bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I Study of a Third-Generation Selective Estrogen Receptor Modulator, LY353381.HCl, in Metastatic Breast Cancer
Authors: Münster Pamela N. , Buzdar Aman , Dhingra Kapil , Enas Nathan , Ni Lan , Major Maureen , Melemed Allen , Seidman Andrew , Booser Daniel , Theriault Richard , Norton Larry , Hudis Clifford
Published: February 2017

PURPOSE: We conducted this phase I trial to determine the safety and toxicity profile of LY353381.HCl—a novel, potent, third-generation selective estrogen receptor modulator (SERM)—because this benzothiophene derivative demonstrated an SERM profile in preclinical studies.

PATIENTS AND METHODS: We studied 32 patients with recurrent or metastatic breast cancer. Patients were treated in four cohorts with oral daily doses of 10, 20, 50, and 100 mg. Pharmacokinetic sampling was performed during the first 72 hours following the first dose on day 1 and during the 24 hours after the day 57 dose. Eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 to 2; no significant major organ dysfunction; and at least 3 weeks elapsed since most recent hormonal therapy, chemotherapy, and estrogen replacement therapy.

RESULTS: The median patient age was 56 years (range, 30 years to 76 years). The median number of prior chemotherapies for metastatic disease was one (range, zero to four), while the median number of prior hormone regimens for metastatic disease was two (range, zero to five). Receptor status was estrogen receptor (ER) positive and progesterone receptor (PR) positive, 19 patients; ER positive and PR negative, eight patients; ER positive and PR unknown, two patients; and ER and PR unknown, three patients. Dose-limiting toxicity was not observed. Treatment was well tolerated with mild to moderate hot flashes in 18 of 32 patients (56%) at all dose levels. Transvaginal ultrasound performed at baseline and after 12 weeks of treatment showed no endometrial thickening. Of the 32 patients evaluable for response, six patients had stable disease for at least 6 months with a median duration of 7.7 months (range, 6.2 months to 33.8 months). The pharmacokinetics of LY353381.HCl were generally linear with respect to time and studied dose range.

CONCLUSION: As predicted in preclinical testing, daily oral LY353381.HCl is safe, is well tolerated at all tested dose levels, and may be clinically beneficial in patients with extensively pretreated metastatic breast cancer. Further studies with LY353381 to evaluate the efficacy in patients with or without prior exposure to tamoxifen and fewer overall prior regimens are under way.
Low-Volume Nodal Metastases Detected at Retroperitoneal Lymphadenectomy for Testicular Cancer: Pattern and Prognostic Factors for Relapse
Authors: Rabbani Farhang , Sheinfeld Joel , Farivar-Mohseni Hesam , Leon Antonio , Rentzepis Michael J. , Reuter Victor E. , Herr Harry W. , McCaffrey John A. , Motzer Robert J. , Bajorin Dean F. , Bosl George J.
Published: February 2017

PURPOSE: To determine the incidence, pattern, and predictive factors for relapse in patients with low-volume nodal metastases (stage pN1) at retroperitoneal lymphadenectomy (RPLND) and identify who may benefit from chemotherapy in the adjuvant or primary setting.

PATIENTS AND METHODS: Fifty-four patients with testicular nonseminomatous germ cell tumor had low-volume retroperitoneal metastases (pathologic stage pN1, 1997 tumor-node-metastasis classification) resected at RPLND, 50 of whom were managed expectantly without adjuvant chemotherapy. The dissection was bilateral in 12 and was a modified template in 38 patients. Retroperitoneal metastases were limited to microscopic nodal involvement in 14 patients. Follow-up ranged from 1 to 106 months (median, 31.4 months).

RESULTS: Eleven patients (22%) suffered a relapse at a median follow-up of 1.8 months (range, 0.6 to 28 months). The most frequent form of recurrence was marker elevation in nine (18%) patients. Persistent marker elevation after orchiectomy and before retroperitoneal lymphadenectomy was a significant independent predictor of relapse (relative risk, 8.0; 95% confidence interval, 2.3 to 27.8; P = .001). Four of five (80%) patients with elevated markers (alpha-fetoprotein alone in three, alpha-fetoprotein and beta human chorionic gonadotropin in one) suffered a relapse, compared with seven of 45 (15.6%) patients with normal markers.

CONCLUSION: Clinical stage I and IIA patients with normal markers who have low-volume nodal metastases have a low incidence of relapse and can be managed by observation only if compliance can be assured. In contrast, patients with elevated markers before retroperitoneal lymphadenectomy have a high rate of relapse and should be considered for primary chemotherapy.
Comparison of Oral Capecitabine Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Treatment in 605 Patients With Metastatic Colorectal Cancer: Results of a Randomized Phase III Study
Authors: Hoff Paulo M. , Ansari Rafat , Batist Gerald , Cox John , Kocha Walter , Kuperminc Mario , Maroun Jean , Walde David , Weaver Charles , Harrison Evelyn , Burger Hans U. , Osterwalder Bruno , Wong Alfred O. , Wong Ralf
Published: February 2017

PURPOSE: To compare the response rate, efficacy parameters, and toxicity profile of oral capecitabine with bolus intravenous (IV) fluorouracil plus leucovorin (5-FU/LV) as first-line treatment in patients with metastatic colorectal cancer.

PATIENTS AND METHODS: We prospectively randomized 605 patients to treatment with oral capecitabine for 14 days every 3 weeks or 5-FU/LV by rapid IV injection daily for 5 days in 4-week cycles.

