bluuebunny/crossref_metadata_2025 huggingface dataset:
Interferon Alfa Consolidation After Intensive Chemotherapy Does Not Prolong the Progression-Free Survival of Patients With Low-Grade Non-Hodgkin’s Lymphoma: Results of the Southwest Oncology Group Randomized Phase III Study 8809
Authors: Fisher Richard I. , Dana Bruce W. , LeBlanc Michael , Kjeldsberg Carl , Forman Jeffrey D. , Unger Joseph M. , Balcerzak Stanley P. , Gaynor Ellen R. , Roy Vivek , Miller Thomas
Published: February 2017

PURPOSE: S8809 is a randomized phase III trial determining whether intensive cytoreductive treatment, followed by interferon consolidation at the time of minimal residual disease, prolongs the progression-free survival (PFS) or overall survival (OS) of indolent lymphoma patients.

PATIENTS AND METHODS: Five hundred seventy-one patients with previously untreated stage III or IV low-grade non-Hodgkin’s lymphoma were registered. Patients received six to eight cycles of prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide/mechlorethamine, vincristine, procarbazine, and prednisone (ProMACE[day 1]-MOPP[day 8]) chemotherapy or chemotherapy plus radiotherapy. Responding patients were randomized to observation alone or to interferon consolidation. Interferon alfa-2b 2 mU/m2 was given subcutaneously three times weekly for 2 years.

RESULTS: Two hundred sixty-eight eligible patients were randomized to interferon alfa consolidation (n = 144) or observation alone (n = 124). With a median follow-up time from randomization among patients still alive of 6.2 years, the median PFS time was 4.1 years for patients who received interferon consolidation therapy and 3.2 years for patients who were observed after ProMACE-MOPP induction (P = .25). The adjusted hazard ratio for relapse for observation to interferon was 0.83 (95% confidence interval [CI], 0.61 to 1.13). The median OS has not been reached in either group. At 5 years, OS is 78% for the interferon group and 77% for the observation group (P = .65). The adjusted hazard ratio for survival for observation to interferon is 1.11 (95% CI, 0.69 to 1.79).

CONCLUSION: Interferon alfa consolidation therapy after intensive treatment with anthracycline-containing combination chemotherapy and involved-field radiation therapy does not prolong the PFS or OS of patients with low-grade non-Hodgkin’s lymphoma.
Prognostic Value of Histologic Grade and Proliferative Activity in Axillary Node–Positive Breast Cancer: Results From the Eastern Cooperative Oncology Group Companion Study, EST 4189
Authors: Simpson Jean F. , Gray Robert , Dressler Lynn G. , Cobau Charles D. , Falkson Carla I. , Gilchrist Kennedy W. , Pandya Kishan J. , Page David L. , Robert Nicholas J.
Published: February 2017

PURPOSE: The identification of a subset of patients with axillary lymph node–positive breast cancer with an improved prognosis would be clinically useful. We report the prognostic importance of histologic grading and proliferative activity in a cohort of patients with axillary lymph node–positive breast cancer and compare these parameters with other established prognostic factors.

PATIENTS AND METHODS: This Eastern Cooperative Oncology Group laboratory companion study (E4189) centered on 560 axillary lymph node–positive patients registered onto one of six eligible clinical protocols. Flow cytometric (ploidy and S-phase fraction [SPF]) and histopathologic analyses (Nottingham Combined Histologic Grade and mitotic index) were performed on paraffin-embedded tissue from 368 patients.

RESULTS: Disease recurred in 208 patients; in 161 (77%), within the first 5 years. Mitotic index and grade were associated with both ploidy and SPF (P ≤ .01). Within the first 5 years of follow-up, mitotic index (P = .004), grade (P = .004), ploidy (P = .006), and SPF (P = .05) were associated with time to recurrence; there was also a significant association with survival. The effect of mitotic index was largely a result of the difference between 0 to 2 mitoses/10 high-power fields (HPF; 5-year recurrence of 31%) and more than 2 mitoses/10 HPF (5-year recurrence of 52%). The 0 to 2 mitoses/10 HPF group was independently associated with improved prognosis at 5 years (P = .002) in regression models that included other standard prognostic factors.

CONCLUSION: A subset of axillary lymph node–positive patients with improved prognosis may be identified using a lower (< 3 mitoses/10 HPF) mitotic count than is usually performed.
Evaluation of the Predictive Value of Her-2/neu Overexpression and p53 Mutations in High-Risk Primary Breast Cancer Patients Treated With High-Dose Chemotherapy and Autologous Stem-Cell Transplantation
Authors: Nieto Yago , Cagnoni Pablo J. , Nawaz Samia , Shpall Elizabeth J. , Yerushalmi Ronit , Cook Bret , Russell Peggy , McDermit Janet , Murphy James , Bearman Scott I. , Jones Roy B.
Published: February 2017

PURPOSE: To ascertain the predictive value of Her-2/neu overexpression and p53 mutations, assessed by immunohistochemistry, in high-risk primary breast cancer (HRPBC) treated with high-dose chemotherapy (HDCT).

PATIENTS AND METHODS: We obtained paraffin-embedded tumor blocks from 146 HRPBC patients previously enrolled at our program onto clinical trials of HDCT for four to nine involved axillary lymph nodes, ≥ 10 involved axillary nodes, or inflammatory carcinoma. All patients received the same HDCT regimen, with cyclophosphamide, cisplatin, and carmustine (STAMP-I), followed by autologous stem-cell transplantation. Median follow-up was 42 months (range, 5 to 90 months). The same pathologist, blinded to clinical outcome, reviewed all immunostained slides.

