bluuebunny/crossref_metadata_2025 huggingface dataset:
Carboplatin Plus Paclitaxel in Unknown Primary Carcinoma: A Phase II Hellenic Cooperative Oncology Group Study
Authors: Briasoulis Evangelos , Kalofonos Haralambos , Bafaloukos Dimitris , Samantas Epaminondas , Fountzilas George , Xiros Nikolaos , Skarlos Dimosthenis , Christodoulou Christos , Kosmidis Paris , Pavlidis Nicholas
Published: February 2017

PURPOSE: To evaluate the efficacy of the carboplatin/paclitaxel combination in patients with carcinoma of unknown primary site (CUP).

PATIENTS AND METHODS: Seventy-seven consecutive CUP patients (45 women and 32 men; median age, 60 years) were treated with carboplatin at target area under the curve 6 mg/mL/min followed by paclitaxel 200 mg/m2 as a 3-hour infusion and granulocyte colony-stimulating factor from days 5 to 12. Treatment courses were repeated every 3 weeks to a maximum of eight cycles. Forty-seven patients had adenocarcinomas, 27 had undifferentiated carcinomas, and three had squamous cell carcinomas. Thirty-three patients presented with liver, bone, or multiple organ metastases, 23 with predominantly nodal/pleural disease, and 19 (16 women) with peritoneal carcinomatosis.

RESULTS: The overall response rate by intent-to-treat analysis was 38.7% (95% confidence interval, 27.5% to 49.9%). There were no differences in response between adenocarcinomas and undifferentiated carcinomas, but efficacy varied among clinical subsets. The response rates and median survival times in the three clinically defined subsets were 47.8% and 13 months, respectively, for patients with predominantly nodal/pleural disease, 68.4% and 15 months, respectively, in women with peritoneal carcinomatosis, and 15.1% and 10 months, respectively, in patients with visceral or disseminated metastases. Chemotherapy was well-tolerated.

CONCLUSION: Carboplatin plus paclitaxel combination chemotherapy is effective in patients with predominantly nodal/pleural metastases of unknown primary carcinoma and in women with peritoneal carcinomatosis. However, in patients with liver, bone, or multiple organ involvement, the combination offers limited benefit. The investigation of novel treatment approaches is highly warranted for this group of patients.
Rituximab Anti-CD20 Monoclonal Antibody Therapy in Non-Hodgkin’s Lymphoma: Safety and Efficacy of Re-Treatment
Authors: Davis Thomas A. , Grillo-López Antonio J. , White Christine A. , McLaughlin Peter , Czuczman Myron S. , Link Brian K. , Maloney David G. , Weaver Robin L. , Rosenberg Jay , Levy Ronald
Published: February 2017

PURPOSE: This phase II trial investigated the safety and efficacy of re-treatment with rituximab, a chimeric anti-CD20 monoclonal antibody, in patients with low-grade or follicular non-Hodgkin’s lymphoma who relapsed after a response to rituximab therapy.

PATIENTS AND METHODS: Fifty-eight patients were enrolled onto this study, and two were re-treated within the study. Patients received an intravenous infusion of 375 mg/m2of rituximab weekly for 4 weeks. All patients had at least two prior therapies and had received at least one prior course of rituximab, with a median interval of 14.5 months between rituximab courses.

RESULTS: Most adverse experiences (AEs) were transient grade 1 or 2 events occurring during the treatment period. Clinically significant myelosuppression was not observed; hematologic toxicity was generally mild and reversible. No patient developed human antichimeric antibodies after treatment. The type, frequency, and severity of AEs in this study were not apparently different from those reported in the phase III trial of rituximab. The overall response rate in 57 assessable patients was 40% (11% complete response and 30% partial responses). Median time to progression (TTP) in responders and median duration of response (DR) have not been reached, but Kaplan-Meier estimated medians are 17.8 months (range, 5.4+ to 26.6 months) and 16.3 months (range, 3.7+ to 25.1 months), respectively. These estimated medians are longer than the medians achieved in the patients’ prior course of rituximab (TTP and DR of 12.4 and 9.8 months, respectively, P > .1) and in a previously reported phase III trial (TTP in responders and DR of 13.2 and 11.6 months, respectively). Responses are ongoing in seven of 23 responders.

CONCLUSION: In this re-treatment population, safety and efficacy were not apparently different from those after initial rituximab exposure.
Selective Estrogen Receptor Modulators: Structure, Function, and Clinical Use
Authors: Osborne C. Kent , Zhao Hong (Holly) , Fuqua Suzanne A. W.
Published: February 2017

ABSTRACT: The sex hormone estrogen is important for many physiologic processes. Prolonged stimulation of breast ductal epithelium by estrogen, however, can contribute to the development and progression of breast cancer, and treatments designed to block estrogen’s effects are important options in the clinic. Tamoxifen and other similar drugs are effective in breast cancer prevention and treatment by inhibiting the proliferative effects of estrogen that are mediated through the estrogen receptor (ER). However, these drugs also have many estrogenic effects depending on the tissue and gene, and they are more appropriately called selective estrogen receptor modulators (SERMs). SERMs bind ER, alter receptor conformation, and facilitate binding of coregulatory proteins that activate or repress transcriptional activation of estrogen target genes. Theoretically, SERMs could be synthesized that would exhibit nearly complete agonist activity on the one hand or pure antiestrogenic activity on the other. Depending on their functional activities, SERMs could then be developed for a variety of clinical uses, including prevention and treatment of osteoporosis, treatment and prevention of estrogen-regulated malignancies, and even for hormone replacement therapy. Tamoxifen is effective in patients with ER-positive metastatic breast cancer and in the adjuvant setting. The promising role for tamoxifen in ductal carcinoma-in-situ or for breast cancer prevention is evolving, and its use can be considered in certain patient groups. Other SERMs are in development, with the goal of reducing toxicity and/or improving efficacy, and future agents have the potential of providing a new paradigm for maintaining the health of women.
Soft Tissue Leiomyosarcomas and Malignant Gastrointestinal Stromal Tumors: Differences in Clinical Outcome and Expression of Multidrug Resistance Proteins
Authors: Plaat Boudewijn E. C. , Hollema Harry , Molenaar Willemina M. , Broers Gerben H. Torn , Pijpe Justin , Mastik Mirjam F. , Hoekstra Harald J. , van den Berg Eva , Scheper Rik J. , van der Graaf Winette T. A.
Published: February 2017

