bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non–Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy
Authors: Shepherd Frances A. , Dancey Janet , Ramlau Rodryg , Mattson Karin , Gralla Richard , O’Rourke Mark , Levitan Nathan , Gressot Laurent , Vincent Mark , Burkes Ronald , Coughlin Susan , Kim Yong , Berille Jocelyne
Published: February 2017

PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non–small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life.

PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non–small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m2 (49 patients) or 75 mg/m2 (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks.

RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7.1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P < .001), as was median survival (7.0 v 4.6 months; log-rank test, P = .047). The difference was more significant for docetaxel 75 mg/m2 patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P = .010; 1-year survival, 37% v 11%; χ2 test, P = .003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m2, three of whom died, and in one patient treated with docetaxel 75 mg/m 2 . Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups.

CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m2, the benefits of docetaxel therapy outweigh the risks.
Molecular Remission After Allogeneic or Autologous Transplantation of Hematopoietic Stem Cells for Multiple Myeloma
Authors: Martinelli Giovanni , Terragna Carolina , Zamagni Elena , Ronconi Sonia , Tosi Patrizia , Lemoli Roberto M. , Bandini Giuseppe , Motta Maria Rosa , Testoni Nicoletta , Amabile Marilina , Ottaviani Emanuela , Vianelli Nicola , de Vivo Antonio , Gozzetti Alessandro , Tura Sante , Cavo Michele
Published: February 2017

PURPOSE: To assess the clinical relevance of minimal residual disease (MRD) in patients with multiple myeloma (MM), 50 patients were monitored while they were in complete clinical remission (CCR) after autologous or allogeneic stem-cell transplantation.

PATIENTS AND METHODS: Stringent molecular monitoring using clonal markers based on rearranged immunoglobulin heavy-chain genes was performed in 44 of 50 MM patients in CCR. Molecular clinical remission (MCR) was defined as more than one consecutive negative polymerase chain reaction (PCR) test result.

RESULTS: Twelve (27%) of 44 molecularly monitored patients achieved MCR; four of the 12 became PCR-positive, and one of these four relapsed. In comparison with patients who did not achieve MCR, patients who achieved MCR had a significantly lower relapse rate (41% v 16%; P < .05) and longer relapse-free survival (35 v 110 months; P < .005). Fourteen of 26 patients in CCR who had received allografts were evaluated on a molecular basis: seven (50%) of the 14 achieved MCR and did not relapse; one of the seven remaining patients relapsed. Thirty of 47 patients in CCR who received autografts were evaluated on a molecular basis: five (16%) of the 30 achieved MCR; two of these five became PCR-negative, and one of these two relapsed. Ten of the 25 remaining patients later relapsed. For these nonrandomized groups, the higher MCR rate after allograft procedures was statistically significant (P < .01; Fisher’s exact test).

CONCLUSION: MCR can be obtained in a relatively high proportion of MM patients who have achieved CCR after undergoing allograft procedures and in a smaller fraction of patients after undergoing autograft procedures. In approximately one fourth of MM patients who achieve CCR after transplantation, it may be possible to keep the disease burden constantly below the PCR threshold. Because MCR was associated with prolonged relapse-free survival, these patients could have a relatively favorable clinical outcome.
Benefit of Intensified Therapy for Patients With Local or Regional Embryonal Rhabdomyosarcoma: Results From the Intergroup Rhabdomyosarcoma Study IV
Authors: Baker K. Scott , Anderson James R. , Link Michael P. , Grier Holcombe E. , Qualman Stephen J. , Maurer Harold M. , Breneman John C. , Wiener Eugene S. , Crist William M.
Published: February 2017

PURPOSE: To compare failure-free survival (FFS) and survival for patients with local or regional embryonal rhabdomyosarcoma treated on the Intergroup Rhabdomyosarcoma Study (IRS)–IV with that of comparable patients treated on IRS-III.

PATIENTS AND METHODS: Patients were retrospectively classified as low- or intermediate-risk. Low-risk patients were defined as those with primary tumors at favorable sites, completely resected or microscopic residual, or orbit/eyelid primaries with gross residual disease and tumors less than 5 cm at unfavorable sites but completely resected. Intermediate-risk patients were all other patients with local or regional tumors.

RESULTS: Three-year FFS improved from 72% on IRS-III to 78% on IRS-IV for patients with intermediate-risk embryonal rhabdomyosarcoma (P = .02). Subset analysis revealed two groups that benefited most from IRS-IV therapy. FFS at 3 years for patients with resectable node-positive or unresectable (group III) embryonal rhabdomyosarcoma arising at certain favorable sites (head and neck [not orbit/eyelid or parameningeal] and genitourinary [not bladder or prostate]) improved from 72% on IRS-III to 92% on IRS-IV (P = .01). Similarly, 3-year FFS for patients with completely resected tumor or with only microscopic disease remaining (group I or II) at unfavorable sites improved from 71% on IRS-III to 86% on IRS-IV (P = .04). Only patients with unresectable embryonal rhabdomyosarcoma (group III) at unfavorable sites had no improvement in outcome on IRS-IV (3-year FFS for IRS-III and IRS-IV, 72% and 75%, respectively; P = .31).