RESULTS: Positive results for Her-2/neu and p53 were found in 44.5% and 34% of the patients, respectively. Positivity for Her-2/neu was significantly associated with increased risk of relapse and death. No correlation was found between p53 mutations and relapse-free survival (RFS) or overall survival (OS). Multivariate analyses included Her-2/neu overexpression and the following variables previously identified as independent predictors of outcome in this population: tumor size, nodal ratio (number of involved nodes/number of dissected nodes), and hormone receptor status. All four variables had independent value.

CONCLUSION: Her-2/neu overexpression is an independent negative predictor of RFS and OS in HRPBC treated with HDCT. Its inclusion in our previously described predictive model increases the predictive capacity of this model for the low-risk subgroup. In contrast, p53 mutations lack predictive value in this setting.
Anticipated Versus Actual Emotional Reactions to Disclosure of Results of Genetic Tests for Cancer Susceptibility: Findings From p53 and BRCA1 Testing Programs
Authors: Dorval Michel , Patenaude Andrea Farkas , Schneider Katherine A. , Kieffer Stephanie A. , DiGianni Lisa , Kalkbrenner Kathy J. , Bromberg Jonas I. , Basili Laura A. , Calzone Kathleen , Stopfer Jill , Weber Barbara L. , Garber Judy E.
Published: February 2017

PURPOSE: We examined the ability of individuals undergoing genetic testing for cancer susceptibility in two structured research protocols to accurately anticipate emotional reactions to disclosure of their test result. We explored whether accuracy of emotional anticipation was associated with postdisclosure psychologic adjustment.

METHODS: Data from 65 individuals were analyzed; 24 members of Li-Fraumeni cancer syndrome families were tested for p53 mutations (all 24 were unaffected), and 41 subjects with hereditary breast-ovarian cancer susceptibility were tested for BRCA1 mutations (34 were unaffected and seven were affected). Subjects were from families in which a germline mutation had been previously identified. At the pretest session, subjects rated the extent to which they anticipated feeling each of six emotional states (relief, happiness, sadness, guilt, anger, and worry) after disclosure that they did or did not carry the familial mutation. After receiving their test result, they rated their feelings on the same scale of emotions for the appropriate condition. Extent of accuracy and association with psychologic distress at 6 months, as assessed with standardized measures, were evaluated.

RESULTS: Overall, mean levels of emotional reactions after receiving test results were not different from those anticipated before result disclosure. However, affected BRCA1 carriers experienced higher levels of anger and worry than they had anticipated. Underestimation of subsequent distress emotions related to test result was associated with a significant increase in general psychologic distress at 6 months.

CONCLUSION: Unaffected individuals in cancer-predisposition testing programs are generally accurate in anticipating emotional reactions to test results. However, cancer patients may underestimate their distress after disclosure of positive results and could benefit from intervention strategies.
Population-Based Molecular Detection of Hereditary Nonpolyposis Colorectal Cancer
Authors: Salovaara Reijo , Loukola Anu , Kristo Paula , Kääriäinen Helena , Ahtola Heikki , Eskelinen Matti , Härkönen Niilo , Julkunen Risto , Kangas Eero , Ojala Seppo , Tulikoura Jukka , Valkamo Erkki , Järvinen Heikki , Mecklin Jukka-Pekka , Aaltonen Lauri A. , de la Chapelle Albert
Published: February 2017

PURPOSE: Cancer morbidity and mortality can be dramatically reduced by colonoscopic screening of individuals with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, creating a need to identify HNPCC. We studied how HNPCC identification should be carried out on a large scale in a sensitive and efficient manner.

PATIENTS AND METHODS: Colorectal cancer specimens from consecutive newly diagnosed patients were studied for microsatellite instability (MSI). Germline mutations in the MLH1 and MSH2 genes were searched for in MSI(+) individuals.

RESULTS: Among 535 colorectal cancer patients, 66 (12%) were MSI(+). Among these, 18 (3.4% of the total) had disease-causing germline mutations in MLH1 or MSH2. Among these 18 patients, five were less than 50 years old, seven had a previous or synchronous colorectal or endometrial cancer, and 15 had at least one first-degree relative with colorectal or endometrial cancer. Notably, 17 (94%) of 18 patients had at least one of these three features, which were present in 22% of all 535 patients. Combining these data with a previous study of 509 patients, mutation-positive HNPCC accounts for 28 (2.7%) of 1,044 cases of colorectal cancer, predicting a greater than one in 740 incidence of mutation-positive individuals in this population.

CONCLUSION: Large-scale molecular screening for HNPCC can be done by the described two-stage procedure of MSI determination followed by mutation analysis. Efficiency can be greatly improved by using three high-risk features to select 22% of all patients for MSI analysis, whereby only 6% need to have mutation analysis. Sensitivity is only slightly impaired by this procedure.
Escalated Focal Liver Radiation and Concurrent Hepatic Artery Fluorodeoxyuridine for Unresectable Intrahepatic Malignancies
Authors: Dawson Laura A. , McGinn Cornelius J. , Normolle Daniel , Ten Haken Randall K. , Walker Suzette , Ensminger William , Lawrence Theodore S.
Published: February 2017

PURPOSE: To evaluate the response, time to progression, survival, and impact of radiation (RT) dose on survival in patients with intrahepatic malignancies treated on a phase I trial of escalated focal liver RT.

PATIENTS AND METHODS: From April 1996 to January 1998, 43 patients with unresectable intrahepatic hepatobiliary cancer (HB; 27 patients) and colorectal liver metastases (LM; 16 patients) were treated with high-dose conformal RT. The median tumor size was 10 × 10 × 8 cm. The median RT dose was 58.5 Gy (range, 28.5 to 90 Gy), 1.5 Gy twice daily, with concurrent continuous-infusion hepatic arterial fluorodeoxyuridine (0.2 mg/kg/d) during the first 4 weeks of RT.