PURPOSE: Several studies have reported clinical behavior and chemotherapy resistance in leiomyosarcomas, but these studies did not differentiate between soft tissue leiomyosarcomas (LMS) and malignant gastrointestinal stromal tumors (GIST). Multidrug resistance (MDR) has been associated with the expression of P-glycoprotein (P-gp), multidrug resistance protein (MRP1), and lung resistance protein (LRP). The aim of the present study was to compare LMS and GIST with respect to clinical outcome and MDR parameters.

PATIENTS AND METHODS: Clinical outcome was evaluated in 29 patients with a primary deep-seated LMS and 26 patients with a primary malignant GIST. Paraffin-embedded material, available for 26 patients with LMS and 25 with GIST, was used for immunohistochemical detection of P-gp, MRP1, LRP, and c-kit.

RESULTS: Mean overall survival (OS) was 72 months for LMS patients and 31 months for GIST patients (P < .05). Metastases occurred in 16 (59%) of 27 assessable LMS patients and in 10 (56%) of 18 assessable GIST patients. LMS predominantly metastasized to the lungs (14 of 16 patients), whereas GIST tended to spread to the liver (five of 10 patients) and the abdominal cavity (three of 10 patients; P < .001). P-gp and MRP1 expression was more pronounced in GIST than in LMS (P < .05): the mean percentage of P-gp expressing cells was 13.4% in patients with LMS and 38.4% in patients with GIST, and the mean percentage MRP1 expressing cells was 13.3% in patients with LMS and 35.4% in patients with GIST. LRP expression did not differ between LMS and GIST. c-kit was expressed in 5% of the LMS patients and in 68% of the GIST patients.

CONCLUSION: LMS patients have a better survival than GIST patients, and the metastatic pattern is different. Expression of MDR proteins in LMS is less pronounced than in GIST.
Activation (Tyrosine Phosphorylation) of ErbB-2 (HER-2/neu): A Study of Incidence and Correlation With Outcome in Breast Cancer
Authors: Thor A.D. , Liu S. , Edgerton S. , Moore D. , Kasowitz K.M. , Benz C.C. , Stern D.F. , DiGiovanna M.P.
Published: February 2017

PURPOSE: We hypothesize that phosphorylated ErbB-2 (P-ErbB-2, identified by a novel antibody PN2A) may provide either more significant or additional prognostic marker data for breast cancer patients. This study was designed to compare the incidence and prognostic value of ErbB-2 (HER-2/neu) and P-ErbB-2 immunoexpression in archival breast cancer samples.

MATERIALS AND METHODS: Eight hundred sixteen invasive breast cancers with a median of 16.3 years of follow-up were immunostained for ErbB-2 (using antibody CB11) and P-ErbB-2 (using antibody PN2A). ErbB-2 and P-ErbB-2 data were compared with clinical, histologic, immunohistochemical, and outcome variables.

RESULTS: Of 816 primary breast cancers, 307 (38%) were positive for ErbB-2 and 37 (12% of ErbB-2 positive and 5% of the study population) expressed P-ErbB-2. P-ErbB-2 was not detected in ErbB-2–negative cases (n = 509). ErbB-2 immunohistochemical data were bimodal; patients with ≥ 80% cellular expression had the shortest disease-free and disease-specific survival. P-ErbB-2 was associated with a higher percentage of ErbB-2–positive cells, a higher number of positive lymph nodes, and cellular proliferation. ErbB-2 and P-ErbB-2 were indicators of poor prognosis in node-positive patients in both univariate and multivariate analyses. We found that either P-ErbB-2 expression or high (≥ 80%) ErbB-2 expression provided the most significant prognostic value in node-positive cases by multivariate analyses. There were too few P-ErbB-2–positive cases and events in the node-negative patient group to allow statistical analysis of P-ErbB-2 in that subgroup.

CONCLUSION: PN2A immunostaining identified a subset (approximately 12% of ErbB-2–positive breast cancers) with activation (phosphorylation) of the receptor ErbB-2. P-ErbB-2 expression was strongly associated with higher levels of ErbB-2 expression (≥ 80%), although it was not a surrogate. Identification of cases with a high percentage of invasive breast cancer cells expressing ErbB-2 or determination of receptor activation via P-ErbB-2 may provide additional prognostic value in node-positive breast cancers.
Phase III Randomized Trial of Amifostine as a Radioprotector in Head and Neck Cancer
Authors: Brizel David M. , Wasserman Todd H. , Henke Michael , Strnad Vratislav , Rudat Volkar , Monnier Alain , Eschwege Francois , Zhang Jay , Russell Lesley , Oster Wolfgang , Sauer Rolf
Published: February 2017

PURPOSE: Radiotherapy for head and neck cancer causes acute and chronic xerostomia and acute mucositis. Amifositine and its active metabolite, WR-1065, accumulate with high concentrations in the salivary glands. This randomized trial evaluated whether amifostine could ameliorate these side effects without compromising the effectiveness of radiotherapy in these patients.

PATIENTS AND METHODS: Patients with previously untreated head and neck squamous cell carcinoma were eligible. Primary end points included the incidence of grade ≥ 2 acute xerostomia, grade ≥ 3 acute mucositis, and grade ≥ 2 late xerostomia and were based on the worst toxicity reported. Amifostine was administered (200 mg/m2 intravenous) daily 15 to 30 minutes before irradiation. Radiotherapy was given once daily (1.8 to 2.0 Gy) to doses of 50 to 70 Gy. Whole saliva production was quantitated preradiotherapy and regularly during follow-up. Patients evaluated their symptoms through a questionnaire during and after treatment. Local-regional control was the primary antitumor efficacy end point.