RESULTS: The overall objective tumor response rate among all randomized patients was significantly higher in the capecitabine group (24.8%) than in the 5-FU/LV group (15.5%; P = .005). In the capecitabine and 5-FU/LV groups, median times to disease progression were 4.3 and 4.7 months (log-rank P = .72), median times to treatment failure were 4.1 and 3.1 months (P = .19), and median overall survival times were 12.5 and 13.3 months (P = .974), respectively. Capecitabine, compared with bolus 5-FU/LV treatment, produced a significantly lower incidence (P < .0002) of diarrhea, stomatitis, nausea, and alopecia. Patients treated with capecitabine also displayed lower incidences of grade 3/4 stomatitis and grade 3/4 neutropenia (P < .0001) leading to significantly less neutropenic fever/sepsis. Grade 3 hand-foot syndrome (P < .00001) and grade 3/4 hyperbilirubinemia were the only toxicities more frequently associated with capecitabine than with 5-FU/LV treatment.

CONCLUSION: Oral capecitabine was more active than 5-FU/LV in the induction of objective tumor responses. Time to disease progression and survival were at least equivalent for capecitabine compared with the 5-FU/LV arm. Capecitabine also demonstrated clinically meaningful benefits over bolus 5-FU/LV in terms of tolerability.
Phase I and Pharmacokinetic Study of BMS-184476, a Taxane With Greater Potency and Solubility Than Paclitaxel
Authors: Hidalgo Manuel , Aylesworth Cheryl , Hammond Lisa A. , Britten Carolyn D. , Weiss Geoffrey , Stephenson Joseph , Schwartz Garry , Patnaik Amita , Smith Lon , Molpus Kathleen , Felton Sally , Gupta Elora , Ferrante Karen J. , Tortora Anne , Sonnichsen Daryl S. , Skillings Jamey , Rowinsky Eric K.
Published: February 2017

PURPOSE: To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks.

PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474.

RESULTS: Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m2. Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m2 dose level. In contrast, of 15 assessable patients treated at the 60 mg/m2 dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m2 dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean ± SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 ± 89 mL/min/m2, 402 ± 231 L/m2, and 40.8 ± 21.8 hours, respectively.

CONCLUSION: The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m2 as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.
Health Outcomes After External-Beam Radiation Therapy for Clinically Localized Prostate Cancer: Results From the Prostate Cancer Outcomes Study
Authors: Hamilton A. S. , Stanford J. L. , Gilliland F. D. , Albertsen P. C. , Stephenson R. A. , Hoffman R. M. , Eley J. W. , Harlan L. C. , Potosky A. L.
Published: February 2017

PURPOSE: Studies reporting effects of radiotherapy for prostate cancer on sexual, bowel, and urinary function have been conducted primarily in referral centers or academic institutions. Effects of external-beam radiotherapy for prostate cancer among a population-based cohort were assessed.

PATIENTS AND METHODS: The study population included 497 white, Hispanic, and African-American men with localized prostate cancer from six US cancer registries who were diagnosed between October 1, 1994, and October 31, 1995, and treated initially with external-beam radiotherapy. They were interviewed at regular intervals, and medical records were reviewed. Distributions of responses for bowel-, urinary-, and sexual-related functions at 6, 12, and 24 months after diagnosis and adjusted mean composite change scores for each domain were analyzed.

RESULTS: Declines of 28.9% in the sexual function score and 5.4% in the bowel function score occurred by 24 months, whereas at this time, the urinary function score was relatively unchanged. A total of 43% of those who were potent before diagnosis became impotent after 24 months. More than two thirds of the men were satisfied with their treatment and would make the same decision again.

CONCLUSION: Sexual function was the most adversely affected quality-of-life domain, with problems continuing to increase between 12 and 24 months. Bowel function problems increased at 6 months, with partial resolution observed by 24 months. Despite the side effects, satisfaction with therapy was high. These results are representative of men in community practice settings and may be of assistance to men and to clinicians when making treatment decisions.
Pharmacodynamic Studies of the Epidermal Growth Factor Receptor Inhibitor ZD1839 in Skin From Cancer Patients: Histopathologic and Molecular Consequences of Receptor Inhibition
Authors: Albanell Joan , Rojo Federico , Averbuch Steve , Feyereislova Andrea , Mascaro Jose Manuel , Herbst Roy , LoRusso Patricia , Rischin Danny , Sauleda Silvia , Gee Julia , Nicholson Robert I. , Baselga Jose
Published: February 2017

PURPOSE: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca Pharmaceuticals, Alderley Park, United Kingdom) is under development as an anticancer agent. We studied the pharmacodynamic effects of ZD1839 on EGFR in the skin, an EGFR-dependent tissue, in cancer patients participating in ZD1839 phase I clinical trials.

PATIENTS AND METHODS: We studied 104 pre– and/or on–ZD1839 therapy (≈ at day 28 of therapy) skin biopsies from 65 patients receiving escalating doses of daily oral ZD1839. We measured ZD1839 effects on EGFR activation by immunohistochemistry using an antibody specific for the activated (phosphorylated) EGFR. Effects on receptor signaling (activated mitogen-activated protein kinase [MAPK]), proliferation, p27KIP1, and maturation were also assessed.

RESULTS: Histopathologically, the stratum corneum of the epidermis was thinner during therapy (P < .001). In hair follicles, prominent keratin plugs and microorganisms were found in dilated infundibula. ZD1839 suppressed EGFR phosphorylation in all EGFR-expressing cells (P < .001). In addition, ZD1839 inhibited MAPK activation (P < .001) and reduced keratinocyte proliferation index (P < .001). Concomitantly, ZD1839 increased the expression of p27KIP1 (P < .001) and maturation markers (P < .001) and increased apoptosis (P < .001). These effects were observed at all dose levels, before reaching dose-limiting toxicities.

