxel (TAX) was conducted to determine the toxicity and recommended phase II dose of this combination. Pharmacodynamic studies were performed to determine whether CRA and IFNα could modulate bcl-2 expression in vitro and in patients.

PATIENTS AND METHODS: Twenty-two patients with prostate cancer or other advanced malignancies were treated with CRA/IFNα and escalating doses of TAX. The effect of CRA/IFNα on TAX pharmacokinetics was analyzed in both patients and human liver microsomes. The effect of CRA/IFNα on bcl-2 expression was assessed in vitro and in peripheral-blood mononuclear cells (PBMCs) by immunoblotting.

RESULTS: CRA 1 mg/kg on days 1 to 4, IFNα 6 MU/m2 subcutaneously on days 1 to 4, and TAX 175 mg/m2 onday 3 was well tolerated. Pharmacokinetic studies demonstrated that CRA/IFNα caused a 33% decrease in TAX clearance and a 23% decrease in the area under the concentration-time curve values of the TAX metabolite 6-alfa-hydroxytaxol (6-HT). CRA alone reduced conversion of TAX to 6-HT by 41% in human liver microsomes. CRA/IFNα decreased bcl-2 expression in vitro and in PBMCs.

CONCLUSION: CRA/IFNα and TAX is a well-tolerated regimen. CRA/IFNα increases TAX area under the concentration-time curve through an inhibitory effect of CRA on the metabolism of TAX to 6-HT. CRA/IFNα can modulate bcl-2 expression in vitro and demonstrates similar biologic activity in patients. Further studies will determine the activity of CRA/IFNα/TAX and validate the assessment of bcl-2 in PBMCs as a marker of tumor response.
Analysis of Factors That Correlate With Mucositis in Recipients of Autologous and Allogeneic Stem-Cell Transplants
Authors: Rapoport Aaron P. , Miller Watelet Luc F. , Linder Tammy , Eberly Shirley , Raubertas Richard F. , Lipp Joanna , Duerst Reggie , Abboud Camille N. , Constine Louis , Andrews Jessica , Etter Mary Ann , Spear Linda , Powley Elizabeth , Packman Charles H. , Rowe Jacob M. , Schwertschlag Ullrich , Bedrosian Camille , Liesveld Jane L.
Published: February 2017

PURPOSE: To identify predictors of oral mucositis and gastrointestinal toxicity after high-dose therapy.

PATIENTS AND METHODS: Mucositis and gastrointestinal toxicity were prospectively evaluated in 202 recipients of high-dose therapy and autologous or allogeneic stem-cell rescue. Of 10 outcome variables, three were selected as end points: the peak value for the University of Nebraska Oral Assessment Score (MUCPEAK), the duration of parenteral nutritional support, and the peak daily output of diarrhea. Potential covariates included patient age, sex, diagnosis, treatment protocol, transplantation type, stem-cell source, and rate of neutrophil recovery. The three selected end points were also examined for correlation with blood infections and transplant-related mortality.

RESULTS: A diagnosis of leukemia, use of total body irradiation, allogeneic transplantation, and delayed neutrophil recovery were associated with increased oral mucositis and longer parenteral nutritional support. No factors were associated with diarrhea. Also, moderate to severe oral mucositis (MUCPEAK ≥ 18 on a scale of 8 to 24) was correlated with blood infections and transplant-related mortality: 60% of patients with MUCPEAK ≥ 18 had positive blood cultures versus 30% of patients with MUCPEAK less than 18 (P = .001); 24% of patients with MUCPEAK ≥ 18 died during the transplantation procedure versus 4% of patients with MUCPEAK less than 18 (P = .001).

CONCLUSION: Gastrointestinal toxicity is a major cause of transplant-related morbidity and mortality, emphasizing the need for corrective strategies. The peak oral mucositis score and the duration of parenteral nutritional support are useful indices of gastrointestinal toxicity because these end points are correlated with clinically significant events, including blood infections and treatment-related mortality.
Hydrocortisone With or Without Mitoxantrone in Men With Hormone-Refractory Prostate Cancer: Results of the Cancer and Leukemia Group B 9182 Study
Authors: Kantoff Philip W. , Halabi Susan , Conaway Mark , Picus Joel , Kirshner Jeffrey , Hars Vera , Trump Donald , Winer Eric P. , Vogelzang Nicholas J.
Published: February 2017

PURPOSE: Approximately 40,000 men die each year of hormone-refractory prostate cancer (HRPC). The results of treatment with chemotherapy have been disappointing to date, with no trials demonstrating a benefit with respect to survival duration. Corticosteroids and mitoxantrone each have been shown to be active agents in this disease. The purpose of this study was to demonstrate an advantage of mitoxantrone and hydrocortisone (M+H) over hydrocortisone alone with respect to survival duration.