RESULTS: Nausea, vomiting, hypotension, and allergic reactions were the most common side effects. Fifty-three percent of the patients receiving amifostine had at least one episode of nausea and/or vomiting, but it only occurred with 233 (5%) of 4,314 doses. Amifostine reduced grade ≥ 2 acute xerostomia from 78% to 51% (P < .0001) and chronic xerostomia grade ≥ 2 from 57% to 34% (P = .002). Median saliva production was greater with amifostine (0.26 g v 0.10 g, P = .04). Amifostine did not reduce mucositis. With and without amifostine, 2-year local-regional control, disease-free survival, and overall survival were 58% versus 63%, 53% versus 57%, and 71% versus 66%, respectively.

CONCLUSION: Amifostine reduced acute and chronic xerostomia. Antitumor treatment efficacy was preserved.
Phase III Comparative Study of High-Dose Cisplatin Versus a Combination of Paclitaxel and Cisplatin in Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Gatzemeier Ulrich , von Pawel Joachim , Gottfried Maya , Velde G.P. M. ten , Mattson Karin , DeMarinis Filipo , Harper Peter , Salvati Franco , Robinet Gilles , Lucenti Antonio , Bogaerts Jan , Gallant Gilles
Published: February 2017

PURPOSE: New effective chemotherapy is needed to improve the outcome of patients with advanced non–small-cell lung cancer (NSCLC). Paclitaxel administered as a single agent or in combination with cisplatin has been shown to be a potentially new useful agent for the treatment of NSCLC.

PATIENTS AND METHODS: Between January 1995 and April 1996, 414 patients with stage IIIB or IV NSCLC were randomized to received either a control arm of high-dose cisplatin (100 mg/m2) or a combination of paclitaxel (175 mg/m2, 3-hour infusion) and cisplatin (80 mg/m2) every 21 days.

RESULTS: Compared with the cisplatin-only arm, there was a 9% improvement (95% confidence interval, 0% to 19%) in overall response rate for the paclitaxel/cisplatin arm (17% v 26%, respectively; P = .028). Median time to progression was 2.7 and 4.1 months in the control and paclitaxel/cisplatin arm, respectively (P = .026). The study, however, failed to show a significant improvement in median survival for the paclitaxel/cisplatin arm (8.6 months in the control arm v 8.1 months in the paclitaxel/cisplatin arm, P = .862). There was more hematotoxicity, peripheral neuropathy, and arthralgia/myalgia on the paclitaxel/cisplatin arm, whereas the high-dose cisplatin arm produced more ototoxicity, nausea, vomiting, and nephrotoxicity. Quality of life (QOL) was similar overall between the two arms.

CONCLUSION: This large randomized phase III trial failed to show a significant improvement in survival for the paclitaxel/cisplatin combination compared with high-dose cisplatin in patients with advanced NSCLC. However, the paclitaxel/cisplatin combination did produce a better clinical response, resulting in an increased time to progression while providing a similar QOL.
Contribution of Dexamethasone to Control of Chemotherapy-Induced Nausea and Vomiting: A Meta-Analysis of Randomized Evidence
Authors: Ioannidis John P. A. , Hesketh Paul J. , Lau Joseph
Published: February 2017

PURPOSE: To synthesize the available randomized evidence on the efficacy of dexamethasone when used for protection against acute and delayed nausea and vomiting in patients receiving highly or moderately emetogenic cancer chemotherapy.

MATERIALS AND METHODS: A meta-analysis was performed using trials identified through MEDLINE (1966 to April 1999), Embase, Derwent Drug File, and the Cochrane Library’s Database of Controlled Trials. Data on acute and delayed emesis and nausea were collected. All randomized studies comparing dexamethasone to placebo, no treatment, or other antiemetics qualified, including cross-over trials providing first-cycle data.

RESULTS: Of 1,200 citations screened, 32 studies with 42 pertinent comparisons and 5,613 patients were included in the meta-analysis. Dexamethasone was superior to placebo or no treatment for complete protection from acute emesis (odds ratio, 2.22; 95% confidence interval [CI], 1.89 to 2.60) and for complete protection from delayed emesis (odds ratio, 2.04; 95% CI, 1.63 to 2.56). The results were similar for complete protection from nausea. The pooled risk difference for complete protection from emesis was 16% for both the acute and delayed phases (95% CI, 13% to 19% and 11% to 20%, respectively). The beneficial effect was similar in subgroups defined by various study design parameters. No trial addressed the efficacy of dexamethasone in the delayed phase without having administered dexamethasone for acute-phase protection as well.

CONCLUSION: Dexamethasone is clearly effective in protecting from emesis both in the acute and delayed phases, with emesis avoided in one patient out of six treated. Future trials should determine whether the delayed-phase effect is independent of the acute-phase benefit.
Enhancement of Fluorouracil Uptake in Human Colorectal and Gastric Cancers by Interferon or by High-Dose Methotrexate: An In Vivo Human Study Using Noninvasive 19F-Magnetic Resonance Spectroscopy
Authors: Presant Cary A. , Wolf Walter , Waluch Victor , Wiseman Charles L. , Weitz Ilene , Shani Jashovam
Published: February 2017

PURPOSE: To study whether two modulators, high-dose methotrexate (MTX) and interferon alfa-2a (IFNα-2a) will alter the intratumoral pharmacokinetics of fluorouracil (5-FU).

PATIENTS AND METHODS: Five patients, two with gastric cancer and three with colorectal cancer, who had metastatic tumor nodules in their livers were studied dynamically in vivo after 5-FU injection. In a magnetic resonance imaging unit, noninvasive 19F-magnetic resonance spectroscopy (MRS) was used to detect 19F signals from 5-FU and its metabolites.