CONCLUSION: IRS-IV therapy benefited certain subgroups of patients with intermediate-risk embryonal rhabdomyosarcoma. A doubling of the intensity of cyclophosphamide (or ifosfamide equivalent) dosing per cycle between IRS-III and IRS-IV is thought to be a key contributing factor for this improvement.
What Would You Do? Specialists’ Perspectives on Cancer Genetic Testing, Prophylactic Surgery, and Insurance Discrimination
Authors: Matloff Ellen T. , Shappell Heather , Brierley Karina , Bernhardt Barbara A. , McKinnon Wendy , Peshkin Beth N.
Published: February 2017

PURPOSE: To examine what cancer genetics specialists predict they would do personally if they were at 50% risk of carrying a mutation that predisposes to hereditary breast/ovarian cancer (BRCA1/BRCA2) and hereditary nonpolyposis colon cancer (HNPCC).

METHODS: Questionnaire survey of the membership of the National Society of Genetic Counselors (NSGC) Special Interest Group (SIG) in Cancer.

RESULTS: Of the 296 active members of the NSGC Cancer-SIG surveyed, 163 (55%) responded. Eighty-five percent predicted that if they had a 50% risk of carrying a BRCA1/BRCA2 mutation, they would pursue genetic testing. If they tested positive for a mutation at age 35, 25% predicted they would pursue prophylactic bilateral mastectomies and 68%, prophylactic oophorectomy. Ninety-one percent of respondents believe they would pursue genetic testing for HNPCC, and 17% would elect prophylactic colectomy; 54%, prophylactic hysterectomy; and 52%, prophylactic oophorectomy if they tested positive for a mutation. The majority (68%) would not bill their insurance companies for genetic testing because of fear of discrimination, and 26% would use an alias when undergoing testing. Fifty-seven percent of counselors would seek professional psychologic support to help them cope with the results of testing.

CONCLUSION: A large percentage of cancer genetic counseling providers predicted they would opt for prophylactic surgery at a young age if they carried a BRCA or HNPCC mutation, and most would seek professional psychologic assistance when undergoing testing. More than half of respondents would not bill their insurance companies for genetic testing, largely because of fear of genetic discrimination. The vast majority of those providers most familiar with cancer genetic testing and its associated medical, psychologic, and legal implications would still pursue genetic testing.
Randomized, Dose-Escalation Study of SD/01 Compared With Daily Filgrastim in Patients Receiving Chemotherapy
Authors: Johnston Eileen , Crawford Jeffrey , Blackwell Susan , Bjurstrom Toni , Lockbaum Pamela , Roskos Lorin , Yang Bing-Bing , Gardner Sheila , Miller-Messana Mary Ann , Shoemaker Debra , Garst Jennifer , Schwab Gisela
Published: February 2017

PURPOSE: To explore the use of SD/01 (a polyethylene glycol–conjugated filgrastim shown in preclinical studies to have a prolonged half-life) in patients with chemotherapy-induced neutropenia.

PATIENTS AND METHODS: Thirteen patients with non–small-cell lung cancer were randomized to receive daily filgrastim (5 μg/kg/d) or a single injection of SD/01 (30, 100, or 300 μg/kg) 2 weeks before chemotherapy and again 24 hours after administration of carboplatin and paclitaxel. Pharmacodynamic, pharmacokinetic, and safety analyses were performed.

RESULTS: Peak serum concentrations of SD/01 and the duration of increased serum concentrations were dependent on the SD/01 dose. SD/01 concentrations remained increased longer in patients with chemotherapy-induced neutropenia. Prechemotherapy median absolute neutrophil counts (ANCs) in patients receiving SD/01 were increased in a dose-dependent fashion, with the duration of this effect also being dose dependent. After chemotherapy, median ANC nadirs were similar in the filgrastim cohort and the cohort receiving SD/01 30 μg/kg, with higher nadirs seen in the cohorts receiving SD/01 100 or 300 μg/kg. Dose-limiting toxicities were not noted. CD34+ cells were mobilized in all cohorts.

CONCLUSION: A single dose of SD/01 increases the serum concentration of SD/01 for several days in a dose-dependent fashion and is not associated with significant toxicity. The effects of SD/01 on ANC and CD34+ cell mobilization are comparable or greater than those achieved with daily filgrastim. The self-regulation of this molecule provides a potential therapeutic advantage in a variety of clinical settings associated with neutropenia.
Prospective Observational Study of Sentinel Lymphadenectomy Without Further Axillary Dissection in Patients With Sentinel Node–Negative Breast Cancer
Authors: Giuliano Armando E. , Haigh Philip I. , Brennan Meghan B. , Hansen Nora M. , Kelley Mark C. , Ye Wei , Glass Edwin C. , Turner Roderick R.
Published: February 2017

PURPOSE: Immediate complete axillary lymphadenectomy (ALND) after sentinel lymphadenectomy (SLND) has confirmed that tumor-negative sentinel nodes accurately predict tumor-free axillary nodes in breast cancer. Therefore, we hypothesized that SLND alone in patients with tumor-negative sentinel nodes would achieve axillary control, with minimal complications.