PATIENTS AND METHODS: Two hundred forty-two patients with HRPC were randomized to receive either M+H or hydrocortisone alone. Patients were monitored for survival, time to disease progression, time to treatment failure, response, and quality-of-life (QOL) parameters.

RESULTS: Treatment in both arms was well tolerated. Although there was a delay in time to treatment failure and disease progression in favor of M+H over hydrocortisone alone, there was no difference in overall survival (12.3 months for M+H v 12.6 months for hydrocortisone alone). There was an indication that QOL was better with M+H, in particular with respect to pain control.

CONCLUSION: M+H generated more frequent responses and a delay in both time to treatment failure and disease progression compared with hydrocortisone alone. In addition, there was a possible benefit of M+H with respect to pain control over hydrocortisone alone. No improvement in survival was observed. Although M+H could be viewed as a palliative option for patients with HRPC, new drugs and novel strategies are needed to improve survival for this disease.
Phase I Trial to Determine the Safety, Pharmacodynamics, and Pharmacokinetics of RSR13, a Novel Radioenhancer, in Newly Diagnosed Glioblastoma Multiforme
Authors: Kleinberg L. , Grossman S. A. , Piantadosi S. , Pearlman J. , Engelhard H. , Lesser G. , Ruffer J. , Gerber M.
Published: February 2017

PURPOSE: To determine the safety, pharmacokinetics, and pharmacodynamic effect of 2-[4-(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylproprionic acid (RSR13) 100 mg/kg/d with radiation therapy (RT) for glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin (HgB), is a novel radioenhancing agent that noncovalently binds to HgB, thereby reducing oxygen binding affinity and increasing tissue oxygen release to hypoxic tissues.

PATIENTS AND METHODS: In this multi-institutional, dose frequency–seeking trial, 19 adult patients with newly diagnosed GBM received RSR13 100 mg/kg every other day or daily along with cranial RT (60 Gy/30 fractions). RSR13 was given over 1 hour by central venous access with 4 L/min of O2 by nasal cannula, followed by RT within 30 minutes. Pharmacokinetic (PK) and pharmacodynamic (PD) determinations were performed. The PD end point was shift in P50, the oxygen half-saturation pressure of HgB.

RESULTS: Grade 3 dose-limiting toxicity occurred innone of the patients with every-other-day dosing and in two of the 10 patients with daily dosing. Grade 2 or greater toxicity occurred in three out of nine and six out of 10, respectively. PK and PD data demonstrate that a substantial PD effect was reliably achieved, that PD effect was related to RBC RSR13 concentration, and that there was no significant drug accumulation even with daily dosing. The mean shift in P50 was 9.24 ± 2.6 mmHg (a 34% increase from baseline), which indicates a substantial increase in tendency toward oxygen unloading.

CONCLUSION: Daily RSR13 (100 mg/kg) during cranial RT is well tolerated and achieves the desired PD end point. A phase II trial of daily RSR13 for newly diagnosed malignant glioma is currently accruing patients within the New Approaches to Brain Tumor Therapy Central Nervous System Consortium to determine survival outcome.
Phase I and Pharmacokinetic Study of Temozolomide on a Daily-for-5-Days Schedule in Patients With Advanced Solid Malignancies
Authors: Hammond Lisa A. , Eckardt John R. , Baker Sharyn D. , Eckhardt S. Gail , Dugan Margaret , Forral Kelly , Reidenberg Pascale , Statkevich Paul , Weiss Geoffrey R. , Rinaldi David A. , Von Hoff Daniel D. , Rowinsky Eric K.
Published: February 2017

PURPOSE: To determine the principal toxicities, characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-for-5-days schedule, and recommend a dose for subsequent disease-directed studies in both minimally pretreated (MP) and heavily pretreated (HP) patients.

PATIENTS AND METHODS: Patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150, and 150 to 200 mg/m2/d in separate cohorts of MP and HP patients. PK plasma was sampled on days 1 and 5. TMZ concentrations were analyzed and pertinent PK parameters were related to the principal toxicities of TMZ in PD analyses.