CONCLUSION: ZD1839 inhibits EGFR activation and affects downstream receptor-dependent processes in vivo. These effects were profound at doses well below the one producing unacceptable toxicity, a finding that strongly supports pharmacodynamic assessments to select optimal doses instead of a maximum-tolerated dose for definitive efficacy and safety trials.
Randomized, Controlled, Dose-Range Study of Ro 25-8315 Given Before and After a High-Dose Combination Chemotherapy Regimen in Patients With Metastatic or Recurrent Breast Cancer Patients
Authors: Viens P. , Chabannon C. , Pouillard P. , Janvier M. , Brugger W. , Blay J. Y. , Oberling F. , Capdeville R. , Newman C. , Méresse V. , Xu Z. X. , Platzer E. , Van der Auwera P. , Maraninchi D.
Published: February 2017

PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of three different dose levels of pegylated granulocyte colony-stimulating factor (Ro 25-8315) on progenitor cell mobilization and hematologic recovery in cancer patients.

PATIENTS AND METHODS: Breast cancer patients (n = 36) were randomly assigned to receive before (part I) and after (part II) chemotherapy either a single-dose injection of Ro 25-8315 (20 μg/kg, n = 9; 60 μg/kg, n = 9; 100 μg/kg, n = 10) or a standard daily dose of filgrastim (part I, 10 μg/kg/d; part II, 5 μg/kg/d) (control group, n = 8).

RESULTS: Overall, Ro 25-8315 was well tolerated. In part I, more progenitor cell mobilization was observed with Ro 25-8315 100 μg/kg. The peak of circulating CD34+ cells was obtained at day +5 in the four groups, and the absolute neutrophil count (ANC) returned to less than 20 × 109/L by day +15. In part II, high levels of circulating CD34+ cells (> 20 cells/μL) were obtained in all four groups. The chemotherapy-induced neutropenia (< 1 × 109/L) was similar in the four groups. Ro 25-8315 100 μg/kg was more effective than filgrastim in reducing the number of patients with an ANC less than 0.5 × 109/L on day +12 after chemotherapy.

CONCLUSION: A single injection of Ro 25-8315 100 μg/kg might be the optimal dose for steady-state peripheral-blood progenitor cell mobilization. A single injection of 20, 60, or 100 μg/kg could be as efficient as daily administration of filgrastim to correct chemotherapy-induced cytopenia. The optimal dose of Ro 25-8315 should be determined according to the planned chemotherapy regimen.
Salvage Chemotherapy for Patients With Advanced Pure Seminoma
Authors: Vuky Jacqueline , Tickoo Satish K. , Sheinfeld Joel , Bacik Jennifer , Amsterdam Alison , Mazumdar Madhu , Reuter Victor , Bajorin Dean F. , Bosl George J. , Motzer Robert J.
Published: February 2017

PURPOSE: We describe the response to conventional or high-dose salvage chemotherapy in patients with advanced seminoma who experience disease progression after receiving first-line platinum-based treatment.

PATIENTS AND METHODS: Twenty-seven patients with progressive, advanced, pure seminoma were treated with salvage chemotherapy. Fifteen patients were treated with conventional-dose cisplatin-and-ifosfamide combination chemotherapy. Twelve patients were treated with high-dose chemotherapy followed by autologous stem-cell rescue.

RESULTS: Fifteen patients (56%) achieved a complete response (CR), nine achieved CR with a conventional-dose cisplatin and ifosfamide program, and six experienced CR after high-dose chemotherapy. Fourteen patients (52%) are alive and disease-free, with 13 (48%) continuously disease-free at a median follow-up of 72 months. Twelve (57%) of 21 patients whose pretreatment tumors were studied morphologically were found to have seminoma with atypia. Eight patients underwent resection after salvage chemotherapy; six with histologic findings of necrotic debris/fibrosis alone are alive and disease-free at last follow-up. Both patients with viable seminoma found at surgery died of disease.

CONCLUSION: Most patients with advanced seminoma are cured with standard first-line programs of cisplatin and etoposide with or without bleomycin. A small minority of patients with pure seminoma have resistant tumors and require salvage chemotherapy. In this setting, approximately 50% of patients with recurrent pure seminoma achieve durable CR with conventional or high-dose salvage chemotherapy. Identification of biologic markers to predict clinical outcome and an enhanced understanding of the basic biologic features of seminoma may lead to improvements in the management of this disease.
Quality of Life in Long-Term Survivors of Testicular Cancer: A Population-Based Case-Control Study
Authors: Joly F. , Héron J. F. , Kalusinski L. , Bottet P. , Brune D. , Allouache N. , Macé-Lesec’h J. , Couëtte J. E. , Pény J. , Henry-Amar M.
Published: February 2017

PURPOSE: To evaluate quality of life and social problems in long-term survivors of testicular cancer.

PATIENTS AND METHODS: In 1998, 71 testicular cancer survivors (cases) identified from the Calvados General Tumor Registry were enrolled onto a case-control study. One hundred nineteen healthy control subjects (controls), matched by age and location of residence, were selected at random from electoral rolls. Three self-administered questionnaires were used: two health-related quality-of-life questionnaires (Short Form-36 and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 core questionnaires) and one life situation questionnaire. Specific questions concerning sexuality were also added.