RESULTS: The intratumoral half-life (t1/2) of 5-FU in these tumors ranged from 18.8 minutes to 42.3 minutes. Four of the five patients exhibited increases in the t1/2 of 5-FU after intravenous (IV) administration of MTX or IFNα-2a. In the two patients with gastric cancer who received IV high-dose MTX followed by IV 5-FU, increases were seen in either the total t1/2 of 5-FU (41.8%) or in the t1/2 of the α phase (150%). In the three patients with colorectal cancer who received IV IFNα-2a followed by IV 5-FU, the two patients with partial responses had increases in the t1/2 of 5-FU of 41% and 30.2%, whereas the nonresponder had a nonsignificant increase (5.6%) in the t1/2 of 5-FU.

CONCLUSIONS: These results document that the in vivo modulation of the tumoral pharmacokinetics of 5-FU can be measured noninvasively by 19F-MRS and suggest that such information correlates with subsequent clinical outcomes. The findings also indicate that IFNα-2a and high-dose MTX can increase the intratumoral 5-FU in some patients. Such information, obtained prospectively in vivo, may assist in better individual cancer patient management and in developing novel drug combinations.
HER-2/neu Amplification in Benign Breast Disease and the Risk of Subsequent Breast Cancer
Authors: Stark Azadeh , Hulka Barbara S. , Joens Scott , Novotny Debra , Thor Ann D. , Wold Lester E. , Schell Michael J. , Melton L. Joseph , Liu Edison T. , Conway Kathleen
Published: February 2017

PURPOSE: The purpose of this study was to determine whether the presence of HER-2/neu gene amplification and/or overexpression in benign breast disease was associated with an increased risk of subsequent breast cancer.

PATIENTS AND METHODS: We conducted a nested case-control study of a cohort of women who were diagnosed with benign breast disease at the Mayo Clinic and who were subsequently observed for the development of breast cancer. Patients who developed breast cancer formed the case group, and a matched sample from the remaining cohort served as controls. Benign tissue samples from 137 cases and 156 controls and malignant tissues from 99 cases provided DNA or tissue for evaluation of HER-2/neu amplification and protein overexpression.

RESULTS: Among the controls, seven benign tissues (4.5%) demonstrated low-level HER-2/neu amplification, whereas 13 benign (9.5%) and 18 malignant (18%) tissue specimens from cases exhibited amplification. HER-2/neu amplification in benign breast biopsies was associated with an increased risk of breast cancer (odds ratio [OR] = 2.2; 95% confidence interval [CI], 0.9 to 5.8); this association approached statistical significance. The risks for breast cancer associated with benign breast histopathologic diagnoses were OR = 1.1 (95% CI, 0.6 to 1.9) for lesions exhibiting proliferation without atypia and OR = 1.5 (95% CI, 0.4 to 5.6) for the diagnosis of atypical ductal hyperplasia. For women having both HER-2/neu amplification and a proliferative histopathologic diagnosis (either typical or atypical), the risk of breast cancer was more than seven-fold (OR = 7.2; 95% CI, 0.9 to 60.8). Overexpression of the HER-2/neu protein product, defined as membrane staining in 10% or more of epithelial cells, was found in 30% of the breast tumors but was not detected in any of the benign breast tissues. Case patients who had HER-2/neu gene amplification in their malignant tumor were more likely to have had HER-2/neu amplification in their prior benign biopsy (P = .06, Fisher’s exact test).

CONCLUSION: Women with benign breast biopsies demonstrating both HER-2/neu amplification and a proliferative histopathologic diagnosis may be at substantially increased risk for subsequent breast cancer.
Pilot Trial of the Safety, Tolerability, and Retinoid Levels of N-(4-hydroxyphenyl) Retinamide in Combination With Tamoxifen in Patients at High Risk for Developing Invasive Breast Cancer
Authors: Conley Barbara , O’Shaughnessy Joyce , Prindiville Sheila , Lawrence Julia , Chow Catherine , Jones Elizabeth , Merino Maria J. , Kaiser-Kupfer Muriel I. , Caruso Rafael C. , Podgor Marvin , Goldspiel Barry , Venzon David , Danforth David , Wu Suhlan , Noone Marianne , Goldstein Jennifer , Cowan Kenneth H. , Zujewski JoAnne
Published: February 2017

PURPOSE: N-(4-hydroxyphenyl) retinamide ([4-HPR], Fenretinide; R.W. Johnson Pharmaceutical Research Institute, Springhouse, PA) and tamoxifen (TAM) have synergistic antitumor and chemopreventive activity against mammary cancer in preclinical studies. We performed a pilot study of this combination in women at high risk for developing breast cancer.

PATIENTS AND METHODS: Thirty-two women were treated with four cycles of 4-HPR, 200 mg orally (PO) for 25 days of each 28-day cycle, and TAM, 20 mg PO once daily for 23 months beginning after 1 month of 4-HPR alone. Tolerability, dark adaptometry, tissue biopsies, and retinoid plasma concentrations (Cp) were evaluated.

RESULTS: Symptomatic reversible nyctalopia developed in two patients (6%) on 4-HPR, but 16 (73%) of 22 patients had reversible changes in dark adaptation, which correlated with relative decrease in Cp retinol (P ≤ .01). Four patients stopped treatment for side effects, and 84% of patients had hot flashes. Other commonly reported (grade ≤ 2) reversible toxicities included skin and ocular dryness, fatigue, and mood changes. Serum high-density lipoprotein increased and cholesterol decreased from baseline to month 4. Baseline mean ± SD Cp retinol was 708 ± 280 ng/mL. Mean ± SD Cp of 4-HPR, N-(4-methoxyphenyl) retinamide (4-MPR), and retinol after 1 month of 4-HPR were 0.34 ± 0.21 μmol/L, 0.28 ± 0.21 μmol/L, and 282 ± 127 ng/mL, respectively. Mean retinoid Cps did not change after 3 months of 4-HPR + TAM.