RESULTS: Twenty-four patients were treated with 85 courses of TMZ. Thrombocytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive effects was unacceptably high at TMZ doses exceeding 150 mg/m2/d in both MP and HP patients. TMZ was absorbed rapidly with maximum concentrations achieved in 0.90 hours, on average, and elimination was rapid, with a half-life and systemic clearance rate (ClS/F) averaging 1.8 hours and 115 mL/min/m2, respectively. When clearance was normalized to body-surface area (BSA), interpatient variability in ClS/F was reduced from 20% to 13% on day 1 and from 16% to 10% on day 5. Patients who experienced DLT had significantly higher maximum drug concentration (median 16 v 9.5 μg/mL, P = .0084) and area under the concentration-time curve (median 36 v 23 μg-h/mL, P = .0019) values on day 5.

CONCLUSION: Prior myelosuppressive therapy was not a determinant of toxicity. TMZ 150 mg/m2/d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by MP and HP patients, with higher doses resulting in unacceptably high rates of severe hematologic toxicity. TMZ doses should be individualized according to BSA rather than use of a prespecified oral dose for all individuals. TMZ is an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies.
Outpatient-Based Bone Marrow Transplantation for Hematologic Malignancies: Cost Saving or Cost Shifting?
Authors: Rizzo J. Douglas , Vogelsang Georgia B. , Krumm Sharon , Frink Barbara , Mock Victoria , Bass Eric B.
Published: February 2017

PURPOSE: To determine whether a shift in care from an inpatient-based to an outpatient-based bone marrow transplantation (BMT) program decreased charges to payers without increasing clinical complications or out-of-pocket costs to patients.

PATIENTS AND METHODS: This nonrandomized prospective cohort study compared clinical and economic outcomes for 132 consecutive BMT patients with hematologic malignancies who received either inpatient- or outpatient-based BMT care.

RESULTS: Seventeen of 132 BMT patients underwent outpatient-based BMT. Compared with the inpatient-based group, the outpatient-based group had a markedly lower mean number of inpatient hospital days (22 v 47; P < .001) and decreased mean inpatient facility charges ($61,059 less per patient; P < .0001) but had higher mean outpatient facility charges ($49,732 higher; P < .0001). Total professional fees were similar for the groups. The mean total charge to payers was only 7% less ($12,652; P = .21) for outpatient-based BMT than for inpatient-based BMT, but total charge was 34% less for outpatient compared with inpatient BMT ($54,240; P = 0.056) in a subset of patients who had a standard rather than high risk of treatment failure. There was no significant difference between groups in out-of-pocket costs for transportation, lodging, meals, home nursing, household assistance, child care, medication expenses, or unreimbursed medical bills. There also was no significant difference between groups in reported income lost, involuntary unemployment, or months of disability. The two groups had similar rates of major complications, including death, significant acute graft-versus-host disease, and veno-occlusive disease of the liver.

CONCLUSION: Increased use of outpatient-based BMT should produce substantial cost savings for payers without adverse effects on patients for those patients who do not have a high risk of treatment failure.
Immunocytoma: A Retrospective Analysis From St Bartholomew's Hospital—1972 to 1996
Authors: Papamichael D. , Norton A. J. , Foran J. M. , Mulatero C. , Mathews J. , Amess J. A.L , Bradburn M. , Lister T. A. , Rohatiner A. Z.S.
Published: February 2017

PURPOSE: To analyze the presentation features and outcome for patients with immunocytoma (IMC) managed at St Bartholomew's Hospital (SBH), London, United Kingdom, between 1972 and 1996. Outcome was compared with that of patients with small lymphocytic lymphoma (SLL)/B-cell chronic lymphocytic leukemia (B-CLL) treated at SBH during the same period.

PATIENTS AND METHODS: One hundred twenty-six patients with newly diagnosed IMC were identified. Patients were subclassified (using the Kiel classification) as having lymphoplasmacytoid (n =92), lymphoplasmacytic (n = 24), polymorphous (n = 9), or undetermined (n = 1) IMC. Six patients (5%) had stage I to IIE disease; the rest had advanced disease. Treatment was given according to disease stage. Seven patients were managed expectantly.

RESULTS: Eighty-two (69%) of 119 patients responded to treatment, but complete remission was seen in only 15 (13%) of 119. Treatment failed in 29 (24%) of 119 patients. There were three treatment-related deaths; five patients were not assessable for response. When survival of patients with IMC was compared with that of patients with B-CLL/SLL, a significant difference was found (P < .01); this difference was maintained when only patients in whom the diagnosis was based on lymph node biopsy were considered (P = .01). A comparison of the three IMC subgroups showed that there was a trend (P = .06) toward a difference between B-CLL/SLL and the lymphoplasmacytoid subtype.