RESULTS: With a mean follow-up of 11 years, health-related quality-of-life scores did not differ significantly between cases and controls, nor did general symptom scores. Psychosocial problems were reported equally by cases and controls. Cases reported more modification of sexual life (P = .04) with decreased sexual enjoyment (P < .01), decreased desire (P = .02), and infertility (P < .01). Cases did not report more divorce than controls; they reported fewer changes in relationships with friends (P = .03). Although a similar proportion of cases and controls were at work, cases expressed less ambitious professional plans (P = .002). Cases had greater difficulty in borrowing from banks (P < .001).

CONCLUSION: French long-term survivors of testicular cancer do not express more impairment of health-related quality of life or familial or professional life in comparison with healthy men. They did have more sexual life problems and found difficulty in borrowing from banks. This information should be used by practitioners to help their patients cope with their disease and return to normal life.
Outcomes of Tamoxifen Chemoprevention for Breast Cancer in Very High-Risk Women: A Cost-Effectiveness Analysis
Authors: Hershman Dawn , Sundararajan Vijaya , Jacobson Judith S. , Heitjan Daniel F. , Neugut Alfred I. , Grann Victor R.
Published: February 2017

PURPOSE: To estimate the effects on survival, quality-adjusted survival, and health care costs of using tamoxifen for primary prevention in subgroups of women at very high risk for breast cancer.

PATIENTS AND METHODS: A decision analysis was performed using a hypothetical cohort of women that included subgroups with atypical hyperplasia, Gail risk greater than 5, lobular carcinoma-in-situ, or two or more first-degree relatives with breast cancer. Data sources were the Breast Cancer Prevention Trial, the Surveillance, Epidemiology, and End-Results program, time trade-off preference ratings, the Group Health Cooperative of Puget Sound, and the United States Health Care Financing Administration.

RESULTS: Our model predicted that tamoxifen would prolong the average survival of cohort members initiating use at ages 35, 50, and 60 years by 70, 42, and 27 days, respectively. It would prolong survival even more for those in the higher-risk groups, especially those with atypical hyperplasia (202, 89, and 45 days). Tamoxifen use was also projected to extend quality-adjusted survival by 158, 80, and 50 days in the atypical hyperplasia group. For younger women in the highest risk groups, chemoprevention with tamoxifen was estimated to have cost savings or be cost-effective, both with and without quality adjustments.

CONCLUSION: Chemoprevention with tamoxifen may be particularly beneficial to women with atypical hyperplasia, 5-year Gail model risk greater than 5%, lobular carcinoma-in-situ, or two or more first-degree relatives with breast cancer. The benefits may be greater if tamoxifen is initiated before age 50 years rather than after and if the breast cancer risk reduction conferred by tamoxifen lasts longer than 5 years. For women with a very high risk of invasive breast cancer, chemoprevention with tamoxifen seems to be cost-effective.
Granulocyte Colony-Stimulating Factor in Induction Treatment of Children With Non-Hodgkin’s Lymphoma: A Randomized Study of the French Society of Pediatric Oncology
Authors: Patte C. , Laplanche A. , Bertozzi A. I. , Baruchel A. , Frappaz D. , Schmitt C. , Mechinaud F. , Nelken B. , Boutard P. , Michon J.
Published: February 2017

PURPOSE: To determine whether granulocyte colony-stimulating factor (G-CSF; lenograstim) decreases the incidence of febrile neutropenia after induction courses in treatment of childhood non-Hodgkin’s lymphoma (NHL).

PATIENTS AND METHODS: Patients were randomized to receive (G-CSF+) or not receive (G-CSF−) prophylactic G-CSF, 5 μg/kg/d, from day 7 until an absolute neutrophil count ≥ 500/μL was sustained over 48 hours, after two consecutive induction courses of cyclophosphamide 1.5 or 3 g/m2, vincristine 2 mg/m2, prednisone 60 mg/m2/d × 5, doxorubicin 60 mg/m2, high-dose methotrexate 3 or 8 g/m2, and intrathecal injections (COPAD[M]) on protocols LMB89, LMT89, and HM91 of the French Society of Pediatric Oncology.

RESULTS: One hundred forty-eight patients were assessable, 75 G-CSF+ and 73 G-CSF−. Although duration of neutropenia less than 500/μL was 3 days shorter in G-CSF+ patients (P = 10−4), incidence of febrile neutropenia (89% v 93% in the first course, 88% v 88% in the second course), durations of hospitalization and antimicrobial therapy, percentages of infections, mucositis, and transfusions were not significantly different. Although the percentage of G-CSF+ patients commencing the following course on day 21 was significantly higher (84% v 68% after the first and 57% v 38% after the second course; P < .05), the median delay between the two courses was only 1 day less in G-CSF+ patients (median delay after first COPAD(M), 19 v 20 days, P = .01; after second, 21 v 22 days, P = not significant). Remission and survival rates were similar in both arms.

CONCLUSION: This study demonstrates that G-CSF did not decrease treatment-related morbidity, nor increase the dose-intensity in children undergoing COPAD(M) induction chemotherapy for NHL.
Intensive Salvage Therapy With High-Dose Chemotherapy for Patients With Advanced Hodgkin’s Disease in Relapse or Failure After Initial Chemotherapy: Results of the Groupe d’Études des Lymphomes de l’Adulte H89 Trial
Authors: Fermé Christophe , Mounier Nicolas , Diviné Marine , Brice Pauline , Stamatoullas Aspasia , Reman Oumedaly , Voillat Laurent , Jaubert Jérôme , Lederlin Pierre , Colin Philippe , Berger Françoise , Salles Gilles
Published: February 2017

PURPOSE: To evaluate prospectively the feasibility and efficacy of early intensive therapy, including intensified cytoreductive chemotherapy (CT) and high-dose CT (HDCT) followed by autologous stem-cell transplantation (ASCT), in patients with advanced Hodgkin’s disease (HD) who failed to respond completely or relapsed after initial treatment.