CONCLUSIONS: TAM administration did not affect Cp 4-HPR or 4-MPR. Reversible nyctalopia correlated with relative decrease in Cp retinol but was not symptomatic for most patients. TAM + 4-HPR has acceptable tolerability for this high-risk cohort.
Treatment of Primary Progressive Hodgkin’s and Aggressive Non-Hodgkin’s Lymphoma: Is There a Chance for Cure?
Authors: Josting Andreas , Reiser Marcel , Rueffer Ulrich , Salzberger Bernd , Diehl Volker , Engert Andreas
Published: February 2017

PURPOSE: To determine differences in prognosis between primary progressive Hodgkin’s disease (HD) and aggressive non-Hodgkin’s lymphoma (NHL), we retrospectively analyzed patients with progressive lymphoma who were treated with different salvage chemotherapy regimens including high-dose chemotherapy (HDCT) followed by autologous stem-cell support (ASCT).

PATIENTS AND METHODS: One hundred thirty-one patients with primary progressive lymphoma (HD, n = 67; NHL, n = 64) were enrolled. Primary progressive disease was defined as disease progression during first-line chemotherapy or only transient response (complete or partial response lasting ≤ 90 days) after induction treatment. Patients 60 years or younger with progressive lymphoma were eligible to receive HDCT with ASCT.

RESULTS: The overall response rate after salvage chemotherapy for patients with primary progressive HD and NHL was 33% and 15%, respectively. Twenty-five HD patients (37%) received HDCT. Most patients with NHL had progressive disease under salvage treatment, with only six patients (10%) receiving HDCT. Of those, only two patients were alive and in continuous complete remission 3 and 12 months after HDCT. No patient with NHL survived longer than 26 months after first diagnosis. Actuarial OS after 5 years was 19% for all HD patients; 53% for HD patients receiving HDCT, and 0% for patients who did not receive HDCT. In HD patients, multivariate regression analysis identified chemosensitive disease on salvage treatment (P = .0001) and HDCT (P = .031) as significant prognostic factors for freedom from treatment failure. Significant prognostic factors for OS are chemosensitive disease (P = .0005), HDCT (P = .039), and B symptoms at the time of progress (P = .046).

CONCLUSION: There are striking differences in the prognosis of patients with progressive HD and aggressive NHL. The prognosis of progressive NHL patients is dismal. Most patients have rapidly progressive disease after salvage treatment and are, therefore, excluded from HDCT programs. In contrast, progressive HD patients can achieve long-term survival after HDCT.
Comparison of Preparative Regimens in Transplants for Children With Acute Lymphoblastic Leukemia
Authors: Davies Stella M. , Ramsay Norma K. C. , Klein John P. , Weisdorf Daniel J. , Bolwell Brian , Cahn Jean-Yves , Camitta Bruce M. , Gale Robert Peter , Giralt Sergio , Heilmann Carsten , Henslee-Downey P. Jean , Herzig Roger H. , Hutchinson Raymond , Keating Armand , Lazarus Hillard M. , Milone Gustavo A. , Neudorf Steven , Perez Waleska S. , Powles Ray L. , Prentice H. Grant , Schiller Gary , Socié Gérard , Vowels Marcus , Wiley Joseph , Yeager Andrew , Horowitz Mary M.
Published: February 2017

PURPOSE: Preparative regimens involving total-body irradiation (TBI) produce significant late toxicities in some children who receive bone marrow transplants, including impaired growth and intellectual development. Busulfan is often used as an alternative to TBI, but there are few data regarding its relative efficacy.

PATIENTS AND METHODS: We compared outcomes of HLA-identical sibling transplants for acute lymphoblastic leukemia (ALL) in children (< 20 years of age) who received cyclophosphamide plus TBI (CY/TBI) (n = 451) versus those who received busulfan plus cyclophosphamide (Bu/CY) (n = 176) for pretransplant conditioning. Patients received transplants between 1988 and 1995 and their results were reported to the International Bone Marrow Transplant Registry by 144 participating institutions. The CY/TBI and Bu/CY groups did not differ in gender, immune phenotype, leukocyte count at the time of diagnosis, chromosome abnormalities, remission status, or length of initial remission. T-cell depletion was used more frequently in the CY/TBI group; the Bu/CY group included a higher proportion of children who were less than 5 years of age. The median follow-up period was 37 months.

RESULTS: The 3-year probabilities of survival were 55% (95% confidence interval [CI], 50% to 60%) with TBI/CY and 40% (95% CI, 32% to 48%) with Bu/CY (univariate P = .003). The 3-year probabilities of leukemia-free survival were 50% (95% CI, 45% to 55%) and 35% (95% CI, 28% to 43%), respectively (univariate P = .005). In a multivariate analysis, the risks of relapse were similar in the two groups (relative risk [RR], 1.30 for Bu/CY v CY/TBI; P = .1). Treatment-related mortality was higher in the Bu/CY group (RR, 1.68; P = .012). Death and treatment failure (relapse or death, inverse of leukemia-free survival) were more frequent in the Bu/CY group (RR, 1.39; P = .017 for death; RR, 1.42; P = .006 for treatment failure).

CONCLUSION: These data indicate superior survival with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical sibling bone marrow transplants in children with ALL.
Flavopiridol, A Novel Cyclin-Dependent Kinase Inhibitor, in Metastatic Renal Cancer: A University of Chicago Phase II Consortium Study
Authors: Stadler Walter M. , Vogelzang Nicholas J. , Amato Robert , Sosman Jeffery , Taber David , Liebowitz David , Vokes Everett E.
Published: February 2017

PURPOSE: Flavopiridol is the first cyclin-dependent kinase (cdk) inhibitor to enter clinical trials. Serum levels of flavopiridol obtained during phase I studies were sufficient to inhibit in vitro cancer cell growth. Because responses were observed in kidney cancer patients in the phase I trials, we performed a phase II trial of flavopiridol in this patient population.