RESULTS: The response rate in 25 assessable patients was 68% (16 partial and one complete response). With a median potential follow-up period of 26.5 months, the median times to progression for all tumors, LM, and HB were 6, 8, and 3 months, respectively. The median survival times of all patients, patients with LM, and patients with HB were 16, 18, and 11 months, respectively. On multivariate analyses, escalated RT dose was independently associated with improved progression-free and overall survival. The median survival of patients treated with 70 Gy or more has not yet been reached (16.4+ months), compared with 11.6 months in patients treated with lower RT doses (P = .0003).

CONCLUSION: The excellent response rate, prolonged intrahepatic control, and improved survival in patients treated with RT doses of 70 Gy or more motivate continuation of dose-escalation studies for patients with intrahepatic malignancies.
Phase I Trial of the Anti–Lewis Y Drug Immunoconjugate BR96-Doxorubicin in Patients With Lewis Y–Expressing Epithelial Tumors
Authors: Saleh Mansoor N. , Sugarman Steve , Murray James , Ostroff Joy B. , Healey Diane , Jones Dennie , Daniel Carol R. , LeBherz Donna , Brewer Hannah , Onetto Nicole , LoBuglio Albert F.
Published: February 2017

PURPOSE: We conducted a phase I clinical trial of BR96-Doxorubicin (BR96-Dox), a chimeric anti–Lewis Y (LeY) monoclonal antibody conjugated to doxorubicin, in patients whose tumors expressed the LeY antigen. The study aimed to determine the toxicity, maximum-tolerated dose, pharmacokinetics, and immunogenicity of BR96-Dox.

PATIENTS AND METHODS: This was a phase I dose escalation study. BR96-Dox was initially administered alone as a 2-hour infusion every 3 weeks. The occurrence of gastrointestinal (GI) toxicity necessitated the administration of BR96-Dox as a continuous infusion over 24 hours and use of antiemetics and antigastritis premedication. Patients experiencing severe GI toxicity underwent GI endoscopy. All patients underwent restaging after two cycles.

RESULTS: A total of 66 patients predominantly with metastatic colon and breast cancer were enrolled onto the study. The most common side effects were GI toxicity, fever, and elevation of pancreatic lipase. At higher doses, BR96-Dox was associated with nausea, vomiting, and endoscopically documented exudative gastritis of the upper GI tract, which was dose-limiting at a maximum dose of 875 mg/m2 (doxorubicin equivalent, 25 mg/m2) administered every 3 weeks. Toxicity was reversible and generally of short duration. Premedication with the antiemetic Kytril (granisetron hydrochloride; SmithKline Beecham, Philadelphia, PA), the antacid omeprazole, and dexamethasone was most effective in ameliorating GI toxicity. A dose of 700 mg/m2 BR96-Dox (doxorubicin equivalent, 19 mg/m2) every 3 weeks was determined to be the optimal phase II dose when administered with antiemetic and antigastritis prophylaxis. BR96-Dox deposition on tumor tissue was documented immunohistochemically and by confocal microscopy. At the 550-mg/m2 dose, the half-life (mean ± SD) of BR96 and doxorubicin was 300 ± 95 hours and 43 ± 4 hours, respectively. BR96-Dox elicited a weak immune response in 37% of patients. Objective clinical responses were seen in two patients.

CONCLUSION: BR96-Dox provides a unique strategy to deliver doxorubicin to LeY-expressing tumor and was well tolerated at doses of 700 mg/m2 every 3 weeks. BR96-Dox was not associated with the typical side-effect profile of native doxorubicin and can potentially deliver high doses of doxorubicin to antigen-expressing tumors. A phase II study in doxorubicin-sensitive tumors is warranted.
Psychiatric Side Effects of Interferon Therapy: Prevalence, Proposed Mechanisms, and Future Directions
Authors: Trask Peter C. , Esper Peg , Riba Michelle , Redman Bruce
Published: February 2017

ABSTRACT: The increasing use of interferon (IFN) in treating a variety of disorders including, malignant melanoma and hepatitis C, has resulted in the identification and increasing concern about the psychiatric side effects that can result from treatment. These effects can occur either shortly after beginning IFN therapy or later as a result of continued treatment. Studies have reported the incidence of later side effects, which include symptoms of depression, anxiety, and occasional suicidal ideation, to be from 0% to 70%. Case studies have demonstrated that pharmacologic interventions are beneficial in reducing iatrogenic psychiatric symptoms while allowing patients to maintain IFN therapy. The present article provides an overview of the psychiatric effects of IFN therapy, the proposed mechanisms of these side effects, and case studies that provide mechanistic support. In addition, limitations of the current literature are provided with suggestions for treating physicians and a discussion of possible future research directions.
Complementary/Alternative Medicine Use in a Comprehensive Cancer Center and the Implications for Oncology
Authors: Richardson Mary Ann , Sanders Tina , Palmer J. Lynn , Greisinger Anthony , Singletary S. Eva
Published: February 2017

PURPOSE: Oncologists are aware that their patients use complementary/alternative medicine (CAM). As cancer incidence rates and survival time increase, use of CAM will likely increase. This study assessed the prevalence and predictors of CAM use in a comprehensive cancer center.

SUBJECTS AND METHODS: Subjects were English-speaking cancer patients at least 18 years of age, attending one of eight outpatient clinics at The University of Texas M.D. Anderson Cancer Center, Houston, TX, between December 1997 and June 1998. After giving written informed consent, participants completed a self-administered questionnaire. Differences between CAM users and nonusers were assessed by χ2 and univariate logistic regression analysis. A multivariate logistic regression model identified the simultaneous impact of demographic, clinical, and treatment variables on CAM use; P values were two-sided.