PATIENTS AND METHODS: Among 533 eligible patients with newly diagnosed stage IIIB-IV HD enrolled in the H89 trial, all 157 patients with induction failure (IF) (n = 67), partial response (PR) of less than 75% (n = 22), or relapse (n = 68) were included in this study. Planned salvage therapy included mitoguazone, ifosfamide, vinorelbine, and etoposide monthly for two to three cycles followed by high-dose carmustine, etoposide, cytarabine, and melphalan with ASCT.

RESULTS: With a median follow-up of 50 months, the 5-year survival estimates were 30%, 72%, and 76% for the IF, PR, and relapse groups, respectively (P = .0001), 71% for the 101 patients given HDCT, and 32% for the 48 patients treated without HDCT (P = .0001). Multivariate analysis using time-dependent Cox model indicated that B symptoms at progression, salvage without HDCT, and chemoresistant disease before HDCT were significantly associated with shorter overall survival.

CONCLUSION: Early intensive therapy improves the outcomes of patients with advanced HD who failed to respond completely to initial treatment and those who relapsed with adverse prognostic factors. However, for patients with IF and chemoresistant disease, this approach remains unsatisfactory.
13-cis Retinoic Acid and Complete Androgen Blockade in Advanced Hormone-Naive Prostate Cancer Patients: Report of a Phase II Randomized Study
Authors: Ferrari Anna C. , Stone Nelson , Stock Richard , Bednar Myron , Esseesse Isaac , Singh Harvinder , Baldwin Yvonne , Mandeli John
Published: February 2017

PURPOSE: 13 cis Retinoic acid (isotretinoin) is a retinoid with preclinical evidence of anti–prostate cancer activity. This phase II, cross-over, randomized study of advanced, predominantly androgen-dependent prostate cancer patients was designed to assess primarily the effect on prostate-specific antigen (PSA) decline and toxicity of adding isotretinoin to hormonal therapy and, secondarily, the potential antitumor activity of the combination.

PATIENTS AND METHODS: Thirty-seven D0 to D2 patients were randomized soon after initiating luteinizing hormone–releasing hormone agonist with antiandrogen treatment to add (arm 1) or not (arm 2) isotretinoin from weeks 1 to 12. After cross-over on week 13, patients in arm 1 discontinued while patients in arm 2 added isotretinoin from weeks 14 to 25. Observation on hormonal therapy alone continued until week 49.

RESULTS: Baseline and randomization median PSA for 30 assessable patients were, respectively, 34 and 18.2 ng/mL for arm 1 and 31 and 13.4 ng/mL for arm 2. Median PSA at week 13 was 0.5 ng/mL (range, < 0.05 to 136 ng/mL) for arm 1 and 0.7 ng/mL (range, < 0.05 to 4.4 ng/mL) for arm 2; at week 25, 0.1 ng/mL (range, < 0.05 to 121 ng/mL) and 0.4 ng/mL (range, < 0.05 to 3.1 ng/mL), respectively. At week 49, arm 1 had median PSA of 0.1 ng/mL (range, < 0.05 to 345 ng/mL) and arm 2, 0.3 ng/mL (range, < 0.05 to 8.8 ng/mL); seven of 15 and three of 15 patients, respectively, had undetectable PSA levels (P = .12). Frequent isotretinoin-related toxicity included grade 1 cheilitis (76%), skin dryness (43%), and elevated triglycerides (50%).

CONCLUSION: Isotretinoin does not impair PSA decline or add significant toxicity to hormonal therapy. An adequately powered, randomized study would be required to determine whether the combination is superior to standard hormonal treatment.
Lymphatic Mapping and Sentinel Node Identification in Patients With Cervix Cancer Undergoing Radical Hysterectomy and Pelvic Lymphadenectomy
Authors: Levenback Charles , Coleman Robert L. , Burke Thomas W. , Lin W. Michael , Erdman William , Deavers Michael , Delpassand Ebrahim S.
Published: February 2017

PURPOSE: The purpose of this study was to determine the feasibility of sentinel node identification in patients with invasive cervix cancer undergoing radical hysterectomy and pelvic lymphadenectomy using preoperative and intraoperative lymphatic mapping.

PATIENTS AND METHODS: Thirty-nine patients at two institutions were enrolled onto this institutional review board–approved study. All underwent preoperative lymphoscintigraphy and intraoperative lymphatic mapping with blue dye and a handheld gamma probe. Radical hysterectomy was aborted in four patients because metastatic disease was discovered on frozen section analysis of the sentinel node.

RESULTS: Preoperative lymphoscintigraphy revealed at least one sentinel node in 33 patients (85%), including 21 (55%) with bilateral sentinel nodes. All 39 patients had at least one sentinel node identified intraoperatively. Eighty percent of sentinel nodes were in three pelvic locations: iliac, obturator, and parametrial (in descending order of frequency). The remaining sentinel nodes were in the common iliac and para-aortic nodal basins. A total of 132 nodes were identified clinically as sentinel nodes; 65 (49%) were both blue and hot, 35 (27%) were blue only, and 32 (24%) were hot only. Eight patients (21%) had metastatic disease. In five of these patients, sentinel nodes were the only positive lymph nodes. One patient had false-negative sentinel nodes. She had four microscopically positive parametrial nodes that were resected in continuity with the uterus. The sensitivity of the sentinel node was 87.5% and the negative predictive value was 97%.