PATIENTS AND METHODS: Thirty-five minimally pretreated patients were accrued using a standard two-step mechanism. Flavopiridol (50 mg/m2/d) was administered by continuous infusion for 72 hours every 2 weeks, and response was evaluated every 8 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, at completion of drug infusion, and on day 7 of the first therapy cycle, and cell cycle parameters after phytohemagglutinin and interleukin-2 stimulation were assessed.

RESULTS: There were two objective responses (response rate = 6%, 95% confidence interval, 1% to 20%). The most common toxicities were asthenia, occurring in 83% of patients (grade 3 or 4 in 9%), and diarrhea, occurring in 77% of patients (grade 3 or 4 in 20%). Also, nine patients (26%) experienced grade 3 or 4 vascular thrombotic events, including one myocardial infarction, two transient neurologic ischemic attacks, four deep venous thrombosis, and two pulmonary emboli. Cell cycle studies did not reveal any effect of flavopiridol on stimulated PBMCs.

CONCLUSION: Flavopiridol, at the dose and schedule administered in this trial, is ineffective in metastatic renal cancer. In addition to the diarrhea observed in phase I studies, we also observed a higher incidence of asthenia and serious vascular thrombotic events than expected.
Sex Differences in Fluorouracil-Induced Stomatitis
Authors: Sloan Jeff A. , Loprinzi Charles L. , Novotny Paul J. , Okuno Scott , Nair Suresh , Barton Debra L.
Published: February 2017

PURPOSE: A meta-analysis of six North Central Cancer Treatment Group (NCCTG) trials involving patients receiving their first ever fluorouracil (5-FU)–based chemotherapy was undertaken to explore the association of sex with reports of the incidence and severity of stomatitis.

PATIENTS AND METHODS: Data were obtained on a total of 731 patients (402 men and 329 women). Comparisons of incidence and severity rates and average stomatitis across sex were performed using standard binomial testing and t tests, respectively. Logistic regression analysis and a weighted analysis using data summarized to study level served as evidence of cross-validation.

RESULTS: Women reported stomatitis both more often and with greater severity than did men. The incidence of any stomatitis for women was 63% versus 52% for men (P = .002). The incidence of severe or very severe stomatitis for men and women was 22% and 12%, respectively (P = .0006). On average, women reported stomatitis of roughly 0.4 points higher than men on a 0 to 4 ordinal scale (P < .00001). Comparison of results across treatment and placebo arms was carried out to validate the initial findings. Logistic regression modelling further confirmed the results conditional on the presence of a number of potentially confounding covariates. Women were also 11% more likely than men to experience leukopenia of common toxicity criteria grade ≥ 1, (70% v 59%, respectively; P < .00001) and grade 3+ (18% v 11%, respectively; P = .004).

CONCLUSION: More women than men reported 5-FU–induced stomatitis. The precise mechanism resulting in different degrees of stomatitis across sex is not evident.
HER-2/neu and p53 Expression Versus Tamoxifen Resistance in Estrogen Receptor–Positive, Node-Positive Breast Cancer
Authors: Berry Donald A. , Muss Hyman B. , Thor Ann D. , Dressler Lynn , Liu Edison T. , Broadwater Gloria , Budman Dan R. , Henderson I. Craig , Barcos Maurice , Hayes Daniel , Norton Larry
Published: February 2017

PURPOSE: An association between the overexpression of proto-oncogene HER-2/neu and resistance to tamoxifen in estrogen receptor (ER)–positive primary and metastatic breast cancer has been suggested. We examine a possible interaction between HER-2/neu or p53 expression and tamoxifen effectiveness in patients with ER-positive, node-positive disease treated with cyclophosphamide, doxorubicin, and fluorouracil in a large adjuvant chemotherapy trial (Cancer and Leukemia Group B [CALGB] 8541). Tamoxifen assignment was not randomized—physician discretion was used for premenopausal and postmenopausal women. Trial protocol then specified assignment to postmenopausal women with ER-positive tumors, although not all took tamoxifen.

PATIENTS AND METHODS: CALGB 8541 assessed HER-2/neu expression in patients with ER-positive disease by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) and amplification by differential polymerase chain reaction (PCR). IHC assessed expression of p53. Univariate and multivariate proportional hazards models assessed tamoxifen–HER-2/neu status interactions and tamoxifen-p53 status interactions.

RESULTS: HER-2/neu status was available for 651 patients with ER-positive disease; 650, 608, and 353 patients were assessed by IHC, PCR, and FISH, respectively. Approximately one half received tamoxifen. Reduction in risk of disease recurrence or death resulting from tamoxifen was approximately 37% (32% with overexpression and 39% with normal expression of HER-2/neu; n = 155 by IHC). The tamoxifen–HER-2/neu status interaction was not significant in multivariate analysis of all three HER-2/neu assessment methods. Tamoxifen-p53 interaction did not significantly predict outcome.

CONCLUSION: Disease-free and overall survival benefit of tamoxifen in patients with ER-positive, node-positive breast cancer does not depend on HER-2/neu or p53 status. Our data suggest that neither HER-2/neu nor p53 expression should be used to determine assignment of tamoxifen.
Tamoxifen Adjuvant Treatment Duration in Early Breast Cancer: Initial Results of a Randomized Study Comparing Short-Term Treatment With Long-Term Treatment
Authors: Delozier Thierry , Spielmann Marc , Macé-Lesec’h Josette , Janvier Maud , Hill Catherine , Asselain Bernard , Julien Jean-Pierre , Weber Béatrice , Mauriac Louis , Petit Jean-Christophe , Kerbrat Pierre , Malhaire Jean-Pierre , Vennin Philippe , Leduc B. , Namer for the Moïse ,   Fédération Nationale des Centres de Lutte Contre le Cancer Breast Group
Published: February 2017

PURPOSE: In 1986, The Fédération Nationale des Centres de Lutte Contre le Cancer Breast Group initiated a multicenter randomized trial to assess the usefulness of long-term adjuvant tamoxifen treatment. Short-term adjuvant tamoxifen treatment was to be compared with lifelong adjuvant tamoxifen treatment.