PATIENTS AND METHODS: Between October 1995 and July 1997, 133 consecutive women who had primary invasive breast tumors clinically ≤ 4 cm in diameter and no axillary lymphadenopathy were prospectively entered onto a trial of SLND using vital blue dye. Sentinel nodes were examined by standard microscopy or immunohistochemistry. SLND was the only axillary surgery if sentinel nodes were tumor-free. Completion ALND was performed only if sentinel nodes contained metastases or if they were not identified. Excluded from subsequent analysis were patients with unsuspected multifocal carcinoma and those who refused completion ALND. The complication and axillary recurrence rates after SLND without ALND were determined.

RESULTS: Sentinel nodes were identified in 132 (99%) of 133 patients. Eight patients were excluded from further analysis. Of the 125 assessable patients, 57 had tumor-positive sentinel nodes and one had an unsuccessful mapping procedure; these patients underwent completion ALND. In the remaining 67 patients (54%), SLND was the only axillary procedure. Complications occurred in 20 patients (35%) undergoing ALND after SLND but in only two patients (3%) undergoing SLND alone (P = .001). There were no local or axillary recurrences at a median follow-up of 39 months.

CONCLUSION: Complication rates are negligible after SLND alone. An absence of axillary recurrences supports SLND as an accurate staging alternative for breast cancer and suggests that routine ALND can be eliminated for patients with histopathologically negative sentinel nodes.
Sentinel Lymph Node Biopsy for Breast Cancer: A Suitable Alternative to Routine Axillary Dissection in Multi-Institutional Practice When Optimal Technique Is Used
Authors: McMasters Kelly M. , Tuttle Todd M. , Carlson David J. , Brown C. Matthew , Noyes R. Dirk , Glaser Rebecca L. , Vennekotter Donald J. , Turk Peter S. , Tate Peter S. , Sardi Armando , Cerrito Patricia B. , Edwards Michael J.
Published: February 2017

PURPOSE: Previous studies have demonstrated the feasibility of sentinel lymph node (SLN) biopsy for nodal staging of patients with breast cancer. However, unacceptably high false-negative rates have been reported in several studies, raising doubt about the applicability of this technique in widespread surgical practice. Controversy persists regarding the optimal technique for correctly identifying the SLN. Some investigators advocate SLN biopsy using injection of a vital blue dye, others recommend radioactive colloid, and still others recommend the use of both agents together.

PATIENTS AND METHODS: A total of 806 patients were enrolled by 99 surgeons. SLN biopsy was performed by single-agent (blue dye alone or radioactive colloid alone) or dual-agent injection at the discretion of the operating surgeon. All patients underwent attempted SLN biopsy followed by completion level I/II axillary lymph node dissection to determine the false-negative rate.

RESULTS: There was no significant difference (86% v 90%) in the SLN identification rate among patients who underwent single- versus dual-agent injection. The false-negative rates were 11.8% and 5.8% for single- versus dual-agent injection, respectively (P < .05). Dual-agent injection resulted in a greater mean number of SLNs identified per patient (2.1 v 1.5; P < .0001). The SLN identification rate was significantly less for patients older than 50 years as compared with that of younger patients (87.6% v 92.6%; P = .03). Upper-outer quadrant tumor location was associated with an increased likelihood of a false-negative result compared with all other locations (11.2% v 3.9%; P < .05).

CONCLUSION: In multi-institutional practice, SLN biopsy using dual-agent injection provides optimal sensitivity for detection of nodal metastases. The acceptable SLN identification and false-negative rates associated with the dual-agent injection technique indicate that this procedure is a suitable alternative to routine axillary dissection across a wide spectrum of surgical practice and hospital environments.
Fractionated Cyclophosphamide and Etoposide for Children With Advanced or Refractory Solid Tumors: A Phase II Window Study
Authors: Mantadakis Elpis , Herrera Larry , Leavey Patrick J. , Bash Robert O. , Winick Naomi J. , Kamen Barton A.
Published: February 2017

PURPOSE: Cyclophosphamide (CPA) has a broad spectrum of activity against solid tumors. Hepatic self-induction of the active metabolite 4-hydroxycyclophosphamide occurs after repeated administration. We evaluated the clinical efficacy of a window regimen that administers fractionated CPA in conjunction with etoposide (VP16) in children with advanced or refractory solid tumors.

PATIENTS AND METHODS: Seventeen children with advanced (n = 12) or refractory (n = 5) solid tumors were entered onto this phase II window study. The treatment regimen consisted of intravenous (IV) CPA 500 mg/m2/d and IV VP16 100 mg/m2/d. Both drugs were administered daily by short infusions for 5 consecutive days.

RESULTS: A total of 34 courses were administered, with a median of two courses per patient. The median interval between chemotherapy courses was 21 days (range, 17 to 35 days). Thirty-three courses were assessable for toxicity, and all patients were assessable for response. No life-threatening toxicities were observed. The incidence of grade 3 or 4 neutropenia was 94% and of fever and neutropenia 38%. Fever and neutropenia occurred after 12 of 26 courses without recombinant human granulocyte colony-stimulating factor (rhG-CSF) and after one of eight courses with rhG-CSF (P = .09). Grade 3 or 4 thrombocytopenia occurred after 10 courses (29%). There were no positive blood cultures. One heavily pretreated patient developed a localized perirectal abscess that required drainage. There were 10 patients (59%) with partial responses, four (23.5%) with stable disease, and three with progressive disease.