CONCLUSION: Preoperative lymphoscintigraphy and intraoperative lymphatic mapping were highly successful at identifying sentinel nodes in patients undergoing radical hysterectomy.
Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer
Authors: Vogel Charles L. , Cobleigh Melody A. , Tripathy Debu , Gutheil John C. , Harris Lyndsay N. , Fehrenbacher Louis , Slamon Dennis J. , Murphy Maureen , Novotny William F. , Burchmore Michael , Shak Steven , Stewart Stanford J. , Press Michael
Published: February 2017

PURPOSE: To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer.

PATIENTS AND METHODS: One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly.

RESULTS: The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events.

CONCLUSION: Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.
Influence of Letrozole and Anastrozole on Total Body Aromatization and Plasma Estrogen Levels in Postmenopausal Breast Cancer Patients Evaluated in a Randomized, Cross-Over Study
Authors: Geisler Jürgen , Haynes Ben , Anker Gun , Dowsett Mitch , Lønning Per Eystein
Published: February 2017

PURPOSE: To compare the effects of the two novel, potent, nonsteroidal aromatase inhibitors anastrozole and letrozole on total-body aromatization and plasma estrogen levels.

PATIENTS AND METHODS: Twelve postmenopausal women with estrogen receptor–positive, metastatic breast cancer were treated with anastrozole 1 mg orally (PO) and letrozole 2.5 mg PO once daily, each given for a time interval of 6 weeks in a randomized sequence. Total-body aromatization was determined before treatment and at the end of each treatment period using a dual-label isotopic technique involving isolation of the metabolites with high-performance liquid chromatography. Plasma levels of estrone (E1), estradiol (E2), and estrone sulfate (E1S) were determined in samples obtained before each injection using highly sensitive radioimmunoassays.

RESULTS: Pretreatment aromatase levels ranged from 1.68% to 4.27%. On-treatment levels of aromatase were detectable in 11 of 12 patients during treatment with anastrozole (mean percentage inhibition in the whole group, 97.3%) but in none of the 12 patients during treatment with letrozole (> 99.1% suppression in all patients; Wilcoxon, P = .0022, comparing the two drug regimens). Treatment with anastrozole suppressed plasma levels of E1, E2, and E1S by a mean of 81.0%, 84.9%, and 93.5%, respectrively, whereas treatment with letrozole caused a corresponding decrease of 84.3%, 87.8% and 98.0%, respectively. The suppression of E1 and E1S was found to be significantly better during treatment with letrozole compared with anastrozole (P = .019 and .0037, respectively).

CONCLUSION: This study revealed letrozole (2.5 mg once daily) to be a more potent suppressor of total-body aromatization and plasma estrogen levels compared with anastrozole (1 mg once daily) in postmenopausal women with metastatic breast cancer.
Acute Side Effects and Complications After Short-Term Preoperative Radiotherapy Combined With Total Mesorectal Excision in Primary Rectal Cancer: Report of a Multicenter Randomized Trial
Authors: Marijnen C. A.M. , Kapiteijn E. , van de Velde C. J.H. , Martijn H. , Steup W. H. , Wiggers T. , Kranenbarg E. Klein , Leer J. W.H. ,   the Cooperative Investigators of the Dutch Colorectal Cancer Group
Published: February 2017

PURPOSE: Total mesorectal excision (TME) surgery in the treatment of rectal cancer has been shown to result in a reduction in the number of local recurrences in retrospective studies. Reports on improved local control after preoperative, hypofractionated radiotherapy (RT) have led to the introduction of a prospective randomized multicenter trial, in which the effect of TME surgery with or without preoperative RT were evaluated. Any benefit in regard to a reduced local recurrence rate and possible improved survival must be weighed against potential adverse effects in both the short-term and the long-term. The present study was undertaken to assess the acute side effects of short-term, preoperative RT in rectal cancer patients and to study the influence of five doses of 5 Gy on surgical parameters, postoperative morbidity and mortality in patients randomized in the Dutch TME trial.

PATIENTS AND METHODS: We analyzed 1,530 Dutch patients entered onto a prospective randomized trial, comparing preoperative RT with five doses of 5 Gy followed by TME surgery with TME surgery alone, of which 1,414 patients were assessable. Toxicity from RT, surgery characteristics, and postoperative complications and mortality were compared.

RESULTS: Toxicity during RT hardly occurred. Irradiated patients had 100 mL more blood loss during the operation (P < .001) and showed more perineal complications (P = .008) in cases of abdominoperineal resection. The total number of complications was slightly increased in the irradiated group (P = .008). No difference was observed in postoperative mortality (4.0% v 3.3%) or in the number of reinterventions.

CONCLUSION: Preoperative hypofractionated RT is a safe procedure in patients treated with TME surgery, despite a slight increase in complications when compared with TME surgery only.
Immunohistochemistry Versus Microsatellite Instability Testing in Phenotyping Colorectal Tumors
Authors: Lindor Noralane M. , Burgart Lawrence J. , Leontovich Olga , Goldberg Richard M. , Cunningham Julie M. , Sargent Daniel J. , Walsh-Vockley Catherine , Petersen Gloria M. , Walsh Michael D. , Leggett Barbara A. , Young Joanne P. , Barker Melissa A. , Jass Jeremy R. , Hopper John , Gallinger Steve , Bapat Bharati , Redston Mark , Thibodeau Stephen N.
Published: February 2017

PURPOSE: To compare microsatellite instability (MSI) testing with immunohistochemical (IHC) detection of hMLH1 and hMSH2 in colorectal cancer.