PATIENTS AND METHODS: Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen treatment were eligible for the trial. From September 1986 to May 1995, 3,793 patients were randomized from France, Belgium, and Argentina. A total of 1,882 patients stopped tamoxifen (short-term group), and 1,911 patients were to continue tamoxifen for life (long-term group) at the same dose as previously prescribed. The protocol was modified in February 1997, limiting tamoxifen treatment to 10 years after randomization, thus giving a comparison between a 2- to 3-year treatment and a 12- to 13-year treatment. To date, the median duration of tamoxifen treatment is 30 months in the short-term group, and 70 months in the long-term group.

RESULTS: Overall, longer tamoxifen treatment induced a 23% reduction in relapse rates, leading to a 7-year disease-free survival rate of 78%, compared with 72% in the shorter-treatment group. In contrast, overall survival did not differ between the two groups, with a 79% overall survival rate in both groups. This improvement in disease-free survival could be observed in node-positive patients (P = .001); however, it was not found in node-negative patients. Prolonged tamoxifen treatment corresponded to a significant increase in disease-free survival in estrogen receptor–positive patients (P = .03) as well as in estrogen receptor–negative patients (P = .05). Furthermore, longer treatment reduced contralateral breast cancers and did not increase the number of endometrial cancers.

CONCLUSION: : Although no survival advantage was noted, patients did benefit from longer tamoxifen treatment over 3 years and had significantly better disease-free survival compared with patients who stopped hormonal treatment. Long-term follow-up is needed to assess these results. Most patients in the long-term group are still receiving treatment. Comparison of results as time passes will enable conclusions to be made on the value of long-term treatment over 5 years compared with 2 to 3 years.
Homoharringtonine and Low-Dose Cytarabine in the Management of Late Chronic-Phase Chronic Myelogenous Leukemia
Authors: Kantarjian Hagop M. , Talpaz Moshe , Smith Terry L. , Cortes Jorge , Giles Francis J. , Rios Mary Beth , Mallard Susie , Gajewski James , Murgo Anthony , Cheson Bruce , O’Brien Susan
Published: February 2017

PURPOSE: : To evaluate the efficacy andtoxicity profiles of a combination regimen of homoharringtonine (HHT)and low-dose cytarabine (ara-C) in patients with Philadelphiachromosome (Ph)–positive chronic myelogenous leukemia (CML) whohad experienced treatment failure with interferon alfa (IFNα)therapy.

PATIENTS AND METHODS: One hundred five patients were treated: 100 in chronicphase (15 with cytogenetic clonal evolution) and five in acceleratedphase. Their median age was 52 years; all had been treatedunsuccessfully with IFNα; 94% were in late chronic phase; 43% hadbeen exposed to ara-C and 11% had been exposed to HHT. Patientsreceived HHT 2.5 mg/m2 by continuousinfusion daily for 5 days and ara-C 15mg/m2 daily in two subcutaneous injectionsfor 5 days every 4 weeks. The outcome of the 100 patients in chronicphase was compared with a previous study group of 73 patients treatedwith HHT alone.

RESULTS: Overall, the complete hematologic response (CHR) rate in chronic phasewas 72%; the cytogenetic response rate was 32% (major response, 15%;complete response, 5%). Toxicities were acceptable, mostly related tomoderate diarrhea (3%), headaches (3%), cardiovascular events (3%),and myelosuppression-associated complications (3% to 14%). With amedian follow-up period of 25 months, the estimated 4-year survivalrate was 55%. Response rates were identical with HHT plus ara-C versusHHT alone, but the survival was significantly longer with thecombination after accounting for differences in the study groups andby multivariate analysis.

CONCLUSION: The combination regimen of HHT and ara-C is effective andsafe in patients with CML who have experienced treatment failure withIFNα and needs to be investigated together with IFNα as partof front-line CML therapy. The addition of ara-C did not improve theresponse rates but may have improved survival, perhaps throughsuppression of clones related to diseasetransformation.
Phase I Chemotherapy Study of Biochemical Modulation of Folinic Acid and Fluorouracil by Gemcitabine in Patients With Solid Tumor Malignancies
Authors: Madajewicz S. , Hentschel P. , Burns P. , Caruso R. , Fiore J. , Fried M. , Malhotra H. , Ostrow S. , Sugarman S. , Viola M.
Published: February 2017

PURPOSE: This phase I biochemical modulation study evaluated the maximum-tolerated dose (MTD), toxicity, and effectiveness of the combination of folinic acid (FA)/fluorouracil (5-FU) followed by escalated dose levels of gemcitabine (FFG) in patients with advanced solid tumors.

PATIENTS AND METHODS: Patients were refractory to primary treatment and/or without effective treatment options. Twenty-eight patients received an intravenous (IV) infusion of FA 100 mg/m2 over 1 hour and a 5-FU 450 mg/m2 IV bolus in the middle of the FA infusion. After the FA infusion, gemcitabine was administered at a steady rate of infusion of 10 mg/m2/min over initially 30 minutes and with increases of an additional 15 minutes at each given level. One cycle consisted of six weekly treatments followed by a 2-week rest.

RESULTS: The MTD of gemcitabine was established at 900 mg/m2 given over 90 minutes. Eight patients of 21 with metastatic colorectal cancer achieved responses (one complete response; seven partial responses), for a response rate of 38%. Responses were seen across the gemcitabine doses of 300 to 900 mg/m2. One patient had prior treatment with FA/5-FU for advanced disease. Patients with colorectal carcinoma had a median survival of 18 months, and the patient with lung carcinoma has been alive for 24+ months.