CONCLUSION: Fractionated IV CPA and VP16 over 5 days can be safely administered in children with advanced or refractory solid tumors and has notable antineoplastic activity.
Gemcitabine Treatment in Pretreated Cutaneous T-Cell Lymphoma: Experience in 44 Patients
Authors: Zinzani Pier Luigi , Baliva Gianandrea , Magagnoli Massimo , Bendandi Maurizio , Modugno Gino , Gherlinzoni Filippo , Orcioni Giulio Fraternali , Ascani Stefano , Simoni Romeo , Pileri Stefano A. , Tura Sante
Published: February 2017

PURPOSE: To evaluate the efficacy and toxicity of gemcitabine, a novel pyrimidine antimetabolite with a low-toxicity profile and activity in several solid tumors, in patients with relapsed or refractory cutaneous T-cell lymphomas.

PATIENTS AND METHODS: Between May 1997 and February 1999, 44 previously treated patients with mycosis fungoides (MF; n = 30) and peripheral T-cell lymphoma unspecified (PTCLU) with exclusive skin involvement (n = 14) were enrolled onto a two-institution, phase II trial and treated with gemcitabine. This drug was given on days 1, 8, and 15 of a 28-day schedule at a dose of 1,200 mg/m2 intravenously over 30 minutes for a total of three courses.

RESULTS: Of the 44 patients, five (11.5%) achieved complete responses (CRs), 26 (59%) partial responses (PRs), and the remaining 13 showed no benefit from the treatment. Two of the CRs were histologically confirmed. The CR and PR rates were the same for patients with MF and those with PTCLU, respectively. No difference in terms of overall response rate was observed between relapsed and refractory patients. The median durations of CR and PR were 15 months (range, 6 to 22 months) and 10 months (range, 2 to 15 months), respectively. Treatment was well tolerated; hematologic toxicity was mild, and no nausea/vomiting or organ toxicity was recorded.

CONCLUSION: The results of the present phase II study show activity of gemcitabine as a single agent in patients with pretreated cutaneous T-cell lymphoma. Further studies that use gemcitabine alone or in combination with other drugs in earlier stages of the disease are needed.
Acquired Chromosome 11q Deletion Involving the Ataxia Teleangiectasia Locus in B-Cell Non-Hodgkin’s Lymphoma: Correlation With Clinicobiologic Features
Authors: Cuneo Antonio , Bigoni Renato , Rigolin Gian Matteo , Roberti Maria Grazia , Milani Raffaella , Bardi Antonella , Minotto Claudia , Agostini Paola , De Angeli Cristiano , Narducci Maria Grazia , Sabbioni Silvia , Russo Giandomenico , Negrini Massimo , Castoldi Gianluigi
Published: February 2017

PURPOSE: To study the clinicobiologic significance of acquired 11q deletions involving the ataxia teleangiectasia locus (ATM+/−) in B-cell non-Hodgkin’s lymphomas (NHL).

PATIENTS AND METHODS: Fifty-three indolent lymphomas and 82 aggressive lymphomas were studied by conventional cytogenetic analysis and by fluorescence in situ hybridization using an 11q22–23 probe recognizing ATM sequences. Pertinent clinical data were collected.

RESULTS: A hemizygous ATM deletion was seen in 44% to 88% of the interphase cells in 15 cases (11.1%); four patients had an indolent lymphoma (follicular center cell lymphoma), and 11 patients had an aggressive lymphoma (five mantle-cell lymphomas [MCLs] and six diffuse large-cell lymphomas). Dual-color hybridization studies showed ATM deletion to be possibly a secondary aberration in three patients with MCL. Ten out of 15 ATM+/− patients had a complex karyotype, 11 out of 15 had more than 90% abnormal metaphases (AA karyotype status), and +12, 13q14 deletion, and 17p13 deletion were seen in seven, four, and five cases, respectively. Patients with ATM+/− more frequently had a complex karyotype (P = .01) and the AA karyotype (P = .04) compared with patients without ATM+/−. With the exception of a poor performance status (P = .001), no correlation was found between ATM+/−, initial clinical variables, and complete remission rate; whereas a highly significant association was found with shorter survival (P < .0001). This cytogenetic lesion maintained its prognostic importance in multivariate analysis (P = .0004), along with performance status (P = .0006), serum lactate dehydrogenase level (P = .03), splenomegaly (P = .01), and histologic grade (P = .03). When analyzing indolent lymphomas and aggressive lymphomas separately, ATM+/− maintained its prognostic importance as an independent variable in both histologic groups (P = .0001 and P = .016, respectively).