RESULTS: Of the 453 participants (response rate, 51.4%), 99.3% had heard of CAM. Of those, 83.3% had used at least one CAM approach. Use was greatest for spiritual practices (80.5%), vitamins and herbs (62.6%), and movement and physical therapies (59.2%) and predicted (P < .001) by sex (female), younger age, indigent pay status, and surgery. After excluding spiritual practices and psychotherapy, 95.8% of participants were aware of CAM and 68.7% of those had used CAM. Use was predicted (P < .0001) by sex (female), education, and chemotherapy.

CONCLUSION: In most categories, CAM use was common among outpatients. Given the number of patients combining vitamins and herbs with conventional treatments, the oncology community must improve patient-provider communication, offer reliable information to patients, and initiate research to determine possible drug-herb-vitamin interactions.
Use of Complementary/Alternative Medicine by Breast Cancer Survivors in Ontario: Prevalence and Perceptions
Authors: Boon Heather , Stewart Moira , Kennard Mary Ann , Gray Ross , Sawka Carol , Brown Judith Belle , McWilliam Carol , Gavin Alan , Baron Ruth Anne , Aaron Dorothy , Haines-Kamka Theresa
Published: February 2017

PURPOSE: To determine the prevalence of use of complementary/alternative medicine (CAM) by breast cancer survivors in Ontario, Canada, and to compare the characteristics of CAM users and CAM nonusers.

PATIENTS AND METHODS: A questionnaire was mailed to a random sample of Ontario women diagnosed with breast cancer in 1994 or 1995.

RESULTS: The response rate was 76.3%. Overall, 66.7% of the respondents reported using CAM, most often in an attempt to boost the immune system. CAM practitioners (most commonly chiropractors, herbalists, acupuncturists, traditional Chinese medicine practitioners, and/or naturopathic practitioners) were visited by 39.4% of the respondents. In addition, 62.0% reported use of CAM products (most frequently vitamins/minerals, herbal medicines, green tea, special foods, and essiac). Almost one half of the respondents informed their physicians of their use of CAM. Multiple logistic regression analysis determined that support group attendance was the only factor significantly associated with CAM use.

CONCLUSION: CAM use is common among Canadian breast cancer survivors, many of whom are discussing CAM therapy options with their physicians. Knowledge of CAM therapies is necessary for physicians and other health care practitioners to help patients make informed choices. CAM use may play a role in the positive benefits associated with support group attendance.
Southwest Oncology Group Study of Paclitaxel and Carboplatin for Advanced Transitional-Cell Carcinoma: The Importance of Survival as a Clinical Trial End Point
Authors: Small Eric J. , Lew Danika , Redman Bruce G. , Petrylak Daniel P. , Hammond Neel , Gross Howard M. , Eastham James A. , Crawford E. David
Published: February 2017

PURPOSE: The combination of paclitaxel and carboplatin for the treatment of advanced transitional-cell carcinoma (TCC) of the urothelium has promising activity and acceptable toxicity. The purpose of this trial was to evaluate the efficacy of this regimen in a cooperative group setting.

PATIENTS AND METHODS: Twenty-nine patients with advanced TCC were treated every 21 days with paclitaxel 200 mg/m2, administered as a 3-hour infusion, followed by carboplatin dosed to an area under the curve of 5. Prior systemic adjuvant or neoadjuvant platinum-based therapy was not permitted unless completed at least 1 year before enrollment. Patients were evaluated for response every three cycles, and follow-up was conducted to determine survival.

RESULTS: Twenty-nine patients were enrolled and were assessable. Four (14%) had received prior adjuvant or neoadjuvant therapy. Node-only disease was present in 24%, and 76% of patients had extranodal disease. The median number of cycles received was five. Grade 4 toxicity consisted primarily of neutropenia (38% of patients). Neurologic toxicity was noted in 16 patients (grade 1 in four patients, grade 2 in five patients, grade 3 in six patients, and grade 4 in one patient). Six partial responses and no complete responses were noted, for a response proportion of 20.7% (95% confidence interval, 8% to 40%). Median progression-free survival time was 4 months, and overall survival time was 9 months.

CONCLUSION: The combination of paclitaxel and carboplatin for the treatment of advanced TCC is reasonably well tolerated. However, a response proportion considerably lower than that previously reported was noted. In addition, the median survival time of 9 months was less than the survival time previously reported for patients treated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin. Although our results may reflect enrollment of patients with poor prognostic features, they also call into question the utility of this regimen.
Randomized Comparison of Cisplatin/Vincristine/Fluorouracil and Cisplatin/Continuous Infusion Doxorubicin for Treatment of Pediatric Hepatoblastoma: A Report From the Children’s Cancer Group and the Pediatric Oncology Group
Authors: Ortega Jorge A. , Douglass Edwin C. , Feusner James H. , Reynolds Marleta , Quinn John J. , Finegold Milton J. , Haas Joel E. , King Denis R. , Liu-Mares Wen , Sensel Martha G. , Krailo Mark D.
Published: February 2017

PURPOSE: Previous studies demonstrated that chemotherapy with either cisplatin, vincristine, and fluorouracil (regimen A) or cisplatin and continuous infusion doxorubicin (regimen B) improved survival in children with hepatoblastoma. The current trial is a randomized comparison of these two regimens.

PATIENTS AND METHODS: Patients (N = 182) were enrolled onto study between August 1989 and December 1992. After initial surgery, patients with stage I–unfavorable histology (UH; n = 43), stage II (n = 7), stage III (n = 83), and stage IV (n = 40) hepatoblastoma were randomized to receive regimen A (n = 92) or regimen B (n = 81). Patients with stage I–favorable histology (FH; n = 9) were treated with four cycles of doxorubicin alone.