CONCLUSION: The combination chemotherapy of FFG was well tolerated and may benefit patients with advanced colorectal carcinoma. A phase II evaluation in this patient population is in progress.
Prospective Trial of the Herbal Supplement PC-SPES in Patients With Progressive Prostate Cancer
Authors: Small Eric J. , Frohlich Mark W. , Bok Robert , Shinohara Katsuto , Grossfeld Gary , Rozenblat Zinovi , Kelly Wm. Kevin , Corry Michele , Reese David M.
Published: February 2017

PURPOSE: PC-SPES is an herbal supplement for which there are anecdotal reports of anti–prostate cancer activity. This phase II study was undertaken to assess the efficacy and toxicity of PC-SPES in prostate cancer patients.

PATIENTS AND METHODS: Thirty-three patients with androgen-dependent prostate cancer (ADPCa) and 37 patients with androgen-independent prostate cancer (AIPCa) were treated with PC-SPES at a dose of nine capsules daily. Clinical outcome was assessed with serial serum prostate-specific androgen (PSA) level measurement and imaging studies.

RESULTS: One hundred percent of ADPCa patients experienced a PSA decline of ≥ 80%, with a median duration of 57+ weeks. No patient has developed PSA progression. Thirty-one patients (97%) had declines of testosterone to the anorchid range. Two ADPCa patients had positive bone scans; both improved. One patient with a bladder mass measurable on computed tomography scan experienced disappearance of this mass. Nineteen (54%) of 35 AIPCa patients had a PSA decline of ≥ 50%, including eight (50%) of 16 patients who had received prior ketoconazole therapy. Median time to PSA progression was 16 weeks (range, 2 to 69+ weeks). Of 25 patients with positive bone scans, two had improvement, seven had stable disease, 11 had progressive disease, and five did not have a repeat bone scan because of PSA progression. Severe toxicities included thromboembolic events (n = 3) and allergic reactions (n = 3). Other frequent toxicities included gynecomastia/gynecodynia, leg cramps, and grade 1 or 2 diarrhea.

CONCLUSION: PC-SPES seems to have activity in the treatment of both ADPCa and AIPCa and has acceptable toxicity. Further study is required to determine whether its effects exceed those expected with estrogen therapy.
High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Transplantation for Advanced Soft Tissue Sarcoma in Adults
Authors: Blay J-Y. , Bouhour D. , Ray-Coquard I. , Dumontet C. , Philip T. , Biron P.
Published: February 2017

PURPOSE: Patients with metastatic or locally advanced, unresectable soft tissue sarcoma (ASTS) are seldom curable, with 5-year survival rates of less than 10% in all large series. The role of high-dose chemotherapy (HDCT) with hematopoietic stem-cell support in this disease is not established.

PATIENTS AND METHODS: Between 1988 and 1994, 30 patients with ASTS who responded to a standard chemotherapy regimen were included in a prospective pilot study of HDCT as consolidation therapy using ifosfamide (12 g/m2), etoposide (800 mg/m2), and cisplatin (200 mg/m2) (VIC).

RESULTS: The median duration of grade 4 neutropenia and thrombocytopenia was 14 and 10 days, respectively. Nineteen patients (63%) experienced grade 1 or higher renal toxicity. All eight patients in complete remission (CR) before HDCT were still in CR at day 60. Of the 22 patients in partial remission (PR) or with a minor response to conventional chemotherapy, CR, PR, and stable disease were achieved in four (18%), three (13%), and 12 patients (54%), respectively, by day 60, while three patients (14%) progressed. With a median follow-up of 94 months, overall and progression-free survival rates at 5 years after HDCT were 23% and 21%, respectively. Patients in CR before HDCT had a significantly superior 5-year overall survival rate compared with other patients (75% v 5%; P = .001).

CONCLUSION: Despite the toxicity of the VIC regimen, a high survival rate was observed in HDCT-treated patients who were in CR after conventional chemotherapy. A phase III randomized trial is required to establish the role of HDCT in ASTS.
Time to Clinical Response: An Outcome of Antibiotic Therapy of Febrile Neutropenia With Implications for Quality and Cost of Care
Authors: Elting Linda S. , Rubenstein Edward B. , Rolston Kenneth , Cantor Scott B. , Martin Charles G. , Kurtin Danna , Rodriguez Saul , Lam Tony , Kanesan Krishnakumari , Bodey Gerald
Published: February 2017

PURPOSE: To determine whether antibiotic regimens with similar rates of response differ significantly in the speed of response and to estimate the impact of this difference on the cost of febrile neutropenia.

METHODS: The time point of clinical response was defined by comparing the sensitivity, specificity, and predictive values of alternative objective and subjective definitions. Data from 488 episodes of febrile neutropenia, treated with either of two commonly used antibiotics (coded A or B) during six clinical trials, were pooled to compare the median time to clinical response, days of antibiotic therapy and hospitalization, and estimated costs.

RESULTS: Response rates were similar; however, the median time to clinical response was significantly shorter with A-based regimens (5 days) compared with B-based regimens (7 days; P = .003). After 72 hours of therapy, 33% of patients who received A but only 18% of those who received B had responded (P = .01). These differences resulted in fewer days of antibiotic therapy and hospitalization with A-based regimens (7 and 9 days) compared with B-based regimens (9 and 12 days, respectively; P < .04) and in significantly lower estimated median costs ($8,491 v $11,133 per episode; P = .03). Early discharge at the time of clinical response should reduce the median cost from $10,752 to $8,162 (P < .001).

CONCLUSION: Despite virtually identical rates of response, time to clinical response and estimated cost of care varied significantly among regimens. An early discharge strategy based on our definition of the time point of clinical response may further reduce the cost of treating non–low-risk patients with febrile neutropenia.