CONCLUSION: Though possibly not representing a primary genetic lesion in the majority of cases, the acquired ATM+/− status has clinicobiologic importance in NHL, possibly representing a major cytogenetic determinant of outcome.
Final Results of a Randomized Phase III Trial of Sequential High-Dose Methotrexate, Fluorouracil, and Doxorubicin Versus Etoposide, Leucovorin, and Fluorouracil Versus Infusional Fluorouracil and Cisplatin in Advanced Gastric Cancer: A Trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group
Authors: Vanhoefer Udo , Rougier Philippe , Wilke Hansjochen , Ducreux Michel P. , Lacave Angel J. , Van Cutsem Eric , Planker Manfred , Santos José Guimaraes Dos , Piedbois Pascal , Paillot Bernard , Bodenstein Heinrich , Schmoll Hans-Jochen , Bleiberg Harry , Nordlinger Bernard , Couvreur Marie-Laure , Baron Benoit , Wils Jacques A.
Published: February 2017

PURPOSE: To compare the efficacy and tolerability of etoposide, leucovorin, and bolus fluorouracil (ELF) or infusional fluorouracil plus cisplatin (FUP) with that of the reference protocol of fluorouracil, doxorubicin, and methotrexate (FAMTX) in advanced gastric cancer.

PATIENTS AND METHODS: A total of 399 patients with advanced adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, and progression-free and overall survival. Only reviewed and confirmed responses were considered. The analysis of remission was based on assessable patients with documented measurable lesions. The intent-to-treat principle, log-rank test, and Cox regression model were used for the statistical analysis of time-to-event end points.

RESULTS: The overall response rate for 245 eligible patients with measurable disease was 9% with ELF, 20% with FUP, and 12% with FAMTX, with no significant differences. One hundred twelve patients were eligible for efficacy in assessable, nonmeasurable disease. No change was observed in 66% of patients treated with ELF, 56% with FUP, and 55% with FAMTX. Two patients achieved a complete tumor regression (one each for ELF and FAMTX). With a median follow-up time of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with FUP, and 6.7 months with FAMTX, respectively, with no significant differences. Nonhematologic and hematologic toxicities of ELF, FUP, and FAMTX were acceptable, with neutropenia being the major toxicity for all three regimens. Seven treatment-related deaths occurred (two with FUP and five with FAMTX).

CONCLUSION: All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as standard treatment for advanced gastric cancer. New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer.
Randomized Phase III Study Comparing Conventional-Dose Doxorubicin Plus Ifosfamide Versus High-Dose Doxorubicin Plus Ifosfamide Plus Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor in Advanced Soft Tissue Sarcomas: A Trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group
Authors: Le Cesne A. , Judson I. , Crowther D. , Rodenhuis S. , Keizer H.J. , Van Hoesel Q. , Blay J.Y. , Frisch J. , Van Glabbeke M. , Hermans C. , Van Oosterom A. , Tursz T. , Verweij J.
Published: February 2017

PURPOSE: This randomized multicenter study was designed to compare the activity of a high-dose doxorubicin-containing chemotherapy regimen with a conventional standard-dose regimen in adult patients with advanced soft tissue sarcomas (ASTS).

PATIENTS AND METHODS: Between 1992 and 1995, 314 patients were randomized to receive a standard-dose regimen (arm A), containing doxorubicin (50 mg/m2 on day 1) and ifosfamide (5 g/m2 on day 1), or an intensified regimen (arm B), combining doxorubicin (75 mg/m2 on day 1), the same ifosfamide dose, and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; sargramostim, 250 μg/m2 on days 3 to 16); all courses were repeated every 3 weeks.

RESULTS: The median age of the 294 eligible patients was 50 years. They received a median of five chemotherapy cycles. The median dose and relative doxorubicin dose-intensity achieved were 245 mg and 97% in arm A and 360 mg and 99% in arm B, respectively. Thirty-eight percent and 23% of patients presented with leiomyosarcomas and liver metastases, respectively. Objective responses were observed in 31 (21%) of 147 assessable patients in arm A and in 31 (23.3%) of 133 in arm B (P = .65). No change was observed in 41.6% and 46.2% of patients in arm A and B, respectively. Progression-free survival (PFS) was significantly longer in the intensive arm (P = .03). The median duration of the time to progression was 19 weeks in the conventional arm and 29 weeks in the intensified arm. There was no difference in overall survival (P = .98) between the two therapeutic arms. Toxicities were manageable in both arms. A grade 3/4 neutropenia and infection occurred in 92% and 4.6% of patients in arm A, respectively, and in 90% and 16.6% in arm B, respectively. Grade 3/4 thrombocytopenia was more frequent in arm B.

CONCLUSION: The use of rhGM-CSF allowed safe escalation of chemotherapy doses. Despite a 50% increase of the doxorubicin dose-intensity, the high-dose regimen failed to demonstrate any impact on survival in patients with ASTS. The low complete response rate, the high incidence of leiomyosarcomas, and liver metastases may in part explain these results. However, the lengthening of the PFS in the intensive arm, because of the quality of stable disease and inappropriate tumor evaluation policies that potentially lead to an underestimation of antitumor activity, does not definitively refute the use of a high-dose chemotherapy regimen in selected patients with ASTS.
MDR1 Gene Expression and Outcome in Osteosarcoma: A Prospective, Multicenter Study
Authors: Wunder Jay S. , Bull Shelley B. , Aneliunas Vicky , Lee Peter D. , Davis Aileen M. , Beauchamp Chris P. , Conrad Ernest U. , Grimer Robert J. , Healey John H. , Rock Michael J. , Bell Robert S. , Andrulis Irene L.
Published: February 2017

PURPOSE: Increased expression of the multidrug resistance gene (MDR1) has been implicated in osteosarcoma prognosis. This study represents the first prospective assessment of the prognostic value of MDR1 mRNA expression in patients with newly diagnosed extremity osteosarcoma.