PATIENTS AND METHODS: Colorectal cancers from 1,144 patients were assessed for DNA mismatch repair deficiency by two methods: MSI testing and IHC detection of hMLH1 and hMSH2 gene products. High-frequency MSI (MSI-H) was defined as more than 30% instability of at least five markers; low-level MSI (MSI-L) was defined as 1% to 29% of loci unstable.

RESULTS: Of 1,144 tumors tested, 818 showed intact expression of hMLH1 and hMSH2. Of these, 680 were microsatellite stable (MSS), 27 were MSI-H, and 111 were MSI-L. In all, 228 tumors showed absence of hMLH1 expression and 98 showed absence of hMSH2 expression: all were MSI-H.

CONCLUSION: IHC in colorectal tumors for protein products hMLH1 and hMSH2 provides a rapid, cost-effective, sensitive (92.3%), and extremely specific (100%) method for screening for DNA mismatch repair defects. The predictive value of normal IHC for an MSS/MSI-L phenotype was 96.7%, and the predictive value of abnormal IHC was 100% for an MSI-H phenotype. Testing strategies must take into account acceptability of missing some cases of MSI-H tumors if only IHC is performed.
Role of Health-Related Quality of Life in Palliative Chemotherapy Treatment Decisions
Authors: Detmar S. B. , Muller M. J. , Schornagel J. H. , Wever L. D.V. , Aaronson N. K.
Published: February 2017

PURPOSE: To determine the frequency with which health-related quality-of-life (HRQL) considerations lead to modification or discontinuation of palliative chemotherapy, and the association between physicians’ ratings of patients’ HRQL and such treatment decisions.

METHODS: Four consecutive medical consultations of 203 patients receiving outpatient palliative chemotherapy were tape-recorded and the content was analyzed to determine the frequency of and reasons for treatment alterations. Physicians rated their patients’ HRQL by using the COOP/WONCA health assessment charts. Data on tumor response and treatment toxicity were obtained from the audiotapes and, when necessary, were confirmed by medical chart audits.

RESULTS: Treatment was modified in 54 cases (26%) and discontinued in 40 (20%). The primary reasons for modifying treatment were toxicity (n = 22), HRQL considerations (n = 18), and tumor progression (n = 14). The primary reasons for discontinuation of treatment were tumor progression (n = 23), HRQL considerations (n = 6), and toxicity (n = 3). For eight patients, a combination of tumor progression and HRQL issues resulted in discontinuation of treatment. Treatment decisions were associated significantly with physicians’ global ratings of patients’ HRQL but not with more specific HRQL domains. In the presence of tumor progression or serious toxicity, HRQL considerations played little or no role in treatment decisions. Furthermore, approximately 70% of patients without evidence of tumor progression or toxicity, but with seriously impaired HRQL, continued to receive their treatment as planned.

CONCLUSION: Contrary to previous findings based on physicians’ self-report data, HRQL considerations seem to play a relatively minor role in decisions regarding modification or discontinuation of palliative chemotherapy.
Novel Artificial Neural Network for Early Detection of Prostate Cancer
Authors: Djavan Bob , Remzi Mesut , Zlotta Alexandre , Seitz Christian , Snow Peter , Marberger Michael
Published: February 2017

PURPOSE: Two artificial neural networks (ANN) for the early detection of prostate cancer in men with total prostate-specific antigen (PSA) levels from 2.5 to 4 ng/mL and from 4 to 10 ng/mL were prospectively developed. The predictive accuracy of the ANN was compared with that obtained by use of conventional statistical analysis of standard PSA parameters.

PATIENTS AND METHODS: Consecutive men with a serum total PSA level between 4 and 10 ng/mL (n = 974) and between 2.5 and 4 ng/mL (n = 272) were analyzed. A separate ANN model was developed for each group of patients. Analyses were performed to determine the presence of prostate cancer.

RESULTS: The area under the receiver operator characteristic (ROC) curve (AUC) was 87.6% and 91.3% for the 2.5 to 4 ng/mL and 4 to 10 ng/mL ANN models, respectively. For the latter model, the AUC generated by the ANN was significantly higher than that produced by the single variables of total PSA, percentage of free PSA, PSA density of the transition zone (TZ), and TZ volume (P < .01), but not significantly higher compared with multivariate analysis. For the 2.5 to 4 ng/mL model, the AUC of the ANN ROC curve was significantly higher than the AUCs for percentage of free PSA (P = .0239), PSA-TZ (P = .0204), and PSA density and total prostate volume (P < .01 for both).

CONCLUSION: The predictive accuracy of the ANN was superior to that of conventional PSA parameters. ANN models might change the way patients referred for early prostate cancer detection are counseled regarding the need for prostate biopsy.
Age, Sex, and Racial Differences in the Use of Standard Adjuvant Therapy for Colorectal Cancer
Authors: Potosky Arnold L. , Harlan Linda C. , Kaplan Richard S. , Johnson Karen A. , Lynch Charles F.
Published: February 2017

PURPOSE: Dissemination of efficacious adjuvant therapies for resectable colorectal cancer has not been comprehensively described. Trends, patterns, and outcomes of adjuvant therapy for colorectal cancer, focusing on age, sex, and racial/ethnic differences, are reported.