RESULTS: There were no events among patients with stage I-FH disease. Five-year event-free survival (EFS) estimates were 57% (SD = 5%) and 69% (SD = 5%) for patients on regimens A and B, respectively (P = .09) with a relative risk of 1.54 (95% confidence interval, 0.93 to 2.5) for regimen A versus B. Toxicities were more frequent on regimen B. Patients with stage I-UH, stage II, stage III, or stage IV disease had 5-year EFS estimates of 91% (SD = 4%), 100%, 64% (SD = 5%), and 25% (SD = 7%), respectively. Outcome was similar for either regimen within disease stages. At postinduction surgery I, patients with stage III or IV disease who were found to be tumor-free had no events; those who had complete resections achieved a 5-year EFS of 83% (SD = 6%); other patients with stage III or IV disease had worse outcome.

CONCLUSION: Treatment outcome was not significantly different between regimen A and regimen B. Excellent outcome was achieved for patients with stage I-UH and stage II hepatoblastoma and for subsets of patients with stage III disease. New treatment strategies are needed for the majority of patients with advanced-stage hepatoblastoma.
Sentinel Lymph Node Procedure Is Highly Accurate in Squamous Cell Carcinoma of the Vulva
Authors: de Hullu J.A. , Hollema H. , Piers D.A. , Verheijen R.H. M. , van Diest P.J. , Mourits M.J. E. , Aalders J.G. , van der Zee A.G. J.
Published: February 2017

PURPOSE: To determine the diagnostic accuracy of the sentinel lymph node procedure in patients with squamous cell carcinoma of the vulva and to investigate whether step sectioning and immunohistochemistry of sentinel lymph nodes increase the sensitivity for detection of metastases.

PATIENTS AND METHODS: Between July 1996 and July 1999, 59 patients with primary vulvar cancer were entered onto a two-center prospective study. All patients underwent sentinel lymph node procedure with the combined technique (preoperative lymphoscintigraphy with technetium-99m–labeled nanocolloid and intraoperative blue dye). Radical excision of the primary tumor with uni- or bilateral inguinofemoral lymphadenectomy was performed subsequently. Sentinel lymph nodes and lymphadenectomy specimens were sent for histopathologic examination separately. Sentinel lymph nodes, negative at the time of routine pathologic examination, were re-examined with step sectioning and immunohistochemistry.

RESULTS: In 59 patients, 107 inguinofemoral lymphadenectomies were performed (11 unilateral and 48 bilateral). All sentinel lymph nodes, as observed on preoperative lymphoscintigram, were identified successfully intraoperatively. Routine histopathologic examination showed lymph node metastases in 27 groins, all of which were detected by the sentinel lymph node procedure. The negative predictive value for a negative sentinel lymph node was 100% (97.5% confidence interval [CI], 95% to 100%). Step sectioning and immunohistochemistry showed four additional metastases in 102 sentinel lymph nodes (4%; 95% CI, 1% to 9%) that were negative at the time of routine histopathologic examination.

CONCLUSION: Sentinel lymph node procedure with the combined technique is highly accurate in predicting the inguinofemoral lymph node status in patients with early-stage vulvar cancer. Future trials should focus on the safe clinical implementation of the sentinel lymph node procedure in these patients. Step sectioning and immunohistochemistry slightly increase the sensitivity of detecting metastases in sentinel lymph nodes and should be included in these trials.
Enhancement of Platelet Recovery After Myelosuppressive Chemotherapy by Recombinant Human Megakaryocyte Growth and Development Factor in Patients With Advanced Cancer
Authors: Basser Russell L. , Underhill Craig , Davis Ian , Green Michael D. , Cebon Jonathan , Zalcberg John , MacMillan Jamie , Cohen Brian , Marty Jennifer , Fox Richard M. , Begley C. Glenn
Published: February 2017

PURPOSE: To explore the influence of dose and schedule on the ability of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) to abrogate thrombocytopenia after multiple cycles of chemotherapy and to mobilize peripheral-blood progenitor cells (PBPC).

PATIENTS AND METHODS: In this open-label study, 68 patients with advanced cancer were randomized to receive PEG-rHuMGDF subcutaneously at different doses and durations before administration of carboplatin 600 mg/m2, cyclophosphamide 1,200 mg/m2, and filgrastim 5 μg/kg/d. PEG-rHuMGDF was not given after the first cycle of chemotherapy but was given after the second and subsequent cycles. Chemotherapy was given every 28 days for up to six cycles.

RESULTS: In patients who received the same dose of chemotherapy for at least two cycles, the platelet nadir was significantly higher (47.5 × 109/L v 35.5 × 109/L; P = .003) and duration of grade 3 or 4 thrombocytopenia significantly shorter (0 v 3 days; P = .004) when PEG-rHuMGDF was administered after chemotherapy. There was no evidence of an effect of PEG-rHuMGDF when it was given before chemotherapy. Platelet recovery after the first cycle of chemotherapy was no different for different PEG-rHuMGDF regimens, and there was no difference between patients treated with PEG-rHuMGDF and historical controls treated with identical chemotherapy. There was a modest dose-related increase in progenitor cell levels after administration of PEG-rHuMGDF alone. Peak levels of PBPC occurred later in cycle 2 than in cycle 1 but were not different in magnitude.

CONCLUSION: PEG-rHuMGDF abrogated severe thrombocytopenia after dose-intensive chemotherapy. However, it had only a modest effect on progenitor cell levels and did not enhance progenitor cell mobilization after chemotherapy and filgrastim.
Multicenter Phase II Study to Evaluate a 28-Day Regimen of Oral Fluorouracil Plus Eniluracil in the Treatment of Patients With Previously Untreated Metastatic Colorectal Cancer
Authors: Mani Sridhar , Hochster Howard , Beck Thomas , Chevlen Eric M. , O’Rourke Mark A. , Weaver Charles H. , Bell William N. , White Robin , McGuirt Chip , Levin Jeremey , Hohneker John , Schilsky Richard L. , Lokich Jacob
Published: February 2017

PURPOSE: To determine the efficacy of fluorouracil (5-FU) plus eniluracil when administered to patients with previously untreated metastatic colorectal cancer.