PATIENTS AND METHODS: A series of patients with high-grade, nonmetastatic extremity osteosarcoma were enrolled from six tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 30 months). All patients were treated with (neo)adjuvant chemotherapy and surgery. Tumors from 123 patients were analyzed for MDR1 mRNA expression. The association of the level of MDR1 expression with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors.

RESULTS: Using the highest MDR1 value for each patient, a dose-response relationship was not identified between the level of MDR1 expression and systemic relapse (relative risk, 1.15; P = .44). Analyses based on biopsy or resection values alone gave similar results (P = .11 and .41, respectively, log rank test). In multivariate analysis, large tumor size (> 9 cm) was the only significant independent predictor of systemic outcome (relative risk, 2.8; P = .002).

CONCLUSION: We did not identify any correlation between MDR1 mRNA expression and disease progression in patients with osteosarcoma. It is likely that alterations in other genes are involved in resistance to chemotherapy in osteosarcoma and that they play a more critical role than MDR1 in this disease.
Cognitive Function in Breast Cancer Patients Receiving Adjuvant Chemotherapy
Authors: Brezden Christine B. , Phillips Kelly-Anne , Abdolell Mohamed , Bunston Terry , Tannock Ian F.
Published: February 2017

PURPOSE: Breast cancer patients receiving chemotherapy have complained of difficulties in their ability to remember, think, and concentrate. This study assessed whether there are differences in cognitive function between breast cancer patients treated with standard-dose adjuvant chemotherapy compared with healthy controls.

PATIENTS AND METHODS: The High Sensitivity Cognitive Screen and the Profile of Mood States (POMS) were used to assess cognitive function and mood in a group of 107 women. The women consisted of 31 breast cancer patients receiving adjuvant chemotherapy (group A), 40 breast cancer patients who had completed adjuvant chemotherapy a median of 2 years earlier (group B), and 36 healthy controls (group C).

RESULTS: Univariate analysis showed statistically significant differences (P = .009) in overall cognitive function scores between groups A and C, with poorer function in patients receiving adjuvant chemotherapy. These differences remained significant (P = .046) when controlling for age, education level, and menopausal status. More patients had moderate or severe cognitive impairment in groups A and B than in controls (P ≤ .002). There were no significant differences in POMS scores between the groups, suggesting that the differences seen in cognitive scores were unlikely to be because of mood disturbance.

CONCLUSION: Cognitive differences were observed in breast cancer patients receiving adjuvant chemotherapy compared with healthy controls. These differences did not seem to be caused by significant differences in mood disturbance between the two groups. If confirmed, these results have substantial implications for informed consent, counseling, and psychosocial support of patients receiving adjuvant chemotherapy for breast cancer.
Cyclophosphamide, Methotrexate, and Fluorouracil Versus Tamoxifen Plus Ovarian Suppression as Adjuvant Treatment of Estrogen Receptor–Positive Pre-/Perimenopausal Breast Cancer Patients: Results of the Italian Breast Cancer Adjuvant Study Group 02 Randomized Trial
Authors: Boccardo F. , Rubagotti A. , Amoroso D. , Mesiti M. , Romeo D. , Sismondi P. , Giai M. , Genta F. , Pacini P. , Distante V. , Bolognesi A. , Aldrighetti D. , Farris A. ,   for the Italian Breast Cancer Adjuvant Study Group
Published: February 2017

PURPOSE: To compare the efficacy of chemotherapy versus that of tamoxifen plus ovarian suppression in pre-/perimenopausal estrogen receptor–positive patients with early breast cancer.

PATIENTS AND METHODS: Patients were randomly assigned to receive either six cycles of a standard regimen of cyclophosphamide 100 mg/m2 orally days 1 to 14, methotrexate 40 mg/m2 intravenously (IV) days 1 and 8, and fluorouracil 600 mg/m2 IV days 1 and 8 (CMF), with all drugs restarted on day 29, or 5 years of tamoxifen, 30 mg/d, plus ovarian suppression with surgical oophorectomy, ovarian irradiation, or monthly goserelin 3.6-mg injections. Disease-free survival was the main study end point. Overall survival and toxicity were additional end points.

RESULTS: Between 1989 and 1997, 120 patients were assigned to CMF and 124 to tamoxifen and ovarian suppression (oophorectomy, n = 6; ovarian irradiation, n = 31; and goserelin injections, n = 87). At the time of analysis (median follow-up time, 76 months; range, 9 to 121 months), 82 patients had relapsed and 39 had died. No difference between groups had emerged with respect to either disease-free or overall survival. Treatments were comparable even in respect to age, tumor size, and nodal status, although a nonsignificant trend favored patients with poorly differentiated tumors treated with CMF. Leukopenia, nausea, vomiting, stomatitis, and alopecia were significantly more common in patients treated with CMF. There were few patients who developed benign gynecologic changes in either group, and numbers were comparable.