MATERIALS AND METHODS: Population-based random samples of patients diagnosed with colorectal cancer diagnosed in nine geographic areas were collected annually between 1987 and 1991 and in 1995 (n = 4,706). Data were obtained from medical record reviews. Multiple logistic regression was used to assess the use of standard adjuvant chemotherapy for colon and rectal cancers. The Cox proportional hazards model was used to assess 9-year mortality.

RESULTS: From 1987 until 1995, the use of adjuvant therapy increased in all age groups. There was an increase starting in 1989 for colon and in 1988 for rectal cancer. Use of standard therapy was 78% for those younger than 55 years and 24% for those older than 80 years. White patients received standard therapy more frequently than African-Americans (odds ratio, 1.75; 95% confidence interval [CI], 1.09 to 2.83). All-cause and cancer-specific mortality exceeding 9 years were lower in those who received standard therapy (all-cause risk ratio [RR], 0.73; 95% CI, 0.61 to 0.88; cancer-specific RR, 0.87; 95% CI, 0.70 to 1.09).

CONCLUSION: Standard adjuvant therapies for colorectal cancer disseminated into community practices during the 1990s. However, evidence exists of differential use of therapies by older patients and by African-Americans. The use of standard therapies in the general population is associated with lower mortality. Improved dissemination of standard adjuvant therapies to all segments of the population could help reduce mortality.
Marginal Decrease in Mortality and Marked Increase in Incidence as a Result of Neuroblastoma Screening at 6 Months of Age: Cohort Study in Seven Prefectures in Japan
Authors: Yamamoto Keiko , Ohta Shigeru , Ito Etsuro , Hayashi Yutaka , Asami Tadashi , Mabuchi Osamu , Higashigawa Masamune , Tanimura Masako
Published: February 2017

PURPOSE: To determine the usefulness of 6-month screening for neuroblastoma.

PATIENTS AND METHODS: The cumulative incidence rates (IRs) and cumulative mortality rates (MRs) of neuroblastoma in children younger than 60 months of age were analyzed for control (n = 713,025), qualitative screening (Qual Screen, n = 1,142,519), and quantitative screening (Quan Screen, n = 550,331) cohorts, and for Screened and Unscreened subgroups within screening cohorts.

RESULTS: IRs (per 100,000) for infants aged 6 to 11 months were 1.12 in Control, 5.69 in Qual Screen (P < .0001), and 17.81 in Quan Screen (P < .0001); IRs for children aged 12 to 59 months were 7.29 in Control, 5.86 in Qual Screen (P = .28), and 6.36 in Quan Screen (P = .60). IRs for children aged 12 to 59 months in Unscreened or Screened subgroups remained at the same level. When patients diagnosed at younger than 6 months of age were excluded, the MR (per 100,000) under 60 months for Control was 4.21; those in Unscreened and Screened subgroups were 3.84 and 2.53 in Qual Screen (P = .30), and 3.20 and 1.97 in Quan Screen (P = .73), respectively; MRs between Control and Unscreened subgroups revealed no significant differences (P = .89 in Qual Screen, P = .85 in Quan Screen).

CONCLUSION: Six-month screening resulted in a marked increase in incidence for infants with no significant decrease in incidence for children older than 1 year of age. A decrease in mortality was observed, but it was not significant. The usefulness of screening is questionable, because the decrease of mortality should be balanced against the adverse effect of overdiagnosis and the psychological burden on parents and children.
Incidence and Prognostic Significance of Complete Axillary Downstaging After Primary Chemotherapy in Breast Cancer Patients With T1 to T3 Tumors and Cytologically Proven Axillary Metastatic Lymph Nodes
Authors: Rouzier Roman , Extra Jean-Marc , Klijanienko Jerzy , Falcou Marie-Christine , Asselain Bernard , Vincent-Salomon Anne , Vielh Philippe , Bourstyn Edwige
Published: February 2017

PURPOSE: To determine the incidence and prognostic significance of eradication of cytologically proven axillary lymph node metastases in breast cancer patients treated with primary chemotherapy.

PATIENTS AND METHODS: Between January 1985 and December 1994, 152 breast cancer patients with invasive T1 to T3 tumors and axillary metastases cytologically proven by fine-needle sampling underwent primary chemotherapy followed by lumpectomy or mastectomy, level I and II axillary lymph node dissection, and irradiation. We studied pathologic complete responses (pCRs) of axillary nodes and breast tumors, as well as predictors of distant metastases.

RESULTS: Thirty-five patients (23%) had axillary pCRs, and 20 patients (13.2%) had pCRs of primary breast tumors. Scarff-Bloom-Richardson grade 3 tumors (P = .04) and a clinical response to chemotherapy ≥ 50% (P = .003) were associated with negative axillary status at dissection. An initial tumor size ≤ 3 cm (63 patients) was associated with pCR of the primary tumor (P = .02) but not with complete histologic clearance of axillary lymph nodes. The median length of follow-up was 75 months. In the univariate analysis, age greater than 40 years (P = .003), absence of residual nodal disease (P = .01), and pCR of the tumor (P = .05) were associated with better distant disease-free survival. Five-year distant disease-free survival rates were 73.5% ± 14.9% among patients with no involved nodes at the time of surgery and 48.7% ± 9.2% among patients with residual nodal disease. In the multivariate Cox regression analysis, parameters associated with poor distant disease-free survival were age ≤ 40 years (P = .002), persistence of nodal involvement (P = .03), and S-phase fraction greater than 4% (P = .02).

CONCLUSION: Our results suggest that axillary status is a better prognostic factor than response of the primary tumor to primary chemotherapy.