PATIENTS AND METHODS: In this single-arm phase II study, patients with previously untreated metastatic colorectal cancer received oral eniluracil plus 5-FU (10:1 dose ratio), at 5-FU doses of 1.00 mg/m2or 1.15 mg/m2twice daily (every 12 hours) for 28 consecutive days repeated every 5 weeks (one cycle). Treatment continued until there was documented disease progression or unacceptable toxicity.

RESULTS: Thirty and 25 patients were enrolled at a starting dose of 1.00 mg/m2and 1.15 mg/m2, respectively. Fourteen (25%) of 55 patients (95% confidence interval, 15% to 39%) had a partial response, and 20 patients (36%) had stable disease. The median durations of the partial responses and stable disease were 23.9 weeks (range, 12.3 to 52.1+ weeks) and 24.1 weeks (range, 17.1 to 55.6+ weeks), respectively. The median durations of progression-free and overall survival were 22.6 weeks (range, 21.0 to 29.0 weeks) and 59 weeks (range, 4 to 84+ weeks), respectively. The response rate in the 1.15 mg/m2–dose group was similar to the 1.00 mg/m2–dose group (28% v 23%, respectively). Severe (grade 3/4) nonhematologic treatment-related toxicity included diarrhea (nine patients), nausea/vomiting (one patient each), mucositis (two patients), and anorexia (one patient). Severe hematologic toxicities were rare. At the 1.15 mg/m2–dose level, two patients exhibited grade 3 granulocytopenia, and two patients had grade 3 anemia.

CONCLUSION: The response rate with oral 5-FU plus eniluracil is comparable with that observed with infusional 5-FU or bolus 5-FU and leucovorin. The toxicity profile of this oral regimen is acceptable for use in an outpatient home-based setting.
Phase I Study of Paclitaxel, Carboplatin, and Increasing Days of Prolonged Oral Etoposide in Ovarian, Peritoneal, and Tubal Carcinoma: A Gynecologic Oncology Group Study
Authors: Rose Peter G. , Rodriguez Michael , Waggoner Steven , Greer Benjamin E. , Horowitz Ira R. , Fowler Jeffrey M. , McGuire William P.
Published: February 2017

PURPOSE: Given the activity of prolonged oral etoposide in platinum and paclitaxel-resistant ovarian carcinoma, a phase I trial was conducted that combined increasing days of oral etoposide therapy with paclitaxel and carboplatin in chemotherapy-naive patients with ovarian peritoneal and tubal carcinoma to establish a maximum-tolerated dose (MTD) of this combination.

PATIENTS AND METHODS: Paclitaxel at 175 mg/m2 given over 3 hours and carboplatin at an area under the curve of 5 were administered on day 1 followed by oral etoposide 50 mg/m2/d beginning on day 2. The number of days of etoposide therapy was escalated on the basis of toxicity. Toxicity end points included neutropenic sepsis, grade 4 thrombocytopenia, or grade 3 neutropenia or thrombocytopenia during etoposide administration. Cycles were repeated every 21 days for a maximum of six courses. Due to hematologic toxicity, the duration of the paclitaxel infusion was decreased to 1 hour for a second stage of accrual.

RESULTS: Of 52 patients studied, 29 were in the first stage of accrual. Dose-limiting toxicity occurred with 8 days of oral etoposide, making the MTD six days of therapy. Twenty-three patients were entered into the second stage of accrual. Dose-limiting toxicity occurred at 12 days of oral etoposide, making the MTD 10 days of therapy. Three patients developed acute myeloid leukemia 16, 27, and 35 months after receiving a cumulative dose of 200 mg/m2, 1,200 mg/m2, and 2,400 mg/m2, respectively.

CONCLUSION: One-hour paclitaxel, carboplatin, and oral etoposide at 50 mg/m2/d for 10 days is tolerable without supportive therapy. The leukemogenic potential is cause for concern and precludes its use in chemotherapy-naive ovarian carcinoma.
Independent Prognostic Value of Serum Hepatocyte Growth Factor in Bladder Cancer
Authors: Gohji Kazuo , Nomi Masashi , Niitani Yoshiyuki , Kitazawa Sohei , Fujii Akio , Katsuoka Yoji , Nakajima Motowo
Published: February 2017

PURPOSE: We retrospectively investigated whether the level of serum hepatocyte growth factor could predict the prognosis and extent of transitional-cell carcinoma of the urinary bladder.

PATIENTS AND METHODS: Serum samples were collected from 113 patients with bladder cancer and from 200 healthy controls. Of the 113 patients, 59 had superficial bladder cancer and 54 had muscle-invasive cancer. Thirteen bladder cancer tissues (eight superficial and five muscle-invasive) were also collected. The levels of hepatocyte growth factor in the serum and tissues of these individuals were measured by enzyme-linked immunoadsorbent assay using hepatocyte growth factor antibodies.

RESULTS: The levels of hepatocyte growth factor in the serum and tissues of patients with muscle-invasive cancer were significantly higher than those of patients with superficial bladder cancer (P < .0001 and P = .0054, respectively). The degree of elevation above the normal level of serum hepatocyte growth factor of the former (61.1%) was significantly higher than that of the latter (8.4%; P < .0001). The elevation was highest in patients with visceral metastasis (93.3%). Among patients with superficial bladder cancer, the overall survival rate of those with low levels of serum hepatocyte growth factor was significantly greater than that of those with high levels (P = .005). Among patients with minimally invasive bladder cancer, the disease-free and overall survival rates of those with high levels of serum hepatocyte growth factor were significantly lower than the same rates of those with low levels (P < .001 and P = .0028, respectively).