CONCLUSION: The combination of tamoxifen with ovarian suppression seems to be safe and to yield comparable results relative to standard CMF.
Docetaxel for Patients With Paclitaxel-Resistant Müllerian Carcinoma
Authors: Verschraegen Claire F. , Sittisomwong Tul , Kudelka Andrzej P. , Guedes Ernesto de Paula , Steger Melissa , Nelson-Taylor Tarra , Vincent Monique , Rogers Roger , Atkinson E. Neely , Kavanagh John J.
Published: February 2017

PURPOSE: To determine the efficacy and toxicity of docetaxel in patients with müllerian carcinoma resistant to paclitaxel.

PATIENTS AND METHODS: Thirty-two patients with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who failed paclitaxel-based chemotherapy received either 100 or 75 mg/m2 of docetaxel every 3 weeks. Resistance to paclitaxel was defined as either progression of disease during treatment, failure to achieve regression of disease after at least four courses, or rapid recurrence (within 6 months) after completion of therapy.

RESULTS: Eighteen patients were treated on a formal protocol and fourteen with the commercially available docetaxel. Thirty were assessable for response. Toxicities were thoroughly evaluated in the 18 patients on protocol. Twenty-seven patients (85%) had epithelial ovarian cancer. The overall response rate was 23% (one complete and six partial responses), with a median survival time of 44 weeks (9.5 months). Nine patients had stable disease and 14 progressive disease. Among 19 patients who progressed during prior paclitaxel treatment, two (11%) responded to docetaxel, compared with five (45%) of 11 patients in other paclitaxel-resistance categories. The responders had a median taxane-free interval (ie, the time between the last paclitaxel and first docetaxel treatment) of 73 weeks, compared with 19 weeks for the nonresponder group. Toxic effects were as expected.

CONCLUSION: Docetaxel is an active chemotherapeutic agent in patients with müllerian carcinoma previously treated with paclitaxel-based chemotherapy, especially in the patients who had a long taxane-free interval after a previous short response to paclitaxel.
Phase I Clinical and Pharmacokinetic Study of Oral S-1 in Patients With Advanced Solid Tumors
Authors: van Groeningen Cees J. , Peters Godefridus J. , Schornagel Jan H. , Gall Helen , Noordhuis Paul , de Vries Martin J. , Turner Sue L. , Swart Martha S. , Pinedo Herbert M. , Hanauske Axel R. , Giaccone Giuseppe
Published: February 2017

PURPOSE: To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate.

PATIENTS AND METHODS: Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter.

RESULTS: Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m2. The MTD was initially found at 45 mg/m2, with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m2, which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 μmol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU.

CONCLUSION: The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m2 bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m2 bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment.
Leucovorin and Fluorouracil With or Without Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer
Authors: de Gramont A. , Figer A. , Seymour M. , Homerin M. , Hmissi A. , Cassidy J. , Boni C. , Cortes-Funes H. , Cervantes A. , Freyer G. , Papamichael D. , Le Bail N. , Louvet C. , Hendler D. , de Braud F. , Wilson C. , Morvan F. , Bonetti A.
Published: February 2017

PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point.

PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m2/d) followed by a 5FU bolus (400 mg/m2/d) and 22-hour infusion (600 mg/m2/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m2 as a 2-hour infusion on day 1.

RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P = .0003) and better response rate (50.7% v 22.3%; P = .0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P = .12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41.7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P = .004).

CONCLUSION: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.
Cisplatin, Ifosfamide, Oral Etoposide, and Concurrent Accelerated Hyperfractionated Thoracic Radiation for Patients With Limited Small-Cell Lung Carcinoma: Results of Radiation Therapy Oncology Group Trial 93-12
Authors: Glisson Bonnie , Scott Charles , Komaki Ritsuko , Movsas Benjamin , Wagner Henry
Published: February 2017

PURPOSE: The combination of cisplatin, ifosfamide, and oral etoposide (PIEo) given concurrently with accelerated hyperfractionated thoracic radiation was studied in patients with limited small-cell lung cancer in a phase II trial to assess response, survival, and toxicity.

PATIENTS AND METHODS: Sixty-seven patients were accrued between March 1994 and April 1996. Chemotherapy doses were cisplatin 20 mg/m2 and ifosfamide 1,200 mg/m2 on days 1 to 3 and etoposide 40 mg/m2 administered orally days 1 through 14. Radiation consisted of accelerated hyperfractionated thoracic radiation (AHTRT) 1.5 Gy bid × 30 fractions (total 45 Gy) days 1 through 19, concurrent with cycle 1 of chemotherapy. Three additional cycles of chemotherapy were given every 4 weeks after completion of chemoradiation. Prophylactic cranial radiation (25 Gy in 10 fractions) was offered to patients for whom complete response (CR) after completion of chemotherapy was achieved.

RESULTS: An overall objective response rate of 78% (41 CRs [67%] and seven partial responses [11%]) was seen in 61 patients whose disease response could be evaluated. Median progression-free and overall survival estimates were 12.7 and 23.7 months, respectively. Two- and 3-year survival rates were estimated at 50% and 39%, respectively. Major toxic effects included grade 4 granulocytopenia in 34 (55%), grade 4 thrombocytopenia in 16 (26%), grade 3 to 5 fever/infection in six (10%; with one death resulting from sepsis), and grade 3/4 esophagitis in 27 patients (43%). Other nonhematologic toxic greater than grade 2 occurred in 11 patients (18%).