CONCLUSION: Patients diagnosed with IMC are generally older and present with advanced disease. Conventional therapies usually result in incomplete responses of short duration. Overall, these results support the proposed World Health Organization reclassification of IMC to include lymphoplasmacytoid lymphoma (Kiel classification) as a variant of B-CLL/SLL.
Characteristics and Outcome of Children With Beckwith-Wiedemann Syndrome and Wilms’ Tumor: A Report From the National Wilms Tumor Study Group
Authors: Porteus Matthew H. , Narkool Patricia , Neuberg Donna , Guthrie Katherine , Breslow Norman , Green Daniel M. , Diller Lisa
Published: February 2017

PURPOSE: Children with Beckwith-Wiedemann syndrome (BWS) are at increased risk for developing Wilms’ tumor (WT). We reviewed the National Wilms Tumor Study Group (NWTSG) records to assess clinical characteristics and outcome of patients with WT and BWS.

METHODS: In the NWTSG, treating clinicians were asked to report, for each enrolled patient, whether the patient had BWS. Between 1980 and 1995, 4,669 patients were treated on two consecutive NWTSG protocols (NWTS 3 and NWTS 4). We retrospectively reviewed the clinical characteristics and treatment outcomes of BWS patients compared with patients with WT without BWS.

RESULTS: Fifty-three children enrolled onto NWTS 3 and 4 were reported to have BWS. BWS patients were more likely to present with lower-stage tumors (P = .0001), with more than half (27 of 53) presenting with stage I disease. The overall treatment outcomes for the BWS patients were nearly identical to those without BWS, with overall survival at 4 years from diagnosis at 89% and 90%, respectively. Overall, 21% of the patients with BWS had bilateral disease, either at diagnosis (nine of 53) or as metachronous contralateral recurrence (two of 53). BWS patients enrolled onto NWTS 4 had smaller tumors than those enrolled onto NWTS 3 (P = .02), a trend not seen in the non-BWS patients.

CONCLUSION: Like children without BWS, children with BWS and WT have an excellent prognosis with modern treatment regimens. There is a high risk of bilateral disease, and increasingly smaller tumors are being detected. This suggests that a national trial assessing the role of ultrasound screening followed by nephron-sparing surgery for some patients may be appropriate.
Sequence Effect of Epirubicin and Paclitaxel Treatment on Pharmacokinetics and Toxicity
Authors: Venturini Marco , Lunardi Gianluigi , Del Mastro Lucia , Vannozzi Maria Ornella , Tolino Giuseppina , Numico Gianmauro , Viale Maurizio , Pastrone Ilaria , Angiolini Catia , Bertelli Gianfilippo , Straneo Manuela , Rosso Riccardo , Esposito Mauro
Published: February 2017

PURPOSE: Sequence-dependent clinical and pharmacokinetic interactions between paclitaxel and doxorubicin have been reported. Some data have shown an influence of paclitaxel on epirubicin metabolism, but no data are available about the effect of diverse sequences of these drugs. We investigated whether reversing the sequence of epirubicin and paclitaxel affects the pattern or degree of toxicity and pharmacokinetics.

PATIENTS AND METHODS: Patients receiving epirubicin 90 mg/m2 by intravenous bolus followed by paclitaxel 175 mg/m2 over 3-hour infusion or the opposite sequence every 3 weeks for four cycles were eligible. Toxicity was recorded at nadir. Pharmacokinetic data were evaluated at the first and the second cycle and were correlated with toxicity parameters.

RESULTS: Thirty-nine consecutive stage II breast cancer patients were treated. Twenty-one patients received epirubicin followed by paclitaxel (ET group), and 18 received the opposite sequence (TE group). No significant difference in nonhematologic toxicity was seen. A lower neutrophil and platelet nadir and a statistically significant slower neutrophil recovery was observed in the TE group. Area under the concentration-time curve (AUC) of epirubicin was higher in the TE group (2,346 ng/mL · h v 1,717 ng/mL · h; P = .002). An inverse linear correlation between epirubicin AUC and neutrophil recovery was also observed (P = .012). No difference was detected in paclitaxel pharmacokinetics.

CONCLUSION: Our results support a sequence-dependent effect of paclitaxel over epirubicin pharmacokinetics that is associated with increased myelotoxicity. Because schedule modifications of anthracyclines and paclitaxel can have clinical consequences, the classical way of administration (ie, anthracyclines followed by paclitaxel) should be maintained in clinical practice.