CONCLUSION: Our study suggests that the level of hepatocyte growth factor in serum could be a predictor of patient survival and extent of bladder cancer.
Phase III Trial of Interferon Alfa-2a With or Without 13-cis-Retinoic Acid for Patients With Advanced Renal Cell Carcinoma
Authors: Motzer Robert J. , Murphy Barbara A. , Bacik Jennifer , Schwartz Lawrence H. , Nanus David M. , Mariani Tania , Loehrer Patrick , Wilding George , Fairclough Diane L. , Cella David , Mazumdar Madhu
Published: February 2017

PURPOSE: A randomized phase III trial was conducted to determine whether combination therapy with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFNα2a) is superior to IFNα2a alone in patients with advanced renal cell carcinoma (RCC).

PATIENTS AND METHODS: Two hundred eighty-four patients were randomized to treatment with IFNα2a plus 13-CRA or treatment with IFNα2a alone. IFNα2a was given daily subcutaneously, starting at a dose of 3 million units (MU). The dose was escalated every 7 days from 3 to 9 MU (by increments of 3 MU), unless ≥ grade 2 toxicity occurred, in which case dose escalation was stopped. Patients randomized to combination therapy were given oral 13-CRA 1 mg/kg/d plus IFNα2a. Quality of life (QOL) was assessed.

RESULTS: Complete or partial responses were achieved by 12% of patients treated with IFNα2a plus 13-CRA and 6% of patients treated with IFNα2a (P = .14). Median duration of response (complete and partial combined) in the group treated with the combination was 33 months (range, 9 to 50 months), versus 22 months (range, 5 to 38 months) for the second group (P = .03). Nineteen percent of patients treated with IFNα2a plus 13-CRA were progression-free at 24 months, compared with 10% of patients treated with IFNα2a alone (P = .05). Median survival time for all patients was 15 months, with no difference in survival between the two treatment arms (P = .26). QOL decreased during the first 8 weeks of treatment, and a partial recovery followed. Lower scores were associated with the combination therapy.

CONCLUSION: Response proportion and survival did not improve significantly with the addition of 13-CRA to IFNα2a therapy in patients with advanced RCC. 13-CRA may lengthen response to IFNα2a therapy in patients with IFNα2a-sensitive tumors. Treatment, particularly the combination therapy, was associated with a decrease in QOL.
Survival of Patients With Resected N2 Non–Small-Cell Lung Cancer: Evidence for a Subclassification and Implications
Authors: Andre Fabrice , Grunenwald Dominique , Pignon Jean-Pierre , Dujon Antoine , Pujol Jean Louis , Brichon Pierre Yves , Brouchet Laurent , Quoix Elisabeth , Westeel Virginie , Le Chevalier Thierry
Published: February 2017

PURPOSE: Patients who suffer from non–small-cell lung cancer (NSCLC) with ipsilateral mediastinal lymph node involvement (N2) belong to a heterogeneous subgroup of patients. We analyzed the prognosis of patients with resected N2 NSCLC to propose homogeneous patient subgroups.

PATIENTS AND METHODS: The present study comprised 702 consecutive patients from six French centers who underwent surgical resection of N2 NSCLC. Initially, two groups of patients were defined: patients with clinical N2 (cN2) and those with minimal N2 (mN2) disease were patients in whom N2 disease was and was not detected preoperatively at computed tomographic scan, respectively.

RESULTS: The median duration of follow-up was 52 months (range, 18 to 120 months). A multivariate analysis using Cox regression identified four negative prognostic factors, namely, cN2 status (P < .0001), involvement of multiple lymph node levels (L2+; P < .0001), pT3 to T4 stage (P < .0001), and no preoperative chemotherapy (P < .01). For patients treated with primary surgery, 5-year survival rates were as follows: mN2, one level involved (mN2L1, n = 244): 34%; mN2, multiple level involvement (mN2L2+, n = 78): 11%; cN2L1 (n = 118): 8%; and cN2L2+ (n = 122): 3%. When only patients with mN2L1 disease were considered, the site of lymph node involvement according to the American Thoracic Society numbering system had no prognostic significance (P = .14). Preoperative chemotherapy was associated with a better prognosis for those with cN2 (P < .0001). Five-year survival rates were 18% and 5% for cN2 patients treated with and without preoperative chemotherapy, respectively.

CONCLUSION: This study has identified homogeneous N2 NSCLC prognostic subgroups and suggests different therapeutic approaches according to the subgroup profile.
Incidence of Recurrent Thromboembolic and Bleeding Complications Among Patients With Venous Thromboembolism in Relation to Both Malignancy and Achieved International Normalized Ratio: A Retrospective Analysis
Authors: Hutten Barbara A. , Prins Martin H. , Gent Michael , Ginsberg Jeff , Tijssen Jan G. P. , Büller Harry R.
Published: February 2017

PURPOSE: Initial heparinization followed by vitamin K antagonists is the treatment of choice for patients with venous thromboembolism. There is controversy whether known malignancy is a risk factor for recurrences and bleeding complications during this treatment. Furthermore, the incidence of such events in these patients is dependent on the achieved International Normalized Ratio (INR). The aim of this study was to assess the incidence of venous thromboembolic recurrence and major bleeding among patients with venous thromboembolism in relation to both malignancy and the achieved INR.

PATIENTS AND METHODS: In a retrospective analysis, the INR-specific incidence of venous thromboembolic and major bleeding events during oral anticoagulant therapy was calculated separately for patients with and without malignancy. Eligible patients participated in two multicenter, randomized clinical trials on the initial treatment of venous thromboembolism. Patients were initially treated with heparin (standard or low-molecular weight). Treatment with vitamin K antagonists was started within 1 day and continued for 3 months, with a target INR of 2.0 to 3.0.

RESULTS: In 1,303 eligible patients (264 with malignancy), 35 recurrences and 12 bleeds occurred. Patients with malignancy, compared with nonmalignant patients, had a clinically and statistically significantly increased overall incidence of recurrence (27.1 v 9.0, respectively, per 100 patient-years) as well as bleeding (13.3 v 2.1, respectively, per 100 patient-years). In both groups of patients, the incidence of recurrence was lower when the INR was above 2.0 compared with below 2.0.