CONCLUSION: Relative to conventional etoposide/cisplatin and concurrent AHTRT, chemoradiation with PIEo produced similar median and 2-year survival rates and a higher rate of acute esophageal toxicity. However, the locoregional control rate with a minimum follow-up of 2 years is excellent at 80%. It is conceivable that longer follow-up will prove this regimen more promising. Research efforts should focus on other methods to improve disease control in all potential sites of recurrence.
The Multinational Association for Supportive Care in Cancer Risk Index: A Multinational Scoring System for Identifying Low-Risk Febrile Neutropenic Cancer Patients
Authors: Klastersky Jean , Paesmans Marianne , Rubenstein Edward B. , Boyer Michael , Elting Linda , Feld Ronald , Gallagher James , Herrstedt Jorn , Rapoport Bernardo , Rolston Kenneth , Talcott James ,   for the Study Section on Infections of Multinational Association for Supportive Care in Cancer
Published: February 2017

PURPOSE: Febrile neutropenia remains a potentially life-threatening complication of anticancer chemotherapy, but some patients are at low risk for serious medical complications. The purpose of this study was to develop an internationally validated scoring system to identify these patients.

MATERIALS AND METHODS: Febrile neutropenic cancer patients were observed in a prospective multinational study. Independent factors assessable at fever onset, predicting low risk of complications, on a randomly selected derivation set, were assigned integer weights to develop a risk-index score, which was subsequently tested on a validation set.

RESULTS: On the derivation set (756 patients), predictive factors were a burden of illness indicating absence of symptoms or mild symptoms (weight, 5; odds ratio [OR], 8.21; 95% confidence interval [CI], 4.15 to 16.38) or moderate symptoms (weight, 3; OR, 3.70; 95% CI, 2.18 to 6.29); absence of hypotension (weight, 5; OR, 7.62; 95% CI, 2.91 to 19.89); absence of chronic obstructive pulmonary disease (weight, 4; OR, 5.35; 95% CI, 1.86 to 15.46); presence of solid tumor or absence of previous fungal infection in patients with hematologic malignancies (weight, 4; OR, 5.07; 95% CI, 1.97 to 12.95); outpatient status (weight, 3; OR, 3.51; 95% CI, 2.02 to 6.04); absence of dehydration (weight, 3; OR, 3.81; 95% CI, 1.89 to 7.73); and age less than 60 years (weight, 2; OR, 2.45; 95% CI, 1.51 to 4.01). On the validation set, a Multinational Association for Supportive Care in Cancer risk-index score ≥ 21 identified low-risk patients with a positive predictive value of 91%, specificity of 68%, and sensitivity of 71%.

CONCLUSION: The risk index accurately identifies patients at low risk for complications and may be used to select patients for testing therapeutic strategies that may be more convenient or cost-effective.
Phase II Study of Liposomal Doxorubicin in Platinum- and Paclitaxel-Refractory Epithelial Ovarian Cancer
Authors: Gordon Alan N. , Granai C.O. , Rose Peter G. , Hainsworth John , Lopez Ana , Weissman Charles , Rosales Rosemary , Sharpington Timothy
Published: February 2017

PURPOSE: Stealth liposomal doxorubicin (Alzal Corp, Palo Alto, CA) has a slower clearance rate than free doxorubicin, resulting in sustained serum levels. Liposomal encapsulation also leads to increased concentration of drug in tumor tissue. Meta-analysis of previous studies has shown that doxorubicin has activity in epithelial ovarian cancer. The current study was developed to examine the activity of Stealth liposomal doxorubicin in platinum- and paclitaxel-refractory ovarian cancer.

PATIENTS AND METHODS: Patients had epithelial ovarian cancer that either progressed on or recurred within 6 months of completion of platinum and paclitaxel chemotherapy. All patients had measurable disease. Stealth liposomal doxorubicin was administered at 50 mg/m2 every 4 weeks as a 1-hour infusion.

RESULTS: Eighty-nine patients were treated and included in an intent-to-treat analysis. There were 82 patients who were platinum and paclitaxel refractory and met all study criteria. There was one complete response and 14 partial responses, for a total response rate of 16.9% (95% confidence interval [CI], 9.1% to 24.6%). For platinum- and paclitaxel-refractory patients, the response rate was 18.3% (95% CI, 9.9% to 26.7%). Median time to progression was 19.3 weeks for the entire population. Ten patients (11.2%) withdrew because of adverse events related to the drug (palmar-plantar erythrodysesthesia [PPE], n = 3; asthenia, n = 2; cardiac, n = 2; neutropenia, n = 1; stomatitis, n = 1; and edema, n = 1). There were no drug-related fatal events. There were only eight grade 4 adverse events attributable to the drug. Stomatitis, PPE, and skin lesions were managed with dose reductions and delays in most cases.

CONCLUSION: Stealth liposomal doxorubicin has activity in refractory epithelial ovarian cancer. PPE and stomatitis can usually be managed by dose adjustment. The ease of administration makes this an attractive agent.