CONCLUSION: Although adequately dosed vitamin K antagonists are effective in patients with malignant disease, the incidence of thrombotic and bleeding complications remains higher than in patients without malignancy.
Disease-Free Survival Advantage of Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil in Patients With Node-Negative, Rapidly Proliferating Breast Cancer: A Randomized Multicenter Study
Authors: Amadori Dino , Nanni Oriana , Marangolo Maurizio , Pacini Paolo , Ravaioli Alberto , Rossi Andrea , Gambi Angelo , Catalano Giuseppina , Perroni Davide , Scarpi Emanuela , Giunchi Donata Casadei , Tienghi Amelia , Becciolini Aldo , Volpi Annalisa
Published: February 2017

PURPOSE: According to one of the most recent key scientific questions concerning the use of biomarkers in clinical trials, we investigated whether node-negative breast cancer patients, defined as high-risk cases on the basis of tumor cell proliferation, could benefit from cyclophosphamide, methotrexate, and fluorouracil (CMF) adjuvant therapy.

PATIENTS AND METHODS: Two hundred eighty-one patients with negative nodes and rapidly proliferating tumors, defined according to thymidine labeling index (TLI), were randomized to receive six cycles of CMF or no further treatment after surgery ± radiotherapy.

RESULTS: The 5-year disease-free survival (DFS) was 83% for patients treated with CMF compared with 72% in the control group (P = .028). Adjuvant treatment reduced both locoregional and distant metastases. When clinical outcome was analyzed in cell kinetic subgroups characterized according to tertile criteria, compared with patients in the control arm, 5-year DFS was significantly higher after adjuvant CMF in patients with TLI values in the second (78% v 88%, respectively; P = .037) and third tertiles (58% v 78%, respectively; P = .024).

CONCLUSION: The results from this randomized clinical study indicate that patients with node-negative, rapidly proliferating tumors significantly benefit from adjuvant CMF.
Health-Related Quality of Life in Survivors of Wilms’ Tumor and Advanced Neuroblastoma: A Cross-Sectional Study
Authors: Barr Ronald D. , Chalmers Dawn , De Pauw Sonja , Furlong William , Weitzman Sheila , Feeny David
Published: February 2017

PURPOSE: In pediatric oncology, Wilms’ tumor and advanced neuroblastoma represent opposite ends of the spectra of survival probability and therapeutic intensity. Consequently, it was envisaged that survivors of Wilms’ tumor would enjoy better health status and health-related quality of life (HRQL) than survivors of advanced neuroblastoma.

PATIENTS AND METHODS: Health status questionnaires were sent to the parents of all eligible children and to the children themselves if they were ≥ 8 years of age. Responses were received from 84% of 93 eligible families. Responses were converted by established algorithms into levels of two multiattribute health status classification systems known as Health Utilities Index Mark 2 and Mark 3. These systems are linked to measures of preference, in the form of multiattribute utility functions, which provide scores of morbidity for single-attribute levels and of global HRQL for comprehensive health states.

RESULTS: A greater burden of morbidity was identified in the survivors of advanced neuroblastoma than in survivors of Wilms’ tumor based on the assessments of the parents of these children. In particular, survivors of advanced neuroblastoma exhibited deficits in hearing and speech. It is possible that this morbidity burden reflects the prevalent use of platinum compounds (causing ototoxicity) in this group. Within parent-child dyads there was a high level of percentage agreement on responses in all attributes except cognition.

CONCLUSION: Extension of this study to a larger sample size of patients will provide clarification of these observations.
Pharmacokinetic and Pharmacodynamic Study of the Combination of Docetaxel and Topotecan in Patients With Solid Tumors
Authors: Zamboni William C. , Egorin Merrill J. , Van Echo David A. , Day Roger S. , Meisenberg Barry R. , Brooks Sandra E. , Doyle L. Austin , Nemieboka Noble N. , Dobson Jason M. , Tait Nancy S. , Tkaczuk Katherine H.
Published: February 2017

PURPOSE: The sequence in which chemotherapeutic agents are administered can alter their pharmacokinetics, therapeutic effect, and toxicity. We evaluated the pharmacokinetics and pharmacodynamics of docetaxel and topotecan when coadministered on two different sequences of administration.

PATIENTS AND METHODS: On cycle 1, docetaxel was administered as a 1-hour infusion at 60 mg/m2without filgrastim and at 60, 70, and 80 mg/m2with filgrastim on day 1, and topotecan was administered at 0.75 mg/m2as a 0.5-hour infusion on days 1 to 4. On cycle 2, topotecan was administered on days 1 to 4, and docetaxel was administered on day 4. Cycles were repeated every 21 days. Blood samples for high-performance liquid chromatography measurement of docetaxel (CLDOC) and topotecan (CLTPT) total clearance were obtained on day 1 of cycle 1 and day 4 of cycle 2. CLDOCand CLTPTwere calculated using compartmental methods.

RESULTS: Mean ± SD CLDOCin cycles 1 and 2 were 75.9 ± 79.6 L/h/m2and 29.2 ± 17.3 L/h/m2, respectively (P < .046). Mean ± SD CLTPTin cycles 1 and 2 were 8.5 ± 4.4 L/h/m2and 9.3 ± 3.4 L/h/m2, respectively (P > .05). Mean ± SD neutrophil nadir in cycles 1 and 2 were 4,857 ± 6,738/μL and 2,808 ± 4,518/μL, respectively (P = .02).

CONCLUSION: Administration of topotecan on days 1 to 4 and docetaxel on day 4 resulted in an approximately 50% decrease in docetaxel clearance and was associated with increased neutropenia.